Ethical and 

Policy Issues 

in Research 

Involving 

Human 

Participants

Volume I

Report and 

Recommendations 

of the National 

Bioethics Advisory

Commission

Bethesda, Maryland

August 2001
The National Bioethics Advisory Commission (NBAC) was established by Executive Order 12975,

signed by President Clinton on October 3, 1995. NBAC’s functions are defined as follows: 

a) NBAC shall provide advice and make recommendations to the National Science and Technology

Council and to other appropriate government entities regarding the following matters: 

1) the appropriateness of departmental, agency, or other governmental programs, policies,

assignments, missions, guidelines, and regulations as they relate to bioethical issues arising

from research on human biology and behavior; and

2) applications, including the clinical applications, of that research.

b) NBAC shall identify broad principles to govern the ethical conduct of research, citing specific

projects only as illustrations for such principles. 

c) NBAC shall not be responsible for the review and approval of specific projects. 

d) In addition to responding to requests for advice and recommendations from the National Science

and Technology Council, NBAC also may accept suggestions of issues for consideration from

both the Congress and the public. NBAC also may identify other bioethical issues for the

purpose of providing advice and recommendations, subject to the approval of the National

Science and Technology Council.

National Bioethics Advisory Commission

6705 Rockledge Drive, Suite 700, Bethesda, Maryland 20892-7979

Telephone: 301-402-4242 • Fax: 301-480-6900 • Website: www.bioethics.gov

ISBN 1-931022-16-X
Ethical and 

Policy Issues 

in Research 

Involving 

Human 

Participants

Volume I

Report and 

Recommendations 

of the National 

Bioethics Advisory

Commission

Bethesda, Maryland

August 2001

Table of Contents

Letter of Transmittal to the President

National Bioethics Advisory Commission

National Bioethics Advisory Commission Staff and Consultants

Prologue i

Summary of Recommendations xi

Chapter 1:Introduction—The Need for Change 1

Introduction 1

The Value of Research 1

The Need for Oversight of Research Involving Human Participants 2

Current Factors Influencing the Research Enterprise 4

Major Challenges Facing the Current Oversight System 8

Consequences of a Flawed System 16

Notes 16

References 18

Chapter 2:A Proposal for Oversight 21

Introduction 21

Purpose of Oversight 21

Functions and Responsibilities of the Oversight System 23

Scope and Structure of a Revised Oversight System 26

The Need for a Unified, Comprehensive Federal Policy 28

Definition of Research Involving Human Participants 32

Summary 42

Notes 42

References 43

Chapter 3:Methods for Ensuring Protection:

Education, Certification, and Accreditation 45

Introduction 45

Education and Competence in Conducting Research Involving

Human Participants 45

Mechanisms to Ensure Institutional, Institutional Review Board, 

and Investigator Compliance 50

Conflicts of Interest 58

Summary 64

Notes 64

References 65

Chapter 4:Assessing Risks and Potential Benefits and 

Evaluating Vulnerability 69

Introduction 69

Institutional Review Board Approval of Research 69

Risks of Harms and Potential Benefits to Participants and to Society 71

Vulnerability 85

Summary 93

Notes 93

References 95

Chapter 5:Ensuring Voluntary Informed Consent and 

Protecting Privacy and Confidentiality 97

Introduction 97

Voluntary Informed Consent 97

Privacy and Confidentiality 104

Summary 107

Notes 108

References 108

Chapter 6:Conduct of Research—Selected Issues for 

Local Institutions 111

Introduction 111

Monitoring of Ongoing Research 111

Review of Cooperative Research Studies 117

Compensation for Research-Related Injuries 123

Summary 126

Notes 127

References 128

Chapter 7:Implications of This Report 131

Introduction 131

Resources 131

Future Research 133

The New System as a Dynamic and Responsive Structure 134

General Themes in the Recommendations 135

What This Report Means to Those Who Use the System 136

How This Report Will Affect Institutional Review Boards,

Investigators, and Institutions 136

How This Report Will Affect Research Participants 137

Summary 137

Notes 137

References 138

Appendices

A. Acknowledgments 139

B. May 1999 Letter from Harold T. Shapiro to 

President William J. Clinton and President Clinton’s 

Response 141

C.The Current Oversight System: History and Description 151

D.The Belmont Report 161

E. Code of Federal Regulations, Title 45 Part 46 169

F. Code of Federal Regulations, Title 21 Parts 50 and 56 187

G.Statutory Authority for Agency Human Subjects Protection

Regulations (Common Rule) 205

H.Food and Drug Administration Regulations Requiring 

Reporting of Adverse Events 213

I. Public Comments on NBAC’s December 19, 2000, Draft 217

J. Public and Expert Testimony 221

K.Commissioned Papers and Staff Analysis 225

Index 227



National Bioethics Advisory Commission

Patricia Backlar

Research Associate Professor of Bioethics

Department of Philosophy

Portland State University

Assistant Director

Center for Ethics in Health Care

Oregon Health Sciences University

Portland, Oregon

Arturo Brito, M.D.

Assistant Professor of Clinical Pediatrics

University of Miami School of Medicine

Miami, Florida

Alexander Morgan Capron, LL.B.

Henry W. Bruce Professor of Law

University Professor of Law and Medicine

Co-Director, Pacific Center for Health Policy and Ethics

University of Southern California

Los Angeles, California

Eric J. Cassell, M.D., M.A.C.P.

Clinical Professor of Public Health

Weill Medical College of Cornell University

New York, New York

R. Alta Charo, J.D.

Professor of Law and Bioethics

Law School and Medical School

University of Wisconsin

Madison, Wisconsin

James F. Childress, Ph.D.

Kyle Professor of Religious Studies

Professor of Medical Education

Director, Institute for Practical Ethics

Department of Religious Studies

University of Virginia

Charlottesville, Virginia

David R. Cox, M.D., Ph.D.

Scientific Director 

Perlegen Sciences 

Santa Clara, California 

Rhetaugh Graves Dumas, Ph.D., R.N.

Vice Provost Emerita, Dean Emerita, and 

Lucille Cole Professor of Nursing

University of Michigan

Ann Arbor, Michigan

Laurie M. Flynn*

Senior Research and Policy Associate

Department of Child and Adolescent Psychiatry

Columbia University

New York, New York

Carol W. Greider, Ph.D.

Professor of Molecular Biology and Genetics

Department of Molecular Biology and Genetics

Johns Hopkins University School of Medicine

Baltimore, Maryland

Steven H. Holtzman

Chief Business Officer

Millennium Pharmaceuticals, Inc.

Cambridge, Massachusetts

Bette O. Kramer

Founding President

Richmond Bioethics Consortium

Richmond, Virginia

Bernard Lo, M.D.

Director

Program in Medical Ethics

Professor of Medicine

University of California, San Francisco

San Francisco, California

Lawrence H. Miike, M.D., J.D.

Kaneohe, Hawaii

Thomas H. Murray, Ph.D.

President 

The Hastings Center

Garrison, New York

William C. Oldaker, LL.B.

Senior Partner

Oldaker & Harris, L.L.P.

Washington, D.C.

Co-Founder and General Counsel

NeuralStem Biopharmaceuticals Ltd.

College Park, Maryland

Diane Scott-Jones, Ph.D.

Professor

Psychology Department

Boston College

Chestnut Hill, Massachusetts

*Resigned on May 10, 2001

Harold T. Shapiro, Ph.D., Chair

President Emeritus and Professor of Economics and Public Affairs

The Woodrow Wilson School of Public and International Affairs

Princeton University

Princeton, New Jersey

National Bioethics Advisory 

Commission Staff and Consultants

Executive Director

Eric M. Meslin, Ph.D.*

Project Director

Marjorie A. Speers, Ph.D. 

Research Staff

Douglas Berger, M.Litt., Program Analyst** 

Glen Drew, M.S., J.D., Senior Research Policy Analyst

Elisa Eiseman, Ph.D., Senior Research Analyst

Ellen L. Gadbois, Ph.D., Senior Policy Analyst

Stu Kim, J.D., Program Analyst***

Kerry Jo Lee, Program Analyst* 

Ayodeji Marquis, Intern (June–August 2000) 

Debra McCurry, M.S., Information Specialist

Alice K. Page, J.D., M.P.H., Senior Policy Analyst*

Consultants

Burness Communications, Communications Consultant

Sara Davidson, M.A., Editor

Liza Dawson, Ph.D., Research Consultant

(December 2000–March 2001)

Debra DeBruin, Ph.D., Bioethics Consultant

(July–December 2000)

Kathi E. Hanna, M.S., Ph.D., Editorial Consultant

The Hill Group, Meeting Consultant

Tamara Lee, Graphic Designer

Administrative Staff

Nicole Baker, Administrative Technician

Jody Crank, Assistant to the Executive Director

Evadne Hammett, Administrative Officer

Margaret C. Quinlan, Office Manager

Sherrie Senior, Secretary

* Until July 2001

** Until June 2001

***Until November 2000

Introduction

Protecting the rights and welfare of those who volunteer to participate in research is a fundamental tenet

of ethical research. A great deal of progress has been

made in recent decades in changing the culture of

research to incorporate more fully this ethical responsibility into protocol design and implementation. In the

1960s and 1970s, a series of scandals concerning social

science research and medical research conducted with

the sick and the illiterate underlined the need to systematically and rigorously protect individuals in research

(Beecher 1966; Faden and Beauchamp 1986; Jones 1981;

Katz 1972; Tuskegee Syphilis Study Ad Hoc Advisory

Panel 1973). However, the resulting system of protections that evolved out of these rising concerns—although

an improvement over past practices—is no longer 

sufficient. It is a patchwork arrangement associated with

the receipt of federal research funding or the regulatory

review and approval of new drugs and devices. In addition, it depends on the voluntary cooperation of investigators, research institutions, and professional societies

across a wide array of research disciplines. Increasingly,

the current system is being viewed as uneven in its 

ability to simultaneously protect the rights and welfare of

research participants and promote ethically responsible

research.

Research involving human participants has become a

vast academic and commercial activity, but this country’s

system for the protection of human participants has not

kept pace with that growth. On the one hand, the system

is too narrow in scope to protect all participants, while on

the other hand, it is often so unnecessarily bureaucratic

that it stifles responsible research. Although some reforms

by particular federal agencies and professional societies

are under way,1 it will take the efforts of both the 

executive and legislative branches of government to put 

in place a streamlined, effective, responsive, and comprehensive system that achieves the protection of all

human participants and encourages ethically responsible

research.

Clearly, scientific investigation has extended and

enhanced the quality of life and increased our understanding of ourselves, our relationships with others, and

the natural world. It is one of the foundations of our 

society’s material, intellectual, and social progress. For

many citizens, scientific discoveries have alleviated the

suffering caused by disease or disability. Nonetheless, the

prospect of gaining such valuable scientific knowledge

need not and should not be pursued at the expense 

of human rights or human dignity. In the words of

philosopher Hans Jonas, “progress is an optional goal,

not an unconditional commitment, and...its tempo...

compulsive as it may become, has nothing sacred about

it” (Jonas 1969, 245).

Since the 1974 formation of the National

Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research and the activities in

the early 1980s of the President’s Commission for the

Study of Ethical Problems in Medicine and Biomedical

and Behavioral Research, American leaders have consistently tried to enhance the protections for human

research participants. The research community has, in

large part, supported the two essential protections for

human participants: independent review of research to

assess risks and potential benefits and an opportunity for

people to voluntarily and knowledgeably decide whether

to participate in a particular research protocol.

i

Prologue

Protecting Research Participants—A Time for Change
ii

Prologue

The charter of the National Bioethics Advisory

Commission (NBAC), a presidential commission created

in 1995, makes clear the Commission’s focus: “As a first

priority, NBAC shall direct its attention to consideration

of protection of the rights and welfare of human research

subjects.” In our first five years, we focused on several

issues concerning research involving human participants,

issuing five reports and numerous recommendations

that, when viewed as a whole, reflect our evolving 

appreciation of the numerous and complex challenges

facing the implementation and oversight of any system of

protections.2 The concerns and recommendations

addressed in these reports reflect our dual commitment

to ensuring the protection of those who volunteer for

research while supporting the continued advance of 

science and understanding of the human condition. This

report views the oversight system as a whole, provides 

a rationale for change, and offers an interrelated set of

recommendations to improve the protection of human

participants and enable the oversight system to operate

more efficiently.

Respecting Research Participants

Whether testing a new medical treatment, interviewing

people about their personal habits, studying how people

think and feel, or observing how they live within groups,

research seeks to learn something new about the human

condition. Unfortunately, history has also demonstrated

that researchers sometimes treat participants not as 

persons but as mere objects of study. As Jonas observed:

“Experimentation was originally sanctioned by natural

science. There it is performed on inanimate objects, and

this raises no moral questions. But as soon as animate,

feeling beings become the subject of experiment...this

innocence of the search for knowledge is lost and 

questions of conscience arise” (Jonas 1969, 219).

How, then, should people be studied? For over half a

century, since the revelations of medical torture under

the guise of medical experimentation were described at

the Nuremberg Trials,3 it has been agreed that people

should participate in research only when the study

addresses important questions, its risks are justifiable,

and an individual’s participation is voluntary and

informed.

The principles underlying the Belmont Report: Ethical

Principles and Guidelines for the Protections of Human Subjects

of Research (Belmont Report) (National Commission 1979)

have served for over 20 years as a leading source of guidance regarding the ethical standards that should govern

research with human participants in the United States.

The Belmont Report emphasized that research must

respect the autonomy of participants, must be fair in both

conception and implementation, and must maximize

potential benefits while minimizing potential harms. The

report’s recommendations provided a coherent rationale

for the federal policies and rules that created the current

U.S. system of decentralized, independent research

review coupled with some degree of federal oversight.

But although the Belmont Report is rightly hailed as a key

source of guidance on informed consent, assessment of

risk, and the injustice of placing individuals (and groups)

in situations of vulnerability, the principles the report

espouses and the regulations adopted as federal policy 20

years ago have often fallen short in achieving their overarching goal of protecting human research participants.

Moreover, since the Belmont Report was published, additional concerns have arisen that require much-needed

attention today.

Ensuring Independent Review of Risks

and Potential Benefits

A central protection for research participants is the

guarantee that someone other than the investigator will

assess the risks of the proposed research. No one should

participate in research unless independent review

concludes that the risks are reasonable in relation to

the potential benefits. In the United States, the

Institutional Review Board, or IRB, has been the principal

structure responsible for conducting such reviews.

Independent review of research is essential because it

improves the likelihood that decisions are made free from

inappropriate influences that could distort the central

task of evaluating risks and potential benefits. Certainly,

reviewers should not have a financial interest in the

work, but social factors may be just as crucial. Reviewers

may feel constrained because they are examining the

work of their colleagues or their supervisors, and they

should not participate in protocol review unless they are

able to separate these concerns from their task. All
National Bioethics Advisory Commission

iii

reviewers who themselves are members of the research

community should recognize that their familiarity with

research and (perhaps) their predilection to support

research are factors that could distort their judgment.

Truly independent and sensitive review requires more

involvement of individuals drawn from the ranks of

potential research participants or those who can 

adequately represent the interests of potential research

participants.

A critical purpose of independent review is to ensure

that risks are reasonable in relation to potential personal

and societal benefits. This is a precondition to offering

people the opportunity to volunteer, since informed 

consent alone cannot justify enrollment. When reviewed

for risks and potential benefits, research studies must be

evaluated in their entirety. Studies often include different

components, however, and the risks and potential benefits of each should also be examined separately, lest the

possibility of great benefit or monetary enticement in 

one component cause potential participants or IRBs to

minimize or overlook risk in another. No matter what

potential benefit is offered to individual participants or

society at large, the possibility of benefit from one 

element of a study should not be used to justify otherwise

unacceptable elements. 

In our view, IRBs should appreciate that for some

components of a study, participants might incur risks

with no personal potential benefit—for example, when a

nondiagnostic survey is included among the components

of a psychotherapy protocol or when placebos are given

to some participants in a drug trial. For these elements,

there should be some limitation on the amount of social

and physical risk that can be imposed, regardless of the

participants’ willingness to participate or the monetary

(or other) enticement being offered. Further, the possibility of some benefit from one element of a study should

not be used to justify otherwise unacceptable elements of

research whose potential benefits, if any, accrue, solely to

society at large. If aspects of a study present unacceptable

risks, protocols should not be approved until these elements are eliminated. If removing the risky component

would impair the study as a whole, then the entire study

should be redesigned so that each of its elements presents

risks that are reasonable in relation to potential benefits.

Other parts of studies can obscure risks, such as when

standard medical interventions are compared in a patient

population, leading some participants and researchers 

to discount the risks because they are associated with

known therapies. It is essential that participants and

investigators not be led to believe that participating in

research is tantamount to being in a traditional therapeutic

relationship. Regardless of whether there is the possibility

or even the likelihood of direct benefit from participation

in research, such participation still alters the relationship

between a professional and the participant by introducing

another loyalty beyond that to the participant, to wit, 

loyalty to doing good science. It is too often forgotten

that even though the researchers may consider participants’ interests to be important, they also have a serious,

and perhaps conflicting, obligation to science.

Years of experience with the current system of 

independent review have demonstrated that there are

enduring questions about how to arrive at such impartial

judgments and how to go about deciding when potential

benefits justify risks that are incurred solely by participants or the community from which they come. In recent

years, increasing strains on the system have undermined

the practice of independent review. IRBs are overburdened by the volume of research coming before them, a

strain that is compounded by concerns about training 

of IRB members and possible conflicts of interest. In

addition, the constantly changing nature of research challenges existing notions about what constitutes risks and

potential benefits. 

Because IRBs are so central to the current oversight

system, they need better guidance on how to review and

monitor research, how to assess potential benefits to

research participants and their communities, and how to

distinguish among levels of risk. This report provides

such guidance in the following areas: determining the

type of review necessary for minimal risk research; ensuring that research participants are able to make voluntary

decisions and are appropriately informed prior to giving

consent; providing adequate protections for privacy and

confidentiality; identifying appropriate measures needed

when participants are susceptible to coercion or are otherwise placed in vulnerable situations; and monitoring

ongoing research. In addition, the report recommends
iv

Prologue

that IRB members and staff complete educational and

certification programs on research ethics before being

permitted to review research studies. 

Obtaining Voluntary Informed Consent

Even when risks are reasonable, however, no one should

participate in research without giving voluntary informed consent (except in the case of an appropriate

authorized representative or a waiver). Investigators

must make appropriate disclosures and ensure that

participants have a good understanding of the information and their choices, not only at the time of enrollment, but throughout the research. Engaging in this

process is one of the best ways researchers can demonstrate their concern and respect for those they aim to

enroll in a study. It also serves as the best means for those

who do not wish to participate to protect themselves.4

Recommendations from our previous reports are 

reinforced in this report, which emphasizes the process of

providing information and ensuring comprehension

rather than the form of documentation of the decision 

to give consent. Both the information and the way it is

conveyed—while meeting full disclosure requirements—

must be tailored to meet the needs of the participants in

the particular research context. In addition, documentation requirements must be adapted for varying research

settings, and the criteria for deciding when informed

consent is not necessary must be clarified so that participants’ rights and welfare are not endangered.

The decision to participate in research must not only

be informed, it must be voluntary. Even when risks are

reasonable and informed consent is obtained, it may

nonetheless be wrong to solicit certain people as participants. Those who are not fully capable of resisting the

request to become participants—such as prisoners and

other institutionalized or otherwise vulnerable persons—

should not be enrolled in studies merely because they are

easily accessible or convenient. This historic emphasis 

on protecting people from being exploited as research

participants, however, has failed to anticipate a time

when, at least for some areas of medical research, people

would be demanding to be included in certain studies

because they might provide the only opportunity for

receiving medical care for life-threatening diseases.

Making Research Inclusive While

Protecting Individuals and Categorized

as Vulnerable

Vulnerable individuals need additional protection in

research. Although certain individuals and populations

are more vulnerable as human participants than others,

people whose circumstances render them vulnerable

should not be arbitrarily excluded from research for 

this reason alone. This includes those viewed as more

open to harm (e.g., children), more subject to coercion

(e.g., institutionalized persons), more “complicated”

(e.g., women, who are considered more biologically complicated than men), or more inconvenient (e.g., women

with small children, who are viewed as less reliable

research participants due to conflicting demands on

time). Calling competent people intrinsically “vulnerable” can be both insulting and misleading. It is not their

gender or other group designation that exposes them to

injury or coercion, but rather their situation that can be

exploited by ethically unacceptable research. That is, it 

is their circumstances, which are situational, that create 

the vulnerability. At other times it is the intrinsic characteristics of the person—for example, children or those

with certain mental or developmental disorders—that

make them generally vulnerable in the research setting. 

The response, whenever possible, should not be to

exclude people from research, but instead to change the

research design so that it does not create situations in

which people are unnecessarily harmed. To do otherwise

is to risk developing knowledge that helps only a subset

of the population. To the extent that the results are not

generalizable, the potential societal benefits that justify

doing the research are attenuated. Research participants

must be treated equally and with respect. Whenever

possible, research should be designed to encourage

the participation of all groups while protecting their

rights and welfare.

To accomplish this, we recommend that rather than

focusing primarily on categorizing groups as vulnerable,

investigators and IRBs should also recognize and avoid

situations that create susceptibility to harm or coercion.

Such situations may be as varied as patients being

recruited by their own physicians; sick and desperate

patients seeking enrollment in clinical trials; participants
National Bioethics Advisory Commission

v

being recruited by those who teach or employ them; or

studies involving participants with any characteristic that

may make them less likely to receive care and respect

from others (e.g., convicted criminals or intravenous drug

users). In these circumstances, rather than excluding

whole groups of people, researchers should design studies

that reduce the risk of exploitation, whether by using a

different method of recruitment, by using a recruiter who

shares the participants’ characteristics, or by some other

technique. This is not always easy. It requires researchers

to consider carefully their research design and the potential pool of participants. At times, it will mean anticipating

that otherwise seemingly benign situations may become

more complex because a particular participant or group

of participants will be unusually susceptible to harm 

or manipulation. At other times, the nature of the vulnerability may require using a different research design.

Ethical research does not avoid complexity. Rather, it

acknowledges the full range and realities of the human

condition.

Compensating for Harms

Despite all these precautions, however, some research

participants might be harmed. Participants who are

harmed as a direct result of research should be cared

for and compensated. This is simple justice. The fact

that they offered to participate in no way alters the view

that mere decency calls for us to take care of these 

volunteers. Unfortunately, this is a greater challenge than

it might appear. For those who endure harm while participating in research, it is often very difficult to separate

injuries traceable to the research from those that stem

from the underlying disease or social condition being

studied. For others, appropriate care and compensation

would be far beyond the means of the researchers, their

sponsors, and their institutions. Two decades ago, the

President’s Commission for the Study of Ethical Problems

in Medicine and Biomedical and Behavioral Research

called for pilot studies of compensation programs—a 

recommendation that was not pursued. It is time to

reconsider the need for some type of compensation program and to explore the possible mechanisms that could

be used were one to be adopted. Regardless of individual

motives, research participants are providing a service for 

society, and justice requires that they be treated with

great respect and receive appropriate care for any related

injuries. It should always be remembered that it is a privilege for any researcher to involve human participants in

his or her research.

Establishing a Comprehensive,

Effective, and Streamlined System

In the United States, government regulations, professional guidelines, and the general principles highlighted

in the Belmont Report (1979) form the basis of the current

system of protections. In the earliest stages of adoption,

the federal regulations were fragmented and confusing.

Even today, they apply to most—but not all—research

funded or conducted by the federal government, but

have inconsistent and sometimes no direct application to

research funded or conducted by state governments,

foundations, or industry. They apply to medical drugs

and devices and vaccines approved for interstate sale, but

not to some medical innovations that would remain

wholly within state borders. And they apply to other

research only when the investigators and their institutions volunteer to abide by the rules. 

A comprehensive and effective oversight system is

essential to uniformly protect the rights and welfare

of participants while permitting ethically and scientifically responsible research to proceed without

undue delay. A fundamental flaw in the current oversight system is the ethically indefensible difference in the

protection afforded participants in federally sponsored

research and those in privately sponsored research that

falls outside the jurisdiction of the Food and Drug

Administration. As a result, people have been subjected

to experimentation without their knowledge or informed

consent in fields as diverse as plastic surgery, psychology,

and infertility treatment. This is wrong. Participants should

be protected from avoidable harm, whether the research

is publicly or privately financed. We have repeated

this assertion throughout our deliberations, and recommendations in this regard appear in four previous reports

(NBAC 1997; NBAC 1999a; NBAC 1999b; NBAC 2001).
vi

Prologue

In this report, we recommend that the protections of

an oversight system extend to the entire private sector for

both domestic and international research. A credible,

effective oversight system must apply to all research, and

all people are entitled to the dignity that comes with

freely and knowingly choosing whether to participate in

research, as well as to protection from undue research

risks. This is consistent with our 1997 resolution that no

one should be enrolled in research absent the twin protections of independent review and voluntary informed

consent. 

Even when current protections apply, the interpretation of the federal regulations can vary unpredictably,

depending on which federal agency oversees the

research. Even the most basic, common elements of the

federal rules took a decade to develop into regulations,

because there was no single authority within the government to facilitate and demand cooperation and consistency. There still is no such single authority.5 This has

slowed the diffusion of basic protections and made it

almost impossible to develop consistent interpretations

of the basic protections or those relevant to especially

problematic research, such as studies involving children

or the decisionally impaired. Nor has there been a unified

response to emerging areas of research, such as large-scale

work on medical records and social science databases or

on stored human biological materials.

Today’s research protection system cannot react

quickly to new developments. Efforts to develop rules for

special situations, such as research on those who can no

longer make decisions for themselves, have languished

for decades in the face of bureaucratic hurdles, and there

is no reason to believe that efforts to oversee other emerging research areas will be any more efficient. In addition,

the current system leaves people vulnerable to new, virtually uncontrolled experimentation in emerging fields,

such as some aspects of reproductive medicine and

genetic research.

Indeed, some areas of research are not only uncontrolled, they are almost invisible. In an information age,

poor management of research using medical records,

human tissue, or personal interview data could lead to

employment and insurance discrimination, social stigmatization, or even criminal prosecution.6 The privacy and

confidentiality concerns raised by this research are real,

but the federal response has often been illusory. There is

almost no guidance and certainly no coordination on

these topics. The time has come to have a single source

of guidance for these emerging areas, one that would be

better positioned to effect change across all divisions of

the government and private sector, as well as to facilitate

development of specialized review bodies, as needed.

In this report we propose a new independent oversight office that would have clear authority over all

other segments of the federal government and extend

protections to the entire private sector for both

domestic and international research. A single office

would decide how to introduce consistency or reforms,

and only that office would develop mechanisms to provide specialized review when needed. We recognize the

challenges to such a proposal. For example, an independent office might lack the political support accorded

an existing cabinet-level department. Although assigning

one department, such as the Department of Health and

Human Services, the role of “first among equals” would

allow it to advocate forcefully for uniform rules across the

government, without special provisions it would not have

the authority to require other departments to comply, nor

is it certain to escape the temptation to develop rules

premised on a traditional, biomedical model rather than

the wider range of research to be covered. 

Federal research protections should be uniform

across all government agencies, academe, and the 

private sector, but they should be flexible enough to

be applied in widely different research settings or to

emerging areas of research. Furthermore, any central

coordinating body should be open to public input, have

significant political or legal authority over research

involving human participants—whether in the public or

private sector—and have the support of the executive

and legislative branches of government.

Education as the Key to Promoting

Local Responsibility

Currently, federal protections depend on a decentralized

oversight system involving IRBs, institutions, investigators, sponsors, and participants. We endorse the spirit
National Bioethics Advisory Commission

vii

and intent of this approach, specifically its contention

that the ethical obligation to protect participants lies

first with researchers, their sponsors, and the IRBs

that review their research. Protecting research participants is a duty that researchers, research institutions, and

sponsors cannot delegate completely to others or to the

government. In addition, merely adhering to a set of rules

and regulations does not fulfill this duty. Rather, it is

accomplished by acting within a culture of concern and

respect for research participants.

It is unrealistic to think that ethical obligations can be

fully met without guidance and resources. To help

researchers and IRBs fulfill their responsibilities, the

federal government should promote the development

of education, certification, and accreditation systems

that apply to all researchers, all IRB members and

staff, and all institutions. These tools should help

researchers craft and IRBs review studies that pose few

problems and to know when their work requires special

oversight. Today, investigators and IRBs are rightly confused over issues as basic as which areas of inquiry should

be reviewed and who constitutes a human participant.

Education is the foundation of the oversight system

and is essential to protecting research participants. In all

of our reports, we have highlighted the need to educate

all those involved in research with human participants,

including the public, investigators, IRB members, institutions, and federal agencies. In Cloning Human Beings

(1997), we recommended federal support of public education in biomedical sciences that increasingly affect our

cultural values. In Research Involving Persons with Mental

Disorders That May Affect Decisionmaking Capacity (1998),

we called for practice guidelines and ethics education on

special concerns regarding this population. In Ethical and

Policy Issues in International Research: Clinical Trials in

Developing Countries (2001), we recommended measures

to help developing countries build their capacity for

designing and conducting clinical trials, for reviewing the

ethics and science of proposed research, and for using

research results after a trial is completed.

In this report, we again acknowledge the inadequacy

of educational programs on research ethics in the United

States. This deficiency begins at the highest level within

the federal oversight system and extends to the local level

at individual institutions. We recommend that investigators

and IRB members and staff successfully complete educational programs on research ethics and become certified

before they perform or review research, that research

ethics be taught to the next generation of scientists, and

that research ethics be included in continuing education

programs.

Clarifying the Scope of Oversight

Many areas of scientific inquiry are “research,” and many

of these involve human participants, but only some need

federal oversight, while others might be better regulated

through professional ethics, social custom, or other state

and federal law. For example, certain types of surveys and

interviews are considered research, but they can be well

managed to avoid harms without federal oversight, as the

risks are few and participants are well situated to decide

for themselves whether to participate. On the other hand,

certain studies of medical records, databases, and discarded surgical tissue are often perceived as something

other than human research, even when the information

retrieved is traceable to an identifiable person. Such

research does need oversight to avoid putting people at

risk of identity disclosure or discrimination without their

knowledge. Federal policies should clearly identify

the kinds of research that are subject to review and

the types of research participants to whom protections should apply. When research poses significant

risks or when its risks are imposed on participants 

without their knowledge, it clearly requires oversight.

However, meaningless or overly rigid oversight engenders

disdain on the part of researchers, creates an impossible

and pointless workload for IRBs, and deters ethically

sound research from going forward.

Ensuring That the Level of Review

Corresponds to the Level of Risk

Even within areas of research that need oversight, many

individual studies will involve little or no risk to participants. Although current federal policies allow for some

distinction between research involving minimal risk and

research involving more than minimal risk, the distinction operates mostly in terms of how the research will be
viii

Prologue

reviewed—that is, how procedures are to be followed.

But the distinction should be based on how the research

is pursued, how the participants are treated, and how the

work is monitored over time. Overall, the emphasis

should be on knowing how to protect participants rather

than on knowing how to navigate research regulations.

Instead of focusing so much on the period during which

a research design is reviewed, oversight should also

include an ongoing system of education and certification

that helps researchers to anticipate and minimize

research risks. Oversight should also make it easier for

researchers to collaborate with their colleagues here and

abroad without the burden of redundant reviews.

Research review and monitoring should be intensified

as the risk and complexity of the research increase

and at all times should emphasize protecting participants rather than following rigid rules. In addition,

the review process should facilitate rather than hinder

collaborative research among institutions and across

national boundaries, provided that participants are

protected.

Providing Resources for the Oversight

System

Creating a system that protects the rights and welfare of

participants and facilitates responsible research demands

political and financial support from the federal government as well as the presence of a central coordinating

body to provide guidance and oversee education and

accreditation efforts. The oversight system should be

adequately funded at all levels to ensure that research

continues in a manner that demonstrates respect and

concern for the interests of research participants.

Conclusions

The current system for protecting human participants in

research is in need of reform. It does not protect all

research participants, and where protection is offered, it

is often burdened by excessive bureaucracy, confusing or

conflicting interpretations of rules, and an inability to

respond to emerging areas of research. We recommend

that a new oversight system be adopted that is led 

by a responsive and authoritative federal office, that

emphasizes researcher education and research design as

the primary means to protect participants, and that

encourages responsible research while protecting all

research participants.

Notes

1 For example, the Office for Human Research Protections is

implementing a new process by which institutions assure future

compliance with human participant protections. The Institute of

Medicine has recently issued a report on accreditation standards

for IRBs (IOM 2001). Public Responsibility in Medicine and

Research has established training programs and has co-founded a

new organization, the Association for the Accreditation of Human

Research Protection Programs. 

2 To date, NBAC has issued five reports: Cloning Human Beings

(NBAC 1997), Research Involving Persons with Mental Disorders 

That May Affect Decisionmaking Capacity (NBAC 1998), Ethical Issues

in Human Stem Cell Research (NBAC 1999a), Research Involving

Human Biological Materials: Ethical Issues and Policy Guidance

(NBAC 1999b), and Ethical and Policy Issues in International

Research: Clinical Trials in Developing Countries (NBAC 2001).

3 United States v. Karl Brandt et al., Trials of War Criminals Before

the Nuremberg Military Tribunals Under Control Council Law 10.

Nuremberg, October 1946–April 1949. Volumes I–II. Washington,

D.C.: U.S. Government Printing Office.

4 There are, of course, some circumstances in which consent 

cannot be obtained and in which an overly rigid adherence to 

this principle would preclude research that is either benign or

potentially needed by the participant him- or herself. Thus, NBAC

endorses the current exceptions for research that is of minimal risk

to participants and for potentially beneficial research in emergency

settings where no better alternative for the participants exists.

NBAC also urges attention to emerging areas of record, database,

and tissue bank research in which consent serves only as a sign 

of respect and in which alternative ways to respect participants 

do exist (NBAC 1999b; 21 CFR 50.24). In a previous report, the

Commission made recommendations regarding persons who lack

decisionmaking capacity and from whom informed consent cannot

be obtained (NBAC 1998).

5 Porter, J., Testimony before NBAC. November 23, 1997.

Bethesda, Maryland. See McCarthy, C.R., “Reflections on the

Organizational Locus of the Office for Protection from Research

Risks.” This background paper was prepared for NBAC and is

available in Volume II of this report.

6 See Goldman, J., and A. Choy, “Privacy and Confidentiality in

Health Research” and Sieber, J., “Privacy and Confidentiality: 

As Related to Human Research in Social and Behavioral Science.”

These background papers were prepared for NBAC and are 

available in Volume II of this report. See also Ferguson v. City of

Charleston 121 S. Ct. 1281. (2001).
National Bioethics Advisory Commission

ix

References

Beecher, H.K. 1966. “Ethics and Clinical Research.” New England

Journal of Medicine 274(24):1354–1360.

Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of

Informed Consent. New York: Oxford University Press.

Institute of Medicine (IOM). 2001. Preserving Public Trust:

Accreditation and Human Research Participant Protection Programs.

Washington, D.C.: National Academy Press.

Jonas, H. 1969. “Philosophical Reflections on Experimenting with

Human Subjects.” Daedalus 98:219–247.

Jones, J.H. 1981. Bad Blood: The Tuskegee Syphilis Experiment.

New York: The Free Press.

Katz, J. 1972. Experimentation with Human Beings. New York:

Russell Sage Foundation.

National Bioethics Advisory Commission (NBAC). 1997. Cloning

Human Beings. 2 vols. Rockville, MD: U.S. Government Printing

Office.

———. 1998. Research Involving Persons with Mental Disorders 

That May Affect Decisionmaking Capacity. 2 vols. Rockville, MD:

U.S. Government Printing Office.

———. 1999a. Ethical Issues in Human Stem Cell Research. 3 vols.

Rockville, MD: U.S. Government Printing Office.

———. 1999b. Research Involving Human Biological Materials:

Ethical Issues and Policy Guidance. 2 vols. Rockville, MD: U.S.

Government Printing Office.

———. 2001. Ethical and Policy Issues in International Research:

Clinical Trials in Developing Countries. 2 vols. Bethesda, MD: 

U.S. Government Printing Office.

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission). 1979.

Belmont Report: Ethical Principles and Guidelines for the Protection of

Human Subjects of Research. Washington, D.C.: U.S. Government

Printing Office.

Tuskegee Syphilis Study Ad Hoc Advisory Panel. 1973. Final

Report. Washington, D.C.: U.S. Department of Health, Education,

and Welfare.

Summary of Recommendations

The charter of the National Bioethics Advisory

Commission (NBAC), a presidential commission

created in 1995, states that “[a]s a first priority, NBAC

shall direct its attention to consideration of protection of

the rights and welfare of human research subjects.”

During NBAC’s first five years, the Commission focused

on several special issues surrounding research involving

human participants, issuing five reports and numerous

recommendations that, when viewed as a whole, reflect

an evolving appreciation of the various and complex

challenges facing the implementation and oversight of the

system that protects those who volunteer to participate in

research.

In May 1997, NBAC unanimously resolved that “[n]o

person in the United States should be enrolled in research

without the twin protections of informed consent by an

authorized person and independent review of the risks

and benefits of the research.” In 1999, NBAC indicated to

the White House the following areas of concern regarding

the oversight of human research in the United States: 

1) not all research participants are protected by the federal oversight system; 2) a number of federal departments

and agencies that sponsor primarily nonbiomedical

research or modest amounts of research have failed to

implement fully the federal protections available; 3) the

federal protections do not always include specific provisions for those individuals who are especially vulnerable;

and 4) the federal protections are difficult to enforce and

improve effectively across the government, in part,

because no single authority or office oversees research

protections across all agencies and departments.

Based on these findings and in response to a special

request from the White House Office of Science and

Technology Policy to further develop recommendations

for improving the system for protecting research participants, NBAC undertook a comprehensive examination of

the various aspects of the oversight system, including its

purpose; its structure, including its local configuration—

composed of investigators, institutions, and Institutional

Review Boards (IRBs); and the ethical issues relevant to

review of research. The recommendations contained in

this report reflect a dual commitment to ensuring the

protection of those who volunteer for research while

supporting the continued advancement of science. The

recommendations are based on a view of the oversight

system as a whole and provide both a rationale for

change and an interrelated set of proposals to improve

the protection of human participants and enable the

oversight system to operate more efficiently.

Readers should note that three general themes are

found in the recommendations. First, they suggest that

there should be fewer federal regulations and more

guidance. Second, they generally focus attention on

research for which participants need the most protection

and strive to make the level of protection commensurate

with the level of risk involved in the research. This theme

is strongest in recommendations regarding continuing

review, verification of compliance, adverse event reporting, informed consent, and the review of minimal risk

research. Third, the recommendations both increase the

scope of regulated research and streamline the process of

regulatory compliance.

The most significant proposed change is that of consolidation. In place of the current multiple sets of overlapping regulations, a unified comprehensive policy is

proposed in the form of a single set of regulations with a

single source of guidance and interpretation. Six distinct

functions or responsibilities of a consolidated oversight

xi
xii

Summary of Recommendations

system are recommended: policy development through

regulations and guidance; educational programs aimed

at the responsibilities of all parties; ethical review of

proposed research; monitoring of ongoing research;

enforcement of the requirements; and accountability for

all those involved in the review and conduct of research.

By focusing attention and resources on these functions,

the system will provide the necessary infrastructure for

protecting research participants and promoting ethical

research. To ignore any one of them is to have a system

that functions less than optimally.

Scope and Structure of the 

Oversight System

The entitlements due to all research participants of a

prior independent review of risks and potential benefits

and the opportunity to exercise voluntary informed consent are the most basic and essential protections for all

research participants. However, not all research participants receive these entitlements and not all are protected

by the existing oversight system. The commitment to

protect participants should not be voluntary, nor should

requirements be in place for only some human research.

Extending current protections to all research, whether

publicly or privately funded, and making uniform all 

federal regulations and guidance cannot be accomplished

within the current oversight system, in which no entity has

the authority to act on behalf of all research participants.

Thus, to facilitate the extension of the same protections

to all humans participating in research, a unified, comprehensive federal policy promulgated and interpreted

by a single office is needed. 

Recommendation 2.1: The federal oversight system

should protect the rights and welfare of human

research participants by requiring 1) independent

review of risks and potential benefits and 

2) voluntary informed consent. Protection should

be available to participants in both publicly and

privately sponsored research. Federal legislation

should be enacted to provide such protection.

Recommendation 2.2: To ensure the protection of

the rights and welfare of all research participants,

federal legislation should be enacted to create a

single, independent federal office, the National

Office for Human Research Oversight (NOHRO),

to lead and coordinate the oversight system. This

office should be responsible for policy development,

regulatory reform (see Recommendation 2.3),

research review and monitoring, research ethics

education, and enforcement. 

Recommendation 2.3: A unified, comprehensive

federal policy embodied in a single set of regulations and guidance should be created that would

apply to all types of research involving human

participants (see Recommendation 2.2).

Determining whether particular research activities

involving human participants should be subject to a 

federal oversight system has been a source of confusion

for some time. No regulatory definition of covered

research can be provided that has the sensitivity and

specificity required to ensure that all research activities

that include human participants that should be subject to

oversight are always included and all activities that should

be excluded from oversight protections are always

excluded. Clarification and interpretation of the definition

of what constitutes research involving human participants

will invariably be required if the oversight system is to

work effectively and efficiently. Moreover, there will

always be cases over which experts disagree about the

research status of a particular activity. One of the important

leadership roles the proposed oversight office should fulfill is that of providing guidance on determining whether

an activity is research involving human participants and

is therefore subject to oversight. 

Recommendation 2.4: Federal policy should cover

research involving human participants that entails

systematic collection or analysis of data with 

the intent to generate new knowledge. Research

should be considered to involve human participants when individuals 1) are exposed to manipulations, interventions, observations, or other

types of interactions with investigators or 2) are

identifiable through research using biological

materials, medical and other records, or databases. Federal policy also should identify those

research activities that are not subject to federal

oversight and outline a procedure for determining

whether a particular study is or is not covered by

the oversight system.
National Bioethics Advisory Commission

xiii

The proposed federal office should initiate a process

in which representatives from various disciplines and

professions (e.g., social science, humanities, business,

public health, and health services) contribute to the

development of the definition and the list of research

activities subject to the oversight system. 

Level of Review

Although the definition of research involving human participants should be applied to all disciplines, the risks

differ both qualitatively and quantitatively across the

spectrum of research. Therefore, the oversight system

should ensure that all covered research is subject to basic

protections—such as a process of informed consent—

with the exceptions of the specified conditions for which

these protections can be waived, including protection of

privacy and confidentiality and minimization of risks.

Because the proposed oversight system may include

more research activities, it is more critical than ever that

review mechanisms and criteria for various types of

research are suited to the nature of the research and the

likely risks involved. More specific guidance is needed

for review of different types of research, including appropriate review criteria and IRB composition. For example,

procedures other than full board review could be used for

minimal risk research, and national level reviews could

supplement local IRB review of research involving novel

or controversial ethical issues. 

Recommendation 2.5: Federal policy should

require research ethics review that is commensurate with the nature and level of risk involved.

Standards and procedures for review should 

distinguish between research that poses minimal

risk and research that poses more than minimal

risk. Minimal risk should be defined as the 

probability and magnitude of harms that are 

normally encountered in the daily lives of the

general population (see Recommendation 4.2). 

In addition, the federal government should 

facilitate the creation of special, supplementary

review bodies for research that involves novel 

or controversial ethical issues. 

Education, Certification, and

Accreditation

Protecting the rights and welfare of research participants

is the major ethical obligation of all parties involved in

the oversight system, and to provide these protections, 

all parties must be able to demonstrate competence in

research ethics—that is, conducting, reviewing, or overseeing research involving human participants in an ethically sound manner. Such competence entails not only

being knowledgeable about relevant research ethics

issues and federal policies, but also being able to identify,

disclose, and manage conflicting interests for institutions,

investigators, or IRBs. Finally, the oversight system must

include a sufficiently robust monitoring process to 

provide remedies for lapses by institutions, IRBs, and

investigators.

Recommendation 3.1: All institutions and sponsors

engaged in research involving human participants

should provide educational programs in research

ethics to appropriate institutional officials, 

investigators, Institutional Review Board members,

and Institutional Review Board staff. Among

other issues, these programs should emphasize

the obligations of institutions, sponsors,

Institutional Review Boards, and investigators 

to protect the rights and welfare of participants.

Colleges and universities should include research

ethics in curricula related to research methods,

and professional societies should include research

ethics in their continuing education programs. 

Recommendation 3.2: The federal government, 

in partnership with academic and professional

societies, should enhance research ethics 

education related to protecting human research 

participants and stimulate the development of

innovative educational programs. Professional

societies should be consulted so that educational

programs are designed to meet the needs of all

who conduct and review research. 

Educating all parties in research ethics and human

participant protections is effective only when it results in

the necessary competence for designing and conducting

ethically sound research, including analyzing, interpreting, and disseminating results in an ethically sound 
xiv

Summary of Recommendations

manner. Such competence, however, cannot be assumed

to follow from exposure to an educational course or 

program. As the complexion of research continues to

change and as technology advances, new and challenging

ethical dilemmas will emerge. And, as more people

become involved in research as investigators or in roles

that are specifically related to oversight, it becomes

increasingly important for all parties to be able to demonstrate competence in the ethics of research involving

human participants. 

Although accreditation and certification do not

always guarantee the desired outcomes, these programs,

which generally involve experts and peers developing 

a set of standards that represents a consensus of best

practices, can be helpful in improving performance.

Therefore, the choice of standards for these programs and

the criteria for evaluating whether an institution has met

them are critically important. Accreditation and certification programs should emphasize providing education

and assuring that appropriate protections are in place,

while avoiding excessively bureaucratic procedures. 

Recommendation 3.3: All investigators, Institutional

Review Board members, and Institutional Review

Board staff should be certified prior to conducting

or reviewing research involving human participants.

Certification requirements should be appropriate

to their roles and to the area of research. The federal government should encourage organizations,

sponsors, and institutions to develop certification

programs and mechanisms to evaluate their effectiveness. Federal policy should set standards for

determining whether institutions and sponsors

have an effective process of certification in place. 

Recommendation 3.4: Sponsors, institutions, and

independent Institutional Review Boards should

be accredited in order to conduct or review research

involving human participants. Accreditation should

be premised upon demonstrated competency in

core areas through accreditation programs that

are approved by the federal government.

Assessing and Monitoring Compliance

Assessing institutional, IRB, and investigator compliance

can help to ensure that standards are being followed

consistently. Current mechanisms for assessment include

assurances of compliance issued by the Department of

Health and Human Services and several other federal

departments, site inspections of IRBs conducted by the

Food and Drug Administration, other types of site

inspections for participant protection, and institutional

audits. In addition, some institutions have established

ongoing mechanisms for assessing investigator compliance

with regulations. However, institutions vary considerably

in their efforts and abilities to monitor investigator compliance, from those that have no monitoring programs to

those that conduct random audits. Assessing the behavior

of investigators is an important part of protecting

research participants and should be taken seriously as a

responsibility of each institution. Investigators, IRBs, and

institutions should discuss the many practical issues

involved in monitoring investigators as they conduct their

research studies and provide input into the regulatory

process. 

Recommendation 3.5: The process for assuring

compliance with federal policy should be modified

to reduce any unnecessary burden on institutions

conducting research and to register institutions

and Institutional Review Boards with the federal

government. The assurance process should not

be duplicative of accreditation programs for 

institutions (see Recommendation 3.4). 

Recommendation 3.6: Institutions should develop

internal mechanisms to ensure Institutional

Review Board compliance and investigator 

compliance with regulations, guidance, and 

institutional procedures. Mechanisms should 

be put in place for reporting noncompliance to

all relevant parties.

Managing Conflicts of Interest

A research setting that involves human participants 

necessarily creates a conflict of interest for investigators

who seek to develop or revise knowledge by enrolling

individuals in research protocols to obtain that knowledge. Overzealous pursuit of scientific results could lead

to harm if, for example, investigators design research

studies that pose unacceptable risks to participants,
National Bioethics Advisory Commission

xv

enroll participants who should not be enrolled, or continue studies even when results suggest they should have

been modified or halted. Conflicts of interest can also

exist for IRB members or the institutions in which the

research will be conducted. Thus, it is important to

address prospectively the potentially harmful effects on

participants that conflicts of interest might cause. 

Organizations, particularly academic institutions,

should become more actively involved in managing

investigators’ and IRB members’ conflicts of interest and

increase their efforts for self-regulation in this arena. IRB

review of research studies is one method for identifying

and dealing with conflicts of interest that might face

investigators. By having IRBs review research studies

prospectively and follow an IRB-approved protocol,

investigators and IRBs together can manage conflict

between the investigators’ desire to advance scientific

knowledge and to protect the rights and welfare of

research participants. Financial and other obvious conflicts for IRB members, such as collaboration in a research

study, are often less difficult to identify and manage than

some of the more subtle and pervasive conflicts.

Guidance should be developed to assist IRBs in identifying various types of conflict. 

Recommendation 3.7: Federal policy should define

institutional, Institutional Review Board, and

investigator conflicts of interest, and guidance

should be issued to ensure that the rights and

welfare of research participants are protected. 

Recommendation 3.8: Sponsors and institutions

should develop policies and mechanisms to 

identify and manage all types of institutional,

Institutional Review Board, and investigator 

conflicts of interest. In particular, all relevant

conflicts of interest should be disclosed to 

participants. Policies also should describe 

specific types of prohibited relationships. 

IRB Membership

Appropriate composition of IRB membership ensures that

research studies are reviewed with the utmost regard for

protecting the rights and welfare of research participants.

Current federal regulations require that each IRB have “at

least one member who is not otherwise affiliated with 

the institution and who is not part of the immediate 

family of a person who is affiliated with the institution”

(45 CFR 46.107(d); 21 CFR 56.107(d)). The regulations

also require that each IRB include “at least one member

whose primary concerns are in scientific areas and at

least one member whose primary concerns are in 

non-scientific areas.” Some have raised the concern of

whether only 1 unaffiliated member on an IRB is sufficient to avoid institutional influence, especially when

IRBs have 15 to 21 members on average. In addition,

unaffiliated members do not have to be present for an IRB

to conduct review and approve research studies. Thus,

IRBs can approve research with only institutional representation present as long as a nonscientist and a quorum

are also present. IRBs should strive to complement their

membership by having clearly recognizable members

who are unaffiliated with the institutions, members who

are nonscientists, and members who represent the 

perspectives of participants. However, it is difficult to

require that IRBs increase the presence and participation

of more unaffiliated members to reduce the influence of

institutional interests on IRB decisionmaking, because

finding them can be difficult. Currently, there are no rules

or guidance that describe criteria for meeting the definition of an unaffiliated member, that specify how long

such members should serve, or that provide guidance

regarding under what circumstances they may be

removed or what payment should be provided.

Institutions should be careful to select unaffiliated members who are truly separated from the institution, except

for their role on the IRB. Procedures for the selection and

removal of unaffiliated members should be established in

a way that empowers the independent voices of those

members. In addition, providing reasonable payment to

IRB members who are otherwise unaffiliated with the

institution can be a valuable way to strengthen these

members’ role.

Recommendation 3.9: Federal policy should 

establish standards and criteria for the selection

of Institutional Review Board members. The distribution of Institutional Review Board members

with relevant expertise and experience should 

be commensurate with the types of research

reviewed by the Institutional Review Board 

(see Recommendation 3.10). 
xvi

Summary of Recommendations

Recommendation 3.10: Institutional Review Boards

should include members who represent the 

perspectives of participants, members who are

unaffiliated with the institution, and members

whose primary concerns are in nonscientific

areas. An individual can fulfill one, two, or all

three of these categories. For the purposes of

both overall membership and quorum determinations 1) these persons should collectively 

represent at least 25 percent of the Institutional

Review Board membership and 2) members from

all of these categories should be represented each

time an Institutional Review Board meets (see

Recommendation 3.9). 

Guidance for Assessing Risks and

Potential Benefits

In addition to protecting the rights and welfare of

research participants, it is equally important to protect

them from avoidable harm. Thus, an IRB’s assessment of

the risks and potential benefits of research is central to

determining whether a research study is ethically acceptable. Yet, this assessment can be a difficult one to make,

as there are no clear criteria for IRBs to use in judging

whether the risks of research are reasonable in terms of

what might be gained by the individual or society.

IRBs should be able to identify whether a clear and

direct benefit to society or the research participants might

result from participating in the study. However, IRBs

should be cautious in classifying procedures as offering

the prospect of direct benefit. In fact, if it is not clear that

a procedure also offers the prospect of direct benefit, IRBs

should treat the procedure as one solely designed to

answer the research question(s). A major advantage of

this approach is that it avoids justifying the risks of 

procedures that are designed solely to answer the

research question(s) based on the likelihood that another

procedure in the protocol would provide a benefit.

Recommendation 4.1: An analysis of the risks and

potential benefits of study components should 

be applied to all types of covered research (see

Recommendation 2.4). In general, each component of a study should be evaluated separately,

and its risks should be both reasonable in 

themselves as well as justified by the potential

benefits to society or the participants. Potential

benefits from one component of a study should

not be used to justify risks posed by a separate

component of a study.

Minimal Risk

Determining whether a study poses more than minimal

risk is a central ethical and procedural function of the

IRB. The definition of minimal risk in federal regulations

(45 CFR 46.102(i); 21 CFR 56.102(i)) provides an

ambiguous standard by which risks involved in a

research study are compared to those encountered in

daily life. However, it is unclear whether this applies to

those risks found in the daily lives of healthy individuals

or those of individuals who belong to the group targeted

by the research. If it refers to the individuals to be involved

in the research, then the same intervention could be 

classified as minimal risk or greater than minimal risk,

depending on the health status of those participants and

their particular experiences. According to this understanding, the standard for minimal risk is a relative one. 

This report recommends that IRBs use a standard

related to the risks of daily life that are familiar to the

general population for determining whether the level of

risk is minimal or more than minimal, rather than using

a standard that refers to the risks encountered by particular persons or groups. These common risks would

include, for example, driving to work, crossing the street,

getting a blood test, or answering questions over the 

telephone. Thus, research would involve no more than

minimal risk when it is judged that the level of risk is no

greater than that encountered in the daily lives of the

general population. 

Recommendation 4.2: Federal policy should 

distinguish between research studies that pose

minimal risk and those that pose more than 

minimal risk (see Recommendation 2.5). Minimal

risk should be defined as the probability and

magnitude of harms that are normally encountered in the daily lives of the general population.

If a study that would normally be considered
National Bioethics Advisory Commission

xvii

minimal risk for the general population nonetheless poses higher risk for any prospective 

participants, then the Institutional Review Board

should approve the study only if it has determined that appropriate protections are in place

for all prospective participants.

Evaluating Vulnerability

All segments of society should have the opportunity to

participate in research, if they wish to do so and if they

are considered to be appropriate participants for a given

protocol. However, some individuals may need additional

protections before they can fully participate in the

research study; otherwise they might be more susceptible

to coercion or exploitation. Individuals might be considered vulnerable within the research context because of

intrinsic characteristics (e.g., they are children or have

mental illness or retardation) or because of the situation

in which they find themselves (e.g., they are impoverished,

unemployed, or incarcerated). Recognizing various types

of vulnerability and providing adequate safeguards can

prove challenging for IRBs. 

Appropriate and specific safeguards should be established to protect persons who are categorized as vulnerable. Once safeguards are established, investigators should

not exclude persons categorized as vulnerable from

research involving greater than minimal risk because this

would deprive them of whatever potential direct benefits

they might receive from the research and deprive their

communities and society from the benefit of the knowledge such research might generate. 

Recommendation 4.3: Federal policy should 

promote the inclusion of all segments of society

in research. Guidance should be developed on

how to identify and avoid situations that render

some participants or groups vulnerable to harm

or coercion. Sponsors and investigators should

design research that incorporates appropriate

safeguards to protect all prospective participants.

Emphasizing the Informed Consent

Process

Rather than focusing on the ethical standard of informed

consent and what is entailed in the process of obtaining

informed consent, IRBs and investigators have followed

the lead of the federal regulations and have tended to

focus on the disclosures found in the consent form.

However, from an ethics perspective, the informed consent process, not the form of its documentation, is the

critical communication link between the prospective 

participant and the investigator throughout a study,

beginning when the investigator initially approaches the

participant. Informed consent should be an active

process through which both parties share information

and during which the participant at any time can freely

decide whether to withdraw from or continue to participate in the research. It is time to place the emphasis on

the process of informed consent to ensure that information

is fully disclosed, that competent participants fully

understand the research in order to make informed

choices, and that decisions to participate or not are

always made voluntarily.

Recommendation 5.1: Federal policy should

emphasize the process of informed consent

rather than the form of its documentation and

should ensure that competent participants have

given their voluntary informed consent. Guidance

should be issued about how to provide appropriate

information to prospective research participants,

how to promote prospective participants’ comprehension of such information, and how to ensure

that participants continue to make informed and

voluntary decisions throughout their involvement

in the research.

Waiver of Informed Consent

Obtaining voluntary informed consent should not be a

requirement for every research study. In fact, waiving the

informed consent process is justifiable in research studies

that include no interaction between investigators and

participants, such as in studies using existing identifiable

data (e.g., studies of records) and in studies in which

risks generally are not physical. In these kinds of research,
xviii

Summary of Recommendations

risks are likely to arise from the acquisition, use, or 

dissemination of information resulting from the study

and are likely to involve threats to privacy and breaches

in confidentiality. The criteria for waiving informed 

consent in such instances should be revised, so that if

such studies have protections in place for both privacy

and confidentiality, IRBs may waive the requirement for

informed consent. 

Recommendation 5.2: Federal policy should permit

Institutional Review Boards in certain, limited

situations (e.g., some studies using existing 

identifiable data or some observational studies)

to waive informed consent requirements if all 

of the following criteria are met:

a) all components of the study involve minimal

risk or any component involving more than

minimal risk must also offer the prospect of

direct benefit to participants;

b) the waiver is not otherwise prohibited by

state, federal, or international law;

c) there is an adequate plan to protect the 

confidentiality of the data;

d) there is an adequate plan for contacting 

participants with information derived from

the research, should the need arise; and

e) in analyzing risks and potential benefits, 

the Institutional Review Board specifically

determines that the benefits from the 

knowledge to be gained from the research

study outweigh any dignitary harm associated

with not seeking informed consent.

Documentation of Informed Consent

Although the federal regulations may have been intended

to reflect a legal standard for documentation of informed

consent, NBAC is aware of no case law in which a signed,

written consent form is required. To fulfill the substantive

ethical standard of informed consent, depending on the

type of research proposed, it may be more appropriate to

use other forms of documentation, such as audiotape,

videotape, witnesses, or telephone calls to participants

verifying informed consent and participation in the

research study.

Recommendation 5.3: Federal policy should

require investigators to document that they 

have obtained voluntary informed consent, but

should be flexible with respect to the form of

such documentation. Especially when individuals 

can easily refuse or discontinue participation, or

when signed forms might threaten confidentiality,

Institutional Review Boards should permit 

investigators to use other means of verifying 

that informed consent has been obtained.

Protecting Privacy and Confidentiality

Privacy and confidentiality are complex and poorly

understood concepts in the context of some research.

Privacy refers to the ways and circumstances under

which investigators access information from participants.

Because privacy concerns vary by type and context of

research and the culture and individual circumstances of

participants, investigators should be well informed and

mindful of the cultural norms of the participants. In

addition, investigators should be aware of the various

research procedures and methods that can be used to

respect privacy. Needed is a clear, comprehensive regulatory definition of privacy along with guidance for 

protecting privacy in various types of research.

Like privacy concerns, concerns about confidentiality

vary by the type and context of the research. No one set

of procedures can be developed to protect confidentiality

in all research contexts. Thus, IRBs and investigators

must tailor confidentiality protections to the specific circumstances and methods used in each specific research

study. Further, IRBs and investigators are encouraged to

consider the use of strong confidentiality protections,

which can also reduce some of the violations associated

with privacy. A clear, comprehensive definition of confidentiality is needed, along with guidance for protecting

confidentiality in various types of research. 

Recommendation 5.4: Federal policy should be

developed and mechanisms should be provided

to enable investigators and institutions to reduce

threats to privacy and breaches of confidentiality.

The feasibility of additional mechanisms should

be examined to strengthen confidentiality protections in research studies.
National Bioethics Advisory Commission

xix

Monitoring of Ongoing Research

Continual review and monitoring of research that is in

progress is a critical element of the oversight system.

Such review is necessary to ensure that emerging data or

evidence have not altered the risks/potential benefits

assessment so that risks are no longer reasonable. In

addition, mechanisms are needed to monitor adverse

events, unanticipated problems, and changes to the protocol. IRBs can do a better job in this area with the

appropriate guidance and some restructuring of the

review and monitoring process. 

Currently, the requirement of continuing review is

overly broad. The frequency and need for continuing

review vary depending on the nature of research, with

some protocols not requiring continuing review. In

research involving high or unknown risks, the first few

trials of a new intervention may substantially affect what

is known about the risks and potential benefits of that

intervention. Even if the knowledge does not warrant

changes in study design, it may warrant changes in 

the information presented to prospective and enrolled 

participants.

On the other hand, the ethics issues and participant

protections necessary in minimal risk research are

unlikely to be affected by developments from within or

outside the research—for example, research involving

the use of existing data or research that will no longer

involve contact with participants because it is in the data

analysis phase. Continuing review of such research

should not be required because it is unlikely to provide

any additional protection to research participants and

merely increases the burden of IRBs. However, because

minimal risk research does involve some risk, IRBs may

choose to require continuing review. In these cases, other

types of monitoring may be more appropriate, such as

assessing investigator compliance with the approved protocol or reporting of protocol changes and unanticipated

problems. Clarifying the nature of the continuing review

requirements would allow IRBs to better focus their

efforts on reviewing riskier research and would increase

protections for participants where they are most needed.

Recommendation 6.1: Federal policy should

describe how sponsors, institutions, and 

investigators should monitor ongoing research.

Recommendation 6.2: Federal policy should

describe clearly the requirements for continuing

Institutional Review Board review of ongoing

research. Continuing review should not be

required for research studies involving minimal

risk, research involving the use of existing data,

or research that is in the data analysis phase

when there is no additional contact with participants. When continuing review is not required,

other mechanisms should be in place for ensuring

compliance of investigators and for reporting

protocol changes or unanticipated problems

encountered in the research.

Recommendation 6.3: Federal policy should 

clarify when changes in research design or 

context require review and new approval by 

an Institutional Review Board.

Adverse Event Reporting

Assessing adverse events reports can be a major burden

for IRBs and investigators because of the high volume

and ambiguous nature of such events and the complexity

of the pertinent regulatory requirements. Investigators

have reported frustration in attempting to understand

what constitutes an adverse event, the required reporting

times, and to whom adverse events should be reported.

The regulations need to be simplified, and one set of 

regulations should be available for safety monitoring.

Regulations and guidance should be written so that

investigators and sponsors understand what constitutes

an adverse event, what type of event must be reported

within what time period, and to whom it should be

reported. In addition, regulations and guidance should

be clear regarding whose responsibility it is to analyze

and evaluate adverse event reports and should describe

the required communication and coordination channels

for these reports among IRBs and safety monitoring entities, such as Data Safety Monitoring Boards, investigators,

sponsors, and federal agencies.
xx

Summary of Recommendations

Recommendation 6.4: The federal government

should create a uniform system for reporting and

evaluating adverse events occurring in research,

especially in multi-site research. The reporting

and evaluation responsibilities of investigators,

sponsors, Institutional Review Boards, Data

Safety Monitoring Boards, and federal agencies

should be clear and efficient. The primary concern of the reporting system should be to protect

current and prospective research participants.

Review of Cooperative or Multi-Site

Research Studies

One of the greatest burdens on IRBs and investigators 

is the review of multi-site studies. Requiring multiple

institutions to review the same protocol is unnecessarily

taxing and provides no additional protection to participants. In addition, such review poses problems in the 

initial stages of review as well as in the continual review

and monitoring stages and is especially problematic in

the evaluation of adverse events in clinical research.

Innovative and creative alternative mechanisms and

processes for reviewing protocols in multi-site research

are needed. To allow for such projects and to support a

change in the current system toward a more flexible

review system, federal policy should be clear about the

functions that must be performed, but be less restrictive

about who performs each function. 

Recommendation 6.5: For multi-site research, 

federal policy should permit central or lead

Institutional Review Board review, provided that

participants’ rights and welfare are rigorously

protected.

Compensation for Research-Related

Injuries

Participants who volunteer to be in a research study and

are harmed as a direct result of that study should be cared

for and compensated. However, no adequate database

exists that describes the number of injuries or illnesses

that are suffered by research participants, the proportion

of these illnesses or injuries that are caused by the

research, and the medical treatment and rehabilitation

expenses that are subsequently borne by the participants.

It may be argued that regardless of the magnitude of the

problem, the costs of research injuries should never be

borne by participants. If individuals are injured by

research participation, those who benefit from the

research (e.g., institutions and sponsors) bear some 

obligation to compensate those who risked and suffered

injury on their behalf. At this time, injured research 

participants alone bear both the cost of lost health and

the expense of medical care, unless they have adequate

health insurance or successfully pursue legal action to

gain compensation from the specific individuals or

organizations that were involved in conducting the

research. 

A comprehensive system of oversight of human

research should include a mechanism to compensate 

participants for medical and rehabilitative costs resulting

from research-related injuries. 

Recommendation 6.6: The federal government

should study the issue of research-related

injuries to determine if there is a need for a 

compensation program. If needed, the federal

government should implement the recommendation of the President’s Commission for the

Study of Ethical Problems in Medicine and

Biomedical and Behavioral Research (1982) 

to conduct a pilot study to evaluate possible 

program mechanisms.

The Need for Resources

Adopting the recommendations made in this report will

generate additional costs for institutions, sponsors, and

the federal government (through the establishment of 

a new federal oversight office). Sponsors of research,

whether public or private, should work together with

institutions carrying out the research to make the necessary

funds available.

Recommendation 7.1: The proposed oversight 

system should have adequate resources to ensure

its effectiveness and ultimate success in protecting

research participants and promoting research: 

a) Funds should be appropriated to carry out the

functions of the proposed federal oversight

office as outlined in this report.
National Bioethics Advisory Commission

xxi

b) Federal appropriations for research programs

should include a separate allocation for oversight activities related to the protection of

human participants.

c) Institutions should be permitted to request

funding for Institutional Review Boards and

other oversight activities.

d) Federal agencies, other sponsors, and institutions should make additional funds available

for oversight activities.

Future Research

This report raises many questions about ethical issues

that cannot be answered because of insufficient or nonexistent empirical evidence. Current thinking about 

ethical issues in research—such as analysis of risks and

potential benefits, informed consent, privacy and confidentiality, and vulnerability—would greatly benefit from

additional research. Deserving of more study, for example, are questions regarding the development of effective

approaches for assessing cognitive capacity, for evaluating

what participants want to know about research, and for

determining how to ascertain best practices for seeking

informed consent. Clearer and more effective guidance

could be developed from a stronger knowledge base. In

general, understanding the ethical conduct of research

would be advanced by increased interdisciplinary discussion that would include biomedical and social scientists,

lawyers, and historians. 

Recommendation 7.2: The federal government, in

partnership with academic institutions and professional societies, should facilitate discussion

about emerging human research protection issues

and develop a research agenda that addresses

issues related to research ethics.

Conclusions

This report proposes 30 recommendations for changing

the oversight system at the national and local levels to

ensure that all research participants receive the appropriate

protections. The adoption of these recommendations,

which are directed at all who are involved in the research

enterprise, will not only lead to better protection for 

the participants of research, but will also serve to 

promote ethically sound research while reducing

unnecessary bureaucratic burdens. Achieving these goals

will, in turn, restore the respect of investigators for the

system used to oversee research, support the public’s

trust in the research enterprise, and enhance public

enthusiasm for all research involving human beings.

Introduction

The charter of the National Bioethics Advisory

Commission (NBAC), a presidential commission

created in 1995, states that “[a]s a first priority, NBAC

shall direct its attention to consideration of protection of

the rights and welfare of human research subjects.”

During NBAC’s first five years, the Commission focused

on several issues concerning research involving human

participants,1 issuing five reports and numerous recommendations that, when viewed as a whole, reflect an

evolving appreciation of the various and complex challenges facing the implementation and oversight of the

system that protects those who volunteer to participate in

research.2

In May 1997, NBAC unanimously resolved that “[n]o

person in the United States should be enrolled in

research without the twin protections of informed consent by an authorized person and independent review of

the risks and benefits of the research.”3 In 1999, NBAC

indicated to the White House several areas of concern

regarding the oversight of human research in the United

States and provided preliminary findings. (See Appendix B.) The key concerns identified were as follows:

1) not all research participants are protected by the federal

oversight system;

2) a number of federal departments and agencies that

sponsor primarily nonbiomedical research or modest

amounts of research have failed to implement fully

the federal protections available;

3) the federal protections do not always include specific

provisions for those individuals who are especially

vulnerable; and

4) the federal protections are difficult to enforce and

improve effectively across the government, in part,

because no single authority or office oversees research

protections across all agencies and departments.

Based on these findings, and in response to a special

request from the White House Office of Science and

Technology Policy to further develop recommendations

for improving the system for protecting research participants, NBAC undertook a comprehensive examination of

the various aspects of the oversight system, including its

purpose; its structure, including its local configuration—

composed of investigators, institutions, and Institutional

Review Boards (IRBs); and the ethical issues relevant to

review of research. The recommendations contained in

this report reflect a dual commitment to ensuring the

protection of those who volunteer for research while supporting the continued advancement of science. They are

based on a view of the oversight system as a whole and

provide both a rationale for change and an interrelated

set of proposals to improve the protection of human 

participants and enable the oversight system to operate

more efficiently. 

The Value of Research

Throughout history, the pursuit of knowledge has been a

highly valued human endeavor, and research through

systematic, empirical investigation has become an essential method of attaining this goal. Like other forms of

learning, research is worthwhile because it helps to make

sense of and give meaning to the world and contributes

to a growing knowledge base that also gives rise to a wide

variety of practical benefits. Indeed, the contributions of

1

Introduction— The Need for Change

Chapter One 1
2

Chapter 1: Introduction—The Need for Change

science and technology to our daily lives are so ubiquitous that they are easily taken for granted. Knowledge

developed from a constant and broad-based national

investment in research has resulted in improvements in

health, created valuable new products for everyday living,

provided the capacity to sustain cleaner environments in

a rapidly industrializing world, and facilitated better

personal and family relationships. 

This investment in basic science and clinical and

public health research also has yielded a steady decline in

mortality since the 1950s (National Center for Health

Statistics 2000). Significant advances in treatment and

prevention have reduced the impact of deadly diseases,

such as some cancers (National Center for Health

Statistics 2000; Ries et al. 2000) and cardiovascular diseases (National Center for Health Statistics 2000), as well

as diseases causing morbidity, such as lead poisoning

(CDC 1999a), vaccine-preventable diseases (CDC

1999a), depression (Frank et al. 1993), and sexually

transmitted diseases (CDC 1999b). 

The humanities and social sciences are also central 

to society’s capacity to understand human nature and

biology by informing public and private decisionmaking

and by clarifying the effects of human behavior on wellbeing. For example, long-term studies have increased 

our understanding of poverty and the effects of family

stability on economic well-being, leading to changes in

welfare policy and the tax code (Hurst et al. 1998), and

numerous studies from developmental psychology and

cognitive science have articulated the processes by which

people learn, with important implications for education

(National Research Council 2000). By illuminating the

practices of others, anthropology research has also contributed to better understanding of certain societal

groups, such as the homeless (Baxter and Hopper 1981). 

Many important issues involving health and wellbeing can be studied by looking at how they interface at

the intersection of the humanities, the social sciences,

and the biological sciences. That is, prevention and 

amelioration of many diseases require attention to the

interfaces that exist at the molecular, organismal, psychosocial, and environmental levels. For example, emotional

states and the availability of social resources can influence disease survival rates and recovery and even the

likelihood of developing certain illnesses, indicating that

one’s position in the social hierarchy can be related to

morbidity and mortality. Even gene expression at the 

fundamental level may depend on the general environmental conditions experienced by an organism. Thus,

meaningful studies that will enhance our understanding

of human health and disease will include the study of

biological, psychological, environmental, and societal

factors and will involve the participation of a wide range

of individuals—including the healthy and the sick and

the affluent and the less fortunate—all of whom deserve

to have their rights and welfare protected. 

The Need for Oversight of Research

Involving Human Participants

Although the rewards of research for society can be great,

in some cases research can seriously harm participants.

However noble an investigator’s intentions may be, the

uncertainties that are inherent in any research study raise

the prospect of harms that may be difficult to fully anticipate.4 Thus, a system of protections is needed to minimize harms that might occur. In the United States, the

core aspect of Federal Policy for the Protection of Human

Subjects, known as the Common Rule (Code of Federal

Regulations, Title 45 Part 46 Subpart A), has been the

regulatory policy followed by 17 federal departments and

agencies for protecting human research participants (see

Appendix C for a history of the Common Rule’s development and Appendix E for the regulations [45 CFR 46]).

Each codification of the Common Rule by a department

or agency is equivalent to 45 CFR 46.101–46.124

(Subpart A), the Department of Health and Human Services

(DHHS) codification. Some agencies have promulgated

additional regulations concerning the protection of human

participants in research, for example, those related to privacy. The Common Rule applies to all research involving

human participants “conducted, supported or otherwise

subject to regulation by any federal department or agency

which takes appropriate administrative action to make

this policy applicable to such research.” The Food and

Drug Administration (FDA) also has its own regulatory

authority over research involving food and color additives, investigational drugs for human use, medical devices
National Bioethics Advisory Commission

3

for human use, biological products for human use being

developed for marketing, and electronic products that

emit radiation (21 CFR 50, 56; see Appendix F). To this

research, FDA applies its own set of regulations, which is

generally but not entirely the same as the Common Rule.

Even though the federal regulations cover a large portion

of human research conducted domestically, and in some

cases overseas, they are limited in their reach. In fact, if

federal funds are not involved or if regulatory approval is

not required, research activities involving human participants might not be subject to any form of oversight.

In general, the current research oversight system,

when applicable, adequately protects the rights and welfare of research participants. However, the consequences

of it not working can be tragic. Several recent cases point

to the need for improvements in the current oversight

system. 

For example, in California, a research study of schizophrenic disorders raised concerns about the quality

and completeness of informed consent and about the

risks of research when one of the participants committed suicide (Appelbaum 1996; Katz 1993; OPRR 1994).

The informed consent process for the study did not 

adequately explain the risks associated with receiving

fixed rather than individually tailored doses of medication, receiving no medication at all, or the alternatives

for treatment that were available outside of research

(OPRR 1994).

In 1994, a healthy 19-year-old student at the

University of Rochester died from complications related

to a research study in which she underwent a bronchoscopy, during which investigators took more samples

and used more anesthetic than were called for in the

research protocol as approved by the IRB (New York State

Department of Health 1996; Rosenthal 1996). Her death

illustrates the need for independent review of protocols

accompanied by the assurance that investigators will

adhere to the approved protocol. 

In 1999, the death of a young man, Jesse Gelsinger, in

a gene transfer trial highlighted a number of concerns—

including the role of federal oversight—that arise when

researchers began human trials of new and experimental

approaches to treatment (Marshall 2000; Wolf and Lo

2000). Gelsinger, who had ornithine transcarbamylase

deficiency, a rare genetic disorder that affects the body’s

ability to eliminate ammonia, participated in a gene

transfer trial conducted at the University of Pennsylvania.

The Phase I study was designed to test the safety of a gene

transfer vector that, if successful, would have been used

to treat infants with the fatal form of the disorder.

Gelsinger was in a group receiving the highest dose.

Although he was aware that he was in a research study,

the research may not have been fully or adequately

explained to him. During this study, participants were

not informed about serious adverse events that had been

previously reported, such as significant elevations in liver

enzymes experienced by other participants.5 In addition,

FDA was not notified of results from preclinical animal

studies as required,6 and some participants, including

Gelsinger, did not fit the revised inclusion criteria.7

Moreover, the lead investigator had financial interests in

the company that developed the gene transfer techniques

being studied (Wolf and Lo 2000). Finally, the death of

Jesse Gelsinger raised questions about federal and local

IRB monitoring of previous gene transfer studies when it

was discovered that adverse events from other trials had

not been reported to the National Institutes of Health

(NIH) in a timely manner. As this incident was investigated, it became clear that a mechanism for federal 

agencies to adequately share information was lacking and

that NIH was unaware of the exact nature of adverse

event reports provided to FDA. In addition, an amendment broadening the inclusion criteria for the trial was

implemented without specific FDA approval.8

A number of other cases highlight the limits of the

current oversight system. In the early 1990s, for example, plastic surgeons at a New York City hospital compared two common surgical procedures for facelifts by

performing both procedures on each individual participant, one procedure on each side of the face. The study

was not reviewed by an IRB, and the participants were

not told that they were participating in a research study

(Hilts 1998). The Office for Protection from Research

Risks (OPRR) halted its investigation of the case when it

learned that the research, which involved no federal

funds, was not subject to the federal oversight system.9

In another case, in 1996, according to one news

account, an eye surgeon at the University of South
4

Chapter 1: Introduction—The Need for Change

Florida performed an experiment on at least 60 people

using a cutting tool he developed to accelerate the healing

process after corneal transplantation. However, the surgeon did not have IRB approval to use the experimental

tool on human participants,10 and participants did not

give informed consent.11 Moreover, the press raised concerns about conflicts of interest because the university

held a patent on the cutting tool and listed the surgeon

as a co-inventor. Both stood to benefit financially from

the marketing of the tool (Klein 2000). 

Although the more dramatic examples have occurred

in clinical research, problematic cases are not limited to

this area of investigation. The real and potential harms

involved in these and other well-publicized examples of

the failure to protect the rights and welfare of research

participants erode public trust in the research enterprise

and make it clear that a viable and credible oversight 

system should aim first to protect participants from

undue harm, with the additional goal of creating an environment in which ethically sound and meritorious

research can be conducted with society’s support and

trust. Ideally, the oversight system should avoid needless

complexities and regulation, enhance the quality of

research, and protect participants, a difficult but achievable

balance.

Current Factors Influencing the

Research Enterprise

The conduct of research has been transformed by many

factors over the past 25 years, resulting in a much larger

and more complex enterprise. Changes include shifts in

patterns of research investment; growing stresses on 

academic medical centers and research universities; the

emergence of independent IRBs; changing public perceptions and expectations about research participation;

new technologies that affect risks and potential benefits in research; and growing consideration of the roles 

of groups and communities in research design and 

implementation.

Changes in Trends in Research Investment

In the past two decades, phenomenal growth has

occurred in federally and industry-sponsored biomedical

research. Federal expenditures for medical and health

research conducted in the United States and in foreign

countries almost doubled from $6.9 billion to $13.4 

billion between 1986 and 1995. Roughly half of that

funding went to university-based research programs,

largely to academic medical centers.12 The federal investment in research involving human participants extends

well beyond biomedical research and is extremely diverse

(see Exhibit 1.1). 

Industry expenditures for medical and health-related

research conducted in the United States and in foreign

countries have been rising even faster than those of the

public sector, tripling from $6.2 billion to $18.6 billion

during that same period.13 Research conducted in the

United States sponsored by one segment of industry,

pharmaceutical companies, has experienced particularly

rapid growth, rising 14-fold from $1.5 billion to $22.4

billion between 1980 and 2000 (PhRMA 2000). As a

result, industry funding is playing an increasingly important role in the support and conduct of medical and

health-related research.

Not surprisingly, the rapid rise in industry investment

in research funding has been matched by an accompanying rise in the number of clinical investigators connected

with this activity. For example, the number of investigators participating in FDA-regulated research increased

from 5,500 in 1990 to 25,000 in 1996 (Valigra 1997),

and the total number of U.S. clinical investigators is 

now estimated to be between 45,000 and 50,000

(CenterWatch 2000). Thus, the sheer volume and diversity

of research have placed new strains on the system

designed to oversee the protection of research participants.

Stresses on Academic Medical Centers and

Research Universities

Academic medical centers, traditionally the principal

sites of clinical research, have experienced certain stresses

that offset, in part, the effects of this growth in research

funding. In particular, managed care, price competition

in health care, and cost containment efforts (e.g., the

Balanced Budget Act of 1997)14 have resulted in reductions in net clinical income to academic institutions. This

trend negatively influences their capacity for research and

education, because excess clinical revenue traditionally

has been the means by which academic medical centers

subsidize these activities (Crowley and Thier 1996;
National Bioethics Advisory Commission

5

Exhibit 1.1: The Size and Scope of Federally Funded Research Involving Human Participants

Sixteen federal departments and agencies reported to

NBAC that they conduct or support research involving

human participants, although some components within

departments reported that they do not sponsor or 

conduct such research (e.g., the DHHS Administration

on Aging). Each agency’s research program involving

human participants is distinctive in terms of its size,

scope, organization, and focus, all of which reflect its

primary mission. The following examples illustrate the

diverse types of research conducted or supported by

federal agencies:

■ The Department of Defense (DOD) conducts biomedical and behavioral research involving human participants within each of the military services and through

several additional defense agencies, primarily in

areas supporting the mission of the department.

■ The Department of Veterans Affairs (VA) operates

inpatient medical centers—including short-term 

hospitals, psychiatric and rehabilitation facilities, and

nursing homes—and domiciliary and outpatient 

facilities. The VA’s largely intramural biomedical

research program focuses on the health care needs

of veterans. 

■ The Department of Energy (DOE) conducts and 

supports research involving human participants that

ranges from diagnostic and therapeutic applications

in nuclear medicine to epidemiological and occupational health studies and manages the National

Laboratories, where many other agencies sponsor

biomedical and nonbiomedical research. 

■ The U.S. Coast Guard within the Department of

Transportation (DOT) conducts studies involving

human participants that are currently limited to shipboard crew endurance efforts.

■ The National Aeronautics and Space Administration

conducts ground-based and in-flight biomedical

research related to space life that involves human

participants. 

■ The Census Bureau participates in survey and census design, questionnaire development, geographic

support, and data collection, tabulation, analysis, and

dissemination. 

■ Research studies in the Human Factors Laboratory

at the Federal Highway Administration of DOT

include investigations of drivers’ responses to 

highway design features and in-vehicle information

systems.

■ A major research program of the Substance Abuse

and Mental Health Services Administration (DHHS)

develops knowledge about new ways to improve the

prevention and treatment of substance abuse and

mental illness and new ways to work with state and

local governments, as well as providers, families,

and consumers, to apply that knowledge effectively

in everyday practice.

■ The Health Care Financing Administration (DHHS)

sponsors research designed to study or evaluate

public benefit or service programs, such as

Medicare/Medicaid and the State Children’s Health

Insurance Program.

■ In the area of infectious disease research, the

Centers for Disease Control and Prevention (CDC,

DHHS) conducts studies involving the systematic

collection, analysis, and interpretation of outcomespecific data, closely integrated with timely dissemination of these data to those responsible for

preventing and controlling disease or injury.

■ The Directorate of Social, Behavioral and Economic

Sciences of the National Science Foundation supports research that builds fundamental knowledge 

of human behavior and of social and economic 

systems, organizations, and institutions. 

■ The Environmental Protection Agency sponsors

research on human exposure to environmental

agents, which involves the gathering of physiological

measurements (e.g., monitoring a subject’s cardiorespiratory performance) or the collection of body

fluids, tissue, or expired air from participants.

■ As part of its HIV/AIDS and Pre-Adolescent

Awareness Programs in Africa, the U.S. Agency for

International Development supports activities to 

collect information about what is currently taking

place in schools as well as information about student

sexual awareness and sexual practices. Research

efforts aim to demonstrate what kinds of risk behaviors exist and how curricula can be developed that

will enable students to make informed decisions.15

At least 69 federal departments and agencies are not

covered by the Common Rule. NBAC was unable to

determine which of these departments and agencies

might sponsor or conduct research with human participants; however, at least some of them are involved in

such activities.
6

Chapter 1: Introduction—The Need for Change

Mechanic and Dobson 1996). In addition, clinical

income has been affected by managed care’s scrutiny of

patient-related costs, whereby much routine patient care

is deemed unreimbursable when associated with a clinical

trial or an “experimental” therapy.

One set of responses has been the establishment of

revenue-generating centers for clinical research and the

development of new relations with industry (Gallin and

Smits 1997). Another is the creation of research partnerships with health maintenance organizations (Donahue

et al. 1996). In addition, the burgeoning number of 

academic investigators competing for funding has stimulated many institutions to seek financial support from

industry (Henderson 1999). In some cases, this shift to

more private funding has changed the nature of regulatory oversight.

At the same time, industry-sponsored research is

spreading between and beyond academic medical centers. In 1998, only 40 percent of industry funding for

clinical trials went to academic medical centers, down

from 80 percent in 1991 (Henderson 1999). Large

amounts of research are now managed by private

Contract Research Organizations (CROs), rather than

academic investigators, and there has been significant

growth in Site Management Organizations (SMOs),

which conduct research in dedicated facilities and

through various types of physician networks (Association

of Clinical Research Professionals 1997). Research also

continues to be performed in private medical and diagnostic practices unaffiliated with an SMO (CenterWatch

1998). Thus, increasingly some avenues of clinical

research fall outside the strongest and most experienced

part of the current system of oversight.

To find the large numbers of participants needed to

enroll in clinical studies, sponsors and CROs often conduct a single research study at dozens or even hundreds

of sites. A study may involve numerous academic centers,

as well as community hospitals and private practice

physicians. In order to compete, some academic medical

centers are forming research networks and attempting to

provide services similar to those of for-profit companies

(Bodenheimer 2000). Consequently, the traditional biomedical research model of one research study led by one

investigator at one academic institution now occurs

much less frequently than in the past, a situation that

complicates and often prolongs the review and approval

of research studies (OIG 1998a, 4–5).

The Emergence of Independent IRBs

As clinical research has spread beyond academic institutions, the locus of ethics review also has shifted. In the

United States, the committees that review research with

the mandate to protect the rights and welfare of human

participants—IRBs—have traditionally been located in

the institution in which the research is conducted.

However, IRBs also now exist as separate entities that are

not part of the organizational structure of an institution

that conducts or funds research. Although many labels

are used to describe these groups, this report will use the

term independent IRBs.

16 Independent IRBs, which have

existed for more than 30 years and are growing both in

size and in the number of protocols they review, usually

are for-profit entities that operate on a fee-for-service

basis (OIG 1998b). Traditionally, independent IRBs 

primarily have reviewed industry-funded clinical

research, but since 1995 they also have been permitted to

review federally funded research.17 It should be noted

that some institutionally affiliated IRBs have begun to

charge for review of certain types of protocols (e.g.,

industry-sponsored research), and may even conduct

reviews for other, unaffiliated or loosely affiliated groups,

thus acting much like independent IRBs.

Changing Public Perspectives About Research

Participation

The growth and spread of clinical research also

reflects a growing demand by patients for access to

clinical trials. People with difficult-to-treat, life-threatening

diseases often see clinical trials as offering the benefits of

cutting-edge medicine. In this context, trial participation

is viewed as a benefit to be sought rather than a burden

to be avoided (Kahn et al. 1998). This sentiment was

expressed forcefully by HIV/AIDS activists (Rothman 

and Edgar 1991), some of whom adopted the slogan, 

“A Drug Trial Is Health Care Too” (Annas 1990, 35).

Disease-oriented patient activists have also emphasized

the collective benefits of research for all individuals with
National Bioethics Advisory Commission

7

a specific condition. Advocacy groups commonly lobby

Congress and NIH for more research funding (in particular for clinical trials) for specific diseases and conditions,

not only to benefit individual research participants, but

also to improve treatment for all who are affected by a

given disease or condition.

These calls for access to trials have spurred a “reconceptualization of the concept of justice” in clinical

research (Brody 1998). That is, although the application

of the principle of justice has traditionally focused on

fairly distributing the risks of research—selecting participants equitably meant not targeting individuals considered vulnerable for participation in risky research from

which they were unlikely to receive any direct benefit—

applying the principle of justice now focuses also on

fairly distributing the potential benefits of research.

Selecting participants equitably means not unfairly

excluding certain subgroups of the population from

research and working to ensure that the knowledge

gained in research applies as appropriate across all

groups in society. Routine exclusion of groups—such as

women of childbearing age—once seen as appropriate

and protective, is now seen as arbitrary and paternalistic.

Therefore, several federal agencies have developed policies

to promote, for example, inclusion of women and/or

minorities in research, as well as data analysis relevant 

to these groups.18 Other policies that reflect a growing

emphasis on access to participation in research include

FDA’s regulations granting an exception from informed

consent requirements for some emergency research

(21 CFR 50.24), the promotion of the inclusion of children

in research,19 and the provision of Medicare payment for

the routine costs of clinical trials and items and services

that are otherwise generally available to beneficiaries.20

New Technologies Posing New Challenges to

Risk/Potential Benefit Analysis

Research both produces and is affected by advances in

technology. However, although advances in genetics, the

rise of the Internet, and the growth of informatics are all

providing important new capabilities for research, these

advances also can raise new ethical challenges. For example, although genetic research may pose no physical risk

beyond that of drawing blood, it can pose significant 

psychological and economic risks if participants—or

their insurers or employers—learn that they are predisposed to an untreatable condition. NBAC has addressed

some of these issues in a previous report (NBAC 1999b).

New information technologies can provide opportunities for medical, health-related, and social science

research while also raising ethical challenges regarding

the protection of confidentiality of the resulting data. The

computerization of medical records, which greatly facilitates retrospective analysis of patients’ medical records,

has also prompted discussion about the legitimate

access to and use of medical records in the new electronic environment (Etzioni 1999; National Research

Council 1997). Such new technologies might, in this

case, increase threats to privacy by making it easier to

identify patients from combinations of seemingly

unidentifiable data, such as age and date of hospital

admission (Sweeney 1997; Woodward 1999). As with

medical records, computerization has prompted discussion about the ability to restrict access to and use of

employment or school records, financial information,

and large survey data sets (Garfinkel 2000; White 2000). 

The Internet has also given rise to new research

opportunities and risks by allowing investigators to reach

a wide pool of participants, although participants’

assumptions about the anonymity, security, and privacy

of Internet connections might not be justified. The ease

with which investigators can misrepresent themselves

online raises new questions about the propriety of deception research carried out in this context. The possibility

for online misrepresentation by participants is also of

concern; for example, investigators may have no way of

knowing whether children are participants in online

research and are therefore in need of special protections

(Frankel and Siang 1999).

Growing Consideration of Groups and

Communities

Social science research also is undergoing a number

of important changes that affect the protection of

research participants. Beginning with the cardiovascular

disease primary prevention trials conducted in various

communities and sponsored by the National Heart,

Lung, and Blood Institute in the 1980s (Carleton et al.
8

Chapter 1: Introduction—The Need for Change

1995; Farquhar et al. 1985; Jacobs et al. 1986), there has

been an increase in the number of research studies conducted in community settings (Mittelmark et al. 1993).

As the behavioral and social determinants of more 

diseases are known (e.g., HIV/AIDS, lung cancer, heart

attack, stroke), the focus of intervention strategies has

broadened from the individual to the population, and the

research setting has in some cases moved into the community (Schneiderman and Speers 2000). For example,

research on cigarette smoking once focused on cessation

efforts, and interventions were targeted at individuals

(DiClemente et al. 1991). Now, with the emphasis on

prevention of smoking behavior, research interventions

are often targeted at particular populations and carried

out at the community level (Cummings 1999). With such

community-oriented research interventions, defining the

research participants and identifying the appropriate

participant protections can be difficult.

Increasingly, research is conducted with communities,

not on communities (Bracht 1991; George et al. 1996).

Local community groups and organizations often act as

collaborative investigators by sharing responsibility with

academic investigators in designing and implementing a

research study (Hatch et al. 1993). However, this new

collaborative role of the community raises many issues

related to research infrastructure and oversight. For

example, it is unclear when community groups must

have an IRB and how to build capacity within the community to carry out these regulatory responsibilities.

Issues related to just what individual or which group

speaks for the community as a whole and how to obtain

community input or consent are continuing challenges to

conducting such research.

Major Challenges Facing the Current

Oversight System

Huge financial investments, expansion of the research

enterprise, and new technology have all stressed a system

of oversight that is less than optimal. A major overarching

challenge that faces the entire system is a lack of adequate

resources, both financial and human. Scarce resources

limit the functioning of the oversight system at every

level and often prevent federal offices, institutions, and

IRBs from implementing initiatives that would improve

the system. 

A 1996 General Accounting Office report, conducted

at the request of the Senate Committee on Governmental

Affairs, found the current system for protecting participants in scientific research to be deficient because of

heavy workloads and competing demands on IRBs, a

lack of preparedness of IRBs to review complex research,

limited funds for federal inspections, and over-reliance

on investigators’ willingness to comply with regulatory

requirements (GAO 1996).

In June 1998, the DHHS Office of Inspector General

(OIG) sounded a “warning signal” that the system had

not adapted sufficiently to the changing research environment (OIG 1998a). This warning accompanied and

was followed by a series of reports on specific aspects of

the oversight of research, particularly the role of IRBs

(OIG 1998b–e; OIG 2000a–d). The OIG reports found

that many IRBs are simply overwhelmed by the volume

and complexity of the research they review, by a lack of

financial, administrative, and educational resources, and

by a regulatory system that often distracts from rather

than focuses on key ethical issues. These pressures make

the system inefficient and strain its capacity to protect

participants.

A related report sponsored by the NIH Office of

Extramural Research provided quantitative information

about IRBs’ workloads (Bell et al. 1998). Based on a

survey of 491 institutions holding Multiple Project

Assurances (MPAs),21 this report provided a sense of the

scale of the human research enterprise and noted that

some IRBs review a striking number of protocols. Indeed,

the highest volume IRBs, about 10 percent, were found

to account for 37 percent of the total reviews (Bell et al.

1998, 8).

Recent actions of the federal Office for Human

Research Protections (OHRP) (formerly OPRR) within

DHHS highlight the existence of systemic problems of

the oversight system at the institutional level. For example,

OHRP has restricted or suspended MPAs and required

corrective actions at nearly a dozen academic institutions.

These sanctions were imposed by OHRP when it found

“numerous deficiencies and concerns regarding systemic

protections for human subjects” (OHRP 2000). As previous reports have suggested, deficiencies occurred in areas
National Bioethics Advisory Commission

9

such as IRB membership, education of IRB members and

investigators, institutional commitment, IRB initial and

continuing review of protocols, review of protocols

involving vulnerable persons, and procedures for obtaining

voluntary informed consent.

The recent academic literature regarding the current

oversight system for the protection of human research

supports many of the findings from these reports (Edgar

and Rothman 1995; Moreno et al. 1998; Phillips 1996;

Snyderman and Holmes 2000; Woodward 1999). There

is general recognition that because the nature and context

of research have changed, the nature and structure of the

oversight of research also must change. For example,

Moreno et al. argue that the federal regulations should be

revised to reflect changes that have affected the nature

and context of research, such as the increased importance

of multi-site studies (1998). They also argue that the 

federal regulations should be responsive to certain

needed protections that have been identified, but were

not enacted when the Common Rule was issued (e.g.,

protections for individuals categorized as vulnerable).

Others, including Edgar and Rothman, argue that the

expansion of the scientific frontier requires that ethics

review mechanisms other than local IRBs should be considered, such as national, topic-specific advisory panels

(1995). Edgar and Rothman also characterize the local

IRB as a “paper tiger,” buried in paperwork and often

unable to deal effectively with ethical issues (1995). 

While more protection may be needed in some areas,

another concern is the overwhelming burden that is

placed on IRBs and investigators and the extent to which

unnecessary paperwork requirements are displacing a

focus on important ethical issues. For example, Phillips

points to the growing frustration among investigators and

IRBs that has resulted from the increase in administrative

and regulatory requirements without a commensurate

increase in protection (1996). Some support the need for

oversight while still perceiving regulatory and compliance

mechanisms, such as reporting requirements, as difficult

to interpret, redundant, and inefficient (Snyderman and

Holmes 2000). 

Others perceive the problems with the current oversight system as failures to address such issues as inadequate funding, lack of adequate education for IRB

members and investigators, and insufficient focus on

conflicts of interest in research (Amdur 2000; Shamoo

1994; Snyderman and Holmes 2000; Sugarman 2000).

Overall, there is broad agreement in the academic

literature that the current oversight system is in need of

improvement.

Inconsistent Interpretation and Implementation

of the Regulations by Federal Agencies

The creation of the Common Rule (see Appendix C)

provided significant unification in the language of federal

regulations for the protection of human research participants. However, the Common Rule did not create a

shared mechanism for interpreting and implementing the

regulations at the federal level. In the absence of a formal

mechanism, OHRP sometimes acts as a de facto reference

point and consensus builder among federal agencies,

even though it has no congressional or executive authority

to do so. Moreover, some other departments have not

established offices comparable to OHRP for interpreting

and implementing the regulations; in some cases, a single

individual is responsible for oversight activities. Thus,

the ability to coordinate oversight among the departments is weak, leading departments and agencies bound

to the Common Rule potentially to interpret regulatory

requirements differently (see Exhibit 1.2). In addition to

varying substantive interpretations of the regulations,

departments and agencies use different procedures to

ensure compliance. This issue is further discussed in

Chapter 2.

Incomplete Protection of Individuals

Considered Vulnerable

Some federal departments have supplemented the

Common Rule with additional regulations and policies.

For example, DHHS provides additional protections for

pregnant women and fetuses, prisoners, and children 

(45 CFR 46 Subparts B, C, and D).22 The Central Intelligence Agency and the Social Security Administration (SSA)

also follow these regulations for groups that are considered

vulnerable. The Department of Education has adopted

protections for children (34 CFR 97 Subpart D), and the

Department of Justice has adopted protections for research

conducted within the Bureau of Prisons (28 CFR 512). In

addition, although FDA’s regulations do not include
10

Chapter 1: Introduction—The Need for Change

Exhibit 1.2: Examples of Inconsistencies Among Agencies Bound to the Common Rule

There is wide variation among federal departments and agencies regarding their policies and procedures for determining whether a research activity is exempt from the federal regulations (45 CFR 46.101). Differences could be due

to the variability in the types of research sponsored; however, they also could be due in part to inconsistent interpretation of the regulations. As shown in Table 1.1, many agencies report that all, or nearly all, of the research that

they conduct or sponsor is exempt from the federal regulations.

The procedures used to make these determinations vary across agencies. In general, agencies use their IRB chair

to determine whether research conducted by the agency is exempt, and a combination of technical and legal staff

determine exemptions for human participant research sponsored through grants and contracts. Some agencies have

customized administrative mechanisms for making these determinations. For example, the Census Bureau considers all of its research to be exempt under Federal Policy 15 CFR 27.101 (b)(3)(ii), which exempts survey procedures

if “federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will

be maintained throughout the research and hereafter.” However, privacy and confidentiality issues that relate to

human participants are brought to the Census Bureau’s Policy Office. The Census Bureau’s Disclosure Review

Board has primary responsibility for ensuring confidentiality in published reports and data products.

SSA does not have an IRB, because it claims that all of its research is exempt. This exemption took effect on April

4, 1983,23 as a result of a final DHHS rule published on March 4, 1983. Research carried out under section 1110(b)

of the Social Security Act, however, remains subject to the Common Rule’s informed consent requirements. The 1983

notice states that “[i]n order to insure the continued protection of human subjects participating in such [otherwise

exempt] research activity, the Department is adding a specific requirement of written, informed consent in any

instance, not reviewed by an IRB, in which the Secretary determines that the research activity presents a danger to

the physical, mental, or emotional well-being of a participant.”24 In the case of biomedical and behavioral research,

in the 1983 Federal Register notice, DHHS makes clear the need for IRB review, but states that such review would

be “unnecessary and burdensome in the context of research under the Social Security Act and otherwise.” 25 DHHS 

discusses, but rejects, several proposals for IRB review of research and demonstrations to support public benefit or

service programs and concluded that “ethical and other problems raised by research in benefit programs will be

addressed by the officials who are familiar with the programs and responsible for their successful operations under

state and federal law.” 26 SSA reviewed the 1983 regulation with OHRP/OPRR and concluded that it continues to

apply to SSA research and demonstrations. In 1999, SSA did not conduct any extramural human participant research

or demonstrations under section 1110(b).

The Health Resources and Services Administration (HRSA, DHHS) reported that nearly all of its research

activity comprises program evaluation or evaluation of demonstration projects, which are considered to be exempt

from the federal regulations under the public “benefit and service” criterion. However, HRSA requires such a claim of

exemption to be approved by the HRSA Human Subjects Committee. Otherwise IRB oversight is required.27

Furthermore, even within DHHS, both substantive and procedural differences can be found, notably between FDA

and DHHS regulations. These differences relate to informed consent, the definition of research, emergency research,

assurances of compliance, inspections by the sponsoring agency, sanctions for noncompliance, and additional 

protections for vulnerable populations.

Whatever the source, inconsistency among departments and agencies can lead to confusion and frustration

among some investigators and IRBs28 and can render the oversight system unnecessarily confusing and open to 

misinterpretation. Not only do different rules apply to different research studies, but a single study may be subject to

more than one set of regulations if it is sponsored or conducted by institutions that are required to follow more 

than one set of rules. IRBs and investigators are often uncertain which rules apply or to whom they must report. For

example, an NIH-funded study involving an FDA-regulated investigational drug conducted in a VA hospital would be

subject to the regulations and oversight of three different departments or agencies (45 CFR 46; 21 CFR 50,56; 

38 CFR 16).
National Bioethics Advisory Commission

11

protections for vulnerable individuals analogous to the DHHS subparts, a law passed in

2000 requires DHHS to apply Subpart D of 45

CFR 46 to all research conducted, supported,

or regulated by the department, including

research regulated by FDA.29 FDA subsequently

issued an interim rule incorporating Subpart D

into its regulations.30 It is noteworthy, however,

that so few Common Rule signatories have

adopted additional protections for individuals

who are considered vulnerable, in effect 

providing incomplete protection for human

research participants. (The protection of individuals and groups that are categorized as vulnerable is discussed in detail in Chapter 4.)

Lack of Adaptability

Some of the regulatory challenges are exacerbated by the fact that the Common Rule is 

difficult to amend. Amending the Common

Rule requires that each signatory agency first

agree to a revision before the 15 agencies with

regulations go through the rulemaking process

to revise the regulations.31 This weakness

results in a set of regulations for which no 

system-wide change is possible. Obtaining

concurrence of the departments and agencies

on any regulatory change so far has proven

impossible, although not because of lack of

need or effort.32 The addition of regulations to

the Common Rule specific to classified

research, for example, has not been achieved

despite three years of effort, a Presidential

Memorandum directing the change, and a

challenge in a U.S. District Court.33

Unable to change the regulations, some

departments have attempted to make modifications by issuing regulatory guidance, a strategy

used by the VA in issuing regulations for 

providing treatment for injuries resulting from

participation in research (38 CFR 17.85).

However, the power of such changes is limited,

and because guidance is usually department

specific, it promotes inconsistency and undermines the very unification the Common Rule is

Table 1.1: Percent of Human Participants Research

Determined to Be Exempt by Federal Agencies

Agency Estimated Percent 

of Human 

Participants 

Research 

Deemed Exempt*

Central Intelligence Agency 0

Department of Commerce 60–100

Department of Defense 80

Department of Education 60

Department of Energy unknown

Department of Health and Human Services 

Administration for Children and Families 0

Administration on Aging unknown

Agency for Healthcare Research and Quality 20–90

Centers for Disease Control and Prevention 10

Food and Drug Administration <10

Health Care Financing Administration 100

Health Resources and Services Administration 100

Indian Health Service 20

National Institutes of Health <10

Substance Abuse and Mental Health 

Services Administration ~100

Department of Housing and Urban Development 40

Department of Justice 0–80

Department of Transportation 5

Department of Veterans Affairs unknown

National Aeronautics and Space Administration 0

National Science Foundation 80–100

Social Security Administration 100

Agency for International Development 50

Consumer Product Safety Commission 50–100

Environmental Protection Agency 3–5

*Some departments reported data for several units. The range represents the differences in data reported.

Source: NBAC, “Federal Agency Survey of Policies and Procedures for the Protection

of Human Subjects in Research.” This staff analysis is available in Volume II of this

report.
12

Chapter 1: Introduction—The Need for Change

supposed to establish. (Further discussion of this issue

and recommendations appear in Chapter 2.)

Limited Scope

The Common Rule was intended to both provide uniformity across federal departments and expand the scope

of regulations to federal departments that previously had

none. However, although it marked a significant expansion in scope, the Common Rule still does not apply to

all federally sponsored research.

Existing regulations also do not apply to many areas

of research funded and conducted by businesses, private

nonprofit organizations, and state or local agencies,

although such research may be subject to federal regulation if it involves the development of medical devices or

drugs requiring approval by the FDA or if it is conducted

at an institution that has voluntarily agreed to apply

Common Rule requirements to all research it conducts.

An unknown amount of nonfederally funded research is

completely unregulated under the federal system. This

research may include experimental surgical techniques,

research on reproductive technologies, some uses of

approved drugs and medical devices, and research use of

private, identifiable data.34 In some cases, nonfederally

funded research may be subject to state regulations, or

investigators may voluntarily meet federal requirements

to reduce research-related liability. (Recommendations

regarding expanding the scope of the system to include

such research appear in Chapter 2.)

Enforcement Weaknesses

Even for research that is subject to federal regulations,

the mechanisms for enforcing them suffer from three

potential weaknesses; the lines of enforcement authority

are awkward and sometimes isolated; there is a limited

repertoire of sanctions to match the range of possible 

violations; and the oversight and monitoring process is

uneven.

First, there is no clear line of authority or system for

the federal government as a whole to sanction serious or

repeated noncompliance by investigators or institutions.

This results from the dispersion of enforcement functions

among various departments and agencies, which weakens

the sanctions any one department can impose because

investigators could continue research overseen by a different authority. Each federal department that adheres to

the Common Rule has the authority to enforce its own

codification of the Common Rule for research it conducts

or sponsors. However, federal agencies and institutions

with assurances of compliance (formal commitments by

institutions to the government stating that they comply

with federal regulations) from OHRP are subject to

enforcement from that office as well. In the case of DHHS

grantees and contractors, the enforcement authority is

clear because OHRP is part of DHHS. But, when the

assurance holder is the grantee of another department,

OHRP decisions come from outside the regular reporting

line of authority. Additionally, departments that do use

the OHRP assurance process may have their own separate

systems for enforcement, and there is little coordination

among the various offices responsible for ensuring 

compliance with the Common Rule. 

Second, concerns have emerged that enforcement

authorities do not have or use an adequate range of sanctions to respond to various forms of noncompliance.

Federal regulations give department and agency heads

the authority to terminate or suspend funding for

research projects that are not in compliance with the 

regulations (45 CFR 46.123(a)). Common enforcement

tools are the requirement of written responses or the

enactment of specific changes to address the identified

deficiencies; those who grant assurances can also restrict

or suspend institutional assurances. Under its regulations,

FDA can withhold approval of new studies, prohibit

enrollment of new subjects, and terminate studies. FDA

can also issue warning letters and can restrict or disqualify

investigators, IRBs, or institutions from conducting or

reviewing research with investigational products.35

However, a more complete range of sanctions should be

considered for enforcement authorities.

Third, any system of sanctions can only be as good as

the monitoring and investigating processes that are used

to determine their need. The Common Rule does not set

out agency responsibilities for monitoring IRBs or investigators. Some agencies, such as DOE, have a program of

routine site reviews.36 Other agencies, such as DHHS,

conduct only “for cause” investigations, generally

because limited budgets do not permit more proactive
National Bioethics Advisory Commission

13

monitoring. Investigations often take a long time (in

some instances over a year)37 and usually do not include

on-site visits (OIG 1998a). 

This lack of centralized enforcement authority, proportionate sanctions, and active research oversight serves

to weaken severely the system for protecting human

research participants. Any one of these weaknesses alone

or in combination can lead to unnecessary bureaucracy

and burden that could be reduced by a unified office for

oversight, which could serve to simplify the bureaucratic

complexity and lead to improved monitoring and

enforcement. 

Overemphasis on Procedural Requirements

Rather Than Ethical Principles

In addition to the challenges described above, the

current regulations suffer from other weaknesses. For

example, they do not sufficiently embody and reflect the

substantive ethical principles and standards that should

govern behavior, but instead focus on the procedural

aspects of IRB review. Thus, although IRBs may review

research in accordance with an appropriate focus on 

ethical behavior, they are ultimately held responsible 

primarily for procedure and documentation. OHRP’s

Compliance Activities: Common Findings and Guidance

(OHRP 2000) reflects this emphasis on the regulations 

by focusing on the procedures by which protocols are

reviewed—for example, inappropriate use of expedited

review and exemptions, lack of a quorum, less than

annual continuing review, and failure to document

required findings or votes (OHRP 2000). The emphasis

by regulators on procedure is frustrating to IRBs and

investigators38 and also contributes to an atmosphere in

which review of research becomes an exercise in avoiding sanctions and liability rather than in maintaining

appropriate ethical standards and protecting human 

participants. (Chapters 4 and 5 offer recommendations

regarding IRB review and the emphasis on procedural

requirements.)

Regulations Not Adequately Addressing All

Types of Research

Another weakness in the current regulations is that

they fail to adequately address unique ethical issues that

arise in different types of research. Although federal 

regulations for human research have long applied to the

social sciences and humanities as well as biomedical

research, their articulation reflects a persistent emphasis

on clinical or biomedical research. Indeed, with regard 

to nonclinical activities, it is sometimes difficult to 

determine which activities constitute human research

and are therefore subject to the regulatory requirements.

In addition, quality improvement studies in health care

organizations, public health studies, program evaluation,

and humanities research may require review by an IRB in

some institutions, but not in others.

Applied to nonclinical research and particularly to the

humanities and social science research, the regulatory

requirements seem to be either irrelevant or insufficient

to provide protection, depending on the type of research.

For example, requirements for written documentation of

consent may be inappropriate for some survey and

anthropological research. Recently, the Association of

American University Professors issued a report stating

that IRBs often “mistakenly apply standards of clinical

and biomedical research” to social science and historical

research, which adversely affects not only the quality of

the research but inadequately protects human research

participants (AAUP 2000). In other areas, the regulations

are insufficient—for example, with regard to protecting

privacy and confidentiality. Although the regulations

require “adequate provisions” to protect privacy and confidentiality, nonphysical harms, such as those resulting

from breaches of confidentiality, are often difficult for

IRBs to assess without more specific regulatory guidance

(45 CFR 46.111(a)(7); 21 CFR 56.111(a)(7)). Much of

the difficulty in applying the federal regulations is due to

differences in the nature of the risks associated with nonclinical research. For example, physical harms are rarely

a concern in nonclinical research, while psychological,

social, economic, and legal harms are more likely to

occur and should be the primary concern of IRB review. 

IRB Burdens

The quality of IRB review is often compromised by

the burden of excessive paperwork, because although

IRBs are broadly charged with ethical review, in practice

they also must fulfill many procedural requirements.

While some of these requirements are designed to ensure

compliance with ethical standards (e.g., documentation
14

Chapter 1: Introduction—The Need for Change

of waiver of informed consent), others appear to have 

little relevance to ethical standards or the protection of

participants (e.g., requirements for documentation in

meeting minutes). In all of their deliberations, IRBs must

keep track of a range of detailed regulations and document

the grounds on which they make decisions in accordance

with them. In addition, IRBs must comply with numerous

regulations regarding their operations. However, some of

the regulatory and paperwork requirements governing

IRBs are difficult to interpret (NBAC 1999b), unnecessarily burdensome, and often not commensurate with

their contribution to protecting research participants.

One particularly time-consuming task for investigators, IRBs, and institutional officials is the preparation of

assurances. Although many domestic research institutions

have an MPA, which covers all research and generally

needs to be renewed every five years, other institutions

must obtain a separate assurance for each funded project

(i.e., a Single Project Assurance, or SPA). For multi-site

and international research, this process can be particularly

time consuming. Even institutions with an MPA must

often revise or amend that document to include changing

institutional affiliates as well as affiliation agreements

between specific investigators and individual physicians,

practice plans, and health care institutions.39

In addition, many IRBs lack the basic resources of

staff, space, and technology (Sugarman 2000). Without

strong professional and clerical support, busy IRBs

remain mired in paperwork and are often unable to focus

on ethical considerations. One can get a sense of the

unmet resource needs of IRBs from the institutional

responses to OPRR shutdowns; large institutions are 

routinely creating several new IRBs to share the review

workload and adding several additional full-time IRB

staff (Desruisseaux 2000; Phillips 2000).40

Because of the large workload, serving as an IRB

member or chair requires a significant time commitment,

with many hours spent in and out of meetings reviewing

protocols and writing reports. Few IRB members receive

compensation or recognition for their efforts. Thus, with

little financial or academic support for IRB membership,

IRBs must rely heavily on the goodwill of individual

members, which can make it difficult to attract and retain

members. (Recommendations related to reducing burdens on IRBs are discussed in Chapters 4, 5, and 6.) 

Multi-Site Research Studies

Multi-site research, discussed further in Chapter 6,

poses its own set of problems for local IRBs. The growing

importance of multi-site research has challenged fundamental assumptions about the importance of local review,

for the more IRBs duplicate each other’s work by reviewing the same protocols, the more pressure there is to

show why multiple local reviews of identical research

protocols are needed. Although local review can provide

insight about the social and cultural context of a study,

the facilities in which it will be carried out, and any local

laws or policies that might affect the study, IRBs may 

be squandering precious resources when dozens or 

hundreds of them must review all aspects of a single,

multi-site protocol when the design and methods are

unlikely to be changed. 

IRBs are not the only groups frustrated by multi-site

research. Investigators and sponsors are discouraged by

having to submit protocols to multiple boards, particularly because changes requested by one board usually

have to be approved by the others, a repetitive process

that is labor intensive and that can significantly delay

research, with little resulting benefit.

Another difficulty is that local IRBs are sometimes

poorly situated to review multi-site research. Although

IRBs and institutions have the authority to require

changes for their site or to refuse to approve a multi-site

study about which they hold serious reservations, in

practice they are hesitant to use that authority. Thus,

although local IRBs may modify recruitment procedures

and consent forms, it may be that no single IRB has the

power to require substantive changes to a study design,

which must remain standardized across sites.

Multi-site research also poses problems with regard to

continuing review (mandated, periodic review of

research in progress) and review of adverse events. Many

IRBs find themselves reviewing a staggering number of

reports of adverse events that have occurred at other

sites, often without any context, such as the total number

of participants in a protocol or whether an adverse event

occurred with the experimental or control intervention.

Even when they have this information, IRBs sometimes

lack the expertise to assess its significance in terms of the

risks and potential benefits to trial participants.
National Bioethics Advisory Commission

15

Educational Needs

Some of the weaknesses in the implementation of the

federal regulations are being overcome by knowledgeable

and creative IRBs, investigators, and institutional 

officials. But more can be done (see Chapter 3).

Knowledgeable IRBs can find in the regulations extensive

discretion in the types of protocols that may be approved.

Investigators attentive to regulatory requirements can

design research with protections that will easily satisfy

ethical and regulatory requirements. Institutions can 

prepare policies and procedures that clarify, extend, and

apply regulations to fit the local and institutional research

context. Unfortunately, this kind of expertise is not widespread, and at all levels, from investigators to IRBs to

institutions, there is frequently a lack of understanding of

research ethics. In some cases, for example, investigators

and IRB members might assume that research ethics

means their own personal ethics rather than a common

set of established ethical principles, standards, and procedures. The current system simply fails to ensure 

adequate education or preparation of individuals and

institutions that wish to conduct and review research. 

Two key tasks of institutions are supporting and educating IRB members. Currently, however, many IRB

members receive little or no formal training in the relevant ethical analysis or federal regulations. A 1995 survey

of 186 IRBs at major universities found that almost half

provided no training or less than an hour of training to

board members (Hayes et al. 1995). Without trained

members, IRBs may act with little knowledge of or attention to the regulations or ethical principles they are supposed to implement. On-the-job-training of new IRB

members reinforces IRBs’ isolation from each other and

encourages inconsistency between IRBs. Most important,

lack of training for IRB members leads even the best

intentioned IRBs to consistently miss or ignore important

ethical issues. IRB review can only be as good as the IRB

members’ judgment. Without standards for IRBs and IRB

members, IRB review is likely to be of uneven quality.

Education is essential not only for IRB members, but

also for investigators and research staff. If investigators do

not know that a specific project is subject to regulations,

the entire system of protections is undermined. Even

when investigators know that a research study must be

reviewed by an IRB, they may not understand their continuing responsibilities as well as the IRB’s responsibility

for the continuing oversight of the research. Investigators

may be unfamiliar with their obligations to report certain

adverse events and have protocol amendments approved

by the IRB and must be able to recognize their responsibilities beyond securing and maintaining IRB approval,

including explaining protocols to prospective participants

and answering their questions.

Responses to Concerns

Public and private sector groups have taken steps to

improve protections for those who participate in

research. A number of professional organizations, such as

Public Responsibility in Medicine and Research, the Applied

Research Ethics National Association, the Association of

American Medical Colleges, and the Association of

American Universities, have contributed to this area by

issuing policy statements, instituting workshops and

training, or encouraging their member organizations to

strengthen their protections procedures. In addition,

industry,41 advocacy groups (Shamoo and Irving 1993;

Sharav 1994),42 and members of the media (Sloat and

Epstein 1996; Whitaker and Kong 1998) have been vocal

in calling for stronger protections.

To date, two federal departments also have moved to

strengthen and streamline the oversight system. DHHS

elevated its oversight office from NIH to the Office of the

Secretary, reorganizing OPRR into OHRP.43 (Chapter 2

discusses this transition in more detail.) OHRP now has

more visible authority over the 11 agencies within

DHHS. However, OHRP’s authority does not extend to

other departments and their research programs, although

it often attempts to perform a government-wide role

without specific authority. FDA has centralized and elevated its coordination of participant protection activities

into a new Office of Clinical Science. DHHS instituted,

through NIH or FDA, several initiatives to require education and training of investigators, improve monitoring of

safety for those participating in clinical trials, address

financial conflicts of interest, and seek civil, monetary

penalties for noncompliance (DHHS 2000). In December

2000, OHRP revised its assurance process and is planning to work with other departments to create a unified
16

Chapter 1: Introduction—The Need for Change

system of registering IRBs. VA has strengthened oversight

of research conducted at its facilities by developing a 

system of independent accreditation for all of its IRBs

(VA 2000).

Notwithstanding these new initiatives, some of the

basic problems with the current system have not been

addressed and continue to burden sponsors, institutions,

IRBs, and investigators with unnecessary delays and

costs. While overall improvement of the system is

needed, reform is particularly needed to direct attention

to those research studies that pose the greatest risk to

participants.

Consequences of a Flawed System

Faced with all of these challenges, the oversight system

for protecting research participants is losing credibility

among some investigators, IRBs, institutions, and, perhaps

most important, the public, causing more frustration and

less willingness to commit time and resources to the

system. This could result in IRBs providing inadequate

reviews; investigators not following the IRB-approved

protocol or even submitting the protocol for IRB review;

institutions not supporting their IRBs; and assurances

being restricted or suspended. These possibilities are real

and serious and are made more pressing by the continuing

and rapid growth of the research enterprise.

The challenges facing the current system for research

participant protection are significant and call for major

change. Although there will always be ambiguity and 

difficult ethical decisions to make in reviewing the risks

and potential benefits of research, and competing principles might apply in challenging new situations, the need

for the protection of human participants requires a 

unified and consistent commitment on the part of the

federal government, research organizations, sponsors, the

research community, and the public. 

Unfortunately, the history of human research protection demonstrates that knowing how to design research

procedures generally has not always been translated into

developing practices that are sound and ethical.

Although there have been important improvements in

research design over the past 50 years that enhance the

protection of research participants, it is worth noting that

many of these advances were motivated by reactions to

various problematic situations. However, given the great

progress in all areas of research and the rapid increase in

the number of research protocols that involve human

participants, the time is right to create a system of oversight that provides appropriate participant protection

and encourages ethically sound research. 

With this objective in mind, this report offers a 

number of recommendations aimed at modifying the

current oversight system, although this may involve 

certain trade-offs. For example, enhancing consistency

across federal departments raises concerns that oversight

mechanisms will be tailored primarily to the clinical or

biomedical model and ignore the ethical and research

issues in other disciplines,44,45,46,47 and increased oversight

intended to provide more complete protections could

lead to more unnecessary bureaucratic requirements and

delays. It is not NBAC’s intention to recommend changes

that will add burdens without demonstrable increases in

protections for human research participants. It is important to understand that because comprehensive oversight

is necessarily complex, with interconnected components,

changes in any one part of the structure will affect 

the entire system. Chapter 7 discusses some of these 

interconnections and how the proposed system would

function as a whole.

Notes

1 Traditionally, and in current regulations, those studied in 

experimental research are referred to as research subjects. This term

accurately captures an important aspect of the relationship between

an investigator and the individual being studied. However, the term

subject also connotes society’s worst fears about research participation,

rather than its aspirations. There are methods, such as obtaining

voluntary informed consent, by which investigators can show

respect for the human dignity of those involved in research. By

securing consent, individuals become volunteers, not mere subjects,

who are active participants in the research process. Therefore, this

report uses the term human participants to refer to those who are

studied in research protocols. See Chapter 2 for a more extensive

discussion of this topic. 

2 To date, NBAC has issued five reports: Cloning Human Beings

(NBAC 1997), Research Involving Persons with Mental Disorders That

May Affect Decisionmaking Capacity (NBAC 1998), Ethical Issues in

Human Stem Cell Research (NBAC 1999a), Research Involving Human

Biological Materials: Ethical Issues and Policy Guidance (NBAC

1999b), and Ethical and Policy Issues in International Research:

Clinical Trials in Developing Countries (NBAC 2001).
National Bioethics Advisory Commission

17

3 NBAC Meeting, 17 May, 1997. Arlington, Virginia. 

4 Those who conduct research are usually referred to as either

researchers or investigators. NBAC uses the terms interchangeably.

5 FDA “Warning Letter” from S.A. Masiello, FDA, to James M.

Wilson, University of Pennsylvania. March 3, 2000. Available at

http://www.fda.gov/foi/warning.htm. Last accessed November 17, 2000.

6 Ibid.

7 Ibid. 

8 Ibid.

9 OPRR letter from S.L. Crandall to G. Sarkar, Manhattan Eye, Ear,

and Throat Hospital. May 8, 1998.

10 OHRP letter from M.A. Carome to G.R. Newkome, 

University of South Florida. September 28, 2000. Available at

http://ohrp.osophs.dhhs.gov/detrm_letrs/sep00f.pdf. Last accessed

May 21, 2001.

11 Ibid.

12 NIH Extramural Data and Trends. Available at http://grants.

nih.gov/grants/award/trends95/annotate.htm. Last accessed

November 13, 2000.

13 Estimates of National Support for Health R&D by Source 

or Performer, 1986–1995. Available at http://grants.nih.gov/

grants/award/trends95/pdfdocs/fedtabl1.pdf. Last accessed

November 13, 2000.

14 Pub. Law 33, 105th Congress.

15 See NBAC, “Federal Agency Survey on Policies and Procedures

for the Protection of Human Subjects in Research.” This staff analysis

is available in Volume II of this report.

16 See Heath, E., “The History, Function, and Future of

Independent Institutional Review Boards.” This background paper

was prepared for NBAC and is available in Volume II of this report.

17 Ibid.

18 FDA, 1993, “Guideline for the Study and Evaluation of Gender

Differences in the Clinical Evaluation.” 22 July. 58 Fed. Reg. 39406;

NIH, 1994, Guidelines on the Inclusion of Women and Minorities

as Subjects in Clinical Research. 28 March. 59 Fed. Reg. 14508;

CDC, 1995, Policy on the Inclusion of Women and Racial and

Ethnic Minorities in Externally Awarded Research. 15 September.

60 Fed. Reg. 47947.

19 Pub. Law 115, 105th Congress.

20 White House, 2000, “Taking New Action to Encourage

Participation in Clinical Trials.” [Press Release.] 7 June. Available 

at http://www.whitehouse.gov/WH/html/briefroom.html. Last

accessed 12/10/00. See also Medicare Coverage Policy. Available 

at http://www.hcfa.gov/coverage/default.htm. Last accessed

December 10, 2000.

21 A Multiple Project Assurance is an agreement between an 

institution and the federal government in which the institution

pledges to comply with regulations.

22 Subpart B of 45 CFR 46 pertains to research involving fetuses,

pregnant women, and human in vitro fertilization. Subpart C 

pertains to research involving prisoners. Subpart D pertains to

research involving children.

23 48 Fed. Reg. 9266.

24 Ibid.

25 Ibid.

26 Ibid.

27 HRSA Circular 96.05.

28 NBAC Town Meetings: February 9, 2000, Houston, Texas; April

5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando, Florida;

June 7, 2000, Chicago, Illinois; August 14, 2000, Portland, Oregon.

29 Pub. Law 310, 106th Congress.

30 66 Fed. Reg. 20589. 

31 Porter, J., Testimony before NBAC. November 23, 1997.

Bethesda, Maryland. See McCarthy, C.R., “Reflections on the

Organizational Locus of the Office for Protection from Research

Risks.” This background paper was prepared for NBAC and is

available in Volume II of this report.

32 There has been a change in the categories of research that IRBs

may review through an expedited procedure (63 Fed. Reg. 60364).

However, this change did not require amendment of the Common

Rule. The Common Rule does not contain the list of categories, but

rather refers to such a list, to be periodically revised and published

by the Secretary, DHHS. There are no similar provisions for modification elsewhere in the Common Rule.

33 Russell-Einhorn, M., Testimony before NBAC. March 1, 2000.

Herndon, Virginia. 

34 See Gunsalus, C.K., “An Examination of Issues Presented by

Proposals to Unify and Expand Federal Oversight of Human

Subject Research.” This background paper was prepared for NBAC

and is available in Volume II of this report.

35 21 CFR 56.120–121; 21 CFR 312.70; 21 CFR 812.119; Lepay,

D., Testimony before NBAC, September 13, 2000. Washington, D.C.

36 See NBAC, “Federal Agency Survey on Policies and Procedures

for the Protection of Human Subjects in Research.” This staff analysis

is available in Volume II of this report.

37 NBAC Town Meetings: February 9, 2000, Houston, Texas; April

5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando, Florida;

June 7, 2000, Chicago, Illinois; August 14, 2000, Portland, Oregon.

38 Ibid.

39 Stinson, R., Testimony before NBAC. July 11, 2000. Bethesda,

Maryland. 
18

Chapter 1: Introduction—The Need for Change

40 Letter from E. Gislason, University of Illinois at Chicago to 

M. Carome, OPRR, and C. Weil, OPRR. September 30, 1999.

Available at http://www.uic.edu/depts/ovcr/oprr/nih09-30-99.html.

Last accessed December 5, 2000.

41 Spilker, B., Testimony before NBAC. April 7, 2000.

Washington, D.C.

42 For example, National Organization for Rare Disorders, Inc.,

Policy Position: Patient Protection in Clinical Trials. Available at

http://www.rarediseases.org/new/patpro.htm. Last accessed 

August 22, 2000.

43 65 Fed. Reg. 37136–37137.

44 Consortium of Social Science Associations, Public comment

submitted to NBAC. Received February 16, 2001.

45 American Sociological Association, Public comment submitted

to NBAC. Received February 20, 2001.

46 Shopes, L., Public comment submitted to NBAC. Received

February 17, 2001.

47 American Psychological Association, Public comment submitted

to NBAC. Received February 16, 2001.

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Practice. OEI-01-97-00196. Washington, D.C.: DHHS.

Office for Protection from Research Risks (OPRR). 1994. Evaluation

of Human Subject Protections in Schizophrenia Research Conducted by

the University of California Los Angeles. Rockville, MD: OPRR.

Pharmaceutical Research and Manufacturers of America (PhRMA).

2000. Pharmaceutical Industry Profile 2000. Washington, D.C.:

PhRMA.

Phillips, D.F. 1996. “Institutional Review Boards Under Stress: 

Will They Explode or Change?” Journal of the American Medical

Association 276(20):1623–1626.

———. 2000. “IRBs Search for Answers and Support During a

Time of Institutional Change.” Journal of the American Medical

Association 283(6):729–730.

Ries, L.A.G., P.A. Wingo, D.S. Miller, H.L. Howe, H.K. Weir, H.M.

Rosenberg, S.W. Vernon, K. Cronin, and B.K. Edwards. 2000. 

“The Annual Report to the Nation on the Status of Cancer,

1973–1997, with a Special Section on Colorectal Cancer.”

Cancer 88(10):2398–2424.

Rosenthal, E. 1996. “New York Seeks to Tighten Rules on Medical

Research.” New York Times, 27 September, B-4.

Rothman, D.J., and H. Edgar. 1991. “AIDS, Activism, and Ethics.”

Hospital Practice 26(7):135–142.

Schneiderman, N., and M.A. Speers. 2000. Behavioral Science,

Social Science, and Public Health in the 21st Century. In Integrating

Behavioral and Social Sciences with Public Health. Washington, D.C.:

American Psychological Association.

Shamoo, A.E. 1994. “Our Responsibilities Toward Persons with

Mental Illness as Human Subjects in Research.” Journal of the

California Alliance for the Mentally Ill 5(1):14–16.

Shamoo, A.E., and D.N. Irving. 1993. “Accountability in Research:

Using Persons with Mental Illness.” Accountability in Research

3:1–17.

Sharav, V.H. 1994. “What Is Ethical? What Is Not? Where Do You

Draw the Line?” Journal of the California Alliance for the Mentally Ill

5(1):4–5.

Sloat, B., and K.C. Epstein. 1996. “Using Our Kids as Guinea Pigs,

An Investigation of Medical Research Records Shows the U.S.

Government Is Still in the Business of Conducting and Paying for

Tests on Unsuspecting Americans.” Plain Dealer, 16 December, 1-A.

Snyderman, R., and E.W. Holmes. 2000. “Oversight Mechanisms

for Clinical Research.” Science 287(5453):595–597.

Sugarman, J. 2000. “The Role of Institutional Support in Protecting

Human Research Subjects.” Academic Medicine 75(7):687–692.

Sweeney, L. 1997. “Weaving Technology and Policy Together to

Maintain Confidentiality.” Journal of Law Medicine and Ethics

25:98–110.

Valigra, L. 1997. “Rooting Out Rogue Investigators.”

CenterWatch 4(7):1, 5.

Whitaker, R., and D. Kong. 1998. “Doing Harm: Research on the

Mentally Ill.” 4 parts. Boston Globe. 15–18 November, A-1.

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Chronicle of Higher Education. 30 June, B-4.

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282(20):1947–1952.
Introduction

This chapter proposes an enhanced system of U.S.

oversight of research involving human participants,

specifically addressing its purpose and functions, the

parties involved, and its scope and structure. The chapter

also focuses on the definitions of research and human

participant, terms that are crucial to delineating the scope

of the oversight system. Although some of the components

of the proposed system already exist in total or in part

within the current system, certain alterations and additions

are required. Specifically, what is needed is a more

effectively coordinated system:

■ in which coverage, in terms of protections, is not

dependent on source of funding;

■ that can propose and implement reforms in a timely

manner;

■ that can issue uniform interpretations of regulations,

across the government and the private sector, and that

can make the rules work both for medical and nonmedical research;

■ that relies on certification and education to better

ensure ethical research and that promotes guidance in

lieu of regulation;

■ that streamlines review in a manner commensurate

with research risks;

■ that better reflects the ways in which participants may

become vulnerable and the ways this can be avoided;

■ that can facilitate multi-site review efforts and specialized review mechanisms;

■ that continues to rely on decentralized review and

monitoring, overseen by a more coordinated collection

of adverse event reporting;

■ that has a wide array of enforcement tools that can be

tailored more effectively to the nature of the problems

encountered; and

■ that facilitates studying compensation possibilities for

those injured in the course of research.

Discussion and recommendations pertaining to each

of these criteria are found in this and subsequent chapters

of this report. The most significant change proposed is

that of consolidation—that is, where there are now multiple sets of overlapping regulations, the National Bioethics

Advisory Commission (NBAC) suggests a unified comprehensive policy in the form of a single set of regulations

and a single source of guidance and interpretation. This

consolidated structure would allow for much needed 

regulatory flexibility and, in certain areas, a greater use of

guidance with less regulation. Of course, an effective

oversight system consists of more than governmental

regulation. Indeed, it should be devoid of excessive regulation, relying, when appropriate, on the ethical behavior and commitments of all individuals and entities—

federal and nonfederal—engaged in research involving

human participants. 

Purpose of Oversight

For many involved in the oversight system, the bureaucratic procedural requirements (as opposed to ethical

principles) that characterize the current federal regulatory system for human research have become synonymous with the purpose, intent, and implementation of

the oversight system itself. As a result, some investigators

and Institutional Review Board (IRB) members perceive

the regulations as lacking an ethical foundation and view

them merely as a set of formal procedural requirements,

21

A Proposal for Oversight

Chapter Two 2
22

Chapter 2: A Proposal for Oversight

some of which protect human participants (e.g., informed

consent), but others of which have little to do with such

protection (e.g., assurances of compliance and record

keeping).1,2 Unless the regulations and guidance appear

ethically substantive, investigators will view them simply

as irritating obstacles to doing important, socially valuable

work, while IRB members, who are responsible for

applying the rules, will become frustrated with investigators’ resistance. In such cases, when the largely procedural

requirements are perceived as ineffective in improving

protections, some investigators might avoid submitting

research protocols to IRBs or fail to disclose certain

aspects of the protocol (Ferraro et al. 1999; Liddle and

Brazalton 1996), behavior that could place participants at

risk and compromise public trust in the oversight system.

Some of this frustration could be alleviated if all who

are involved in the human research enterprise recognize

that the overarching purpose of the system should be to

ensure the protection of the participants in a manner that

encourages and facilitates research that is consistent with

accepted ethical principles. There is no necessary conflict

between the goal of promoting research and its benefits

and that of protecting human research participants. In

previous reports, NBAC has reinforced the importance of

these dual goals (NBAC 1999a, 1999b). In a paper 

prepared for NBAC, for example, Harold Vanderpool

articulated this perspective:

The purposes of protecting human subjects and

enhancing the benefits of biomedical and behavioral

research are fully justifiable, although their balance

should be critically and periodically reassessed. It is a

mistake to assume that the relationship between these

purposes has to be a zero sum game, whereby

increased protection for subjects subtracts from the

conducting of research.3

As discussed in Chapter 1, a credible system for the

protection of research participants promotes research by

encouraging public support and participation. In addition,

by requiring careful consideration of the implications of

study design on the ethical acceptability of a protocol 

and independent review prior to the involvement of

human participants, the oversight system often leads to

improvements in research design. The system also can

promote research by providing a prospective mechanism for discussion and review of controversial research,

moving many innovative research studies forward. 

Protection of human participants should never be an

afterthought. Rather, it should be a factor in decisionmaking by everybody involved throughout the conception, design, review, and performance of human research.

The oversight system should act to forbid research

designs that are clearly unethical. In areas of less ethical

certainty, the system should ensure protection of research

participants by providing mechanisms for applying

accepted ethical principles and seeking independent

review and public input to resolve issues of uncertainty.

But the system should allow the majority of research, for

which there is clear ethical acceptance, to proceed with

minimal delay. An oversight system succeeds to the

extent that it encourages the protection of participants in all

aspects of research, but does not create any unnecessary

barriers to the conduct of research.

Although the need to protect human research participants is a well-accepted norm, controversy arises over the

amount of protection that should be required. Jonathan

Moreno provides a useful framework for considering the

levels of protectionism that are needed. Weak protectionism

requires that participants be provided at least the protection of informed consent, but it relies on the virtue and

commitment of the investigators to provide that protection

without any external involvement by an outside entity. 

In moderate protectionism, the investigators remain

responsible for providing protection, including obtaining

informed consent from participants, but the research

study undergoes an independent external review. A system

of strong protectionism would greatly reduce reliance on

the investigator for providing substantive protections to

participants by, for example, increasing the use of third

parties for monitoring the conduct of the research.4 The

current system of requiring prior approval of research by

IRBs and informed consent by participants is a moderately protectionist approach that is appropriate because it

can protect participants while not imposing inappropriate

delays in initiating ethically sound research. 
National Bioethics Advisory Commission

23

Functions and Responsibilities of the

Oversight System

The oversight system should include several interrelated

but distinct functions and responsibilities. It should establish clear and effective policies in the form of regulations

or guidance; provide education and assistance to all

parties; require review of research to determine whether

it is ethically acceptable; monitor ongoing research and

the operation and behavior of institutions, IRBs, and

investigators; enforce requirements; and maintain public

accountability.

Policy: Regulation and Guidance

Establishing policy by providing regulations or guidance provides a necessary framework for the entire oversight system. It also provides leadership by setting the

direction, approach, and tone. Policies must be established

by the federal government in order to ensure uniform

protection of research participants regardless of the

source of the research funding. In addition, whether

issued as regulations or nonbinding guidance, policies

must be presented in an understandable form. 

Regulations alone are unlikely to be sufficient to

address all types of research (e.g., clinical trials, surveys,

records review studies, studies using stored human biological materials, behavioral experiments, or oral history

studies). Therefore, guidance, because it establishes standards of acceptable practice while allowing for reasoned

deviations, can be used to supplement regulations by

indicating how substantive ethical principles can be

implemented in particular circumstances.5 Moreover,

guidance can be particularly helpful in areas of emerging

research where the ethical standards and associated procedures are not entirely clear or well developed. In such

situations, thoughtful discussion within the framework

of existing guidance may be sufficient to allow innovative

research to move forward, and if not, new guidance can

be developed promptly.

No matter how well regulations and guidance are written,

situations will arise in which it is unclear how ethical principles should be applied or regulations should be interpreted.

Policy interpretation and consultation, provided by a

federal oversight office, would be particularly helpful to

IRBs struggling with especially complex or difficult

research studies.

Education

Understanding basic ethical principles and how they

apply in various research situations is the best way to

avoid inadvertent harm to the rights and welfare of 

participants. Education can also prepare individuals to

understand and resolve ethical issues, especially novel

ethical problems, as they arise in specific research studies.

(Educational programs are discussed in more detail in

Chapter 3.)

An effective oversight system helps make education

available to all relevant parties. Investigators, IRB staff

and members, contract research organizations (CROs),

institutional officials, and sponsors (public and private)

are the primary audiences for education. Educational

activities, however, should be tailored to the particular

role of each party in the research enterprise and be relevant

to different types of research.

It is also important to educate prospective participants and the general public. Education directed at these

audiences should strive to increase the public’s awareness

of the system’s functions and operations, which can

encourage informed decisionmaking by prospective

participants, increase public input regarding policies for

the protection of research participants, and increase and

sustain the willingness of the public to participate in and

support the research enterprise.

Review of Research

In the United States, independent review of proposed

research to determine whether it is ethically acceptable is

largely performed by local IRBs and is one of the primary

means by which the current system provides protection

to research participants.6 Such review should be responsive to the nature of risk and commensurate with the

level of risk involved. For example, the risks and potential benefits arising in a clinical trial are generally different

from those arising in a study using existing data.

Likewise, social science and humanities research raises

risks and potential benefits that differ from those raised

by clinical research. Harms may vary from physical to

psychological, social, or legal. Within each of these

domains, the risk of harm may range from low to high.

Review criteria and mechanisms should be matched to

the ethical issues arising from the research. IRBs, as full
24

Chapter 2: A Proposal for Oversight

committees, should review research involving more than

minimal risk; however, IRBs should be able to develop

procedures other than full board review for research

involving no more than minimal risk. 

Research involving difficult ethical considerations,

such as highly innovative interventions or technologies,

should be reviewed by a body with particular expertise

and experience in these special issues, in addition to the

local IRB, unless the local IRB is especially qualified to

review such research. Several options should be available

for providing such heightened review, including specially

trained and accredited local IRBs or specially created

regional or national review bodies. Often, these special

bodies would be reviewing classes of research rather than

individual research protocols in order to assist in the

development of guidance to local IRBs regarding the

criteria for approval. For example, NBAC previously

recommended the use of a special standing panel to

review research studies involving persons with mental

disorders that may affect their decisionmaking capacity

and a national-level review for certain types of stem cell

research (NBAC 1998; NBAC 1999a). However, because

national or special review panels could increase delays or

even prevent some research from being conducted, steps

must be taken to ensure that the system does not impose

undue delays on the approval of ethically sound research. 

IRB Review of Research Involving No More Than

Minimal Risk

IRBs should be allowed to use procedures that are

more expeditious than full board review for research that

involves no more than minimal risk. Such procedures

should also be permitted for handling other researchrelated matters, such as determining whether an activity

is research and subject to oversight, reviewing minor

proposed changes to an approved protocol, conducting

some types of continuing review, and reviewing some

reports of unanticipated problems. Under the current

system, the expedited review process is akin to the procedures proposed here, which are intended to replace the

expedited review process and to expand the activities that

could be handled by the IRB more expeditiously than

through a full board meeting. Generally, IRBs should be

able to use more efficient procedures to handle most, if

not all, research-related issues, with the exception of

protocols involving more than minimal risk.

Such procedures would differ from the current expedited review in several ways:

■ All research involving no more than minimal risk

would be eligible for review under these more expeditious processes (see Chapter 4).

■ The IRB chair or a designee would not need to carry

out these more expeditious processes. Instead, NBAC

proposes that a minimum requirement of review be

carried out by a certified IRB professional who may be

a member of the IRB or an IRB administrator. The

individual(s) conducting the review might act alone,

ask for advice from an IRB member or from a consultant, or refer the protocol for full IRB review. IRBs

may also choose an individual or a small group of IRB

members to conduct such reviews. However, those

responsible for reviews must be certified. (Chapter 3

discusses certification in more detail.)

■ The full IRB would not need to be informed of

approvals granted through this process. 

■ These procedures would be used to review research

involving human participants that is currently

exempt from the Common Rule, but that is deemed

to be covered by the oversight system. One of the

advantages of including research that is now exempt

is that it would allow institutions to track their

human research portfolios. 

■ IRBs would use more discretion in reviewing research

involving little or no risk so that they can move such

research quickly through the IRB process. Using these

proposed procedures, IRBs would review minimal

risk research in accordance with all regulatory

requirements; however, they would have discretion

with respect to applying the requirements so that the

required levels of scrutiny and protections are commensurate with the risks associated with the research.

The use of such procedures should take less time than

full IRB review and would reduce the workload of the

full board and expedite the review process. 

Monitoring

The monitoring of activities is an important component

of an effective oversight system. One type of monitoring

should occur at the federal level, with the federal oversight office (see discussion later in this chapter) monitoring

the implementation of oversight activities by federal

agencies. Such monitoring should include, for example,
National Bioethics Advisory Commission

25

ensuring that all federal agencies sponsoring or conducting research follow appropriate policies, regulations, and

guidance and report violations, noncompliance, and

other unanticipated problems. The federal oversight

office should also ensure that accrediting or certifying

bodies apply standards applicable to assessing a core set

of competencies that has been approved by the federal

oversight office and should also play a role in monitoring

sponsors and institutions from the private sector when

these entities are not monitored either by another federal

agency (for example, the Food and Drug Administration

[FDA], which oversees research involving investigational

new drugs) or by an accrediting body. The goal is to

ensure that all parties involved in the various aspects of

research protect research participants, both at the time

studies are initially approved and throughout the

research process. The efforts of the federal oversight

office should complement but not duplicate the activities

of the accrediting and certifying bodies. 

A second type of monitoring involves establishing

mechanisms to ensure that institutions, IRBs, and

investigators are following regulations and guidance.

This type of monitoring is described further in Chapter 3

as verification of compliance. Responsibility for verifying

compliance should be shared by different parties. For

example, accrediting bodies should be responsible for

monitoring accredited institutions and independent

IRBs. However, institutions should also establish procedures to monitor their IRBs. They could, for example,

have an internal audit process for reviewing, on a sample

basis, whether IRB decisions are consistent with regulatory

requirements. Institutions also should implement such

procedures to determine whether investigators are

complying with regulatory requirements and conducting

research according to IRB-approved protocols. 

The third type of monitoring assesses the progress

of research through conducting continuing review of

ongoing research and monitoring the safety of research

participants and whether unanticipated problems or

events occur. Investigators, IRBs, sponsors, or those

acting on behalf of sponsors, such as CROs or Data and

Safety Monitoring Boards, generally carry out these activities. Monitoring should provide the information needed

to evaluate whether the oversight system is achieving its

purpose. If gaps exist between purpose and performance,

monitoring should help to identify their nature, magnitude, and location and should ensure the development of

measures to close them. The results of monitoring might

also show a need for changes in policy, additional or

enhanced education, or enforcement measures.

Enforcement

The provision of enforcement measures makes all

parties aware that the system must be taken seriously and

ensures the public’s continuing trust. Monitoring is used

as an additional mechanism to prevent harm to participants, to promote improved practices, and to assess

whether any violations are inadvertent or intentional.

When investigators are unwilling or unable to provide

appropriate protection to participants, enforcement

should stop individuals and possibly their institutions

from conducting human research. Enforcement should

complement policy, education, and monitoring of compliance to ensure that research participants are protected;

however, it should not be the primary focus of an oversight system. 

Sanctions are necessary in serious cases of noncompliance or in the case of repeat offenses. Most sanctions

involve administrative action by a government agency

against an individual or organization for failure to comply

with regulatory requirements. The oversight system should

include a range of sanctions, including halting research 

at an institution; de-accrediting an IRB or institution;

requiring special training and probation accompanied by

mentoring; disqualifying or debarring an investigator

from conducting research involving human participants;

removing the investigator from a particular research

study; issuing letters of reprimand to investigators, IRBs,

or institutions; conducting special monitoring of investigators or IRBs; refusing to publish the research results

that do not meet all the ethical obligations to human

participants (NBAC 1999b); and levying civil monetary

penalties. However, enforcement also might include 

judicial action. Regulatory agencies have the authority to

initiate and conduct such actions, but in a broader sense,

enforcement includes all the ways in which the oversight

system induces actions that support the purposes of the

system. Thus, many parties carry responsibility for
26

Chapter 2: A Proposal for Oversight

enforcement, including regulators, sponsors, institutions,

IRBs, professional societies, editors of scientific publications, and accrediting and certifying bodies.

Accountability

The proposed oversight system is strengthened when

its policies, interventions, and outcomes are open to public view and input. In addition, dissemination of results

of research studies and of research protection creates a

public record that can form the basis for trust. Easily

accessed systems for registering concerns and complaints

help to bring problems to the attention of those who can

resolve them and offer necessary safeguards to those who

believe they have been harmed in the course of research

participation.7 See Exhibit 2.1 for a description of the

responsibilities of those involved in the oversight system.

Scope and Structure of a Revised

Oversight System

Scope of Oversight

In 1997, NBAC unanimously adopted a resolution that

“[n]o person in the United States should be enrolled in

research without the twin protections of informed consent

by an authorized person and independent review of the

risks and benefits of the research.” NBAC adopted this

resolution based on the conviction that the entitlement to

an independent review of risks and potential benefits 

and the opportunity to exercise informed consent are

grounded in civil and human rights. Whether or not 

participants in currently unregulated research are

harmed in greater numbers or to a greater degree than

those in regulated research is not and cannot be known

because of a lack of data at the national level. Nonetheless, protecting the rights and welfare of all participants is

necessary to maintain public trust in the research community as well as to guard against the actual harm of

research participants.

However, not all research participants are protected

by the Common Rule (see Figures 2.1 and C.1). Some

institutions conduct research that is not covered by the

Common Rule or regulated as research by FDA, and

unless those institutions voluntarily commit to reviewing

Exhibit 2.1: Responsibilities of Those

Involved in the Oversight System

Participants: Even though investigators are obligated

to adequately inform participants about research,

competent participants have a responsibility to

become knowledgeable about a prospective research

study and to use the information to make an informed

decision about participation. During the research

study, participants are responsible for staying

informed about the research, following the study 

procedures, reporting problems encountered in the

course of research, and informing investigators 

when they move in order to facilitate additional 

contact that may be necessary, as long as they 

voluntarily remain in the study. It is important to

remember that participants also have the right to 

discontinue their participation at any time during 

the study, so they only have a limited, or qualified,

responsibility to follow the study procedures.

Investigators: Investigators have an obligation to

ensure that research studies are scientifically and

ethically sound, are reviewed and approved by an

IRB prior to conducting the study, are conducted in

accordance with an approved protocol, and receive

appropriate safety monitoring and continuing review.

They are also obligated to acknowledge when errors

occur or problems develop and to report them to

appropriate parties, such as the IRB. The FDA regulations contain a specific definition of investigator,

which “...means an individual who actually conducts

or leads a clinical investigation...or, in the event of an

investigation conducted by a team of individuals, is the

responsible leader of that team” (21 CFR 50.3 (d)).

Institutions: Institutions engaged in research may

be public or private entities. They are usually organizations (e.g., universities, medical schools, insurance

companies, research firms, pharmaceutical companies, or dedicated research facilities) that employ

investigators, but may also be facilities in which

research is conducted (e.g., hospitals, prisons,

schools, community-based organizations). For some

research there may be more than one relevant 

institution involved—for example, when a universityaffiliated investigator conducts research in a prison or

in an educational, industrial, or corporate setting, or

when a pharmaceutical company conducts a clinical

trial at multiple sites. By either employing investigators
National Bioethics Advisory Commission

27

Exhibit 2.1 continued

or allowing research to be conducted in its facilities,

each institution engaged in research must take

responsibility for the ethical conduct of that research.

Moreover, each institution has an obligation to ensure

that the research is conducted in accordance with all

applicable federal and state laws, regulations, and 

procedures. Institutions that employ investigators also

have responsibilities for education, monitoring, and

enforcement. Moreover, institutions in which research is

conducted often have other obligations to participants—for example, as patients or students.

IRBs: IRBs serve as a principle component of that part

of the research enterprise charged with protecting

research participants. IRBs are responsible for reviewing human participant research to ensure that the 

proposed study is ethically acceptable prior to initiation

of the study. Once research begins, IRBs have a

responsibility to monitor the progress of the approved

research with the primary goal of protecting participants, but also to ensure that the research is proceeding according to the approved proposal. This is usually

accomplished through the process of periodic review. 

Sponsors: Sponsors are the governmental and private

organizations that fund (through grants and contracts)

research. Sponsors have responsibility for the manner

in which studies are conducted. When sponsors are

federal agencies, they share responsibilities with the

federal oversight office for guidance development,

education, monitoring, and enforcement. However, 

all sponsors share responsibilities for educating 

their employees and the investigators who conduct their

research. Sponsors are responsible for ensuring that

their research has scientific merit and is ethically justifiable prior to funding. For certain types of research (e.g.,

high-risk research), sponsors are responsible for ensuring that additional oversight protections are provided

that allow expert and public vetting of the proposed

research. They are also responsible for ensuring that

investigators and relevant institutions monitor ongoing

progress, and they may have monitoring responsibilities of their own. In conjunction with the federal oversight office, sponsors also may have some enforcement

responsibilities. In contrast to the use of terms in this

report, FDA regulations use the term sponsor in a more

narrow sense. It “...means a person who initiates a 

clinical investigation, but who does not actually conduct

the investigation.... A person other than an individual

(e.g., corporation or agency) that uses one or more of its

own employees to conduct a clinical investigation it has

initiated is considered to be a sponsor (not a sponsorinvestigator), and the employees are considered to be

investigators” (21 CFR 50.3(e)). In contrast, the FDA

regulations state that the term sponsor-investigator

“...means an individual who both initiates and actually

conducts, alone or with others, a clinical investigation....

The term does not include any person other than an

individual, e.g., corporation or agency” (21 CFR 50.3 (f)).

Professional Societies and Advocacy Organizations:

These organizations are valuable resources in the

education process that should encourage their members to seek out educational opportunities, inform them

of professional codes relating to the ethical conduct of

research, and provide relevant materials to them.

Accrediting and Certifying Organizations: Although

there are many accrediting and certifying organizations,

programs for accreditation and certification of those

involved in human research are new or just developing,

although the need for such programs has long been

recognized (IOM 2001; President’s Commission 1983,

114–121).

Editors and Publishers: As arbiters of scientific quality,

scientific editors and publishers are obligated to ensure

that the data they publish were collected and analyzed

according to the ethical standards set forth by the oversight system (NBAC 1998, NBAC 1999b). 

Congress: Congress is responsible for providing the

authorizing language and appropriations for research

programs and agencies that support the oversight 

system. Through its governing authorities, Congress

can monitor the performance of federal officials and

institutions conducting federally regulated research.

State Regulators: Although some states have separate statutes and regulations governing human

research,8 federal and state regulatory systems are not

structurally connected. When federal and state regulations are applicable to a research study, the more protective provisions must be met (45 CFR 46.101(f); 21

CFR 56.103(c)). A state may require greater protection,

but it cannot allow less protection than is mandated by

the federal requirements. 
28

Chapter 2: A Proposal for Oversight

such research according to the Common Rule, participants

might not be protected. The commitment to protect

participants should not be voluntary, nor should

requirements be adhered to for only some human

research (e.g., private organizations following federal

requirements for FDA-regulated research, such as an

investigational new drug study, but not following federal

requirements when conducting an epidemiological

study). All research participants should be protected by

the oversight system, and the system should apply to all

U.S. investigators and sponsors who conduct research

domestically and internationally.

Extending current protections to all privately funded

research and making uniform all federal regulations and

guidance cannot be accomplished within the current

oversight system, which has no authority to act on behalf

of the entire federal government and for the benefit of

research participants. A unified, comprehensive federal

policy promulgated and interpreted by a single office

would facilitate the extension of the same protections to

all humans participating in research.

Recommendation 2.1: The federal oversight 

system should protect the rights and welfare 

of human research participants by requiring 

1) independent review of risks and potential 

benefits and 2) voluntary informed consent.

Protection should be available to participants in

both publicly and privately sponsored research.

Federal legislation should be enacted to provide

such protection.

The Need for a Unified, Comprehensive

Federal Policy

A credible oversight system requires that all federal agencies and private organizations follow the same federal

policy in the forms of regulation and guidance.

Institutions should not be forced to comply with inconsistent regulations when research falls into the jurisdiction of

multiple agencies, such as when an a National Institutes of

Health (NIH)-sponsored clinical trial involves an investigational new drug regulated by the FDA. Currently, under

this circumstance, institutions must follow the Department

of Health and Human Services (DHHS) regulations

(45 CFR 46) and the FDA regulations (21 CFR 50, 56),

which are not entirely consistent with each other. 

Because research inevitably raises new issues that

require responsive policy development and revision,

amending multiple sets of regulations, as would be

required in the Common Rule, is not a viable long-term

option. To achieve consistency and flexibility, there must

be a single set of regulations promulgated and interpreted

by a single office. 

The legal authority of the current oversight system is

not sufficient to expand coverage to all research conducted

by the private sector as proposed here or to promulgate a

unified policy, specifically as one set of regulations.

Recent actions by the Office for Human Research

Protections (OHRP) reflect both the initiatives of an office

committed to improving human participant protections

and its limitations in implementing broad, consistent

change across departments and agencies. However, no

matter how beneficial or needed the new initiatives may

be in order to improve protections, OHRP does not have

the authority to function as the lead organization for other

departments, and it cannot require other departments to

adopt new initiatives or ensure consistency in oversight

across departments and agencies.

The creation of such an oversight system would

require legislation that expands the authority of the current system to cover the private sector beyond the areas

now regulated by the FDA and that creates a single office

to oversee the system. Although an executive order could

extend protections to all departments and agencies, it

could not extend protections beyond federally sponsored

or regulated research. 

To ensure a uniform, comprehensive system of protection, a single, independent office should be created.

Such an office is referred to in this report as the National

Office for Human Research Oversight (NOHRO). Once

established, NOHRO should be given authority to be the

lead office for implementing and enforcing the oversight

system for research involving human participants. 

Recommendation 2.2: To ensure the protection of

the rights and welfare of all research participants,

federal legislation should be enacted to create a

single, independent federal office, the National

Office for Human Research Oversight (NOHRO),
National Bioethics Advisory Commission

29

Figure 2-1. Involvement of Human Subjects in Research

Federal Protection of Human Subjects in Research

Food, Drug, and Cosmetic Act Public Health Service Act

DHHS 16 Departments and 

Agencies

FEDERALLY FUNDED

Food and Drug Administration

Not federally funded and not subject to FDA

• Some colleges and universities 

not receiving federal research funds

• Some in vitro fertilization clinics

• Some weight-loss or diet clinics

• Some physician offices, some dentist offices,

and some psychotherapist offices

• Some legal services clinics

• Some corporate and industrial health, safety,

and fitness programs

• Some developers of genetic tests

• Some Websites Not federally funded and not subject to FDA

• Assured institutions that do not voluntarily 

pledge all activity to 45 CFR Part 46

Source: Office for Protection from Research Risks

Federally funded and not subject to FDA

• Some Department of Labor

• Some Nuclear Regulatory Commission

• Some National Endowment for the Humanities

Informed consent

Institutional Review Boards

IRB inspections

1991

Federal Policy 

for the 

Protection of Human Subjects

45 CFR Part 46

Subpart A

Institutional Assurances

Informed consent

Institutional Review Boards

Subpart B Pregnant women; fetuses

Subpart C Prisoners

Subpart D Children

Site visits

“COMMON RULE”

=
30

Chapter 2: A Proposal for Oversight

to lead and coordinate the oversight system. 

This office should be responsible for policy

development, regulatory reform (see

Recommendation 2.3), research review and 

monitoring, research ethics education, and

enforcement. 

Recommendation 2.3: A unified, comprehensive

federal policy embodied in a single set of regulations and guidance should be created that would

apply to all types of research involving human

participants (see Recommendation 2.2).

If these particular recommendations are not implemented, the federal government should find alternative

approaches for realizing the intention of these and subsequent recommendations in this report.

Advantages and Disadvantages of a Single,

Independent Office

Advantages

Elevating the government entity that oversees research

involving human participants to agency status with

government-wide authority gives the federal commitment

to protect research participants high public visibility.

Empowered with the authorities mentioned above, the

office would be more likely to achieve the desired 

outcomes. Clear, consistent regulations and guidance 

tailored to various types of research would be developed

and modified when needed. Most important, the office

would be capable of prompt, decisive action in response

to new research issues. NBAC envisions the office implementing a dynamic, evolving, and flexible system of

oversight. Even on its first day of operation, the new

office would be an improvement over the current system, because it will provide a focal point for oversight

and a source for information that does not now exist. It

also could begin promptly to develop policy, both regulation and guidance.

NOHRO would also eliminate the inertia that occurs

in the current system because of the lack of a lead office

with authority to direct federal agencies to carry out a

task. One way in which NOHRO could facilitate both

protection of research participants and the promotion of

research is by introducing mechanisms for review of

research that involves complex ethical issues. These

mechanisms might include requesting a federal agency 

to set up a special review body or working with local

institutions in conjunction with a federal agency that is

sponsoring a particular research program.

If the proposed office were located within a department rather than given agency status, special provision

would need to be made to force other departments and

agencies to follow the policies set by that lead agency.

Empowering such a lead agency within one department

with authority over operations of other departments at

the same administrative level presents a difficult arrangement at best. For example, staff of the other agencies may

be subject to competing expectations and demands from

their own agencies as well as the proposed office.

Another concern of locating NOHRO within a single

department is that it could be perceived both externally

and within the department as responsive primarily to that

department’s interests, views, and the type of research it

sponsors or conducts, to the exclusion of other types of

research carried out primarily by other departments. For

example, OHRP, located in DHHS, has interpreted regulations and developed policy generally in response to the

conduct of biomedical research. Furthermore, housing an

oversight office within a department that conducts or supports human research could create a conflict of interest.

Such a potential conflict provided at least part of the 

reason for the recommendation to relocate the Office for

Protection from Research Risks from NIH to the DHHS

Office of the Secretary (OPRR Review Panel 1999). But

this degree of separation may still be insufficient, because

NIH is part of DHHS, and the new office is still regulating

an organization on which it relies for budgetary and other

support. The potential conflict of interest is thus attenuated, but not eliminated.9,10 The ability to act without

approval from the agencies it regulates is essential to both

the perception and reality of NOHRO’s effectiveness.

Disadvantages

Establishing an independent office might have disadvantages. Most notably, an independent office would 

necessarily be smaller than the departments and agencies

affected by the policies it develops and thus might lack

some of the political support it would need to be effective.11
National Bioethics Advisory Commission

31

Creating an independent office could also lead to

increased bureaucracy by adding another layer of oversight. NBAC opposes the creation of another office that

merely adds regulations that do not provide additional

important protections. However, the new office should

reduce unnecessary bureaucratic burden by eliminating

some duplicative procedures currently existing under the

Common Rule. For example, issuing assurances of compliance and registering IRBs should be centralized in the

new office (see Chapter 4). The use of such centralizing

rulemaking procedures eliminates the requirement that

every federal agency bound to the Common Rule institute

its own rulemaking procedures in order to revise the

Common Rule or make new regulations. 

The scarce resources that are currently available to

support the oversight system would be insufficient to 

create and operate the new office. As discussed in

Chapter 7, new funds should be appropriated to support

the office. Although there might be short-term costs, in the

long run, the investment in oversight could ultimately

make more funds available for research by reducing the

duplication in the current oversight system and streamlining a number of functions.

Another potential disadvantage of an independent

office is that its staff may be isolated from those who are

involved in the daily conduct of research. However,

mechanisms could be established that would make an

independent office accountable to the research community,

including the IRB community, participants, and the 

public. First, the office should establish a standing advisory

committee to assist in policy development and interpretation with representation from the appropriate federal

agencies; the private sector; the research community,

including all the major disciplines (e.g., clinical, public

health, social sciences, humanities) that conduct such

research; the IRB and ethics communities; and the public.

Ad hoc advisory committees should be established to

deal with specific issues of ethics and review of research.

Interacting with the research community will help the

office understand and appreciate the nuances in conducting research and deal effectively with emerging

ethical issues. At the same time, this office should be

closely tied to the IRB community so that it can address

issues, problems, or challenges facing IRBs. NOHRO also

should develop mechanisms for public input, not only

into rulemaking procedures, but also into guidance

development procedures. This might include establishing

a process for seeking input into decisions involving

interpretations of regulations or guidance. The office

should also be required to make annual reports to

Congress on the status of oversight for research involving

human participants.

Two examples of this model of independent, 

government-wide regulatory bodies, both of which were

formerly located within agencies performing the activities

they regulated, are the Office of Government Ethics

(OGE) and the Nuclear Regulatory Commission (NRC).

OGE was formerly part of the Office of Personnel

Management and has authority over all federal agencies.

NRC was part of the Department of Energy and has

authority over both the public and private sector. The

creation of OGE and NRC corrected some problems that

NBAC has also observed occurring in the current oversight

system for research.12 These offices act independently and

are free from the interests of other agencies. They are able

to make rules and promulgate guidance, visit and audit

those they oversee, govern pertinent activity within other

federal departments and agencies, and operate with 

adequate resources, including staff.13

Operating Mode of NOHRO

A lead federal office should not carry out the day-today work of protecting research participants. Once created, it would be imperative for the office to review with

all federal agencies their current responsibilities and tasks

so that overlapping activities could be avoided or harmonized. Individual federal offices would be responsible for

interacting with the lead office and for implementing the

oversight system within their departments or agencies.

When appropriate, the office should delegate authority 

to departments or agencies, especially when the implementation of the function will vary by department. For

example, departments must have authority to manage

the implementation of the human research oversight 

system in their extramural programs. OHRP should continue to monitor compliance and investigate allegations

of noncompliance, provide education, and work with the

DHHS agencies in administering their extramural
32

Chapter 2: A Proposal for Oversight

research programs. In fact, OHRP should be able to

expand its activities to cover the 11 agencies within

DHHS in which they have not had much of a presence. 

Generally, NOHRO should be directly responsible 

for policy development and interpretation through regulation and guidance. Rulemaking and guidance development should occur with input from federal departments,

the private sector, academic and research institutions,

IRBs, and the public. Education is a shared function, best

carried out by other parties in the oversight system, such

as academic and other research institutions, public and

private sponsors, and professional societies. However,

NOHRO should serve a coordinating role, ensuring consistency in educational standards and acting as a catalyst

for educational program development. 

NOHRO would not only ensure that review of

research continues to occur through IRBs, but would also

provide the leadership and policy needed to ensure consistency across IRBs. Its role in this function would be to

1) register those institutions and IRBs authorized to

review and conduct research using human participants

and work with credentialing bodies to develop mechanisms to accredit institutions and certify investigators,

IRB members, and IRB staff and 2) coordinate reviews by

specially accredited IRBs or specially created regional or

national review bodies. 

Other responsibilities would include the following:

■ defining the criteria of research studies that should

receive additional review; 

■ defining the criteria for when review should be conducted by a specially accredited IRB or a specially 

created regional or national review body versus

review by a local IRB; 

■ determining the mechanism for communication

between local IRBs and the additional review body 

so that the latter is informed about locally relevant

information and the former about deliberations of the

additional review body; and 

■ exploring whether there is a need to serve a mediation

or arbitration function when IRBs disagree over the

review of the same research study.

Monitoring is another shared function that is best 

carried out by those entities closest to the conduct of

research, such as sponsors and institutions or accrediting

bodies. NOHRO’s role should be to set policy and institute procedures for monitoring the federal agencies that

sponsor research. 

Although the lead office should have final authority

for enforcement, this function should be shared with 

federal departments, institutions, and accrediting bodies.

NOHRO should set policy describing the types of noncompliance, types of sanctions, and use of various types

of sanctions to address noncompliance. It should have

the authority to conduct investigations to detect regulatory noncompliance and should delegate authority to

federal agencies to investigate allegations of noncompliance. Federal agencies, accrediting bodies, and institutions

should be held accountable to report violations to

NOHRO, which should investigate serious violations and

repeat offenders. 

Regulation of Research Involving Human

Participants Sponsored by the Private Sector

NOHRO’s authority would extend to research conducted or sponsored by the private sector. Although FDA

would continue to regulate research conducted in support of licensure of drugs, medical devices, biological

products, or food and color additives, private institutions

conducting human research and IRBs would be required

to register with NOHRO and to be accredited, and investigators, IRB staff, and IRB members would be required

to be certified. Sanctions would apply to both the public

and private sectors.

Definition of Research Involving Human

Participants

Terminology for Those Who Participate in

Research

Thus far, NBAC has defined the scope of the oversight

system in terms of the parties that should be covered and

the functions to be carried out. This section addresses

another aspect regarding scope—that is, which activities

should be covered by the oversight system. This involves

careful consideration of how to define the terms human

participant and research. 

Various terms are used to describe individuals who

participate in research, including subjects, respondents,

observed, interviewees, informants, participants, and volunteers.
National Bioethics Advisory Commission

33

The term subject is generally used in scientific disciplines

in which studies involve experimenting on humans. It

connotes the fact that the individual is “subjected” to an

action by the investigator and highlights an important

aspect of the nature of the relationship between the

investigator and the individual who is the subject of 

the experiment. No other term more accurately portrays

the relationship and the unequal balance of power

between the investigator and the individual in the

research. Subject sometimes portrays another aspect of the

relationship between the investigator and the individual,

referred to as passivity. 

The term subject traditionally is used in clinical

research and was previously used in psychology (it 

continues to be used by some of the other social science

disciplines). Disciplines in which the primary scientific

method is the survey tend to use the term respondent or

interviewee, while disciplines employing purely observational methods may use the term observed (as a noun).

The current federal regulations for protecting those

who volunteer for research use the term subject, because

at the time the regulations were drafted in 1981, the term

was commonly used in clinical research, it had validity in

describing the relationship between the investigator and

the individuals being studied, and sensitivities regarding

the term were less recognized. In the past two decades,

two other terms have been used—participants and volunteers. In fact, the American Psychological Association

began using the term participant in the 1970s (Faden and

Beauchamp 1986, 184–185). Both terms reflect the commitment to the ethical principle of respect for 

persons and the aspiration to make “subjects” more fully

protected in the process. Individuals who participate in

research are assumed to do so based on their own free

will. Thus, the term participant is used. Volunteer is even

more specific because it makes explicit that participation

is voluntary and frequently unpaid. 

Neither of these terms is completely satisfactory in

describing those who participate in research. Volunteer

cannot readily be applied to children or others who may

have diminished decisionmaking capacity and may not

be able to give informed consent. Participant may seem

overly broad and referring to anyone involved in the

research. However, the term is likely to be confusing only

to those unfamiliar with conducting research. In the literature on this topic, only those individuals who are participating in research as subjects or respondents, for

example, are called participants.

Perhaps more important, some individuals who participate in research find the term subject offensive. The

term can be perceived as dehumanizing (Ferré and Jones

1997), and several professional organizations have

stopped using it. At least two professional societies representing the social sciences use the term participant,

14 as

do Public Responsibility in Medicine and Research and

the Applied Research Ethics National Association.

Internationally, there is a trend toward using the term

participant. France,15 Uganda (National Consensus

Conference on Bioethics and Health Research in Uganda

1997), the United Kingdom (MRC 1998), Australia

(NHMRC 1999), and the Joint United Nations

Programme on HIV/AIDS (UNAIDS 2000) have adopted

ethics guidelines, statements, or codes that refer to

human subjects as participants. Others have suggested

that subjects should not be thought of as research material or passive individuals but “simply as persons” and

should be encouraged to be active in their participation

in research (Veatch 1987, 4).

NBAC believes that the terminology should be

changed to human participant.* Even though the term

subject has validity, it seems appropriate to change it in

order to be more respectful to the individuals who participate in research and to emphasize that individuals

should be active, not passive, in the decision to enroll in

research studies.

*Commissioner Capron, joined by Commissioners Backlar and Cassell, 

offers the following observation: “Although I do not believe that we should

employ the word participant in place of the traditional term, subject, I 

recognize that no term is perfect. The traditional term carries a connotation 

of being under the rule of (and being obedient to) the investigator, which

seems to deny a central tenet of research ethics, namely that patients and 

volunteers are autonomous agents, free to choose whether to participate 

and to withdraw from a study. Human participant, the term chosen by the

Commission, overcomes that problem because it suggests a willing partner in

the enterprise, but it fails to convey the fact that among those who participate

in the research enterprise, those being termed participants are the ones subject

to manipulation and observation and are usually the ones bearing the risk 

of the research. Participant might be fine as a term of aspiration, but it is premature to adopt the term, because today too many patients and volunteers

who are enrolled in research studies are still not free and equal participants 

in the research; indeed, changing the term could send a false signal that less

vigilance is needed to protect human subjects or that investigators and IRBs

need not expend further effort to move to a system in which the people being

studied are truly research participants.”
34

Chapter 2: A Proposal for Oversight

Defining Research Involving Human Participants

and Determining What Is Covered by the

Oversight System

Many activities involve interactions between people

in which one party does something to another party

(manipulates) and in the process of that interaction

obtains or analyzes data. For example, physicians diagnose and treat patients, public health officials investigate

disease outbreaks in the population, journalists conduct

interviews, teachers test students, credit card companies

obtain credit information, police officers question suspects

and witnesses, the Internal Revenue Service (IRS) audits

citizens’ tax returns, and investigators conduct various

activities with participants in research. All of these activities involve not only human interaction, but also the 

collection or analysis of data about individuals. Yet, it is

intuitively if not explicitly clear that only some of these

activities should be regulated under the proposed system

of oversight. 

The proposed oversight system is not intended to

protect the rights and welfare of individuals in all activities involving interactions between people in which one

party manipulates another party and in the process of

that interaction obtains or analyzes data. To do so would

be impractical and inappropriate, because other systems

of protection exist to provide those protections in particular circumstances (e.g., state laws related to disease

reporting, the legal system for suspects and witnesses in

court proceedings, or ethics codes for the practice of

medicine). 

Research Versus Practice

Drawing the line between research that should be regulated and that which should not be can be difficult.

During each of the town meetings conducted by NBAC,

questions were raised about the definition of research.

For certain professions—such as medicine, public health,

psychology, social work, and education—both practice

and research activities are conducted, and the line

between the two types of activities can be easily blurred,

leading to genuine disagreement or difficult judgments.

In other professional areas, there may be only practice

activities, but the methods used in these activities are

similar to those used in research. For example, the survey

methods used in political polls are the same as those used

in health research surveys. 

As discussed in Appendix C, the United States began

to seriously focus on regulating research after the Nazi

war crimes trials and the opening of the NIH Clinical

Center. Given the historical context, the focus was on

differentiating clinical research from clinical practice.

Thus, the National Commission for the Protection of

Human Subjects of Biomedical and Behavioral Research

(National Commission) was charged16 with distinguishing

between research and practice in medical, behavioral,

and social interventions and produced eight papers

addressing this issue (Campbell and Cecil 1979; Gallant

1979; Goldiamond 1979; Levine 1979; London and

Klerman 1979; Robertson 1979; Sabiston 1979; Tropp

1979). Because the National Commission focused its

attention on medicine, it used a framework of “the individual versus the group.” The basic element of this 

distinction was that the practice of medicine referred to

activities designed solely to enhance the well-being of 

the specific patient, while research, often using many

individuals, was designed to develop or contribute to

generalizable knowledge.

Of great interest to the National Commission were

ways in which to classify innovative therapies or practices

(London and Klerman 1979; Robertson 1979; Sabiston

1979). It was widely recognized that a common practice

in medicine involved physicians trying therapies or

administering drugs in a manner that differed from

generally accepted practice standards. Such innovative

practices were considered not to be research because they

are generally not carried out in a systematic fashion and

they do not generate generalizable knowledge. In addition, there is no built-in conflict of interest between the

physician and the patient, because it is presumed that the

sole interest of the physician is to provide potential benefit

to the patient. However, the National Commission recommended that innovative practices be studied under a

research protocol as soon as it became appropriate to

study them systematically (National Commission 1979).

NBAC agrees with the views and recommendations of

the National Commission regarding the handling of

innovative therapies.
National Bioethics Advisory Commission

35

Missing from the National Commission’s deliberations,

however, were activities outside clinical or behavioral 

settings. For example, public health and certain types of

research in the humanities and social sciences (e.g., oral

history) were only minimally addressed in the National

Commission’s reports. Thus, a definition of research

emerged that differentiated clinical practice from clinical

research, but did little to help differentiate practice from

research activities in other areas.

The National Commission offered its definition of

research in the Belmont Report: Ethical Principles and

Guidelines for the Protection of Human Subjects of Research

(Belmont Report) as an “activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to

develop or contribute to generalizable knowledge

(expressed, for example, in theories, principles, and

statements of relationships).” The Belmont Report states

further that research is “usually described in a formal

protocol that sets forth an objective and a set of procedures designed to reach that objective.” Practice is

defined as “interventions that are designed solely to

enhance the well-being of an individual patient or client

and that have reasonable expectation of success”

(National Commission 1979, 2). Although the definition

of practice is explicit that interventions are undertaken to

benefit individuals, in the definition of research, it is

implicit that some, if not all, benefit is to the investigator

and to society through the potential advancement of 

scientific understanding or knowledge.

When the federal regulations were revised following

the publication of the Belmont Report, the definition in

the Belmont Report was incorporated, but only to a limited degree. Since 1981, the regulatory definition of

research in 45 CFR 46.102 has been as follows: “Research

means a systematic investigation, including research

development, testing and evaluation, designed to

develop or contribute to generalizable knowledge.” This

regulatory definition has been used to identify the universe of activities covered under the Common Rule, but

does not include the important distinguishing concept of

who benefits from the activity. Clinical practice activities

directly benefit those receiving them; the relationship

between the professional and the individual is presumed

to be unambiguous with the intent presumed to be that

of benefiting the individual. In research, however, the

relationship between the investigator and the individual

is different; investigators use those participating in

research to generate knowledge that is of primary benefit

to society. Thus, a potential conflict of interest always

exists between investigators’ desire to pursue knowledge

and their obligation to protect the rights and welfare of

research participants.

Another shortcoming of the current definition is the

use of the term generalizable. By not including a fuller

definition of generalizable knowledge that would

include, for example, theories, principles, statements of

relationship, or attempts to develop answers to a particular question, the term is left to be defined by those

attempting to apply the research definition to their activities. For example, without clarifying what is meant by

generalizable knowledge, journalistic activities, marketing

surveys, political polls, or police investigations could be

included in the definition of research because they

involve using individuals to gain information for the benefit of those who are gathering the information. However,

although these activities generate useful, important information that is of general interest, they normally do not

produce new knowledge that can be used to develop or

revise theories or principles. NBAC does not consider these

activities to fall within the scope of research involving

human participants that is subject to oversight.

The current definition of research, though, is even

more difficult to use in sorting activities at the boundary

between research and practice (e.g., surveillance, program

evaluation, quality improvement, innovative therapy, or

medical monitoring) or for activities that focus on populations (e.g., public health and health services) rather

than on individuals. Public health activities and health

services studies are two examples for which the current

definition of research is problematic.

Public Health Activities

State and local health departments have broad, legally

mandated roles to protect the health of the community

through data collection and analysis that target public

health actions for disease prevention and control. For

many public health practice activities, systematically
36

Chapter 2: A Proposal for Oversight

collected data and scientific methods are used to enhance

knowledge. In some cases, the knowledge gained from

public health practice could be used to develop or refine

knowledge. Although the individuals who participate in

these activities rarely benefit directly, the intent of public

health practice is always to prevent or control disease and

improve health or to improve a public health program or

service in a specific population (i.e., the “public health

patient“) (CDC 1999). In public health practice, immediate action is taken based on the analysis of the data to

improve the health of the specific population in question.

Indeed, carrying out such practices is usually done as

part of activity mandated by state statute. These activities

are similar to certain medical interventions in which the

individual participant does not directly benefit, but

others do (e.g., blood donation, skin grafts, organ

transplants). In addition, the role of the public health

professional usually can be considered more akin to that

of the physician than that of the investigator, because the

public health professional performs the activities for

the benefit of the population being served, just as the

physician performs activities for the benefit of the

patient.

One could argue that individuals who participate in

public health practice activities should be protected

because in some sense they are being used just as individuals who participate in research. However, other

mechanisms exist to protect the interests of individuals

who participate in public health activities. State and local

laws address the requirements for informed consent, 

protections for privacy and confidentiality, procedures 

for collecting and handling information (e.g., disease

reporting and surveillance systems), and penalties for

public health professionals when they do not comply

with legal requirements.17 Any remaining deficiencies in

these protection mechanisms should be evaluated and

addressed through state and local laws.

On the other hand, public health professionals also

conduct research in conjunction with routine public

health practice activities. To provide clarification on

applying the current definition of research to public

health, the Centers for Disease Control and Prevention

(CDC) has developed specific guidance on this matter

(CDC 1999), much of which is devoted to clarifying the

term designed in a context in which data on populations

are routinely and systemically collected and analyzed

with the intention of providing an immediate benefit to

individuals or their community (practice). This contrasts

with activities that are involved in generating knowledge

that would have no direct or immediate benefit for 

the participants or their community, but that would be

applicable elsewhere (research).

Public health activities that meet the definition of

research involving human participants must be subject to

the proposed oversight system; however, public health

practice (as defined above) would not be considered

research for this purpose. For example, outbreak investigations that do not provide information beyond the

scope of the investigation are public health practice and

not human participant research. In addition, requirements for disease reporting, monitoring, and other data

collection activities conducted under state statute or

under recognized public health authority are not research

that would fall under the oversight system. However, such

data may be used for research purposes, in which case

the use, not the initial collection of the data, constitutes

research involving human participants and is subject to

the oversight system (e.g., use of state cancer registry data

for research).

Health Services Research and Program Evaluation

Another area in which it is difficult to apply the 

definition of research is the delivery of health services. A

recent Institute of Medicine report defined health services

research as “the study of the effects of using different

modes of organization, delivery and financing for health

care services” (IOM 2000, 1). Health services research

differs from clinical research in that it concentrates on the

study of intervention effectiveness in applied settings,

while clinical research concentrates on studying the

efficacy of interventions in controlled settings. Eisenberg

describes health services research as part of a broader

continuum of health-related research, in which the

boundaries between biomedical and health services

research are blurred (Eisenberg 1998). Yet, some data

collection and analysis activities in health services are not

intended to generate scientific knowledge, but rather are

used as management tools to improve the provision of
National Bioethics Advisory Commission

37

services to a specific health care population (IOM 2000).

These activities, generally referred to as program evaluation or quality improvement, are not intended to have

any application beyond the specific organization in

which they are conducted. As is true in the area of public

health, because populations are the subject of study and

because the methods used in program evaluation or

quality improvement are the same as those used in

research, it is often difficult to determine whether an

activity is research that falls under the oversight system.

Definitional issues regarding program evaluation or

quality improvement are not limited to health care delivery. They also occur in industrial or educational settings

and in social science and operations research. However,

if the purpose is to assess the success of an established

program, and the information gained from the evaluation

will be used to improve that program, the activity should

not be considered research involving human participants. Evaluation is a program monitoring tool, and the

information gained will immediately benefit the program

and/or the individuals involved. 

However, when quality improvement involving

human participants is undertaken to test a new, modified,

or previously untested intervention, service, or program

to determine whether it is effective and can be used elsewhere, the activity is human participant research and

subject to the oversight system.

Certain Types of Research That Might Not

Require Federal Oversight

In some disciplines, especially the social sciences and

humanities, it is unclear whether it is appropriate to

include certain types of research in the federal oversight

system.18 Although no one would question that the 

systematic investigations undertaken in these disciplines

are research, the interpretation of the current regulations

and the requirements that IRBs impose on such research

may raise concerns.19 The burden on investigators coupled

with the lack of any perceived benefit in added protection

to participants have led some to suggest that certain types

of research in these areas should not be covered under

the oversight system.

In fact, intending to avoid unnecessarily burdensome

review, the current federal regulations specify six categories

of research as exempt from the federal regulatory system.

A review of the rulemaking process that occurred when

the exemptions were codified indicates that DHHS

assumed that most educational, behavioral, and social

science research involves little or no risk to research participants and should not be regulated.20

Although most educational and social science

research involves no more than minimal risk to participants, some of these research studies present a significant

risk. Because the current regulations do not limit the

exemptions only to research involving little or no risk,

any kind of research that meets the criteria can be

exempted, including, for example, a survey involving

sensitive questions. Moreover, some of the exemption

categories are used for biomedical research that incorporates the study of behavioral processes and employs

behavioral and social science methods. 

Further, current regulations specify that when

research is exempt from the Federal Policy, the research

is exempt from all requirements, not simply from IRB

review. It is clear, however, that although requiring

IRB review might be not be appropriate, it might be

appropriate to require informed consent.

Delineating the criteria for exclusion from coverage is

challenging. For the reasons mentioned above, the criteria

should not be based on research methods alone. Instead,

they should include characteristics of research design

that ensure that there is little, if any, risk to participants

and that there is a clear and easy opportunity for participants to make an informed refusal to participate. For

example, research involving no intervention, the collection

of no sensitive information, and no need by investigators

to act upon the collected information (e.g., mandatory

disclosures) should not be included in the system.

In summary, the definition of covered research can be

improved by avoiding the use of terms that are difficult

to understand or apply. A clear and accurate definition

will help ensure that the federal oversight system will

cover activities within its scope. These activities should

include those involving the systematic collection or

analysis of data with the intent of generating new knowledge, principles, or theories and studies that generate

information that revises or improves on an existing

principle, theory, or body of knowledge. Some research
38

Chapter 2: A Proposal for Oversight

activities that are conducted in fields that do not rely

solely on clinical scientific procedures—such as some

types of anthropological or humanities research—should

be included under this definition. Among those activities

that are considered research, however, some should not

be covered under the federal oversight system, especially

when they pose little or no risk to participants and allow

them to make an informed refusal to participate.

Furthermore, although the definition of research need

not explicitly state the nature of the relationship between

investigators and participants, it should be clear that in

those activities defined as research, participants are used

at least to some extent by investigators to achieve their

research objectives, which might or might not benefit the

participants.

In developing one set of regulations and a definition

of research, it will be important to harmonize that definition with FDA’s definition of regulated activities to ensure

that FDA-regulated activities are included. For example,

FDA regulations relating to the use of test articles involving experiments with one or more human participants

require protections for human participants even if the

activity does not involve “research” (21 CFR 56.102(c);

21 CFR 312.3(b)).

Who Should Be Protected by the Oversight System? 

Under the Common Rule, sequential decisions must

be made to determine whether an activity constitutes

human participant research. That is, one must first

determine whether the activity is research; then, if it is

research, one must determine whether it involves human

participants. In making this determination, one must

establish whether private information is obtained and

whether it is individually identifiable (NBAC 1999b),

meaning that the “identity of the subject is or may be

readily ascertained by the investigator or associated with

the information” (45 CFR 46.102(f)(2)). No definition of

“readily ascertained by the investigator” is provided.

Private information includes “information about behavior

that occurs in a context in which an individual can 

reasonably expect that no observation or recording is 

taking place, and information which has been provided

for specific purposes by an individual and which the

individual can reasonably expect will not be made 

public” (45 CFR 46.102(f)(2)).

This algorithm is often poorly understood (NBAC

1999b). A simpler decisionmaking process could be one

that describes human participants who should be covered as those who are exposed to manipulations, interventions, observations, or other types of interactions

(e.g., surveys) with investigators or who are identifiable

through research using biological materials, medical or

other records, or databases. 

Different terms are used by various disciplines to

describe what occurs in the relationship between investigators and participants. Manipulation or intervention

means physical, psychological, or social procedures by

which data are collected or by which the participants or

the participants’ environment are affected as part of the

research. Interaction means communication or interpersonal contact between the investigator and the participant.

Investigators include all who are involved in the 

conduct of a research study, such as scientists, study

coordinators, research staff, and data abstractors.

Student-initiated research in which the intention of the

activity may be as much pedagogical as it is to pursue

knowledge is often difficult to classify,21 but students

conducting research involving human participants

should also be considered investigators. Review of studentinitiated research should be commensurate with the risks

associated with the research; for example much studentinitiated research is likely to involve no more than minimal risk and to be eligible for review using procedures

other than full IRB review.

NBAC developed a definition of identifiable in its

report on the research use of human biological materials

that also applies here, in which coded data are considered identifiable (NBAC 1999b, 17). Coded data were

defined as linked or identifiable because, even though

they do not include any identifying information, such as

names, they have codes that allow the data to be linked

to identifying information (NBAC 1999b).

All coded data are identifiable regardless of the how

difficult it may be to link the data to identifying information. Even when disclosure of the identifying information

is protected under federal or state law and access to the

identifying information would be extremely difficult to

obtain, the coded data remain identifiable. For example,

coded data that are protected under federal confidentiality
National Bioethics Advisory Commission

39

statutes (e.g., statues adhered to by the Departments of

Education and Justice and CDC) should be considered

identifiable, and uses of such data for research purposes

constitute research involving human participants.

Sometimes, investigators who hold coded data will

release it to another investigator for use in a research

study under a written agreement unequivocally prohibiting release of identifying information to the recipient

investigator.22 Even in this instance, the coded data are

identifiable, and studies involving such data constitute

research involving human participants.

Although all research using coded data involves

human participants, the potential to identify individuals

varies. Some coded data are easily identifiable (i.e., investigators have access to the key linking the code to 

identifying information), while other coded data are

more difficult to identify (i.e., the recipient of the coded

data does not have access to the key), and still other

coded data are very difficult if not virtually impossible to

identify (i.e., the key is legally protected and cannot be

disclosed to investigators). IRBs should consider, when

reviewing a particular research study, how easily coded

data can be identified and conduct a review that is 

commensurate with the risks associated with that data.

For example, if the coded data are part of a data set that

is available for public access, such as those from the

National Center for Health Statistics or the Bureau of the

Census, the IRB review may consist of nothing more than

ascertaining that the data are available to the public and

that the owner of the data has taken appropriate steps to 

protect the coded data (e.g., the confidentiality of the

data is protected under federal statute or under state law

or a data repository requires the recipient to sign a legally

binding agreement stipulating permitted uses of the data

and that no identifying information will be released to

the recipient).

Research involving the analysis of existing data that

are unidentifiable does not involve human participants.

NBAC has previously defined two types of unidentifiable

data. One type is unidentified, also referred to as anonymous, which are collected from individuals who were not

identified at the time of collection. The second type of

data is unlinked or anonymized data. Although identifiers were available when the data were collected or

stored, at some point, the identifiers were unlinked.

Thus, unlinked data lack identifiers or codes that can

link the data to identifying information or particular 

individuals (NBAC 1999b).

Information Revealed About Others

Some research involves interaction with the participant

that reveals information about other individuals (e.g.,

family histories and research on familial interactions).

Generally, these other individuals are not considered

research participants, although there have been recent

discussions about how to consider the rights and welfare

of these individuals when constructing appropriate 

protections (Botkin 2001). NBAC concludes that, in 

general, these individuals should not be considered

human participants in research. Nevertheless, there

might be circumstances in which it is appropriate for an

IRB to consider whether their rights and welfare are being

protected, particularly with regard to confidentiality of

data.

Children

Inclusion of children in research raises special issues.

Although research with children is not addressed in this

report, the proposed system could apply to this population as well. Should this report and its recommendations

be implemented, special attention should be given to the

ethical standards and regulatory requirements associated

with providing adequate protections to children who are

research participants.

Embryos and Fetuses

Research involving human fetuses and embryos raises

distinct issues. Additional protection exists in the DHHS

regulations pertaining to research and related activities

involving fetuses, pregnant women, and in vitro fertilization (Subpart B). In 1993, DHHS convened a working

group to revise Subpart B. These revisions were published

in the Federal Register on January 17, 2001, but are not

yet effective.23

Deceased Individuals

Current federal regulations do not cover deceased

individuals, which includes cadavers, biological materials

from cadavers, and data from cadavers. NBAC concurs

with this position and has in part addressed this issue

previously (NBAC 1999b, 29).
40

Chapter 2: A Proposal for Oversight

As discussed in Chapter 4, when living persons may

be affected by research involving the deceased in such a

way that the living might experience social, physical, 

psychological, economic, or legal harm, these risks

should be considered by an IRB. Although deceased individuals do not have independent rights and interests that

need to be protected, living family members might claim

such rights and interests, especially in research in which

the living family members may be contacted or in which

they or others become aware of the research findings

(NBAC 1999b, 49, 73). The burden is on investigators to

be sensitive to these issues.

Materials from deceased individuals that are used in a

current research study may be obtained from previous

research or practice (e.g., specimens collected as part of a

surgical procedure). The understanding of individuals at

the time they are living with respect to future uses of such

materials should be honored following their death

(NBAC 1999b, 49). Consent documents should be

reviewed to ensure that currently proposed research is

not violating the participant’s understanding at the 

time consent was obtained, regardless of whether the 

materials or data were collected as part of a research

study or practice.

This same principle holds true for other types of data.

For example, oral histories are often archived, with

informed consent from the participant for future research

uses, and the data could be used for future research.24

So that data can be used in an ethical manner after a participant’s death, investigators should construct informed

consent processes to describe as many potential uses of

specimens or data after death that can be anticipated at

the time of agreement to participate in the research. In

this way, investigators can respect the wishes of participants and at the same time use valuable data repositories.

Decisions Regarding Whether an Activity Is

Research and Subject to Federal Oversight

This report does not attempt to offer a regulatory

definition of research involving human participants that

would be subject to the oversight system that clearly and

easily identifies all possible activities that must be

included. No regulatory definition of covered research

can be written with the sensitivity and specificity needed

to ensure that all research activities that should be subject

to oversight are always included and all activities that

should be excluded from oversight are always excluded.

Clarification and interpretation will invariably be

required, and ambiguous cases will always arise. 

Recommendation 2.4: Federal policy should 

cover research involving human participants 

that entails systematic collection or analysis of

data with the intent to generate new knowledge.

Research should be considered to involve human

participants when individuals 1) are exposed to

manipulations, interventions, observations, or

other types of interactions with investigators or

2) are identifiable through research using biological materials, medical and other records, or

databases. Federal policy also should identify

those research activities that are not subject to

federal oversight and outline a procedure for

determining whether a particular study is or is

not covered by the oversight system.

One of the important leadership roles NOHRO

should fulfill is to provide guidance on determining

whether an activity is research involving human participants and thus subject to oversight. In addition, it should

generate a list of activities that are normally treated as

human participant research and are therefore subject to

oversight as well those that are not. For example, the list

of activities not covered by the federal oversight system

should include journalism, market surveys, political polls,

police investigations, IRS audits, academic examinations,

athletic competitions, mandatory disease reporting, outbreak investigations, quality improvement or program

evaluation when used as management tools, other

defined practice activities in public health, medicine,

psychology, and social work, and certain types of

research activities posing little or no risk to participants

and offering the opportunity for participants to make an

informed refusal. NOHRO should initiate a process in

which representatives from various disciplines and 

professions (e.g., social sciences, humanities, business,

public health, and health services) contribute to the

development of the definition and the list of research

activities subject to the oversight system. Based on the

recommendations in this report, it is likely that some

research that is currently exempt would be covered
National Bioethics Advisory Commission

41

under the federal oversight system while other, currently

exempt research would not be covered. 

Moreover, at the local level, institutions should

develop policies and procedures for ensuring that a

disinterested third party, who is not the investigator,

determines whether an activity is research involving

human participants and subject to oversight. The third

party should be sufficiently knowledgeable about the

institution’s mission and overall activities to make such

determinations, keeping in mind that all disciplines have

nuances that make each decision about whether an

activity is human participant research unique. Although

IRBs or institutional human research oversight offices are

obvious locations for this process, other models may be

appropriate. In any case, the investigator alone should

not make the determination.

Applicability to Various Types of Research

It is NBAC’s intention that the definition of research

involving human participants be applied in all disciplines. However, because the risks of research differ both

qualitatively and quantitatively across the spectrum of

research disciplines, the oversight system should ensure

that all covered research is subject to basic protections,

such as a process of informed consent, except in the

specified conditions in which it can be waived; protection of privacy and confidentiality; and minimization of

risks. Having potentially included more research under

this proposed system, it is more critical than ever that

review mechanisms and criteria for various types of

research are suited to the nature of the research and the

likely risks. This chapter, for example, has described the

use of procedures that could accelerate, streamline, or

harmonize review, such as less than full board review for

minimal risk research and use of specially accredited

IRBs or special regional or national review of novel or

controversial research to supplement local IRB review.

Moreover, more specific guidance for review of different

types of research is needed, including guidance regarding

review criteria and IRB composition.

Under the proposed oversight system, a wide range of

research activities would be covered, from clinical trials

to observational studies, with a continuum between them

that includes psychological experiments, studies using

existing data, and surveys, with the types and degree of

risks varying substantially among the different types of

research. Thus, review criteria and mechanisms must be

appropriate for the particular type of research. To be

effective and efficient, the oversight system should

encourage flexibility in IRB review; however, the local

IRB should implement a common set of ethical principles

and standards. 

All research studies that are judged to involve no

more than minimal risk should be eligible for IRB review

using more efficient procedures than a full review,

although full board review could be required if deemed

necessary by a local IRB. Most social science and humanities research involves no more than minimal risk and can

be reviewed using a more efficacious procedure than full

IRB review. In addition, many health services research

studies, epidemiological studies, and other studies using

existing data involve no more than minimal risk and can

be reviewed using a less resource-intensive process.

However, even within the IRB review category of no more

than minimal risk, the risk level varies from virtually

none to minimal, and review within the category should

be commensurate with the level of risk.

For example, one significant demarcation along the

continuum of research is whether it involves interaction

with human participants. In research involving the use of

existing data or tissues and no interaction with human

participants, the primary ethical concerns are threats to

privacy and confidentiality (NBAC 1999b). IRBs should

pay attention to these types of ethical concerns and have

or find the needed expertise, for example, in data management, storage, and transmission; computer security;

and other confidentiality protections (e.g., state law).

IRBs that review DNA research on stored tissue samples,

for example, might have expertise in genetics. The expertise of the IRB or access of the IRB to such expertise

(i.e., use of consultants) should be appropriate for

addressing the ethical issues the IRB is likely to face in

reviewing research. Chapter 4 further discusses IRB

review requirements for different types of research.

Recommendation 2.5: Federal policy should

require research ethics review that is commensurate with the nature and level of risk involved.

Standards and procedures for review should 

distinguish between research that poses minimal
42

Chapter 2: A Proposal for Oversight

risk and research that poses more than minimal

risk. Minimal risk should be defined as the 

probability and magnitude of harms that are 

normally encountered in the daily lives of the

general population (see Recommendation 4.2). 

In addition, the federal government should 

facilitate the creation of special, supplementary

review bodies for research that involves novel 

or controversial ethical issues. 

Summary

A comprehensive and effective oversight system is essential to uniformly protect the rights and welfare of research

participants while permitting ethically and scientifically

responsible research to proceed without undue delay. To

achieve these goals, the oversight system should include

several interrelated but distinct functions and responsibilities, including policy development, regulatory reform,

research review and monitoring, research ethics education, and enforcement. Many parties are involved in the

research enterprise and the system of oversight, including

research participants, IRBs, institutions, sponsors, a 

federal oversight office, state regulators, professional

organizations, publishers, Congress, and the public. To

function as intended, the system requires that all parties

act responsibly, even though the ethical obligation to 

protect participants lies primarily with investigators,

sponsors, and IRBs.

All research participants, regardless of whether the

research sponsor is a public or private entity, should be

protected by this oversight system, which should apply

to both domestic and international research. To accomplish this level and extent of protection, the system must

expand beyond its current scope. An independent, single

federal office created to lead and coordinate the oversight

system would be more effective than the current system

and would solve a number of problems. Such an office

should promulgate a unified and comprehensive federal

policy embodied in a single set of regulations and guidance that can be applied to all types of research involving

human participants. Federal protections should be uniform across all sectors of government, academe, and the

private sector, but should be flexible enough to be

applied in widely different research settings or to emerging

areas of research.

Finally, the newly created office should include in its

policy a definition of research involving human participants that is subject to federal protections and develop a

range of review mechanisms for the various types of 

covered research. To meet the goal of protecting those

who participate in research, the scope and relevancy 

of protections must be clear to all. Investigators, IRBs, 

sponsors, and institutions require and must receive

unambiguous guidance on the extent to which their

research activities are covered by the oversight system.

Notes

1 OPRR/FDA Town Hall Meeting: June 16, 2000, Chapel Hill,

North Carolina; Vanderpool, H., Testimony before NBAC. June 6,

2000. San Francisco, California.

2 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

3 See Vanderpool, H., “Unfulfilled Promise: How the Belmont

Report Can Amend the Code of Federal Regulations Title 45 Part 46—

Protection of Human Subjects.” This background paper was prepared

for NBAC and is available in Volume II of this report.

4 See Moreno, J., “Protectionism in Research Involving Human

Subjects.” This background paper was prepared for NBAC and is

available in Volume II of this report.

5 See Chalmers, D., “Research Ethics in Australia.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

6 See Moreno, J., “Protectionism in Research Involving Human

Subjects.” This background paper was prepared for NBAC and is

available in Volume II of this report.

7 See Chalmers, D., “Research Ethics in Australia.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

8 See Schwartz, J., “Oversight of Human Subject Research: The

Role of the States.” This background paper was prepared for NBAC

and is available in Volume II of this report.

9 See McCarthy, C., “Reflections on the Organizational Locus of the

Office for Protection from Research Risks.” This background paper

was prepared for NBAC and is available in Volume II of this report.

10 See Fletcher, J., “Location of the Office for Protection from

Research Risks within the National Institutes of Health: Problems

of Status and Independent Authority.” This background paper was

prepared for NBAC and is available in Volume II of this report.
National Bioethics Advisory Commission

43

11 See McCarthy, C., “Reflections on the Organizational Locus of

the Office for Protection from Research Risks.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

12 Flack, D., Testimony before NBAC. March 1, 2000. Herndon,

Virginia; Ley, J., Testimony before NBAC. March 1, 2000.

Herndon, Virginia. See McCarthy, C., “Reflections on the

Organizational Locus of the Office for Protection from Research

Risks.” This background paper was prepared for NBAC and is

available in Volume II of this report.

13 See Fletcher, J., “Location of the Office for Protection from

Research Risks within the National Institutes of Health: Problems

of Status and Independent Authority.” This background paper was

prepared for NBAC and is available in Volume II of this report.

14 All codes available at American Psychological Association,

http://www.apa.org/ethics/code.html; American Sociological

Association, http://www.asanet.org/members/ecostand.html. 

Both sites last accessed December 12, 2000.

15 Law 88-1138 Regarding the Protection of Persons Agreeing to

Biomedical Research.

16 Pub. Law 348, 93rd Congress, Title II.

17 NBAC Town Meeting: August 14, 2000, Portland, Oregon.

18 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon. 

19 Wax, M., Testimony before NBAC. April 6, 2000. Washington,

D.C.; Sieber, J.E., Testimony before NBAC. April 6, 2000.

Washington, D.C.; Abowd, J.M., Testimony before NBAC. 

April 6, 2000. Washington, D.C.; Shopes, L., Testimony before

NBAC. April 6, 2000. Washington, D.C.

20 46 Fed. Reg. 8366–8391.

21 Public Responsibility in Medicine and Research conference 

on human subjects protections, November 1998, “IRBs and the

Shifting Sands of Public Opinion.” San Diego, California.

22 OHRP Guidance: “Engagement of Institutions in Research.”

January 26, 1999; “Issues to Consider in the Research Use of 

Stored Data or Tissues.” November 7, 1997; “Protections for Human

Subjects in the NIGMS Human Genetic Mutant Cell Repository:

Submission of Non-Identifiable Materials to the Repository.” May 22,

1997; “Guidance on Protections for Human Subjects in the National

Institute of General Medical Sciences Human Genetic Mutant Cell

Repository.” May 21, 1997; “Operation of Human Cell Repositories

Under HHS Regulations at 45 CFR 46.” August 19, 1996. Available at

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/reposit.htm.

Last accessed December 15, 2000.

23 38 Fed. Reg. 3878–3883. 

24 K. Ewing and L.K. George, Duke University, to E.M. Meslin,

NBAC. February 16, 2001. Letter relating to draft of this report.

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Social Science Research? In Appendix to The Belmont Report, vol. 2,

18-1–18-17. Washington, D.C.: DHEW. 

Veatch, R.M. 1987. The Patient as Partner: A Theory of HumanExperimentation Ethics. Bloomington: Indiana University Press.
Introduction

Protecting the rights and welfare of research participantsis the major ethical obligation of all parties in the

oversight system, who, to meet this obligation, must

demonstrate competence in research ethics by being 

able to conduct, review, or oversee research involving

human participants in an ethically sound manner. Such

competence entails not only being knowledgeable about

relevant research ethics issues and federal policies but

also ensuring that conflicting interests for institutions,

investigators, or Institutional Review Boards (IRBs) are

disclosed and managed so that there is no question that

research participants are being protected. Finally, the

oversight system must include a robust monitoring process

so that lapses by institutions, IRBs, and investigators can

be remedied.

This chapter addresses measures needed to ensure

that all parties involved in the research enterprise are

competent with regard to protecting research participants

and are reliably carrying out their responsibilities in this

area. They include measures:

■ to educate all parties involved in research with human

participants about the substantive and procedural

requirements of the system of protections (which

includes demonstrated competence in research

ethics);

■ to provide ongoing mechanisms to ensure that 

institutions, IRBs, and investigators are in compliance

with regulations, guidance, and procedures pertaining

to the protection of research participants; and 

■ to manage conflicts of interest of investigators, IRBs,

and institutions.

Education and Competence in

Conducting Research Involving 

Human Participants

Education is an essential ingredient for developing competence in the ethical conduct of research with human

participants; it can assist not only in the identification of

ethical problems, but also in their resolution. Through

well-designed ongoing educational programs, one can

learn, for example, the most practical and effective steps

for protecting confidentiality or improving the quality of

the informed consent process and its documentation.

Tailored education programs can help prevent routine

ethical issues from becoming needless impediments to

research and can provide basic skills to assist investigators

and IRB members in dealing with new or complex ethical

issues. 

The need for education was a major focus of the

National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research

(National Commission), the President’s Commission for

the Study of Ethical Problems in Medicine and

Biomedical and Behavioral Research (President’s

Commission), and the Advisory Committee on Human

Radiation Experiments (ACHRE). It also has been central

in National Bioethics Advisory Commission (NBAC)

reports. 

The National Commission focused on education of

IRB members and proposed that the federal government

and individual institutions play a role in that effort

(National Commission 1978, 10, 15). The President’s

Commission recommended a broad educational program

targeted to investigators, IRB members, and research

administrators, including site visits to institutions by

45

Methods for Ensuring

Protection: Education,

Certification, and Accreditation

Chapter Three 3
46

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

experienced IRB members and administrators (President’s

Commission 1983, 135–136). ACHRE highlighted the

importance of education by linking the protection of the

rights and interests of research participants to the ability

of investigators to “appreciate sufficiently the moral

aspects of human...research and the value of institutional

oversight” (ACHRE 1995, 817). In two previous reports,

NBAC recommended that professional associations

develop topic-specific educational materials (NBAC

1998; NBAC 1999).

Despite this enduring recognition of the important

role of education, the educational function of the oversight

system has been only minimally implemented through

federal programs. The former Office for Protection from

Research Risks (OPRR) devoted most of its limited

resources to negotiating assurances and overseeing compliance. Aside from the educational activities associated

with obtaining an assurance, regional workshops 

sponsored in conjunction with the Food and Drug

Administration (FDA) were OPRR’s only other sustained

educational program. The lack of focus on education at

the federal level was repeated at the local level, with institutions often failing to provide educational programs to

their investigators, research staff, and IRB members. It

should not be surprising, therefore, that the lack of

appropriate educational programs and the resulting lack

of knowledge about the ethical principles and procedures

relevant to protecting research participants are among the

deficiencies identified in audits and suspensions of

research programs by OPRR, now the Office for Human

Research Protections (OHRP) (OHRP 2000). A National

Institutes of Health (NIH) survey of IRB chairs, members, administrators, institutional officials, and investigators at institutions holding Multiple Project Assurances

(MPAs) found strong support for additional, improved

education (Bell et al. 1998).

Some efforts are currently under way to increase 

educational opportunities. In 1997, two NIH-sponsored

educational programs were initiated as part of the 

government’s apology to the victims and families of the

Tuskegee Syphilis Study. In one program, investigators

receive grants to participate in ethics training programs

tailored to meet their research needs; in another, program

grants are awarded to individuals to develop courses in

research ethics.1 In addition, in 1998 OPRR hired its 

first director of education to develop computer-based

education programs for IRB administrators and institutional officials. Outside government, organizations, such

as Public Responsibility in Medicine and Research

(PRIM&R) and the Association of American Medical

Colleges, have traditionally provided education to their

constituents. Recently, PRIM&R developed a new “IRB

101” course, which is offered before its annual meeting

and at the request of institutions throughout the year.2

In addition, some academic institutions have developed

their own courses (Dunn and Chadwick 1999; Sugarman

2000). 

Recently, NIH implemented a funding eligibility

requirement that all individuals submitting grant applications provide evidence that they have been trained 

in research ethics.3 This requirement has increased the

number of education programs academic institutions

offer to faculty and staff with the goal of raising the level

of knowledge about and awareness of research ethics

among investigators. Although NIH provides a model

education program on its website, no requirements or

guidance are provided regarding what constitutes appropriate training. Investigators and institutions have 

considerable discretion in fulfilling the NIH requirement.

This activity has generated a beneficial exchange of ideas

on how best to teach research ethics to different audiences.

Educational programs should focus on ethical principles, their relationship to ethical standards, and the

procedures necessary to implement them. It is critical to

emphasize the links among these three components.

Because each research study is different and some raise

new ethical issues, investigators and IRBs must be able to

refer to and apply general ethical principles. Yet, it is

equally true that research ethics cannot be taught or

learned entirely in the abstract. As one expert cautioned:

“rote memorization of guidelines, principles, and regulations, absent the ability to apply such concepts in

practical situations, will not ensure the protection of

[research participants].”4 Educational programs should

include problem-solving components in which investigators and IRB members learn ways in which to identify,

discuss, and resolve ethical issues pertinent to specific

types of research studies.
National Bioethics Advisory Commission

47

For the behavioral and social sciences, IRB members

and investigators should be educated in the ethical standards and associated procedures that are appropriate to

human participant research in these disciplines. In addition, IRB members should be familiar with standards in

professional societies’ codes of ethics, particularly for

fieldwork in anthropology or survey research in sociology

or psychology. Such standards address issues of privacy

and confidentiality, informed consent, and community

protection. Complex questions concerning deception or

stigmatization of individuals or communities may need

particular attention, particularly in the context of

research involving individuals with vulnerabilities.

NBAC supports the independence of institutions and

other entities that would enable them to design their own

education programs. However, it is important that all

educational programs provide appropriate coverage of

the ethical principles and standards and current federal

regulations and guidance related to human participant

research. 

Although the primary focus of education is on those

parties involved in the daily conduct of research (e.g.,

investigators and IRBs), other groups that carry important ethical responsibilities are also important targets for

education. For example, sponsors—whether public or

private—often are directly involved in providing advice

and supervision to grantees and contractors. Federal

agencies that have their own oversight offices (see

Chapter 2) also should be competent in research ethics,

regulations, and guidance. 

If investigators are to conduct research ethically and

research participants are to be able to make informed

decisions about participation, education about the ethical

conduct of research needs to be an integral part of science

education in the United States (Pritchard 1999). Even for

those students who do not pursue careers in science or

research, education in research ethics could make them

better informed in terms of future research participation

or in terms of understanding the nature of the research

enterprise. The American Association for the Advancement of Science (AAAS 1993) and the National Academy

of Sciences (National Research Council 1995) have produced documents outlining content standards for science

education, including standards for the ethical treatment

of research participants. 

While some curricula include courses or lectures on

research ethics, such education generally is missing from

most undergraduate and graduate school science curricula

and is seldom required, including for medical and other

health professions education (Coughlin et al. 1999;

Mastroianni and Kahn 1998). This phenomenon is

particularly disturbing because many students conduct

research involving human participants as part of their

graduate educational experience (Gunsalus 1997).

Moreover, a large number of scientists and many health

professionals expect to conduct human research. For

example, in a survey of all graduating medical students

conducted in 1996, 78.3 percent responded that they

expect to be involved in research at least somewhat during their medical career, and 11.9 percent responded that

they expected to be involved exclusively or significantly

involved during their medical career.5 Given the role of

physician-investigators within academic medical centers

and the growing number of community physicians 

conducting research or referring patients to research,

education in research ethics and human research protection should be a meaningful component of medical 

education. Professional societies should assist institutions

in developing educational programs and curricula.

The need for education in research ethics in graduate

curricula extends beyond the health fields. Graduate programs in social sciences and the humanities also should

incorporate curricula relevant to the specific discipline,

which could take advantage of the fact that professional

societies have developed codes of ethics that deal specifically with conducting research involving human beings.

Education also can be extended to other groups likely to

be involved in research. Patient advocacy organizations

can, and often do, provide education to their members.

Informing groups about rights of research participants,

protections afforded, and points to consider in deciding

whether to enroll in research can empower a large 

number of prospective research participants.

Recommendation 3.1: All institutions and sponsors

engaged in research involving human participants

should provide educational programs in research

ethics to appropriate institutional officials, investigators, Institutional Review Board members, and

Institutional Review Board staff. Among other
48

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

issues, these programs should emphasize the

obligations of institutions, sponsors, Institutional

Review Boards, and investigators to protect the

rights and welfare of participants. Colleges and

universities should include research ethics in

curricula related to research methods, and 

professional societies should include research

ethics in their continuing education programs. 

Recommendation 3.2: The federal government, 

in partnership with academic and professional

societies, should enhance research ethics 

education related to protecting human research

participants and stimulate the development of

innovative educational programs. Professional

societies should be consulted so that educational

programs are designed to meet the needs of all

who conduct and review research. 

The federal government should use a variety of incentives to encourage the enhancement of research ethics

education. 

Demonstrating Competence

Certification of Individuals

Educating all parties in research ethics and human

research protections is effective only when it results in

competence to design and conduct ethically sound

research, including analyzing, interpreting, and disseminating results in an ethically sound manner. Such competence, however, cannot be assumed to follow from

exposure to an educational course or program. As the

complexion of research continues to change, new and

challenging ethical dilemmas emerge with advances in

technology, and as more people become involved in

research as investigators or in roles particularly related 

to oversight, it becomes increasingly important for all

parties to demonstrate their competence in the ethics of

research involving human participants.

Currently, there is no regulatory requirement to

demonstrate competence, even when the level of risk is

high or the participants are vulnerable. In recent years,

there has been much discussion about the need to

implement regulations consistently, set standards for

IRBs and measure performance in meeting those 

standards (OIG 1998a), and measure the competency

of investigators (Cohen 2000).

Many IRBs and investigators have suggested that

investigators should be required to demonstrate a certain

level of competence in order to conduct human

research.6 NBAC supports this view. All individuals

directly involved in the protection of human research

participants should be certified, including investigators

and research staff, IRB members and staff, and sponsors.

Individuals employed by sponsors also should be certified when they are directly involved in the conduct or

oversight of research—for example, grants or contracting

officers who might make decisions relevant to human

participant protections. Further details regarding just

which individuals require certification will, of course, be

context dependent.

Because roles vary substantially and among investigations the diversity in research design and subject matter

is great, several certification options should be available.

For example, certification of investigators may need to be

specialized for particular disciplines or in relation to certain subject matter in order to increase its effectiveness.

Different mechanisms for certification should be tested

and evaluated. Currently, under the NIH requirement,

certification of investigators is left entirely up to the 

institution. Certification of IRB staff and members is not

required; however, there is a voluntary certification 

program for IRB administrators. The Council for

Certification of IRB Professionals (CCIP) was formed to

promote IRB administration practice and to advance the

quality of research participant protection programs

through the certification of qualified IRB professionals.

CCIP administered the first certification examination in

October 2000 and announced recently that 107 professionals were certified based on the results of these

exams.7 Certification efforts can surely be improved.

Overall, the goal of such programs should be to ensure

competence and consistency that is relevant to the 

performance of the particular individual parties. 

Recommendation 3.3: All investigators,

Institutional Review Board members, and

Institutional Review Board staff should be 

certified prior to conducting or reviewing

research involving human participants.

Certification requirements should be appropriate
National Bioethics Advisory Commission

49

to their roles and to the area of research. 

The federal government should encourage 

organizations, sponsors, and institutions to

develop certification programs and mechanisms

to evaluate their effectiveness. Federal policy

should set standards for determining whether

institutions and sponsors have an effective

process of certification in place.

Accreditation of Institutions and Independent IRBs

Related to measuring competence in individual investigators and IRB members and staff is measuring a core

set of competencies in independent IRBs or institutions.

In this arena, accreditation programs might be the most

effective mechanisms for measuring compliance of such

entities to a set of standards (Hamm 1997). In this report,

the term accreditation refers to programs directed toward

institutions, and the term certification refers to programs

directed toward individuals. 

Although accreditation and certification do not guarantee desired outcomes, they can be helpful in improving

performance. These programs generally involve experts

and peers developing a set of standards that represents a

consensus of the best practices in the profession.

Therefore, the choice of standards and the criteria for

evaluating whether an institution has met them are 

critically important. The emphasis of these programs

should be on education, on assuring that appropriate

protections are in place, and on avoiding excessively

bureaucratic procedures. Accrediting programs may lose

their value if they are seen as merely another administrative burden.

Despite concerns that accreditation might add

another layer of bureaucracy to an already regulated

environment, several advantages of accreditation programs have been noted. They are generally voluntary and

represent a profession’s desire to self-regulate. Many

accrediting programs strive to meet higher standards

than are required by law, so that having the credential

implies a higher level of competence than what may be

minimally required. Properly governed and organized,

accrediting bodies can improve competence (and thus

performance) within a profession, which helps to achieve

the goals of the profession and build public trust (Hamm

1997). In addition, accreditation serves an educative role.

Institutions seeking accreditation, for example, usually

go through a periodic review process involving a selfstudy and a site visit from a team of experts in the 

profession. The self-evaluation of the institution in

preparation for a site visit helps it identify strengths and

weaknesses in its programs and make improvements.

The site visit can be an especially useful learning experience that encourages the institution to sustain best

practices.

Accrediting programs are widely used in the fields of

health and education. These programs are seen as having

a major and generally positive influence (Hamm 1997).

One highly regarded accrediting program in research is

the Association for Assessment and Accreditation of

Laboratory Animal Care (AAALAC). This private, nonprofit organization “promotes the humane treatment of

animals in science through voluntary accreditation and

evaluation programs.” AAALAC accreditation is regarded

as a validation of having a high-quality operation, and

research programs are willing to spend resources to

obtain such accreditation. AAALAC accreditation

demonstrates that an institution is going beyond the 

minimum required by law, achieving excellence in 

animal care and use (Bayne 1998).

Recently, the Association for the Accreditation of

Human Research Protection Programs (AAHRPP) was

incorporated to “provide a process of voluntary peer

review and education among organizations concerned

with research involving humans.” The overall goal of this

accrediting organization is to improve protection of

human research participants by developing “best practice”

performance standards and by recognizing institutions

that meet those standards. AAHRPP expects to begin

accrediting institutions in the near future.8

The Department of Veterans Affairs (VA) requires all

institutions involved in conducting research sponsored

by the VA to be accredited (VA 2000), but it is the only

federal agency that requires institutions or IRBs to

become accredited. OHRP is also moving in the direction

of accreditation. Commissioned by OHRP to conduct a

study on accreditation and other human participant

research issues, the Institute of Medicine issued a report

on the use of accreditation programs and offered recommendation regarding standards (IOM 2001).
50

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

Moving toward accreditation and certification is a

positive step in ensuring improved oversight of human

research. As the proposed oversight system evolves to include accreditation and certification programs, flexibility

in testing different models and methods of accreditation

and certification should be allowed to ensure that when

these programs become fully functioning they are sensitive to the needs of the system and responsive to the 

various entities seeking accreditation certification. For

example, institutions that do not have IRBs but that are

conducting research involving human participants

should be eligible for accreditation because they have

education, monitoring, and accountability responsibilities;

and independent IRBs that might not perform all the

functions of an institution conducting research also

should be eligible for accreditation to carry out their

more limited responsibilities.

Given the diversity among institutions that might

seek accreditation and the fact that there are likely to be

several accrediting organizations, the proposed federal

oversight office should set criteria for government

approval of accrediting bodies. In addition, the federal

oversight office should develop a mechanism for monitoring accrediting bodies, and accrediting bodies, in turn,

should be monitoring the institutions they accredit for

continued competency. In the end, the office should be

able to evaluate the effectiveness of accreditation.

Although the establishment of accreditation programs

is likely to improve protections to human participants,

such programs will be costly. In addition to the cost of

accreditation itself, all institutions seeking accreditation

will need to devote additional resources and staff to support new functions or strengthen existing functions. For

example, some institutions might need to add educational programs or add monitoring functions. However,

the potential improvements in the system justify these

additional costs.

Recommendation 3.4: Sponsors, institutions, 

and independent Institutional Review Boards

should be accredited in order to conduct or

review research involving human participants.

Accreditation should be premised upon 

demonstrated competency in core areas through 

accreditation programs that are approved by 

the federal government.

Mechanisms to Ensure Institutional,

IRB, and Investigator Compliance

Assessing institutional, IRB, and investigator compliance

can help to ensure that standards are being followed 

consistently. Current mechanisms for assessment include

assurances of compliance issued by the Department of

Health and Human Services (DHHS) and several other

federal departments, site inspections of IRBs conducted

by FDA, other types of site inspections, and institutional

audits. In addition, some institutions have established

ongoing mechanisms for assessing investigator compliance with regulations.9 However, institutions vary 

considerably in their efforts and abilities to monitor

investigator compliance, from those having no monitoring

programs to those conducting random audits.10

Institutional/IRB Compliance

Assurances of Compliance

Assurances of compliance (referred to as assurances)

were developed in the late 1960s when the NIH Division

of Research Grants was assigned responsibility for implementing the federal requirements for protecting human

research participants. (See Appendix C.) Assurances were

negotiated with each institutional grantee, with the negotiations allowing each institution to create its own policies

and procedures for protection as long as they were fully

consistent with federal regulations. The negotiation process

also allowed federal officials to educate institutions about

requirements and procedures for participant protection.

Because the assurance indicated what an institution

intended to do to protect research participants, it was

essentially a pledge or commitment on behalf of the institution to comply with all appropriate regulations and

guidance.

The National Commission believed that there should

be uniform implementation of the federal regulations 

and recommended that each institution engaged in 

regulated research provide assurance to a single office

that all research would be conducted in accordance 

with federal regulations (National Commission 1978).

This perspective was reinforced by the President’s

Commission, which suggested further steps to ensure

that federal monitoring would be coordinated to minimize the bureaucratic burden imposed on institutions.
Table 3.1: Federal Agency Practices Regarding Assurances of Compliance

Agency Issues Assurances Relies on Other 

of Compliance Agency Assurances

Central Intelligence Agency No No

Department of Commerce

National Telecommunications and Information Administration No No

National Institute of Standards and Technology No Department of Health and 

Human Services (DHHS)

Department of Defense Yes DHHS

Department of Education Yes DHHS

Department of Energy Yes DHHS

Department of Health and Human Services Yes No

Department of Housing and Urban Development No Not reported

Department of Justice Some components DHHS

Department of Transportation No DHHS

Department of Veterans Affairs Yes DHHS

National Aeronautics and Space Administration Yes DHHS

National Science Foundation Yes Yes

Social Security Administration No Yes

Agency for International Development Yes DHHS, Department of Defense

Consumer Product Safety Commission Yes DHHS

Environmental Protection Agency Yes DHHS

Source: NBAC, “Federal Agency Survey of Policies and Procedures for the Protection of Human Subjects in Research.” This staff analysis is available 

in Volume II of this report.

National Bioethics Advisory Commission

51

The President’s Commission argued that both assurances

and on-site evaluations were needed to monitor implementation of the federal regulations and that a single

office should coordinate such procedures for all regulated

research (President’s Commission 1983, 133). A single

office was never created. Instead, each federal department and agency may issue its own assurance, although

many rely on DHHS assurances. (See Table 3.1.)

The assurance process provided a means of identifying

certain problems and correcting them before research

was conducted. However, it provided only a limited indication of how an IRB would actually work. The value of

the recommended site visits was the opportunity to learn

how IRBs were actually functioning and for institutions

to receive feedback on their IRBs’ performance. However,

to rely only on after-the-fact, “for-cause” site visits to

determine whether an IRB met basic regulatory requirements is not the most effective strategy for ensuring 

that research protocols are being reviewed by a properly 

constituted and procedurally sound IRB (President’s

Commission 1983).

Although DHHS and some other departments that

adopted the Common Rule continue to issue assurances,

site visits as envisioned by the President’s Commission

were never implemented. In addition, for the most part,

the negotiation process for assurances developed into a
52

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

routinized and somewhat tedious procedure. Standardized documents that mirror the federal regulations 

substitute for the independently negotiated assurances

specific to the institution’s culture, policy, and procedures. The educational function of assurances was lost.11

Currently, few seem to view assurances as meaningful

commitments or pledges by institutions to sustain a

broad-based program of review and monitoring.12

Instead, they are viewed as unnecessary, additional

bureaucratic paperwork with limited, if any, value in

protecting research participants.13 Additional problems

reported to NBAC were long delays in processing assurances (between 6 and 12 months in some cases), when

the expectation is that OHRP should be able to process

assurances in a much shorter period, confusion about

which institutions required assurances, and OHRP’s

review of consent forms submitted by institutions 

seeking an assurance when the same consent form was

reviewed and approved by another collaborating institution with an MPA. Problems with the assurance process

are not unique to domestic research. In the context of

international research, the assurance process was most

often criticized because it requires foreign institutions to

follow rigidly U.S. requirements and procedures. The need

for greater flexibility by the United States in conducting

international research would allow for procedural variations that are responsive to local culture and practice

while still ensuring compliance with substantive ethical

principles (NBAC 2001).

OHRP revised the assurance process effective

December 2000 and is currently testing the new procedures.14 The revised process entails the use of one

Federalwide Assurance (FWA) document for domestic

institutions and another assurance document for foreign

institutions. Each legally separate institution must obtain

its own FWA, and assurances approved under this

process will cover all the institution’s federally supported

research involving human participants. The domestic

assurance replaces MPAs, Single Project Assurances, and

Cooperative Project Assurances. Individual federal agencies can still choose whether to use the new assurance or

issue their own. The assurance document is similar to

previous assurance documents in content. However,

institutions must meet additional requirements, such as

that certain institutional staff complete OHRP’s computerized educational training. The new assurance process is

intended to reduce burden on institutions by allowing all

institutions to qualify for the one FWA that may be

renewed every three years. The revised process also

includes registration of IRBs, regardless of whether they

review research sponsored or regulated by a federal agency

that follows the Common Rule.15 Modification to the

revised system will be made based upon feedback and

experience during the first few months of implementation.

FDA Site Inspections of IRBs

FDA conducts site inspections under its own 

regulations. In 1976, FDA developed its Bioresearch

Monitoring Program in response to Congress’ instruction

to expand its monitoring activity. The program encompasses monitoring of investigators, sponsors, program

monitors (individuals selected by the sponsor to oversee

the clinical investigation), and IRBs. The purpose of the

Bioresearch Monitoring Program is to ensure the quality

and integrity of data submitted to FDA to “demonstrate

the safety and efficacy of regulated products, and to

determine that human rights and the welfare of human

and animal research subjects are adequately protected”

(FDA 1998a). FDA conducts inspections of sponsors to

determine how they ensure the validity of data submitted

to them by investigators and to determine compliance of

sponsors, contract research organizations, and monitors

with applicable regulations (FDA 1998b). The purpose of

FDA inspections of investigators is to help ensure compliance of investigators with the regulations (including

the regulations to protect research participants) and to

assess through audit procedures whether records substantiate data submitted to FDA (FDA 1998a). These

inspections also include assessment of whether the investigator obtained appropriate IRB approval of research

studies and whether participants have signed consent

forms. However, FDA’s own findings for fiscal year 1998

show that for studies involving medical devices, over 

50 percent of sponsors may not be monitoring trials 

adequately (OIG 2000). Most FDA inspections of investigators are conducted after the trial is complete. Thus,

any detected violations of regulations to protect research

participants are found after the point when participants

in the particular trial could have received adequate 
National Bioethics Advisory Commission

53

protections. However, the inspections are helpful in

improving compliance of investigators and, therefore,

protection of participants in future research. More

recently, FDA’s inspection process has focused more on

real-time complaints.16

FDA conducts surveillance (routine) and directed

(when information “calls into question” regulated practices) inspections of IRBs. Usually IRB inspections are

scheduled every five years, although if there are major

problems, inspections can occur more frequently (FDA

1994). During an inspection, an FDA field investigator

(inspector) chooses a few studies that received initial IRB

review within the past three years and follows them

through the IRB review process. Inspectors look at IRB

policies and procedures; minutes; membership; and

records of studies, including protocol, consent form,

investigator’s brochure, and correspondence between the

IRB and investigator. IRBs that are found to be out of

compliance may be subjected to sanctions ranging from

a warning letter to rejection of the data from the trial to

prosecution (FDA 1994). FDA conducts approximately

300 IRB inspections annually as part of its Bioresearch

Monitoring Program.17

FDA does not require its sponsors to provide assurances of compliance; however the agency does require

investigators to provide a written commitment that,

before initiating an investigation subject to an institutional review requirement under 21 CFR 56, an IRB will

review and approve the investigation in accordance with

21 CFR 56 (21 CFR 312.53(c)(1)(vi)(d); 312.53(c)(1)(vii);

21 CFR 812.43(c)(4)(i)). The sponsor makes similar commitments (21 CFR 312.23(a)(1)(iv); 21 CFR 812.20(b)(6)). 

Other Site Inspections

Some other federal departments also conduct site 

visits. For example, the Department of Energy (DOE)

routinely conducts educational site visits at its contract

facilities. A team of experienced IRB professionals reviews

policies and procedures at individual facilities and makes

recommendations for improving protections tailored to

the operation at the local facility.18 The DOE human 

subjects program manager makes determinations of 

noncompliance. 

The Department of Education authorizes its extramural research director to investigate allegations of

noncompliance. At the National Science Foundation,

allegations of noncompliance are referred to the Office of

Inspector General for investigation. The Department of

Veterans Affairs uses several new mechanisms to monitor

compliance. For example, the Multi-Assessment Program

is a systematic, prospective approach to assist VA medical

center research programs and investigators fulfill their

responsibilities to conduct research so that there is adequate protection of human participants. The VA Office of

Research Compliance and Assurance also uses Special

Inquiry Force Teams to investigate allegations of research

noncompliance, and if warranted, may initiate a

Comprehensive Research Integrity Program review. 

OHRP/OPRR also conducts both educational and

“for-cause” site visits. In 1999, OPRR reported conducting “between zero and one not-for-cause site visits a year”

to monitor IRB and institutional compliance with the 

federal regulations (Foubister 1999). In 1998–1999,

OPRR’s number of “for-cause” site visits increased, along

with suspensions of assurances for several prominent

research institutions (Exhibit 3.1).

Institutional Audits

Institutions and IRBs should regularly review policies

and procedures and monitor their implementation.

Moreover, they should take steps to open their activities

to greater public review and accountability. In a previous

report, NBAC suggested that IRBs should make descriptions of their policies and procedures public and provide

annual summary statistics regarding the nature and scope

of the research approved. NBAC also suggested that institutions adopt internal audit procedures to assure themselves that their IRBs are following regulations (NBAC

1998). Institutions can also assume greater responsibility

in ensuring that investigators comply with regulations

and carry out protocols as approved by the IRB, as 

discussed below.

Assurances of compliance, site inspections, and institutional audits are all potentially useful mechanisms for

improving institutional and IRB compliance. No one

mechanism used in isolation of the others will be 

sufficient to monitor compliance. As certification and

accreditation programs become more widespread, the

utility of assurances and site inspections should be 

examined in order to avoid duplication of effort.
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Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

Exhibit 3.1: OPRR Compliance Oversight Investigations Resulting in Restrictions/Actions

to MPAs, January 1990–June 2000

Year Institution and Action by OPRR

1990 Massachusetts Eye and Ear Infirmary. Certain research was excluded under the existing MPA pending

negotiation of a renewed MPA. New participant accruals were suspended pending re-review by appropriately

convened IRB and notification of former participants about inadequate informed consent.

1991 NIH. Certain collaborative research was excluded under the existing MPA. Designation of a signatory official

with authority to ensure institutional human participant protections, modification of institutional policies and

procedures to ensure IRB review of all human participant research, and development of an education 

program were required.

University of California - San Francisco. New participant accruals in all pediatric oncology research were

suspended pending modification of informed consent documents and revised consent for all current pediatric

oncology participants, and mechanisms to ensure regulatory compliance in such research were required.

1992 State University of New York College of Optometry. Use of expedited IRB review procedures was 

suspended. Suspension of human participant involvement in certain research, re-review of research by an

appropriately convened IRB, modification of IRB review and record keeping procedures, and designation of

a signatory official with authority to ensure institutional human participant protections were required.

Florida State University. Use of expedited IRB review procedures was suspended. Re-review of research

by an appropriately convened IRB, modification of IRB review, and record keeping procedures were required.

1993 NIH. Progress reports on implementation of education program were required.

1994 University of California - Los Angeles. Schizophrenia research was excluded under the existing MPA.

Modification of informed consent documents, information materials, and record keeping for schizophrenia

research, the addition of participant representatives to the IRB, and the establishment of a Data and Safety

Monitoring Board for psychiatric disorders research were required.

West Virginia University. Special monitoring of urology department research and modification of IRB review

and record keeping procedures were required.

Memorial-Sloan Kettering Cancer Center. Special monitoring of melanoma immunization research, 

modification of IRB review and record keeping procedures, verification of completeness of informed consent

documents, development of handbook of guidelines for investigators, and designation of a signatory official

with authority to ensure institutional human participant protections were required.

Medical University of South Carolina. Review of research by appropriately convened IRB, modification 

of institutional mechanisms to ensure IRB review of human participant research, and development of an 

education program were required.

University of California - San Diego. Human participant involvement in certain research was suspended,

and re-review of research by an appropriately convened IRB, modification of IRB review and record keeping

procedures, and designation of a signatory official with authority to ensure institutional human participant 

protections were required.

University of Florida. Use of expedited IRB review procedures was suspended. Re-review of research by

an appropriately convened IRB, modification of IRB review and record keeping procedures, and revision of

IRB guidelines for investigators were required.

University of Minnesota. Research conducted by the Department of Surgery was excluded under the existing MPA, and human participant involvement in certain research was suspended. Re-review of research by

an appropriately convened IRB, modification of IRB review, and record keeping procedures were required.
National Bioethics Advisory Commission

55

Exhibit 3.1 continued

1995 University of Virginia. Behavioral and educational research were excluded under the existing MPA, and

human participant involvement in behavioral and educational research and certain medical sciences

research was suspended. Re-review of research by appropriately convened IRBs, modification of IRB review

and record keeping procedures, provision of an enhanced educational program and materials, review of staff

support and resources for IRBs, designation of a signatory official with authority to ensure institutional human

participant protections, and comprehensive review of IRB policies and procedures were required.

Centers for Disease Control and Prevention. Provision of updated information to measles research participants, development of conflict of interest guidelines for IRB members, review of staff support and resources

for IRBs, development of an educational program, a proposal for a mechanism to ensure performance site

assurances for international research, and a comprehensive review of IRB policies and procedures were

required.

University of California - Los Angeles. Development of an educational program, revised IRB guidelines

for investigators and the procedures manual, review of staff support and resources for IRBs, provision of a

locked filing system and computerized tracking system to ensure confidentiality of IRB records, and development of mechanisms to ensure that all human participant research receives IRB review were required.

Center for Molecular Medicine and Immunology. Modification of IRB review and record keeping 

procedures were required.

Veterans Affairs Medical Center, West Los Angeles. Modification of IRB review and record keeping 

procedures were required.

1996 Cook County Hospital Hektoen Institute for Medical Research. Participant enrollment in research not

receiving valid initial or continuing IRB review and use of expedited review procedures were suspended.

Revision of IRB review procedures was required.

Cornell University Medical Center. Enrollment in research not receiving adequate initial or continuing IRB

review was suspended. Modification of IRB review and record keeping procedures, a plan for increased

staffing, a plan for education of IRB members and investigators, and a mechanism for investigation of noncompliance were required.

University of Rochester. Enrollment in research not receiving appropriate initial or continuing IRB was 

suspended. Review and development of written operating procedures and an investigator handbook, a finalized organization structure of institutional human participant protections, and development of an education

program for IRB members and investigators were required.

Wayne State University. Enrollment in research not receiving appropriate initial or continuing IRB review

was suspended. Increased staffing and resources for the IRB, development of a mechanism for prompt

review of adverse event reports, development of an educational program for IRB members and investigators,

and review and revision of IRB policies and procedures were required.

1997 City University of New York. Development of an educational program for IRB members and investigators,

review and revision of IRB policies and procedures, revision of sample informed consent documents to 

comply with DHHS regulations, and revision of IRB record keeping procedures were required.

1998 University of Maryland - Baltimore. Enrollment of participants in research not receiving appropriate initial

or continuing IRB review was suspended. Review and revision of informed consent documents for psychiatric research to ensure compliance with DHHS regulations, development of an educational program for IRB

members and investigators, and revision of IRB review procedures, including procedures for research involving vulnerable participant populations, were required.

University of California - Irvine. Modification of initial review process to ensure compliance with regulations, revision of continuing review and oversight procedures, increased documentation of IRB actions in

accordance with regulations, enhanced education for investigators, IRB members, and staff, and increased

support for social and behavioral sciences IRB were required.

Western Carolina Center. Due to limited DHHS support to the Western Carolina Center, Single Project

Assurances (SPAs) were required for DHHS-supported human participant research, and the MPA was 

deactivated on October 30, 1998.
Exhibit 3.1 continued

Rush Presbyterian St. Lukes Medical Center. OPRR suspended the MPA for five days pending development of adequate corrective action plans. The MPA was subsequently reinstated with restrictions. OPRR

required correction of 17 identified deficiencies in systemic human participant protections, restructuring of

systemic human participant protections including changes in leadership, enhanced institutional commitment,

and expanded IRB membership, development of an education program for IRB members, IRB staff, and

research investigators, suspension of new enrollments in all federally supported research pending review of

all such protocols by the reconstituted, convened IRB, and suspension of IRB review of federally supported

research by expedited review procedures.

Scripps Clinic and Research Foundation:The Scripps Research Institute. OPRR required correction of

20 identified deficiencies in systemic human participant protections, re-review of all DHHS-supported human

participant protocols to include review of complete grant application, development of an educational program

for IRB members, IRB staff, and research investigators, and quarterly progress reports.

Duke University. OPRR restricted the MPA and required several corrective actions. 

Duke University Medical Center. OPRR restricted the Duke University Medical Center MPA and required

several corrective actions.

1999 Friends Research Institute. OPRR removed from coverage under the existing MPA any performance sites

outside the Maryland area, removed recognition of one IRB under the MPA, and withdrew approval of all

inter-institutional and cooperative amendments to the MPA.

Mt. Sinai School Of Medicine. OPRR restricted the MPA and required satisfactory implementation of a

series of corrective action plans.

Veterans Affairs, Greater Los Angeles Health Care System (Formerly Veterans Affairs Medical

Center,West Los Angeles). OPRR deactivated the MPA on March 22, 1999. Enrollment of new participants

in all federally supported research was suspended, and involvement of previously enrolled participants was

allowed only when it was in the best interest of the participant.

Fordham University. Due to the limited number of DHHS-supported projects at Fordham University and 

persistent concerns about compliance with human participant protections requirements, SPAs were required

for all DHHS-supported human participant research, and the MPA was deactivated on May 31, 1999.

Duke University Medical Center. OPRR suspended the MPA for five days. OPRR reinstated the Duke

University Medical Center MPA with restrictions and required several corrective actions, including re-review

of DHHS-supported research by the IRB, implementation of a second IRB, and implementation of appropriate

education programs for IRB members, IRB staff, and all investigators.

University of Illinois at Chicago. OPRR restricted the MPA and required corrective actions in response to

29 identified deficiencies, including revision of the MPA to indicate enhanced institutional commitment to the

protection of human participants and development of an educational program for IRB members, IRB staff,

and research investigators. New enrollments in all federally supported research pending re-review of all such 

protocols were suspended.

St. Jude Children’s Research Hospital. OPRR restricted the MPA and required submission of a progress

report describing implementation of all corrective actions three months after the site visit. 

Virginia Commonwealth University. OPRR restricted the MPA and required corrective actions, including

development of an educational program for IRB members, IRB staff, and research investigators and submission of a list of all active IRB-approved protocols. New participant enrollments in all federally supported

research pending re-review of all such protocols were suspended.

2000 Virginia Commonwealth University. OPRR suspended the MPA and required revised corrective action

plans, including designation of a new signatory official and new IRB chairpersons.

University of Alabama at Birmingham. OPRR restricted the MPA and required suspension of new participant enrollments in all federally supported research that had not had appropriate initial or continuing review.

Submission of corrective action plans to address all deficiencies and concerns related to systemic human

participant protections and submission of an educational plan for all IRB members, all IRB staff, and all

research investigators were required.

Adapted from Compliance Oversight Investigations Resulting in Restrictions/Actions to Multiple Project Assurances, 1/90–11/99 (OPRR 2000).

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Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation
National Bioethics Advisory Commission

57

Monitoring Investigator Compliance with 

IRB-Approved Protocols: Verification

Institutional monitoring to verify that investigators

are following IRB-approved protocols is an important

means of determining whether investigators are actively

meeting their ethical obligations to protect research 

participants while a study is in progress. Such verification

should include activities such as observing research,

especially the enrollment of participants, auditing research

records, and establishing clear procedures for receiving

complaints or concerns from participants or staff.

Some argue that as collegial review bodies, IRBs

should not question the information provided by investigators.19 On the other hand, others have argued that IRBs

should develop mechanisms for continuing review of

research that include verification of the investigator’s 

conduct of the study (Weijer et al. 1995). There are cases

in which investigators’ deviations from IRB-approved

protocols have affected participant protections (OIG

1995). In one instance, a case of financial fraud by two

clinical investigators may also have affected the welfare of

research participants (Teegardin and Whitt 1997).

Failure to follow IRB-approved protocols may not be 

limited to serious abuses. One recent survey of clinical

research professionals found that as many as 40 percent

had encountered cases of questionable consent, and

many had encountered cases of inappropriate alteration

of study eligibility criteria, alteration of care provided to

participants, and breach of confidentiality (Shefrin and

Harper 2000). 

IRB review alone does not address these types of

problems. Although IRBs are not and should not be the

research police, protecting participants will sometimes

require IRBs to verify at least on a sample basis the 

conduct of approved research studies. IRBs are not fully

meeting their responsibilities when they make detailed

changes to the language in a consent form, for example,

but have no way to verify how the consent form is 

discussed with participants.

Under current regulations, IRBs have the authority “to

observe or have a third party observe the consent process

and the research” (45 CFR 46.109(e); 21 CFR 56.109(f)

[FDA regulations differ in reference to regulation]), and

institutions are required to have procedures for reporting

on “serious or continuing noncompliance with this 

policy or the requirements or determinations of the IRB”

(45 CFR 46.103(b)(5); 21 CFR 56.108(b)(2) [FDA regulations differ in reference to regulation]). Few IRBs carry

out this type of monitoring, because they do not have

sufficient resources.20

The desire for such verification is not new. In its

report on IRBs, the National Commission intended for

IRBs to observe investigators and hear directly from

research participants: “At the discretion of the IRB, the

consent process or the research itself may be observed on

a sample or routine basis, subjects may be interviewed

about their experience in research, and research records

(including consent forms) may be reviewed. Also at the

discretion of the IRB, investigators may be required to

provide subjects with a form on which they can report to

the IRB their experiences in research...” (National

Commission 1978, 17). Moreover, noting the difficulty of

such observation, the National Commission made it clear

that these processes were not supererogatory on the part

of IRBs; for at least some research studies, observing the

conduct of research to ensure the protection of the

research participants was an “obligation” (National

Commission 1978, 18).

More recently, the DHHS Office of Inspector General

(OIG) criticized IRBs’ “minimal field presence...[for] as a

result, IRBs typically have little basis to know for themselves how research teams approach the informed consent process, how well human subjects understand the

implications of their participation in research, and how

fully teams remain true to the research design set forth in

their approved protocols” (OIG 1998b, 8). Nevertheless,

there are cases in which IRBs have developed systems for

monitoring compliance. For example, one IRB hired an

intermediary—a person who observes the consent

process in psychiatric research studies. Another IRB randomly selects studies from a list of approved high-risk

research and audits research records, concentrating,

however, primarily on consent forms.21

The President’s Commission also noted the need for

verification and the difficulty it can present for IRBs. It

suggested that institutions, rather than IRBs, develop

mechanisms for receiving complaints and conducting

investigations. As articulated by the President’s
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Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

Commission, “the duty ought to be that of the institution

itself...but need not necessarily be lodged with the IRB”

(President’s Commission 1981, 80). Institutions could

choose to delegate these functions to an IRB or to an

entity other than the IRB. The results of all investigations,

however, should be reported to the IRB.

Another advantage to having someone other than the

IRB monitor investigator compliance is that investigators

may be reluctant to ask informal questions of the IRB if

there is a chance that a question may trigger closer monitoring of a research study. Likewise, IRBs also hesitate to

seek advice from OHRP/OPRR on difficult cases, because

such an inquiry might trigger an investigation.22

Assessing compliance of investigators is an important

part of protecting research participants and should be

taken seriously as a responsibility of each institution.

Although a number of practical issues arise in monitoring

investigators while they conduct their research studies,

investigators, IRBs, and institutions should discuss these

issues and provide input into the regulatory process. 

Recommendation 3.5: The process for assuring

compliance with federal policy should be 

modified to reduce any unnecessary burden on

institutions conducting research and to register

institutions and Institutional Review Boards with

the federal government. The assurance process

should not be duplicative of accreditation programs for institutions (see Recommendation 3.4). 

Recommendation 3.6: Institutions should develop

internal mechanisms to ensure Institutional

Review Board compliance and investigator 

compliance with regulations, guidance, and 

institutional procedures. Mechanisms should be

put in place for reporting noncompliance to all

relevant parties.

Conflicts of Interest

Conflicts of Interest Involving Investigators

A research setting that involves human participants necessarily creates a conflict of interest for investigators who

seek to develop or revise knowledge by using individuals

to obtain that knowledge. In the words of the National

Commission: 

The Commission’s deliberations begin with the 

premise that investigators should not have sole

responsibility for determining whether research

involving human subjects fulfills ethical standards.

Others, who are independent of the research, must

share this responsibility, because investigators are

always in positions of potential conflict by virtue of

their concern with the pursuit of knowledge as well

as the welfare of the human subjects of their research

(National Commission 1978, 1).

Overzealous pursuit of scientific results could lead to

harm if, for example, investigators design research studies

that pose unacceptable risks to participants, enroll participants who should not be enrolled, or continue studies

even when results suggest they should have been modified

or stopped. In addition, decisions about study design,

inclusion criteria, and adverse events require judgment

and discretion on the part of the investigators, who can be

influenced, consciously or unconsciously, by conflicting

interests. Thus, it is important to address prospectively

the potentially harmful effects on participants that conflicts

of interest might cause (Emanuel and Steiner 1995; 

Lo 2000). 

IRB review of research studies is one method for identifying and dealing with conflicts of interest that might

face investigators. By having IRBs review research studies

prospectively and following an IRB-approved protocol,

investigators and IRBs together can manage conflict

between the investigators’ desire to advance scientific

knowledge and the need to protect the rights and welfare

of research participants. IRBs should, for example, determine whether investigators are being paid for enrolling

participants in a research study or whether they or their

family members have a proprietary interest in the outcome

of the research. Steps to strengthen the IRB oversight system should reduce the probability that investigators’ conflicts of interest will cause harm to research participants.

It is worth exploring the problems that result when

successful research creates benefits, such as prestige,

power, and profit, for those who conduct the research

studies. Although conflicting interests associated with

obtaining promotion and tenure have always been present

for academic investigators, recent changes in the research

enterprise increasingly have created opportunities for
National Bioethics Advisory Commission

59

investigators and institutions to profit financially from

research (Steiner 1996). Investigators’ financial conflicts

of interest include capitated payments or bonuses for

enrolling participants, indirect payments through consultantships or honoraria, and equity holdings in companies

or royalties from patents whose value may be affected by

the research. Institutions’ conflicts of interest also include

equity holdings in companies and the economic benefits

of patents they hold. 

As a result, concern is growing that financial conflicts

of interest may compromise scientific objectivity and the

welfare of research participants, ultimately leading to

decreased public trust in the research enterprise

(Bodenheimer 2000; Shalala 2000). The factors contributing to these financial conflicts (e.g., erosion of the

academic medical center’s revenue base, encouragement

by government to transfer technology into the marketplace, and industry’s increasing financial support of

research) are unlikely to wane. In fact, these pressures on

investigators and institutions are likely to increase.

On the surface, financial conflicts are tangible and

extraneous and therefore might be more easily managed

or eliminated than some other conflicts (Angell 2000a;

Angell 2000b). However, simply prohibiting financial

conflicts may not be feasible in an environment in which

private funding of research and new strategies for transferring technology to the marketplace are being encouraged (Emanuel and Steiner 1995; Korn 2000). Thus,

managing financial conflicts of interest will remain an

important part of preserving the public’s trust in research.

IRB review alone, however, is not sufficient to manage

financial conflicts, because the options available to IRBs

to eliminate such conflicts are limited. IRBs can disapprove a research study in which the financial conflicts of

interest of the investigator are perceived to be too high,

or IRBs can require that study design or methods be

altered, but they cannot dictate directly the conduct of

investigators concerning their financial interests.

Moreover, although financial conflicts of interest raise

concerns about bias and the reliability of research results

(Bodenheimer 2000), attention to these concerns should

not rest solely on IRB review. Thus, the responsibility for

the review of investigators’ conflicts should also lie with

sponsors and institutions.

Some have proposed disclosure of conflicts of interest

to institutions (AAMC 1990; AMA 2000), IRBs (DeRenzo

2000), and participants (Cohen 2000) and subsequent

management of these disclosed interests as a mechanism

for dealing with financial conflicts (AAMC 1990).

Although disclosure might encourage investigators to

think carefully before agreeing to arrangements that pose

conflicts or might provide others, such as institutional

officials, an opportunity to assess the risks and potential

benefits of financial arrangements (Blumenthal 1992), it

is not a complete solution (Lo 2000; Thompson 1993).

Organizations, particularly academic institutions,

should become more actively involved in managing

investigators’ financial conflicts and should increase their

self-regulation efforts in this area. Several recently published articles indicate that policies governing conflicts of

interest at major academic research institutions vary

widely and often lack basic safeguards, such as providing

clear guidance regarding the types of relationships that

are prohibited (Cho et al. 2000; Lo et al. 2000; McCrary

et al. 2000). Federal regulations already require recipients

of certain federal funds to establish policies for disclosure,

reduction, management, and elimination of financial

conflicts of interest (42 CFR 50.601–50.607). As a first

step, the regulations and the institutional policies

responding to them could be improved (Cho et al. 2000;

Cohen 2000). FDA also requires financial disclosure 

by investigators as part of its review of marketing applications (21 CFR 54).

Some financial conflicts may be inappropriate regardless of the amount of oversight provided either by the

institution or the IRB. For example, certain per-capita

bonuses are designed solely to provide an incentive to

recruit participants; when such payments are excessive

they serve only to provide an inappropriately strong

incentive to investigators or referring physicians (Lind

1990; Wolf and Lo 2000). Or, in a clinical trial, it might

be unacceptable for investigators to own stock or options

in the company manufacturing the product being tested,

because their remuneration might be greatly influenced

by whether the trial results are favorable or unfavorable

(Healy et al. 1989; Lo et al. 2000; Topol et al. 1992). The

concern would be greatest in a start-up company that has

not yet made a public offering. However, the lack of 
60

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

guidance and policy makes it difficult for individual institutions to set strict standards, especially ones that include

the prohibition of certain types of financial relationships.

Institutions should work with professional societies and

sponsors to clarify types of conflicts and develop mechanisms for managing such conflicts through education and

oversight.

IRBs should be aware of investigators’ financial

arrangements with respect to research under review

(DeRenzo 2000). Most academic medical centers, however, require investigators to disclose financial conflicts of

interest to a university official or to a committee, but not

to the IRB (Lo et al. 2000; McCrary et al. 2000).

Payments to the investigator should not, for example,

affect an IRB’s evaluation of the risks and potential 

benefits of a research study or the equitable selection of 

participants. Rather, the presence of financial conflicts of

interest might affect an IRB’s assessment of the protocol

in its entirety and whether the research should be

approved, or it might affect its assessment with respect to

the amount or type of monitoring needed (AAMC 1990;

Gottlieb 2000).

One area in which an IRB must be involved is determining what information about financial conflicts of

interest should be shared with research participants as

part of the informed consent process. Recently, the

Association of American Medical Colleges added its support to the policy of disclosing of investigators’ financial

conflicts to research participants (Cohen 2000). A number

of concerns surround the issue of disclosure, primarily

related to the privacy of investigators and the relevance

and understandability of the information to participants.

Participants clearly need to understand the nature of the

research study in which they are participating, including

who is likely to benefit from it. Such information may be

relevant to an individual who is deciding whether to 

participate in a research project.23 However, disclosure to

participants should not serve as a substitute for the institutional management of conflicts of interest. Disclosure,

although necessary, is not sufficient for managing and

resolving these issues.

Conflicts of Interest Involving IRBs

Independent review is the primary mechanism for

managing conflicts of interest in research, and assuring

the independence of IRBs has been a matter of concern

since their inception. The federal regulations require two

types of independence for IRBs. First, no IRB member

should participate in the review of “any project in which

the member has a conflicting interest” (45 CFR

46.107(e); 21 CFR 56.107(e)). Second, to prevent the

IRB from representing solely an institutional viewpoint,

at least one IRB member must be unaffiliated with the

institution (45 CFR 46.107(d); 21 CFR 56.107(d)).

These two types of independence specified in the federal

regulations reflect concerns about the personal conflicts

of individual IRB members and the conflicts an IRB may

have as part of the institution.

Individual IRB Members

Conflicts of interest for individual IRB members are

currently addressed in the federal regulations by a

requirement that “no IRB may have a member participate

in the IRB’s initial or continuing review of any project in

which the member has a conflicting interest, except to

provide information requested by the IRB” (45 CFR

46.107(e); 21 CFR 56.107(e)). The most obvious case of

conflict would occur when an IRB member reviews a protocol for which he or she is an investigator. However, the

regulations are often interpreted to include conflicts that

involve finances, collaborations, or even personal relations. NBAC supports this more inclusive interpretation.

Financial and other obvious conflicts of interest for

IRB members, such as collaboration in a research study,

are often less difficult to identify and manage than some

of the more subtle and pervasive conflicts (Francis 1996).

Subtle conflicts are often not detected. For example, IRB

members may have intellectual or practical commitments

related to a research study with which they are not

directly involved. IRB members may also have professional or personal connections to the investigators whose

research they review. Although familiarity with the

research was an intended part of the IRB system, it can

also cause IRBs to become enmeshed in institutional,

interdepartment, or interpersonal interests. Thus, a

trade-off might occur on IRBs between the level of
National Bioethics Advisory Commission

61

expertise of its members and their independence. In

some cases, IRB members may fear that an unfavorable

review might result in personal repercussions. Many IRBs

try to keep board discussions confidential in order to

protect individual members, but some IRB members

have expressed discomfort in reviewing the work of

direct supervisors, for example.

Resolving these tensions is not always easy. In cases of

clear, strong conflict (e.g., an IRB member’s participation

in a research study as an investigator), the member with

the conflict can recuse him or herself from the review.

However, in cases of weaker conflict (e.g., close working

relationship with the investigator; particular academic or

other commitments, but no actual involvement in the

study), disclosure of potential biases to the IRB should be

required and should be sufficient. The IRB should be

confident that each member voting on a specific protocol

provides a knowledgeable, independent assessment of the

research under review.

Guidance should be developed to assist IRBs in identifying various types of conflict. In addition, IRBs can

reduce conflicts that employees of the institution may

have by increasing the number of members who are not

otherwise affiliated with the institution and the number

of members who are nonscientists and are more likely to

represent the views of the prospective participants rather

than the investigators.

The IRB as an Institutional Body

IRBs are institutional entities (Annas 1991), a feature

that was intended to reflect an institution’s commitment

to safe, ethically sound research. An institution designates an IRB and gives it authority to review research,

although the institution retains the power to disapprove

research that has been approved by an IRB (45 CFR

46.112; 21 CFR 56.112). This structure applies even

when an institution relies on an independent IRB or an

IRB at another institution. The IRB’s authority still derives

from the institution that has delegated the power of

review. Because most institutions have an understandable

desire to increase their research activities, institutional

IRBs may, themselves, face conflicts of interest. And, even

independent IRBs have a strong incentive to consider 

the interests of their institutional contractors. As Leslie

Francis notes: “Consistently unfriendly reviews might 

be thought to threaten ongoing relationships between

IRBs and the institution [sic] with which they contract”

(Francis 1996, 424).

Some have suggested that the primary function of

IRBs has shifted from protecting the participant to protecting the institution (Annas 1991). In general, institutional interests in protecting themselves from liability,

bad publicity, and regulatory sanctions are consistent

with an interest in the protection of research participants.

However, institutions can have other interests that conflict

with the goal of participant protection, and such conflicts

might increase when institutions hold equity in companies

whose products are tested in research by their investigators or when they have patent licensing arrangements

whose value may be affected by specific studies.

Institutions therefore aim to maintain a research-friendly

environment. Institutions can reduce such conflicts by

divesting questionable holdings, by not conducting

research that may affect those investments, or by conducting research that affects those investments only as

part of a multi-site trial or with external monitoring

(Emanuel and Steiner 1995). However, the primary 

strategy for limiting the influence of inappropriate institutional interests on IRBs is to impose requirements on

IRB membership. For an IRB, being research friendly can

mean not only being efficient in handling paperwork, but

also being less stringent in its review than it should be.

An IRB that disapproves protocols, that often requires 

significant modifications, that requires investigators to provide frequent and detailed information on research studies

in progress, or that conducts frequent continuing review

might be perceived as overly intrusive or bothersome.

The involvement of particular institutional staff on

IRBs has also been questioned. Recently, OHRP suspended

assurances at some institutions where institutional grants

and contracts officials served as IRB members. OHRP

argued that staff responsible for bringing research funds

into an institution have a fundamental conflict of interest

when they serve on the IRB (OHRP 2000). Such strategies

challenge the balance between functioning independently and having members who are able to provide relevant information about investigators or their research.

Institutional counsel is another example of a potential
62

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

source of conflict. An institution’s attorney is generally

concerned with protecting the institution from liability

and might require that certain language be included in

the consent form to protect the institution, even though

the language might not be understandable to prospective

participants.

IRB membership is one mechanism for reducing institutional conflicts of interest. Current federal regulations

require that each IRB have “at least one member who is

not otherwise affiliated with the institution and who is not

part of the immediate family of a person who is affiliated

with the institution” (45 CFR 46.107(d); 21 CFR 56.107(d)).

Interpreting the definition of not otherwise affiliated

literally can result in only a small degree of separation

between the individual and the institution. For example,

ex-employees are sometimes chosen to serve as the 

unaffiliated member. Moreover, unaffiliated is often interpreted as “representing the community or participants,”

which is incorrect, because unaffiliated members can be

scientists; other professionals, such as lawyers, business

people, or clergy; or individuals who represent participants. The only characteristic that unaffiliated members

share other than participating on the IRB is lack of ties to

the institution.

Concerns have been raised regarding whether having

only one unaffiliated member on an IRB is sufficient to

avoid institutional influence, especially when IRBs have

15 to 21 members on average.24 One or two “outsiders”

might hesitate to mention concerns or challenge the

group (McNeill 1993), and unaffiliated members do not

need to be present in order for the IRB to conduct review

and approve research studies.25 Thus, IRBs can approve

research with only institutional representation present as

long as a nonscientist and a quorum are also present.

Others have proposed requiring the presence and

participation of more unaffiliated IRB members to reduce

the influence of institutional interests on IRB decisionmaking (OIG 1998a). However, finding appropriate

unaffiliated members who are willing to serve on an IRB

can be difficult. Paying unaffiliated members for their

efforts, as originally proposed by the National

Commission (National Commission 1978, 15) might

improve the yield, but excessive compensation could call

their independence into question. Currently, no rules or

guidance are available describing criteria to meet the definition of unaffiliated, how long such members should

serve, under what circumstances they may be removed,

or what payment they should be provided. Institutions

should be careful to select unaffiliated members who are

truly separated from the institution, except for their role

on the IRB. Procedures for the selection and removal of

unaffiliated members should be established in a way that

empowers the independent voices of those members, and

providing reasonable payment to IRB members who 

are otherwise unaffiliated with the institution can be a 

valuable way to strengthen their role.

Another strategy for reducing institutional influence

on an IRB is to use a noninstitutional IRB. These IRBs

review research studies for a number of institutions and

are, therefore, presumed to be less likely to be influenced

by any one institution. It is claimed that one of the

advantages of this system is the almost complete elimination of influence by individual institutional interests.26

However, others have argued that paying IRBs for review

of research, as the United States does when noninstitutional (independent) IRBs are used, constitutes a conflict

of interest.27

It appears that neither system of review—institutionally

based IRBs or fee-for-service independent IRBs—is free

from all real or perceived conflicts of interests. However,

it does seem that institutionally based IRBs can reduce

conflicts of interest by including more members who are

not affiliated with the institution. Independent IRBs, like

institutions, can also reduce conflicts by separating

business functions from review functions and by using

agreements that clearly describe what is covered by the

fee (i.e., the fee is for review only and clearly does not

guarantee approval).

Another way to limit the influence of an institution’s

research interests on an IRB is to ensure that the views of

both scientists and nonscientists are considered. Current

regulations require that each IRB include “at least one

member whose primary concerns are in scientific areas

and at least one member whose primary concerns are in

non-scientific areas.” A scientist is defined by OHRP as a

person who has “substantive training or experience in a

scientific discipline or in the scientific method.”28 Thus,

physicians, nurses, or individuals trained at the bachelor’s,
National Bioethics Advisory Commission

63

master’s, or doctoral level in the basic sciences or social

sciences are all considered scientists. Unlike the requirement for unaffiliated members, at least one nonscientist

must be present for an IRB to review research (45 CFR

46.107(c); 21 CFR 56.107(c)). 

As with unaffiliated members, it is sometimes

assumed that nonscientist members represent the views of

the participants. However, nonscientists might or might

not be members from the community of participants.

Professionals who are nonscientists might be no more

able to represent the view of low-income or seriously ill

participants, for example, than scientists.

From an ethical perspective, balancing the views of

scientists and nonscientists is important, because

although IRBs must be technically competent to identify

and quantify the risks and potential benefits of a protocol, they must also be able to put those risks and benefits

into a social context in order to judge how ordinary citizens would value them. This kind of assessment requires

the input of nonscientists because “experts have a unique

commitment to research that favours the interests of 

science” (McNeill 1993, 184). This is not to suggest that

scientists and nonscientists have different roles on an

IRB, although nonscientists often do tend to focus on the

adequacy of consent documents (Porter 1987). It is

important to remember that all IRB members should

evaluate protocols according to established ethical principles and the federal regulations. It is also important to

remember that they cannot avoid doing so from different

perspectives and with different emphases.

The current IRB system requires that unaffiliated and

nonscientist members serve on these groups. Although

each brings valuable experience, knowledge, and insight

to the IRB, neither may reflect the views of the research

participants. For this reason, IRBs should include members who are specifically chosen because they represent

participants’ interests.

IRBs should strive to complement their membership

with members who are clearly unaffiliated with the institutions, members who are nonscientists, and members

who represent the perspectives of participants. Federal

policy should specify membership and quorum requirements for each of these categories. Individuals who meet

the membership criteria in more than one of these three

categories should be able to fulfill the requirements for

each. For example, a member of the clergy can fulfill both

the nonscientist and unaffiliated membership requirements. NBAC recommends that an IRB have collectively

at least 25 percent of its membership comprised of individuals representing these three categories.

Other IRB Composition Issues

Scientific or discipline expertise on an IRB is clearly

needed to judge the risks and potential benefits of the

research protocols it reviews. However, scientific expertise

is to a large extent discipline specific, meaning that it is

essential that at least some IRB members have expertise

and experience that is directly related to the research

being reviewed. Indeed, federal regulations require that

IRBs possess “the professional competence necessary to

review specific research activities” (45 CFR 46.107; 

21 CFR 56.107). NBAC heard repeatedly from investigators conducting research in the social sciences and

humanities that IRBs with primarily medical expertise

sometimes impose unreasonable, and even irrational,

requirements that are inappropriate for nonbiomedical

research (AAUP 2000). Although ethical principles for

review should be consistent for all research, factors such

as standards for research design, participants’ expectations of privacy and confidentiality, and the appropriate

consent processes to be used can, and often should, vary

by type of research. Appropriate expertise and experience

are essential both for the protection of participants and

the promotion of ethical research. 

At the same time, however, IRBs are intended to be

interdisciplinary and may not “consist entirely of members of one profession” (45 CFR 46.107(b); 21 CFR

56.107(b)). Thus, an appropriate balance must be found,

which for large institutions might mean multiple IRBs

with specific areas of expertise and which for smaller

institutions might mean one IRB with a varied membership and a roster of consultants. In either case, institutions should have discretion in determining the most

appropriate arrangement.
64

Chapter 3: Methods for Ensuring Protection: Education, Certification, and Accreditation

Recommendation 3.7: Federal policy should define

institutional, Institutional Review Board, and

investigator conflicts of interest, and guidance

should be issued to ensure that the rights and

welfare of research participants are protected. 

Recommendation 3.8: Sponsors and institutions

should develop policies and mechanisms to 

identify and manage all types of institutional,

Institutional Review Board, and investigator 

conflicts of interest. In particular, all relevant

conflicts of interest should be disclosed to 

participants. Policies also should describe 

specific types of prohibited relationships. 

Recommendation 3.9: Federal policy should 

establish standards and criteria for the selection

of Institutional Review Board members. The 

distribution of Institutional Review Board 

members with relevant expertise and experience

should be commensurate with the types of

research reviewed by the Institutional Review

Board (see Recommendation 3.10). 

Recommendation 3.10: Institutional Review 

Boards should include members who represent

the perspectives of participants, members who

are unaffiliated with the institution, and members whose primary concerns are in nonscientific

areas. An individual can fulfill one, two, or all

three of these categories. For the purposes of

both overall membership and quorum determinations 1) these persons should collectively

represent at least 25 percent of the Institutional

Review Board membership and 2) members from

all of these categories should be represented 

each time an Institutional Review Board meets

(see Recommendation 3.9). 

Summary

This chapter discussed the important role that education

plays in protecting research participants. Individuals

should be able to demonstrate that they understand their

ethical obligations and how to carry them out. To help

investigators and IRBs fulfill their responsibilities, the

federal government should promote the development of

education and certification programs that apply to all

investigators as well as all IRB members and staff.

Institutions and independent IRBs must do a better

job of meeting their ethical obligations to research participants. Accreditation programs are one way in which all

organizations involved in conducting or reviewing

research can develop highly efficient and effective protection programs.

A key protection is that of ensuring institutional, IRB,

and investigator compliance. At all levels in the system,

various mechanisms, including assurances of compliance,

site inspections, and internal audits, should be used.

Regular periodical monitoring of compliance is the most

likely way to detect and remedy problems.

Institutions and IRBs increasingly are confronting

conflicts of interest as more investigators and institutions

enter into financial arrangements in which they stand to

benefit from the results of their research. Conflicts of

interest are not new, but they have changed and intensified

as the research enterprise has evolved. Disclosure and

management of investigator and institution conflicts still

seem to be the best strategies. Conflicts affecting the IRB

can be handled by increasing the percentage of members

who do not have any direct interests in the institution or

its research program (unaffiliated members). Increasing

the percentage of nonscientists and members who represent the views of participants can also reduce conflicts.

Ultimately, clear policies and guidance will provide the

best way for IRBs to fulfill their responsibilities and meet

their obligations in educating their members, monitoring

for compliance, and avoiding conflicts of interest. 

Notes

1 NIH Guide for Grants and Contracts, “Short Term Courses in

Research Ethics.” PA-99-051. January 22, 1999; NIH Guide for

Grants and Contracts, “Mentored Scientist Development Award 

in Research Ethics.” PAR-98-006. November 7, 1997. Both 

available at http://grants.nih.gov/grants/guide. Last accessed

December 4, 2000.

2 PRIM&R, “IRB 101 On the Road.” Available at http://www.primr.org/

101road.html. Last accessed December 4, 2000.

3 NIH Guide for Grants and Contracts, “Required Education in the

Protection of Human Research Participants.” Notice OD-00-039.

June 5, 2000. Available at http://grants.nih.gov/grants/guide. 

Last accessed December 4, 2000.

4 See Peckman, S., “Local Institutional Review Boards.” This background paper was prepared for NBAC and is available in Volume II

of this report.
National Bioethics Advisory Commission

65

5 Association of American Medical Colleges Medical School

Graduation (GQ) Questionnaire, 1980–1996.

6 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

7 See http://www.ptcny.com/PDF/ccip2000.pdf. Last accessed 

May 1, 2001.

8 See http://www.primr.org/aahrpp.html. Last accessed 

May 1, 2001.

9 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

10 Ibid.

11 See McCarthy, C.R., “Reflections on the Organizational Locus of

the Office for Protection from Research Risks.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

12 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

13 Ibid.

14 OHRP Guidance: “Procedures for Registering Institutional

Review Boards and Filing Federal Wide Assurances of Protection

for Human Subjects.” December 3, 2000. Available at

http://ohrp.osophs.dhhs.gov/irbasur.htm. Last accessed 

December 8, 2000.

15 See http://ohrp.osophs.dhhs.gov/humansubjects/assurance/faq.htm.

16 Letter from D.A. Lepay, Food and Drug Administration, to 

E.M. Meslin, NBAC. February 20, 2001. Providing comments on 

a draft of this report.

17 Lepay, D., 2000, FDA’s Program for Human Subject Protection. 

16 October. Presentation to ORCA Teleconference.

18 NBAC, “Federal Agency Survey on Policies and Procedures for

the Protection of Human Subjects in Research.” This staff analysis

is available in Volume II of this report.

19 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

20 Ibid.

21 NBAC Town Meeting: April 5, 2000, Pittsburgh, Pennsylvania. 

22 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

23 Moore v. The Regents of the University of California et al.

793 P.2d 479. (Cal. 1990).

24 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

25 39 Fed. Reg. 18915. 

26 See Holm, S., “The Danish Research Ethics Committee

System—Overview and Critical Assessment”; Chalmers, D.,

“Research Ethics in Australia”; and Heath, E., “The History,

Function, and Future of Independent Institutional Review Boards.”

These background papers were prepared for NBAC and are 

available in Volume II of this report.

27 See Heath, E., “The History, Function, and Future of

Independent Institutional Review Boards.” This background paper

was prepared for NBAC and is available in Volume II of this report.

28 “Instructions for Registering an IRB or IEC.” Available at

http://OHRP.osophs.dhhs.gov. Last accessed March 7, 2001.

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Introduction

This chapter addresses two issues central to the ethical analysis conducted by Institutional Review

Boards (IRBs)—analysis of risks and potential benefits

and the protection of vulnerable individuals—and recommends policy in the form of regulation and guidance

to govern the review of research. 

The current regulatory requirements relating to these

ethical issues reflect the principles underlying the recommendations of the Belmont Report: Ethical Principles and

Guidelines for the Protection of Human Subjects of Research

(Belmont Report) (National Commission 1979). For example, the application of the ethical principle of respect for

persons gives rise to the concern for vulnerability; the

application of the principle of beneficence leads to 

the necessity of assessing risks and potential benefits; 

and the principle of justice requires investigators to

attend to the process of recruiting research participants,

particularly as it relates to the inclusion of individuals

categorized as vulnerable. 

In protecting the rights and welfare of participants in

research, it is especially important to protect them from

avoidable harm. An IRB’s assessment of risks and potential benefits is central to determining that a research

study is ethically acceptable and would protect participants, which is not an easy task, because there are no

clear criteria for IRBs to use in judging whether the risks

of research are reasonable in relation to what might be

gained by the research participant or society.

When an IRB determines that risks are reasonable, it

must also ensure that all segments of society have the

opportunity to participate, as appropriate. But some

individuals might be considered vulnerable because of

either intrinsic characteristics (e.g., mentally or terminally

ill) or situational factors (e.g., living in poverty, employees

of the institution conducting the research) that render

their fully informed and voluntary participation more

susceptible to coercion or exploitation. Recognizing the

various types of vulnerability and providing adequate

safeguards can also prove challenging for IRBs.

IRB Approval of Research

Current regulations instruct IRBs in approving research

studies as follows:

In order to approve research...the IRB shall determine

that all of the following requirements are satisfied:

1. Risks to subjects are minimized: (i) by using 

procedures which are consistent with sound research

design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using

procedures already being performed on the subjects

for diagnostic or treatment purposes.

2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance

of the knowledge that may reasonably be expected to

result. In evaluating risks and benefits, the IRB should

consider only those risks and benefits that may result

from the research (as distinguished from risks and

benefits of therapies subjects would receive even if

not participating in the research). The IRB should not

consider possible long-range effects of applying

knowledge gained in the research (for example, the

possible effects of the research on public policy) as

among those research risks that fall within the

purview of its responsibility.

69

Assessing Risks and 

Potential Benefits and

Evaluating Vulnerability

4Chapter Four
70

Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

3. Selection of subjects is equitable. In making this

assessment the IRB should take into account the 

purposes of the research and the setting in which the

research will be conducted and should be particularly

cognizant of the special problems of research involving

vulnerable populations, such as children, prisoners,

pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons.

4. Informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent

required by 46.116.

5. Informed consent will be appropriately documented, in accordance with, and to the extent

required by 46.117.

6. When appropriate, the research plan makes adequate provision for monitoring the data collected to

ensure the safety of subjects.

7. When appropriate, there are adequate provisions

to protect the privacy of subjects and to maintain the

confidentiality of data.

8. When some or all of the subjects are likely to 

be vulnerable to coercion or undue influence, such as

children, prisoners, pregnant women, mentally disabled

persons, or economically or educationally disadvantaged persons, additional safeguards have been

included in the study to protect the rights and welfare

of these subjects (45 CFR 46.111; 21 CFR 56.111

[FDA regulations differ only in regulation citations]).

Scrutinizing research studies according to these criteria is not always a straightforward process, because it is

difficult for any set of regulations to fully anticipate the

variety of research situations that might arise and because

the federal regulations often lack specificity with respect

to a particular requirement (e.g., protecting privacy or

confidentiality). Moreover, little guidance is available to

assist IRBs in their reviews. For example, the IRB

Guidebook, published by the former Office for Protection

from Research Risks (OPRR), has not been updated since

1993 (OPRR 1993). Consequently, IRBs often tend to

focus more on matters where clearer regulatory direction

is available—for example, reviewing the language used for

consent forms—rather than on areas that require more

judgment. Furthermore, investigators have a tendency to

mimic their IRBs in this respect and focus on the more

straightforward ethical issues (e.g., avoiding easily recognizable physical harms) and easily defined bureaucratic

requirements (e.g., a signed consent form).

This pragmatic focus is understandable, given the

limited guidance provided for interpreting many aspects

of the regulations. For example, with the exception of

those populations that are protected by additional regulatory requirements (i.e., fetuses and pregnant women,

prisoners, and children), the federal oversight system

offers no direction regarding the types of additional protections that are needed for other vulnerable individuals,

even for those identified in the regulations—such as

mentally disabled persons and economically or educationally disadvantaged persons. In addition, investigators

and IRBs often struggle with the meaning of crucial terms

such as minimal risk, minor change, and minor increase 

over minimal risk, on which key ethical and regulatory

decisions rest.1 Applying these regulatory requirements

to nonclinical research is even more difficult and cumbersome, because the limited regulatory detail provided

is written in the context of clinical research (i.e., “that the

research presents no more than minimal risk of harm to

subjects and involves no procedures for which written

consent is normally required outside of the research 

context” (45 CFR 117(c)(2)).

Aside from the challenges involved in understanding

and applying the federal regulations, changes in the

research environment have influenced how investigators

conduct research and, to some degree, how regulatory

requirements are applied. For example, growth of

Internet-accessible health information databases has raised

novel concerns about protecting privacy and confidentiality;2 increased interest in the study of social problems

that may uncover illicit behavior has heightened awareness regarding the importance of confidentiality protections (Fitzgerald and Hamilton 1996; Fitzgerald and

Hamilton 1997); and increases in overall educational

attainment for Americans (Census Bureau 2000) have

raised questions concerning which groups should be

labeled educationally disadvantaged. In addition to the

effects that these types of social and technological

changes can have in the research environment, 10 years

of experience with the Common Rule and 20 years of
National Bioethics Advisory Commission

71

experience with the Department of Health and Human

Services (DHHS) and the Food and Drug Administration

(FDA) regulations suggest that it is time to re-examine

the criteria for research approval as described in the

regulations (45 CFR 46.111; 21 CFR 56.111). Clarity in

both the regulations and guidance would help investigators and IRBs more effectively and efficiently carry out

their responsibilities, thereby improving protections,

increasing public trust in the enterprise, and promoting

research involving human participants. 

Risks of Harms and Potential Benefits

to Participants and to Society

The principle of beneficence states that persons should

be “treated in an ethical manner not only by respecting

their decisions and protecting them from harm, but also

by making efforts to secure their well-being” (National

Commission 1979, 6). Therefore, the principle requires

that investigators attempt to maximize possible benefits

and minimize possible harms. In research, however, the

process of gathering data to gain knowledge of benefit to

society may expose some individuals to harm, and IRBs

must determine, therefore, “when it is [ethically] justifiable

to seek certain benefits despite the risks involved, and

when the [potential] benefits should be foregone because

of the risks” (National Commission 1979, 7). 

In the simplest terms, IRBs assess risks and benefits.

However, risk refers both to the probability that harm

may occur and its magnitude. Thus, the term small risk is

ambiguous, for it could mean that the probability of the

harm is small, or that the magnitude (i.e., seriousness) of

the possible harm is insignificant, or both. On the other

hand, benefit refers only to the magnitude of the positive

outcome, not to its probability. Thus, harms are properly

contrasted with benefits, and risks (i.e., possible harms)

with potential benefits.

Federal regulations incorporate the obligation of

beneficence by requiring IRBs to ensure that risks are

minimized to the extent possible, given the research

question, and are reasonable in relation to potential benefits (45 CFR 46.111(a)(1)-(2); 21 CFR 56.111(a)(1)-(2)).

Such an analysis of risks and potential benefits often will

be complex, because IRBs are called on to assess the balance between any number and type of risks and potential

benefits. The current regulations do not further elaborate

how risks and potential benefits are to be assessed, and

little additional guidance is available to IRBs. The National

Bioethics Advisory Commission (NBAC) discussed these

issues at some length in two previous reports (NBAC

1998; NBAC 1999b) and has made specific recommendations in this area. Among the important considerations

NBAC has raised is how IRBs and prospective participants

might not evaluate risks and potential benefits in the

same way. To account for this factor, in making assessments of risks and potential benefits, IRBs must find

ways to be sensitive to the perspectives of prospective

participants (NBAC 1998).

Types of Harms

Harms can be categorized broadly as physical, psychological, social, economic, legal, or dignitary; these

categories are not mutually exclusive, however, and more

than one type of harm might be present in a given

research study. The terms harm and injury have distinct

meanings in law, but as in the work of the Health

Education and Welfare Task Force (DHEW 1977) and

the President’s Commission (1982), the terms are used

interchangeably in this report.

Physical harms include injury, illness, pain, suffering,

or discomfort. This category encompasses such diverse

harms as death in a cancer study, myocardial infarction

related to a maximal exercise treadmill test, and discomfort related to the requirement to lie still in an MRI

machine for an extended period during an imaging

study.3

Psychological harms include the research participant’s

negative perception of self, emotional suffering (e.g., anxiety or shame), or aberrations in thought or behavior.

Examples of such harms were found in Milgram’s

“Obedience to Authority” experiments (Milgram 1974).

Psychological harms also include distress, anger, or guilt

related to the disclosure of sensitive or embarrassing

information (NBAC 1999a) and distress and fear upon

learning of one’s likelihood of developing a disease for

which there is no treatment or cure (Glass et al. 1997;

Marteau and Croyle 1998; Meiser and Dunn 2000).

Psychological harms also could be associated with refusal

to participate in a research study, such as the guilt that

arises when a prospective participant does not wish to
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

donate allogeneic bone marrow to be used in an experimental manner to treat a patient with AIDS.4

Social harms involve the negative effects on one’s

interactions or relationships with others.5 For example,

research findings or even study participation itself may

expose participants to insurance or employment discrimination or other forms of social stigmatization (NBAC

1999b). Research findings may also damage a participant’s

relationship with others—for example, when paternity

status is disclosed in genetic or child development studies.6

Economic harms involve the imposition, direct or

indirect, of financial costs on participants.7 For example,

participants in clinical research may incur financial 

obligations for treatments that are higher than those associated with standard therapies. In some studies, participants may need to take time off from work or pay for

transportation or childcare to enable them to take part in

the research. They also may be faced with loss of health

insurance, or even loss of employment.8

Legal harms are legal actions that could be taken

against the participant, such as arrest, conviction, incarceration, or lawsuits. Such harms could occur, for example, in

studies of possession or use of illicit drugs, sexual abuse,

or workplace theft.9

Dignitary harms are those incurred when individuals

are not treated as persons with their own values, preferences, and commitments,10 but rather as mere means, not

deserving of respect.11 Such harms occur in failures to

respect personhood or in violations of justice. These

types of harms might be present, for example, in research

studies in which informed consent is not obtained or in

genetic research that results in the discrimination against

the individual participant (NBAC 1999b, 45–46). 

Determinations concerning the probability of physical harms are often easier to make than those involving

the probability of nonphysical harms. For example, the

magnitude and probability of harms associated with a

blood draw are well known and can be objectively quantified. This is generally not the case for psychological,

social, economic, and legal harms. Although IRBs are

able to identify such nonphysical potential harms, it is

often difficult to determine the probabilities of their

occurrence. IRBs, therefore, can err in either direction, by

assuming a higher probability and recommending

unnecessary protections or preventing research from

being conducted or by assuming a lower probability and

allowing research to occur without all the appropriate

protections. Although a good deal of information has

been gathered about some nonphysical harms—for

example, the risks from disclosures associated with transmitting or storing certain types of information—the possibility of such harms is not widely appreciated. Efforts

should be made to ensure that IRBs are sensitive to the

possibility that nonphysical harms might occur and that

they better understand how to consider such risks in

their assessments.

Risks to Those Other Than Participants

Risks may accrue not only to research participants,

but also to persons not directly involved in research, such

as to the participants’ family, loved ones, other contacts,

social groups, and to society in general (National

Commission 1979; NBAC 1999b). For example, in a previous report, NBAC recommended that to the extent that

risks of harm to groups can be anticipated, investigators

should design their research studies to minimize these

risks and should consult with representatives of relevant

groups regarding study design (NBAC 1999b). This recommendation was directed to investigators as one important measure that could be taken without revising the

federal regulations. However, encouraging investigators

may not be sufficient. Both individuals and other groups

experience research risks, so it is appropriate for IRBs 

to be given explicit authority and guidance in how to

consider them.

All of the types of risks described above could accrue

to others affected by the research. For example, in a study

of a new live virus vaccine, there may be risks to participants’ family members or other contacts who could contract the attenuated disease. In some states, there may be

legal risk to parents whose minor children participate in

a study of illegal activity.12 Genetic research may result in

certain groups being associated with certain diseases,

thus exposing members of those groups to the possibility

of stigmatization or discrimination in insurance or

employment.13 Society in general may incur harm related

to research involving procedures, such as xenotransplantation or studies of viruses in which there may be some

potential of releasing pathogenic organisms.14
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73

Current regulations focus only on individual participants. However, other individuals and communities not

directly involved in research can also bear risks that are

associated with a research study, but that are not

acknowledged or mentioned in the regulations. If IRBs

focus only on risks to individual research participants,

they fail to apply fully the principle of beneficence,

because the scope of this principle can extend beyond the

individual participants in the research.15

Minimizing Risks

Once risks have been identified, IRBs and investigators

must ensure that they are minimized to the extent possible

within the limitations imposed by the nature of the

research study. Risks may be reduced in a variety of

ways—for example, by assuring that the study design is

valid; the investigator and research study personnel are

qualified; the necessary infrastructure is in place to conduct the research and deal with any harmful sequelae;

participant privacy and confidentiality are adequately

protected; participants are properly monitored; criteria for

participant enrollment and withdrawal are appropriate; 

a timely treatment plan is in place; and prospective 

participants at undue risk of harm are excluded.16

Types of Potential Benefits

IRBs should identify potential benefits associated with

a research study. Generally, IRBs consider potential benefits as accruing either to society or to participants. Just as

research studies might involve risks to individuals other

than the participants, they might also provide potential

benefits to others, especially the participants’ community.

Potential Benefits to Society

The goal of research is to develop knowledge that is

beneficial to society. In considering whether to approve a

proposed research study, IRBs must make judgments

about the importance of the knowledge that is likely to

result from research studies. The importance of the

knowledge to be gained may increase when significant

new findings are expected; when it may result in new

products, treatments, or cures; or when it is applicable to

many different social groups.

The assessment of whether risks are reasonable in

relation to the potential gain in knowledge is difficult to

make, because those who participate in research and who

will be exposed to the risks are often not the same individuals who stand to benefit from the research. Thus, the

IRB must be able to clearly identify what might be

learned from the research and decide whether the gain in

knowledge justifies the exposure of participants to harm.

For studies involving little risk, this assessment is not so

difficult. However, when the research involves significant

risks to human participants—for example, death or 

disability—the IRB must carefully weigh the risks and 

the potential gain in knowledge. 

Potential Benefits to Participants

Individuals may directly benefit from participation in

certain types of research, such as studies designed to offer

interventions or procedures that offer a prospect of 

benefit. For example, potential benefits include receiving

clinically significant information that could be used to

influence the care provided, receiving standard treatments or interventions as part of the research, such as

counseling and testing, or gaining access to experimental

therapies that may improve the participant’s health 

status. These types of benefits are to be contrasted with

unplanned or unanticipated benefits that are secondary

to the objectives of the study. Sometimes, unanticipated

direct benefits can result that are relevant to the research

objectives. For example, in a research study on treatment

for injection drug users, participants were asked to keep

daily diaries as a data collection strategy, which served to

raise self-awareness about the effect of daily habits on

drug use. As a result, some users sought treatment

(Singer 2000; Singer et al. 2000). When identifying

potential direct benefits to participants, however, IRBs

should consider only those that might result strictly from

study participation.

Individuals might also benefit indirectly from participation in certain types of research, from experiencing

increased social contact, sharing information with

another person, or gaining personal satisfaction from 

participating in the research (NBAC 1998). Indirect 

benefits typically are not planned by investigators in 

their research design and do not relate to the objectives

of the research study. In addition, they are likely to vary

among research participants. Although these benefits
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

should be acknowledged, they should not weigh in the

judgment of IRBs regarding the balance of risks and

potential benefits to the participant. To the extent that

indirect benefits can be anticipated, however, investigators should design research to increase them.

For purposes of IRB review, incentives for and 

payments associated with participation in research 

(e.g., remuneration for transportation, childcare, or lost

work time) should not be considered potential benefits to

research participants (OPRR 1993). Such potential benefits to research participants make it feasible to participate,

but they do not result directly from study procedures in

which the individuals participate. Including such incentives as potential benefits in the IRB assessment would

inappropriately skew judgments concerning risks and

potential benefits, because nearly any level of research

risk could be offset by such gains if they were significant

enough—for example, if participants were promised

large sums of money for participating in research.

Although IRBs should not consider such incentives or

payments as benefits, they should recognize that

prospective participants might consider them as such.

Thus, IRBs should determine whether incentives or payments are set so high that they induce prospective participants to enroll without carefully considering the risks

involved in participation.

Potential Benefits to Others

Research institutions, social groups, or communities

also can benefit from research. Institutions benefit, for

example, from enhanced capacity to conduct research or

by receiving resources to improve a program as a result of

a research study. Communities can benefit through

improved access to programs or through the emergence

of programs targeted to specific groups within the community. Research can result in the preservation of local

history, customs, or practices that might otherwise be

lost. IRBs should acknowledge that these potential benefits might be present and should consider ways to

increase their likelihood as part of the research design.

However, they should not weigh them in assessing risks

and potential direct benefits to the participants.

Relation of Risks to Potential Benefits

Once risks and potential societal and direct benefits

have been identified and ways to minimize risks have

been considered, IRBs must judge whether the risks are

reasonable in relation to potential benefits. These can be

difficult judgments to make, because IRBs might have to

compare the significance of different types of risks and

potential benefits, which are often difficult to quantify

(Martin et al. 1995). Further, IRBs have little guidance on

how to classify and compare risks and potential benefits.

It would be impossible to provide IRBs with a single 

algorithm for making such decisions that would do justice to the large variety of cases that might come before

them. However, the counsel provided in the Belmont

Report should guide IRB deliberations: 

It is commonly said that potential benefits and risks

must be ‘balanced’ and shown to be ‘in a favorable

ratio.’ The metaphorical character of these terms

draws attention to the difficulty of making precise

judgments. Only on rare occasions will quantitative

techniques be available for the scrutiny of research

protocols. However, the idea of systematic, nonarbitrary analysis of risks and benefits should be emulated

insofar as possible. This ideal requires those making

decisions about the justifiability of research to be

thorough in the accumulation and assessment of

information about all aspects of the research, and to

consider alternatives systematically. This procedure

renders the assessment of research more rigorous and

precise, while making communication between

review board members and investigators less subject

to misinterpretation, misinformation and conflicting

judgments (National Commission 1979, 16–17).

An IRB may approve a research proposal only if it

judges that the risks are reasonable in relation to potential

benefits (National Commission 1979). This judgment

may be an IRB’s single most important and difficult determination, because it ensures that when research participants voluntarily consent to participate in a research

study, they are offered a “reasonable choice.”17 Research

with significant risks could be approved after such an

analysis if the potential benefit is significant. However,

this does not imply that there is no upper limit to the

determination of acceptable risk. For any research study

involving significant risk, not only should the local IRB
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75

find the risks reasonable in relation to the potential benefits, but also so should a larger community of investigators,

IRBs, and the public.

Historical Perspective: The Foundation

Provided by the National Commission

A coherent conceptual framework is needed for the

analysis of risks and potential benefits, and yet there is

evidence that this is not provided by current regulations.

For example, it has been suggested that the National

Commission espoused three distinct views on the analysis of risk: risk assessment based on an analysis of the

whole protocol, analysis of risks for whole protocols

based on the combined analysis of each of the particular

components within a protocol; and distinct analyses of

risks for individual components of research protocols

without judging the whole protocol as a single unit.18

Each of these views is reflected in the current federal

regulations. 

In its first report, Research on the Fetus, the National

Commission presented a framework for risk analysis

that relies on categorizing research studies into two

types, therapeutic and nontherapeutic (National Commission 1975) and made separate recommendations concerning the evaluation of risks for each type of research.

Current DHHS regulations concerning fetal research 

(45 CFR 46 Subpart B) incorporate this framework.19

According to some commentators, this “whole protocol” approach, which requires that entire research studies

be classified as either therapeutic or nontherapeutic, is

flawed (Levine 1986).20 The National Commission characterized therapeutic research as “designed to improve

the health condition of the research subject by prophylactic, diagnostic, or treatment methods that depart from

standard medical practice but hold out a reasonable

expectation of success” (National Commission 1975, 6).

Levine has argued that the concept of therapeutic

research is a contradiction in terms: 

There is, of course, no such thing as a ‘systematic 

collection of data or observations...designed to

improve the health condition of a research subject...

that departs from standard medical practice.’ Thus, the

[National] Commission developed recommendations

for the conduct of a nonexistent set of activities...

(Levine 1986, 298).

Because the purpose of research is to acquire knowledge, no research study as a whole can be accurately 

classified as therapeutic research. Indeed, for this reason

the National Commission later rejected this whole protocol

framework. NBAC has also recognized the difficulty of

such a framework (NBAC 1998, 46). As a result of this

conceptual flaw, the whole protocol framework allows

any research study to be classified as therapeutic as long

as it contains at least one component that offers the

potential of direct benefit to the participant. However,

such research might include nontherapeutic components

involving significant risk. For example, a pharmacokinetic

study might involve the administration of a standard

therapy followed by extensive nontherapeutic testing. In

the whole protocol approach, the entire protocol would

be classified as therapeutic and there would be no limit

to the number of nontherapeutic procedures that could

be administered to participants with the protocol still

classified as therapeutic. Indeed, IRBs might fail to consider the risk associated with the nontherapeutic procedures, because the conceptual framework encourages

them to think about the entire protocol as offering the

prospect of some direct benefit. Thus, it is difficult to

envision research participants being adequately protected

under such a framework.21

In its reports Research Involving Prisoners (1976) 

and Research Involving Children (1977), the National

Commission rejected the distinction between therapeutic

and nontherapeutic research, recognizing that an entire

research study could not be considered fully therapeutic,

but that, instead, protocols might contain therapeutic or

nontherapeutic components. Thus, the National

Commission eliminated the conceptual problem that

stems from the category of “therapeutic research.” However, the National Commission did not avoid the ethical

problems described above. It adopted the language of

components, but retained an analytical model based on

assessing the protocol as a whole. For example, in its

report on research on children, the National Commission

endorsed one set of recommendations for research

involving no more than minimal risk, another for

research involving therapeutic components that exceed

the minimal risk threshold, and yet another for research

involving nontherapeutic components that exceed this

threshold. It has been argued that this framework also
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

suffers from several weaknesses.22 All research studies

containing components that offer the prospect of direct

benefit to research participants also contain components

that do not offer the prospect of benefit and only answer

the research question(s). Thus, two different sets of recommendations for assessing risks would apply in a research

study involving children that contains both therapeutic

and nontherapeutic components in which both components involve more than minimal risk. Because the recommendations that comprise this framework refer to a

research study as a whole involving a particular type of

component, it is unclear how multiple recommendations

could be applied simultaneously to an entire study.

Although the model avoids the linguistic confusion associated with a “whole protocol” approach, it still fails to

analyze risk and potential benefits separately for therapeutic and nontherapeutic components.23 Nevertheless,

current DHHS regulations concerning research involving

prisoners (45 CFR 46 Subpart C) and children (45 CFR

46 Subpart D) incorporate this framework.24

Finally, in its report Institutional Review Boards (1978)

the National Commission began to move toward a framework that involved the analysis of components of a

research study rather than the study as a whole; however,

it did not adopt specific recommendations for performing

such an analysis of risk. Requirements relating to analysis

of risks and potential benefits in the Common Rule 

(45 CFR 46 Subpart A) seem to be based on this framework.25 The lack of a single coherent, fully developed

conceptual framework hinders the efforts of IRBs to

assess and evaluate risks and potential benefits of

research studies. At best, the terms therapeutic and nontherapeutic are confusing. By labeling research or procedures as therapeutic, it implies that these activities are

beneficial when, in fact, the very purpose of research is to

make that determination. NBAC has not used these terms

in its previous reports, and it does not do so here. Rather,

components should be assessed on the basis of whether

they offer the prospect of direct benefits to the individuals

being studied or general, more indirect benefits to society.

A Framework for the Analysis of Risks of

Harms and Potential Benefits

Charles Weijer has proposed a framework based on a

“component analysis” that he believes provides a better

ethical analysis of research that contains a mixture of

components—some that offer the prospect of direct

benefit to research participants and others with the sole

intent of answering the research question(s).26 In the

context of a research study, all components are designed

to answer the research question(s). Components may

include one or more procedures. However, some components also offer the prospect of direct benefit to research

participants, while others do not; the latter solely offer the

potential societal benefit of knowledge. For example, a

research study designed to test whether aspirin or acetaminophen reduces fever more effectively uses a number

of procedures, including the administration of aspirin to

one group; the administration of acetaminophen to

another group; the randomization of participants to these

two groups; and the measurement of fever. All of these

procedures are included in the study design because they

are needed to answer the research question(s). However,

some of these procedures are also designed to offer the

prospect of direct benefit to participants—for example,

the administration of aspirin or of acetaminophen.

Others, such as randomization, temperature taking, and

chart comparisons, do not offer the prospect of such

direct benefits; their sole intent is to answer the research

question(s). Although a research study must be examined

in its entirety, the two types of components should be

judged differently. 

The component-based approach to the analysis of

risks and potential benefits requires IRBs to sort research

study procedures into these two types of components to

determine their ethical acceptability. The first type consists of those components containing particular procedures that may offer the prospect of direct benefit to

participants. The second type includes procedures that

do not. Most procedures in a research study are easily classified into one of these two types of components.

However, in some studies, it might not be clear into

which component the procedures best fit—for example,

a survey involving a questionnaire and measurements of

health in which clinically meaningful results (e.g., blood

pressure) are reported back to participants, but no treatment is offered. Further, in any research study using

diagnostic procedures that might provide useful health

information to the participant in addition to the information provided for the study—such as the use of CAT
National Bioethics Advisory Commission

77

scans to study brain activity that could also identify

tumors—the classification of such procedures may be

ambiguous and therefore requires careful consideration

by the IRB. 

IRBs should be able to identify whether a clear and

direct benefit to society or the research participants might

result from participating in the study. However, IRBs

should be cautious in classifying procedures as offering

the prospect of direct benefit. In fact, if it is not clear that

a procedure also offers the prospect of direct benefit, IRBs

should treat the procedure as one solely designed to

answer the research question(s). A major advantage of

this approach is that it avoids justifying the risks of procedures that are designed solely to answer the research

questions based on the likelihood that another procedure

in the protocol is likely to provide a benefit.

To the extent possible, IRBs should independently

weigh the risks and potential benefits of each type of procedure. The risks associated with individual procedures

offering the prospect of direct benefits are justified in

relation to their potential to benefit the participant in

addition to their potential to generate knowledge, and

those procedures designed solely to answer the research

question(s) are justified in relation to their potential to

generate knowledge. 

Recommendation 4.1: An analysis of the risks and

potential benefits of study components should 

be applied to all types of covered research (see

Recommendation 2.4). In general, each component of a study should be evaluated separately,

and its risks should be both reasonable in 

themselves as well as justified by the potential

benefits to society or the participants. Potential

benefits from one component of a study should

not be used to justify risks posed by a separate

component of a study.

Components Designed Solely to Answer the

Research Question(s)

All research involves the administration of procedures

and use of methods solely for the purpose of answering

the research question(s). These procedures or methods

can be questionnaires, interviews, chart reviews and use

of existing data, observations, randomization, and clinical

procedures such as blood draws. Many health services

studies and most epidemiological, behavioral, and social

science studies as well as historical research involve only

such components. 

By definition, risks associated with components containing procedures designed solely to answer the research

question(s) can be justified only by the potential benefit

associated with the knowledge gained, not by the potential direct benefits to individual participants. Freedman

argued that this judgment requires the opinion of both

scientific experts and community representatives

(Freedman 1987b). Community representatives might

come from geographic areas or from affected participant

communities (e.g., persons with a particular disorder). 

Involving community representatives can be challenging, as it is sometimes difficult to define relevant

groups or individuals who can represent the community

(Davis 2000). As risks increase, scrutiny from the communities that may be affected by the research findings

will help to ensure public confidence and trust that 

participants are offered “reasonable choices.”

Components That Also Offer the Prospect of 

Direct Benefits

Clinical and other types of research studies might

include procedures that, in addition to answering the

research question(s), also offer the prospect of direct 

benefit to participants, such as drug interventions, surgical

and medical procedures, or educational, psychological,

and behavioral interventions. They might also include

diagnostic and other procedures that guide the administration of treatment, even if these procedures are not

routinely administered.27 Studies with components containing procedures of this kind pose their own distinctive

challenge in the ethical analysis of risks and potential

benefits.

Here too, IRBs must determine whether the relation

between risks and potential benefits is reasonable. To do

so, IRBs should determine whether the procedures meet

the criteria of research equipoise (see Exhibit 4.1) in addition to being justified in terms of the potential knowledge

gain for society. Investigators and IRBs should understand that the term research equipoise applies to any type

of research involving interventions or procedures that

offer the prospect of direct benefit to participants, which
78

Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

would include, for example, health education interventions, clinical psychology interventions, and public

health interventions. 

Clinical trials involving the use of drugs, vaccines, or

other biologic products are other examples of research

studies in which IRBs would subject the experimental

procedures to a test of research equipoise. However, such

a test would also need to be applied to research studies

involving the evaluation of any intervention that is

designed to benefit those who would receive it. For

example, educational interventions, such as teaching

reading skills or providing public health interventions,

such as smoking cessation and psychological interventions, should also be subject to the test of research

equipoise. 

Procedure for Assessing the Balance Between

Risks and Potential Benefits

Figure 4.1 outlines the framework for risk and 

potential benefit analysis that IRBs should undertake in

reviewing research. The proposed component analysis

offers several advantages.

First, the model can be applied to all types of

research. Second, it focuses the attention of the IRB

appropriately on distinct procedures for which the ethical

analysis is different. Components designed solely to

answer the research question(s) are judged based on an

analysis of whether the risks are reasonable in relation to

the potential gain in knowledge, while components that

also offer the prospect of direct benefit must meet an

additional standard of research equipoise. That is, the

balance of risks and potential benefits associated with the

study interventions are equivalent to those associated

with accepted practice and, therefore, there is genuine

uncertainty (among experts) about whether the study

intervention or accepted practice is preferred. Third,

under this model, components that are designed only to

answer the research question(s) cannot be justified based

on the inclusion of other procedures that offer the

prospect of direct benefit. This aspect of the model prevents investigators conducting clinical trials, for example,

from including additional procedures, such as biopsies,

blood tests, or scans, that are unlikely to yield any information of benefit to society by justifying them on the

basis of including an intervention that holds the prospect

of direct benefit, such as an experimental oncology

treatment.

The proposed ethical analysis should be performed

after risks have been identified and, to the extent possible, minimized by investigators. Only that part of the

framework that is relevant to a particular research study

should be used. In the case in which a research study

Exhibit 4.1: Research Equipoise

Research equipoise, a new term introduced in this

report, describes the state in which genuine uncertainty exists regarding which intervention—experimental or control (including placebos)—is better

(Freedman 1987a, 144). Normally, this concept is

referred to as clinical equipoise, because it is used

in medicine. However, because the concept can be

applied to other areas of practice, such as public

health or psychology, the term should be broadened.

Accepted practice is defined as practice that falls

within the bounds of what is considered standard—

that is, what the community of expert practitioners

accepts. The standard of research equipoise recognizes explicitly that it is the community of experts

that establishes standards of practice (Freedman

1987a). Thus, the judgment that a state of research

equipoise exists is an acknowledgement that study

interventions are thought to be fully consistent with

accepted practice.28

A judgment of research equipoise relies on a

comparison of the risks and potential benefits of

the proposed study interventions with those of

accepted practice. Research equipoise does not

require numeric equality of intervention risks or

potential benefits. Rather, research equipoise

requires approximate equality in the relation

between the risks and potential benefits of the

study and control interventions. A variety of 

intervention-related factors are likely to contribute

to the determination of this assessment, including,

among others, the relative efficacy of the intervention, the probability and magnitude of side

effects, ease of administration, and participant

compliance.29 An experimental intervention may

pose greater risk to participants than accepted

practice, as long as it also offers the prospect of

greater direct benefit to the participant and the 

relation between the risks and potential benefits

falls within a range of equivalency to accepted 

practice.30
National Bioethics Advisory Commission

79

Figure 4-1. Process of IRB Review Including Analysis of Risks and Potential Benefits

COMPONENTS DESIGNED SOLELY

TO ANSWER THE RESEARCH 

QUESTION(S)

COMPONENTS THAT ALSO OFFER

THE PROSPECT OF DIRECT

BENEFITS TO PARTICIPANTS

STUDY ACCEPTABLE ONLY IF ALL COMPONENTS PASS ETHICAL TESTS.

ARE THE RISKS REASONABLE 

IN RELATION TO POTENTIAL

BENEFITS OF KNOWLEDGE?

■ Requires assessment of the study’s

objective.

■ May require input from experts and 

community representatives.

ARE THE RISKS REASONABLE 

IN RELATION TO POTENTIAL

BENEFITS TO PARTICIPANTS?

■ Assessment of risks and potential 

benefits made separately for 

experimental and control procedures.

■ Does study pass test of research

equipoise?

— Insufficient data exist to validate

whether control or experimental 

procedure more likely to provide 

more favorable risk/benefit 

combination.

— May require input from experts 

and community representatives.

Protocol submitted to 

IRB for review.

IRB’s ethical analysis of risks and potential benefits after risks identified and minimized, possible

benefits identified.

■ IRB staff review to ensure all requirements addressed, protocol ready for IRB review.

■ Return for revision and resubmission as necessary.

IRB reviews to

■ Identify risks and potential benefits to participants and others.

■ Minimize risks.
80

Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

involves only the use of components designed solely to

answer the research question(s), the IRB and investigators

would follow only the left side of Figure 4.1. For example,

in a study involving the economic analysis of identifiable

data, only the part of the framework relating to components designed solely to answer the research question(s)

is used. Likewise, for any research study that does not

involve components that hold the prospect of direct benefit to participants, the relevant ethical analysis is only

that part of the model relating to components designed

solely to answer the research question(s). Examples of

such procedures are surveys, records review, blood

draws, and other procedures used solely to identify

health conditions. Procedures administered in experiments as part of data collection, such as using varying

stimuli in a psychological perception experiment or using

drugs to alter cognitive states, are evaluated only by the

components outlined on the left side of Figure 4.1.

For research involving both types of components

(those that solely answer the research question[s] and that

also offer the prospect of direct benefit to participants),

IRBs should follow both sides of Figure 4.1. Whether one

side or both sides of the suggested framework are used, each

component of the protocol is considered in turn. IRBs should

conclude that risks are reasonable in relation to the potential

benefits only when all of the individual procedures have met

their respective ethical criteria (see examples in Exhibit

4.1). In the end, an IRB must determine that the research

study in its entirely is ethically acceptable.

Standard procedures may be used in a research study

in at least four ways, and in each case, they are evaluated

differently. First, standard procedures might be used as a

control. When standard procedures are used as a control

to evaluate the experimental intervention, IRBs must

assess them as they do experimental procedures by following the right side of Figure 4.1. (See Exhibit 4.2 for

an example.) Second, standard procedures might be used

solely to answer the research question(s), such as blood

draws or CAT scans. IRBs should follow the left side of

Figure 4.1 to assess such procedures. Third, standard

procedures might be offered in conjunction with a

research study, but not as part of the research study. For

example, in a study involving known cases of HIV, participants might be offered counseling and testing for

other sexually transmitted diseases (STDs). However,

because the STD counseling and testing procedures do

not relate to the research question(s) and are instead

offered as part of standard practice in a STD clinic, the

use of standard procedures in this case should not be factored into the ethical analysis by the IRB. Fourth, some

research studies might involve the evaluation of an ongoing standard procedure. That is, the standard procedure

would occur or be offered regardless of the existence of a

research study. For example, a research study might be

designed to evaluate the sensitivity and specificity of a

surveillance system to detect cases of disease, with the

surveillance system a standard, ongoing procedure, and

additional data collection techniques added in order to

evaluate the surveillance system. In this scenario, the surveillance system is not part of the research study and

should not be part of the ethical analysis of the research

study. But the additional data collection is research and

should be part of the ethical analysis.

Minimal Risk

Current federal regulations for the protection of

research participants call for the classification of research

as involving either minimal risk or greater than minimal

risk.31 As defined in the federal regulations: 

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater in and of themselves than

those ordinarily encountered in daily life or during

the performance of routine physical or psychological

examinations or tests (45 CFR 46.102(i); 21 CFR

56.102(i)).

This classification is ethically relevant, because it is

intended to provide protection to human participants by

focusing IRBs’ attention on riskier research. 

When used as a sorting mechanism, this classification

determines the level of review required of an IRB.32 For

example, under the current regulations, if a research

study is determined to pose only minimal risk and

involves a procedure contained on the expedited review

list, it may be evaluated using the expedited review

process in which the IRB chair or a designee may review

the research study in accordance with all the required
National Bioethics Advisory Commission

81

Exhibit 4.2: Using the Framework to Assess Risks and Potential Benefits

The following examples are taken from recently published research to show how research procedures can be separated into those solely designed to answer the research question(s) and those that also offer the prospect of direct

benefit to participants. The risk/potential benefit analysis can be used with studies involving no more than minimal

risk as well as studies involving more than minimal risk. 

Example 1: Analysis of Existing Data

Investigators studied gender differences in industry wages by analyzing data from the 1988 Current Population

Survey. Variables in the analysis include hourly wage, level of education, years of work experience, size of the 

metropolitan area in which workplace is located, whether the workplace is in an urban or rural area, geographical

region of the United States, marital status, race, type of occupation, and type of industry. 

If the data are unidentifiable, the research should not be covered under the oversight system, because no human

participants are involved. If the data are identifiable (i.e., coded), then an IRB should review the research. In this case,

risks are associated with breaches in confidentiality, and the IRB should determine whether confidentiality protections

are appropriate. Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society.

Based on this analysis, this study should be eligible for review using procedures other than the full board because

it involves no more than minimal risk.

Example 2: Face-to-Face Interviews Involving Sensitive Issues and a Small Sample

Investigators studied the effect of traumatic experiences on memory. Five individuals who were incarcerated between

1942 and 1945 in Auschwitz were the participants. A detailed questionnaire was given concerning personal characteristics (e.g., age, education, and place of work), concentration camp characteristics, daily routine at the camp, and

events that occurred while there. They were also shown ten photos of famous Nazis who were either known nationally or active at Auschwitz. Interviewers administered the questionnaires in the participants’ homes and conducted

interviews in Hebrew or German. Investigators analyzed responses for accuracy based on historical accounts. 

Concerns of the IRB should be threats to privacy, breaches in confidentiality, and psychological risks, such as 

distress. The sample size may result in individuals being identified even if no direct identifiers are maintained.

Because none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis

involves judging whether the risks are reasonable in relation to the potential gains in knowledge for society.

Investigators might argue that participants might feel better after the interview and derive some satisfaction from 

talking about their experiences. However, these types of indirect benefits should not be taken into consideration in

the risk/potential benefit analysis.

Based on the analysis of the components of this study, it should receive full IRB review because some components pose more than minimal risk.

Example 3: Observational Study Using Mail Questionnaires to Evaluate the Effects of State Law on Behavior

Investigators studied the effects of two divorce laws on the functioning of parents and children immediately after separation and two years later. In this state, until 1987 the divorce law was no-fault and permissive of joint custody. In

1988, a new law went into effect that focused on parental functions and responsibilities rather than custody.

Investigators identified divorcing couples through their divorce petitions. One hundred couples were identified in 1987

and 100 in 1988 and were sent a questionnaire at the time of separation. If they responded to the questionnaire, they

were sent another questionnaire two years later. Individuals were asked to respond to questions about themselves

regarding depression, social withdrawal, irritability, work problems, and childrearing problems. They were asked to

answer questions about their children regarding depression, anxiety, eating behavior, sleeping patterns, nighttime

fears, and withdrawal. They also responded to questions regarding the circumstances of the separation, including

parental substance abuse and child abuse.

Primary concerns of the IRB should be threats to privacy and breaches in confidentiality. Privacy and confidentiality risks related to psychological, social, and legal harms are heightened, because divorcing spouses might

attempt to obtain through legal mechanisms information about the other or physically harm the other based on information disclosed in the survey. Other issues would include whether cases of child abuse must be reported. Because

none of the research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves 

judging whether the risks are reasonable in relation to the potential gains in knowledge for society. Thus, the study

should receive full IRB review.
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

Exhibit 4.2 continued

Example 4: Psychological Experiment to Study Human Cognition and Behavior 

Investigators studied the relationship between task difficulty and performance, because performance sometimes

improves when tasks become more difficult. In this experiment, motor difficulty and cognitive difficulty were manipulated in a recognition task. Sitting in front of a computer, student participants were instructed to move the cursor using

a standard analog joystick as quickly and accurately as possible into contact with an image that they thought matched

the sample image. Within the different experimental groups, exposure time of the sample stimulus was altered (fast

versus slow), and ease of moving the joystick was altered (easy versus hard). Students were offered course credit

for participating in the study.

Primary concerns of the IRB should be whether offering course credit for participation is an undue inducement;

whether there are any physical risks associated with operating a hard-to-move joystick; and whether there are any

psychological risks associated with task difficulty, such as frustration or loss of self-confidence. Because none of the

research procedures offer the prospect of direct benefit, the risk/potential benefit analysis involves judging whether

the risks are reasonable in relation to the potential gains in knowledge for society. This study should be eligible for

review using procedures other than full board review because it involves no more than minimal risk.

Example 5: Clinical Trial to Determine Safety and Immunogenicity of a Vaccine

Investigators conducted a Phase I, dose-escalating trial of a prophylactic recombinant human papillomavirus vaccine

candidate in healthy participants. The study was designed to evaluate the safety and immunogenicity of two dose 

levels of the vaccine in a double-blind, randomized, placebo-controlled trial. To determine whether the dose of the

vaccine or the addition of alum or MF59 adjuvant would influence the reactogenicity or immune response, a doseescalation design was used, starting with the lower dose of the vaccine alone, then with alum added to the vaccine,

then with MF59 added to the vaccine, and the design repeated with the higher dose of the vaccine. Assessments

included a physical examination and laboratory tests prior to enrollment and clinical evaluations and clinical and

immunologic tests before each injection at 0, 1, and 4 months and 1 month after each injection.

The trial was not designed to offer a potential direct benefit (protection from human papillomavirus) to participants.

The vaccine, the design of the trial, and all of the assessments were administered solely to answer the research 

question(s) related to safety and immunogenicity. Because none of the research procedures offer the prospect of

direct benefit, the risk/potential benefits analysis involves judging whether the risks are reasonable in relation to the

potential gains in knowledge for society. Thus, the study should receive full IRB review.

Example 6: Clinical Trial to Test Efficacy of a Drug

Investigators conducted a trial to determine whether paroxetine, an antidepressant, would reduce depressive symptoms in patients with malignant melanoma who were treated with a high dose of interferon therapy. The investigators

used a double-blind, placebo-controlled trial design. Participants were randomly assigned to either the experimental

arm or the control arm of the trial. Paroxetine or placebo was administered for two weeks before initiation of the interferon therapy as well as during the treatment period. Participants were evaluated at regularly scheduled intervals for

depressive symptoms. Assessments included depression and anxiety rating scales, a neurotoxicity rating scale used

in the measurement of psychiatric and physical symptoms related to cytokine therapy, and a psychiatric evaluation.

This trial was designed to offer the prospect of direct benefit to participants in addition to answering the research

question(s). In this study, the research (whether paroxetine reduces depression-like symptoms) takes place in the

context of providing standard medical care (interferon therapy). The use of standard medical care should not be 

factored into the risk/potential benefit analysis of the IRB. The research study procedures are of two types. The first

type, designed solely to answer the research question, includes the trial design (randomization and double-blindness)

and the assessment measures. The risk/potential benefit analysis involves judging whether the risks are reasonable

in relation to the potential gains in knowledge for society. The other types of procedures are those that offer the

prospect of direct benefits. These procedures are the experimental and control conditions. In addition to determining

that these procedures will yield potentially useful societal knowledge, they are evaluated in terms of whether they

meet the test of research equipoise—that is, whether there is disagreement among experts as to whether either

should be preferred as accepted practice.

This study should receive full IRB review.
National Bioethics Advisory Commission

83

regulations (45 CFR 46.110(b); 21 CFR 56.110(b)).

Research involving more than minimal risk requires full

IRB review. As the risk of research increases above the

minimal risk threshold, protections for participants

become more stringent. For example, with greater than

minimal risk research the process of informed consent

cannot be waived or altered (45 CFR 46.116(d)).

Definition of Minimal Risk

The definition of minimal risk in federal regulations

(45 CFR 46.102(i); 21 CFR 56.102(i)) does not specify

an unambiguous standard. That is, risks involved in the

research study are compared to those encountered in

daily life, but it is unclear whether daily life applies to

healthy individuals or the target group of the research.

Existing sources of guidance offer conflicting interpretations of the standard to be used in determining level of

risk.33 In the context of its discussion of research involving children, the National Commission defined a so-called

absolute standard when it defined minimal risk as “the

probability and magnitude of physical or psychological

harm that is normally encountered in the daily lives, or

in the routine medical or psychological examination, of

healthy children” (National Commission 1977). This

standard was not adopted in the regulations pertaining to

research involving children (45 CFR 46 Subpart D).

However, DHHS regulations concerning research involving prisoners limit minimal risk to the experience of

healthy individuals. In 1993, OPRR endorsed such an

absolute standard interpretation for Subpart A (Ellis

1995). OPRR’s interpretation is inconsistent with DHHS’

intention as expressed in the preamble of the 1981 version

of 45 CFR 46 which stated that “the risks of harm ordinarily encountered in daily life means those risk encountered in the daily lives of the subjects of the research.”34

If minimal risk is not characterized in terms of the

daily life and experiences of healthy individuals, then it

might be taken to refer to the daily life and experiences

of research participants. If this is the case, then the same

intervention could be classified as minimal risk or greater

than minimal risk, depending on the health status of the

research participants and their particular experiences.

For example, a bone marrow aspiration would not be

considered minimal risk in relation to the daily life of a

healthy individual, but it might well be determined to fall

within this category in relation to the experience of a person with acute leukemia. Such an understanding entails

a relative standard for minimal risk.

A relative standard for minimal risk would allow ill

participants to be exposed to greater risks than healthy

participants. Such a standard would impose disproportionate burdens of research on the ill and provide weaker

protections for them than for healthy individuals. This

would violate the ethical principle of justice.

IRBs should use a standard related to the risks of daily

life that are familiar to the general population for determining whether the level of risk is minimal or more than

minimal. The standard should not refer to the particular

risks encountered by particular persons or groups. It

should refer, therefore, to common risks—for example,

driving to work, crossing the street, getting a blood test,

or answering questions over the telephone.35 Research,

then, involves no more than minimal risk when it is

judged that the level of risk is no greater than that

encountered in the daily lives of those in the general 

population. The general population standard is less

restrictive than the healthy individuals standard; however,

the general population standard more accurately captures

the risks that are familiar to most persons.

When a research study is determined to involve no

more than minimal risk, the IRB should also consider

whether the procedures in question pose additional risks

to some of the potential research participants. In such

cases, additional protections might be required to reduce

the level of risk among that subgroup. For example,

drawing a small quantity of blood would normally be

considered a minimal risk procedure; its risks do not

exceed those normally encountered by the general population. However, if a particular research study involved

participants with immunosuppressive disorders, a blood

draw may present a higher level of risk, and additional

procedures to reduce exposure to infections may be

required.

It must be stressed that, in making the determination

that a research study involves no more than minimal risk,

the IRB must take into consideration all types of risk

posed. For example, a research study involving a blood

draw to study HIV might involve not only the relatively

inconsequential physical risks associated with a blood

draw, but also all the nonphysical risks mentioned earlier
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

that might be associated with, for example, learning one’s

HIV status or having that information released to people

other than the investigators.

Use of the Concept of Minimal Risk as a

Sorting Mechanism

The concept of minimal risk serves to focus the IRB’s

attention on riskier research. Minimal risk is used in

determining which research studies can be reviewed

using procedures other than the full IRB (see Chapter 2).

Currently, research studies that are judged to be minimal

risk and fall into one of nine categories of study types

may be reviewed using the expedited process. For purposes of determining level of review, there are no relevant

ethical differences between studies involving minimal

risk that do not fall into one of these categories and those

that do. Therefore, all studies judged to involve no more

than minimal risk should be eligible for review using

procedures other than full IRB review.

Limited Utility of the Category of Minimal Risk

The current regulatory system and IRBs place too

much attention on determining whether research fits into

the minimal risk category. As suggested in the framework

proposed above for the analysis of risks and potential

benefits, risks fall into a two-dimensional continuum of

the likelihood of the harm (probability) and the severity

of the harm if it were to occur (magnitude). Likelihood of

harm runs from very low to high, and the severity of the

harm runs from trivial to fatal. IRBs must judge the combination of these two dimensions. A low likelihood of a

trivial harm would engender little concern, a high likelihood of a trivial harm or a low likelihood of a severe

harm tends to raise more concern, and a high likelihood

of a severe harm is of the greatest concern. Investigators

and IRBs can seek to minimize risks by designing the

study in such a way that there is a reduced likelihood of

possible harms, that the magnitude of possible harms is

reduced, or both. To establish norms for separating risks

into two categories without acknowledging the degree of

variation in those risks might foster a misrepresentation

of the nature of risk, which might result in an inadequate

appreciation of the IRB’s responsibility to insist on appropriate protections and to evaluate and minimize all the

risks involved in a research study.

Indeed, as discussed in Chapter 2, for research studies

involving novel or controversial ethical issues, no single

local IRB should assume sole responsibility for conducting

the analysis of risks and potential benefits. The proposed

National Office for Human Research Oversight should

work with the research community to define such

research. This pool of research is not likely to be large

and might include, for example, certain gene therapy

studies that present novel issues or significant unknown

risk, xenotransplantation studies, studies involving

genetically altered vectors to control certain infectious

diseases, or some studies involving low doses of toxic

substances in humans to test antidotes that present novel

issues or significant and perhaps unknown risks. Some of

these kinds of studies are ethically acceptable and should

be conducted. However, this type of research would 

benefit from additional scrutiny, such as a national review

panel, with public input into the review process. In fact,

investigators should engage the target community of participants in discussion regarding this research, because

having only one or two members who represent the pool

of prospective participants on the IRB might not provide

a sufficient perspective. The purpose of additional review

would be to provide the expertise and experience for

these types of studies and to offer guidance so that they

could be reviewed ultimately by local IRBs.

In two previous reports, NBAC has recommended the

use of national panels for such review—in some areas of

research involving persons with mental disorders that

may affect decisionmaking capacity and for research

using human embryonic stem cells—and the need to

involve the public (NBAC 1998; NBAC 1999b). In both

reports, NBAC asserted that oversight at the national

level could provide the public and policymakers with

additional assurance that research involving high risks is

being carefully reviewed. Some public commentators

expressed strong concerns that such national review

could be burdensome and unnecessarily delay

research.36,37,38 These are legitimate concerns. However,

with careful planning, national oversight mechanisms

could be implemented in ways that are constructive and

that ensure efficiency and timeliness. 
National Bioethics Advisory Commission

85

Recommendation 4.2: Federal policy should 

distinguish between research studies that 

pose minimal risk and those that pose more 

than minimal risk (see Recommendation 2.5). 

Minimal risk should be defined as the probability and magnitude of harms that are normally

encountered in the daily lives of the general 

population. If a study that would normally be

considered minimal risk for the general population nonetheless poses higher risk for any

prospective participants, then the Institutional

Review Board should approve the study only if 

it has determined that appropriate protections

are in place for all prospective participants.

Vulnerability

Because most research involves uncertainty, all research

participants are vulnerable in some sense. However, it

has been suggested that vulnerability, in the context of

research, should be understood to be a condition, either

intrinsic or situational, of some individuals that puts them

at greater risk of being used in ethically inappropriate

ways in research.39

Individuals can be used in ethically inappropriate

ways even if they have given their informed consent to

participate in a research study. For example, poor individuals are enrolled in research even though the benefits

of the research will be used primarily by more economically privileged individuals (Cohen 1996; Kolata and

Eichenwald 1999). In addition, numerous studies have

revealed specific disease associations in certain groups

(e.g., sickle cell disease in African Americans, Tay Sachs

disease and breast cancer in Ashkenazi Jews), which has

led to discrimination and stigmatization when research

results are inappropriately reported (King 1998; Weijer

1999a; Weijer 1999b; Wilkinson 1974). More recently, in

a study testing whether an experimental measles vaccine

could be used in infants too young to receive the standard vaccine, African American and Latino families were

not told that the vaccine was experimental or that it had

been associated with increased death rates in Africa

(Cimons 1996; Gamble 1997; Glenn 1996).

In general, persons are vulnerable in research either

because they have difficulty providing voluntary,

informed consent arising from limitations in decisionmaking capacity (as in the case of children) or situational

circumstances (as in the case of prisoners), or because

they are especially at risk for exploitation (as in the case

of persons who belong to undervalued groups in our

society). An adequate characterization of vulnerability

must attend to both types of concern. 

Current Protections

Subpart A of the federal regulations describes two

requirements related to the enrollment of vulnerable 

persons in research. First, IRBs must determine that “the

selection of subjects is equitable,” and, in so doing,

should be “particularly cognizant of the special problems

of research involving vulnerable populations, such as

children, prisoners, pregnant women, mentally disabled

persons, or economically or educationally disadvantaged

persons” (45 CFR 46.111(a)(3); 21 CFR 56.111(a)(3)).

Second, IRBs must ensure that “when some or all of the

subjects are likely to be vulnerable...additional safeguards have been included in the study to protect the

rights and welfare of these subjects” (45 CFR 46.111(b));

21 CFR 56.111(b) [FDA regulations differ only in sentence

structure]).

Some federal departments have additional regulations

that provide protection for specific groups. The

Department of Education has additional regulations 

protecting children, the Department of Justice has regulations protecting prisoners, and DHHS has additional

protections for selected vulnerable populations: Subpart

B pertains to pregnant women and fetuses, Subpart C to

prisoners, and Subpart D to children. The Central

Intelligence Agency (CIA) and the Social Security

Administration follow the DHHS subparts. From this

summary, it is clear that coverage of vulnerable individuals is uneven across the federal government. This lack of

additional protection is particularly worrisome because,

as shown in Table 4.1, every department (except CIA and

the Department of Transportation) responding to a 

survey conducted by NBAC indicated that it sponsored

or conducted research involving individuals who are 

vulnerable in some way.40

The subparts in the DHHS regulations provide two

general types of substantive protections. First, in some
86

Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

Table 4.1: Agency Sponsorship or Conduct of Research That Targets Participants with

Vulnerabilities*

Mentally Economically Educationally

Pregnant Disabled Disadvantaged Disadvantaged

Agency Children Prisoners Women Fetuses Persons Persons Persons Other

CIA

DOC

NTIA X X X X X X X

NIST X X X

Census X

DOD X X X X X Military

Students

ED X X X X X X

DHHS

ACF X X X X

AHRQ X X X X X

CDC X X X X X X X

FDA X X X

HCFA X X X Elderly

HRSA X X X

IHS X X X X X X X X

NIH X X X X X X X X

OPRR

SAMHSA X X X X X X

HUD X X

DOE X X Workers

DOJ

OJP X X X X X X

COPS X X X X

BOP X X X X

FBI X

DOT

FAA

USCG

FHA

NHTSA

VA X X X X X X Veterans

NASA Workers

NSF X X X X X X X

SSA X X X X

CPSC X

EPA X X X

USAID X X X X

TOTALS 13/16 6/16 8/16 4/16 9/16 10/16 10/16

*Categories of participants are based on the vulnerable groups identified in 45 CFR 46. 

Source: NBAC, “Federal Agency Survey on Policies and Procedures for the Protection of Human Subjects in Research.” This staff analysis is available in

Volume II of this report.
National Bioethics Advisory Commission

87

instances, the regulations limit the level of risk to which

participants with vulnerabilities may be exposed. For

example, two of the four categories of research involving

prisoners are permitted only if the research is no more

than minimal risk and are described as follows: 

(A) study of the possible causes, effects, and processes

of incarceration, and of criminal behavior, provided

that the study presents no more than minimal risk and

no more than inconvenience to the subjects;

(B) study of prisons as institutional structures or of

prisoners as incarcerated persons, provided that the

study presents no more than minimal risk and no more

than inconvenience to the subjects (45 CFR 46.306).

Second, in some cases, the subparts impose stricter

informed consent requirements for vulnerable individuals

as compared to the requirements for competent adult

participants. For example, in the regulations governing

research involving children, permission of the child’s 

parent or guardian (in some cases, permission of both

parents) and assent of the child (if the child is capable of

giving assent) are required before enrollment of the child

can proceed (45 CFR 46.408). 

The current DHHS regulations regarding vulnerable

individuals are beset with various conceptual and practical difficulties. For example, the subparts offer no 

definition of vulnerability and no analysis of the types of

characteristics that render persons vulnerable.41 The list

of vulnerable groups (children, prisoners, pregnant

women, fetuses, mentally disabled persons, and economically and educationally disadvantaged persons) provided

in Subpart A, 45 CFR 46.111 and 21 CFR 56.111 is

incomplete on the one hand and overly broad on the

other. For example, injection drug users, the seriously ill,

the elderly, and undocumented immigrants could, in particular circumstances, also be considered vulnerable.42

On the other hand, vulnerability is sensitive to context,

and individuals may be vulnerable in one situation but

not in another. For example, people of low income are

rendered vulnerable in studies offering large financial

incentives to take on research risk. In addition, the regulations provide inadequate guidance about the types of

safeguards that would be appropriate to protect against

the risks associated with vulnerability. Subpart A of the

regulations requires IRBs to ensure that such individuals

are protected, but it does not describe how to achieve

such protection.43

In addition to the shortcomings in the regulations, at

least two aspects of the current research enterprise suggest a need to evaluate the protections for vulnerable

research participants. Increases in research funding are

leading to more research involving human participants,

and as more people become research participants, more

individuals with vulnerabilities are likely to be included.

Moreover, because clinical research often holds the

prospect of direct benefit and may be perceived as a

means of access to health care, serious illness or lack of

health insurance may significantly intensify a person’s

desire to be involved in research.

Although the use of subparts in the DHHS regulations

makes it clear which groups should be considered 

vulnerable, this advantage is outweighed by several 

disadvantages. Given the limited required safeguards, the

current regulations provide insufficient respect for persons

and are not sufficiently responsive to the full array of 

vulnerability experienced by prospective participants.

The use of regulatory subparts is not the optimal means

by which to protect vulnerable individuals for the 

following reasons:

■ Providing protections for all potentially vulnerable

groups would require developing an unwieldy list of

additional subparts.

■ To the extent that different groups may require the

same types of protection, the addition of a long list of

subparts may introduce unnecessary duplication in

the regulations.

■ A group-based approach to vulnerability leaves unanswered questions about how to safeguard persons

with multiple vulnerabilities.

■ The status of particular groups may change. For

example, as members of a particular group become

increasingly less subjected to stereotypes, they

become increasingly less prone to social vulnerability.

Although IRBs and investigators should remain concerned about this general category of vulnerability,

their treatment of this particular group should reflect

its changing social status. Accommodating such a

changing social reality would require regulatory

change to a group-based subpart approach to vulnerability, but not to an analytical approach. In order to
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

improve the protections found in the current subparts, each subpart would have to be revised based on

an analytical understanding of vulnerability in order

to fully reflect its nature and variability and to contain

appropriate safeguards.

■ Group-based subparts classify certain persons as 

vulnerable, rather than classifying situations in which

individuals might be considered vulnerable. For example, persons with severe illnesses for which there are

no acceptable treatments may be medically vulnerable

in certain kinds of clinical trials, but not vulnerable at

all in many other types of research (e.g., survey

research). 

An analytic approach provides a context-sensitive

understanding of vulnerability that avoids the implementation of unnecessary protections, which not only impede

the progress of research, but also fail to respect the personhood of the potential participants. Thus, an analytical

approach not only provides for greater regulatory efficiency than group-based categorization, but it provides

more appropriate safeguards. Further discussion is

needed regarding the issue of whether a subpart

approach to regulation provides appropriate safeguards.

Nonetheless, the current system of protections should

be revised to accommodate different types of vulnerability.

An analysis of these characteristics or circumstances provides a list of at least six types of vulnerability.44 Each type

of vulnerability is discussed below, and suggestions are

made about the types of safeguards that should be

required to prevent harming participants who are vulnerable in these ways. Historically, such safeguards have

been designed to be protectionistic, focusing exclusively

on the risks involved in research. Thus, vulnerable persons

have too often simply been excluded from research that

might have yielded benefits to them or the groups to

which they belong. In developing appropriate safeguards,

a balance should be reached between protecting vulnerable persons from harm in research and allowing them to

share in its potential benefits (Backlar 2000; Kahn et al.

1998; NBAC 1998).45

Cognitive or Communicative Vulnerability

Prospective research participants who are insufficiently able to comprehend information, deliberate, and

make decisions about participation in a proposed

research study have a cognitive or communicative vulnerability. Prospective participants might be vulnerable in

this way for one of three reasons. First, those with capacityrelated cognitive vulnerability, such as young children, or

adults with cognitive impairments that affect decisionmaking, to some extent lack capacities to make informed

choices. Second, those with situational cognitive vulnerability do not lack capacity, but are in situations that do not

allow them to exercise their capacities effectively, such as

stressful emergencies.46 Third, those with a communicative

vulnerability, such as participants who speak or read 

different languages than do investigators, do not lack

capacity, but are in situations that do not allow them to

exercise their capacities effectively. This type of vulnerability heightens the risk that investigators will not fully

respect the prospective participants because standard

informed consent procedures will not suffice. Because this

report focuses on competent adults, only situational cognitive and communicative vulnerability will be discussed.

Every effort must be made to enable prospective

research participants to exercise autonomous choice

(NBAC 1998, 9, 57), and investigators should make

every effort to reduce situational barriers that impinge on

the ability of prospective participants to exercise their

authority. Sometimes, when a situational barrier is temporary, it might be possible to delay enrollment of

prospective participants until the situation has passed. In

other cases, it might be best to obtain informed consent

from participants before exposure to the situation that

limits autonomy, for example, obtaining consent from

pregnant women who will be studied during labor and

delivery. Sometimes such situations are structural. For

example, sometimes investigators and prospective participants speak different languages. Language barriers can

be reduced by using translators or translating consent

forms.

Institutional Vulnerability

Prospective participants may have an institutional

vulnerability when they have the cognitive capacity to

consent but are subject to the formal authority of others

who may have independent interests in whether the

prospective participant agrees to enroll in the research

study. The most commonly cited examples of individuals
National Bioethics Advisory Commission

89

facing such institutional influences are prisoners and

enlistees in the military, but the category also includes

college students when they are required to be research

participants for course credit or when such participation

could affect their grades. This type of vulnerability

increases the risk that one’s decision concerning participation will not be truly voluntary, consequently

increasing the risk that one’s personhood will not be fully

respected.47 In addition, it presents the risk that the subordinated status of these individuals will be exploited.

To safeguard against the ethically inappropriate

enrollment of institutionally vulnerable persons, special

attention should be paid to both participant selection and

the voluntariness of the choice of prospective participants. Ways to reduce vulnerability might include

working with institutional officials before initiating the

research study to ensure that there are no inappropriate

incentives or pressures to enroll, and when possible, not

informing institutional staff about which individuals are

participating. For example, if study participation takes

one hour, those who refuse could be offered the option of

staying in the study area for an hour. In this way, institutional staff would not know who participated and who

did not.

Selection of participants from within the institutional

setting should be fair and immune from the influence of

institutional authorities. For example, in the informed

consent process, investigators should emphasize that participation is voluntary, and protections should be in place

to protect prospective participants from possible retaliation

for their decisions (e.g., no effect on parole status or

grades). In addition, during the informed consent process,

no institutional authority should be present, except for

possibly an ombudsperson.

Deferential Vulnerability

Prospective participants might have a deferential 

vulnerability when they have the cognitive capacity to

consent but are subject to the authority of others who

might have independent interests in whether prospective

participants agree to enroll in the research study. This 

category raises the concern that the interests of the

prospective participants could be subordinated to those

of others. However, with deferential vulnerability, the

subordination is affected not by formal hierarchies (as it is

with institutional vulnerability), but instead by informal

ones.48 Such informal power relationships can be socially

constructed (e.g., based on gender, race, or class inequalities, or they can be inequalities of power and knowledge

of the kind that occur in doctor-patient relationships), or

they can be more subjective in nature (e.g., parents who

regularly defer to the wishes of their adult children

regardless of their own concerns).49 In any case, deferential vulnerability may be subtle. Like institutional vulnerability, deferential vulnerability heightens the risk that

the prospective participant’s decisions will not be truly

voluntary. In addition, it presents the special risk that the

subordinated status of these individuals will be used to

someone else’s advantage, resulting in their exploitation.

It should be noted that not all deferential behavior is

subordinating. For example, some individuals might so

trust their physicians’ expertise that they defer to them

about enrolling in a research study. Physician-investigators

should be especially aware of this vulnerability, because

when they approach their patients about enrolling in a

research study, they could be concerned that refusing will

negatively affect attitudes toward them or the quality of

care they will receive. Here, as with institutional vulnerability, care must be taken to design the research study to

ensure that the informed consent process is truly voluntary and that investigators do not take advantage of the

subordinated status of prospective participants.

Safeguards might include employing research staff who

are sensitive to such deference and who can assess

whether the participant is truly exercising autonomy and

who can adjust the informed consent process to the

prospective participant. Investigators should consider

whether to have discussions with the prospective participant with or without the presence of the party to whom

he or she ordinarily defers.

Medical Vulnerability

This category concerns potential participants who

have serious health conditions for which there are no

satisfactory standard treatments (e.g., metastatic cancer

or rare disorders).50 Seriously ill individuals are often

drawn to research because they or their physicians

believe it is the best alternative to standard treatment. In

these dire circumstances it can be difficult for prospective

participants to weigh the risks and potential benefits
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

associated with the research. This type of vulnerability

increases the risk that informed consent might be based

on misunderstanding potential benefits or might be

motivated by a desire to find a treatment. It also increases

the risk that these participants will be exploited, because

either they have unreasonable expectations about the

potential benefits or investigators mislead them about

risks and potential benefits, and the risks are not reasonable in relation to the potential benefits (Brody 1998).51

In research involving the medically vulnerable, every

effort must be made to ensure that prospective participants are presented with accurate information (to avoid

exploitation) and that they comprehend that information. Assuring appropriate comprehension might require

more than attending to the clarity of information provided. Because physician-investigators might harbor

unrealistic expectations for their patients-participants,

and because patients-participants too easily blur the roles

played by physician-investigators, these situations can

lead to what has been called the therapeutic misconception

(Appelbaum et al. 1987; Fost 1998; Levine 1992). In

these cases, medical vulnerability could be reduced by

having an impartial third party approach prospective 

participants about enrollment and conduct the informed

consent process or by having investigators make third

parties available to discuss the research. Prospective participants could also be given time to consider the risks

and potential benefits of the study and make a decision

about participation. As much as possible, individuals

should not learn of a diagnosis or that a standard treatment has failed at the same time that they are being asked

to participate in a research study.

Some safeguards relating to physician-investigators

can be used. Separating the multiple roles of physicians

can help to reduce the therapeutic misconception. For

example, when possible, the treating physician should

not be the investigator. In addition, regular and ongoing

education of physicians regarding the informed consent

process will reduce the likelihood of overemphasizing

potential benefits and underemphasizing risks.

To avoid the exploitation of prospective participants,

every effort should be made to optimize the balance

between risks and potential benefits in such research

without compromising its scientific integrity (Brody

1998).52 IRBs can play a significant role in reducing 

medical vulnerability by carefully weighing the risks and

potential benefits to be certain that procedures that offer

the prospect of direct benefit are not used to justify procedures that involve considerable risk and no prospect of

direct benefit. Further, in doing so, IRBs would ensure

that prospective participants are offered a “reasonable

choice.”

Economic Vulnerability

Prospective participants might have an economic 

vulnerability when they have the cognitive capacity to

consent but are disadvantaged in the distribution of

social goods and services such as income, housing, or

health care. This type of vulnerability heightens the risk

that the potential benefits from participation in the

research study might constitute undue inducements to

enroll, threatening the voluntary nature of the choice and

raising the danger that the potential participant’s distributional disadvantage could be exploited. For example,

offers of large sums of money as payment for participation or access to free health care services (for conditions

not related to the research) could lead some prospective

participants to enroll in a research study when it might be

against their better judgment and when otherwise they

would not do so. To safeguard against this vulnerability,

IRBs should make certain that research offers a “reasonable choice” to prospective participants. This might be an

easy assessment for the IRB reviewing a research study in

which payment is involved, and the amount of payment

could be reduced. However, it can be more difficult for

the IRB when the potential benefits include access to free

medical care or social or other services.

Social Vulnerability

Prospective participants might have a social vulnerability when they have the cognitive capacity to consent

but belong to undervalued social groups. The treatment

of members of such groups is not simply attributable to

their economic vulnerability, although it is true that

members of undervalued groups often lack financial

resources. Social vulnerability is a function of the social

perception of certain groups, which includes stereotyping

and can lead to discrimination. In any case, the perceptions devalue members of such groups, their interests,

their welfare, or their contributions to society.
National Bioethics Advisory Commission

91

These social perceptions are pervasive and often

insidious and can affect persons’ conceptions of certain

groups. Thus, investigators, IRB members, and research

sponsors should be sensitive to such social perceptions

and their effects, and efforts should be made to allow

members of such groups to participate in decisionmaking

and oversight processes (CDC et al. 1998; Eckenwiler

1999; Eckenwiler 2000). Involving the community in the

various stages of the research process, especially in study

planning, can be helpful in reducing stereotyping and

stigmatization. Also, investigators and IRBs should consider whether studies can be designed to include participants from all segments of society, rather than only or

primarily from socially undervalued segments.

Aligning Protections with Vulnerabilities

Although there may be some overlap among the six

distinct, ethically relevant types of vulnerability

described above, each depicts a particular susceptibility

to be used in ethically inappropriate ways in research.

Moreover, many individuals might experience more than

one of these vulnerabilities. For example, prospective

participants might be poor, seriously ill, and not conversant in English. When multiple vulnerabilities exist,

appropriate safeguards to address each vulnerability

should be in place.

This model improves on the current DHHS regulations, which focus on groups of vulnerable people rather

than on types of vulnerability, in three ways. First, it recognizes a fuller array of vulnerabilities that might be

experienced by members of a particular group, while

current regulations often fail to recognize that members

of a vulnerable group might be vulnerable in more than

one way. For example, current regulations recognize the

institutional vulnerability of prisoners, but not their economic or social vulnerability. Second, the model portrays

certain individuals as vulnerable in certain circumstances, while the current regulations classify entire

groups as vulnerable. For example, current regulations

classify all pregnant women as vulnerable, even though

women are seldom vulnerable because of the pregnancy

itself. Rather, pregnant women might at certain times be

medically vulnerable (e.g., during labor). In addition, the

current regulations classify economically disadvantaged

persons as vulnerable, but, in certain situations, they

would not be (e.g., certain types of survey research

involving no remuneration). 

The proposed model better expresses respect for 

persons by allowing people to be treated as individuals

rather than as members of a group. Such an analytical

model both challenges investigators and enables them

and IRBs to extend their consideration of vulnerability

beyond the incomplete list of vulnerable groups provided

in the current regulations and to account for variations

among prospective participants. 

Third, the model also suggests appropriate safeguards

for each type of vulnerability. The current system proposes two general sorts of safeguards: limiting the risk to

which participants may be exposed and implementing

stricter consent requirements. Given the limited variety

of substantive safeguards required, current regulations

are not sufficiently responsive to the full array of vulnerabilities. Safeguards must be tailored to respond to 

particular types and should avoid the exclusively protectionistic attitude toward vulnerability inherent in the

current regulations. In general, the suggested safeguards

have been designed to strike a balance between protecting vulnerable persons from harm and allowing them to

reap the potential benefits of participation in research.

For all types of vulnerability, IRBs should ensure that

the risks to which vulnerable persons are exposed would

be acceptable to all prospective participants, i.e., those

who are vulnerable as well as those who are not. Because

the perspectives and experiences of vulnerable persons

can differ considerably from those who are not vulnerable,

vulnerable persons should be encouraged to participate

in the study design and oversight processes (CDC et al.

1998; Eckenwiler 1999; Eckenwiler 2000).53 Such participatory processes serve as important safeguards in

research involving vulnerable persons and can help to

build trust in the research enterprise.

In designing a research study, investigators should

consider how they would handle prospective participants

who are vulnerable. To the extent possible, investigators

and IRBs should try to identify, at the time of the IRB’s

initial review of a research study, the types of vulnerabilities of individuals who might be enrolled. In many

studies, enrolling prospective participants who might be
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

vulnerable can be anticipated by its stated purpose and

design or by the inclusion criteria. When such individuals

can be identified up front, IRBs can require that appropriate safeguards be in place before the initiation of the

study. However, in some studies, it might not be possible

to anticipate the inclusion of prospective participants

with vulnerabilities until enrollment. In general, such

prospective participants should not be enrolled until the

protocol has been discussed with the IRB and then

potentially revised and approved. IRBs should not halt

the study, but should consider delaying enrollment of

these individuals. In addition, IRBs should develop

mechanisms for reviewing such protocols.

Finally, unless the particular research study requires

such an approach (e.g., a research study of the efficacy of

a particular drug when used in children), as a matter of

justice, it is never appropriate to target persons with vulnerabilities for disproportionate inclusion or exclusion in

research. This position is endorsed in a previous NBAC

report (NBAC 1998).

Use of Minimal Risk as It Relates to

Vulnerability

It has been suggested that research involving no more

than minimal risk should receive full IRB board review if

it involves vulnerable persons.54 However, this is not 

necessarily true. If all types of risk are identified and considered and research components are appropriately

determined to involve no more than minimal risk, then

such research should be eligible for review using procedures other than full IRB review, because such research,

by definition, involves no more risk than is normally

encountered in the daily life of the general population. To

require full board review for research involving such 

little potential for harm is to adopt an unsupportable protectionist stance that imposes unnecessary bureaucratic

procedures. The protection of vulnerable research participants must be balanced with the pursuit of benefits both

to those participants and to society. At the same time, any

review of research involving vulnerable individuals is

responsible for ensuring that the protections include

appropriate safeguards to protect against the particular

vulnerabilities involved. However, as the level of risk

increases above minimal risk, the level of scrutiny should

also increase, as should the protections required by an

IRB.

Appropriate type-specific safeguards should be put in

place to protect persons with such vulnerabilities. For

example, for research involving socially vulnerable persons, it is appropriate to educate investigators, IRBs, and

sponsors about stigmatizing and discriminatory social

conceptions of these persons and to design studies to

avoid the reflection or perpetuation of such problematic

social conceptions. Given the existence of such safeguards, investigators should not exclude such persons

from research involving greater than minimal risk in any

of the components, for to exclude them would be to

deprive them of whatever potential direct benefits they

might receive from the research and to deprive their 

communities and society in general from the benefit of

knowledge the research might generate. Moreover, to

exclude these persons would be to treat them as though

they are not autonomous agents, which would be a violation of the principle of respect for personhood. Once

safeguards are in place that are tailored to address their

particular variety (or varieties) of vulnerability, vulnerable persons who have the cognitive capacity to provide

informed consent should be allowed to exercise

autonomous choice about their participation in research.

IRBs should exclude such persons from research studies

only if they determine that appropriate safeguards cannot

satisfactorily be put in place. However, efforts must be

made to institute these safeguards and to allow for the

inclusion of such persons in the research study.

Recommendation 4.3: Federal policy should 

promote the inclusion of all segments of society

in research. Guidance should be developed on

how to identify and avoid situations that render

some participants or groups vulnerable to harm

or coercion. Sponsors and investigators should

design research that incorporates appropriate

safeguards to protect all prospective participants.
National Bioethics Advisory Commission

93

Summary

No person should be enrolled in research until an IRB

concludes that the risks are reasonable in relation to the

potential benefits. Research studies often involve multiple

components or procedures. With some components, the

procedures that participants will endure will involve

some risk with no direct potential benefit accruing to

them. In these situations, some limitation should be

placed on the amount of risk that can be imposed, regardless of the participants’ willingness to participate. Other

components of a study might involve procedures that also

offer the prospect of direct benefit—for example, when

standard medical interventions are being compared in a

patient population. In such cases, it is essential that participants and investigators do not fall into the therapeutic

misconception, in which they come to believe that 

participating in research is tantamount to being in a more

traditional therapeutic relationship. Thus, for research

that has both types of components, it is important that

risks and potential benefits be appropriately evaluated by

the IRB. In other words, the possibility that one component of a study will provide benefits should not be used

to justify otherwise unacceptable elements of the

research, the potential benefits of which (if any) accrue

solely to society.

Even when risks are reasonable and informed consent

is obtained, it may nonetheless be wrong to enroll certain

individuals as participants. Although individuals should

not be arbitrarily excluded from research because they

are viewed as vulnerable, often it is not any personal

characteristic that causes this vulnerability, but certain

situations that make individuals prone to exploitation.

Often, safeguards can be provided in the research so that

it does not create situations in which people are unnecessarily harmed and so that it protects their rights and

welfare. Research participants should be treated equally

and with respect, and whenever possible, research

should be designed to encourage the participation of all

groups, while protecting their rights and welfare.

Notes

1 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

2 See Goldman, J., “Privacy and Confidentiality in Health

Research.” This background paper was prepared for NBAC and 

is available in Volume II of this report.

3 See Prentice, E.D., and B.G. Gordon, “Institutional Review Board

Assessment of Risks and Benefits Associated with Research.” This

background paper was prepared for NBAC and is available in

Volume II of this report.

4 Ibid.

5 Ibid.

6 Ibid.

7 See Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” This background paper was 

prepared for NBAC and is available in Volume II of this report.

8 See Prentice, E.D., and B.G. Gordon, “Institutional Review Board

Assessment of Risks and Benefits Associated with Research.” This

background paper was prepared for NBAC and is available in

Volume II of this report.

9 See Prentice, E.D., and B.G. Gordon, “Institutional Review Board

Assessment of Risks and Benefits Associated with Research.” This

background paper was prepared for NBAC and is available in

Volume II of this report.

10 See Buchanan, A., “An Ethical Framework for Biological

Samples Policy.” This background paper was prepared for NBAC

and is available in Volume II of Research Involving Human Biological

Materials: Ethical Issues and Policy Guidance, B-1–B-31, 1999.

11 Ibid.

12 See Prentice, E.D., and B.G. Gordon, “Institutional Review

Board Assessment of Risks and Benefits Associated with Research.”

This background paper was prepared for NBAC and is available in

Volume II of this report.

13 See Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” This background paper was 

prepared for NBAC and is available in Volume II of this report.

14 See Prentice, E.D., and B.G. Gordon, “Institutional Review

Board Assessment of Risks and Benefits Associated with Research.”

This background paper was prepared for NBAC and is available in

Volume II of this report.

15 IRBs should recognize, however, in their deliberations that

some risks to others should not be considered in their assessment—for example, financial losses to a company in a research

study involving a licensed product, reputational damage to an

institution, or inability of the investigator to publish study results. 
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Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

16 See Prentice, E.D., and B.G. Gordon, “Institutional Review

Board Assessment of Risks and Benefits Associated with Research.”

This background paper was prepared for NBAC and is available in

Volume II of this report.

17 See Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” This background paper was 

prepared for NBAC and is available in Volume II of this report..

18 Ibid.

19 Ibid.

20 Ibid.

21 Ibid.

22 Ibid.

23 Ibid.

24 Ibid.

25 Ibid.

26 Ibid.

27 Ibid.

28 Ibid.

29 Ibid.

30 Ibid.

31 The Commission has discussed the concept of minimal risk at

some length (NBAC 1998).

32 See Prentice, E.D., and B.G. Gordon, “Institutional Review

Board Assessment of Risks and Benefits Associated with Research,”

and Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” These background papers were

prepared for NBAC and are available in Volume II of this report. 

33 Ibid.

34 46 Fed. Reg. 8366. 

35 See Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” This background paper was 

prepared for NBAC and is available in Volume II of this report.

36 Letter from J.E. Fanale, American Geriatrics Society, to H.T.

Shapiro. February 15, 2001. Providing comments on a draft of this

report.

37 Letter from M.J. Werner, Biotechnology Industry Organization,

to NBAC. February 16, 2001. Providing comments on a draft of

this report.

38 Letter from S. McConnell, Alzheimer’s Association, to H. T.

Shapiro. February 19, 2001. Providing comments on a draft of 

this report.

39 See Kipnis, K., “Vulnerability in Research Subjects: A Bioethical

Taxonomy,” and Moreno, J, “Protectionism in Research Involving

Human Subjects.” These background papers were prepared for

NBAC and are available in Volume II of this report. See Fisher,

C.B., “Relational Ethics and Research with Vulnerable Populations.”

This background paper was prepared for NBAC and is available 

in Volume II of the report Research Involving Persons with Mental

Disorders That May Affect Decisionmaking Capacity, 29–49, 1998. 

40 NBAC, “Federal Agency Survey on Policies and Procedures for

the Protection of Human Subjects in Research.” This staff analysis

is available in Volume II of this report.

41 See Kipnis, K., “Vulnerability in Research Subjects: A Bioethical

Taxonomy.” This background paper was prepared for NBAC and is

available in Volume II of this report.

42 Ibid.

43 Ibid.

44 Ibid.

45 Ibid.

46 Ibid.

47 Ibid. 

48 Ibid.

49 Ibid. 

50 Ibid. 

51 Ibid.

52 Ibid. 

53 See Fisher, C.B., “Relational Ethics and Research with

Vulnerable Populations.” This background paper was prepared 

for NBAC and is available in Volume II of the report Research

Involving Persons with Mental Disorders That May Affect

Decisionmaking Capacity, 29–49, 1998.

54 See Weijer, C., “The Ethical Analysis of Risks and Potential

Benefits in Human Subjects Research: History, Theory, and

Implications for U.S. Regulation.” This background paper was 

prepared for NBAC and is available in Volume II of this report.
National Bioethics Advisory Commission

95

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Eckenwiler, L.A. 1999. “Pursuing Reform in Clinical Research:

Lessons from Women’s Experience.” Journal of Law, Medicine, and

Ethics 27(2):158–170.

———. 2000. “Moral Reasoning and Review of Research Involving

Human Subjects.” Unpublished Manuscript. NBAC archives.

Ellis, G.B. 1995. Federal Policy for the Protection of Human

Subjects. In Report on the Public Forum on Informed Consent in

Clinical Research Conducted in Emergency Circumstances.

Rockville/Bethesda, MD: FDA/NIH.

Fitzgerald, J.L., and M. Hamilton. 1996. “The Consequences of

Knowing Ethical and Legal Liabilities in Illicit Drug Research.”

Social Science and Medicine 43(11):1591–1600.

———. 1997. “Confidentiality, Disseminated Regulation and

Ethico-Legal Liabilities in Research with Hidden Populations of

Illicit Drug Users.” Addiction 92(9):1099–1107.

Fost, N. 1998. “Ethical Dilemmas in Medical Innovation and

Research: Distinguishing Experimentation from Practice.” Seminars

in Perinatology 22(3):223–232.

Freedman, B. 1987a. “Equipoise and the Ethics of Clinical

Research.” New England Journal of Medicine 317(3):141–145.

———. 1987b. “Scientific Value and Validity as Ethical

Requirements for Research: A Proposed Explication.” IRB: A Review

of Human Subjects 9(6):7–10.

Gamble, V.N. 1997. “Under the Shadow of Tuskegee: African

Americans and Health Care.” American Journal of Public Health

87(11):1773–1778.

Glass, K.C., C. Weijer, T. Lemmens, R.M. Palmour, and S.H.

Shapiro. 1997. “Structuring the Review of Human Genetics

Protocols, Part II: Diagnostic and Screening Studies.” IRB: A Review

of Human Subjects Research 19(3–4):1–13.

Glenn, B. 1996. “Bad Blood Once Again.” St. Petersburg Times, 21

July, 5-D.

Kahn, J.P., A.C. Mastroianni, and J. Sugarman, eds. 1998. Beyond

Consent: Seeking Justice in Research. New York: Oxford University

Press.

King, P.A. 1998. “Race, Justice, and Research.” In Beyond Consent:

Seeking Justice in Research, eds. J.P. Kahn, A.C. Mastroianni, and 

J. Sugarman, 88–110. New York: Oxford University Press.

Kolata, G., and K. Eichenwald. 1999. “Stopgap Medicine: A Special

Report. For the Uninsured, Drug Trials are Health Care.” New York

Times, 22 June, A-1.

Levine, R.J. 1986. Ethics and Regulation of Clinical Research. 2d ed.

New Haven: Yale University Press.

———. 1992. “Clinical Trials and Physicians as Double Agents.”

Yale Journal of Biology and Medicine 65(2):65–74.

Marteau, T.M., and R.T. Croyle. 1998. “Psychological Responses to

Genetic Testing.” British Medical Journal 316(7132):693–696.

Martin, D.K., E.M. Meslin, N. Kohut, and P.A. Singer. 1995. “The

Incommensurability of Research Risks and Benefits: Practical Help

for Research Ethics Committees.” IRB: A Review of Human Subjects

Research 17(2):8–10.

Meiser, B., and S. Dunn. 2000. “Psychological Impact of Genetic

Testing for Huntington’s Disease: An Update of the Literature.”

Journal of Neurology, Neurosurgery and Psychiatry 69(5):574–578.

Milgram, S. 1974. Obedience to Authority: An Experimental View. 

1st ed. New York: Harper and Row.

National Bioethics Advisory Commission (NBAC). 1998. 

Research Involving Persons with Mental Disorders That May Affect

Decisionmaking Capacity. 2 vols. Rockville, MD: U.S. Government

Printing Office.

———. 1999a. Ethical Issues in Human Stem Cell Research. 3 vols.

Rockville, MD: U.S. Government Printing Office.
96

Chapter 4: Assessing Risks and Potential Benefits and Evaluating Vulnerability

———. 1999b. Research Involving Human Biological Materials:

Ethical Issues and Policy Guidance. 2 vols. Rockville, MD: U.S.

Government Printing Office.

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission). 1975.

Report and Recommendations: Research on the Fetus. Washington,

D.C.: DHEW. 

———. 1976. Report and Recommendations: Research Involving

Prisoners. Washington, D.C.: DHEW.

———. 1977. Report and Recommendations: Research Involving

Children. Washington, D.C.: DHEW.

———. 1978. Report and Recommendations: Institutional Review

Boards. Washington, D.C.: U.S. Government Printing Office.

———. 1979. Belmont Report: Ethical Principles and Guidelines for

the Protection of Human Subjects of Research. Washington, D.C.: 

U.S. Government Printing Office.

Office for Protection from Research Risks (OPRR). 1993. 

Protecting Human Research Subjects. Institutional Review Board

Guidebook. Washington, D.C.: U.S. Government Printing Office.

President’s Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research (President’s

Commission). 1982. Compensating for Research Injuries: The 

Ethical and Legal Implications of Programs to Redress Injured Subjects.

Washington, D.C.: U.S. Government Printing Office.

Singer, M. 2000. Qualitative Methods and Preliminary Findings on

Sterile Syringe Access and Use Among Injection Drug Users in Three

Northeastern Cities. 20 September. Presentation at Centers for

Disease Control and Prevention. Atlanta, Georgia. 

Singer M., T. Stopka, C. Siano, K. Springer, G. Barton, K.

Khoshnood, A.G. de Puga, and R. Heimer. 2000. “The Social

Geography of AIDS and Hepatitis Risk: Qualitative Approaches 

for Assessing Local Differences in Sterile-Syringe Access Among

Injection Drug Users.” American Journal of Public Health

90(7):1049–1056.

Weijer, C. 1999a. “Selecting Subjects for Participation in 

Clinical Research: One Sphere of Justice.” Journal of Medical 

Ethics 25:31–36.

———. 1999b. “Protecting Communities in Research:

Philosophical and Pragmatic Challenges.” Cambridge Quarterly of

Healthcare Ethics 8(4):501–513. 

Wilkinson, D.Y. 1974. “For Whose Benefit? Politics and Sickle

Cell.” The Black Scholar 5:26–31.
Introduction

Two analyses that are central to the ethical review

conducted by Institutional Review Boards (IRBs) are

an appraisal of the informed consent process to be used

in a proposed research study and a determination of the

extent to which the privacy and confidentiality of the

potential participants will be protected. The current regulatory requirements relating to these ethical issues

reflect the concept of respect for persons, as espoused in

the Belmont Report: Ethical Principles and Guidelines for the

Protection of Human Subjects of Research (Belmont Report)

(National Commission 1979). Informed consent

becomes an essential protection, however, only after

research has been determined to be ethically justifiable in

terms of beneficence and justice. Adherence to these

principles in the review of research serves a gatekeeper

function, permitting only ethically acceptable research

involving human participants to proceed.1

Voluntary Informed Consent

The principle of respect for persons requires that 1) individuals are treated as autonomous agents and 2) that persons with diminished autonomy are protected (National

Commission 1979). (This report addresses informed

consent only in the context of research involving competent adults.) An autonomous agent is “an individual

capable of deliberation about personal goals and of

acting under the direction of such deliberation” (National

Commission 1979, 5). Respect for persons requires that

prospective research participants “be given the opportunity to choose what shall or shall not happen to them”

and thus necessitates adequate standards for informed

consent (National Commission 1979, 10). As Vanderpool

notes, the Belmont Report’s insistence on informed consent

“accords with the fundamental moral values of a free and

democratic society.” 2

The informed consent process involves three elements:

1) disclosing information to potential research participants, 2) ascertaining that they understand what has

been disclosed, and 3) ensuring their voluntariness in

agreeing to participate in research (Faden and

Beauchamp 1986). The disclosure of information should

be sufficient “such that persons...can decide whether

they wish to participate in the furthering of knowledge”

(National Commission 1979, 11). Even when some

direct benefit to participants may be anticipated, this

high standard for disclosure should be met, because

research inherently involves uncertainty and is always

designed to acquire knowledge. To ensure comprehension,

the presentation of information must be adapted to the

potential participant’s capacities and characteristics, and

great care must be taken to ascertain that the prospective

participant understands the information. Extra efforts

may be warranted to verify comprehension when risks

are especially high or there is uncertainty whether the

prospective participants are capable of understanding the

risks. For consent to be voluntarily given, the process

must be free of coercion and undue influence.

In previous reports, NBAC has focused much of its

attention on addressing specific issues related to

informed consent that arise from the interpretation of

existing regulations. (See Exhibit 5.1.) This chapter looks

beyond current regulations to focus on the overall scope

and structure of the requirements for informed consent

and focuses specifically on four issues: 1) emphasis on

97

Ensuring Voluntary Informed

Consent and Protecting Privacy

and Confidentiality

Chapter Five 5
98

Chapter 5: Ensuring Voluntary Informed Consent and Protecting Privacy and Confidentiality

disclosure; 2) appropriateness of informed consent

processes for different types of research; 3) waiver of the

informed consent process; and 4) documentation of the

informed consent process. 

Deficiencies with the Current Regulations

Federal regulations permit IRBs to approve research

when informed consent is sought and documented from

each prospective participant (45 CFR 46.111(a)(4)-(5);

21 CFR 56.111(a)(4)-(5)). Requirements for informed

consent are further described in two sets of federal 

regulations in 45 CFR 46.116 and 45 CFR 46.117, and

21 CFR 50.20, 50.25, 50.27 and 56.109. There are substantial differences between the two sets of requirements;

the most notable being that the FDA regulations do not

contain the criteria for waiver or alteration of informed

consent as described in 45 CFR 46.116(d). The current

regulatory system specifies eight basic elements of information disclosure that must be provided to prospective

participants during the informed consent process, except

in cases of an approved waiver or alteration of the consent

process by the IRB. (See Exhibit 5.2.)

Also specified are six additional elements of disclosure that must be included when appropriate (46 CFR

46.116(b); 21 CFR 50.25(b)). The regulations for documentation require that, except in specified circumstances, “informed consent shall be documented by the

use of a written consent form approved by the IRB and

signed by the subject or the subject’s legally authorized

representative” (45 CFR 46.117(a); 21 CFR 50.27(a)

[FDA regulations differ in requiring that the form be

dated at the time the consent form is signed]). 

Emphasis on Disclosure

Although the regulations pertaining to informed

consent (45 CFR 46.116; 21 CFR 50.20) begin with a

paragraph from the Belmont Report related to the “three

elements” of consent—information, comprehension, and

voluntariness—the actual procedures emphasize disclosure requirements, and in so doing may distort the

understanding of the ethical principle of respect for

persons.3 Especially in the context of requirements that

informed consent be documented using signed, written

forms, this exclusive emphasis on information leads

Exhibit 5.1:

Previous NBAC Recommendations

Regarding Informed Consent

NBAC has addressed the issue of informed consent

in four previous reports (NBAC 1998; NBAC 1999a;

NBAC 1999b; NBAC 2001), and, because the topic is

central to the protections offered to research participants, recommendations regarding informed consent

have played a key role in each of these reports.

NBAC, for example:

1. fully supports the principle of voluntary informed

consent as an essential safeguard to protect 

participants’ rights and welfare (NBAC 1998;

NBAC 1999a; NBAC 1999b; NBAC 2001);

2. has acknowledged that certain research contexts

may require greater flexibility in procedures used

to obtain consent, for example, where cultural or

language differences exist (NBAC 1999b; NBAC

2001);

3. recognizes the importance of appropriate limitations regarding the use of substitute or third-party

consent (NBAC 1998);

4. recommends that individuals be provided with 

certain options for providing informed consent

regarding future research studies (NBAC 1998;

NBAC 1999b);

5. acknowledges that it is sometimes difficult to 

distinguish between research and treatment and

has suggested that the distinction needs to be

clear to participants (NBAC 1998; NBAC 1999b;

NBAC 2001); 

6. recognizes the importance of limiting coercion or

undue influence in obtaining voluntary informed

consent (NBAC 1999b; NBAC 2001); 

7. recognizes that informed consent should be

sought from donors who are contributing biological

materials to research (NBAC 1999b); and

8. emphasizes that informed consent is a process

and not merely a form to be signed in a routine

manner (NBAC 1998; NBAC 1999b; NBAC 2001).
National Bioethics Advisory Commission

99

investigators and IRBs to equate informed consent with

the information provided in a consent form and to focus

mostly on disclosures to participants.4 Thus, these regulations fail to emphasize the informed consent process

and to attend to the importance of comprehension and

voluntariness, a failure the implications of which have

been described in previous NBAC reports (NBAC 1998;

NBAC 2001). Moreover, others have noted that the 

particular emphasis on disclosure in informed consent is

a product of legal and regulatory thinking that equates

informed consent solely with the requirements to disclose information (Beauchamp and Childress 1994, 145).

This emphasis is not, however, fully conducive to the

more comprehensive view of informed consent, which

emphasizes the aspects of understanding, capacity to

consent, voluntariness, and features of decisionmaking,

including who may authorize consent (Beauchamp and

Childress 1994; Faden and Beauchamp 1986).

Empirical evidence suggests that these regulatory

shortcomings all too frequently result in failures to

achieve voluntary informed consent (Verheggen et al.

1996; Waggoner and Mayo 1995). For example, a study

by the Advisory Committee on Human Radiation

Experiments (ACHRE) reviewed materials submitted to

and approved by IRBs from a sample of federally funded

studies. Generally, consent forms were difficult to understand, requiring an advanced reading level and including

technical language and overwhelming level of detail

(ACHRE 1995, 707). Difficulty in understanding consent

forms has been reported in many research studies

(Blenkinsop 1997; Hochhauser 1997; Waggoner and

Mayo 1995; Young et al. 1990). Indeed, another study by

ACHRE found that at least some individuals failed even

to understand whether they had participated in research

at all. At least 5 percent of patients who reported they

were not research subjects actually were, and at least 6

percent of patients who reported they were in research

actually were not (ACHRE 1995, 736). In general, these

studies reveal the deficiencies in the standard practice of

seeking informed consent. Anecdotal evidence in support of these findings was provided at each of the five

town meetings held by NBAC. For example, IRBs are

concerned that there is too much emphasis on consent

forms, that forms are too long and written at a reading

level that is too advanced, and most important, that 

participants often do not understand to what they are

giving their consent.5

Rather than focusing on the ethical standard of

informed consent and what that entails for the process of

obtaining informed consent, IRBs and investigators have

Exhibit 5.2: Required Elements of

Disclosure

1. A statement that the study involves research, an

explanation of the purposes of the research and

the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which

are experimental.

2. A description of any reasonably foreseeable risks

or discomforts to the subject.

3. A description of any benefits to the subject or to

others which may reasonably be expected from

the research.

4. A disclosure of appropriate alternative procedures

or courses of treatment, if any, that might be

advantageous to the subject.

5. A statement describing the extent, if any, to which

confidentiality of records identifying the subject will

be maintained.

6. For research involving more than minimal risk, an

explanation as to whether any compensation and

an explanation as to whether any medical treatments are available if injury occurs, and, if so,

what they consist of or where further information

may be obtained.

7. An explanation of whom to contact for answers to

pertinent questions about research and research

subjects’ rights, and whom to contact in the event

of a research-related injury to the subject.

8. A statement that participation is voluntary, refusal

to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and

the subject may discontinue participation at any

time without penalty or loss of benefits to which

the subject is otherwise entitled (45 CFR

46.116(a); 21 CFR 50.25(a) [FDA regulations 

differ in requiring an additional statement that 

FDA may inspect records]).
100

Chapter 5: Ensuring Voluntary Informed Consent and Protecting Privacy and Confidentiality

followed the lead of the regulations and tended to focus

on disclosures found in the consent form. However, from

an ethics perspective, the informed consent process is the

critical communication link between the prospective participant and the investigator, beginning with the initial

approach of the investigator to the participant (e.g., via a

flyer, brochure, or any advertisement regarding the

research study) and continuing until the end of the project. It should be an active process of sharing information

by both parties throughout which the participant at any

time is able to freely decide whether to withdraw or continue participating in the research. The consent form, if

there is one, is intended only to document the interaction

between the participant and the investigator, and it is

only one part of the informed consent process. It is time

to emphasize the process of informed consent, with the

goals of ensuring that information is fully disclosed, that

competent participants fully understand the research so

that they can make informed choices, and that their decisions whether to participate are always made voluntarily.

Informed Consent Processes Appropriate for

Various Research Settings

Although placing greater emphasis on the informed

consent process is crucial, it is also important to tailor the

process to suit the type of research being proposed and

the interests and situations of the potential participants.

The eight basic elements of disclosure specified in 

45 CFR 46.116(a) and 21 CFR 50.25(a) are appropriate

for clinical research, but some of them are inappropriate

to the point of being nonsensical for other types of

research, especially behavioral and social science or historical research. For example, the basic element requiring

“a disclosure of appropriate alternative procedures or

courses of treatment, if any, that might be advantageous

to the subject” (45 CFR 46.116(a)(4); 21 CFR 50.25(a)(4))

makes little sense for research studies involving no interventions. Because of this requirement, forms often contain

illogical statements that can confuse participants. Some

IRBs and the Office for Human Research Protections

(OHRP) require a statement in the consent form, for

example, that the advantageous alternative procedure or

treatment is to not participate in the research. Similarly,

including a statement that refusal to participate will

involve no penalty or loss of benefits (45 CFR

46.116(a)(8); 21 CFR 5025(a)(8)) raises concerns in

some survey research in which there are no benefits to be

lost; in such cases, participants may become unduly

alarmed (McQuillan et al. 2000).

Although any of these basic elements of consent can

be altered or waived, the current criteria for doing so are

often difficult to meet. One of the criteria for alteration 

or waiver is that the research could not practicably be

carried out without the waiver or alteration (45 CFR

46.116(d)(3)). Because IRBs often interpret “could not

practicably be carried out” to mean impossible to carry

out, they require the element of disclosure to be

included, often in a less than meaningful way (NBAC

1999b). In other cases, investigators and IRBs spend much

time documenting alteration or waiver justifications in

order to meet the stringent standards set in the criteria,

even though those criteria are not relevant within the

context of the research.

Moreover, when considering what information

should be provided to prospective participants, IRBs and

investigators should strive to ascertain what would be

important to the prospective participants from the 

participants’ perspectives. For example, before initiating

research on genetic screening for breast cancer, investigators held focus groups with prospective participants to

ask them what they were interested in knowing about the

proposed research. Rather than being solely interested in

the type of information required under the regulations

for disclosure, prospective participants were interested in

knowing about options to reduce the risk of developing

cancer, the cost of testing, and insurance coverage for the

test. This information would not have been included in

the informed consent process without input from

prospective participants (Bernhardt et al. 1997).

Moreover, this information was as relevant to their 

decisionmaking as the information required under the

regulations. Elsewhere, NBAC has recommended that

prospective participants can provide valuable input into

the type of information other prospective participants

might want to learn by involving them in the design of

studies and the informed consent process (NBAC 1998;

NBAC 1999b; NBAC 2001).
National Bioethics Advisory Commission

101

One specific type of research worthy of mention is

deception research. Methods related to deception are

sometimes the only valid ones for addressing an issue or

question (e.g., study of prejudice). There has been longstanding debate among psychologists and ethicists about

the merits of this research (Nicks et al. 1997). In all imaginable cases, deception research involves interaction with

participants and thus the opportunity for an informed

consent process. In all cases, the informed consent

process must be tailored so that the research study can be

carried out. Participants cannot be told the true purpose

of the research until after the study is over, or participants

can be told some, but not all, purposes of the research

until the end of the study. When IRBs approve research

studies that involve deception, an informed consent

process should be designed that is appropriate to the

purpose of the study and that provides adequate protection for the participants. For example, in a study

designed to determine whether the stereotypical belief

that women are not as proficient as men in mathematics

adversely affects women’s test scores, two groups of participants were asked to take the same math test, but were

given opposite information about whether the test had

been shown to produce gender differences. Some or all of

this information was false. The study was not intended to

reveal whether the test itself produced gender differences

in test scores, but rather whether the threat of stereotyping led to gender difference in test scores. Participants

were told the true purpose of the study when the study

was completed (Spencer et al. 1999). 

Although it is tempting to require a set of basic 

elements of disclosure to be used during the informed

consent process, it is unlikely that any single set of basic

elements can be applied feasibly and credibly to all types

of research. Whether an investigator has included the

eight basic elements of disclosure is often open to interpretation. Further guidance is needed not only to

describe required elements for different types of research,

but also to describe procedures for ascertaining what

information should be included in a particular research

study. 

In certain circumstances, monitoring the informed

consent process could increase participant protection,

and monitoring procedures could be used to measure

participants’ understanding of the nature of the research

and the risks involved. Such circumstances might

include research involving significant risk, research

enrolling participants who might have difficulty in

understanding the risks associated with the study, or

research for which the IRB is concerned about whether

the informed consent is being carried out according to

the stipulations in the approved protocol. In these cases,

IRBs should require some type of monitoring of the

informed consent process, although it need not perform

the monitoring itself. These mechanisms could be either

temporary, lasting until the concerns of the IRB are satisfied, or permanent, for the duration of the research study.

Prospective Participants Who Cannot Give

Voluntary Informed Consent

The discussion thus far has focused on obtaining

informed consent from competent adults.6 When individuals who do not have the capacity or who have lost the

capacity to provide voluntary informed consent are

enrolled in research, other mechanisms must be used to

satisfy the ethical requirement of informed consent. A previous NBAC report has addressed this issue with respect to

research involving individuals who have a mental disorder

that may affect decisionmaking capacity (NBAC 1998).

Other situations in which adults are unable to give voluntary informed consent also should be examined.

Recommendation 5.1: Federal policy should

emphasize the process of informed consent

rather than the form of its documentation 

and should ensure that competent participants

have given their voluntary informed consent.

Guidance should be issued about how to provide

appropriate information to prospective research

participants, how to promote prospective participants’ comprehension of such information, and

how to ensure that participants continue to make

informed and voluntary decisions throughout

their involvement in the research.

Waiver of Informed Consent

Although NBAC supports the ethical standard of

informed consent in research, circumstances arise in

which the requirement of seeking informed consent from

competent participants may be waived (NBAC 1998;
102

NBAC 1999a; NBAC 1999b; NBAC 2001).7 One circumstance involves the use of existing identifiable data. As

noted in an earlier NBAC report on research involving

the use of human biological materials, when the study

offers the potential to gain important knowledge, poses

little or no risk to participants, and consent would be 

difficult or impossible to obtain, it is appropriate to waive

the informed consent requirement (NBAC 1999b).

The current federal regulations stipulate four criteria

that must all be met to waive informed consent:

1. The research involves no more than minimal risk to

the participants.

2. The waiver will not adversely affect the rights and

welfare of the participants.

3. The research could not practicably be carried out

without the waiver.

4. Whenever appropriate, the participants will be provided with additional pertinent information after participating (45 CFR 46.116(d); 21 CFR 50.23, 50.24)

[FDA regulations only provide for waiver of informed

consent in limited emergency situations]).

At the time these requirements were written, one set

of criteria was wanted that would address waivers and

alterations for both biomedical and behavioral research.

Although the third and fourth criteria appear to apply

primarily to deception research (Dresser 1981) and are

useful in an IRB’s deliberation about altering the

informed consent process in deception research, they are

not readily applied to other types of research in which an

alteration is requested or even when a waiver of the entire

informed consent process is requested. As mentioned

earlier, one of the most poorly understood terms by IRBs

and investigators is practicably.

8 Only in a few research

studies would it be impossible to obtain informed consent;

however, in many studies the financial cost and time

required to obtain informed consent would be prohibitive and a potentially poor use of limited research

resources.

Indeed, four recommendations in NBAC’s report on

the use of human biological materials address the interpretation of these waiver criteria when conducting

research with stored biological material (NBAC 1999b).

These recommendations, displayed in Exhibit 5.3, were

intended to add clarity to the regulations, not to change

them.

Chapter 5: Ensuring Voluntary Informed Consent and Protecting Privacy and Confidentiality

Exhibit 5.3: Previous NBAC

Recommendations Regarding Waiver 

of Informed Consent 

■ Recommendation 10: IRBs should operate on

the presumption that research on coded samples

is of minimal risk to the human subject if the study

adequately protects the confidentiality of personally identifiable information obtained in the course

of research, the study does not involve the inappropriate release of information to third parties,

and the study design incorporates an appropriate

plan for whether and how to reveal findings to the

sources or their physicians should the findings

merit such disclosure.

■ Recommendation 11: In determining whether a

waiver of consent would adversely affect subjects’

rights and welfare, IRBs should be certain to consider whether the waiver would violate any state or

federal statute or customary practice regarding

entitlement to privacy or confidentiality, whether

the study will examine traits commonly considered

to have political, cultural, or economic significance

to the study subjects, and whether the study’s

results might adversely affect the welfare of the

subject’s community.

■ Recommendation 12: If research using existing

coded or identified human biological materials is

determined to present minimal risk, IRBs may presume that it would be impracticable to meet the

consent requirement (45 CFR 46.116(d)(3)). This

interpretation of the regulations applies only to the

use of human biological materials collected before

the adoption of the recommendations contained in

this report (specifically Recommendations 6

through 9 regarding informed consent). Materials

collected after that point must be obtained according to the recommended informed consent

process and, therefore, IRBs should apply their

usual standard for the practicability requirement.

■ Recommendation 13: OPRR [now OHRP]

should make clear to investigators and IRBs that

the fourth criterion for waiver, that “whenever

appropriate, the subjects will be provided with

additional pertinent information after participation”

(45 CFR 46.116(d)(4)), usually does not apply to

research using human biological materials.
National Bioethics Advisory Commission

103

As a matter of policy, two options are available. The

first, which NBAC recommended in previous reports, is

to specify the clarifications necessary to existing regulations for granting waivers (NBAC 1999b; NBAC 2001).

The second is to revise the regulations, given a broader

understanding of the ethical standards of informed 

consent. With this second approach, criteria for altering

the consent process would no longer be needed if

Recommendation 5.1 of this report were adopted. However, criteria for waiving the informed consent process

altogether would still be required.

Waiver of the informed consent process is justifiable

in research studies when there is no interaction between

investigators and participants, such as in studies using

existing identifiable data (e.g., studies of records). In a

previous report, NBAC discussed risks associated with

research involving the use of existing data (NBAC

1999b), noting that in such studies, risks will usually not

be physical and instead are likely to arise from the acquisition, use, or dissemination of information from the

research study and thus are likely to involve threats to

privacy and breaches in confidentiality. As discussed 

in the following section, many steps can be taken to 

protect both privacy and confidentiality, and with such

protections in place, IRBs may waive the requirement for

informed consent. The criteria for waiving informed 

consent in such instances should be revised.

Recommendation 5.2: Federal policy should permit

Institutional Review Boards in certain, limited

situations (e.g., some studies using existing identifiable data or some observational studies) to

waive informed consent requirements if all of the

following criteria are met:

a) all components of the study involve minimal

risk or any component involving more than

minimal risk must also offer the prospect of

direct benefit to participants;

b) the waiver is not otherwise prohibited by state,

federal, or international law;

c) there is an adequate plan to protect the confidentiality of the data;

d) there is an adequate plan for contacting participants with information derived from the

research, should the need arise; and

e) in analyzing risks and potential benefits, the

Institutional Review Board specifically determines that the benefits from the knowledge to

be gained from the research study outweigh

any dignitary harm associated with not seeking

informed consent.

The first criterion is intended to limit exposure to

riskier research when informed consent is not obtained,

except in circumstances in which a component involving

more than minimal risk also offers the prospect of direct

benefit. The second criterion is intended to protect participants’ rights existing under federal, state, or international statute. Protecting welfare is removed from the text

of the criterion because welfare is protected through 

criterion a, c, or e in Recommendation 5.2. The third and

fourth criteria are recommended on the assumption that

strong confidentiality protections can reduce violations of

privacy (see discussion below). The fifth criterion is 

recommended based on the discussion above regarding

the justification of research through risk/potential benefit analysis. A criterion related to practicability is not

included, because it would not add to the protection of

participants if the other criteria are met.

Documentation of Informed Consent

A similar sort of flexibility is needed for the documentation of informed consent. Current regulations

require, with limited exception, that informed consent be

documented using a written consent form approved by

the IRB and signed by the participant (45 CFR 46.117(a);

21 CFR 40.27(a), 56.109(c), (d)). As NBAC noted previously, this requirement could pose inappropriate barriers

to conducting useful and ethically sound research that

otherwise conforms to regulatory requirements related to

informed consent (NBAC 2001), an observation that is

made elsewhere as well (Singer 1978).9 A signed, written

consent form may be problematic in at least two ways: it

must be signed, and it is in writing. In some cultures,

both in the United States and in other countries, requesting a signature raises issues of trust and might suggest

inappropriate gravity regarding the research. In addition,

a written form has little utility with illiterate populations.

In certain types of research, such as survey research,

signed, written consent forms are not considered part of
104

the standard methodology. For example, telephone surveys (such as those used by telemarketers) and face-toface interviews are often encountered as part of daily

living, and individuals either freely participate or refuse,

for example, by hanging up the telephone. For these

reasons, NBAC has distinguished between the substantive

ethical standard of informed consent and the procedures

by which consent is obtained and has recommended that

investigators should not deviate from the substantive

ethical standards, although the procedures by which

informed consent is obtained could vary if approved by

the IRB (NBAC 2001).

Although the federal regulations may have been

attempting to reflect a legal standard for documentation

of informed consent, NBAC is aware of no case law in

which a signed, written consent form is required.10 To fulfill the substantive ethical standard of informed consent,

depending upon the sort of research being proposed, it

may be more appropriate to use other forms of documentation, such as audiotape, videotape, witnesses, or

telephone calls to participants to verify informed consent

and participation in the research study.

Recommendation 5.3: Federal policy should

require investigators to document that they 

have obtained voluntary informed consent, but

should be flexible with respect to the form of

such documentation. Especially when individuals

can easily refuse or discontinue participation, or

when signed forms might threaten confidentiality,

Institutional Review Boards should permit 

investigators to use other means of verifying 

that informed consent has been obtained.

Privacy and Confidentiality

All research, whether clinical, epidemiological, health

services, or social science, involves issues related to protecting privacy and confidentiality. In fact, in some

research the invasion of privacy or breaches in confidentiality are the only research-related risks to which participants might be exposed (e.g., some anthropological,

psychological, and historical research studies; records

review studies; and secondary analysis of existing data).

Privacy and confidentiality, however, tend to be poorly

understood concepts, often mistakenly used interchangeably, and either ignored or inappropriately handled by

investigators and IRBs.11

Privacy refers to persons and to their interests in controlling access of others to themselves (Boruch and Cecil

1979). In the research context, privacy refers to how

investigators collect or access identifiable data from participants. Protection of privacy naturally follows as an

application of the ethical principle of respect for persons,

because in respecting the personhood and autonomy of

individuals, investigators must be sensitive in the ways in

which they interact with participants who are deciding

whether to reveal or withhold information. Americans

value their privacy and are concerned about the circumstances under which they share information about themselves and, once shared, how the information will be

handled (IOM 2000).

Confidentiality, on the other hand, refers to identifiable data and relates to agreements between the participant and the investigator about how the participant’s data

will be handled and to whom it will be disclosed. It is an

extension of the concept of privacy.12 Participants are

concerned about unauthorized or inadvertent disclosures

of their data, and although participants and the public

are generally supportive of research, they often want to

be assured that they are in control of access to their information and that potential breaches in confidentiality are

minimized.13

Current federal regulations incompletely address privacy and confidentiality issues in research. IRBs may only

approve a research study when the research study is

judged to have adequate provisions to protect the privacy

of participants and to maintain the confidentiality of data

(45 CFR 46.111(a)(7); 21 CFR 56.111(a)(7)). Federal

regulations do not provide any additional requirements,

stipulate acceptable protection provisions, or define the

terms. 

Some federal departments have established additional

protections relating to privacy and confidentiality that are

applicable to research. The Department of Education

complies with the Family Education Rights and Privacy

Act of 1974, which is designed to protect student records

from disclosure without consent from parents or students

over 18 years of age. In addition, the Protection of Pupil

Chapter 5: Ensuring Voluntary Informed Consent and Protecting Privacy and Confidentiality
National Bioethics Advisory Commission

105

Rights Amendment gives parents the right to consent for

their children to participate in sensitive research. The

Department of Justice provides additional regulatory protections for prisoners (28 CFR 512) that give prisoners

control over their data, require at least one prisoner and

a majority who are not prison personnel to be members

of the IRB reviewing the research, and prohibit prison

administrators from accessing research data.

Additional confidentiality protections are provided in

the National Center for Educational Statistics

Confidentiality Statute and the Public Health Service Act

for the Centers for Disease Control and Prevention’s

(CDC’s) assurance of confidentiality. These statutes limit

the use of research data to those purposes for which 

the participants consent and prohibit the disclosure of

identifiable data to anyone without the consent of 

participants.

The Health Insurance Portability and Accountability

Act of 199614 required that legislation regarding standards for the privacy of individually identifiable health

information be enacted by August 21, 1999, or DHHS

would be required to issue regulations. Because Congress

did not pass such legislation, on December 20, 2000,

DHHS announced regulations entitled “Standards for

Privacy of Individually Identifiable Health Information,”

which became effective April 14, 2001. Although these

regulations provide some confidentiality protections for

individually identifiable health information, their application in the research context is limited because the

regulations apply only to health plans, health care clearinghouses, and health care providers. The regulations

outline conditions under which individually identifiable

health information held by any of the three entities may

be disclosed without the individual’s authorization to

investigators. Such disclosures may be made if an IRB or

“privacy board” (as defined in the rule) approves a waiver

of authorization based on certain criteria, if the information is sought solely for review preparatory to research, 

or if the research is on a decedent’s information.

Notwithstanding these additional federal protections of

privacy and confidentiality, there is little federal guidance

for IRBs and investigators regarding the protection of 

privacy and confidentiality. 

Privacy

Respecting privacy involves more than seeking

informed consent from participants to access their data.

Obtaining informed consent serves a vital role in providing participants with control over whether they will allow

investigators to have access to them and to data about

them. Privacy is influenced by the culture and individual

circumstances of participants, the nature and context of

the research, and the particular social and political environment in which the research and use of the data will

occur. Individuals have different views on what is 

considered private. For example, telling an investigator

about one’s sexual practices is acceptable to some participants, but highly offensive to others. It may be even

more difficult to respect a participant’s privacy when he

or she is different from the investigator in terms of age,

ethnicity, locale, socioeconomic status, or gender.15

Privacy refers to the ways and circumstances in which

investigators access information about participants.

Consent processes can protect the aspect of privacy that

deals with seeking permission to access data, but other

research procedures are needed to protect the aspect of

privacy related to the circumstances surrounding the

actual accessing of that data. Privacy can be respected by

using procedures such as written questionnaires rather

than face-to-face interviews, by using techniques in

which responses are signaled on the telephone touch pad

rather than verbally during telephone interviews, or by

using private rooms for disrobing for clinical examinations. To respect privacy is to let participants control the

access of others to themselves, to provide conditions in

which the investigator’s inquiries are welcome, and to

provide an opportunity for participants to decline or

restrict access.16

To breach privacy is to violate participants’ space or to

intrude where one is not welcome or not trusted. In fact,

the mere act of contacting people about participating in a

research study may be a violation of their privacy, particularly when the prospective participants are identified as

having a stigmatizing condition (e.g., HIV/AIDS, drug

addiction). Research in which management gives consent

to conduct research on employees, or deception research,

in which participants are led to behave in a way that they

would not wish to be seen, are examples of invasions of
106

privacy.17 Although there are few publicized cases of violations of privacy, the invasion of privacy may cause any

of the following harms: psychological (e.g., worry, irritation, fear, embarrassment, self-doubt), legal (e.g., arrest),

social (e.g., stigmatization), or economic (e.g., blackmail

or unemployment).18

Because privacy concerns vary by type and by context

of research, as well as by the culture and individual 

circumstances of participants, investigators should be

well informed and mindful of participants’ cultural

norms. Investigators also need to be aware of the various

research procedures and methods that can be used to

respect privacy. In addition, a clear, comprehensive regulatory definition of privacy along with guidance for 

protecting privacy in various types of research is

needed.19 NBAC proposes the following as a regulatory

definition of privacy: Privacy interests are persons’ interests

in controlling access of others to themselves and to information

about them. Privacy and confidentiality have long been

concerns of social scientists and oral historians, and

many professional societies for these disciplines have

developed ethics codes and guidance describing specific

privacy and confidentiality issues and protections for

their disciplines (e.g., psychology, anthropology, and oral

history).20 In developing new guidance, policymakers

should consult existing codes and guidance.

Guidance can be instrumental in helping investigators

and IRBs raise concerns and issues about privacy, however it cannot be expected to provide all of the solutions.

It is incumbent on investigators and IRBs, therefore, to

tailor research procedures to protect privacy as appropriate

for each research study. In addition, IRBs and investigators

must be familiar with a variety of procedures and methods

that prevent violations of privacy.

Confidentiality

Applied to research, confidentiality, like privacy, is a

complex, multifaceted issue. Privacy is an agreement

between the investigator and participant regarding disclosures of the participant’s identifiable data and how that

data will be handled. Confidentiality involves informing

the participant about mandatory reporting requirements

(e.g., reports of child abuse), plans for sharing identifiable data with other investigators or interested parties

(e.g., FDA), and the extent to which confidentiality can

be protected by law—that is, investigators could be subpoenaed to release identifiable data. In addition, state law

must be taken into account in describing confidentiality

protection. IRBs and investigators are expected to be

knowledgeable about applicable state laws involving 

privacy and confidentiality, which vary in their coverage

of types of data and disclosure requirements.21

Confidentiality also involves informing participants

about how the data will be managed. Inherent in this 

disclosure is review by the IRB of the actual procedures

used to ensure protection of confidentiality, which

include those used in handling and transmitting data,

eliminating linkages of data and identifiers, storing raw

data (e.g., questionnaires, records, abstract forms) and

data sets, and planning for long-term storage and use,

including sharing the data with other investigators.

Research procedures unrelated to data management

but generally related to research might compromise 

confidentiality. For example, reimbursing participants 

by check or reporting results back to participants could

provide a link between the research and the participants

that would not otherwise exist. In longitudinal studies,

calling or mailing participants might identify them with 

a research study. IRBs and investigators should review 

all of the proposed research procedures for possible 

compromises to confidentiality.

Making stronger legal protections available to all

investigators could enhance confidentiality protections.

In examining such options and designing such protections,

mandatory federal or state reporting requirements (e.g.,

mandatory child abuse disclosures) should be considered.

In addition to the federal statutes mentioned earlier,

another mechanism available to protect confidentiality is

the Certificate of Confidentiality. Under the Public Health

Service Act, DHHS agencies may issue Certificates of

Confidentiality to investigators authorizing them to withhold identifiable data about research participants that

may be summoned under federal, state, or local civil,

judicial, administrative, legislative, or other proceedings.

DHHS regards the certificate’s protection as superceding

state law, and some case law supports this position.22

However, Certificates of Confidentiality do not provide

the same degree of protection as that provided under

Chapter 5: Ensuring Voluntary Informed Consent and Protecting Privacy and Confidentiality
National Bioethics Advisory Commission

107

CDC’s and the Department of Education’s National

Center for Educational Statistics Confidentiality Statutes,

because although certificates protect against compulsory

disclosures by the investigator, they do not prohibit

investigators from making disclosures unauthorized by

the participant.

In addition, certificates, which are specific to a

research study and not to an investigator or institution,

are issued sparingly and only when it is determined that

the data are sensitive and that issuance will increase

study participation. Stronger confidentiality protections

are needed for all research involving sensitive, identifiable data. At a minimum, Certificates of Confidentiality

should be issued on request to investigators when it is

determined that the research involves sensitive, identifiable data and no other legal protections apply. Much

stronger protection of confidentiality would be afforded 

if a mechanism such as a Certificate of Confidentiality

also prohibited investigators from making unauthorized

disclosures, however, such additional protection should

be imposed cautiously because it may entail serious

costs, as investigators would not be able to share data

with others without the participant’s permission. 

Like privacy, confidentiality concerns vary by

research type and context, and no one set of procedures

to protect confidentiality can be developed that would

cover all types of research contexts. IRBs and investigators

must tailor confidentiality protections to the specific 

circumstances and methods used in each specific

research study. A recent Institute of Medicine (IOM)

report describes procedures investigators can easily adopt

to reduce the risks associated with breaches of confidentiality (IOM 2000). This report suggests that IRBs consider recommending or requiring such procedures when

appropriate and it encourages IRBs and investigators to

consider using strong confidentiality protections to

reduce some of the violations associated with privacy. A

clear, comprehensive definition of confidentiality along

with guidance for protecting confidentiality in various

types of research is needed. NBAC offers the following

definition of confidentiality: Confidentiality is the protection of identifiable data through agreements between 

participants and investigators about who may have access to

the data and how the data will be managed in order to control

access.

Recommendation 5.4: Federal policy should be

developed and mechanisms should be provided

to enable investigators and institutions to reduce

threats to privacy and breaches of confidentiality.

The feasibility of additional mechanisms should

be examined to strengthen confidentiality 

protections in research studies.

Summary

Once an IRB has determined that risks of a given protocol

are reasonable in relation to potential benefits, no person

should participate in that research without his or her 

voluntary informed consent (or that of an appropriate

representative). However, for some studies that pose

minimal risk, it might be possible to waive this requirement. The process of informed consent involves investigators making appropriate disclosures about their research

and participants developing a good understanding of the

information provided and their choices regarding participation in a study. Participating in the process of

informed consent is one of the best ways investigators

can demonstrate their concern and respect for those they

wish to enroll in a study. 

In this report, NBAC reinforces previous recommendations from earlier reports by recommending that the

process of providing information and ensuring comprehension should be emphasized, rather than the documentation of the decision to give consent, and that both

the information and the way it is conveyed—while meeting full disclosure requirements—should be tailored to

meet the needs of the participants in a particular research

context. NBAC also recommends that documentation

requirements should be adapted for varying research 

settings and that the criteria for deciding when informed

consent is not necessary should be clarified to better

ensure that participants are protected. Finally, because

there are no clear policies on protecting privacy interests

and confidentiality in the research context, the informed

consent process alone is sometimes insufficient for 

protecting the rights and welfare of participants. Federal

policy should be clarified and strengthened in this area 

to assist investigators in ensuring that the interests of 

participants are protected.
108

Notes

1 See Vanderpool, H., “Unfulfilled Promise: How the Belmont

Report Can Amend the Code of Federal Regulations Title 45 

Part 46—Protection of Human Subjects.” This background paper 

was prepared for NBAC and is available in Volume II of this report.

2 Ibid.

3 Ibid. 

4 Ibid. 

5 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

6 Informed consent requirements pertaining to research involving

children are not addressed in the Common Rule. However, DHHS

regulations include specific requirements relating to research

involving children (45 CFR 46 Subpart D). DHHS regulations

require that “when in the judgment of the IRB” children are capable of providing assent (their affirmative agreement to participate),

they are asked to do so. In addition, at least one parent or guardian

and in some instances both parents or guardians are required to

give permission for the child to participate in the research. NBAC

has not addressed ethical issues pertaining to children participating

in research. Attention should be given to the ethical standards and

regulatory requirements for adequately protecting children.

7 It should be noted that special provisions exist for waiving 

consent in the context of emergency research.

8 Ibid.

9 Ibid.

10 See Schwartz, J., “Oversight of Human Subject Research: The

Role of the States.” This background paper was prepared for NBAC

and is available in Volume II of this report.

11 See Goldman, J., “Privacy and Confidentiality in Health

Research.” This background paper was prepared for NBAC and is

available in Volume II of this report.

12 See Sieber, J., “Privacy and Confidentiality: As Related to

Human Research in Social and Behavioral Science.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

13 See Goldman, J., “Privacy and Confidentiality in Health

Research.” This background paper was prepared for NBAC and is

available in Volume II of this report.

14 Pub. Law 191, 104th Congress.

15 See Sieber, J., “Privacy and Confidentiality: As Related to

Human Research in Social and Behavioral Science.” This background paper was prepared for NBAC and is available in Volume II

of this report. 

16 Ibid.

17 Ibid. 

18 See Goldman, J., “Privacy and Confidentiality in Health

Research.” This background paper was prepared for NBAC and is

available in Volume II of this report.

19 In DHHS’ response to NBAC’s report, Research Involving 

Human Biological Materials: Ethical Issues and Policy Guidance, it 

was noted that NBAC’s recommendations regarding identifiability

and privacy might be inconsistent with proposed medical record

rules promulgated by DHHS. 

20 Anthropology: http://www.aaanet.org/committees/ethics/

ethcode.htm; Psychology: http://www.apa.org/ethics/code.html; 

Oral History: http://www.dickinson.edu/organizations/oha/

evaluationguidelines.html. Each last accessed September 4, 2000.

21 See Schwartz, J., “Oversight of Human Subject Research: The

Role of the States.” This background paper was prepared for NBAC

and is available in Volume II of this report.

22 People v. Newman (32 N.Y.2d 379, 298 N.E.2d 651, 

345 N.Y.2d 502, 1973).

References

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Office.

Beauchamp, T.L., and J.F. Childress. 1994. Principles of Biomedical

Ethics, 4th ed. New York: Oxford University Press.

Bernhardt, B.A., G. Geller, M. Strauss, K.J. Helzsouer, M. Stefanek,

P.M. Wilcox, and N.A. Holtzman. 1997. “Toward a Model

Informed Consent Process for BRCA1 Testing: A Qualitative

Assessment of Women’s Attitudes.” Journal of Genetic Counseling

6(2):207–222.

Blenkinsop, S. 1997. “Whatever Happened to Plain English? 

The Gobbledygook Smokescreen that Baffles Research Subjects.”

In Volunteers in Research and Testing, eds. B. Close, R. Combes, 

A. Hubbard, and J. Illingworth, 89–98. Bristol, PA: Taylor and

Francis.

Boruch, R.F., and J.S. Cecil. 1979. Assuring the Confidentiality of

Social Research Data. Philadelphia: University of Pennsylvania

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Dresser, R.S. 1981. “Deception Research and the HHS Final

Regulations.” IRB: A Review of Human Subject Research 3(4):3–4.

Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of

Informed Consent. New York: Oxford University Press.

Hochhauser, M. 1997. “Can Patients Understand Their Consent

Forms?” Bender’s Health Care Monthly April:8–10.

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National Bioethics Advisory Commission

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Institute of Medicine (IOM). 2000. Protecting Data Privacy in Health

Services Research. Washington, D.C.: National Academy Press.

McQuillan, G., M.A. Speers, and V. Burt. 2000. “Applying the

Federal Regulations for Protecting Human Subjects in Survey

Research: The NHANES Experience.” Unpublished manuscript.

NBAC archive.

National Bioethics Advisory Commission (NBAC). 1998. 

Research Involving Persons with Mental Disorders That May Affect

Decisionmaking Capacity. 2 vols. Rockville, MD: U.S. Government

Printing Office.

———. 1999a. Ethical Issues in Human Stem Cell Research. 

3 vols. Rockville, MD: U.S. Government Printing Office.

———. 1999b. Research Involving Human Biological Materials:

Ethical Issues and Policy Guidance. 2 vols. Rockville, MD: U.S.

Government Printing Office.

———. 2001. Ethical and Policy Issues in International Research:

Clinical Trials in Developing Countries. 2 vols. Bethesda, MD: U.S.

Government Printing Office.

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission). 1979.

Belmont Report: Ethical Principles and Guidelines for the Protection of

Human Subjects of Research. Washington, D.C.: U.S. Government

Printing Office.

Nicks, S.D., J.H. Korn, and T. Mainieri. 1997. “The Rise and 

Fall of Deception in Social Psychology and Personality Research.”

Ethics and Behavior 7(1):69–77.

Singer, E. 1978. “Informed Consent: Consequences for Response

Rate and Response Quality in Social Surveys.” American Sociological

Review 43(2):144–162.

Spencer S.J., C.M. Steele, and D.M. Quinn. 1999. “Stereotype

Threat and Women’s Math Performance.” Journal of Experimental

Social Psychology 35:4–28.

Verheggen, F., R. Jonkers, and G. Kok. 1996. “Patients’ Perceptions

on Informed Consent and the Quality of Information Disclosure in

Clinical Trials.” Patient Education and Counseling 29(2):137–153. 

Waggoner, W.C., and D.M. Mayo. 1995. “Who Understands? 

A Survey of 25 Words or Phrases Commonly Used in Proposed

Clinical Research Consent Forms.” IRB: A Review of Human 

Subjects 17(1):6–9.

Young, D.R., D.T. Hooker, and F.E. Freeberg. 1990. “Informed

Consent Documents: Increasing Comprehension by Reducing

Reading Level.” IRB: A Review of Human Subjects Research 12(3):1–5.

Conduct of Research— Selected Issues for 

Local Institutions

Chapter Six 6

Introduction

This chapter addresses three issues regarding the roles

and responsibilities of local institutions and their

Institutional Review Boards (IRBs) in protecting research

participants:

■ the monitoring of ongoing research;

■ the review of cooperative or multi-site research studies;

and 

■ the provision of compensation for research-related

injuries.

Continual review and monitoring of research in

progress is a critical part of the oversight system. Regular,

continual review is necessary to ensure that emerging

data or evidence have not altered the risks/potential

benefits assessment so that risks are no longer reasonable.

In addition, mechanisms are needed to monitor adverse

events, unanticipated problems, and changes to a protocol.

IRBs could increase their effectiveness in meeting these

responsibilities with better guidance and some restructuring of the review and monitoring process. 

One of the greatest burdens on IRBs and investigators

today is review of multi-site studies. Requiring multiple

institutions to review the same protocol is unnecessarily

taxing and provides no real added value to protection of

participants. Multi-site review poses problems in the 

initial stages of review as well as in the continual review

and monitoring stages, especially in the evaluation of

adverse events in clinical research.

A comprehensive system of oversight of human

research should include a mechanism to compensate

participants for medical and rehabilitative costs resulting

from research-related injuries. Participants who volunteer

to be in a research study and are harmed as a direct result

should be cared for and compensated. This obligation

fulfills the principle of justice. 

Monitoring of Ongoing Research

Oversight of research should not end once the study

begins. Reports have consistently pointed out that

research must be monitored once in progress to minimize

harms to research participants (OIG 1998a; OIG 1998c;

GAO 1996). This section addresses issues related to

monitoring the progress of research, including conducting continuing review, reporting protocol changes and

unanticipated problems, and ensuring participants’

safety. 

Continuing Review

One means of monitoring ongoing research is the

continuing review process. As research progresses, investigators might learn more about the risks and potential

benefits of an experimental intervention or how other

new research findings might affect judgments about risks

and potential benefits. Such changes may warrant modifications to the informed consent process, for example, to

include the risk of a newly reported side effect. Other

developments might also require modifications to protocol design, or in the extreme case, stopping a research

study. A continuing review process generally focuses on

updated information provided by investigators, including

the status of participant enrollment, summary of changes

to the protocol, relevant new reports in the literature,

unanticipated problems, and plans for changes to the

protocol.

111
112

Chapter 6: Conduct of Research—Selected Issues for Local Institutions

Continuing review has been a major problem for IRBs

for some time. A 1975 study of 61 institutions conducted

for the National Commission for the Protection of

Human Subjects of Biomedical and Behavioral Research

(National Commission), found that roughly half of IRBs

seldom or never reviewed interim reports from investigators (Cooke and Tannenbaum 1978, I-44). The National

Commission went on to recommend, at a minimum,

annual continuing review for research studies involving

more than minimal risk or vulnerable populations

(National Commission 1978, 16). The President’s

Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research

(President’s Commission) concluded that “many IRBs do

not understand what is expected in the way of ‘continuing review’...[and] the problems manifested in these

studies clearly need attention” (President’s Commission

1981, 47). More than 15 years later, the Office of

Inspector General (OIG) of the Department of Health

and Human Services (DHHS) found that IRBs “conduct

minimal continuing review of approved research” and

that the reviews are “hurried and superficial” (OIG

1998a; OIG 1998c). 

As noted in the OIG reports, continuing review suffers

in part because of excessive IRB workloads and insufficient regulatory guidance (OIG 1998a; OIG 1998c).

Regulations currently require that “an IRB shall conduct

continuing review...at intervals appropriate to the degree

of risk, but not less than once per year” (45 CFR

46.109(e); 21 CFR 56.109(f)). However, the regulations

do not specify the purpose or content of that review.

Continuing review should not be a repetition of the initial

review, because applying all of the requirements of initial

review to continuing review is rarely necessary. Rather,

IRBs should be looking for specific new developments

that may affect participant protections. Because the federal

regulations are incomplete in describing what should be

considered in continuing review, it is understandable that

IRBs do not always conduct appropriate review. Thus,

additional guidance is needed.1

Moreover, the requirement of continuing review itself

is overly broad, as the frequency and need for continuing

review vary depending on the nature of research. For the

purpose of continuing review, IRBs should focus their

attention primarily on research initially determined to

involve more than minimal risk. In research involving

high or unknown risks, the first few trials of a new intervention may substantially affect what is known about the

risks and potential benefits of that intervention. On the

other hand, the ethics issues and participant protections

necessary in minimal risk research are unlikely to be

affected by developments from within or outside the

research, in, for example, research involving the use of

existing data or in research that is in the data analysis

phase when there is no additional contact with participants. Continuing review of such research should not be

required because it is unlikely to provide any additional

protection to research participants and would merely

increase IRB burden. However, because minimal risk

research does involve some risk, IRBs may choose to

require continuing review when they have concerns. In

these cases, other types of monitoring would be more

appropriate, such as assessing investigator compliance

with the approved protocol or requiring reporting of 

protocol changes and unanticipated problems. Although

such efforts might fail to detect some protocol problems,

the resource requirement inherent in conducting continuing reviews for all protocols and the distraction of 

the IRB’s attention from riskier research do not justify

devoting a disproportionate amount of resources to continuing review. Clarifying the nature of the continuing

review requirements would allow IRBs to better focus

their efforts on reviewing riskier research and thereby

increase protection for participants where it is most

needed.

Reporting Protocol Changes and Unanticipated

Problems

In addition to the periodic re-evaluation of risks and

potential benefits as part of continuing review, IRBs conduct as-needed reviews when investigators request an

amendment to approved protocols or in the event of

unanticipated problems with a research study. Indeed,

current regulations require institutions to create written

procedures for “ensuring prompt reporting to the IRB of

proposed changes in a research activity, and for ensuring

that such changes in approved research, during the

period for which IRB approval has already been given,
National Bioethics Advisory Commission

113

may not be initiated without IRB review and approval

except when necessary to eliminate apparent immediate

hazards to the subject” (45 CFR 46.103(b)(4)(iii); 21 CFR

56.108(a)(3)(4)). Institutions are also required to ensure

reporting to the IRB “any unanticipated problems involving risks to subjects or...any suspension or termination

of IRB approval” (45 CFR 46.103(b)(5); 21 CFR

56.108(b)(1)(3)).

Both requirements are ethically relevant; however,

they could be more useful to IRBs with additional guidance, as guidance is slim regarding what types of protocol

amendments must be reported to an IRB. Currently, IRBs

spend time reviewing amendments that do not include

material changes to the protocol, while changes that may

affect the rights and welfare of participants at times go

unreported or unaddressed. For example, IRBs often find

themselves reviewing amendments requesting a change

of mailing address or telephone number contacts, while

at the same time, investigators sometimes alter recruitment criteria or make substantive changes in consent

forms without IRB approval. Guidance is needed regarding the types of changes that must be reported to IRBs as

well as those that do not need to be reported, the types

of amendments eligible for review using procedures

other than a full IRB review (see Chapter 2), and the

types of amendments that must be reviewed by the full

IRB, so that IRBs can focus on what is important—

ethically significant changes to research protocols.

Similar issues arise with regard to the requirement

that unanticipated problems be reported to the IRB and

to federal agencies, such as when consent forms or 

questionnaires containing identifiable information are

lost. Interpreting the requirements for reporting unanticipated problems to federal agencies has been a significant

problem for IRBs and their institutions.2 IRBs and investigators need additional guidance regarding the types of

unanticipated problems that must be reported and how

they should be addressed. 

Monitoring the Safety of Participants

Reporting and reviewing adverse events are particularly important in clinical research. Although regulations

and guidance are available for IRBs, investigators, and

sponsors to follow in reporting and evaluating adverse

events, they have not been revised to reflect changes in

the way research is conducted (e.g., movement toward

more multi-site clinical trials). Moreover, other entities

not considered in federal regulations (45 CFR 46 Subpart

A), such as Data and Safety Monitoring Boards (DSMBs),

are beginning to play an increasingly important role in

safety monitoring (DeMets et al. 1999; Gordon et al.

1998) and are potentially well situated for this role

because they review data from all participating sites and

have access to unblinded data. Just how such safety 

monitoring is consonant with current requirements for

continuing review, reporting of unanticipated problems,

and reporting of adverse events should be clarified. Until

recently, communication among federal agencies requiring reporting of adverse events has been lacking to the

extent that relevant agencies, IRBs, and investigators 

are not all adequately informed (Prentice and Gordon

1997).3 However, new efforts are under way to improve

communication and to harmonize the reporting requirements among federal agencies (DHHS 2000).4

Reporting of Adverse Events

As one of the requirements for approval of research,

IRBs must ensure that as “...appropriate, the research

plan makes adequate provision for monitoring the data

collected to ensure the safety of subjects” (45 CFR

46.111(a)(6); 21 CFR 56.111(a)(6)). Although this

requirement was designed with clinical research in mind,

it provides little guidance about what is required of 

IRBs or investigators conducting clinical research. The

National Institutes of Health (NIH) recently issued 

guidance on data and safety monitoring in Phase I and II

trials,5 and because much clinical research involves the

use of an investigational drug, device, or biologic product,

the Food and Drug Administration (FDA) regulations

also apply and are much more specific than the Common

Rule. (Citations, language, and annotation of the FDA’s

reporting regulations appear in Appendix H.)

FDA Requirements for Adverse Event Reporting

FDA regulations generally refer to five phases in the

development and marketing of products, which include

three phases of product development and two distinct

post-market approval phases. All three stages of drug and

biologic product development are classified as research
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

(21 CFR 312.21). Phase I includes safety studies of the

product’s initial use in humans, in which a small number

of participants (20 to 80) receive the drug to verify its

safety. Phase II includes early controlled clinical trials to

obtain preliminary effectiveness data and information on

short-term side effects, with a larger number of participants (sometimes several hundred). Phase III includes

expanded controlled and uncontrolled studies to gather

information about the effectiveness and safety of products

and usually involve several hundred to several thousand

participants. After Phase III studies, FDA grants or denies

market approval. All adverse events must be reported

during the three phases of product development, and

some mandatory post-approval reporting requirements

must also be met, particularly for medical devices.

Although these three phases comprise the research portion

of product development, information continues to be

gathered after market approval. Medical device development follows a similar process, although it is not defined

as three distinct phases in the regulations (21 CFR

812.25, 812.35).

Drugs and biologic products have two distinct postmarket approval phases, while for devices, there is only

one. FDA may require sponsors to conduct Phase IV

studies after drug approval to obtain further information

about risks, potential benefits, and optimal use of a drug

(21 CFR 312.85). However, only some Phase IV studies

might be research, and there is no equivalent Phase IV

reporting for medical devices. Accumulating information

on the public’s experience with the approved drug or

other FDA-regulated product could be considered a fifth

phase (21 CFR 314.80, 314.81, 814.82, 814.34). (FDA

refers to this phase as post-marketing reporting.) Phase V

primarily includes voluntary reporting to FDA on product

experience, but some mandatory reporting also occurs

regarding the effectiveness of new medical devices. After

device approval, user facilities are required by federal 

regulations to report medical device-related deaths to

FDA and the device manufacturer and medical devicerelated serious injuries to device manufacturers (21 CFR

Part 803), but other reporting of adverse events with

approved products is voluntary.

FDA reporting requirements pertain to investigators

and sponsors, and the requirements differ for drugs and

biologic products and devices. The various types of

adverse events are defined in regulations along with

required timeframes for reporting. (See Exhibit 6.1.) For

example, FDA regulations contain definitions of the

following terms: life-threatening adverse drug experience,

serious adverse drug experience, unexpected adverse drug experience, associated with the use of the drug, and unanticipated

adverse device effect (21 CFR 312.32(a); 21 CFR 812.2(s)).

Investigators are required to report to the sponsor

“any adverse effect that may reasonably be regarded as

caused by, or probably caused by, the drug” being studied

(21 CFR 312.64(b)) or to the sponsor and the investigator’s IRB any unanticipated adverse device effect (21 CFR

812.150(a)(1)). Serious adverse drug effects are to be

reported by sponsors to FDA (21 CFR 312.32(c)(1)(i)(A)

and (c)(1)(ii)), and unanticipated adverse device effects

are to be reported by sponsors to FDA and all reviewing

IRBs (21 CFR 812.150(b)(1)). 

Review of Adverse Events

Reporting of adverse events is only the first step in

monitoring safety; evaluation of reports and distribution

of findings to all relevant parties are also critical. Under

45 CFR 46 Subpart A, IRBs are required to evaluate

adverse events, and FDA regulations contain requirements

for evaluation of reports and reporting back findings 

(21 CFR 312.56(c)-(d); 21 CFR 812.46(b)(1)-(2)).

Multi-site clinical trials pose special challenges for IRBs

because a single IRB is unable to review and evaluate

adverse event reports for these trials. Even if local IRBs

were to receive all adverse event reports from all institutions with complete information in a timely fashion, and

even if each IRB, through its membership or the use of

consultants, had the expertise to analyze these events, it

would be inefficient to have hundreds of local IRBs

duplicatively perform this meticulous and time-consuming

task (Prentice and Gordon 1997), when one complete

and reliable analysis should be sufficient. Thus, the burden

on local IRBs could be greatly reduced and participant

protections improved if a mechanism were put in place

to handle all required safety monitoring at the level of the

sponsor, or the lead organization managing the research

study, rather than the local IRB.

More important, local IRBs that receive an adverse

event report cannot determine whether the event is
National Bioethics Advisory Commission

115

frequent or rare, whether it is caused by the research as

opposed to the underlying illness or standard treatment,

or whether the adverse event is more common in the

intervention group than in the control groups. Local IRBs

lack access to the essential data needed to evaluate

adverse event reports and are thus not only are wasting

time attempting to analyze them but are also unable to

make use of the data.

DSMBs, as monitoring bodies independent from

investigators conducting the research, are one such

mechanism growing in use. DSMBs monitor the safety

and effectiveness of the experimental intervention and

recommend stopping a trial if significant benefits or risks

have developed or if the trial is unlikely to be concluded

successfully (DeMets et al. 1999; Gordon et al. 1998).

Membership qualifications, composition, functions, and

Exhibit 6.1: FDA Requirements for Adverse Event Reporting

The FDA regulations include several definitions to assist in identifying what constitutes an adverse event that triggers

each of the various reporting requirements. These definitions include the following:

For drugs and biologic products:

Associated with the use of the drug. There is a reasonable possibility that the experience may have been caused by

the drug.

Disability. A substantial disruption of a person’s ability to conduct normal life functions.

Life-threatening adverse drug experience. Any adverse drug experience that places the patient or subject, in the view

of the investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that,

had it occurred in a more severe form, might have caused death.

Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the 

following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of

existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important

medical events that may not result in death, be life-threatening, or require hospitalization may be considered a 

serious adverse drug experience when, based on appropriate medical judgment, they may jeopardize the patient or

subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room

or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug

dependency or drug abuse. 

Unexpected adverse drug experience. Any adverse drug experience, the specificity or severity of which is not 

consistent with the current investigator brochure; or, if an investigator brochure is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or

elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be 

unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or

hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater

specificity) if the investigator brochure only listed cerebral vascular accidents. Unexpected, as used in this definition,

refers to an adverse drug experience that has not been previously observed (e.g., included in the investigator

brochure) or anticipated based on the pharmacological properties of the pharmaceutical product (21 CFR 312.32(a)).

For devices:

Unanticipated adverse device effect. Any serious adverse effect on health or safety or any life-threatening problem 

or death caused by or associated with a device, if that effect, problem, or death was not previously identified in nature,

severity, or degree of incidence in the investigational plan or application (including a supplementary plan or 

application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, 

or welfare of subjects (21 CFR 812.2(s)).
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

oversight of DSMBs generally differ from those of IRBs.

NIH has issued several policies regarding data and safety

monitoring and now requires the use of DSMBs for

multi-site clinical trials involving interventions that entail

potential risk to the participants,6,7 and NIH institutes

and centers have flexibility in implementing the requirement for DSMBs—that is, they may conduct or sponsor

the monitoring activities or delegate such responsibility

to a grantee or contractor.

NIH policy also requires that adverse events be

reported to IRBs. This reporting includes communication

between the IRB and DSMB when one is used and

requires that investigators submit any reports from the

DSMB to the IRB. Most recently, NIH has issued a policy

requiring a monitoring plan as part of all Phase I and

Phase II clinical trials.8 Unlike the FDA regulations, NIH

policy is not specific regarding what constitutes an

adverse event, in what timeframe it must be reported,

and to whom. Further, unlike FDA regulations, DHHS

regulations (45 CFR 46) are silent regarding the reporting

of adverse events, except to require that institutions provide written procedures for reporting any unanticipated

problems involving risks to participants.

Difficulties in Following Reporting Requirements

Because of the sheer volume and quality of reports

and the complexity of the regulatory requirements,

assessing reports of adverse events is a major burden for

IRBs and investigators (Prentice and Gordon 1997). In

every town meeting conducted by the National Bioethics

Advisory Commission (NBAC), IRB members said that

they were inundated with adverse event report forms and

they often had little understanding of the context in

which to evaluate the event in a multi-site trial.9

Investigators reported frustration with their lack of

understanding of what constituted an adverse event,

required reporting times, and to whom adverse events

should be reported, and they reported confusion about

knowing when reporting is mandatory or voluntary and

which reporting requirements apply to the FDA’s five

phases of product development and use. Investigators

also complained about the requirement to report separately to sponsors, NIH, and their IRBs. These findings

echo those of the OIG (OIG 1998a; OIG 1998c).

Because protecting the rights and welfare of participants should be the top priority of IRBs and investigators,

having a monitoring system that is effective, easy to use,

efficient, and responsive to serious events should be the

goal of all who participate in the review process. Several

deficiencies are noted in the current system, including

complex, confusing, and fragmented regulations; regulations that may not be fully enforced; and lack of effective

communication among the relevant parties. Although the

FDA regulations for reporting adverse events are detailed,

they are complex, fragmented, and often confusing, and

investigators suggest that they cannot understand the

regulations as they are written.10 For example, there

appears to be a range of views about what constitutes 

an adverse event and what should be reported, from

reporting practically all physical problems (e.g., spiked

temperature) to suggestions that adverse events are “trade

secrets” that should not be reported.11

In addition, the relationship between holding information as confidential and reporting adverse events

requires clarification. There are many potential reasons

companies might consider such information confidential—

for example, new indications regarding existing products,

the nature of new drugs under study, the specific populations under study, or a proprietary study design—and

handling the reporting and evaluation of adverse events

when some, if not all, information about the trial is

confidential can be difficult. Adverse events that are

related to investigational drugs must be reported to sponsors by investigators (21 CFR 312.64(b)), who must, in

turn, report serious adverse events to FDA and all participating investigators. Reporting requirements are different

for investigational medical devices, however. For devices,

investigators must report adverse events to sponsors and

their reviewing IRBs (21 CFR 812.150(a)(1)). Sponsors,

in turn, must report significant new information to all

reviewing IRBs, participating investigators, and FDA

(21 CFR 812.150(b)(1)). Problems potentially arise

when sharing information about adverse events may

involve disclosing confidential information about the

study. However, protecting research participants should

take priority over protecting the financial interests of

sponsors.
National Bioethics Advisory Commission

117

One set of simplified regulations for safety monitoring

is needed, and regulations and guidance should be written

so that investigators and sponsors understand what constitutes an adverse event, what type of event must be

reported within what time period, and to whom an event

should be reported. In addition, regulations and guidance should be clear regarding whose responsibility it is

to analyze and evaluate adverse event reports and should

describe the required communication and coordination

channels among IRBs and safety monitoring entities,

such as DSMBs, investigators, sponsors, and federal

agencies.

NBAC could not determine the extent to which evaluation of adverse events and the reporting of resulting

findings are a problem. Although investigators and IRBs

attending NBAC’s town meetings suggested that they

were either not receiving reports or not receiving them in

a timely fashion from sponsors,12 NBAC also heard from

witnesses that whenever adverse event reports are serious

or unexpected, sponsors of drug trials go to great lengths

to investigate them, including interviewing investigators

and conducting site visits.13 Nevertheless, a more transparent and effective system is needed for reporting,

evaluating, and reporting back results of adverse events.

Recommendation 6.1: Federal policy should

describe how sponsors, institutions, and 

investigators should monitor ongoing research.

Recommendation 6.2: Federal policy should

describe clearly the requirements for continuing

Institutional Review Board review of ongoing

research. Continuing review should not be

required for research studies involving minimal

risk, research involving the use of existing data,

or research that is in the data analysis phase

when there is no additional contact with participants. When continuing review is not required,

other mechanisms should be in place for ensuring

compliance of investigators and for reporting

protocol changes or unanticipated problems

encountered in the research.

Recommendation 6.3: Federal policy should 

clarify when changes in research design or 

context require review and new approval by 

an Institutional Review Board.

Recommendation 6.4: The federal government

should create a uniform system for reporting and

evaluating adverse events occurring in research,

especially in multi-site research. The reporting

and evaluation responsibilities of investigators,

sponsors, Institutional Review Boards, Data

Safety Monitoring Boards, and federal agencies

should be clear and efficient. The primary concern of the reporting system should be to protect

current and prospective research participants.

Review of Cooperative Research

Studies

The Range of Cooperative Research

One of the major challenges facing IRBs is the review of

cooperative research or multi-site studies, or research

involving multiple institutions. Although most collaborative studies occur at multiple institutions, investigators

from different institutions might collaborate in conducting

research at a single site. Research of all types can be

conducted cooperatively and can involve hundreds of

institutions. Each institution might perform experimental

interventions (e.g., clinical trials) or simply provide

investigators access to data (e.g., epidemiological studies).

In clinical research, for example, institutions might all

perform the same or different functions (e.g., one institution collects tissue samples, another analyzes them)

and may be geographically proximate or on different

continents.

Some cooperative research involves investigators or

institutions that conduct little or no research and are too

small to establish their own IRBs, such as a single community physician, a small private practice unaffiliated

with a larger institution, or a small college. In some cases,

it may be possible to rely on an IRB at a neighboring

institution, which could provide some degree of local

review because of its familiarity with the community

from which the participants come, although it would not

necessarily be familiar with the investigators or the circumstances under which the research will be conducted.

Some institutions do not take advantage of this option

because of concerns regarding potential institutional 

liability.
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

Current Requirements and Problems

Each institution engaged in cooperative research must

comply with the federal regulations (45 CFR 46.114). In

practical terms, this means that each institution must

have its IRB review the research protocol or make other

arrangements for review, which must be approved by the

department or agency head. For example, an institution

that does not have its own IRB could use an IRB from

another institution or an independent IRB to review its

research (45 CFR 46.114). This requirement is imposed

on IRBs that must follow the Common Rule (45 CFR 46

Subpart A), but is not on IRBs that must comply only

with the FDA regulations, which do not require that all

institutions or individuals engaged in the research have

their IRBs review the research protocol. Instead, FDA

requires only one IRB to review the protocol (21 CFR

56.103(a)). As discussed in Chapter 1, a research study

may be subject to review under the Common Rule if it is

conducted or funded by a federal department or agency

bound to the Common Rule or if it is conducted at one

of the institutions that has voluntarily agreed to apply the

requirements of the Common Rule to all research that is

conducted as part of a Multiple Project Assurance (MPA).

The federal requirements regarding collaborative

studies are problematic for several reasons. Investigators

and sponsors are frustrated by having to submit protocols

to multiple IRBs, particularly because changes requested

by any one board establish a new round of discussions

and negotiations among all the collaborating IRBs, a

repetitive process that causes time delays and increased

costs and that is perceived as providing little or no additional protection to the research participants.14 IRBs are

frustrated because they are spending scarce resources on

reviewing the same research protocol that, in some cases,

is being reviewed by hundreds of other IRBs, even when

overall design and methods can only be changed with

great difficulty. Moreover, investigators, sponsors, and

IRBs all believe that multiple reviews of the same 

protocol usually do not increase protection of research

participants.15

Moreover, in large multi-site research studies, local

IRBs often have little or no substantive authority over

protocol design, short of disapproving local participation

in the protocol. Although local IRBs can make changes to

consent forms, often they find sponsors unreceptive to

questions or proposed changes to study design.16 In part,

this reluctance may reflect the need for protocol standardization across institutions, as procedures at each site

must be sufficiently similar to allow data aggregation.

Sponsors pressed for time also may be reluctant to make

changes to the protocol in response to a single, local IRB,

because each modification to the protocol requires resubmission to each of the IRBs that had already approved the

protocol. Moreover, private sponsors of research are not

required to follow the IRB review requirements in the

Common Rule; rather they are only required to follow

the FDA regulations, which do not require each institution participating in the research to provide an IRB

review of the research. Academic institutions with MPAs,

on the other hand, are almost always required to follow

two sets of regulations in multi-site research involving

FDA-regulated investigational products: one set that

requires them to review the research unless other

arrangements are made (45 CFR 46) and the other that

does not require every institution to review the research

(20 CFR 50). The result is that the institutions are held

responsible for IRB review even when they have little

direct control over research design.

Arguments in Favor of Local IRB Review

In the United States, independent review of research

involving human participants primarily occurs at the

local level. The development of local review grew out of

the peer review process used to evaluate scientific merit

and the NIH requirement that grantee institutions take

responsibility for the ethical conduct of human research.

It is a model of review that reflected the nature of

research at the time—single research studies conducted

by one investigator from a single institution.17 At the time

of inception of review committees, local institutional

review was seen as offering distinct advantages, and 

in its early evaluation of the IRB system, the National

Commission supported the use of “local review 

committees...located in institutions where research is

conducted,” suggesting that such committees have four

advantages:
National Bioethics Advisory Commission

119

1. Local committees are familiar with the “actual conditions surrounding the conduct of research.”

2. Local committees “can work closely with investigators” to ensure that participants are protected and

investigators are treated fairly.

3. Local committees can serve as a resource and assist

in educating investigators and the public.

4. Local committees can communicate with federal 

officials and among themselves about protection and

ethical issues (National Commission 1978, 1–2).

In recent years, the first of these advantages has been

given particular prominence and was largely supported

and promulgated by the Office for Protection from

Research Risks (OPRR). As stated by Gary Ellis, former

director of OPRR:

We embrace the local IRB at the research site as the

cornerstone of the American system of protection of

human subjects....It is local review by individuals

who are in the best position to know the research at

the site, the resources at the institution, the capabilities and the reputations of the investigators and staff,

the prevailing attitudes and ethics of the community

and most importantly, the likely subject population

(Ellis 1994, 31–32).

Features of the local community and participant population may be relevant, for example, in determining

whether the selection of participants is equitable and

whether consent forms and materials are likely to be

understandable. Institutional factors, such as the availability of emergency care or patient record keeping, may

be relevant in determining whether risks are minimized

and confidentiality is assured.

There are additional advantages to using local IRBs.

For example, Steven Peckman, director of an academic

human participant protection program, argues that not

only do local IRBs have knowledge about the local setting, they serve other important functions: “The local IRB

demystifies the review process and creates an environment of collegiality.” 18 Further, local IRBs interact with

investigators, with each party able to discuss concerns

about the research study. Peckman also argues that local

IRBs hear the concerns of prospective research participants either by having them sit as IRB members or by

seeking their input in other ways. Local IRBs also provide

a place for investigators and participants to address 

complaints. 

Why IRB Review Need Not Always Be Local

Although there are advantages to local review—that

is, situating IRBs in the institutions that are conducting

the research and that are geographically close to the

research site—they should not be overstated. For example, factual information about an institution, such as

facilities and policies, is usually easy to determine by

asking an investigator or institutional official. Moreover,

in a small institution, more subtle institutional information, such as that regarding an investigator’s work experience, may be available to an institutional IRB, but in large

institutions, this might not be the case.

Similar caveats apply to knowledge of a local community. Geographically remote IRBs can learn the basic

demographic characteristics of a community from afar.

Moreover, information about the local (geographic) 

community is often of questionable relevance. In few

cases do geographic communities have sufficiently uniform and distinct beliefs relevant to research to judge a

protocol as ethical in one locale but not in another. On

the other hand, in the town meetings NBAC conducted,

IRBs frequently reported turning down protocols that

had been approved by other IRBs,19 although, in such

cases the declining IRB rarely thought that it was a local

factor that rendered the protocol inappropriate and

instead turned it down because it found some aspect of

study design, such as fees paid to participants, inappropriate. Although the absence of data is not equivalent to

the absence of a problem, no data are available regarding

specific research studies that after some negotiation

became acceptable in one community but not in another.

Moreover, institutions that enroll participants from a

defined geographic community might not enroll participants from a single cultural community. In a paper supporting local review, Peckman notes the wide range of

linguistic and cultural groups in Los Angeles, illustrating

that even within one metropolitan area, an IRB might

encounter numerous diverse groups.20 When an institution

serves a wide range of communities, it is unclear how the

beliefs of any one group should inform IRB decisions.

There are, of course, a few cases in which geographically cohesive groups have readily identifiable beliefs 
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

relevant to the interests of research participants (e.g., some

American Indian communities); but these cases appear to

be the exception rather than the rule (Norton and

Manson 1996; Sharp and Foster 2000). 

One ethical requirement for which sensitivity to local

cultures has clear relevance is the review of the consent

process, especially consent forms. Institutions that serve

diverse communities must be attentive to the information

needs of participants from various cultural backgrounds,

even as local variability in, for example, language and

educational attainment, influences IRB review of protocols. However, the use of such community-wide generalizations must not overshadow the importance of

individual variability. Similarly, consent forms should 

differ between an institution enrolling primarily collegeeducated participants and one enrolling participants who

generally have less than a high school education. Thus,

although there may be ways in which knowledge of local

factors affects local IRB decisions about protocols, the

importance of such knowledge should not be overstated,

and community differences should not be used as an

explanation for variable decisionmaking by IRBs when

the differences have no substantive bearing on the review.

As discussed earlier, there are other advantages of using

local IRBs, which can sometimes more easily engage local

investigators, for example, by routinely inviting them to

meetings at which their protocols are discussed.

However, the advantages of local IRB review, in terms of

both factual knowledge and local access, may not be as

significant as they initially appear to be. For example, for

an institution that infrequently conducts research involving human participants, relying on a remote IRB with 

frequent meetings rather than a local IRB that meets

infrequently may actually improve communication

between investigators and the board, and for multi-site

research, local investigators often have little direct control

over issues of protocol design, which must be standardized across sites. For them, the only decision is whether

to participate. In fact, with large multi-site studies, a system of exclusively local IRB review undermines precisely

the kind of interaction between investigator and IRB that

was intended when the IRB system was created. If the

investigators who designed the study are not affiliated

with any institution conducting the research, it may be

that there is no IRB interaction with the investigators who

actually design and run the study, such as the staff of an

industry sponsor of research. In the case of such studies,

a single, central IRB would foster significantly more relevant IRB-investigator interaction. 

Alternatives to Local IRB Review

Although many acknowledge the arguments that

favor local IRB review, they also recognize that local

review is not always necessary or appropriate. Even the

National Commission, which strongly supported a system

of local IRBs, recognized that in some cases, research

studies did not require review by an IRB located in or

near the institution where the research would be conducted. For small institutions, other arrangements, such

as use of another institution’s IRB or several institutions

forming a joint IRB, were acceptable (National

Commission 1978). For multi-site research studies, the

National Commission stated that:

Review by one IRB (generally at the entity most substantially involved with the research) should satisfy

statutory and regulatory requirements. Other entities

that are involved with the research may also require

review by their IRBs, however. In such instances, IRBs

should give priority to consideration of protocols that

are receiving multiple review, in order to reduce the

extended time period that such review may entail

(National Commission 1978, 8).

These exceptions suggest that the National

Commission did not view local IRB review as an absolute

requirement.

Although IRBs must have knowledge of the local

community, there are no regulatory requirements that

preclude review by IRBs that are not organizationally part

of the institution(s) conducting research and/or are not

geographically close to the research site. What is required

is that the IRB has sufficient knowledge of the local

research context—in terms of the relevant institution(s),

the relevant investigators, and the relevant community(ies)—to conduct an effective review (45 CFR

46.107, 46.111(a)(3)-(4), (7), (b), 46.116).21 As mentioned

above, since 1981 FDA has allowed nonlocal review of

research (review by an IRB geographically remote from the
National Bioethics Advisory Commission

121

research site and/or independent of the institution conducting the research), as long as the IRB obtains sufficient

knowledge of the local research context (21 CFR 56.107,

56.111(a)(3), 56.111(a)(7), 56.111(b); FDA 1998, 19–20).

In recent years, guidance from the Office for Human

Research Protections (OHRP)/OPRR also has moved in

this direction, emphasizing the types of local knowledge

that may be required for different types of studies.22

OHRP allows “institutional sites that are geographically

close enough to comfortably contribute membership to a

common IRB” to create such a shared, or common, IRB.23

In addition, in 1995, OPRR began approving assurances

in which an institution designates an independent IRB

(OIG 1998b). Recently, OHRP has approved a pilot program using a central IRB for review of certain National

Cancer Institute-funded cooperative cancer trials and a

cooperative review arrangement by a group of geographically disparate institutions.24 OHRP has also joined FDA

in accepting IRBs that routinely meet by teleconference,

facilitating the work of IRBs whose members are truly

representative of various geographic areas.25

Models of IRB Review in Other Countries

Although the United States has generally conducted

ethics reviews using committees located within institutions, several countries have established systems of

regional review committees that are not affiliated with a

particular institution (e.g., Denmark). In addition to using

regional review committees, these systems generally have

a central or national review committee that provides

guidance to the regional committees and resolves disagreements. For example, Denmark has a national

research ethics committee that holds higher authority

than its regional research ethics committees.26

Whether a regional review committee system functions better or worse than the individual institutional

review system is unclear. The major advantages of

regional review systems are their independence and

ability to review expeditiously multi-site studies, and at

least in one instance, a regional system seems to be more

efficient and effective.27 In Denmark, the regional review

system is established and supported by the government

with virtually no influence from the local institutions

conducting the research. Local institutions have no

choice over the committee that reviews their research and

have no power to appoint members to that committee.

Thus, the independence of the review system is attributed both to the location of the review committee outside

the institutions conducting the research and to the selection process for review committee members. This means,

in a sense, that in a system that uses institutionally based

review committees (e.g., IRBs), greater independence

could be achieved by selecting members who are not

affiliated with the institution.28

The United Kingdom makes use of local review committees for most research, but has created an additional

layer of regional committees for multi-site research. Once

a multi-center protocol has been approved by a regional

committee, all local review committees are to review

expeditiously the protocol by the executive subcommittee,

considering only matters that may affect local acceptability,

such as the qualifications of the investigators, the suitability of the site and prospective participants, and the

language and information in the consent form. Even

though problems have been noted with this system (AlShahi and Warlow 1999; Lux et al. 2000), critics suggest

the regional system is better than the solely local system

used previously in the United Kingdom (Alberti 2000;

Tully et al. 2000).

In Denmark, review of multi-site studies is handled

by assigning their review to the lead investigator’s review

committee, which is then responsible for seeking input

from the other participating investigators’ review committees. Søren Holm has reported that multi-site studies

are generally reviewed and approved in a relatively short

period (fewer than 60 days).29 The advantages to this

review process for multi-site studies are that the lead

investigator has contact with only one regional review

committee, changes to the protocol are negotiated with

only one investigator, and there is only one approved

protocol from which all investigators conduct the study.

On the other hand, a regional system of review may

have at least two disadvantages, especially in a large

country. Regional review committees may lack knowledge about the institutions in which the research will be

conducted and the investigators who carry it out. This is

not an uncommon problem in large institutions in which

the IRBs may lack certain types of knowledge about the
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

investigators or the context of the research. Another disadvantage is that the regional review committee may not

be able to adequately monitor the research study once it

is approved. However, even if regional review systems are

more effective than local institutional review systems, it is

unclear that a model of regional review, such as a system

of government-run regional review committees and a 

single, national committee with authority to manage

appeals, could be adopted effectively in the United States,

which differs from other countries in terms of population

size and geographic area and the number of research

studies that are conducted annually.30

Role of Local IRBs and Institutions

Discussions about IRB review of multi-site research

studies often confuse local institutional control of

research with local institutional review. Local institutions

must be able to maintain some oversight over the

research their investigators conduct, and each institution

must decide whether it wants to participate in a multisite research study and must maintain its authority to

decline to participate, even if another IRB has approved

the research. As long as an accredited IRB reviews and

approves the research protocol, multiple IRB reviews of

the same research protocol are not always necessary to

ensure the protection of research participants. For

research studies conducted solely by one institution, it

often makes sense for that institution’s IRB to conduct the

review. But for cooperative research, IRB review by all

institutions participating in the research should be the

exception.

A number of arrangements between a local institution

and the reviewing IRB could be possible. The reviewing,

or lead, IRB might be, for example, the IRB of the institution where the research study was developed, an IRB at

a participating institution with particular expertise in the

areas of research, or an independent IRB. It is essential

that the terms of the arrangement are clearly defined in

advance with respect to the roles and responsibilities to

be assumed by each party. It must be clear who will have

responsibility for providing ongoing educational programs for investigators and staff, who will be responsible

for conducting appropriate verification activities, to

whom participants’ complaints and concerns should be

addressed, and how local knowledge will be brought to

bear on IRB review. For example, if an institution has its

own IRB and programs in education and verification, the

institution might retain those responsibilities. Members

of the local IRB could provide local knowledge to the

external IRB during its review or by reviewing the decisions of the lead IRB as part of local control. Alternatively,

the local IRB might arrange to have the option of tailoring the consent process and documentation to the needs

of the local institution and participants. In either case,

the lead IRB assumes responsibility only for review, while

the local institution retains most of the other responsibilities. Institutional IRBs might be willing to take on the

primary responsibility of review voluntarily or for a fee.

If, on the other hand, the local institution has had 

little experience with research and does not have its own

IRB, it may be appropriate for the reviewing IRB to

assume more responsibilities, such as those for providing

education and verification. The IRB also might be

required to gather information about the local institution

and community, as independent IRBs do now. Creative

pilot projects are needed to identify those cooperative

models that work best. In the cooperative model, the lead

IRB must assume a number of responsibilities beyond the

review of the protocol. Institutional and independent

lead IRBs may wish to charge for such services. 

It is clear that innovative and creative alternative

mechanisms and processes for reviewing protocols in

multi-site research are needed. To allow for such projects

and to support a change in the current system toward a

more flexible review system, federal policy should be

clear about the functions that must be performed, but

less restrictive about who performs each function.

Institutions have research responsibilities, such as providing education and monitoring investigator compliance, that go beyond conducting IRB reviews, and

reliance on a nonlocal IRB must not allow those other

activities to go unfulfilled. The same considerations apply

to studies conducted at a single site.

Recommendation 6.5: For multi-site research, 

federal policy should permit central or lead

Institutional Review Board review, provided that

participants’ rights and welfare are rigorously

protected.
National Bioethics Advisory Commission

123

Compensation for Research-Related

Injuries

A comprehensive system of oversight of human research

should include a mechanism to compensate participants

for medical and rehabilitative costs resulting from

research-related injuries. The inclusion of this mechanism has long been justified on ethical grounds. First,

research participants are entitled to be left no worse off

than they would have been had they not participated in

the research.31 Second, without compensation, those with

limited access to health care services may not be able to

afford treatment and rehabilitation for research-related

injuries (Kolata and Eichenwald 1999; Vasgird 

et al. 2000). Third, even if consent forms and the disclosures within them are comprehensive, completely

unforeseen iatrogenic harms might occur in research

(President’s Commission 1982, 58). Fourth, research participation is often an act of social beneficence in which

people agree to volunteer in order to further larger societal

goals. Thus, injuries should not be summarily dismissed

merely because the individuals were provided information in the consent process and agreed to accept the risk

of certain harms (President’s Commission 1982, 59–60).

NBAC supports those arguments favoring compensation for research-related injuries, and other international

ethics and research bodies support the principle of 

compensating research injuries in various ways as well. A

previous report (NBAC 2001) identified 15 international

research ethics policies with statements that address

compensation for research-related injuries, including the

Council of Europe (Council of Europe 1997), the

Council for International Organizations of Medical

Sciences (CIOMS 1991; CIOMS 1993), the International

Conference on Harmonization (ICH 1996), and the Joint

United Nations Programme on HIV/AIDS (UNAIDS

2000). In addition, a number of national guidelines and

policies also support this principle, including Australia

(NHMRC 1999), Brazil (NHC 1996), China (Committee

on Research Involving Human Subjects 1998), France,32

India (Indian Council of Medical Research 2000), the

Netherlands,33 New Zealand (Health Research Council of

New Zealand 1997), South Africa (Medical Research

Council of South Africa 1993), Uganda (National

Consensus Conference on Bioethics and Health Research

in Uganda 1997), and the United Kingdom (MRC 1998).

In addition to the ethical arguments for a researchrelated compensation program, a practical argument can

be made in the context of the previous discussion on the

review of cooperative research. The parties, including the

institution(s), the investigator(s), the sponsor(s), and the

product manufacturer (if not the sponsor and the injury

involves a product), that benefit directly from research in

which participants suffer injury are primary candidates

for bearing liability for compensation. However, because

research involves risk, which can manifest itself as an

actual harm, research participants can suffer injury even

if all parties perform to the highest standard. As a result,

liability for research-related injuries is one of the concerns institutions often raise when considering whether

to rely on an IRB other than their own to review a multisite research study. Therefore, developing systems for

review of cooperative research will depend in part on

addressing issues related to institutional liability for

harms, as institutions hesitate to relinquish control of

local review if they retain the same degree of liability.

Thus, centralizing IRB review would be more acceptable

to such institutions if liability were also centralized in

some way.

Current Regulatory Requirements

Current federal regulations do not impose requirements for compensating participants injured by research

(45 CFR 46 Subpart A; 21 CFR 50, 56).34 Regulations

require only that the informed consent process for

research involving more than minimal risk contains “an

explanation as to whether any compensation and an

explanation as to whether any medical treatments are

available if injury occurs and, if so, what they consist of,

or where further information may be obtained” (45 CFR

46.116(a); 21 CFR 56.116(a)). However, the regulations

also prohibit exculpatory language in the informed consent process—that is, language that makes the participant

“waive or appear to waive any...legal rights, or releases or

appears to release the investigator, the sponsor, the institution or its agents from liability for negligence” (45 CFR

46.116; 21 CFR 50.20). Thus, in cases in which no compensation will be made available, investigators and IRBs
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Chapter 6: Conduct of Research—Selected Issues for Local Institutions

must craft language that fits both of these requirements.

OHRP guidance suggests the use of language such as the

following: “This hospital makes no commitment to provide free medical care or payment for any unfavorable

outcomes resulting from participation in this research.

Medical services will be offered at the usual charge.” 35

Previous Recommendations for a

Compensation Program

Because the regulations do not require compensation

to research participants who are injured in the course of

research, and because few institutions offer such compensation, the only option an injured participant has to

obtain compensation for research-related injuries is

through legal action. For over 30 years, various parties

have discussed alternatives to this option (Bergen 1967;

Ladimer 1963), and many national panels and advisory

groups in the United States have recommended the

establishment of a compensation program (ACHRE

1995; President’s Commission 1982; DHEW 1977;

Tuskegee Syphilis Study Ad Hoc Advisory Panel 1973).

The Tuskegee Syphilis Study Ad Hoc Advisory Panel, in

its 1973 Final Report, noted that: 

No policy for the compensation of research subjects

harmed as a consequence of their participation in

research has been formulated, despite the fact that no

matter how careful investigators may be, unavoidable

injury to a few is the price society must pay for the

privilege of engaging in research which ultimately

benefits the many. Remitting injured subjects to the

uncertainties of the law court is not a solution

(Tuskegee Syphilis Study Ad Hoc Advisory Panel

1973, 23).

The panel recommended the development of a “nofault” clinical research insurance plan, in which receipt of

compensation does not depend on the establishment of

wrongdoing or negligence.36 The same year, the

Department of Health, Education, and Welfare’s (DHEW,

now DHHS) Medical Malpractice Commission recommended to the Secretary that federal research grants

include funding for institutions to purchase insurance or

to self-insure in order to provide compensation for 

participants injured in research. DHEW formed the

Secretary’s Task Force on the Compensation of Injured

Research Subjects in 1974, and in 1977 the task force

recommended that participants injured in Public Health

Service-sponsored research be compensated to the extent

that injuries exceeded those reasonably associated with

their disease and treatment (DHEW 1977). The National

Commission endorsed the task force recommendations,

but it could not prepare a report on this topic before it

expired. The DHEW Ethics Advisory Board next took up

the issue; however, this board was terminated in 1980.

Finally, in 1982, the President’s Commission issued a

report on the subject entitled Compensating for Research

Injuries, in which it recommended that an experiment be

conducted that would have entailed providing federal

support to a small number of institutions to cover the

costs associated with providing compensation on a nonfault basis to injured research participants (President’s

Commission 1982). Results from the experiment were

intended for use in a report to DHHS about the need for

a full-fledged compensation program.

However, the experiment was never conducted, and

the issue of compensation was not addressed until the

Advisory Committee on Human Radiation Experiments

(ACHRE) recommended in its 1995 Final Report that the

federal government should consider a system of compensation for injuries to research participants resulting

from participation in federally funded research. ACHRE

supported the approach recommended by the President’s

Commission, noting that “so that years from now others

do not have to revisit and struggle with this issue, the

federal government must take steps now to address the

issue of compensation for injured research subjects”

(ACHRE 1995, 827). The federal government’s response

to the ACHRE recommendation reflected a concern

regarding the extent of research-related injuries:

In the absence of a finding that a significant number

of modern research subjects are unfairly denied compensation, the Administration is not prepared to 

propose a system outside the existing network of

Federal and state liability and insurance systems. The

Administration does, however, view the debate over

the extent and effectiveness of our current human

subject protections to encompass this issue. The
National Bioethics Advisory Commission

125

Administration would be open to considering any

recommendations from NBAC or legislation from

Congress that seek to address this issue. The desire 

to spread the cost of research injury is a reason to

consider a compensation scheme (Human Radiation

Interagency Working Group 1997, 17). 

The Current Situation

The availability, circumstances, and procedures for

compensating injured research participants have

remained unchanged from those observed by the

Tuskegee Advisory Panel. Unless a participant is privately

insured or is injured at one of the few research sites that

provide treatment or compensation (Marwick 1998), he

or she must take legal action through filing a lawsuit and

showing that one or more wrongful acts (e.g., battery) or

a breach of duty was committed (e.g., negligence in performance or failure to perform contractual obligations)

by someone involved in the research and that the wrongful act(s) caused the injury. Because research participants

also can be injured by their underlying conditions or by

the research itself, even if all parties perform their tasks

with the greatest care, it is often difficult to determine

whether a specific injury arises directly from a research

intervention. Further, even where warranted and successful, such lawsuits are costly and slow and thus are of

limited value at the time the injury is incurred.

Nevertheless, the threat of legal action often forces

institutions to adopt procedures to protect themselves.

For example, consent forms often disclose every foreseeable risk, and institutions require comprehensive and

multiple IRB reviews of multi-site studies in order to

ensure that the associated risks and potential benefits are

acceptable to the various sites as well as to the research

participants.

In addition, the threat of legal action often leads to

difficult negotiations between research institutions and

sponsors regarding the type and amount of compensation that can be offered or what is to be stated in the 

consent form.37 In some cases, sponsors wish to offer 

more treatment and compensation than do institutions,

and in other cases, institutions are prepared to offer more

than the sponsors will permit. Further, institutions want

to include their own language in the consent form

regarding the availability of compensation rather than 

the sample language proposed by the sponsor. When 

differences between institutions and sponsors arise, the

negotiations are often time consuming and contentious,

with institutions finding themselves in a compromised

position because they do not want to lose the opportunity

to collaborate in the research. 

The Need for a Compensation System

No adequate database exists that describes the number of injuries or illnesses that are suffered by research

participants, the proportion of these illnesses or injuries

that are caused by the research, and the medical treatment and rehabilitation expenses that are subsequently

borne by the participants. It may be argued that, regardless of the magnitude of the problem, the costs of

research injuries should never be borne by participants.

If they are injured by research participation, those who

benefit from the research (e.g., institutions and sponsors)

bear some obligation to compensate participants who

risked and suffered injury on their behalf. However, currently, injured research participants alone bear both the

cost of lost health and the expense of medical care, unless

they are adequately insured or pursue successful legal

action to gain compensation from specific individuals or

organizations involved in conducting the research.

Although the adoption of a system of universal health

care or a national health insurance program in the United

States would eliminate some, if not all, medical costs

incurred by research participants, under the current 

system, even though institutions and sponsors are most

likely to be required to provide such compensation, ultimately institutions pass the costs on to sponsors, who in

turn pass the costs on to society in the form of higher

prices or taxes. A national compensation program outside

the current fault-based system would mean that research

participants would not have to bear the burden of seeking

compensation, and at the same time the costs of compensation would not be imposed unfairly on investigators, institutions, or sponsors in cases in which no

negligence or wrongdoing might have occurred.

Arguably, this would be appropriate, because the public

ultimately benefits from the results of research through

new and improved products and services.
126

Chapter 6: Conduct of Research—Selected Issues for Local Institutions

Because the costs of research injuries should not be

borne by the injured participants and because support

for a compensation system should be provided by those

most likely to profit or derive other benefits from it, 

sponsors and institutions should be assigned responsibility

for funding such a system. The funding mechanism

could be flexible and could include options such as privately purchased liability insurance, self-insurance, or a

centrally administered fund supported by premiums paid

by sponsors and institutions.

More information is needed about the nature and

extent of research-related injuries and uncompensated

research injuries. Efforts are needed to obtain information from both public and private sponsors of research as

well as to develop effective systems for collecting data

regarding the nature and extent of research-related

injuries. The Department of Veterans Affairs (VA), for

example, has adopted regulations requiring compensation for research-related injuries to individuals who

participate in VA-funded research, but the agency does

not have a central mechanism for collecting local data on

research-related injuries (38 CFR 17.85). 

However, any such data collection efforts, whether

centralized or not, should use existing sources of data—

for example, reports to FDA of serious adverse events.

Information regarding the extent of injuries also would

be needed as part of the development and evaluation of

a compensation program.

The scope and nature of a national research-related

injury compensation system should support the system’s

goals of providing the following: 

■ coverage for medical treatment and rehabilitation of

those whose injuries are caused by their participation

in research;

■ coverage for research-related injuries, regardless of

fault;

■ prompt decisions on whether compensation will or

will not be provided in each case;

■ coordination with, but not replacement of, the existing

fault-based liability system; and 

■ costs that are spread widely across the entire research

enterprise.

Recommendation 6.6: The federal government

should study the issue of research-related

injuries to determine if there is a need for a 

compensation program. If needed, the federal

government should implement the recommendation of the President’s Commission for the

Study of Ethical Problems in Medicine and

Biomedical and Behavioral Research (1982) 

to conduct a pilot study to evaluate possible 

program mechanisms.

Summary

Local institutions have three major responsibilities in the

conduct of research involving human participants. Initial

IRB review is a powerful tool for protecting participants

because, when used appropriately, it can prevent abuses

before the research begins. Oversight, however, should

not end when the research begins, and continuing review

and monitoring should be intensified as the risk and

complexity of the research increase. These processes at 

all times should emphasize the protection of research

participants.

In addition, the review process should facilitate rather

than hinder collaborative research among institutions,

provided that participants are protected. Local institutional review has many advantages and is appropriate for

studies conducted by a single institution. However, when

multiple institutions engage in a collaborative study, the

local review system can become cumbersome and less

effective. Alternative review mechanisms, such as the use

of a lead or central IRB, should be encouraged, tested,

and evaluated.

Ultimately, however, even with all the available protective mechanisms in place, some participants will be

harmed by participating in research, and these participants should be cared for and compensated for this

harm. This presents an enormous challenge, because it 

is often difficult to separate injuries traceable to the

research from those that stem from the underlying 

disease being studied. However, this challenge should

not deter movement toward the development of an

appropriate compensation program for those who are

harmed by participating in research. 
National Bioethics Advisory Commission

127

Notes

1 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

2 Ibid.

3 Ibid.

4 Notice of proposed actions under the NIH Guidelines for

Research Involving Recombinant DNA Molecules. 65 Fed. Reg.

77655–77659.

5 NIH Guide for Grants and Contracts, “Further Guidance on a 

Data and Safety Monitoring for Phase I and Phase II Trials.”

Notice OD-00-038. June 5, 2000. Available at http://grants.nih.gov/

grants/guide. Last accessed December 4, 2000.

6 NIH Guide for Grants and Contracts, “Further Guidance on a 

Data and Safety Monitoring for Phase I and Phase II Trials.” Notice

OD-00-038. June 5, 2000; “Guidance on Reporting Adverse Events

to Institutional Review Boards for NIH-Supported Multicenter

Clinical Trials.” Notice 99-107. June 11, 1999; “NIH Policy for

Data and Safety Monitoring.” Notice 98-084. June 10, 1998. All

available at http://grants.nih.gov/grants/guide. Last accessed

December 4, 2000.

7 NIH Guide for Grants and Contracts, “NIH Policy for Data and

Safety Monitoring.” Notice 98-084. June 10, 1998. Available at

http://grants.nih.gov/grants/guide. Last accessed December 4,

2000.

8 NIH Guide for Grants and Contracts, “Further Guidance on a 

Data and Safety Monitoring for Phase I and Phase II Trials.” Notice

OD-00-038. June 5, 2000. Available at http://grants.nih.gov/

grants/guide. Last accessed December 4, 2000.

9 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

10 Ibid.

11 Recombinant DNA Advisory Committee Meeting, NIH. 8–10

December, 1999. Bethesda, Maryland.

12 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

13 Personal communication from B. Spilker, PhRMA, to M. Speers,

NBAC. October 24, 2000.

14 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

15 Ibid.

16 Ibid. 

17 See McCarthy, C.R., “Reflections on the Organizational Locus of

the Office for Protection from Research Risks.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

18 See Peckman, S., “Local Institutional Review Boards.” This

background paper was prepared for NBAC and is available in

Volume II of this report.

19 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

20 See Peckman, S., “Local Institutional Review Boards.” This

background paper was prepared for NBAC and is available in

Volume II of this report.

21 OHRP Guidance: “IRB Knowledge of Local Research Context.”

September 27, 1998 (Updated July 21, 2000). Available at

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/local.htm.

Last accessed December 4, 2000.

22 Ibid. 

23 OHRP Guidance: “General Guidance on the Use 

of Another Institution’s IRB.” August 9, 1991. Available at

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/irb-rely.htm.

Last accessed December 4, 2000.

24 Personal communication from J. Goldberg, National Cancer

Institute, to NBAC staff. May 23, 2000; Schuster, D.P., Testimony

before NBAC. September 12, 2000. Washington, D.C.

25 OHRP Guidance: “IRB Meetings Convened via 

Telephone Conference Call.” March 28, 2000. Available at

http://ohrp.osophs.dhhs.gov/references/irbtel.pdf. Last accessed

December 8, 2000.

26 See Holm, S., “The Danish Research Ethics Committee

System—Overview and Critical Assessment.” This background

paper was prepared for NBAC and is available in Volume II of 

this report. 

27 Holm, S., Testimony before NBAC. September 12, 2000.

Washington, D.C.

28 See Holm, S., “The Danish Research Ethics Committee

System—Overview and Critical Assessment.” This background

paper was prepared for NBAC and is available in Volume II of 

this report. 

29 Ibid. 

30 Ibid.

31 Faden, R., Testimony before NBAC. January 13, 2000.

Washington, D.C.
128

Chapter 6: Conduct of Research—Selected Issues for Local Institutions

32 Law 88-1138 Regarding the Protection of Persons Agreeing to

Biomedical Research.

33 Law of 26 February 1998, containing regulations with regard to

medical-scientific research on humans, Staatblad (Official Law

Gazette of the Netherlands) 161.

34 The Department of Veterans Affairs adopted regulations to 

provide medical treatment for research-related injuries. These 

regulations are not part of the Common Rule, but are supplemental. 

35 OHRP Guidance: “‘Exculpatory Language’ in Informed Consent.”

November 15, 1996. Available at http://ohrp.osophs.dggs.gov/

humansubjects/guidance/exculp.htm. Last accessed December 4, 2000.

36 Since the time of the Tuskegee Ad Hoc Advisory Panel’s report,

no fault has come to have a very specific meaning in the context 

of automotive insurance. As the automotive context is not strictly

analogous, we will use the term nonfault rather than no fault to

refer to compensation that does not depend on establishment of

wrongdoing or negligence.

37 NBAC Town Meetings: February 9, 2000, Houston, Texas; 

April 5, 2000, Pittsburgh, Pennsylvania; May 3, 2000, Orlando,

Florida; June 7, 2000, Chicago, Illinois; August 14, 2000,

Portland, Oregon.

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Department of Health and Human Services (DHHS). 2000.

“Secretary Shalala Bolsters Protections for Human Research Subjects.”

[Press Release.] 23 May. Available at http://www.hhs.gov/news/.

Last accessed November 6, 2000.

Department of Health, Education, and Welfare (DHEW).

Secretary’s Task Force on the Compensation of Injured Research

Subjects. 1977. Final Report. Pub. OS-77-003. Bethesda, MD:

DHEW.

Ellis, G. 1994. “Perspectives from OPRR.” In Changes and Choices

for Institutional Review Boards: The Inclusion of Women and Minorities,

and Other Emerging Issues in Research, 31–32. Boston: Public

Responsibility in Medicine and Research.

Food and Drug Administration (FDA). 1998. Information Sheets:

Guidance for Institutional Review Boards and Clinical Investigators.

Available at http://www.fda.gov/oc/ohrt/irbs/default.htm. Last

accessed December 8, 2000.

General Accounting Office (GAO). 1996. Scientific Research:

Continued Vigilance Critical to Protecting Human Subjects.

GAO/HEHS-96-72. Washington, D.C.: GAO. 

Gordon, V.M., J. Sugarman, and N. Kass. 1998. “Toward a More

Comprehensive Approach to Protecting Human Subjects.” IRB: A

Review of Human Subjects Research 20(1):1–5.

Health Research Council of New Zealand. 1997. HRC Guidelines on

Ethics in Health Research. Auckland, New Zealand: Health Research

Council of New Zealand. 

Human Radiation Interagency Working Group. 1997. Building

Public Trust: Actions to Respond to the Report of the Advisory

Committee on Human Radiation Experiments. Washington, D.C.: 

U.S. Government Printing Office.

Indian Council of Medical Research. 2000. Ethical Guidelines on

Biomedical Research Involving Human Subjects. New Delhi: Indian

Council of Medical Research.

International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human 

Use (ICH). 1996. ICH Harmonised Tripartite Guideline. Guideline

for Good Clinical Practice. Geneva: ICH Secretariat, International

Federation for Pharmaceutical Manufacturers Association.

Joint United Nations Programme on HIV/AIDS (UNAIDS). 2000.

Guidance Document: Ethical Considerations in HIV Preventive Vaccine

Research. Geneva: UNAIDS.

Kolata, G., and K. Eichenwald. 1999. “Stopgap Medicine: A Special

Report for the Uninsured, Drug Trials Are Health Care.” New York

Times, 22 June, A-1.
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Ladimer, I. 1963. “Clinical Research Insurance.” Journal of Chronic

Diseases 16:1229, 1233.

Lux, A.L., S.W. Edwards, and J.P. Osborne. 2000. “Responses of

Local Research Ethics Committees to a Study with Approval from 

a Multicentre Research Ethics Committee.” British Medical Journal

320(7243):1182–1183.

Marwick, C. 1998. “Compensation for Injured Research Subjects.”

Journal of the American Medical Association 279(23):1854.

Medical Research Council (MRC). 1998. Guidelines for Good Clinical

Practice in Clinical Trials. London: MRC.

Medical Research Council of South Africa. 1993. Guidelines on

Ethics for Medical Research. South Africa: Medical Research Council

of South Africa.

National Bioethics Advisory Commission (NBAC). 2001. Ethical

and Policy Issues in International Research: Clinical Trials in Developing

Countries. 2 vols. Bethesda, MD: U.S. Government Printing Office.

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Biomedical and Behavioral Research (National Commission). 1978.

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Washington, D.C.: U.S. Government Printing Office.

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in Uganda. 1997. Guidelines for the Conduct of Health Research

Involving Human Subjects in Uganda. Kampala, Uganda.

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Research Involving Human Subjects. Brazil: NHC. Addition: 1997.

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NHC.

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Indian and Alaska Native Communities Navigating the Cultural

Universe of Values and Process.” Journal of Consulting and Clinical

Psychology 64(5):856–860.

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Review Boards: A Time for Reform. OEI-01-97-00193. Washington,

D.C.: DHHS.

———. 1998b. Institutional Review Boards: The Emergence of

Independent Boards. OEI-01-97-00192.Washington, D.C.: DHHS.

———. 1998c. Institutional Review Boards: Their Role in Reviewing

Approved Research. OEI-01-97-00190. Washington, D.C.: DHHS.

Prentice, E.D., and B. Gordon. 1997. “IRB Review of Adverse

Events in Investigational Drug Studies.” IRB: A Review of Human

Subjects Research 19(6):1–4.

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Medicine and Biomedical and Behavioral Research (President’s

Commission). 1981. Protecting Human Subjects. Washington, D.C.:

U.S. Government Printing Office.

———. 1982. Compensating for Research Injuries: The Ethical 

and Legal Implications of Programs to Redress Injured Subjects.

Washington, D.C.: U.S. Government Printing Office.

Sharp, R.R., and M.W. Foster. 2000. “Involving Study Populations

in the Review of Genetic Research.” Journal of Law, Medicine, and

Ethics 28(1):41–51.

Tully, J., N. Ninis, R. Booy, and R. Viner. 2000. “The New System

of Review by Multicentre Research Ethics Committees: Prospective

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Final Report. Washington, D.C.: DHEW.

Vasgird, D.R., M. Hensleigh, A. Berkman, E. Schachne, and C.

Trinh. 2000. “Protecting the Uninsured Human Research Subject.”

Journal of Public Health Management Practice 6(6):37–47.

7

Implications of This Report 

Chapter Seven

Introduction

This report proposes an oversight system for research

involving human participants that addresses the

needs, interests, and responsibilities of all parties

involved in the research enterprise. Adopting the recommendations in this report will lead to better protection of

human participants while also promoting ethically sound

research and reducing unnecessary bureaucratic burdens.

Achieving these goals will, in turn, support the public’s

trust in research, enhance enthusiasm for all research

involving human beings, and restore the respect of investigators for the oversight system. Ultimately, the needs of

the American people will be better met through research

that is both ethically sound and of the highest scientific

quality.

Resources

The recommendations made in this report will generate

additional costs for institutions, sponsors, and the federal

government (through the establishment of a new federal

oversight office). The importance of identifying the needed

resources to support a robust system of protection of

research participants has long been a concern. In 1978,

the National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research

(National Commission), concerned that Institutional

Review Boards (IRBs) could not function without adequate resources, recommended that the oversight system

be appropriately funded (National Commission 1978).

In 1998, the Department of Health and Human Service

(DHHS) Office of Inspector General called attention to

the critical shortage of resources, including staff, office

space, and information technology, and recommended

that IRBs be given access to adequate resources (OIG

1998). The scarcity of resources for IRBs has been

attributed to low levels of support from sponsors and

institutions (GAO 1996).

In previous reports, the National Bioethics Advisory

Commission (NBAC) recognized that research should

not be thwarted because resources are not available to

provide the necessary protections for human participants

and that compliance would require additional resources

(NBAC 1998; NBAC 1999). Sponsors of research,

whether public or private, should work together with

institutions conducting research to make the necessary

resources available.

Limited information is available concerning the

human and financial resources that federal agencies,

other sponsors, and research institutions dedicate to

oversight. In fact, the only information NBAC could

obtain in this regard was for the federal agencies.

However, it is clear that the current system relies on other

sponsors and research institutions also contributing 

substantial resources to oversight. Thus, the information

presented below is an incomplete picture of the current

resources used to support the oversight system.

Human and financial resources that directly support

human research protection activities are limited at the

federal level.1 As shown in Table 7.1, of the 16 federal

agencies responding to an NBAC survey, 5 have no 

dedicated administrative unit or staff. Even within

DHHS, four agencies have no dedicated administrative

units or staff. Most departments spend only 1 to 2 percent of their human research budget on protection activities. The National Institutes of Health (NIH) spent less

131
Chapter 7: Implications of This Report

Table 7.1: Federal Agency Support for Research Participant Protections for FY 1999

Budget for Human

Agency Dedicated Administrative Unit Dedicated Research

Human Research Administrative Unit Budget

Central Intelligence Agency Yes, Chief of Human Subjects Research Panel and

Contracting Officer’s Technical Representatives Classified Classified

Department of Commerce National Telecommunications and Information 

Administration - No None reported $17,600,000

National Institute of Standards and Technology (NIST)- 

personnel in Office of NIST Counsel and elsewhere $41,024,000

Census - No $158,500,000

Department of Defense 60 full-time equivalents (FTEs) $3,500,000 $37,100,000

Department of Education 1.5 FTEs $200,000 $50,000,000

Department of Energy 2 FTEs $425,000 $27,000,000

Department of Health 

and Human Services

Administration for Children 

and Families No None reported $30,000,000

Agency for Healthcare 

Research and Quality No None reported $109,411,000 

Centers for Disease 

Control and Prevention 6 FTEs $651,505 $172,025,000

Food and Drug Administration ~200 FTEs ~$37,000,000 $11,329,000

Health Care Financing 

Administration 6 FTEs None reported $15,000,000

Health Resources and 

Services Administration No None reported $75,908,000

Indian Health Service 4.7 FTEs $1,000,000 $22,400,000

National Institutes of Health 4 FTEs in Office of Human Subjects Research, $480,000 $8,580,000,000

another 10.73 in Institute’s administrative units, $334,965

19 FTEs in OPRR* $2,700,000 for OPRR

Substance Abuse and Mental 

Health Services Administration No None reported $338,349,000

Department of Housing No (Office of Lead Hazard Control conducts None reported $11,000,000

and Urban Development some oversight)

Department of Justice 2 part-time employees Not available $110,705,000

Department of Transportation No None reported Not reported 

Department of Veterans 3 units, 3 FTEs** None reported 

Affairs (VA) for FY 1999 $175,600,000

National Aeronautics and 

Space Administration 5.9 FTEs $625,000 $20,000,000

National Science Foundation Part-time employee None reported $150,360,000 

Social Security Administration No None reported $40,000,000

Agency for International 

Development Cognizant Human Subjects Officers None reported $60,000,000

Consumer Product Safety 

Commission No None reported <$100,000

Environmental Protection Agency No None reported $ 76,000,000

*Until June 2000, OPRR was the administrative unit within DHHS that provided assurances for all DHHS agencies as well as other federal departments. 

**During FY 2000, VA planned to increase to 8 FTE, and in FY 2001 there will be 12 FTE in Headquarters. There are plans for five field offices to be established

in FY 2000.

Source: NBAC, “Federal Agency Survey on Policies and Procedures for the Protection of Human Subjects in Research.” This staff analysis is available in Volume II of

this report.

132
National Bioethics Advisory Commission

133

than .05 percent of its human research budget directly on

protection activities, even when the Office for Protection

from Research Risks (OPRR) was administratively part of

the agency. 

The lack of adequate resources also has been noted in

site visits by the Office for Human Research Protections

(OHRP), formerly OPRR, and in testimony presented to

NBAC. For example, in a site visit by OPRR to Duke

University, OPRR found that the university had assigned

only 2.5 to 3 full-time staff members to the IRB, even

though the university reviewed over 1,700 protocols

annually.2 IRB administrators, in particular, who testified

to NBAC described the need for resources and strongly

encouraged NBAC to consider the issue of resources in its

recommendations.3 A report commissioned by NIH,

Reducing Regulatory Burden, noted that resources available

to IRBs are decreasing despite increases in workload and

recommended providing additional federal resources

when adding to IRB duties (Mahoney 1999).

Data estimating the costs of institutional protection

programs are nearly 20 years old (Brown et al. 1979;

Cohen 1982). In 1982, it was estimated that the total cost

(administrative plus meeting costs) of IRB review at universities without medical schools was $137 per protocol,

$154 at universities with medical schools, and $207 at

hospitals. Adjusting these cost estimates for inflation

using the Consumer Price Index, the total cost of IRB

review at universities without medical schools would

currently be estimated at $245 per protocol, $275 per

protocol at universities with medical schools, and $369

per protocol at hospitals. Based on these inflationadjusted figures, the current cost of protecting human

research participants at research institutions nationwide

is estimated to be $32.12 million. It is difficult, however,

to estimate IRBs’ costs at academic institutions, because

costs are not itemized separately in grant applications;

rather they are part of the costs recovered, at least partly

though the indirect cost mechanism (Goldman and

Williams 2000).

Some information, however, is available about the

prices (which may be higher or lower than costs) being

charged for IRB review. One commentator reported that

her independent IRB charged $1,000 for an initial review

of a protocol and $275 for initial review of a research

site.4 Another commentator estimated that the average fee

for a protocol review was $1,000.5 The number of academic institutions charging for IRB review of research

that is not federally funded has been increasing in the

past few years, with fees ranging from $500 to $2,000 for

initial review and an average fee of $1,130.6

In addition to the call for additional resources, academic institutions have expressed concerns about the

costs of the IRB being billed through the indirect cost

mechanism, because an administrative capitation prevents them from requesting additional resources (AAU

2000). Alternatives, such as a direct budget line for 

protection of research participants, have been suggested

(AAU 2000).

Recommendation 7.1: The proposed oversight 

system should have adequate resources to ensure

its effectiveness and ultimate success in protecting research participants and promoting research: 

a) Funds should be appropriated to carry out the

functions of the proposed federal oversight

office as outlined in this report.

b) Federal appropriations for research programs

should include a separate allocation for oversight activities related to the protection of

human participants.

c) Institutions should be permitted to request

funding for Institutional Review Boards and

other oversight activities.

d) Federal agencies, other sponsors, and institutions should make additional funds available

for oversight activities.

Future Research

This report has raised many questions about ethical

issues that could not be answered because of insufficient

or nonexistent empirical evidence. Little research has

been conducted on the actual conduct of research,

although some studies are under way.7 Current thinking

about ethical issues in research—including the importance of conducting analyses of risks and potential benefits, obtaining informed consent, protecting privacy and

confidentiality, and protecting those who are vulnerable—

would greatly benefit from research designed to address
134

Chapter 7: Implications of This Report

these specific issues. For example, approaches for assessing cognitive competency, evaluating what participants

want to know about research, and ascertaining best

practices for seeking informed consent are deserving of

more study. Clearer guidance could be developed from a

stronger knowledge base.

In addition, although a good deal of ethical analysis

has been conducted on many research issues, some (e.g.,

ethical standards for informed consent) have received

more attention from ethicists than others (e.g., understanding what constitutes undue inducement or exploitation in research). In general, increased interdisciplinary

discussion that includes biomedical and social scientists,

lawyers, and historians would advance understanding of

the ethical conduct of research.

Recommendation 7.2: The federal government, 

in partnership with academic institutions and

professional societies, should facilitate discussion about emerging human research protection

issues and develop a research agenda that

addresses issues related to research ethics.

The New System as a Dynamic and

Responsive Structure

Research is an ever-evolving enterprise, responding to

scientific interests, the biological and social condition of

humans, the practicalities of resource availability, and

competing demands on academic institutions and others

involved in sponsoring or conducting research. Thus, the

oversight system also must be dynamic and should be

enhanced in order to ensure that sound ethical principles

and standards are followed, while interpretation and

application of those principles and standards accommodate and remain relevant to new discoveries, influences,

and ethical challenges. The system should provide both

the stable foundation and the flexibility necessary to

respond to the changing research enterprise.

The proposed oversight system reflects a rethinking

of the entire structure for protecting research participants, taking into account the roles of various parties,

including participants, investigators, institutions, IRBs,

sponsors, and other entities, such as professional societies, a federal oversight office, state regulators, Congress,

and the public. Articulating the roles of each of these 

parties serves several purposes. It encourages a range of

individuals, organizations, and communities to take

more seriously their roles in the protection of research

participants and holds them accountable for their

actions. Distributing roles and responsibilities among

more parties in the oversight system also reduces the 

burden placed on any one entity, such as IRBs. In articulating roles in various areas, such as monitoring and education, responsibility should be delegated to one or more

parties, such as a central IRB, a local IRB, another entity

within an institution, a Data and Safety Monitoring

Board, or the research sponsor. It is critical that all parties

understand their responsibilities and those of others in

the system.

Once these roles have been articulated, it becomes

clear that the oversight system must be more than a federal structure. Outside parties play a crucial role. Indeed,

the system functions in large part because of the goodwill

of the thousands of people who aspire to meet their 

obligations to conduct research ethically. Although attention is often focused on those who do not take their 

ethical obligations seriously, a majority of those involved

in research are committed to ethical behavior. However,

the awareness of and commitment to ethically sound

research can be strengthened and enriched by educational

institutions, credentialing and professional organizations,

editors and publishers, and advocacy groups, organizations

that have tremendous influence over their constituencies

and that are in an excellent position to harness the energy

of their members to support an efficient and effective

oversight system.

Six distinct functions or responsibilities of a consolidated oversight system are recommended: policy development through regulations and guidance; educational

programs aimed at the responsibilities of all parties; 

ethical review of proposed research; monitoring of ongoing

research; enforcement of the requirements; and accountability for all those involved in the review and conduct of

research. By focusing attention and resources on these

functions, the system will provide the necessary infrastructure for protecting research participants and promoting research. To ignore any one of them is to have a

system that functions less than optimally.
National Bioethics Advisory Commission

135

The functions of the system are, and should be, interconnected, with changes in one function affecting outcomes in another. For example, the creation of a single

set of regulations and a single office to promulgate them

makes it possible to implement specific regulatory

changes without amending the regulations of each of the

agencies, as is now required. Creation of a single, independent oversight office would also facilitate issuance of

regulatory guidance, because direction from that office

would apply to all parties conducting research involving

human participants.

The greater flexibility proposed for IRBs in deciding

what information must be provided to participants and

in determining frequency of continuing review demands

a higher level of competency among IRBs. Certification of

IRB members and staff and accreditation of institutions

can validate such competency. Higher and consistent

standards for IRB members will ensure more effective

assessments of risks and potential benefits as well as

determinations of vulnerability. Similarly, certification of

investigators allows for flexibility in implementing the

recommended informed consent process. More education

should make certification of investigators easier to

achieve, because investigators will receive the knowledge

and skills necessary for certification as part of their 

professional training. The recommendations regarding

verification, adverse event monitoring, and accreditation

of research institutions all make single review of multi-site

research more feasible. 

Thus, just as the oversight functions are interconnected, so too are the recommendations for improving

them, and, therefore, consideration should be given to

adopting them more or less in total, for to do otherwise

may result in diminished success in implementing many

of the recommendations in this report. For example, a

crucial component of the proposed system is the creation

of a new independent oversight office. If this new office

were not created, it would be imperative to find an alternative mechanism that would allow the Common Rule to

be modified more easily. 

Now is the time for strategic change. With more than

20 years of experience with much of the current regulatory language and 10 years of experience with the

Common Rule structure, all parties understand the

strengths and weaknesses of the current oversight system, and it is evident that making minor tactical changes

to it will not result in the corrections that are needed.

However, the proposed changes should be implemented

in a planned, phased-in fashion, to avoid creating major

disruptions that could compromise the protection of

research participants or the conduct of ethical research.

General Themes in the

Recommendations

Three general themes are found in this report. First, the

recommendations related to policy generally suggest that

there should be fewer regulations and more guidance,

which clarifies regulatory responsibilities, suggests ways

of fulfilling those responsibilities, and assists institutions

in formulating institution-specific policies—improving

consistency across institutions. At the same time, guidance permits reasoned deviations from the regulations.

Second, the recommendations generally focus

attention on research in which participants need the most

protection, striving to make the level of protection commensurate with the level of risk. This theme is strongest

in the recommendations regarding continuing review,

verification, reporting of adverse events, informed consent, review of minimal risk research, and additional

scrutiny for research involving a high level of risk. 

Third, the recommendations somewhat increase the

scope of regulated research while streamlining the

process of regulatory compliance. The recommendations

regarding privately funded research and the removal of

exemptions close some gaps in the current system and

thus increase the amount of research subject to regulation. However, it is also recommended that requirements

for initial and continuing review of all minimal risk

research be reduced. Thus, although the scope of the

oversight system is broadened, changes are proposed that

will streamline the system and attenuate the need for

additional resources by increasing efficiency, making it

safer and more productive.
136

Chapter 7: Implications of This Report

What This Report Means to Those Who

Use the System

One unified and comprehensive federal policy embodied

in a single set of regulations and guidance should govern

all research with human participants. Furthermore, one

office should have the authority to promulgate those 

regulations and issue appropriate guidance (see

Recommendations 2.1–2.3). At the same time, there is a

continuing role for the various federal departments and

agencies that conduct and fund research with human

participants—a role focused particularly on education,

monitoring, and enforcement (see Chapter 2).

Nonfederal accreditation and certification bodies should

be created to improve the quality and accountability of

institutions and bodies responsible for the review and

conduct of research (see Recommendations 3.3 and 3.4).

In addition, it is time to encourage and foster the participation of groups often overlooked in the protection of

research participants, including professional organizations, journal editors, and patient advocacy groups (see

Chapters 2 and 3).

As a whole, these recommendations strengthen

oversight by dispersing responsibilities more widely.

However, although a new federal oversight office will

provide much needed leadership and uniformity in the

system, the research community must move to implement self-regulation through nonfederal credentialing

organizations. The desired outcome of these reforms

would be a system that emphasizes education as a means

for improving protections and avoiding the need for

large-scale federal enforcement actions.

How This Report Will Affect IRBs,

Investigators, and Institutions

Almost all of the recommendations in this report directly

or indirectly affect investigators, IRBs, and institutions

by increasing their responsibilities. For example, it is

recommended that the scope of regulated research be

expanded (see Recommendations 2.1 and 2.4); that

risky research be more closely monitored (see

Recommendations 6.1–6.4); and that additional educational and credentialing requirements be imposed on

those who conduct and review human research (see

Recommendations 3.1–3.4). Although these increased

responsibilities are significant, numerous changes are

proposed that would reduce the regulatory burden on

IRBs, investigators, and institutions. Under the recommendations, these groups would be required to follow

only one set of rules (see Recommendation 2.3), would

have one office providing authoritative interpretation 

(see Recommendation 2.2), and would be given more

guidance on issues not requiring a regulatory response

(see Recommendations 4.1–4.3 and 5.1–5.4). Specifically, investigators, IRBs, and institutions would have

greater flexibility to:

■ create arrangements in which multi-site studies are

reviewed by only one IRB (see Recommendation 6.5);

■ approve minimal risk studies through procedures

other than full IRB review (see Recommendations 2.5

and 4.2);

■ use a range of means to communicate information to

prospective research participants and document

informed consent (see Recommendations 5.1 and 5.3);

■ waive the requirement of informed consent when

appropriate (see Recommendation 5.2); and

■ conduct continuing review of research as appropriate

(see Recommendation 6.2). 

These changes, as well as the recommendation that

the distribution of IRB members with relevant expertise

and experience should be commensurate with the types

of research reviewed by the IRB (see Recommendation

3.9), should make the oversight system more applicable

to research in the social sciences and humanities.

Overall, the recommendations suggest three broad

changes for IRBs, investigators, and institutions. First,

they shift requirements away from procedure and toward

competence. That is, although investigators and IRB

members are given greater discretion, they are also

required to demonstrate appropriate levels of competence in the protection of research participants. Second,

the recommendations encourage more strategic use of

IRB review, with IRBs reviewing more protocols, but

doing so using mechanisms that would allow them to

focus on riskier research. Third, the recommendations

propose a more strategic use of monitoring by increasing
National Bioethics Advisory Commission

137

the focus primarily and more intensely on risky research

and by reducing the monitoring requirements for less

risky research. 

How This Report Will Affect Research

Participants

Although the recommendations in this report aim to

improve the operation of the oversight system, they are

not intended simply to reduce inefficiency and needless

regulatory burden. Rather, they seek to effect real change

in the protections offered to research participants. Under

the proposed system, with one oversight office providing

enforcement authority and accountability for the oversight of all research:

■ Research participants would be protected in all types

of research regardless of funding source. Gaps that

currently leave participants in some research unprotected would be eliminated (see Recommendations

2.1, 2.2, and 2.4).

■ Individuals and institutions conducting and reviewing research would be appropriately credentialed (see

Recommendations 3.3 and 3.4). 

■ The information on which potential participants rely

to decide whether to enroll in a research study would

be improved. By focusing federal policy on the

process of informed consent (see Recommendation

5.1) and requiring education for investigators (see

Recommendations 3.1 and 3.3), participants would

better understand the nature of research and have an

opportunity to ask questions before deciding whether

to enroll in research, rather than simply sign an often

long and confusing consent form.

■ Because research involves risk, a system for compensating participants for research-related injuries would

receive further analysis (see Recommendation 6.6). 

■ Changes would be made to improve protections for

vulnerable research participants, while at the same

time ensuring that vulnerability does not become an

excuse for arbitrarily excluding some people from

research (see Recommendation 4.3). 

■ A model is proposed for use in assessing risks (see

Recommendation 4.1), and methods are suggested

that would improve protections related to privacy and

confidentiality (see Recommendation 5.4).

■ Finally, one location would be established to which

participants and others could report problems (see

Recommendation 2.2).

Summary

This report proposes 30 recommendations for changing

the oversight system. These changes are proposed at both

the national and local levels and are directed at all who

are involved in the research enterprise. The time is right

for changes of such magnitude and breadth, because only

such across-the-board modifications will reform the

oversight system so that it is capable of adequately protecting the rights and welfare of research participants

while promoting ethically sound research. 

Notes

1 NBAC, “Federal Agency Survey on Policies and Procedures for

the Protection of Human Subjects in Research.” This staff analysis

is available in Volume II of this report.

2 Telephone conversation between M. Carome, OHRP, and M. Speers,

NBAC. November 13, 2000.

3 Keane, M.A., and Nelson, D.K., Testimony before NBAC. 

July 11, 2000. Bethesda, Maryland. 

4 Heath, E., Testimony before NBAC. June 6, 2000. 

San Francisco, California. 

5 Spilker, B., Testimony before NBAC. April 7, 2000. 

Washington, D.C.

6 Baylor College of Medicine. “Fees for IRB Review.” Available 

at http://research.bcm.tmc.edu/A_C/a_c.html. Last accessed

December 11, 2000.

7 NIH Guide for Grants and Contracts, “Informed Consent in

Research Involving Human Participants.” September 27, 1996.

Request for Applications RFA-OD-97-001. Available at

http://grants.nih.gov/grants/guide. Last accessed December 4, 2000.
138

Chapter 7: Implications of This Report

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Brown, J.H.U., L.S. Schoenfeld, and P.W. Allan. 1979. “The Costs

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Cohen, J. 1982. The Costs of IRB Review. In Human Subjects

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Goldman, C.A., and T. Williams. 2000. Paying for University

Research Facilities and Administration. Washington, D.C.: RAND. 

Mahoney, J. 1999. NIH Initiative to Reduce Regulatory Burden:

Identification of Issues and Potential Solutions. Bethesda, MD:

National Institutes of Health. Available at http://grants.nih.gov/

grants/policy/regulatoryburden/index.htm. Last accessed 

November 29, 2000.

National Bioethics Advisory Commission (NBAC). 1998. 

Research Involving Persons with Mental Disorders That May Affect

Decisionmaking Capacity. 2 vols. Rockville, MD: U.S. Government

Printing Office.

———. 1999. Ethical Issues in Human Stem Cell Research. 3 vols.

Rockville, MD: U.S. Government Printing Office

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission). 1978.

Report and Recommendations: Institutional Review Boards.

Washington, D.C.: U.S. Government Printing Office.

Office of Inspector General (OIG), Department of Health and

Human Services (DHHS). 1998. Institutional Review Boards: A Time

for Reform. OEI-01-97-00193. Washington, D.C.: DHHS.
Acknowledgments

Appendix A

139

This report benefited from the input of manyindividuals and groups. The Commission asked the

following individuals to review portions of the draft

report or to assist Commission staff in data collection and

analysis. The contributions made by these individuals

improved the quality and outcome of the report and are

greatly appreciated:

■ Sanford Chodosh (Public Responsibility in Medicine

and Research; Boston, Massachusetts)

■ Paula Knudson (The University of Texas Houston

Health Science Center; Houston, Texas) 

■ David Korn (Association of American Medical

Colleges; Washington, D.C.) 

■ Bonnie M. Lee (Food and Drug Administration;

Rockville, Maryland) 

■ Kate MacQueen (Centers for Disease Control and

Prevention; Atlanta, Georgia)

■ Daniel K. Nelson (University of North Carolina;

Chapel Hill, North Carolina)

■ Stuart Plattner (National Science Foundation;

Arlington, Virginia)

■ Ivor Pritchard (Department of Education;

Washington, D.C.)

■ J. Thomas Puglisi (PricewaterhouseCoopers LLP;

Washington, D.C.)

■ Joan Rachlin (Public Responsibility in Medicine and

Research; Boston, Massachusetts)

■ Susan L. Rose (Department of Energy; Gaithersburg,

Maryland) 

■ Angela L. Sharpe (Consortium of Social Science

Associations; Washington, D.C.)

■ Allan C. Shipp (Association of American Medical

Colleges; Washington, D.C.)

May 1999 

Letter from Harold T. Shapiro

to President William J. Clinton

and President Clinton’s

Response

Appendix B

141

6100 Executive Blvd

Suite 5B01

Rockville, MD

20892-7508

Telephone

301-402-4242

Facsimile

301-480-6900

Website

www.bioethics.gov

Harold T. Shapiro, Ph.D.

Chair

Patricia Backlar

Arturo Brito, M.D.

Alexander Morgan Capron, LL.B.

Eric J. Cassell, M.D., M.A.C.P.

R. Alta Charo, J.D.

James F. Childress, Ph.D.

David R. Cox, M.D., Ph.D.

Rhetaugh Graves Dumas, Ph.D., R.N.

Laurie M. Flynn

Carol W. Greider, Ph.D.

Steven H. Holtzman

Bette O. Kramer

Bernard Lo, M.D.

Lawrence H. Miike, M.D., J.D.

Thomas H. Murray, Ph.D.

Diane Scott-Jones, Ph.D.

Eric M. Meslin, Ph.D.

Executive Director

N ATIONAL BIOETHICS A DVISORY C OMMISSION

The President

The White House

Washington, DC 20005

Dear Mr. President: May 4, 1999

Consistent with your October 3,1995, Executive Order 12975, the National Bioethics

Advisory Commission has focused a good deal of its efforts over the last three years on

issues surrounding the protection of human research subjects. I know of your interest,

as well as that of the Congress, which has rightfully inquired about the adequacy of

existing protections. To supplement the reports we have already submitted, I take this

opportunity to provide you with a summary of our concerns and preliminary findings,

some of which will, in our judgment, require further actions by the Federal 

Government. The attached memo provides additional details, but our key concerns are

the following:

● Federal protections for persons serving as human research subjects do not yet 

extend to all Americans.

● Despite widespread implementation of federal regulations by those departments 

and agencies sponsoring substantial amounts of biomedical research, a number of

departments and agencies who sponsor primarily non-biomedical research or little

research overall have failed to implement these federal protections.

● Federal protections do not always include specific provisions for especially 

vulnerable populations of research subjects.

● Many federal agencies find the interpretation and implementation of the Common

Rule confusing and/or unnecessarily burdensome.

● Federal protections are difficult to enforce and improve effectively throughout the

Federal Government, in part because no single authority or office oversees research

protections across all government agencies and departments.

● New techniques are needed to ensure implementation at the local level.

We will submit a more comprehensive report to you in the coming months, which will

provide specific recommendations for changes in the federal system for protecting

human subjects. Of course, as with all NBAC studies, we will continue to ensure that

the public, the research community, and the agencies of the Federal Government have 

an opportunity to participate in the report’s preparation.

Sincerely,

Harold T. Shapiro

Chair 

National Bioethics Advisory Commission

145

NBAC Summary of Preliminary Findings:

Adequacy of Federal Protections for Human Subjects in Research

Extending Federal Protections for Human Research Subjects to All Americans

In 1997, President Clinton stated that “science must respect the dignity of every American. We must never allow our

citizens to be unwitting guinea pigs in scientific experiments....” That same month, the National Bioethics Advisory

Commission (NBAC) resolved, as a matter of ethical principle, that no person should be enrolled in research without

the twin protections of informed consent and independent review of the research. NBAC notes with concern that this

goal remains unmet.

In particular, the protections of the Federal Policy for the Protection of Human Subjects, also known as the Common

Rule, do not extend to all Americans; the Common Rule applies only to subjects in research regulated by the Food

and Drug Administration (FDA) or to subjects in research sponsored by some Federal departments and agencies.i

Among the Common Rule’s most important protections are the requirements for informed consent by research 

subjects and for independent review of the research by a local Institutional Review Board (IRB). Despite the fact that

many research institutions voluntarily apply the Common Rule—even to their privately financed research—there are

other significant sectors of privately funded research that remain ungoverned either by State or Federal law.

NBAC finds that the absence of Federal jurisdiction over much privately funded research means that the U.S. government cannot know how many Americans currently are subjects in experiments, cannot influence how they have been

recruited, cannot ensure that research subjects know and understand the risks they are undertaking, and cannot

ascertain whether they have been harmed.

Not only does this prevent the Federal Government from protecting Americans enrolling in research, but it affects 

the Federal Government’s ability to craft policies governing emerging technologies. While preparing its 1997 report

Cloning Human Beings, for example, NBAC noted that the Common Rule’s lack of jurisdiction over privately funded

research made it impossible to rely on IRBs as the primary mechanism for protecting human subjects against 

inappropriate uses of those technologies.

Implementation of the Common Rule

Beginning in 1996, Federal departments and agencies responded to NBAC’s request for information pursuant to

Executive Order 12975. NBAC is pleased to report that agencies have responded to the Executive Order not only by

reporting on their current protections, but by evaluating those protections and taking steps to strengthen them. Based

on the agency reports and actions and on its own investigations and contracted studies, NBAC concludes that the

Common Rule has significantly reduced, but not eliminated, the possibility for harm to human subjects. As a result,

NBAC also concludes that there is a need for significant improvement, both to enforce Federal protections and to

make their implementation less burdensome for Federal agencies and researchers.

Research regulated by the FDA or sponsored by one of the Federal departments or independent agencies that have

adopted the Common Rule requires prior approval and continuing oversight by an IRB. NBAC has found that all the

Federal departments and agencies that sponsor substantial amounts of biomedical research with human subjects have

implemented these requirements. On the other hand, several departments and agencies that sponsor behavioral and

other nonbiomedical research have not fully implemented the provisions of the Common Rule, despite the fact that
146

Appendix B: Letters of Request and Response

such research may pose serious nonphysical risks, such as loss of insurance or employment, discrimination, incarceration, and invasion of privacy. Although various Federal regulations do provide protections for certain vulnerable

populations, these are not incorporated in the Common Rule. In addition, NBAC notes that the Common Rule does

not require any special protections for especially vulnerable populations, such as children.

NBAC has identified occasions when nonbiomedical research that posed more than minimal risk was conducted on

certain vulnerable populations; in some of these instances, the research was supported or conducted by one of the

agencies that has not adopted additional protections, such as those found in Subparts B, C, or D of the Department of

Health and Human Services regulations.

Federal departments and agencies do face obstacles in fully implementing the Common Rule. NBAC notes that many

agencies find the Common Rule confusing or its provisions too burdensome in light of the type or amount of research

they sponsor. Although some agencies have been taking steps to bring themselves into compliance with the Common

Rule, nearly all of them agree that increased protection of human subjects cannot be achieved without additional

staffing and highly visible statements of commitment from the leadership of their respective departments. Some also

have suggested that a central authority governing human subjects research could help to interpret the Common Rule’s

requirements, create the oversight structures needed for its implementation, and advise on ethically complex protocols.

NBAC also finds that centralized leadership is needed to achieve consistent interpretation of key statutory and 

regulatory requirements. Lack of a single authority also means that improvement in human subjects protections, 

such as those specific to vulnerable populations, requires that every affected department independently adopt new

regulations. This is inevitably slower and more inefficient than adoption by a central authority.

For example, in its 1998 report Research Involving Persons with Mental Disorders That May Affect Decisionmaking

Capacity, NBAC observed that some affected agencies were hard-pressed to reconcile their agency mission of fostering

much-needed research into the causes and cures for mental illness with the shared Federal commitment to paying

scrupulous attention to the interests of vulnerable human subjects. In addition, the absence of a single, authoritative

Federal office to oversee human subjects protections will make it difficult to ensure that all affected departments will

issue regulations implementing NBAC’s recommendations; indeed, similar recommendations were made 20 years ago

by another national bioethics commission regarding the same population, but they were never adopted.

Ensuring Adequate and Accountable Local Oversight

The decentralized local system is sorely strained by inadequate staffing and education of IRBs; by the explosion in

research activity; by emerging ethical issues arising from ethical issues raised by epidemiological and public health

research; by the trend toward collaborative, multi-centered research; and by an absence of comprehensive public

accountability.

NBAC’s work highlights many of these problems and offers some solutions. Its upcoming report on research involving

human biological materials, for example, suggests some solutions to the difficult problem of applying current Federal

protections to epidemiological research on stored tissue, while its project on international research norms is revealing

the dilemmas posed by collaborative research across national boundaries. Its report, Research Involving Persons With

Mental Disorders That May Affect Decisionmaking Capacity, emphasized the need to maintain the public’s trust in the

integrity of the scientific endeavor. To that end, NBAC suggested “IRBs can effectively use the mechanisms of audit

(both internal and external) and disclosure to improve accountability and inspire public confidence in their oversight

activities.”
National Bioethics Advisory Commission

147

Conclusion

NBAC finds that the current Federal regulations have served to prevent most recurrences of the gross abuses 

associated with biomedical research in the earlier part of this century. Nonetheless, some abuses still occur, and the

system is in need of significant revision in order to provide clear, efficient, and authoritative guidance to Federal

departments and agencies and to ensure that local oversight is effective and accountable to the public. This is 

essential to improving protections for human research subjects. It is also a necessary first step toward extending these

protections to those Americans not yet protected by any State or Federal standards for human subjects in research.

i As of 1997, 16 departments and independent agencies had formally adopted the Common Rule as signatories. In addition, one other independent agency—the Central Intelligence Agency (CIA)—had adopted the Rule in accordance with Executive Order 12333:

Departments

U.S. Department of Agriculture

Department of Commerce

Department of Defense

Department of Education

Department of Energy 

Department of Health and Human Services

Department of Housing and Urban Development

Department of Justice

Department of Transportation

Department of Veterans Affairs

Independent Agencies

International Development Cooperation Agency (Agency for International Development)

Consumer Product Safety Commission

Environmental Protection Agency

National Aeronautics and Space Administration

National Science Foundation

Social Security Administration

Central Intelligence Agency *

Office of Science and Technology Policy **

* As of 1997, the CIA was not a formal signatory to the Common Rule but had adopted the Rule in accordance with Executive Order 12333.

At the time of this report, the CIA is in the process of becoming a formal signatory.

** The Office of Science and Technology Policy is a signatory to the Common Rule, even though it does not itself conduct or support

research directly. It has “accepted” the Common Rule, but does not have its own Code of Federal Regulations.



History

By the early 1900s, concern about the involvement of

human participants in research was part of the

American political agenda, and since that time it has

remained a topic of discussion among policymakers,

most notably as medical research expanded in the 1940s

and 1950s, although discussions during that period were

rarely converted to policy (ACHRE 1995, 83–129). In

the late 1940s, however, formal statements of what was

required to ensure ethically sound research began to

emerge. These early declarations came largely in response

to atrocities committed by Nazi investigators, mostly

physicians, who were tried before the Nuremberg

Military Tribunal.1 A key task of the prosecutors in this

case was to distinguish between the Nazi experiments

and U.S. wartime research, both of which used human

beings. With the trial looming, and prompted by its liaison to the Nuremberg prosecutors, the American Medical

Association adopted its first code of research ethics (AMA

1946), which influenced the American judges’ own set of

standards for ethical research (ACHRE 1995, 133–135;

Moreno 1999, 75). In an unusual move, as part of their

decision the judges presented ten “basic principles” for

research using human participants, now known as the

Nuremberg Code.2,3

However, adherence to such ethical standards was not

automatically assured by the development of formal

codes of ethics. For example, many saw the Nuremberg

Code as an appropriate response to Nazi war crimes but

unnecessary for American medicine (Rothman 1991,

62–63). Additionally, the Nuremberg Code is difficult to

implement because, among things, its first principle, “the

voluntary consent of the human subjects is absolutely

essential,” would appear to allow for no exceptions. This

absolute requirement may reflect the code’s origins in

deliberations about research with healthy rather than sick

participants and with medical research as opposed to

other types of research. Moreover, despite its principled

stringency, the Nuremberg Code embodies a deep trust of

the research community and gives little weight to the

inherent conflicts of interest that might be involved.

Investigators alone would be responsible for obtaining

informed consent and deciding whether their research

met the code’s principles.

Although the Nuremberg Code received little attention in the immediate aftermath of the trial, it was not

entirely ignored. In 1953, U.S. Secretary of the

Department of Defense (DOD), Charles Wilson, issued a

Top Secret memorandum establishing policy for research

related to atomic, biological, and chemical warfare

(Wilson 1953). The policy incorporated the principles of

the Nuremberg Code and two additional protections—a

prohibition on research involving prisoners of war and a

requirement that the Secretary of the appropriate military

service approve research studies.

Later that year the National Institutes of Health (NIH)

Clinical Center opened and established a policy requiring

independent review of research and participants’ written

consent, at least for research involving patient volunteers

and/or “unusual hazard” (NIH 1953). In 1954, these protections of independent review and written informed

consent were extended to all NIH intramural research

involving “normal volunteers.”4

These bold statements of policy did not lead immediately to dramatic shifts in actual research practices. The

DOD policy remained largely Top Secret and was not 

151

The Current Oversight System:

History and Description

Appendix C
152

Appendix C: The Current Oversight System: History and Description

disseminated to investigators (ACHRE 1995, 108), and at

the NIH Clinical Center, procedures for independent

review were rarely invoked (Rothman 1991, 56).

Moreover, both the DOD and NIH policies were

limited by confusion over the definition of research. It is

not clear whether the Nuremberg Code was meant to

apply to research with patients as participants or only to

research with healthy individuals. As a result, until 1961,

the NIH Clinical Center policy did not require independent review for most research with patients.5 In part,

policymakers were concerned about intruding into the

doctor-patient relationship. More generally, though, until

the late 1960s, concern about human protections seemed

unnecessary to many observers. The development of

penicillin, the conquest of polio, and the emergence 

of new medical devices and procedures—all apparently

unmarked by inappropriate conduct—bolstered the 

public prestige of and trust in the biomedical research

community.6

In 1962, fetal abnormalities linked to maternal use of

thalidomide shook public confidence in the regulation of

drug-related research. In response, Congress passed the

Kefauver-Harris amendments to the Federal Food, Drug,

and Cosmetic Act, requiring the Food and Drug

Administration (FDA) to evaluate new drugs for efficacy

in addition to safety.7 The amendments also specifically

required the informed consent of participants in the testing of investigational drugs, but this requirement was

weakened by vague language outlining permissible

exceptions. Nonetheless, the Kefauver-Harris amendments gave FDA broad authority to regulate drug-related

research.

Other events soon influenced NIH policy. A 1962

NIH-commissioned study found that few institutions had

their own policies for the protection of research participants (ACHRE 1995, 174; Faden and Beauchamp 1986,

158). The potential for problems was borne out when, in

early 1964, newspapers began to describe an NIHfunded study at the Brooklyn Jewish Chronic Disease

Hospital in which investigators had injected cancerous

cells into elderly patients. The investigators claimed to

have obtained informed consent, but many of the

patients were incapacitated or did not speak English, and

those able to give consent were not told that the cells to

be injected were cancerous (Faden and Beauchamp

1986, 161; Jonsen 1998, 143).

In response (and against the recommendations of 

a committee appointed to examine the issue), NIH

Director James Shannon argued that the institutes should

take more responsibility for research ethics (Faden and

Beauchamp 1986, 208). At Shannon’s request, the Public

Health Service (PHS) issued a policy for extramural 

projects (PHS 1966). The initiative was important, but the

policy was primarily procedural. It required independent

review of research by a committee of the investigator’s

“institutional associates,” but offered little guidance about

the content of that review (PHS 1966, 475). The policy

did not originally specify the composition of the review

committee, but an accompanying memo stated that a

group of people from different disciplines, familiar with

the investigator but “free to assess his judgment without

placing in jeopardy their own goals,” would be required

(Stewart 1966, 474). Importantly, it marked a shift away

from sole “reliance on the judgment and virtue of the

individual researcher” in the assessment of the ethics of

research.8

At NIH, the PHS policy was implemented through the

Institutional Relations Branch of the Division of Research

Grants. The branch addressed this policy in the way it

handled other matters of institutional relations, by negotiating “assurances of compliance” with the PHS policy

from each institution receiving funding. For enforcement, the branch could withhold, or, more likely,

threaten to withhold funds.9 The NIH Institutional

Relations Branch later became the NIH Office for

Protection from Research Risks (OPRR) and assumed a

lead role in the protection of research participants within

the Department of Health and Human Services (DHHS).

In June 2000, OPRR was moved out of NIH to the Office

of the Secretary, DHHS, becoming the Office for Human

Research Protections (OHRP).10

However, in 1966, the PHS “Policy for Clinical

Investigations with Human Subjects” applied only to

extramural research, and the Division of Research Grants

dealt only with NIH grantees. Also in 1966, the NIH

Clinical Center strengthened its separate system of independent review (Faden and Beauchamp 1986, 209). At

the same time, FDA issued guidance to clarify the
National Bioethics Advisory Commission

153

requirements for and exceptions from informed consent

as specified in the Kefauver-Harris amendments (Faden

and Beauchamp 1986, 204).

While NIH and FDA were revising their policies for

the protection of human subjects, Henry Beecher published a damning indictment of contemporary research

practice in the United States (Beecher 1966). He presented

22 examples of “unethical or questionably ethical 

studies” published in major medical journals. The article

was influential largely because it showed that abuses

were occurring in research conducted by mainstream

investigators (Rothman 1991, 75). A review of published

studies conducted in Great Britain revealed similar

abuses (Pappworth 1962).

Several years after Beecher’s article, one of the studies he

had discussed became a subject of particular controversy—

an investigation of hepatitis involving the injection of 

a mild strain of the virus into children at the time of

admission to the Willowbrook State School for the

Retarded in New York. Parental consent was obtained,

but the consent form may have been misleading, and

desperate parents may have been unduly influenced by

the availability of preferential and later exclusively

research-related admissions to the institution. One

notable feature of the case was that the Willowbrook

research had been reviewed and approved by the Armed

Forces Epidemiological Board, which funded the

research, as well as a local review committee for human

experimentation (ACHRE 1995, 178; Faden and

Beauchamp 1986, 163–164).

The debates about the Willowbrook State School

experiments became part of a more general concern that

local institutional review was not adequately protecting

individuals who participated in research (Faden and

Beauchamp 1986, 211). In 1971, five years after the PHS

policy was put into place, the then Department of Health

Education and Welfare (DHEW) developed more

detailed guidance and justification for review committees

in the form of the “Yellow Book” (DHEW 1971).

In the summer of 1972, the New York Times published

details of the Tuskegee Syphilis Study, sponsored by PHS

since the early 1930s (Heller 1972). Although a formal

protocol never existed, the study intended to trace the

natural history of syphilis in poor African American

males living in Macon County, Alabama. Participants

were not told of the purpose of the study; in fact, they

were misled into believing that they were being treated

for syphilis. Throughout this project, research-related

procedures, such as lumbar punctures, were described as

“special free treatments.” Investigators continued the

study even after penicillin became widely available and

prescribed for the treatment of syphilis. In exchange for

participation, the men received some unrelated health

care, free meals, and transportation, and later in the study,

to encourage autopsy, a $50 burial stipend (Jones 1981). 

Following media attention about the study, a PHS

Advisory Panel was formed to examine whether it was

justified at its inception or after penicillin became generally available, to recommend whether the study should

be continued, and to determine whether existing human

research protection policies were adequate. The study

was found to be ethically unjustified; it was halted, and

surviving participants were offered treatment. In addition, the Advisory Panel determined that existing procedures for protecting research participants were not

adequate. They recommended that “Congress should

establish a permanent body with the authority to regulate

at least all Federally-supported research involving human

subjects” (Tuskegee Syphilis Study Ad Hoc Advisory

Panel 1973, 23).

In 1973, the Senate Labor and Public Welfare

Committee began a series of hearings on human experimentation (Jonsen 1998, 92–98). Interest was intensified

by controversy over NIH-funded research involving

aborted fetuses (Cohn 1973). A number of bills were 

circulated, including one that would have created a

National Human Experimentation Board.11 However, it

became clear that there was not enough support for such

a body, and a compromise was reached. The proposal for

a national oversight board was dropped in exchange for

an agreement that DHEW would issue regulations governing research with human subjects (ACHRE 1995,

181).12 DHEW quickly developed regulations based on

existing “Yellow Book” policies. The regulations were

issued by DHEW in May of 1974,13 and the National

Research Act was signed in July of that year.14

The National Research Act also established the

National Commission for the Protection of Human
154

Appendix C: The Current Oversight System: History and Description

Subjects of Biomedical and Behavioral Research

(National Commission) to provide ethical and policy

analysis related to conducting human research. The

National Commission produced ten reports and is best

known for the Belmont Report (National Commission

1979) (see Appendix D), which identified three fundamental ethical principles applicable to research with

human participants—respect for persons, beneficence,

and justice—which translated respectively into provisions

for informed consent, assessment of risk and potential

benefits, and selection of participants.

The Belmont Report was important primarily because

it linked desired ethical standards and practices and

existing concerns to fundamental ethical principles.

DHEW regulations already contained specific provisions

for obtaining and documenting informed consent and

guidance on assessing risk and benefit. The report 

recommended that additional attention be given to the

equitable selection of participants. In response to the

Belmont Report, DHHS and FDA simultaneously revised

their regulations. Thus, the two sets of regulations were

unified in significant ways. In January 1981, the DHHS

Secretary signed the revised regulations (45 CFR 46; 

21 CFR 50, 56).15

The revisions, however, did not incorporate many 

of the National Commission’s recommendations. The

regulations still placed their greatest emphasis on obtaining and documenting voluntary informed consent, while

giving minimal attention to the assessment of risk and

potential benefit or the selection of participants.

Moreover, the regulations were not supplemented with

the substantive ethical rationale that the Belmont Report

provided, leaving the regulations less detailed and potentially more difficult to interpret. By 1981, the recommendations in the National Commission’s report on fetal

research were codified as a separate Subpart of the DHHS

regulations (Subpart B),16 as had the recommendations

from their report on research with prisoners (Subpart C).17

However, their recommendations regarding children and

those institutionalized as mentally infirmed were not

implemented.

In 1981, the President’s Commission for the Study 

of Ethical Problems in Medicine and Biomedical and

Behavioral Research (President’s Commission) was

established. In its first of two biennial reports on

research, the President’s Commission examined the 

general structure of research protections (President’s

Commission 1981). The second biennial report

(President’s Commission 1983) focused on their implementation. (See Exhibit C.1.)

Agency responses to the President’s Commission 

recommendations were mixed. In 1983, DHHS promulgated regulations governing research with children

(Subpart D).18 OPRR took steps to improve interpretation

and implementation of the regulations, such as sponsoring regional workshops, issuing regulatory guidance in

the form of OPRR Reports, and chairing the Human

Subjects Research Subcommittee of the Committee on

Science, National Science and Technology Council,

Office of the President.

Perhaps the most promising area of agency action was

in the standardization of regulations across agencies and

departments. The White House convened an interagency

ad hoc committee to develop what would become the

“Common Rule” (the Federal Policy for the Protection of

Human Subjects [Federal Policy]), a set of identical 

regulations codified by various agencies. Initially, the

group worked under the Federal Coordinators Council

for Science, Engineering, and Technology. The standardization process was slow. In addition, in a time of severe

budget constraints, few were willing to issue new regulations and establish new offices, and many departments

requested extra protections or specific exceptions from

any proposed rule.19

Nevertheless, in 1991, the regulations known as the

Common Rule were simultaneously published in the

Federal Register by 15 departments and agencies.20 The

Common Rule expanded the scope of regulated research

and provided some standardization across departments,

with DHHS, primarily through OPRR, playing a key role

in its development.

Description of the Federal Regulatory

Structure

This history has resulted in a complex and sometimes

overlapping, but also incomplete, structure for the protection of human research participants. Each codification
National Bioethics Advisory Commission

155

of the Common Rule by a department or agency is equivalent to 45 CFR 46.101–46.124 (Subpart A), the DHHS

codification. The DHHS codification is cited throughout

this report when referring to the 15 sets of regulations

promulgated by federal departments that comprise the

Common Rule.21

The Office of Science and Technology Policy (OSTP)

did not codify the Common Rule, even though it signed

the Federal Policy, because it does not conduct or sponsor research. The Common Rule also regulates research

conducted or sponsored by two other agencies that are

not signatories to the Common Rule but that are bound

Exhibit C.1: Recommendations of the President’s Commission’s First Biennial Report—

Protecting Human Subjects (1981)

■ All federal agencies should adopt the regulations of DHHS (45 CFR 46).

■ The Secretary, DHHS, should establish an office to coordinate and monitor government-wide implementation of

the regulations.

■ Each federal agency should apply one set of rules consistently to all its subunits and funding mechanisms.

■ Principal investigators should be required to submit annual data on the number of subjects in their research and

the number and nature of adverse events. 

■ The National Commission’s recommendations on research involving children and the mentally disabled should be

acted upon promptly.

■ “Private” research organizations receiving direct congressional appropriations should be required to follow federal

regulations for the protection of human subjects (President’s Commission 1981). 

Recommendations of the President’s Commission’s Second Biennial Report—

Implementing Human Research Regulations (1983)

■ Congressional committees with oversight responsibilities for biomedical and behavioral research should monitor

the progress of the administrative agencies in responding to the recommendations of the Commission’s 1981 and

1982 reports on protecting human subjects.

■ An Ethics Advisory Board should be reestablished within DHHS either through congressional action, as part of the

authorization of the NIH and Alcohol, Drug Abuse and Mental Health Administration (ADAMHA) research programs, or by the DHHS Secretary.

■ Federal agencies should clarify the meaning of certain procedural requirements of present regulations, particularly

what is meant by “IRB review.”

■ A uniform system for implementing all federal rules to protect human subjects should be established under a

single office and should include both assurances of regulatory compliance provided in advance by research 

institutions and periodic site visits to the institutions. Federal agencies that do not already do so should, as soon

as practicable, identify the IRBs responsible for the initial and continuing review of research for which they have

regulatory authority.

■ The prospective review of institutional assurances of compliance with applicable regulations should consider the

amount and types of research that each IRB anticipates reviewing and should determine that requirements regarding IRB composition are met, that sound procedures have been established for the IRB’s review of the research,

and that the institution understands its responsibilities for protecting human subjects.

■ A broad educational and monitoring program covering the protection of human subjects and designed to reach

investigators, IRB members, and research administrators should be conducted. Among the various activities

included in the program should be site visits of research institutions using experienced IRB members and staff as

site visitors (President’s Commission 1983).
156

Appendix C: The Current Oversight System: History and Description

to DHHS regulations and therefore to the Common Rule

either through public law (the Social Security

Administration),22 or Executive Order (the Central

Intelligence Agency).23 Thus, the Common Rule has 15

codifications and 16 signatories, and it covers 18 federal

agencies—17 by force of law. Its structure is depicted in

Figure C.1.

The Common Rule applies to all research involving

human participants “conducted, supported or otherwise

subject to regulation by any federal department or agency

which takes appropriate administrative action to make

this policy applicable to such research.” Thus, it specifically allows agencies with regulatory authority (notably,

FDA) to apply the Common Rule to regulated research

(45 CFR 46.101(a)). However, DHHS does not require

FDA to apply the Common Rule to the research FDA 

regulates. FDA also has its own regulatory authority over

research involving food and color additives, investigational drugs for human use, medical devices for human

use, biological products for human use being developed

for marketing, and electronic products that emit radiation (e.g., microwave ovens, laser printers, sun lamps,

diagnostic x-ray equipment). FDA also regulates research

intended to support a change in the labeling of marketed

products. To this regulated research, FDA applies its own

set of regulations (21 CFR 50, 56) that are generally, but

not entirely the same as the Common Rule (45 CFR 46

Subpart A). However, FDA is bound to DHHS regulations when it conducts its own research. 

Recent Events

Since the creation of the Common Rule, government

agencies, Congress, academic scholars, and the private

sector have called attention to problems with the current

oversight system and have recommended or taken steps

to improve it.

Government Activities

In 1994, the Advisory Committee on Human

Radiation Experiments (ACHRE) was created to investigate reports of federally sponsored human research

involving radioactive materials conducted between 1944

and 1972 and to assess the current state of protections for

research participants. Concerning the latter charge they

found, “evidence of serious deficiencies in some parts of

the current system” (ACHRE 1995, 797). Specifically,

ACHRE was concerned with variability in the quality of

IRBs, persistent confusion among human participants

regarding whether they were involved in research or

therapy, and insufficient attention to the implications of

diminished decisionmaking capacity in the consent

process. Several of the committee’s recommendations

addressed the protection of the rights and welfare of

human research participants in the future and are directly

related to the present report. (Relevant recommendations

are reproduced in their entirety in Exhibit C.2.)

Congressional Interest

In general, Congress has been a generous and enthusiastic supporter of biomedical research, but at the same

time some members of Congress have expressed concerns

about the adequacy of oversight of human research.24 In

recent years, several congressional committees have held

hearings on various aspects of protection, including overall DHHS oversight of human research, oversight of gene

therapy trials,25 privacy in health research,26 the administration of investigational drugs to members of the armed

forces,27 and the use of placebo-controls and washout

periods in clinical trials.28 Legislation to strengthen the

system of protection has been introduced, although none

has been enacted. In addition, the Children’s Research

Act of 200029 included provisions to extend protections

for children participating in research.
Figure C-1: Common Rule and Agency-Specific Human Research Protection Regulations

Department of Education

34 CFR 97**

Federal Policy for the Protection of 

Human Subjects*

(“Common Rule”)

45 CFR 46 Subpart A

Department 

of Agriculture

7 CFR 1c**

Department of

Commerce

15 CFR 27**

Department of Defense

32 CFR 219**

Department of Energy

10 CFR 745**

Department of Health

and Human Services

45 CFR 46 Subpart A**

Department of Housing and

Urban Development

24 CFR 60**

Department of

Justice

28 CFR 46**

Department of

Veterans Affairs

38 CFR 16** Department of Transportation

49 CFR 11**

Consumer Product Safety

Commission

16 CFR 1028**

Environmental

Protection Agency

40 CFR 26**

Agency for

International

Development

22 CFR 225**

National Aeronautics and

Space Administration

14 CFR 1230**

National

Science

Foundation

45 CFR 690**

Central 

Intelligence 

Agency

Executive Order 12333**

Office of Science 

and Technology 

Policy

Social Security

Administration

P.L. 103-296**

Food and Drug 

Administration 

21 CFR 50 and 56**

38 CFR 17.85

M-3, Part 1, Chapters 9 and 15** 28 CFR 512**

45 CFR 46

Subparts B, C, D

Order 1300.3**

Order 481.1**

34 CFR 97 Subpart D**34 CFR 98**34 CFR 99**34 CFR 350.4(c)**34 CFR 356.3(c)**

10 USC 980 AR 40-38**DoDD 3216.2 SECNAVINST 3900.39B**DoDD 6000.8 NMRDCINST 3900.2**AFI 40-402 BUMEDINST 6000.12**AFI 40-403 NSHSBETHINST 6000.41A**AR 70-25 USUHS Instruction 3201**

* = policy** = statute, regulation, directive, executive order

= signatory to Common Rule= signatory to Common Rule; no regulatory responsibility

❏ = additional human subjects protection beyond Common Rule

LEGEND
Notes

1 United States v. Karl Brandt et al. (“The Medical Case”), Trials of

War Criminals Before the Nuernberg Military Tribunals Under

Control Council Law 10. Nuernberg, October 1946–April 1949.

Volumes I–II. Washington, D.C.: U.S. Government Printing Office.

2 United States v. Karl Brandt, et al. (“The Medical Case”), Trials of

War Criminals Before the Nuernberg Military Tribunals Under

Control Council Law 10. Nuernberg, October 1946–April 1949.

Volumes I–II. Washington, D.C.: U.S. Government Printing Office.

The Nuremberg Code has been widely reproduced. See, e.g.,

Shuster 1997.

3 During World War II, unethical medical experiments were also

performed by the Japanese, primarily against Chinese prisoners.

However, these incidents played less of a role in the development

of U.S. policy, partly because the researchers were not prosecuted.

Some have alleged that the U.S. government traded immunity for

investigators’ data (Harris 1994).

4 See Fletcher, J., “Location of the Office for Protection from

Research Risks Within the National Institutes of Health: Problems

of Status and Independent Authority.” This background paper was

prepared for NBAC and is available in Volume II of this report.

5 Ibid.

158

Appendix C: The Current Oversight System: History and Description

Exhibit C.2: ACHRE Recommendations Relevant to This Report

■ Recommendation 9: The Advisory Committee recommends to the Human Radiation Interagency Working Group

[the cabinet-level group to which ACHRE reported] that efforts be undertaken on a national scale to ensure the

centrality of ethics in the conduct of scientists whose research involves human subjects. 

■ Recommendation 10: The Advisory Committee recommends to the Human Radiation Interagency Working Group

that the IRB component of the federal system for the protection of human subjects be changed in at least the five

critical areas described below. 

1. Mechanisms for ensuring that IRBs appropriately allocate their time so they can adequately review studies that

pose more than minimal risk to human subjects. This may include the creation of alternative mechanisms for

review and approval of minimal-risk studies. 

2. Mechanisms for ensuring that the information provided to potential subjects 1) clearly distinguishes research

from treatment, 2) realistically portrays the likelihood that subjects may benefit medically from their participation

and the nature of the potential benefits, and 3) clearly explains the potential for discomfort and pain that may

accompany participation in the research. 

3. Mechanisms for ensuring that the information provided to potential subjects clearly identifies the federal agency

or agencies sponsoring or supporting the research project in whole or in part and all purposes for which the

research is being conducted or supported. 

4. Mechanisms for ensuring that the information provided to potential subjects clearly identifies the financial 

implications of deciding to consent to or refuse participation in research. 

5. Recognition that if IRBs are to adequately protect the interests of human subjects, they must have the responsibility to determine that the science is of a quality to warrant the imposition of risk or inconvenience on human

subjects and, in the case of research that purports to offer a prospect of medical benefit to subjects, to determine that participating in the research affords patient-subjects at least as good an opportunity of securing this

medical benefit as would be available to them without participating in research.

■ Recommendation 11: The Advisory Committee recommends to the Human Radiation Interagency Working Group

that a mechanism be established to provide for the continuing interpretation and application of ethics rules and

principles for the conduct of human subject research in an open and public forum. This mechanism is not provided

for in the Common Rule.

■ Recommendation 13: The Advisory Committee recommends that the Human Radiation Interagency Working

Group take steps to improve three elements of the current federal system for the protection of the rights and 

interests of human subjects—oversight, sanctions, and scope: 1) oversight mechanisms to examine outcomes

and performance, 2) appropriateness of sanctions for violations of human subjects protections, and 3) extension

of human subjects protections to nonfederally funded research (ACHRE 1995, 816–826).
National Bioethics Advisory Commission

159

6 See Moreno, J., “Protectionism in Research Involving Human

Subjects.” This background paper was prepared for NBAC and is

available in Volume II of this report.

7 Pub. Law 781, 87th Congress.

8 See Moreno, J., “Protectionism in Research Involving Human

Subjects.” This background paper was prepared for NBAC and is

available in Volume II of this report.

9 See McCarthy, C.R., “Reflections on the Organizational Locus of

the Office for Protection from Research Risks.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

10 65 Fed. Reg. 37136.

11 S. 934, 93rd Congress.

12 See McCarthy, C.R., “Reflections on the Organizational Locus 

of the Office for Protection from Research Risks.” This background

paper was prepared for NBAC and is available in Volume II of this

report.

13 39 Fed. Reg. 18914–18920.

14 Pub. Law 348, 93rd Congress.

15 46 Fed. Reg. 8366; 46 Fed. Reg. 8942.

16 40 Fed. Reg. 33526.

17 43 Fed. Reg. 53655.

18 48 Fed. Reg. 9814.

19 Porter, J., Testimony before NBAC. November 23, 1997.

Bethesda, Maryland; see McCarthy, C.R., “Reflections on the

Organizational Locus of the Office for Protection from Research

Risks.” This background paper was prepared for NBAC and is

available in Volume II of this report.

20 56 Fed. Reg. 28002–28023.

21 The 15 signatories to the Common Rule are the Department 

of Agriculture, the Department of Commerce, the Department of

Defense, the Department of Education, the Department of Energy,

the Department of Health and Human Services, the Department of

Housing and Urban Development, the Department of Justice, the

Department of Transportation, the Department of Veterans Affairs,

the Agency for International Development, the Consumer Product

Safety Commission, the Environmental Protection Agency, the

National Aeronautics and Space Administration, and the National

Science Foundation. 

22 Pub. Law 296, 103rd Congress.

23 Executive Order. “United States Intelligence Activities,

Executive Order 12333.” 46 Fed. Reg. 59941.

24 U.S. Congress. House. Committee on Government Reform.

Subcommittee on Criminal Justice, Drug Policy and Human

Resources. Human Subject Research Protections. 106th Congress, 

2nd sess., 3 May 2000; U.S. Congress. House. Committee on

Government Reform. Subcommittee on Criminal Justice, Drug

Policy and Human Resources. Protecting Human Clinical Research

Patients. 105th Congress, 2nd sess., 11 June 1998; U.S. Congress.

House. Committee on Government Reform. Subcommittee on

Criminal Justice, Drug Policy and Human Resources. Oversight of

HHS: Bioethics and the Adequacy of Informed Consent. 105th

Congress, 1st sess., 8 May 1997.

25 U.S. Congress. Senate. Committee on Health, Education, Labor,

and Pensions. Subcommittee on Public Health. Gene Therapy: What

Is the Federal Response for Patient Safety? 106th Congress, 2nd sess.,

25 May 2000; U.S. Congress. Senate. Committee on Health,

Education, Labor, and Pensions. Subcommittee on Public Health.

Gene Therapy: Is There Oversight for Patient Safety? 106th Congress,

2nd sess., 2 February 2000.

26 For example, U.S. Congress. House. Committee on Commerce.

Subcommittee on Health and Environment. Medical Records

Confidentiality in the Modern Delivery of Health Care. 106th

Congress, 1st Session, 27 May 1999; U.S. Congress. Senate.

Committee on Health, Education, Labor, and Pensions. Privacy

Under a Microscope: Balancing the Needs of Research and

Confidentiality. 106th Congress, 1st sess., 24 February 1999.

27 U.S. Congress. House. Committee on Government Reform.

Subcommittee on National Security, Veterans Affairs, and

International Relations. Force Protection: Improving Safeguards 

for Administration of Investigational New Drugs to Members of the

Armed Forces. 106th Congress, 1st sess., 9 November 1999.

28 U.S. Congress. House. Committee on Veterans Affairs.

Subcommittee on Oversight and Investigations and Subcommittee

on Health. Suspension of Medical Research at West Los Angeles and

Sepulveda VA Medical Facilities and Informed Consent and Patient

Safety in VA Medical Research. 106th Congress, 1st sess., 21 April

1999; U.S. Congress. House. Committee on Government Reform.

Clinical Trial Subjects: Adequate FDA Protection? 105th Congress,

2nd sess., 22 April 1998.

29 Pub. Law 310, 106th Congress.

References

Advisory Committee on Human Radiation Experiments (ACHRE).

1995. Final Report. Washington, D.C.: U.S. Government Printing

Office.

American Medical Association (AMA). Judicial Council. 1946.

“Supplementary Report of the Judicial Council of the American

Medical Association.” Journal of the American Medical Association

132:1090.

Beecher, H.K. 1966. “Ethics and Clinical Research.” New England

Journal of Medicine 274(24):1354–1360.

Cohn, V. 1973. “Live-Fetus Research Debated.” Washington Post, 

10 April, A-1.
160

Department of Health, Education, and Welfare (DHEW). 1971. The

Institutional Guide to DHEW Policy on Protection of Human Subjects.

Washington, D.C.: U.S. Government Printing Office.

Faden, R.R., and T.L. Beauchamp. 1986. A History and Theory of

Informed Consent. New York: Oxford University Press.

Harris, S.H. 1994. Factories of Death: Japanese Biological Warfare,

1932–1945, and the American Cover-Up. New York: Routledge. 

Heller, J. 1972. “Syphilis Victims in U.S. Study Went Untreated for

40 Years.” New York Times, 26 July, A-1.

Jones, J.H. 1981. Bad Blood: The Tuskegee Syphilis Experiment.

New York: The Free Press.

Jonsen, A.R. 1998. The Birth of Bioethics. New York: Oxford

University Press.

Moreno, J.D. 1999. Undue Risk: Secret State Experiments on Humans.

New York: W.H. Freeman.

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission). 1979.

Belmont Report: Ethical Principles and Guidelines for the Protection of

Human Subjects of Research. Washington, D.C.: U.S. Government

Printing Office.

National Institutes of Health (NIH). 1953. Group Consideration of

Clinical Research Procedures Deviating from Accepted Medical

Practice or Involving Unusual Hazard. In Final Report,

Supplemental Vol. I, 321–324. Washington, D.C.: U.S.

Government Printing Office.

Pappworth, M.H. 1962. “Human Guinea Pigs: A Warning.”

Twentieth Century Autumn:66–75.

President’s Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research (President’s

Commission). 1981. Protecting Human Subjects. First Biennial Report

on the Adequacy and Uniformity of Federal Rules and Policies, and of

their Implementation, for the Protection of Human Subjects.

Washington, D.C.: U.S. Government Printing Office.

———. 1983. Implementing Human Research Regulations. Second

Biennial Report on the Adequacy and Uniformity of Federal Rules and

Policies, and of their Implementation, for the Protection of Human

Subjects. Washington, D.C.: U.S. Government Printing Office.

Public Health Service (PHS). 1966. Clinical Investigations Using

Human Subjects. In Final Report, Supplemental Vol. I, 475–476.

Washington, D.C.: U.S. Government Printing Office.

Rothman, D.J. 1991. Strangers at the Bedside: A History of How 

Law and Bioethics Transformed Medical Decision Making. New York:

Basic Books.

Shuster, E. 1997. “Fifty Years Later: The Significance of the

Nuremberg Code.” New England Journal of Medicine

337(20):1436–1440.

Stewart, W.H. 1966. Clinical Research Investigations Using Human

Subjects. In Final Report, Supplemental Vol. I, 473–474.

Washington, D.C.: U.S. Government Printing Office.

Tuskegee Syphilis Study Ad Hoc Advisory Panel. 1973. Final

Report. Washington, D.C.: DHEW.

Wilson, C. 1953. Memorandum for the Secretary of the Army,

Secretary of the Navy, Secretary of the Air Force. In Final Report,

Supplemental Vol. I, 308–310. Washington, D.C.: U.S.

Government Printing Office.

Appendix C: The Current Oversight System: History and Description
The Belmont Report

Ethical Principles and Guidelines for the Protection of Human Subjects of Research

The National Commission for the Protection of Human Subjects of Biomedical and

Behavioral Research

April 18, 1979

Appendix D

Ethical Principles and Guidelines for

Research Involving Human Subjects

Scientific research has produced substantial social

benefits. It has also posed some troubling ethical

questions. Public attention was drawn to these questions

by reported abuses of human subjects in biomedical

experiments, especially during the Second World War.

During the Nuremberg War Crime Trials, the Nuremberg

code was drafted as a set of standards for judging 

physicians and scientists who had conducted biomedical

experiments on concentration camp prisoners. This code

became the prototype of many later codes intended to

assure that research involving human subjects would be

carried out in an ethical manner.

The codes consist of rules, some general, others 

specific, that guide the investigators or the reviewers of

research in their work. Such rules often are inadequate 

to cover complex situations; at times they come into 

conflict, and they are frequently difficult to interpret or

apply. Broader ethical principles will provide a basis on

which specific rules may be formulated, criticized and

interpreted.

Three principles, or general prescriptive judgments,

that are relevant to research involving human subjects are

identified in this statement. Other principles may also be

relevant. These three are comprehensive, however, and

are stated at a level of generalization that should assist

scientists, subjects, reviewers and interested citizens to

understand the ethical issues inherent in research involving human subjects. These principles cannot always 

be applied so as to resolve beyond dispute particular ethical problems. The objective is to provide an analytical

framework that will guide the resolution of ethical problems arising from research involving human subjects.

This statement consists of a distinction between

research and practice, a discussion of the three basic 

ethical principles, and remarks about the application of

these principles.

A. Boundaries Between Practice and

Research

It is important to distinguish between biomedical and

behavioral research, on the one hand, and the practice of

accepted therapy on the other, in order to know what

activities ought to undergo review for the protection of

human subjects of research. The distinction between

research and practice is blurred partly because both often

occur together (as in research designed to evaluate a 

therapy) and partly because notable departures from

standard practice are often called “experimental” when

the terms “experimental” and “research” are not carefully

defined.

For the most part, the term “practice” refers to interventions that are designed solely to enhance the well

being of an individual patient or client and that have 

a reasonable expectation of success. The purpose of 

medical or behavioral practice is to provide diagnosis,

preventive treatment or therapy to particular individuals.

By contrast, the term “research” designates an activity

designed to test an hypothesis, permit conclusions to be

drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories,

principles, and statements of relationships). Research is

usually described in a formal protocol that sets forth an

objective and a set of procedures designed to reach that

objective.

161
162

Appendix D: The Belmont Report

When a clinician departs in a significant way from

standard or accepted practice, the innovation does not, in

and of itself, constitute research. The fact that a procedure is “experimental,” in the sense of new, untested or

different, does not automatically place it in the category

of research. Radically new procedures of this description

should, however, be made the object of formal research

at an early stage in order to determine whether they are

safe and effective. Thus, it is the responsibility of medical

practice committees, for example, to insist that a major

innovation be incorporated into a formal research project.

Research and practice may be carried on together

when research is designed to evaluate the safety and 

efficacy of a therapy. This need not cause any confusion

regarding whether or not the activity requires review; the

general rule is that if there is any element of research in

an activity, that activity should undergo review for the

protection of human subjects.

B. Basic Ethical Principles

The expression “basic ethical principles” refers to those

general judgments that serve as a basic justification for

the many particular ethical prescriptions and evaluations

of human actions. Three basic principles, among those

generally accepted in our cultural tradition, are particularly relevant to the ethic of research involving human

subjects: the principles of respect for persons, beneficence and justice. 

1. Respect for Persons. Respect for persons incorporates at least two ethical convictions; first, that individuals should be treated as autonomous agents, and

second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons

thus divides into two separate moral requirements: the

requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.

An autonomous person is an individual capable of

deliberation about personal goals and of acting under the

direction of such deliberation. To respect autonomy is to

give weight to autonomous persons’ considered opinions

and choices while refraining from obstructing their

actions unless they are clearly detrimental to others. To

show lack of respect for an autonomous agent is to 

repudiate that person’s considered judgments, to deny 

an individual the freedom to act on those considered

judgments, or to withhold information necessary to

make a considered judgment, when there are no compelling reasons to do so.

However, not every human being is capable of selfdetermination. The capacity for self-determination

matures during an individual’s life, and some individuals

lose this capacity wholly or in part because of illness,

mental disability, or circumstances that severely restrict

liberty. Respect for the immature and the incapacitated

may require protecting them as they mature or while they

are incapacitated.

Some persons are in need of extensive protection,

even to the point of excluding them from activities which

may harm them; other persons require little protection

beyond making sure they undertake activities freely and

with awareness of possible adverse consequences. The

extent of protection afforded should depend upon the

risk of harm and the likelihood of benefit. The judgment

that any individual lacks autonomy should be periodically reevaluated and will vary in different situations.

In most cases of research involving human subjects,

respect for persons demands that subjects enter into the

research voluntarily and with adequate information. In

some situations, however, application of the principle is

not obvious. The involvement of prisoners as subjects of

research provides an instructive example. On the one

hand, it would seem that the principle of respect for 

persons requires that prisoners not be deprived of the

opportunity to volunteer for research. On the other hand,

under prison conditions they may be subtly coerced or

unduly influenced to engage in research activities for

which they would not otherwise volunteer. Respect for

persons would then dictate that prisoners be protected.

Whether to allow prisoners to “volunteer” or to “protect”

them presents a dilemma. Respecting persons, in most

hard cases, is often a matter of balancing competing

claims urged by the principle of respect itself.

2. Beneficence. Persons are treated in an ethical manner

not only by respecting their decisions and protecting them

from harm, but also by making efforts to secure their well

being. Such treatment falls under the principle of beneficence. The term “beneficence” is often understood to
National Bioethics Advisory Commission

163

cover acts of kindness or charity that go beyond strict

obligation. In this document, beneficence is understood

in a stronger sense. as an obligation. Two general rules

have been formulated as complementary expressions of

beneficent actions in this sense: (1) do not harm and 

(2) maximize possible benefits and minimize possible

harms.

The Hippocratic maxim “do no harm” has long been

a fundamental principle of medical ethics. Claude

Bernard extended it to the realm of research, saying that

one should not injure one person regardless of the benefits that might come to others. However, even avoiding

harm requires learning what is harmful; and, in the

process of obtaining this information, persons may be

exposed to risk of harm. Further, the Hippocratic Oath

requires physicians to benefit their patients “according to

their best judgment.” Learning what will in fact benefit

may require exposing persons to risk. The problem

posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved,

and when the benefits should be foregone because of the

risks.

The obligations of beneficence affect both individual

investigators and society at large, because they extend

both to particular research projects and to the entire

enterprise of research. In the case of particular projects,

investigators and members of their institutions are

obliged to give forethought to the maximization of benefits and the reduction of risk that might occur from the

research investigation. In the case of scientific research in

general, members of the larger society are obliged to give

forethought the longer term benefits and risks that may

result from the improvement of knowledge and from the

development of novel medical. psychotherapeutic. and

social procedures.

The principle of beneficence often occupies a welldefined justifying role in many areas of research involving human subjects. An example is found in research

involving children. Effective ways of treating childhood

diseases and fostering healthy development are benefits

that serve to justify research involving children - even

when individual research subjects are not direct beneficiaries. Research also makes is possible to avoid the harm

that may result from the application of previously

accepted routine practices that on closer investigation

turn out to be dangerous. But the role of the principle of

beneficence is not always so unambiguous. A difficult

ethical problem remains, for example, about research

that presents more than minimal risk without immediate

prospect of direct benefit to the children involved. Some

have argued that such research is inadmissible, while 

others have pointed out that this limit would rule out

much research promising great benefit to children in the

future. Here again, as with all hard cases, the different

claims covered by the principle of beneficence may come

into conflict and force difficult choices.

3. Justice. Who ought to receive the benefits of

research and bear its burdens? This is a question of justice, in the sense of “fairness in distribution” or “what is

deserved.” An injustice occurs when some benefit to

which a person is entitled is denied without good reason

or when some burden is imposed unduly. Another way of

conceiving the principle of justice is that equals ought to

be treated equally. However, this statement requires

explication. Who is equal and who is unequal? What

considerations justify departure from equal distribution?

Almost all commentators allow that distinctions based on

experience, age, deprivation, competence, merit and

position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary,

then, to explain in what respects people should be

treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits.

Each formulation mentions some relevant property on

the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an

equal share, (2) to each person according to individual

need, (3) to each person according to individual effort,

(4) to each person according to societal contribution, and

(5) to each person according to merit.

Questions of justice have long been associated with

social practices such as punishment, taxation and political representation. Until recently these questions have

not generally been associated with scientific research.

However, they are foreshadowed even in the earliest

reflections on the ethics of research involving human

subjects. For example, during the 19th and early 20th

centuries the burdens of serving as research subjects fell
164

Appendix D: The Belmont Report

largely upon poor ward patients, while the benefits of

improved medical care flowed primarily to private

patients. Subsequently, the exploitation of unwilling

prisoners as research subjects in Nazi concentration

camps was condemned as a particularly flagrant injustice. In this country, in the 1940’s, the Tuskegee syphilis

study used disadvantaged, rural black men to study 

the untreated course of a disease that is by no means

confined to that population. These subjects were

deprived of demonstrably effective treatment in order

not to interrupt the project, long after such treatment

became generally available. 

Against this historical background, it can be seen how

conceptions of justice are relevant to research involving

human subjects. For example, the selection of research

subjects needs to be scrutinized in order to determine

whether some classes (e.g., welfare patients, particular

racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because

of their easy availability, their compromised position, or

their manipulability, rather than for reasons directly

related to the problem being studied. Finally, whenever

research supported by public funds leads to the development of therapeutic devices and procedures, justice

demands both that these not provide advantages only to

those who can afford them and that such research should

not unduly involve persons from groups unlikely to be

among the beneficiaries of subsequent applications of the

research.

C. Applications

Applications of the general principles to the conflict of

research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and

the selection of subjects of research.

1. Informed Consent. Respect for persons requires that

subjects, to the degree that they are capable, be given the

opportunity to choose what shall or shall not happen to

them. This opportunity is provided when adequate standards for informed consent are satisfied. While the

importance of informed consent is unquestioned, controversy prevails over the nature and possibility of an

informed consent. Nonetheless, there is widespread

agreement that the consent process can be analyzed as

containing three elements: information, comprehension

and voluntariness.

Information. Most codes of research establish specific

items for disclosure intended to assure that subjects are

given sufficient information. These items generally

include: the research procedure, their purposes, risks and

anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the

opportunity to ask questions and to withdraw at any time

from the research. Additional items have been proposed,

including how subjects are selected, the person responsible

for the research, etc.

However, a simple listing of items does not answer

the question of what the standard should be for judging

how much and what sort of information should be 

provided. One standard frequently invoked in medical

practice, namely the information commonly provided by

practitioners in the field or in the locale, is inadequate

since research takes place precisely when a common

understanding does not exist. Another standard, currently popular in malpractice law, requires the practitioner to reveal the information that reasonable persons

would wish to know in order to make a decision regarding their care. This, too, seems insufficient since the

research subject, being in essence a volunteer, may wish

to know considerably more about risks gratuitously

undertaken than do patients who deliver themselves into

the hand of a clinician for needed care. It may be that a

standard of “the reasonable volunteer” should be proposed: the extent and nature of information should be

such that persons, knowing that the procedure is neither

necessary for their care nor perhaps fully understood, can

decide whether they wish to participate in the furthering

of knowledge. Even when some direct benefit to them is

anticipated, the subjects should understand clearly the

range of risk and the voluntary nature of participation.

A special problem of consent arises where informing

subjects of some pertinent aspect of the research is likely

to impair the validity of the research. In many cases, it is

sufficient to indicate to subjects that they are being

invited to participate in research of which some features

will not be revealed until the research is concluded. In all

cases of research involving incomplete disclosure, such
National Bioethics Advisory Commission

165

research is justified only if it is clear that (1) incomplete

disclosure is truly necessary to accomplish the goals of

the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an 

adequate plan for debriefing subjects, when appropriate,

and for dissemination of research results to them.

Information about risks should never be withheld for the

purpose of eliciting the cooperation of subjects, and

truthful answers should always be given to direct 

questions about the research. Care should be taken to

distinguish cases in which disclosure would destroy or

invalidate the research from cases in which disclosure

would simply inconvenience the investigator.

Comprehension. The manner and context in which

information is conveyed is as important as the information itself. For example, presenting information in a 

disorganized and rapid fashion, allowing too little time

for consideration or curtailing opportunities for questioning, all may adversely affect a subject’s ability to make

an informed choice.

Because the subject’s ability to understand is a function of intelligence, rationality, maturity and language, it

is necessary to adapt the preservation of the information

to the subject’s capabilities. Investigators are responsible

for ascertaining that the subject has comprehended 

the information. While there is always an obligation to

ascertain that the information about risk to subjects is

complete and adequately comprehended, when the risks

are more serious, that obligation increases. On occasion,

it may be suitable to give some oral or written tests of

comprehension.

Special provision may need to be made when 

comprehension is severely limited—for example, by 

conditions of immaturity or mental disability. each class

of subjects that one might consider as incompetent (e.g.,

infants and young children, mentally disabled patients,

the terminally ill and the comatose) should be considered

on its own terms. Even for these persons, however,

respect requires giving them the opportunity to choose to

the extent they are able, whether or not to participate in

research. The objections of these subjects to involvement

should be honored, unless the research entails proproviding them a therapy unavailable elsewhere. Respect

for persons also requires seeking the permission of other

parties in order to protect the subjects from harm. Such

persons are thus respected both by acknowledging their

own wishes and by the use of third parties to protect

them from harm.

The third parties chosen should be those who are

most likely to understand the incompetent subject’s 

situation and to act in that person’s best interest. The 

person authorized to act on behalf of the subject should

be given an opportunity to observe the research as it 

proceeds in order to be able to withdraw the subject from

the research, if such action appears in the subject’s best

interest.

Voluntariness. An agreement to participate in research

constitutes a valid consent only if voluntarily given. This

element of informed consent requires conditions free of

coercion and undue influence. Coercion occurs when an

overt threat of harm is intentionally presented by one

person to another in order to obtain compliance. Undue

influence, by contrast, occurs through an offer of an

excessive, unwarranted, inappropriate or improper

reward or other overture in order to obtain compliance.

Also, inducements that would ordinarily be acceptable

may become undue influences if the subject is especially

vulnerable.

Unjustifiable pressures usually occur when persons 

in positions of authority or commanding influence—

especially where possible sanctions are involved—urge a

course of action for a subject. A continuum of such influencing factors exists, however, and it is impossible to

state precisely where justifiable persuasion ends and

undue influence begins. But undue influence would

include actions such as manipulating a person’s choice

through the controlling influence of a close relative and

threatening to withdraw health services to which an 

individual would otherwise be entitled.

2. Assessment of Risks and Benefits. The assessment of

risks and benefits requires a careful arrayal of relevant

data, including, in some cases, alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility

to gather systematic and comprehensive information about

proposed research. For the investigator, it is a means to

examine whether the proposed research is properly

designed. For a review committee, it is a method for
166

Appendix D: The Belmont Report

determining whether the risks that will be presented 

to subjects are justified. For prospective subjects, the

assessment will assist the determination whether or not

to participate.

The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable

risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that

informed consent be obtained is derived primarily from

the principle of respect for persons.

The term “risk” refers to a possibility that harm may

occur. However, when expressions such as “small risk” or

“high risk” are used, they usually refer (often ambiguously) both to the chance (probability) of experiencing a

harm and the severity (magnitude) of the envisioned

harm.

The term “benefit” is used in the research context to

refer to something of positive value related to health or

welfare. Unlike “risk,” “benefit” is not a term that

expresses probabilities. Risk is properly contrasted to

probability of benefits, and benefits are properly contrasted with harms rather than risks of harm.

Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible

harms and anticipated benefits. Many kinds of possible

harms and benefits need to be taken into account. There

are, for example, risks of psychological harm, physical

harm, legal harm, social harm and economic harm and

the corresponding benefits. While the most likely types

of harms to research subjects are those of psychological

or physical pain or injury, other possible kinds should

not be overlooked.

Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and

society at large (or special groups of subjects in society).

Previous codes and Federal regulations have required

that risks to subjects be outweighed by the sum of both

the anticipated benefit to the subject, if any, and the

anticipated benefit to society in the form of knowledge to

be gained from the research. In balancing these different

elements, the risks and benefits affecting the immediate

research subject will normally carry special weight. On

the other hand, interests other than those of the subject

may on some occasions be sufficient by themselves to

justify the risks involved in the research, so long as the

subjects’ rights have been protected. Beneficence thus

requires that we protect against risk of harm to subjects

and also that we be concerned about the loss of the 

substantial benefits that might be gained from research.

The Systematic Assessment of Risks and Benefits. It 

is commonly said that benefits and risks must be 

“balanced” and shown to be “in a favorable ratio.” The

metaphorical character of these terms draws attention to

the difficulty of making precise judgments. Only on rare

occasions will quantitative techniques be available for 

the scrutiny of research protocols. However, the idea of 

systematic, nonarbitrary analysis of risks and benefits

should be emulated insofar as possible. This ideal

requires those making decisions about the justifiability of

research to be thorough in the accumulation and assessment of information about all aspects of the research, and

to consider alternatives systematically. This procedure

renders the assessment of research more rigorous and

precise, while making communication between review

board members and investigators less subject to misinterpretation, misinformation and conflicting judgments.

Thus, there should first be a determination of the 

validity of the presuppositions of the research; then the

nature, probability and magnitude of risk should be distinguished with as much clarity as possible. The method

of ascertaining risks should be explicit, especially where

there is no alternative to the use of such vague categories

as small or slight risk. It should also be determined

whether an investigator’s estimates of the probability of

harm or benefits are reasonable, as judged by known

facts or other available studies.

Finally, assessment of the justifiability of research

should reflect at least the following considerations: 

(i) Brutal or inhumane treatment of human subjects is

never morally justified. (ii) Risks should be reduced to

those necessary to achieve the research objective. It

should be determined whether it is in fact necessary to

use human subjects at all. Risk can perhaps never be

entirely eliminated, but it can often be reduced by careful attention to alternative procedures. (iii) When

research involves significant risk of serious impairment,

review committees should be extraordinarily insistent 

on the justification of the risk (looking usually to the 
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167

likelihood of benefit to the subject - or, in some rare

cases, to the manifest voluntariness of the participation).

(iv) When vulnerable populations are involved in

research, the appropriateness of involving them should

itself be demonstrated. A number of variables go into

such judgments, including the nature and degree of risk,

the condition of the particular population involved, 

and the nature and level of the anticipated benefits. 

(v) Relevant risks and benefits must be thoroughly

arrayed in documents and procedures used in the

informed consent process.

3. Selection of Subjects. Just as the principle of respect

for persons finds expression in the requirements for 

consent, and the principle of beneficence in risk/benefit

assessment, the principle of justice gives rise to moral

requirements that there be fair procedures and outcomes

in the selection of research subjects.

Justice is relevant to the selection of subjects of

research at two levels: the social and the individual.

Individual justice in the selection of subjects would

require that researchers exhibit fairness: thus, they

should not offer potentially beneficial research only to

some patients who are in their favor or select only “undesirable” persons for risky research. Social justice requires

that distinction be drawn between classes of subjects that

ought, and ought not, to participate in any particular

kind of research, based on the ability of members of that

class to bear burdens and on the appropriateness of 

placing further burdens on already burdened persons.

Thus, it can be considered a matter of social justice that

there is an order of preference in the selection of classes

of subjects (e.g., adults before children) and that some

classes of potential subjects (e.g., the institutionalized

mentally infirm or prisoners) may be involved as research

subjects, if at all, only on certain conditions.

Injustice may appear in the selection of subjects. even

if individual subjects are selected fairly by investigators

and treated fairly in the course of research. Thus injustice

arises from social. racial, sexual and cultural biases 

institutionalized in society. Thus, even if individual

researchers are treating their research subjects fairly, and

even if IRBs are taking care to assure that subjects are

selected fairly within a particular institution. unjust social

patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although

individual institutions or investigators may not be able to

resolve a problem that is pervasive in their social setting.

They can consider distributive justice in selecting

research subjects.

Some populations, especially institutionalized ones,

are already burdened in many ways by their infirmities

and environments. When research is proposed that

involves risks and does not include a therapeutic component, other less burdened classes of persons should be

called upon first to accept these risks of research, except

where the research is directly related to the specific conditions of the class involved. Also, even though public

funds for research may often flow in the same directions

as public funds for health care, it seems unfair that populations dependent on public health care constitute a

pool of preferred research subjects if more advantaged

populations are likely to be the recipients of the benefits. 

One special instance of injustice results from the

involvement of vulnerable subjects. Certain groups, such

as racial minorities, the economically disadvantaged, the

very sick, and the institutionalized may continually be

sought as research subjects, owing to their ready availability in settings where research is conducted. Given

their dependent status and their frequently compromised

capacity for free consent, they should be protected

against the danger of being involved in research solely for

administrative convenience, or because they are easy to

manipulate as a result of their illness or socioeconomic

condition.

Code of Federal Regulations,

Title 45 Part 46

Appendix E

Subpart A: Federal Policy for the

Protection of Human Subjects (Basic

DHHS Policy for Protection of Human

Research Subjects)

Source: 56 FR 28003, June 18, 1991.

§46.101 To what does this policy apply?

(a) Except as provided in paragraph (b) of this section,

this policy applies to all research involving human

subjects conducted, supported or otherwise subject

to regulation by any Federal Department or Agency

which takes appropriate administrative action to

make the policy applicable to such research. This

includes research conducted by Federal civilian

employees or military personnel, except that each

Department or Agency head may adopt such procedural modifications as may be appropriate from an

administrative standpoint. It also includes research

conducted, supported, or otherwise subject to regulation by the Federal Government outside the

United States.

(1) Research that is conducted or supported by a

Federal Department or Agency, whether or not it

is regulated as defined in §46.102(e), must comply with all sections of this policy.

(2) Research that is neither conducted nor supported

by a Federal Department or Agency but is subject

to regulation as defined in §46.102(e) must be

reviewed and approved, in compliance with

§46.101, §46.102, and §46.107 through

§46.117 of this policy, by an Institutional Review

Board (IRB) that operates in accordance with the

pertinent requirements of this policy.

(b) Unless otherwise required by Department or Agency

heads, research activities in which the only involvement of human subjects will be in one or more of

the following categories are exempt from this

policy:1

(1) Research conducted in established or commonly

accepted educational settings, involving normal

educational practices, such as (i) research on

regular and special education instructional

strategies, or (ii) research on the effectiveness of

or the comparison among instructional techniques, curricula, or classroom management

methods.

(2) Research involving the use of educational tests

(cognitive, diagnostic, aptitude, achievement),

survey procedures, interview procedures or

observation of public behavior, unless:

(i) information obtained is recorded in such a

manner that human subjects can be identified,

directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects’ responses outside the research could

reasonably place the subjects at risk of criminal

or civil liability or be damaging to the subjects’

financial standing, employability, or reputation.

(3) Research involving the use of educational tests

(cognitive, diagnostic, aptitude, achievement),

survey procedures, interview procedures, or

observation of public behavior that is not exempt

under paragraph (b)(2) of this section, if:

(i) the human subjects are elected or appointed

public officials or candidates for public office; or

(ii) Federal statute(s) require(s) without exception that the confidentiality of the personally

identifiable information will be maintained

throughout the research and thereafter.

(4) Research involving the collection or study of

existing data, documents, records, pathological

169
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Appendix E: Code of Federal Regulations, Title 45 Part 46

specimens, or diagnostic specimens, if these

sources are publicly available or if the information is recorded by the investigator in such a

manner that subjects cannot be identified,

directly or through identifiers linked to the 

subjects.

(5) Research and demonstration projects which 

are conducted by or subject to the approval 

of Department or Agency heads, and which 

are designed to study, evaluate, or otherwise

examine:

(i) Public benefit or service programs; (ii) procedures for obtaining benefits or services under

those programs; (iii) possible changes in or 

alternatives to those programs or procedures; 

or (iv) possible changes in methods or levels of

payment for benefits or services under those

programs.

(6) Taste and food quality evaluation and consumer

acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is

consumed that contains a food ingredient at or

below the level and for a use found to be safe, or

agricultural chemical or environmental contaminant at or below the level found to be safe, by

the Food and Drug Administration or approved

by the Environmental Protection Agency or the

Food Safety and Inspection Service of the U.S.

Department of Agriculture.

(c) Department or Agency heads retain final judgment

as to whether a particular activity is covered by this

policy.

(d) Department or Agency heads may require that specific research activities or classes of research activities conducted, supported, or otherwise subject to

regulation by the Department or Agency but not

otherwise covered by this policy, comply with some

or all of the requirements of this policy.

(e) Compliance with this policy requires compliance

with pertinent Federal laws or regulations which

provide additional protections for human subjects.

(f) This policy does not affect any State or local laws or

regulations which may otherwise be applicable and

which provide additional protections for human

subjects.

(g) This policy does not affect any foreign laws or regulations which may otherwise be applicable and

which provide additional protections to human 

subjects of research.

(h) When research covered by this policy takes place 

in foreign countries, procedures normally followed

in the foreign countries to protect human subjects

may differ from those set forth in this policy. [An

example is a foreign institution which complies 

with guidelines consistent with the World Medical

Assembly Declaration (Declaration of Helsinki

amended 1989) issued either by sovereign states or

by an organization whose function for the protection

of human research subjects is internationally recognized.] In these circumstances, if a Department or

Agency head determines that the procedures prescribed by the institution afford protections that are

at least equivalent to those provided in this policy,

the Department or Agency head may approve the

substitution of the foreign procedures in lieu of the

procedural requirements provided in this policy.

Except when otherwise required by statute,

Executive Order, or the Department or Agency head,

notices of these actions as they occur will be published in the Federal Register or will be otherwise

published as provided in Department or Agency

procedures.

(i) Unless otherwise required by law, Department or

Agency heads may waive the applicability of some 

or all of the provisions of this policy to specific

research activities or classes or research activities

otherwise covered by this policy. Except when otherwise required by statute or Executive Order, the

Department or Agency head shall forward advance

notices of these actions to the Office for Protection

from Research Risks, National Institutes of Health,

Department of Health and Human Services (DHHS),

and shall also publish them in the Federal Register

or in such other manner as provided in Department

or Agency procedures.1

1 Institutions with DHHS-approved assurances on file will abide 

by provisions of Title 45 CFR Part 46 Subparts A-D. Some of the

other departments and agencies have incorporated all provisions 

of Title 45 CFR Part 46 into their policies and procedures as well.

However, the exemptions at 45 CFR 46.101(b) do not apply to

research involving prisoners, fetuses, pregnant women, or human 

in vitro fertilization, Subparts B and C. The exemption at 45 CFR

46.101(b)(2), for research involving survey or interview procedures

or observation of public behavior, does not apply to research with

children, Subpart D, except for research involving observations of

public behavior when the investigator(s) do not participate in the

activities being observed.
National Bioethics Advisory Commission

171

§46.102 Definitions.

(a) Department or Agency head means the head of any

Federal Department or Agency and any other officer

or employee of any Department or Agency to whom

authority has been delegated.

(b) Institution means any public or private entity or

Agency (including Federal, State, and other 

agencies).

(c) Legally authorized representative means an individual

or judicial or other body authorized under applicable law to consent on behalf of a prospective subject

to the subject’s participation in the procedure(s)

involved in the research.

(d) Research means a systematic investigation, including

research development, testing and evaluation,

designed to develop or contribute to generalizable

knowledge. Activities which meet this definition 

constitute research for purposes of this policy,

whether or not they are conducted or supported

under a program which is considered research for

other purposes. For example, some demonstration

and service programs may include research activities.

(e) Research subject to regulation, and similar terms are

intended to encompass those research activities for

which a Federal Department or Agency has specific

responsibility for regulating as a research activity, 

(for example, Investigational New Drug requirements

administered by the Food and Drug Administration).

It does not include research activities which are incidentally regulated by a Federal Department or

Agency solely as part of the Department’s or Agency’s

broader responsibility to regulate certain types of

activities whether research or non-research in nature

(for example, Wage and Hour requirements administered by the Department of Labor).

(f) Human subject means a living individual about

whom an investigator (whether professional or 

student) conducting research obtains

(1) data through intervention or interaction with 

the individual, or

(2) identifiable private information.

Intervention includes both physical procedures by 

which data are gathered (for example, venipuncture)

and manipulations of the subject or the subject’s environment that are performed for research purposes.

Interaction includes communication or interpersonal

contact between investigator and subject. Private information includes information about behavior that occurs

in a context in which an individual can reasonably

expect that no observation or recording is taking place,

and information which has been provided for specific

purposes by an individual and which the individual can

reasonably expect will not be made public (for example,

a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or

may readily be ascertained by the investigator or associated with the information) in order for obtaining the

information to constitute research involving human

subjects.

(g) IRB means an Institutional Review Board established

in accord with and for the purposes expressed in

this policy.

(h) IRB approval means the determination of the IRB

that the research has been reviewed and may be

conducted at an institution within the constraints 

set forth by the IRB and by other institutional and

Federal requirements.

(i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater in and of themselves than

those ordinarily encountered in daily life or during

the performance of routine physical or psychological

examinations or tests.

(j) Certification means the official notification by the

institution to the supporting Department or Agency,

in accordance with the requirements of this policy,

that a research project or activity involving human

subjects has been reviewed and approved by an IRB

in accordance with an approved assurance.

§46.103 Assuring compliance with this policy

—research conducted or supported by any

Federal Department or Agency.

(a) Each institution engaged in research which is 

covered by this policy and which is conducted 

or supported by a Federal Department or Agency

shall provide written assurance satisfactory to the

Department or Agency head that it will comply with

the requirements set forth in this policy. In lieu of

requiring submission of an assurance, individual

Department or Agency heads shall accept the 
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Appendix E: Code of Federal Regulations, Title 45 Part 46

existence of a current assurance, appropriate for 

the research in question, on file with the Office for

Protection from Research Risks, National Institutes

Health, DHHS, and approved for Federal wide use

by that office. When the existence of a DHHSapproved assurance is accepted in lieu of requiring

submission of an assurance, reports (except certification) required by this policy to be made to

Department and Agency heads shall also be made 

to the Office for Protection from Research Risks,

National Institutes of Health, DHHS.

(b) Departments and agencies will conduct or support

research covered by this policy only if the institution

has an assurance approved as provided in this section, and only if the institution has certified to the

Department or Agency head that the research has

been reviewed and approved by an IRB provided for

in the assurance, and will be subject to continuing

review by the IRB. Assurances applicable to federally

supported or conducted research shall at a minimum include:

(1) A statement of principles governing the institution in the discharge of its responsibilities for

protecting the rights and welfare of human 

subjects of research conducted at or sponsored

by the institution, regardless of whether the

research is subject to Federal regulation. This

may include an appropriate existing code, declaration, or statement of ethical principles, or a

statement formulated by the institution itself.

This requirement does not preempt provisions of

this policy applicable to Department- or Agencysupported or regulated research and need not be

applicable to any research exempted or waived

under §46.101 (b) or (i).

(2) Designation of one or more IRBs established in

accordance with the requirements of this policy,

and for which provisions are made for meeting

space and sufficient staff to support the IRB’s

review and recordkeeping duties.

(3) A list of IRB members identified by name;

earned degrees; representative capacity; indications of experience such as board certifications,

licenses, etc., sufficient to describe each member’s chief anticipated contributions to IRB 

deliberations; and any employment or other

relationship between each member and the 

institution; for example: full-time employee,

part-time employee, member of governing panel

or board, stockholder, paid or unpaid consultant. Changes in IRB membership shall be

reported to the Department or Agency head,

unless in accord with §46.103(a) of this policy,

the existence of a DHHS-approved assurance is

accepted. In this case, change in IRB membership shall be reported to the Office for

Protection from Research Risks, National

Institutes of Health, DHHS.

(4) Written procedures which the IRB will follow 

(i) for conducting its initial and continuing

review of research and for reporting its findings

and actions to the investigator and the institution; (ii) for determining which projects require

review more often than annually and which

projects need verification from sources other

than the investigators that no material changes

have occurred since previous IRB review; and

(iii) for ensuring prompt reporting to the IRB 

of proposed changes in a research activity, and

for ensuring that such changes in approved

research, during the period for which IRB

approval has already been given, may not be 

initiated without IRB review and approval except

when necessary to eliminate apparent immediate

hazards to the subject.

(5) Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials,

and the Department or Agency head of (i) any

unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements

or determinations of the IRB; and (ii) any suspension or termination of IRB approval.

(c) The assurance shall be executed by an individual

authorized to act for the institution and to assume

on behalf of the institution the obligations imposed

by this policy and shall be filed in such form 

and manner as the Department or Agency head

prescribes.

(d) The Department or Agency head will evaluate all

assurances submitted in accordance with this 

policy through such officers and employees of the

Department or Agency and such experts or consultants engaged for this purpose as the Department or
National Bioethics Advisory Commission

173

Agency head determines to be appropriate. The

Department or Agency head’s evaluation will take

into consideration the adequacy of the proposed IRB

in light of the anticipated scope of the institution’s

research activities and the types of subject populations likely to be involved, the appropriateness of

the proposed initial and continuing review procedures in light of the probable risks, and the size and

complexity of the institution.

(e) On the basis of this evaluation, the Department 

or Agency head may approve or disapprove the

assurance, or enter into negotiations to develop an

approvable one. The Department or Agency head

may limit the period during which any particular

approved assurance or class of approved assurances

shall remain effective or otherwise condition or

restrict approval.

(f) Certification is required when the research is supported by a Federal Department or Agency and not

otherwise exempted or waived under §46.101 (b) or

(i). An institution with an approved assurance shall

certify that each application or proposal for research

covered by the assurance and by §46.103 of this

policy has been reviewed and approved by the IRB.

Such certification must be submitted with the application or proposal or by such later date as may be

prescribed by the Department or Agency to which

the application or proposal is submitted. Under 

no condition shall research covered by §46.103

of the policy be supported prior to receipt of the

certification that the research has been reviewed 

and approved by the IRB. Institutions without an

approved assurance covering the research shall 

certify within 30 days after receipt of a request for

such a certification from the Department or Agency,

that the application or proposal has been approved

by the IRB. If the certification is not submitted 

within these time limits, the application or proposal

may be returned to the institution.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§§46.104—46.106 [Reserved]

§46.107 IRB membership.

(a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate

review of research activities commonly conducted by

the institution. The IRB shall be sufficiently qualified

through the experience and expertise of its members, and the diversity of the members, including

consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community

attitudes, to promote respect for its advice and

counsel in safeguarding the rights and welfare of

human subjects. In addition to possessing the professional competence necessary to review specific

research activities, the IRB shall be able to ascertain

the acceptability of proposed research in terms of

institutional commitments and regulations, applicable law, and standards of professional conduct and

practice. The IRB shall therefore include persons

knowledgeable in these areas. If an IRB regularly

reviews research that involves a vulnerable category

of subjects, such as children, prisoners, pregnant

women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion 

of one or more individuals who are knowledgeable

about and experienced in working with these 

subjects.

(b) Every nondiscriminatory effort will be made to

ensure that no IRB consists entirely of men or 

entirely of women, including the institution’s 

consideration of qualified persons of both sexes, 

so long as no selection is made to the IRB on the

basis of gender. No IRB may consist entirely of

members of one profession.

(c) Each IRB shall include at least one member whose

primary concerns are in scientific areas and at least

one member whose primary concerns are in nonscientific areas.

(d) Each IRB shall include at least one member who is

not otherwise affiliated with the institution and who

is not part of the immediate family of a person who

is affiliated with the institution.

(e) No IRB may have a member participate in the IRB’s

initial or continuing review of any project in which

the member has a conflicting interest, except to provide information requested by the IRB.

(f) An IRB may, in its discretion, invite individuals with

competence in special areas to assist in the review of

issues which require expertise beyond or in addition

to that available on the IRB. These individuals may

not vote with the IRB.
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Appendix E: Code of Federal Regulations, Title 45 Part 46

§46.108 IRB functions and operations.

In order to fulfill the requirements of this policy each 

IRB shall:

(a) Follow written procedures in the same detail as

described in §46.103(b)(4) and to the extent

required by §46.103(b)(5).

(b) Except when an expedited review procedure is used

(see §46.110), review proposed research at convened meetings at which a majority of the members

of the IRB are present, including at least one member whose primary concerns are in nonscientific

areas. In order for the research to be approved, it

shall receive the approval of a majority of those

members present at the meeting

§46.109 IRB review of research.

(a) An IRB shall review and have authority to approve,

require modifications in (to secure approval), or disapprove all research activities covered by this policy.

(b) An IRB shall require that information given to subjects as part of informed consent is in accordance

with §46.116. The IRB may require that information, in addition to that specifically mentioned in

§46.116, be given to the subjects when in the 

IRB’s judgment the information would meaningfully

add to the protection of the rights and welfare of

subjects.

(c) An IRB shall require documentation of informed

consent or may waive documentation in accordance

with §46.117.

(d) An IRB shall notify investigators and the institution

in writing of its decision to approve or disapprove

the proposed research activity, or of modifications

required to secure IRB approval of the research

activity. If the IRB decides to disapprove a research

activity, it shall include in its written notification a

statement of the reasons for its decision and give the

investigator an opportunity to respond in person or

in writing.

(e) An IRB shall conduct continuing review of research

covered by this policy at intervals appropriate to the

degree of risk, but not less than once per year, and

shall have authority to observe or have a third party

observe the consent process and the research.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§46.110 Expedited review procedures for 

certain kinds of research involving no more

than minimal risk, and for minor changes in

approved research.

(a) The Secretary, HHS, has established, and published

as a Notice in the Federal Register, a list of categories of research that may be reviewed by the IRB

through an expedited review procedure. The list will

be amended, as appropriate, after consultation with

other departments and agencies, through periodic

republication by the Secretary, HHS, in the Federal

Register. A copy of the list is available from the

Office for Protection from Research Risks, National

Institutes of Health, DHHS, Bethesda, Maryland

20892.

(b) An IRB may use the expedited review procedure to

review either or both of the following:

(1) some or all of the research appearing on the list

and found by the reviewer(s) to involve no more

than minimal risk,

(2) minor changes in previously approved research

during the period (of one year or less) for which

approval is authorized.

Under an expedited review procedure, the review may

be carried out by the IRB chairperson or by one or

more experienced reviewers designated by the chairperson from among members of the IRB. In reviewing

the research, the reviewers may exercise all of the

authorities of the IRB except that the reviewers may 

not disapprove the research. A research activity may be

disapproved only after review in accordance with the

non-expedited procedure set forth in §46.108(b).

(c) Each IRB which uses an expedited review procedure

shall adopt a method for keeping all members

advised of research proposals which have been

approved under the procedure.

(d) The Department or Agency head may restrict, 

suspend, terminate, or choose not to authorize an

institution’s or IRB’s use of the expedited review 

procedure.

§46.111 Criteria for IRB approval of research.

(a) In order to approve research covered by this policy

the IRB shall determine that all of the following

requirements are satisfied:
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175

(1) Risks to subjects are minimized: (i) by using

procedures which are consistent with sound

research design and which do not unnecessarily

expose subjects to risk, and (ii) whenever 

appropriate, by using procedures already being

performed on the subjects for diagnostic or

treatment purposes.

(2) Risks to subjects are reasonable in relation to

anticipated benefits, if any, to subjects, and the

importance of the knowledge that may reasonably be expected to result. In evaluating risks

and benefits, the IRB should consider only those

risks and benefits that may result from the

research (as distinguished from risks and benefits of therapies subjects would receive even if

not participating in the research). The IRB

should not consider possible long-range effects

of applying knowledge gained in the research

(for example, the possible effects of the research

on public policy) as among those research risks

that fall within the purview of its responsibility.

(3) Selection of subjects is equitable. In making this

assessment the IRB should take into account the

purposes of the research and the setting in

which the research will be conducted and

should be particularly cognizant of the special

problems of research involving vulnerable populations, such as children, prisoners, pregnant

women, mentally disabled persons, or economically or educationally disadvantaged persons.

(4) Informed consent will be sought from each

prospective subject or the subject’s legally

authorized representative, in accordance with,

and to the extent required by §46.116.

(5) Informed consent will be appropriately documented, in accordance with, and to the extent

required by §46.117.

(6) When appropriate, the research plan makes 

adequate provision for monitoring the data 

collected to ensure the safety of subjects.

(7) When appropriate, there are adequate provisions

to protect the privacy of subjects and to maintain the confidentiality of data.

(b) When some or all of the subjects are likely to be

vulnerable to coercion or undue influence, such as

children, prisoners, pregnant women, mentally 

disabled persons, or economically or educationally

disadvantaged persons, additional safeguards have

been included in the study to protect the rights and

welfare of these subjects.

§46.112 Review by institution.

Research covered by this policy that has been approved

by an IRB may be subject to further appropriate review

and approval or disapproval by officials of the institution. However, those officials may not approve the

research if it has not been approved by an IRB.

§46.113 Suspension or termination of IRB

approval of research.

An IRB shall have authority to suspend or terminate

approval of research that is not being conducted in

accordance with the IRB’s requirements or that has been

associated with unexpected serious harm to subjects.

Any suspension or termination of approval shall include

a statement of the reasons for the IRB’s action and shall

be reported promptly to the investigator, appropriate

institutional officials, and the Department or Agency

head.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§46.114 Cooperative research.

Cooperative research projects are those projects covered

by this policy which involve more than one institution.

In the conduct of cooperative research projects, each

institution is responsible for safeguarding the rights 

and welfare of human subjects and for complying with

this policy. With the approval of the Department or

Agency head, an institution participating in a cooperative project may enter into a joint review arrangement,

rely upon the review of another qualified IRB, or make

similar arrangements for avoiding duplication of effort.

§46.115 IRB records.

(a) An institution, or when appropriate an IRB, shall

prepare and maintain adequate documentation of

IRB activities, including the following:

(1) Copies of all research proposals reviewed, 

scientific evaluations, if any, that accompany the

proposals, approved sample consent documents,

progress reports submitted by investigators, and

reports of injuries to subjects.
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(2) Minutes of IRB meetings which shall be in sufficient detail to show attendance at the meetings;

actions taken by the IRB; the vote on these

actions including the number of members voting

for, against, and abstaining; the basis for requiring changes in or disapproving research; and a

written summary of the discussion of controverted issues and their resolution.

(3) Records of continuing review activities.

(4) Copies of all correspondence between the IRB

and the investigators.

(5) A list of IRB members in the same detail as

described in §46.103(b)(3).

(6) Written procedures for the IRB in the same detail

as described in §46.103(b)(4) and

§46.103(b)(5).

(7) Statements of significant new findings provided

to subjects, as required by §46.116(b)(5).

(b) The records required by this policy shall be retained

for at least 3 years, and records relating to research

which is conducted shall be retained for at least 3

years after completion of the research. All records

shall be accessible for inspection and copying by

authorized representatives of the Department or

Agency at reasonable times and in a reasonable 

manner.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§46.116 General requirements 

for informed consent.

Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in

research covered by this policy unless the investigator

has obtained the legally effective informed consent of

the subject or the subject’s legally authorized representative. An investigator shall seek such consent only under

circumstances that provide the prospective subject or

the representative sufficient opportunity to consider

whether or not to participate and that minimize the

possibility of coercion or undue influence. The information that is given to the subject or the representative

shall be in language understandable to the subject or

the representative. No informed consent, whether oral

or written, may include any exculpatory language

through which the subject or the representative is made

to waive or appear to waive any of the subject’s legal

rights, or releases or appears to release the investigator,

the sponsor, the institution or its agents from liability

for negligence.

(a) Basic elements of informed consent. Except as 

provided in paragraph (c) or (d) of this section, in

seeking informed consent the following information

shall be provided to each subject:

(1) a statement that the study involves research, an

explanation of the purposes of the research and

the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures

which are experimental;

(2) a description of any reasonably foreseeable risks

or discomforts to the subject;

(3) a description of any benefits to the subject or to

others which may reasonably be expected from

the research;

(4) a disclosure of appropriate alternative procedures or courses of treatment, if any, that might

be advantageous to the subject;

(5) a statement describing the extent, if any, to

which confidentiality of records identifying the

subject will be maintained;

(6) for research involving more than minimal risk,

an explanation as to whether any compensation

and an explanation as to whether any medical

treatments are available if injury occurs and, if

so, what they consist of, or where further information may be obtained;

(7) an explanation of whom to contact for answers

to pertinent questions about the research and

research subjects’ rights, and whom to contact in

the event of a research-related injury to the subject; and

(8) a statement that participation is voluntary,

refusal to participate will involve no penalty or

loss of benefits to which the subject is otherwise

entitled, and the subject may discontinue participation at any time without penalty or loss of

benefits to which the subject is otherwise 

entitled.

(b) additional elements of informed consent. When

appropriate, one or more of the following elements
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177

of information shall also be provided to each 

subject:

(1) a statement that the particular treatment or procedure may involve risks to the subject (or to the

embryo or fetus, if the subject is or may become

pregnant) which are currently unforeseeable;

(2) anticipated circumstances under which the 

subject’s participation may be terminated by 

the investigator without regard to the subject’s

consent;

(3) any additional costs to the subject that may

result from participation in the research;

(4) the consequences of a subject’s decision to 

withdraw from the research and procedures 

for orderly termination of participation by the

subject;

(5) A statement that significant new findings developed during the course of the research which

may relate to the subject’s willingness to continue participation will be provided to the subject; and

(6) the approximate number of subjects involved in

the study.

(c) An IRB may approve a consent procedure which

does not include, or which alters, some or all of the

elements of informed consent set forth above, or

waive the requirement to obtain informed consent

provided the IRB finds and documents that:

(1) the research or demonstration project is to be

conducted by or subject to the approval of state

or local government officials and is designed to

study, evaluate, or otherwise examine: (i) public

benefit or service programs; (ii) procedures for

obtaining benefits or services under those programs; (iii) possible changes in or alternatives to

those programs or procedures; or (iv) possible

changes in methods or levels of payment for

benefits or services under those programs; and

(2) the research could not practicably be carried out

without the waiver or alteration.

(d) An IRB may approve a consent procedure which

does not include, or which alters, some or all of the

elements of informed consent set forth in this section, or waive the requirements to obtain informed

consent provided the IRB finds and documents that:

(1) the research involves no more than minimal risk

to the subjects;

(2) the waiver or alteration will not adversely affect

the rights and welfare of the subjects;

(3) the research could not practicably be carried out

without the waiver or alteration; and

(4) whenever appropriate, the subjects will be 

provided with additional pertinent information

after participation.

(e) The informed consent requirements in this policy

are not intended to preempt any applicable Federal,

State, or local laws which require additional information to be disclosed in order for informed consent

to be legally effective.

(f) Nothing in this policy is intended to limit the

authority of a physician to provide emergency medical care, to the extent the physician is permitted to

do so under applicable Federal, State, or local law.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§46.117 Documentation of informed consent.

(a) Except as provided in paragraph (c) of this section,

informed consent shall be documented by the use 

of a written consent form approved by the IRB and

signed by the subject or the subject’s legally authorized representative. A copy shall be given to the 

person signing the form.

(b) Except as provided in paragraph (c) of this section,

the consent form may be either of the following:

(1) A written consent document that embodies the

elements of informed consent required by

§46.116. This form may be read to the subject

or the subject’s legally authorized representative,

but in any event, the investigator shall give

either the subject or the representative adequate

opportunity to read it before it is signed; or

(2) A short form written consent document stating

that the elements of informed consent required

by §46.116 have been presented orally to the

subject or the subject’s legally authorized representative. When this method is used, there shall

be a witness to the oral presentation. Also, the

IRB shall approve a written summary of what is

to be said to the subject or the representative.
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Only the short form itself is to be signed by the

subject or the representative. However, the witness shall sign both the short form and a copy of

the summary, and the person actually obtaining

consent shall sign a copy of the summary. A

copy of the summary shall be given to the subject or the representative, in addition to a copy

of the short form.

(c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all

subjects if it finds either:

(1) That the only record linking the subject and the

research would be the consent document and

the principal risk would be potential harm

resulting from a breach of confidentiality. Each

subject will be asked whether the subject wants

documentation linking the subject with the

research, and the subject’s wishes will govern; or

(2) That the research presents no more than minimal risk of harm to subjects and involves no

procedures for which written consent is normally

required outside of the research context.

In cases in which the documentation requirement is

waived, the IRB may require the investigator to provide

subjects with a written statement regarding the research.

(Approved by the Office of Management and Budget

under Control Number 9999-0020.)

§46.118 Applications and proposals lacking

definite plans for involvement of human 

subjects.

Certain types of applications for grants, cooperative

agreements, or contracts are submitted to departments

or agencies with the knowledge that subjects may be

involved within the period of support, but definite

plans would not normally be set forth in the application

or proposal. These include activities such as institutional type grants when selection of specific projects is

the institution’s responsibility; research training grants

in which the activities involving subjects remain to be

selected; and projects in which human subjects’ involvement will depend upon completion of instruments,

prior animal studies, or purification of compounds.

These applications need not be reviewed by an IRB

before an award may be made. However, except for

research exempted or waived under §46.101 (b) or (i),

no human subjects may be involved in any project 

supported by these awards until the project has been

reviewed and approved by the IRB, as provided in this

policy, and certification submitted, by the institution, to

the Department or Agency.

§46.119 Research undertaken without the

intention of involving human subjects.

In the event research is undertaken without the intention of involving human subjects, but it is later proposed to involve human subjects in the research, the

research shall first be reviewed and approved by an IRB,

as provided in this policy, a certification submitted, by

the institution, to the Department or Agency, and final

approval given to the proposed change by the

Department or Agency.

§46.120 Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department

or Agency.

(a) The Department or Agency head will evaluate all

applications and proposals involving human subjects

submitted to the Department or Agency through

such officers and employees of the Department or

Agency and such experts and consultants as the

Department or Agency head determines to be appropriate. This evaluation will take into consideration

the risks to the subjects, the adequacy of protection

against these risks, the potential benefits of the

research to the subjects and others, and the importance of the knowledge gained or to be gained.

(b) On the basis of this evaluation, the Department 

or Agency head may approve or disapprove the

application or proposal, or enter into negotiations 

to develop an approvable one.

§46.121 [Reserved]

§46.122 Use of Federal funds.

Federal funds administered by a Department or Agency

may not be expended for research involving human

subjects unless the requirements of this policy have

been satisfied.

§46.123 Early termination of research support:

Evaluation of applications and proposals.

(a) The Department or Agency head may require that

Department or Agency support for any project be 

terminated or suspended in the manner prescribed 
National Bioethics Advisory Commission

179

in applicable program requirements, when the

Department or Agency head finds an institution has

materially failed to comply with the terms of this 

policy.

(b) In making decisions about supporting or approving

applications or proposals covered by this policy the

Department or Agency head may take into account,

in addition to all other eligibility requirements and

program criteria, factors such as whether the applicant has been subject to a termination or suspension

under paragraph (a) of this section and whether the

applicant or the person or persons who would direct

or has/have directed the scientific and technical

aspects of an activity has/have, in the judgment of

the Department or Agency head, materially failed to

discharge responsibility for the protection of the

rights and welfare of human subjects (whether or

not the research was subject to Federal regulation).

§46.124 Conditions.

With respect to any research project or any class of

research projects the Department or Agency head may

impose additional conditions prior to or at the time of

approval when in the judgment of the Department or

Agency head additional conditions are necessary for the

protection of human subjects.

Subpart B: Additional DHHS Protections

Pertaining to Research, Development,

and Related Activities Involving

Fetuses, Pregnant Women, and Human

In Vitro Fertilization

Source: 40 FR 33528, Aug. 8, 1975; 43 FR 1758, 

January 11, 1978; 43 FR 51559, November 3, 1978.

§46.201 Applicability.

(a) The regulations in this subpart are applicable to 

all Department of Health and Human Services 

grants and contracts supporting research, development, and related activities involving: (1) the 

fetus, (2) pregnant women, and (3) human in 

vitro fertilization.

(b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth

herein will in any way render inapplicable pertinent

State or local laws bearing upon activities covered by

this subpart.

(c) The requirements of this subpart are in addition to

those imposed under the other subparts of this part.

§46.202 Purpose.

It is the purpose of this subpart to provide additional

safeguards in reviewing activities to which this subpart

is applicable to assure that they conform to appropriate

ethical standards and relate to important societal needs.

§46.203 Definitions.

As used in this subpart:

(a) “Secretary” means the Secretary of Health and

Human Services and any other officer or employee

of the Department of Health and Human Services

(DHHS) to whom authority has been delegated.

(b) “Pregnancy” encompasses the period of time from

confirmation of implantation (through any of the

presumptive signs of pregnancy, such as missed

menses, or by a medically acceptable pregnancy

test), until expulsion or extraction of the fetus.

(c) “Fetus” means the product of conception from the

time of implantation (as evidenced by any of the

presumptive signs of pregnancy, such as missed

menses, or a medically acceptable pregnancy test),

until a determination is made, following expulsion

or extraction of the fetus, that it is viable.

(d) “Viable” as it pertains to the fetus means being able,

after either spontaneous or induced delivery, to survive (given the benefit of available medical therapy)

to the point of independently maintaining heart beat

and respiration. The Secretary may from time to

time, taking into account medical advances, publish

in the Federal Register guidelines to assist in determining whether a fetus is viable for purposes of this

subpart. If a fetus is viable after delivery, it is a 

premature infant.

(e) “Nonviable fetus” means a fetus ex utero which,

although living, is not viable.

(f) “Dead fetus” means a fetus ex utero which exhibits

neither heart beat, spontaneous respiratory activity,

spontaneous movement of voluntary muscles, nor

pulsation of the umbilical cord (if still attached).

(g) “In vitro fertilization” means any fertilization of

human ova which occurs outside the body of a
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female, either through admixture of donor human

sperm and ova or by any other means.

§46.204 Ethical Advisory Boards.

(a) One or more Ethical Advisory Boards shall be 

established by the Secretary. Members of these

Board(s) shall be so selected that the Board(s) will 

be competent to deal with medical, legal, social, 

ethical, and related issues and may include, for

example, research scientists, physicians, psychologists, sociologists, educators, lawyers, and ethicists,

as well as representatives of the general public. No

Board member may be a regular, full-time employee

of the Department of Health and Human Services.

(b) At the request of the Secretary, the Ethical Advisory

Board shall render advice consistent with the policies and requirements of this part as to ethical

issues, involving activities covered by this subpart,

raised by individual applications or proposals. In

addition, upon request by the Secretary, the Board

shall render advice as to classes of applications or

proposals and general policies, guidelines, and 

procedures.

(c) A Board may establish, with the approval of the

Secretary, classes of applications or proposals which:

(1) must be submitted to the Board, or (2) need not

be submitted to the Board. Where the Board so

establishes a class of applications or proposals which

must be submitted, no application or proposal 

within the class may be funded by the Department

or any component thereof until the application or

proposal has been reviewed by the Board and the

Board has rendered advice as to its acceptability

from an ethical standpoint.

(d) [Nullified under Public Law 103-43, June 10, 1993]

§46.205 Additional duties of the Institutional

Review Boards in connection with activities

involving fetuses, pregnant women, or human

in vitro fertilization.

(a) In addition to the responsibilities prescribed for

Institutional Review Boards under Subpart A of this

part, the applicant’s or offeror’s Board shall, with

respect to activities covered by this subpart, carry

out the following additional duties:

(1) determine that all aspects of the activity meet the

requirements of this subpart;

(2) determine that adequate consideration has been

given to the manner in which potential subjects

will be selected, and adequate provision has

been made by the applicant or offeror for monitoring the actual informed consent process (e.g.,

through such mechanisms, when appropriate, 

as participation by the Institutional Review

Board or subject advocates in: (i) overseeing the

actual process by which individual consents

required by this subpart are secured either by

approving induction of each individual into the

activity or verifying, perhaps through sampling,

that approved procedures for induction of individuals into the activity are being followed, and

(ii) monitoring the progress of the activity and

intervening as necessary through such steps as

visits to the activity site and continuing evaluation to determine if any unanticipated risks have

arisen);

(3) carry out such other responsibilities as may be

assigned by the Secretary.

(b) No award may be issued until the applicant or

offeror has certified to the Secretary that the

Institutional Review Board has made the determinations required under paragraph (a) of this section

and the Secretary has approved these determinations, as provided in §46.120 of Subpart A of this

part.

(c) Applicants or offerors seeking support for activities

covered by this subpart must provide for the designation of an Institutional Review Board, subject to

approval by the Secretary, where no such Board has

been established under Subpart A of this part.

§46.206 General limitations.

(a) No activity to which this subpart is applicable may

be undertaken unless:

(1) appropriate studies on animals and nonpregnant

individuals have been completed;

(2) except where the purpose of the activity is to

meet the health needs of the mother or the particular fetus, the risk to the fetus is minimal and,

in all cases, is the least possible risk for achieving the objectives of the activity;
National Bioethics Advisory Commission

181

(3) individuals engaged in the activity will have no

part in: (i) any decisions as to the timing,

method, and procedures used to terminate the

pregnancy, and (ii) determining the viability of

the fetus at the termination of the pregnancy;

and

(4) no procedural changes which may cause greater

than minimal risk to the fetus or the pregnant

woman will be introduced into the procedure for

terminating the pregnancy solely in the interest

of the activity.

(b) No inducements, monetary or otherwise, may be

offered to terminate pregnancy for purposes of the

activity.

Source: 40 FR 33528, Aug. 8, 1975, as amended at

40 FR 51638, Nov. 6, 1975.

§46.207 Activities directed toward pregnant

women as subjects.

(a) No pregnant woman may be involved as a subject in

an activity covered by this subpart unless: (1) the

purpose of the activity is to meet the health needs of

the mother and the fetus will be placed at risk only

to the minimum extent necessary to meet such

needs, or (2) the risk to the fetus is minimal.

(b) An activity permitted under paragraph (a) of this

section may be conducted only if the mother and

father are legally competent and have given their

informed consent after having been fully informed

regarding possible impact on the fetus, except that

the father’s informed consent need not be secured if:

(1) the purpose of the activity is to meet the health

needs of the mother; (2) his identity or whereabouts

cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted 

from rape.

§46.208 Activities directed toward fetuses 

in utero as subjects.

(a) No fetus in utero may be involved as a subject in 

any activity covered by this subpart unless: (1) the

purpose of the activity is to meet the health needs 

of the particular fetus and the fetus will be placed at

risk only to the minimum extent necessary to meet

such needs, or (2) the risk to the fetus imposed by

the research is minimal and the purpose of the 

activity is the development of important biomedical

knowledge which cannot be obtained by other

means.

(b) An activity permitted under paragraph (a) of this

section may be conducted only if the mother and

father are legally competent and have given their

informed consent, except that the father’s consent

need not be secured if: (1) his identity or whereabouts cannot reasonably be ascertained, (2) he is

not reasonably available, or (3) the pregnancy 

resulted from rape.

§46.209 Activities directed toward fetuses ex

utero, including nonviable fetuses, as subjects.

(a) Until it has been ascertained whether or not a 

fetus ex utero is viable, a fetus ex utero may not be

involved as a subject in an activity covered by this

subpart unless:

(1) there will be no added risk to the fetus resulting

from the activity, and the purpose of the activity

is the development of important biomedical

knowledge which cannot be obtained by other

means, or

(2) the purpose of the activity is to enhance the 

possibility of survival of the particular fetus to

the point of viability.

(b) No nonviable fetus may be involved as a subject in

an activity covered by this subpart unless:

(1) vital functions of the fetus will not be artificially

maintained,

(2) experimental activities which of themselves

would terminate the heartbeat or respiration of

the fetus will not be employed, and

(3) the purpose of the activity is the development of

important biomedical knowledge which cannot

be obtained by other means.

(c) In the event the fetus ex utero is found to be viable,

it may be included as a subject in the activity only to

the extent permitted by and in accordance with the

requirements of other subparts of this part.

(d) An activity permitted under paragraph (a) or (b) of

this section may be conducted only if the mother

and father are legally competent and have given

their informed consent, except that the father’s

informed consent need not be secured if: (1) his
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identity or whereabouts cannot reasonably be ascertained, (2) he is not reasonably available, or (3) the

pregnancy resulted from rape.

§46.210 Activities involving the dead fetus, fetal

material, or the placenta.

Activities involving the dead fetus, mascerated fetal

material, or cells, tissue, or organs excised from a dead

fetus shall be conducted only in accordance with any

applicable State or local laws regarding such activities.

§46.211 Modification or waiver of specific

requirements.

Upon the request of an applicant or offeror (with the

approval of its Institutional Review Board), the Secretary

may modify or waive specific requirements of this subpart, with the approval of the Ethical Advisory Board

after such opportunity for public comment as the

Ethical Advisory Board considers appropriate in the 

particular instance. In making such decisions, the

Secretary will consider whether the risks to the subject

are so outweighed by the sum of the benefit to the subject and the importance of the knowledge to be gained

as to warrant such modification or waiver and that such

benefits cannot be gained except through a modification

or waiver. Any such modifications or waivers will be

published as notices in the Federal Register.

Subpart C: Additional DHHS Protections

Pertaining to Biomedical and

Behavioral Research Involving

Prisoners as Subjects

Source: 43 FR 53655, Nov. 16, 1978.

§46.301 Applicability.

(a) The regulations in this subpart are applicable to all

biomedical and behavioral research conducted or

supported by the Department of Health and Human

Services involving prisoners as subjects.

(b) Nothing in this subpart shall be construed as indicating that compliance with the procedures set forth

herein will authorize research involving prisoners as

subjects, to the extent such research is limited or

barred by applicable State or local law.

(c) The requirements of this subpart are in addition to

those imposed under the other subparts of this part.

§46.302 Purpose.

Inasmuch as prisoners may be under constraints

because of their incarceration which could affect their

ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in

research, it is the purpose of this subpart to provide

additional safeguards for the protection of prisoners

involved in activities to which this subpart is applicable.

§46.303 Definitions.

As used in this subpart:

(a) “Secretary” means the Secretary of Health and

Human Services and any other officer or employee

of the Department of Health and Human Services 

to whom authority has been delegated.

(b) “DHHS” means the Department of Health and

Human Services.

(c) “Prisoner” means any individual involuntarily confined or detained in a penal institution. The term is

intended to encompass individuals sentenced to

such an institution under a criminal or civil statute,

individuals detained in other facilities by virtue of

statutes or commitment procedures which provide

alternatives to criminal prosecution or incarceration

in a penal institution, and individuals detained

pending arraignment, trial, or sentencing.

(d) “Minimal risk” is the probability and magnitude of

physical or psychological harm that is normally

encountered in the daily lives, or in the routine

medical, dental, or psychological examination of

healthy persons.

§46.304 Composition of Institutional Review

Boards where prisoners are involved.

In addition to satisfying the requirements in §46.107 of

this part, an Institutional Review Board, carrying out

responsibilities under this part with respect to research

covered by this subpart, shall also meet the following

specific requirements:

(a) A majority of the Board (exclusive of prisoner members) shall have no association with the prison(s)

involved, apart from their membership on the

Board.

(b) At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate

background and experience to serve in that capacity,
National Bioethics Advisory Commission

183

except that where a particular research project is

reviewed by more than one Board only one Board

need satisfy this requirement.

§46.305 Additional duties of the Institutional

Review Boards where prisoners are involved.

(a) In addition to all other responsibilities prescribed 

for Institutional Review Boards under this part, the

Board shall review research covered by this subpart

and approve such research only if it finds that:

(1) the research under review represents one of the

categories of research permissible under

§46.306(a)(2);

(2) any possible advantages accruing to the prisoner

through his or her participation in the research,

when compared to the general living conditions,

medical care, quality of food, amenities and

opportunity for earnings in the prison, are not of

such a magnitude that his or her ability to weigh

the risks of the research against the value of such

advantages in the limited choice environment of

the prison is impaired;

(3) the risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers;

(4) procedures for the selection of subjects within

the prison are fair to all prisoners and immune

from arbitrary intervention by prison authorities

or prisoners. Unless the principal investigator

provides to the Board justification in writing for

following some other procedures, control subjects must be selected randomly from the group

of available prisoners who meet the characteristics needed for that particular research project;

(5) the information is presented in language which

is understandable to the subject population;

(6) adequate assurance exists that parole boards will

not take into account a prisoner’s participation in

the research in making decisions regarding

parole, and each prisoner is clearly informed in

advance that participation in the research will

have no effect on his or her parole; and

(7) where the Board finds there may be a need for

follow-up examination or care of participants

after the end of their participation, adequate 

provision has been made for such examination

or care, taking into account the varying lengths

of individual prisoners’ sentences, and for

informing participants of this fact.

(b) The Board shall carry out such other duties as may

be assigned by the Secretary.

(c) The institution shall certify to the Secretary, in such

form and manner as the Secretary may require, that

the duties of the Board under this section have been

fulfilled.

§46.306 Permitted research involving prisoners.

(a) Biomedical or behavioral research conducted or supported by DHHS may involve prisoners as subjects

only if:

(1) the institution responsible for the conduct of 

the research has certified to the Secretary that

the Institutional Review Board has approved the

research under §46.305 of this subpart; and

(2) in the judgment of the Secretary the proposed

research involves solely the following:

(A) study of the possible causes, effects, and

processes of incarceration, and of criminal

behavior, provided that the study presents

no more than minimal risk and no more

than inconvenience to the subjects;

(B) study of prisons as institutional structures 

or of prisoners as incarcerated persons, 

provided that the study presents no more

than minimal risk and no more than 

inconvenience to the subjects;

(C) research on conditions particularly affecting

prisoners as a class (for example, vaccine trials and other research on hepatitis which is

much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug

addiction, and sexual assaults) provided that

the study may proceed only after the

Secretary has consulted with appropriate

experts including experts in penology, medicine, and ethics, and published notice, in the

Federal Register, of his intent to approve

such research; or

(D) research on practices, both innovative 

and accepted, which have the intent and 
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Appendix E: Code of Federal Regulations, Title 45 Part 46

reasonable probability of improving the

health or well-being of the subject. In cases

in which those studies require the assignment of prisoners in a manner consistent

with protocols approved by the IRB to 

control groups which may not benefit from

the research, the study may proceed only

after the Secretary has consulted with appropriate experts, including experts in penology,

medicine, and ethics, and published notice,

in the Federal Register, of the intent to

approve such research.

(b) Except as provided in paragraph (a) of this section,

biomedical or behavioral research conducted or 

supported by DHHS shall not involve prisoners as

subjects.

Subpart D: Additional DHHS Protections

for Children Involved as Subjects in

Research

Source: 48 FR 9818, March 8, 1983; 56 FR 28032, 

June 18, 1991.

§46.401 To what do these regulations apply?

(a) This subpart applies to all research involving children as subjects, conducted or supported by the

Department of Health and Human Services.

(1) This includes research conducted by Department employees, except that each head of an

Operating Division of the Department may

adopt such nonsubstantive, procedural modifications as may be appropriate from an 

administrative standpoint.

(2) It also includes research conducted or supported

by the Department of Health and Human

Services outside the United States, but in appropriate circumstances, the Secretary may, under

paragraph (i) of §46.101 of Subpart A, waive the

applicability of some or all of the requirements

of these regulations for research of this type.

(b) Exemptions at §46.101(b)(1) and (b)(3) through

(b)(6) are applicable to this subpart. The exemption

at §46.101(b)(2) regarding educational tests is also

applicable to this subpart. However, the exemption

at §46.101(b)(2) for research involving survey or

interview procedures or observations of public

behavior does not apply to research covered by this

subpart, except for research involving observation 

of public behavior when the investigator(s) do not

participate in the activities being observed.

(c) The exceptions, additions, and provisions for waiver

as they appear in paragraphs (c) through (i) of

§46.101 of Subpart A are applicable to this subpart.

§46.402 Definitions.

The definitions in §46.102 of Subpart A shall be 

applicable to this subpart as well. In addition, as used

in this subpart:

(a) “Children” are persons who have not attained

the legal age for consent to treatments or 

procedures involved in the research, under the

applicable law of the jurisdiction in which the

research will be conducted.

(b) “Assent” means a child’s affirmative agreement to

participate in research. Mere failure to object

should not, absent affirmative agreement, be

construed as assent.

(c) “Permission” means the agreement of parent(s)

or guardian to the participation of their child or

ward in research.

(d) “Parent” means a child’s biological or adoptive

parent.

(e) “Guardian” means an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.

§46.403 IRB duties.

In addition to other responsibilities assigned to IRBs

under this part, each IRB shall review research covered

by this subpart and approve only research which satisfies the conditions of all applicable sections of this 

subpart.

§46.404 Research not involving greater than

minimal risk.

DHHS will conduct or fund research in which the IRB

finds that no greater than minimal risk to children is

presented, only if the IRB finds that adequate provisions

are made for soliciting the assent of the children and the

permission of their parents or guardians, as set forth in

§46.408.
National Bioethics Advisory Commission

185

§46.405 Research involving greater than minimal risk but presenting the prospect of direct

benefit to the individual subjects.

DHHS will conduct or fund research in which the IRB

finds that more than minimal risk to children is presented by an intervention or procedure that holds out

the prospect of direct benefit for the individual subject,

or by a monitoring procedure that is likely to contribute

to the subject’s well-being, only if the IRB finds that:

(a) the risk is justified by the anticipated benefit to the

subjects;

(b) the relation of the anticipated benefit to the risk is at

least as favorable to the subjects as that presented by

available alternative approaches; and

(c) adequate provisions are made for soliciting the

assent of the children and permission of their 

parents or guardians, as set forth in §46.408.

§46.406 Research involving greater than minimal risk and no prospect of direct benefit to

individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or

condition.

DHHS will conduct or fund research in which the IRB

finds that more than minimal risk to children is presented by an intervention or procedure that does not

hold out the prospect of direct benefit for the individual

subject, or by a monitoring procedure which is not

likely to contribute to the well-being of the subject,

only if the IRB finds that:

(a) the risk represents a minor increase over minimal

risk;

(b) the intervention or procedure presents experiences

to subjects that are reasonably commensurate with

those inherent in their actual or expected medical,

dental, psychological, social, or educational 

situations;

(c) the intervention or procedure is likely to yield 

generalizable knowledge about the subjects’ disorder

or condition which is of vital importance for the

understanding or amelioration of the subjects’

disorder or condition; and

(d) adequate provisions are made for soliciting assent 

of the children and permission of their parents or

guardians, as set forth in §46.408.

§46.407 Research not otherwise approvable

which presents an opportunity to understand,

prevent, or alleviate a serious problem affecting the health or welfare of children.

DHHS will conduct or fund research that the IRB does

not believe meets the requirements of §46.404,

§46.405, or §46.406 only if:

(a) the IRB finds that the research presents a reasonable

opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the

health or welfare of children; and

(b) the Secretary, after consultation with a panel of

experts in pertinent disciplines (for example: 

science, medicine, education, ethics, law) and 

following opportunity for public review and 

comment, has determined either:

(1) that the research in fact satisfies the conditions

of §46.404, §46.405, or §46.406, as applicable,

or (2) the following:

(i) the research presents a reasonable opportunity 

to further the understanding, prevention, or 

alleviation of a serious problem affecting the

health or welfare of children;

(ii) the research will be conducted in accordance

with sound ethical principles;

(iii)adequate provisions are made for soliciting the

assent of children and the permission of their

parents or guardians, as set forth in §46.408.

§46.408 Requirements for permission by parents or guardians and for assent by children.

(a) In addition to the determinations required under

other applicable sections of this subpart, the IRB

shall determine that adequate provisions are made

for soliciting the assent of the children, when in the

judgment of the IRB the children are capable of providing assent. In determining whether children are

capable of assenting, the IRB shall take into account

the ages, maturity, and psychological state of the

children involved. This judgment may be made for

all children to be involved in research under a particular protocol, or for each child, as the IRB deems

appropriate. If the IRB determines that the capability

of some or all of the children is so limited that they

cannot reasonably be consulted or that the intervention or procedure involved in the research
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Appendix E: Code of Federal Regulations, Title 45 Part 46

holds out a prospect of direct benefit that is important to the health or well-being of the children and

is available only in the context of the research, the

assent of the children is not a necessary condition

for proceeding with the research. Even where the

IRB determines that the subjects are capable of

assenting, the IRB may still waive the assent requirement under circumstances in which consent may be

waived in accord with §46.116 of Subpart A.

(b) In addition to the determinations required under

other applicable sections of this subpart, the IRB

shall determine, in accordance with and to the

extent that consent is required by §46.116 of

Subpart A, that adequate provisions are made for

soliciting the permission of each child’s parents or

guardian. Where parental permission is to be

obtained, the IRB may find that the permission of

one parent is sufficient for research to be conducted

under §46.404 or §46.405. Where research is covered by §46.406 and §46.407 and permission is to

be obtained from parents, both parents must give

their permission unless one parent is deceased,

unknown, incompetent, or not reasonably available,

or when only one parent has legal responsibility for

the care and custody of the child.

(c) In addition to the provisions for waiver contained in

§46.116 of Subpart A, if the IRB determines that a

research protocol is designed for conditions or for a

subject population for which parental or guardian

permission is not a reasonable requirement to protect the subjects (for example, neglected or abused

children), it may waive the consent requirements in

Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects

in the research is substituted, and provided further

that the waiver is not inconsistent with Federal,

State, or local law. The choice of anappropriate

mechanism would depend upon the nature and purpose of the activities described in the protocol, the

risk and anticipated benefit to the research subjects,

and their age, maturity, status, and condition.

(d) Permission by parents or guardians shall be documented in accordance with and to the extent

required by §46.117 of Subpart A.

(e) When the IRB determines that assent is required, it

shall also determine whether and how assent must

be documented.

§46.409 Wards.

(a) Children who are wards of the State or any other

agency, institution, or entity can be included in

research approved under §46.406 or §46.407 only if

such research is:

(1) related to their status as wards; or

(2) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of

children involved as subjects are not wards.

(b) If the research is approved under paragraph (a) of

this section, the IRB shall require appointment of an

advocate for each child who is a ward, in addition to

any other individual acting on behalf of the child as

guardian or in loco parentis. One individual may

serve as advocate for more than one child. The

advocate shall be an individual who has the background and experience to act in, and agrees to act

in, the best interests of the child for the duration of

the child’s participation in the research and who is

not associated in any way (except in the role as

advocate or member of the IRB) with the research,

the investigator(s), or the guardian organization.
Code of Federal Regulations,

Title 21 Parts 50 and 56

Appendix F

Part 50: Protection of Human Subjects

Subpart A: General Provisions

Source: 45 FR 36390, May 30, 1980, unless otherwise

noted.

§50.1 Scope.

(a) This part applies to all clinical investigations regulated

by the Food and Drug Administration under sections 505(i) and 520(g) of the Federal Food, Drug,

and Cosmetic Act, as well as clinical investigations

that support applications for research or marketing

permits for products regulated by the Food and

Drug Administration, including food and color 

additives, drugs for human use, medical devices for

human use, biological products for human use, and

electronic products. Additional specific obligations

and commitments of, and standards of conduct for,

persons who sponsor or monitor clinical investigations involving particular test articles may also be

found in other parts (e.g., parts 312 and 812).

Compliance with these parts is intended to protect

the rights and safety of subjects involved in investigations filed with the Food and Drug Administration

pursuant to sections 406, 409, 502, 503, 505, 510,

513–516, 518–520, 721, and 801 of the Federal

Food, Drug, and Cosmetic Act and sections 351 

and 354–360F of the Public Health Service Act.

(b) References in this part to regulatory sections of 

the Code of Federal Regulations are to chapter I of

title 21, unless otherwise noted.

§50.3 Definitions.

As used in this part:

(a) Act means the Federal Food, Drug, and Cosmetic

Act, as amended (secs. 201–902, 52 Stat. 1040 

et seq. as amended (21 U.S.C. 321–392)).

(b) Application for research or marketing permit includes:

(1) A color additive petition, described in part 71.

(2) A food additive petition, described in parts 171

and 571.

(3) Data and information about a substance submitted as part of the procedures for establishing that

the substance is generally recognized as safe for

use that results or may reasonably be expected

to result, directly or indirectly, in its becoming a

component or otherwise affecting the characteristics of any food, described in §170.30 and

§570.30.

(4) Data and information about a food additive submitted as part of the procedures for food additives

permitted to be used on an interim basis pending

additional study, described in §180.1.

(5) Data and information about a substance submitted as part of the procedures for establishing

a tolerance for unavoidable contaminants in 

food and food-packaging materials, described 

in section 406 of the act.

(6) An investigational new drug application,

described in part 312 of this chapter.

(7) A new drug application, described in part 314.

(8) Data and information about the bioavailability or

bioequivalence of drugs for human use submitted as part of the procedures for issuing, amending, or repealing a bioequivalence requirement,

described in part 320.

(9) Data and information about an over-the-counter

drug for human use submitted as part of the

procedures for classifying these drugs as generally

recognized as safe and effective and not misbranded, described in part 330.

187
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

(10) Data and information about a prescription 

drug for human use submitted as part of the

procedures for classifying these drugs as 

generally recognized as safe and effective and

not misbranded, described in this chapter.

(11) Data and information about an antibiotic drug

submitted as part of the procedures for issuing,

amending, or repealing regulations for these

drugs, described in §314.300 of this chapter.

(12) An application for a biologics license, described

in part 601 of this chapter.

(13) Data and information about a biological product

submitted as part of the procedures for determining that licensed biological products are

safe and effective and not misbranded,

described in part 601.

(14) Data and information about an in vitro 

diagnostic product submitted as part of the

procedures for establishing, amending, or

repealing a standard for these products,

described in part 809.

(15) An Application for an Investigational Device

Exemption, described in part 812.

(16) Data and information about a medical device

submitted as part of the procedures for classifying these devices, described in section 513.

(17) Data and information about a medical device

submitted as part of the procedures for establishing, amending, or repealing a standard for

these devices, described in section 514.

(18) An application for premarket approval of a

medical device, described in section 515.

(19) A product development protocol for a medical

device, described in section 515.

(20) Data and information about an electronic product

submitted as part of the procedures for establishing, amending, or repealing a standard for

these products, described in section 358 of the

Public Health Service Act.

(21) Data and information about an electronic 

product submitted as part of the procedures 

for obtaining a variance from any electronic

product performance standard, as described in

§1010.4.

(22) Data and information about an electronic 

product submitted as part of the procedures 

for granting, amending, or extending an

exemption from a radiation safety performance

standard, as described in §1010.5.

(c) Clinical investigation means any experiment that

involves a test article and one or more human 

subjects and that either is subject to requirements

for prior submission to the Food and Drug

Administration under section 505(i) or 520(g) of 

the act, or is not subject to requirements for prior

submission to the Food and Drug Administration

under these sections of the act, but the results of

which are intended to be submitted later to, or held

for inspection by, the Food and Drug Administration

as part of an application for a research or marketing

permit. The term does not include experiments 

that are subject to the provisions of part 58 of this

chapter, regarding nonclinical laboratory studies.

(d) Investigator means an individual who actually 

conducts a clinical investigation, i.e., under whose

immediate direction the test article is administered

or dispensed to, or used involving, a subject, or, in

the event of an investigation conducted by a team of

individuals, is the responsible leader of that team.

(e) Sponsor means a person who initiates a clinical

investigation, but who does not actually conduct the

investigation, i.e., the test article is administered or

dispensed to or used involving, a subject under the

immediate direction of another individual. A person

other than an individual (e.g., corporation or

agency) that uses one or more of its own employees

to conduct a clinical investigation it has initiated 

is considered to be a sponsor (not a sponsorinvestigator), and the employees are considered 

to be investigators.

(f) Sponsor-investigator means an individual who both

initiates and actually conducts, alone or with others,

a clinical investigation, i.e., under whose immediate

direction the test article is administered or dispensed

to, or used involving, a subject. The term does not

include any person other than an individual, e.g.,

corporation or agency.

(g) Human subject means an individual who is or

becomes a participant in research, either as a 

recipient of the test article or as a control. A subject

may be either a healthy human or a patient.
National Bioethics Advisory Commission

189

(h) Institution means any public or private entity or

agency (including Federal, State, and other agencies). The word facility as used in section 520(g) of

the act is deemed to be synonymous with the term

institution for purposes of this part.

(i) Institutional review board (IRB) means any board,

committee, or other group formally designated by an

institution to review biomedical research involving

humans as subjects, to approve the initiation of and

conduct periodic review of such research. The term

has the same meaning as the phrase institutional

review committee as used in section 520(g) of the act.

(j) Test article means any drug (including a biological

product for human use), medical device for human

use, human food additive, color additive, electronic

product, or any other article subject to regulation

under the act or under sections 351 and 354-360F

of the Public Health Service Act (42 U.S.C. 262 and

263b–263n).

(k) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater in and of themselves than

those ordinarily encountered in daily life or during

the performance of routine physical or psychological

examinations or tests.

(l) Legally authorized representative means an individual

or judicial or other body authorized under applicable law to consent on behalf of a prospective subject

to the subject’s particpation in the procedure(s)

involved in the research.

(m)Family member means any one of the following

legally competent persons: Spouse; parents; children

(including adopted children); brothers, sisters, and

spouses of brothers and sisters; and any individual

related by blood or affinity whose close association

with the subject is the equivalent of a family 

relationship.

Subpart B: Informed Consent of Human

Subjects

Source: 46 FR 8951, Jan. 27, 1981, unless otherwise

noted.

§50.20 General requirements for informed 

consent.

Except as provided in §50.23 and §50.24, no investigator may involve a human being as a subject in research

covered by these regulations unless the investigator has

obtained the legally effective informed consent of the

subject or the subject’s legally authorized representative.

An investigator shall seek such consent only under 

circumstances that provide the prospective subject or

the representative sufficient opportunity to consider

whether or not to participate and that minimize the

possibility of coercion or undue influence. The information that is given to the subject or the representative

shall be in language understandable to the subject or

the representative. No informed consent, whether oral

or written, may include any exculpatory language

through which the subject or the representative is made

to waive or appear to waive any of the subject’s legal

rights, or releases or appears to release the investigator,

the sponsor, the institution, or its agents from liability

for negligence.

§50.23 Exception from general requirements.

(a) The obtaining of informed consent shall be deemed

feasible unless, before use of the test article (except

as provided in paragraph (b) of this section), both

the investigator and a physician who is not otherwise participating in the clinical investigation certify

in writing all of the following:

(1) The human subject is confronted by a lifethreatening situation necessitating the use of the

test article.

(2) Informed consent cannot be obtained from the

subject because of an inability to communicate

with, or obtain legally effective consent from, the

subject.

(3) Time is not sufficient to obtain consent from the

subject’s legal representative.
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

(4) There is available no alternative method of

approved or generally recognized therapy that

provides an equal or greater likelihood of saving

the life of the subject.

(b) If immediate use of the test article is, in the investigator’s opinion, required to preserve the life of the

subject, and time is not sufficient to obtain the independent determination required in paragraph (a) of

this section in advance of using the test article, the

determinations of the clinical investigator shall be

made and, within 5 working days after the use of

the article, be reviewed and evaluated in writing by

a physician who is not participating in the clinical

investigation.

(c) The documentation required in paragraph (a) or (b)

of this section shall be submitted to the IRB within 

5 working days after the use of the test article.

(d)(1) Under 10 U.S.C. 1107(f) the President may

waive the prior consent requirement for the administration of an investigational new drug to a member

of the armed forces in connection with the member’s

participation in a particular military operation. The

statute specifies that only the President may waive

informed consent in this connection and the

President may grant such a waiver only if the

President determines in writing that obtaining consent: Is not feasible; is contrary to the best interests

of the military member; or is not in the interests of

national security. The statute further provides that in

making a determination to waive prior informed

consent on the ground that it is not feasible or the

ground that it is contrary to the best interests of the

military members involved, the President shall apply

the standards and criteria that are set forth in the

relevant FDA regulations for a waiver of the prior

informed consent requirements of section 505(i)(4)

of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 355(i)(4)). Before such a determination may

be made that obtaining informed consent from military personnel prior to the use of an investigational

drug (including an antibiotic or biological product)

in a specific protocol under an investigational new

drug application (IND) sponsored by the Department

of Defense (DOD) and limited to specific military

personnel involved in a particular military operation

is not feasible or is contrary to the best interests of

the military members involved the Secretary of

Defense must first request such a determination

from the President, and certify and document to the

President that the following standards and criteria

contained in paragraphs (d)(1) through (d)(4) of this

section have been met.

(i) The extent and strength of evidence of the

safety and effectiveness of the investigational

new drug in relation to the medical risk that

could be encountered during the military

operation supports the drug’s administration

under an IND.

(ii) The military operation presents a substantial

risk that military personnel may be subject

to a chemical, biological, nuclear, or other

exposure likely to produce death or serious

or life-threatening injury or illness.

(iii)There is no available satisfactory alternative

therapeutic or preventive treatment in relation to the intended use of the investigational

new drug.

(iv)Conditioning use of the investigational new

drug on the voluntary participation of each

member could significantly risk the safety

and health of any individual member who

would decline its use, the safety of other 

military personnel, and the accomplishment

of the military mission.

(v) A duly constituted institutional review board

(IRB) established and operated in accordance

with the requirements of paragraphs (d)(2)

and (d)(3) of this section, responsible for

review of the study, has reviewed and

approved the investigational new drug 

protocol and the administration of the 

investigational new drug without informed

consent. DOD’s request is to include the 

documentation required by §56.115(a)(2) of

this chapter.

(vi)DOD has explained:

(A)The context in which the investigational drug will 

be administered, e.g., the setting or whether it will

be self-administered or it will be administered by a

health professional;

(B) The nature of the disease or condition for which the

preventive or therapeutic treatment is intended; and
National Bioethics Advisory Commission

191

(C)To the extent there are existing data or information

available, information on conditions that could alter

the effects of the investigational drug.

(vii) DOD’s recordkeeping system is capable 

of tracking and will be used to track the

proposed treatment from supplier to the

individual recipient.

(viii)Each member involved in the military 

operation will be given, prior to the 

administration of the investigational new

drug, a specific written information sheet

(including information required by 10

U.S.C. 1107(d)) concerning the investigational new drug, the risks and benefits of

its use, potential side effects, and other 

pertinent information about the appropriate

use of the product.

(ix) Medical records of members involved in the

military operation will accurately document

the receipt by members of the notification

required by paragraph (d)(1)(viii) of this

section.

(x) Medical records of members involved in the

military operation will accurately document

the receipt by members of any investigational new drugs in accordance with FDA

regulations including part 312 of this 

chapter.

(xi) DOD will provide adequate followup to

assess whether there are beneficial or

adverse health consequences that result

from the use of the investigational product.

(xii) DOD is pursuing drug development,

including a time line, and marketing

approval with due diligence.

(xiii)FDA has concluded that the investigational

new drug protocol may proceed subject to

a decision by the President on the informed

consent waiver request.

(xiv) DOD will provide training to the appropriate medical personnel and potential

recipients on the specific investigational

new drug to be administered prior to its use.

(xv) DOD has stated and justified the time 

period for which the waiver is needed, 

not to exceed one year, unless separately

renewed under these standards and criteria.

(xvi) DOD shall have a continuing obligation to

report to the FDA and to the President any

changed circumstances relating to these

standards and criteria (including the time

period referred to in paragraph (d)(1)(xv)

of this section) or that otherwise might

affect the determination to use an investigational new drug without informed consent.

(xvii)DOD is to provide public notice as soon 

as practicable and consistent with classification requirements through notice in the

Federal Register describing each waiver 

of informed consent determination, a 

summary of the most updated scientific

information on the products used, and

other pertinent information.

(xviii)Use of the investigational drug without

informed consent otherwise conforms with

applicable law.

(2) The duly constituted institutional review board,

described in paragraph (d)(1)(v) of this section,

must include at least 3 nonaffiliated members

who shall not be employees or officers of the

Federal Government (other than for purposes 

of membership on the IRB) and shall be required

to obtain any necessary security clearances. This

IRB shall review the proposed IND protocol at 

a convened meeting at which a majority of the

members are present including at least one

member whose primary concerns are in nonscientific areas and, if feasible, including a majority

of the nonaffiliated members. The information

required by §56.115(a)(2) of this chapter is to

be provided to the Secretary of Defense for 

further review.

(3) The duly constituted institutional review board,

described in paragraph (d)(1)(v) of this section,

must review and approve:

(i) The required information sheet;

(ii) The adequacy of the plan to disseminate

information, including distribution of the

information sheet to potential recipients, on

the investigational product (e.g., in forms

other than written);

(iii)The adequacy of the information and 

plans for its dissemination to health care

providers, including potential side effects,
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

contraindications, potential interactions, and

other pertinent considerations; and

(iv)An informed consent form as required by

part 50 of this chapter, in those circumstances in which DOD determines that

informed consent may be obtained from

some or all personnel involved.

(4) DOD is to submit to FDA summaries of 

institutional review board meetings at which 

the proposed protocol has been reviewed.

(5) Nothing in these criteria or standards is intended

to preempt or limit FDA’s and DOD’s authority

or obligations under applicable statutes and 

regulations.

§50.24 Exception from informed consent

requirements for emergency research.

(a) The IRB responsible for the review, approval, and

continuing review of the clinical investigation

described in this section may approve that investigation without requiring that informed consent of 

all research subjects be obtained if the IRB (with 

the concurrence of a licensed physician who is a

member of or consultant to the IRB and who is not

otherwise participating in the clinical investigation)

finds and documents each of the following:

(1) The human subjects are in a life-threatening 

situation, available treatments are unproven 

or unsatisfactory, and the collection of valid 

scientific evidence, which may include evidence

obtained through randomized placebo-controlled

investigations, is necessary to determine the safety

and effectiveness of particular interventions.

(2) Obtaining informed consent is not feasible

because:

(i) The subjects will not be able to give their

informed consent as a result of their medical

condition;

(ii) The intervention under investigation must 

be administered before consent from the

subjects’ legally authorized representatives 

is feasible; and

(iii)There is no reasonable way to identify

prospectively the individuals likely to

become eligible for participation in the 

clinical investigation.

(3) Participation in the research holds out the

prospect of direct benefit to the subjects

because:

(i) Subjects are facing a life-threatening situation

that necessitates intervention;

(ii) Appropriate animal and other preclinical

studies have been conducted, and the 

information derived from those studies and

related evidence support the potential for 

the intervention to provide a direct benefit 

to the individual subjects; and

(iii)Risks associated with the investigation are

reasonable in relation to what is known

about the medical condition of the potential

class of subjects, the risks and benefits of

standard therapy, if any, and what is known

about the risks and benefits of the proposed

intervention or activity.

(4) The clinical investigation could not practicably

be carried out without the waiver.

(5) The proposed investigational plan defines the

length of the potential therapeutic window based

on scientific evidence, and the investigator has

committed to attempting to contact a legally

authorized representative for each subject within

that window of time and, if feasible, to asking

the legally authorized representative contacted

for consent within that window rather than 

proceeding without consent. The investigator

will summarize efforts made to contact legally

authorized representatives and make this 

information available to the IRB at the time of

continuing review.

(6) The IRB has reviewed and approved informed

consent procedures and an informed consent

document consistent with §50.25. These procedures and the informed consent document are to

be used with subjects or their legally authorized

representatives in situations where use of such

procedures and documents is feasible. The IRB

has reviewed and approved procedures and

information to be used when providing an

opportunity for a family member to object to a

subject’s participation in the clinical investigation

consistent with paragraph (a)(7)(v) of this 

section.
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193

(7) Additional protections of the rights and welfare

of the subjects will be provided, including, at

least:

(i) Consultation (including, where appropriate,

consultation carried out by the IRB) with

representatives of the communities in which

the clinical investigation will be conducted

and from which the subjects will be drawn;

(ii) Public disclosure to the communities in

which the clinical investigation will be 

conducted and from which the subjects will

be drawn, prior to initiation of the clinical

investigation, of plans for the investigation

and its risks and expected benefits;

(iii)Public disclosure of sufficient information

following completion of the clinical investigation to apprise the community and

researchers of the study, including the 

demographic characteristics of the research

population, and its results;

(iv)Establishment of an independent data 

monitoring committee to exercise oversight

of the clinical investigation; and

(v) If obtaining informed consent is not feasible

and a legally authorized representative is not

reasonably available, the investigator has

committed, if feasible, to attempting to 

contact within the therapeutic window the

subject’s family member who is not a legally

authorized representative, and asking

whether he or she objects to the subject’s

participation in the clinical investigation. 

The investigator will summarize efforts made

to contact family members and make this

information available to the IRB at the time

of continuing review.

(b) The IRB is responsible for ensuring that procedures

are in place to inform, at the earliest feasible 

opportunity, each subject, or if the subject remains

incapacitated, a legally authorized representative 

of the subject, or if such a representative is not reasonably available, a family member, of the subject’s

inclusion in the clinical investigation, the details of

the investigation and other information contained 

in the informed consent document. The IRB shall

also ensure that there is a procedure to inform the

subject, or if the subject remains incapacitated, a

legally authorized representative of the subject, or if

such a representative is not reasonably available, a

family member, that he or she may discontinue the

subject’s participation at any time without penalty 

or loss of benefits to which the subject is otherwise

entitled. If a legally authorized representative or

family member is told about the clinical investigation and the subject’s condition improves, the subject is also to be informed as soon as feasible. If a

subject is entered into a clinical investigation with

waived consent and the subject dies before a legally

authorized representative or family member can be

contacted, information about the clinical investigation is to be provided to the subject’s legally authorized representative or family member, if feasible.

(c) The IRB determinations required by paragraph (a) 

of this section and the documentation required by

paragraph (e) of this section are to be retained by

the IRB for at least 3 years after completion of the

clinical investigation, and the records shall be 

accessible for inspection and copying by FDA in

accordance with §56.115(b) of this chapter.

(d) Protocols involving an exception to the informed

consent requirement under this section must be performed under a separate investigational new drug

application (IND) or investigational device exemption (IDE) that clearly identifies such protocols as

protocols that may include subjects who are unable

to consent. The submission of those protocols in a

separate IND/IDE is required even if an IND for the

same drug product or an IDE for the same device

already exists. Applications for investigations under

this section may not be submitted as amendments

under §312.30 or §812.35 of this chapter.

(e) If an IRB determines that it cannot approve a 

clinical investigation because the investigation does

not meet the criteria in the exception provided

under paragraph (a) of this section or because of

other relevant ethical concerns, the IRB must 

document its findings and provide these findings

promptly in writing to the clinical investigator and

to the sponsor of the clinical investigation. The

sponsor of the clinical investigation must promptly

disclose this information to FDA and to the sponsor’s clinical investigators who are participating or

are asked to participate in this or a substantially
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

equivalent clinical investigation of the sponsor, and

to other IRB’s that have been, or are, asked to review

this or a substantially equivalent investigation by

that sponsor.

§50.25 Elements of informed consent.

(a) Basic elements of informed consent. In seeking informed

consent, the following information shall be provided

to each subject:

(1) A statement that the study involves research, 

an explanation of the purposes of the research

and the expected duration of the subject’s 

participation, a description of the procedures 

to be followed, and identification of any 

procedures which are experimental.

(2) A description of any reasonably foreseeable risks

or discomforts to the subject.

(3) A description of any benefits to the subject or to

others which may reasonably be expected from

the research.

(4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might

be advantageous to the subject.

(5) A statement describing the extent, if any, to

which confidentiality of records identifying the

subject will be maintained and that notes the

possibility that the Food and Drug

Administration may inspect the records.

(6) For research involving more than minimal risk,

an explanation as to whether any compensation

and an explanation as to whether any medical

treatments are available if injury occurs and, 

if so, what they consist of, or where further

information may be obtained.

(7) An explanation of whom to contact for answers

to pertinent questions about the research and

research subjects’ rights, and whom to contact 

in the event of a research-related injury to the

subject.

(8) A statement that participation is voluntary, that

refusal to participate will involve no penalty or

loss of benefits to which the subject is otherwise

entitled, and that the subject may discontinue

participation at any time without penalty or loss

of benefits to which the subject is otherwise

entitled.

(b) Additional elements of informed consent. When 

appropriate, one or more of the following elements

of information shall also be provided to each 

subject:

(1) A statement that the particular treatment or procedure may involve risks to the subject (or to the

embryo or fetus, if the subject is or may become

pregnant) which are currently unforeseeable.

(2) Anticipated circumstances under which the 

subject’s participation may be terminated by the

investigator without regard to the subject’s 

consent.

(3) Any additional costs to the subject that may

result from participation in the research.

(4) The consequences of a subject’s decision to 

withdraw from the research and procedures 

for orderly termination of participation by the

subject.

(5) A statement that significant new findings developed during the course of the research which

may relate to the subject’s willingness to continue participation will be provided to the subject.

(6) The approximate number of subjects involved in

the study.

(c) The informed consent requirements in these regulations are not intended to preempt any applicable

Federal, State, or local laws which require additional

information to be disclosed for informed consent to

be legally effective.

(d) Nothing in these regulations is intended to limit the

authority of a physician to provide emergency medical care to the extent the physician is permitted to

do so under applicable Federal, State, or local law.

§50.27 Documentation of informed consent.

(a) Except as provided in §56.109(c), informed consent

shall be documented by the use of a written consent

form approved by the IRB and signed and dated 

by the subject or the subject’s legally authorized 

representative at the time of consent. A copy shall 

be given to the person signing the form.

(b) Except as provided in §56.109(c), the consent form

may be either of the following:
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195

(1) A written consent document that embodies 

the elements of informed consent required by

§50.25. This form may be read to the subject 

or the subject’s legally authorized representative,

but, in any event, the investigator shall give

either the subject or the representative adequate

opportunity to read it before it is signed.

(2) A short form written consent document stating

that the elements of informed consent required

by §50.25 have been presented orally to the 

subject or the subject’s legally authorized representative. When this method is used, there shall

be a witness to the oral presentation. Also, the

IRB shall approve a written summary of what is

to be said to the subject or the representative.

Only the short form itself is to be signed by 

the subject or the representative. However, the

witness shall sign both the short form and a

copy of the summary, and the person actually

obtaining the consent shall sign a copy of the

summary. A copy of the summary shall be given

to the subject or the representative in addition 

to a copy of the short form.

Part 56: Institutional Review Boards

Subpart A: General Provisions

§56.101 Scope.

(a) This part contains the general standards for the 

composition, operation, and responsibility of an

Institutional Review Board (IRB) that reviews clinical

investigations regulated by the Food and Drug

Administration under section 505(i) and 520(g) 

of the act, as well as clinical investigations that 

support applications for research or marketing 

permits for products regulated by the Food and

Drug Administration, including food and color 

additives, drugs for human use, medical devices 

for human use, biological products for human use,

and electronic products. Compliance with this part

is intended to protect the rights and welfare of

human subjects involved in such investigations.

(b) References in this part to regulatory sections of the

Code of Federal Regulations are to chapter I of title

21, unless otherwise noted.

§56.102 Definitions.

As used in this part:

(a) Act means the Federal Food, Drug, and Cosmetic

Act, as amended (secs. 201-902, 52 Stat. 1040 

et seq., as amended (21 U.S.C. 321-392)).

(b) Application for research or marketing permit includes:

(1) A color additive petition, described in part 71.

(2) Data and information regarding a substance submitted as part of the procedures for establishing

that a substance is generally recognized as safe

for a use which results or may reasonably be

expected to result, directly or indirectly, in its

becoming a component or otherwise affecting

the characteristics of any food, described in

§170.35.

(3) A food additive petition, described in part 171.

(4) Data and information regarding a food additive

submitted as part of the procedures regarding

food additives permitted to be used on an 

interim basis pending additional study, described

in §180.1.

(5) Data and information regarding a substance submitted as part of the procedures for establishing

a tolerance for unavoidable contaminants in food

and food-packaging materials, described in 

section 406 of the act.

(6) An investigational new drug application,

described in part 312 of this chapter.

(7) A new drug application, described in part 314.

(8) Data and information regarding the bioavailability

or bioequivalence of drugs for human use 

submitted as part of the procedures for issuing,

amending, or repealing a bioequivalence 

requirement, described in part 320.

(9) Data and information regarding an over-thecounter drug for human use submitted as part 

of the procedures for classifying such drugs as

generally recognized as safe and effective and 

not misbranded, described in part 330.

(10)An application for a biological product license,

described in part 601.

(11)An application for a biologics license, described

in part 601 of this chapter.
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

(12) An Application for an Investigational Device

Exemption, described in parts 812 and 813.

(13) Data and information regarding a medical

device for human use submitted as part of the

procedures for classifying such devices,

described in part 860.

(14) Data and information regarding a medical

device for human use submitted as part of the

procedures for establishing, amending, or

repealing a standard for such device, described

in part 861.

(15) An application for premarket approval of a

medical device for human use, described in 

section 515 of the act.

(16) A product development protocol for a medical

device for human use, described in section 515

of the act.

(17) Data and information regarding an electronic

product submitted as part of the procedures for

establishing, amending, or repealing a standard

for such products, described in section 358 of

the Public Health Service Act.

(18) Data and information regarding an electronic

product submitted as part of the procedures 

for obtaining a variance from any electronic

product performance standard, as described 

in §1010.4.

(19) Data and information regarding an electronic

product submitted as part of the procedures for

granting, amending, or extending an exemption

from a radiation safety performance standard,

as described in §1010.5.

(20) Data and information regarding an electronic

product submitted as part of the procedures for

obtaining an exemption from notification of a

radiation safety defect or failure of compliance

with a radiation safety performance standard,

described in subpart D of part 1003.

(c) Clinical investigation means any experiment that

involves a test article and one or more human 

subjects, and that either must meet the requirements

for prior submission to the Food and Drug

Administration under section 505(i) or 520(g) of 

the act, or need not meet the requirements for prior

submission to the Food and Drug Administration

under these sections of the act, but the results of

which are intended to be later submitted to, or held

for inspection by, the Food and Drug Administration

as part of an application for a research or marketing

permit. The term does not include experiments that

must meet the provisions of part 58, regarding 

nonclinical laboratory studies. The terms research,

clinical research, clinical study, study, and clinical 

investigation are deemed to be synonymous for 

purposes of this part.

(d) Emergency use means the use of a test article on a

human subject in a life-threatening situation in

which no standard acceptable treatment is available,

and in which there is not sufficient time to obtain

IRB approval.

(e) Human subject means an individual who is or

becomes a participant in research, either as a 

recipient of the test article or as a control. A subject

may be either a healthy individual or a patient.

(f) Institution means any public or private entity 

or agency (including Federal, State, and other 

agencies). The term facility as used in section 520(g)

of the act is deemed to be synonymous with the

term institution for purposes of this part.

(g) Institutional Review Board (IRB) means any board,

committee, or other group formally designated by 

an institution to review, to approve the initiation of,

and to conduct periodic review of, biomedical

research involving human subjects. The primary

purpose of such review is to assure the protection of

the rights and welfare of the human subjects. The

term has the same meaning as the phrase institutional

review committee as used in section 520(g) of the act.

(h) Investigator means an individual who actually 

conducts a clinical investigation (i.e., under whose

immediate direction the test article is administered

or dispensed to, or used involving, a subject) or, in

the event of an investigation conducted by a team 

of individuals, is the responsible leader of that team.

(i) Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater in and of themselves than

those ordinarily encountered in daily life or during

the performance of routine physical or psychological

examinations or tests.
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197

(j) Sponsor means a person or other entity that initiates

a clinical investigation, but that does not actually

conduct the investigation, i.e., the test article is

administered or dispensed to, or used involving, a

subject under the immediate direction of another

individual. A person other than an individual (e.g., a

corporation or agency) that uses one or more of its

own employees to conduct an investigation that it

has initiated is considered to be a sponsor (not a

sponsor-investigator), and the employees are 

considered to be investigators.

(k) Sponsor-investigator means an individual who both

initiates and actually conducts, alone or with others,

a clinical investigation, i.e., under whose immediate

direction the test article is administered or dispensed

to, or used involving, a subject. The term does 

not include any person other than an individual,

e.g., it does not include a corporation or agency. 

The obligations of a sponsor-investigator under this

part include both those of a sponsor and those of 

an investigator.

(l) Test article means any drug for human use, 

biological product for human use, medical device for

human use, human food additive, color additive,

electronic product, or any other article subject to

regulation under the act or under sections 351 or

354–360F of the Public Health Service Act.

(m)IRB approval means the determination of the IRB

that the clinical investigation has been reviewed 

and may be conducted at an institution within 

the constraints set forth by the IRB and by other

institutional and Federal requirements.

§56.103 Circumstances in which IRB review 

is required.

(a) Except as provided in §56.104 and §56.105, any

clinical investigation which must meet the requirements for prior submission (as required in parts

312, 812, and 813) to the Food and Drug

Administration shall not be initiated unless that

investigation has been reviewed and approved by,

and remains subject to continuing review by, an 

IRB meeting the requirements of this part.

(b) Except as provided in §56.104 and §56.105, the

Food and Drug Administration may decide not to

consider in support of an application for a research

or marketing permit any data or information that

has been derived from a clinical investigation that

has not been approved by, and that was not subject

to initial and continuing review by, an IRB meeting

the requirements of this part. The determination that

a clinical investigation may not be considered in

support of an application for a research or marketing

permit does not, however, relieve the applicant for

such a permit of any obligation under any other

applicable regulations to submit the results of the

investigation to the Food and Drug Administration.

(c) Compliance with these regulations will in no way

render inapplicable pertinent Federal, State, or local

laws or regulations.

§56.104 Exemptions from IRB requirement.

The following categories of clinical investigations are

exempt from the requirements of this part for IRB

review:

(a) Any investigation which commenced before July 27,

1981 and was subject to requirements for IRB

review under FDA regulations before that date, 

provided that the investigation remains subject to

review of an IRB which meets the FDA requirements

in effect before July 27, 1981.

(b) Any investigation commenced before July 27, 1981

and was not otherwise subject to requirements for

IRB review under Food and Drug Administration

regulations before that date.

(c) Emergency use of a test article, provided that such

emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at

the institution is subject to IRB review.

(d) Taste and food quality evaluations and consumer

acceptance studies, if wholesome foods without

additives are consumed or if a food is consumed

that contains a food ingredient at or below the 

level and for a use found to be safe, or agricultural,

chemical, or environmental contaminant at or 

below the level found to be safe, by the Food 

and Drug Administration or approved by the

Environmental Protection Agency or the Food 

Safety and Inspection Service of the U.S.

Department of Agriculture.
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

§56.105 Waiver of IRB requirement.

On the application of a sponsor or sponsor-investigator,

the Food and Drug Administration may waive any of

the requirements contained in these regulations, including the requirements for IRB review, for specific research

activities or for classes of research activities, otherwise

covered by these regulations.

Subpart B: Organization and Personnel

§56.107 IRB membership.

(a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate

review of research activities commonly conducted by

the institution. The IRB shall be sufficiently qualified

through the experience and expertise of its members,

and the diversity of the members, including consideration of race, gender, cultural backgrounds, and

sensitivity to such issues as community attitudes, 

to promote respect for its advice and counsel in 

safeguarding the rights and welfare of human 

subjects. In addition to possessing the professional

competence necessary to review the specific research

activities, the IRB shall be able to ascertain the

acceptability of proposed research in terms of institutional commitments and regulations, applicable

law, and standards or professional conduct and 

practice. The IRB shall therefore include persons

knowledgeable in these areas. If an IRB regularly

reviews research that involves a vulnerable category

of subjects, such as children, prisoners, pregnant

women, or handicapped or mentally disabled 

persons, consideration shall be given to the 

inclusion of one or more individuals who are 

knowledgeable about and experienced in working

with those subjects.

(b) Every nondiscriminatory effort will be made to

ensure that no IRB consists entirely of men or 

entirely of women, including the institution’s consideration of qualified persons of both sexes, so long 

as no selection is made to the IRB on the basis of

gender. No IRB may consist entirely of members of

one profession.

(c) Each IRB shall include at least one member whose

primary concerns are in the scientific area and at

least one member whose primary concerns are in

nonscientific areas.

(d) Each IRB shall include at least one member who is

not otherwise affiliated with the institution and who

is not part of the immediate family of a person who

is affiliated with the institution.

(e) No IRB may have a member participate in the IRB’s

initial or continuing review of any project in which

the member has a conflicting interest, except to 

provide information requested by the IRB.

(f) An IRB may, in its discretion, invite individuals 

with competence in special areas to assist in the

review of complex issues which require expertise

beyond or in addition to that available on the IRB.

These individuals may not vote with the IRB.

Subpart C: IRB Functions and

Operations

§56.108 IRB functions and operations.

In order to fulfill the requirements of these regulations,

each IRB shall:

(a) Follow written procedures: (1) For conducting its

initial and continuing review of research and for

reporting its findings and actions to the investigator

and the institution; (2) for determining which 

projects require review more often than annually

and which projects need verification from sources

other than the investigator that no material changes

have occurred since previous IRB review; (3) for

ensuring prompt reporting to the IRB of changes in

research activity; and (4) for ensuring that changes

in approved research, during the period for which

IRB approval has already been given, may not be 

initiated without IRB review and approval except

where necessary to eliminate apparent immediate

hazards to the human subjects.

(b) Follow written procedures for ensuring prompt

reporting to the IRB, appropriate institutional officials,

and the Food and Drug Administration of: (1) Any

unanticipated problems involving risks to human

subjects or others; (2) any instance of serious or

continuing noncompliance with these regulations or

the requirements or determinations of the IRB; or

(3) any suspension or termination of IRB approval.
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(c) Except when an expedited review procedure is used

(see §56.110), review proposed research at convened

meetings at which a majority of the members of the

IRB are present, including at least one member

whose primary concerns are in nonscientific areas.

In order for the research to be approved, it shall

receive the approval of a majority of those members

present at the meeting.

(Information collection requirements in this section

were approved by the Office of Management and

Budget (OMB) and assigned OMB control number

0910-0130)

§56.109 IRB review of research.

(a) An IRB shall review and have authority to approve,

require modifications in (to secure approval), or 

disapprove all research activities covered by these

regulations.

(b) An IRB shall require that information given to subjects as part of informed consent is in accordance

with §50.25. The IRB may require that information,

in addition to that specifically mentioned in §50.25,

be given to the subjects when in the IRB’s judgment

the information would meaningfully add to the 

protection of the rights and welfare of subjects.

(c) An IRB shall require documentation of informed

consent in accordance with §50.27 of this chapter,

except as follows:

(1) The IRB may, for some or all subjects, waive the

requirement that the subject, or the subject’s

legally authorized representative, sign a written

consent form if it finds that the research presents

no more than minimal risk of harm to subjects

and involves no procedures for which written

consent is normally required outside the

research context; or

(2) The IRB may, for some or all subjects, find that

the requirements in §50.24 of this chapter for an

exception from informed consent for emergency

research are met.

(d) In cases where the documentation requirement is

waived under paragraph (c)(1) of this section, the

IRB may require the investigator to provide subjects

with a written statement regarding the research.

(e) An IRB shall notify investigators and the institution

in writing of its decision to approve or disapprove

the proposed research activity, or of modifications

required to secure IRB approval of the research

activity. If the IRB decides to disapprove a research

activity, it shall include in its written notification a

statement of the reasons for its decision and give the

investigator an opportunity to respond in person or

in writing. For investigations involving an exception

to informed consent under §50.24 of this chapter,

an IRB shall promptly notify in writing the investigator and the sponsor of the research when an IRB

determines that it cannot approve the research

because it does not meet the criteria in the exception

provided under §50.24(a) of this chapter or because

of other relevant ethical concerns. The written notification shall include a statement of the reasons for

the IRB’s determination.

(f) An IRB shall conduct continuing review of research

covered by these regulations at intervals appropriate

to the degree of risk, but not less than once per year,

and shall have authority to observe or have a third

party observe the consent process and the research.

(g) An IRB shall provide in writing to the sponsor of

research involving an exception to informed consent

under §50.24 of this chapter a copy of information

that has been publicly disclosed under §50.24(a)(7)(ii)

and (a)(7)(iii) of this chapter. The IRB shall provide

this information to the sponsor promptly so that 

the sponsor is aware that such disclosure has

occurred. Upon receipt, the sponsor shall provide

copies of the information disclosed to FDA.

§56.110 Expedited review procedures for 

certain kinds of research involving no more

than minimal risk, and for minor changes in

approved research.

(a) The Food and Drug Administration has established,

and published in the Federal Register, a list of 

categories of research that may be reviewed by the

IRB through an expedited review procedure. The list 

will be amended, as appropriate, through periodic

republication in the Federal Register.
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Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

(b) An IRB may use the expedited review procedure to

review either or both of the following: (1) Some or

all of the research appearing on the list and found

by the reviewer(s) to involve no more than minimal

risk, (2) minor changes in previously approved

research during the period (of 1 year or less) for

which approval is authorized. Under an expedited

review procedure, the review may be carried out by

the IRB chairperson or by one or more experienced

reviewers designated by the IRB chairperson from

among the members of the IRB. In reviewing the

research, the reviewers may exercise all of the

authorities of the IRB except that the reviewers may

not disapprove the research. A research activity may

be disapproved only after review in accordance with

the nonexpedited review procedure set forth in

§56.108(c).

(c) Each IRB which uses an expedited review procedure

shall adopt a method for keeping all members

advised of research proposals which have been

approved under the procedure.

(d) The Food and Drug Administration may restrict,

suspend, or terminate an institution’s or IRB’s use 

of the expedited review procedure when necessary

to protect the rights or welfare of subjects.

§56.111 Criteria for IRB approval of research.

(a) In order to approve research covered by these 

regulations the IRB shall determine that all of the

following requirements are satisfied:

(1) Risks to subjects are minimized: (i) By using

procedures which are consistent with sound

research design and which do not unnecessarily

expose subjects to risk, and (ii) whenever 

appropriate, by using procedures already being

performed on the subjects for diagnostic or

treatment purposes.

(2) Risks to subjects are reasonable in relation to

anticipated benefits, if any, to subjects, and 

the importance of the knowledge that may be

expected to result. In evaluating risks and 

benefits, the IRB should consider only those

risks and benefits that may result from the

research (as distinguished from risks and benefits

of therapies that subjects would receive even if

not participating in the research). The IRB

should not consider possible long-range effects

of applying knowledge gained in the research

(for example, the possible effects of the research

on public policy) as among those research risks

that fall within the purview of its responsibility.

(3) Selection of subjects is equitable. In making 

this assessment the IRB should take into account

the purposes of the research and the setting 

in which the research will be conducted and

should be particularly cognizant of the special

problems of research involving vulnerable 

populations, such as children, prisoners, 

pregnant women, handicapped, or mentally 

disabled persons, or economically or 

educationally disadvantaged persons.

(4) Informed consent will be sought from each

prospective subject or the subject’s legally

authorized representative, in accordance with

and to the extent required by part 50.

(5) Informed consent will be appropriately 

documented, in accordance with and to the

extent required by §50.27.

(6) Where appropriate, the research plan makes 

adequate provision for monitoring the data 

collected to ensure the safety of subjects.

(7) Where appropriate, there are adequate provisions

to protect the privacy of subjects and to maintain

the confidentiality of data.

(b) When some or all of the subjects, such as children,

prisoners, pregnant women, handicapped, or 

mentally disabled persons, or economically or 

educationally disadvantaged persons, are likely 

to be vulnerable to coercion or undue influence

additional safeguards have been included in the

study to protect the rights and welfare of these 

subjects.

§56.112 Review by institution.

Research covered by these regulations that has 

been approved by an IRB may be subject to further

appropriate review and approval or disapproval by 

officials of the institution. However, those officials may

not approve the research if it has not been approved 

by an IRB.
National Bioethics Advisory Commission

201

§56.113 Suspension or termination of IRB

approval of research.

An IRB shall have authority to suspend or terminate

approval of research that is not being conducted in

accordance with the IRB’s requirements or that has been

associated with unexpected serious harm to subjects.

Any suspension or termination of approval shall include

a statement of the reasons for the IRB’s action and shall

be reported promptly to the investigator, appropriate

institutional officials, and the Food and Drug

Administration.

§56.114 Cooperative research.

In complying with these regulations, institutions

involved in multi-institutional studies may use joint

review, reliance upon the review of another qualified

IRB, or similar arrangements aimed at avoidance of

duplication of effort.

Subpart D: Records and Reports

§56.115 IRB records.

(a) An institution, or where appropriate an IRB, shall

prepare and maintain adequate documentation of

IRB activities, including the following:

(1) Copies of all research proposals reviewed, 

scientific evaluations, if any, that accompany the

proposals, approved sample consent documents,

progress reports submitted by investigators, and

reports of injuries to subjects.

(2) Minutes of IRB meetings which shall be in 

sufficient detail to show attendance at the 

meetings; actions taken by the IRB; the vote on

these actions including the number of members 

voting for, against, and abstaining; the basis for

requiring changes in or disapproving research;

and a written summary of the discussion of 

controverted issues and their resolution.

(3) Records of continuing review activities.

(4) Copies of all correspondence between the IRB

and the investigators.

(5) A list of IRB members identified by name;

earned degrees; representative capacity; indications of experience such as board certifications,

licenses, etc., sufficient to describe each member’s

chief anticipated contributions to IRB 

deliberations; and any employment or other

relationship between each member and the 

institution; for example: full-time employee,

part-time employee, a member of governing

panel or board, stockholder, paid or unpaid 

consultant.

(6) Written procedures for the IRB as required by

§56.108 (a) and (b).

(7) Statements of significant new findings provided

to subjects, as required by §50.25.

(b) The records required by this regulation shall be

retained for at least 3 years after completion of the

research, and the records shall be accessible for

inspection and copying by authorized representatives

of the Food and Drug Administration at 

reasonable times and in a reasonable manner.

(c) The Food and Drug Administration may refuse to

consider a clinical investigation in support of an

application for a research or marketing permit if the

institution or the IRB that reviewed the investigation

refuses to allow an inspection under this section.

(Information collection requirements in this section

were approved by the Office of Management and

Budget (OMB) and assigned OMB control number

0910-0130)

Subpart E: Administrative Actions for

Noncompliance

§56.120 Lesser administrative actions.

(a) If apparent noncompliance with these regulations 

in the operation of an IRB is observed by an FDA

investigator during an inspection, the inspector will

present an oral or written summary of observations

to an appropriate representative of the IRB. The

Food and Drug Administration may subsequently

send a letter describing the noncompliance to the

IRB and to the parent institution. The agency will

require that the IRB or the parent institution

respond to this letter within a time period specified

by FDA and describe the corrective actions that 

will be taken by the IRB, the institution, or both to

achieve compliance with these regulations.
202

Appendix F: Code of Federal Regulations, Title 21 Parts 50 and 56

(b) On the basis of the IRB’s or the institution’s

response, FDA may schedule a reinspection to 

confirm the adequacy of corrective actions. In 

addition, until the IRB or the parent institution 

takes appropriate corrective action, the agency may:

(1) Withhold approval of new studies subject to the

requirements of this part that are conducted at

the institution or reviewed by the IRB;

(2) Direct that no new subjects be added to ongoing

studies subject to this part;

(3) Terminate ongoing studies subject to this part

when doing so would not endanger the subjects;

or

(4) When the apparent noncompliance creates a 

significant threat to the rights and welfare of

human subjects, notify relevant State and

Federal regulatory agencies and other parties

with a direct interest in the agency’s action of 

the deficiencies in the operation of the IRB.

(c) The parent institution is presumed to be responsible

for the operation of an IRB, and the Food and Drug

Administration will ordinarily direct any administrative action under this subpart against the institution.

However, depending on the evidence of responsibility

for deficiencies, determined during the investigation,

the Food and Drug Administration may restrict its

administrative actions to the IRB or to a component

of the parent institution determined to be responsible

for formal designation of the IRB.

§56.121 Disqualification of an IRB or an 

institution.

(a) Whenever the IRB or the institution has failed to

take adequate steps to correct the noncompliance

stated in the letter sent by the agency under

§56.120(a), and the Commissioner of Food and

Drugs determines that this noncompliance may 

justify the disqualification of the IRB or of the 

parent institution, the Commissioner will institute

proceedings in accordance with the requirements 

for a regulatory hearing set forth in part 16.

(b) The Commissioner may disqualify an IRB or the parent institution if the Commissioner determines that:

(1) The IRB has refused or repeatedly failed to 

comply with any of the regulations set forth in

this part, and

(2) The noncompliance adversely affects the rights

or welfare of the human subjects in a clinical

investigation.

(c) If the Commissioner determines that disqualification

is appropriate, the Commissioner will issue an order

that explains the basis for the determination and

that prescribes any actions to be taken with regard

to ongoing clinical research conducted under the

review of the IRB. The Food and Drug Administration

will send notice of the disqualification to the IRB

and the parent institution. Other parties with a

direct interest, such as sponsors and clinical 

investigators, may also be sent a notice of the 

disqualification. In addition, the agency may elect 

to publish a notice of its action in the Federal

Register.

(d) The Food and Drug Administration will not approve

an application for a research permit for a clinical

investigation that is to be under the review of a 

disqualified IRB or that is to be conducted at a 

disqualified institution, and it may refuse to consider

in support of a marketing permit the data from 

a clinical investigation that was reviewed by a 

disqualified IRB as conducted at a disqualified 

institution, unless the IRB or the parent institution 

is reinstated as provided in §56.123.

§56.122 Public disclosure of information

regarding revocation.

A determination that the Food and Drug Administration

has disqualified an institution and the administrative

record regarding that determination are disclosable to

the public under part 20.

§56.123 Reinstatement of an IRB or an 

institution.

An IRB or an institution may be reinstated if the

Commissioner determines, upon an evaluation of a

written submission from the IRB or institution that

explains the corrective action that the institution or IRB

plans to take, that the IRB or institution has provided

adequate assurance that it will operate in compliance

with the standards set forth in this part. Notification of

reinstatement shall be provided to all persons notified

under §56.121(c).
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§56.124 Actions alternative or additional to 

disqualification.

Disqualification of an IRB or of an institution is independent of, and neither in lieu of nor a precondition 

to, other proceedings or actions authorized by the act.

The Food and Drug Administration may, at any time,

through the Department of Justice institute any appropriate judicial proceedings (civil or criminal) and any

other appropriate regulatory action, in addition to or 

in lieu of, and before, at the time of, or after, disqualification. The agency may also refer pertinent matters to

another Federal, State, or local government agency for

any action that that agency determines to be appropriate.

Appendix G

Statutory Authority Cited

5 USC 301 Departmental regulations.

The head of an Executive department or military department may prescribe regulations for the government of his

department, the conduct of its employees, the distribution and performance of its business, and the custody, use,

and preservation of its records, papers, and property. This section does not authorize withholding information from

the public or limiting the availability of records to the public.

42 USC 300v-1(b) Duties of Commission.

(b) Recommendations to agencies; subsequent administrative requirements

(1) Within 60 days of the date a Federal agency receives a recommendation from the Commission that the agency

take any action with respect to its rules, policies, guidelines, or regulations, the agency shall publish such recommendation in the Federal Register and shall provide opportunity for interested persons to submit written data, views,

and arguments with respect to adoption of the recommendation.

Department Regulation

Department of Agriculture: 7 CFR 1c Protection of human subjects

Department of Energy: 10 CFR 745 Protection of human subjects

National Aeronautics and Space Administration: 14 CFR 1230 Protection of human subjects

Department of Commerce: 15 CFR 27 Protection of human subjects

Consumer Product Safety Commission: 16 CFR 1028 Protection of human subjects

Agency for International Development: 22 CFR 225 Protection of human subjects

Department of Housing and Urban Development: 24 CFR 60 Protection of human subjects

Department of Justice: 28 CFR 46 Protection of human subjects

Department of Defense: 32 CFR 219 Protection of human subjects

Department of Education: 34 CFR 97 Protection of human subjects

Department of Veterans Affairs: 38 CFR 16 Protection of human subjects

Environmental Protection Agency: 40 CFR 26 Protection of human subjects

Department of Health and Human Services: 45 CFR 46 Protection of human subjects

National Science Foundation: 45 CFR 690 Protection of human subjects

Department of Transportation: 49 CFR 11 Protection of human subjects

205

Statutory Authority for Agency

Human Subjects Protection

Regulations (Common Rule)
206

Appendix G: Statutory Authority for Agency Human Subjects Protection Regulations (Common Rule)

(2) Within the 180-day period beginning on the date of such publication, the agency shall determine whether the

action proposed by such recommendation is appropriate, and, to the extent that it determines that - 

(A) such action is not appropriate, the agency shall, within such time period, provide the Commission with, and 

publish in the Federal Register, a notice of such determination (including an adequate statement of the reasons 

for the determination), or 

(B) such action is appropriate, the agency shall undertake such action as expeditiously as feasible and shall notify

the Commission of the determination and the action undertaken. 

Additional Statutory Authority Cited for Agency Human Subject Protection Regulations 

(Common Rule)

Department of Energy

42 USC 7254 Rules and regulations.

The Secretary is authorized to prescribe such procedural and administrative rules and regulations as he may deem 

necessary or appropriate to administer and manage the functions now or hereafter vested in him.

Department of Housing and Urban Development

42 USC 3535 Administrative provisions. 

(d) Delegation of authority; rules and regulations

The Secretary may delegate any of his functions, powers, and duties to such officers and employees of the

Department as he may designate, may authorize such successive redelegations of such functions, powers, and

duties as he may deem desirable, and may make such rules and regulations as may be necessary to carry out his

functions, powers, and duties.

Department of Justice

28 USC 509 Functions of the Attorney General.

All functions of other officers of the Department of Justice and all functions of agencies and employees of the

Department of Justice are vested in the Attorney General except the functions -

(1) vested by subchapter II of chapter 5 of title 5 in administrative law judges employed by the Department of

Justice; 

(2) of the Federal Prison Industries, Inc.; and 

(3) of the Board of Directors and officers of the Federal Prison Industries, Inc..

28 USC 510 Delegation of authority.

The Attorney General may from time to time make such provisions as he considers appropriate authorizing the 

performance by any other officer, employee, or agency of the Department of Justice of any function of the Attorney

General.

Department of Education

20 USC 1221e-3 General authority of Secretary.

The Secretary, in order to carry out functions otherwise vested in the Secretary by law or by delegation of authority

pursuant to law, and subject to limitations as may be otherwise imposed by law, is authorized to make, promulgate,

issue, rescind, and amend rules and regulations governing the manner of operation of, and governing the applicable

programs administered by, the Department.

20 USC 3474 Rules and regulations.

The Secretary is authorized to prescribe such rules and regulations as the Secretary determines necessary or 

appropriate to administer and manage the functions of the Secretary or the Department.
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Department of Veterans Affairs

38 USC 501 Rules and regulations.

(a) The Secretary has authority to prescribe all rules and regulations which are necessary or appropriate to carry

out the laws administered by the Department and are consistent with those laws, including - 

(1) regulations with respect to the nature and extent of proof and evidence and the method of taking and furnishing them in order to establish the right to benefits under such laws;...

(c) In applying section 552(a)(1) of title 5 to the Department, the Secretary shall ensure that subparagraphs (C), (D),

and (E) of that section are complied with, particularly with respect to opinions and interpretations of the General

Counsel.

38 USC 7331 Informed consent.

The Secretary, upon the recommendation of the Under Secretary for Health and pursuant to the provisions of 

section 7334 of this title, shall prescribe regulations establishing procedures to ensure that all medical and prosthetic

research carried out and, to the maximum extent practicable, all patient care furnished under this title shall be 

carried out only with the full and informed consent of the patient or subject or, in appropriate cases, a representative

thereof.

38 USC 7334 Regulations.

(a) Regulations prescribed by the Secretary under section 7331 of this title, section 7332 of this title with respect to

the confidentiality of alcohol and drug abuse medical records, and section 7333 of this title with respect to alcohol

or drug abusers shall, to the maximum extent feasible consistent with other provisions of this title, make applicable

the regulations described in subsection (b) to the conduct of research and to the provision of hospital care, nursing

home care, domiciliary care, and medical services under this title. 

(b) The regulations referred to in subsection (a) are - 

(1) regulations governing human experimentation and informed consent prescribed by the Secretary of Health 

and Human Services, based on the recommendations of the National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research, established by section 201 of the National Research Act (Public

Law 93-348; 88 Stat. 348); and 

(2) regulations governing (A) the confidentiality of drug and alcohol abuse medical records, and (B) the admission 

of drug and alcohol abusers to private and public hospitals, prescribed pursuant to the Comprehensive Alcohol

Abuse and Alcoholism Prevention, Treatment, and Rehabilitation Act of 1970 (42 USC 4551 et seq.) and the Drug

Abuse Office and Treatment Act of 1972 (21 USC 1101 et seq.). 

(c) Regulations prescribed by the Secretary under sections 7331, 7332, and 7333 of this title may contain such 

definitions, and may provide for such safeguards and procedures (including procedures and criteria for the issuance

and scope of court orders undersection 7332(b)(2)(C) [1] of this title), as are necessary to prevent circumvention

or evasion of such regulations or to facilitate compliance with such regulations. 

(d) In prescribing and implementing such regulations, the Secretary shall, from time to time, consult with the

Secretary of Health and Human Services and, as appropriate, with the President (or the delegate of the President)

in order to achieve the maximum possible coordination of the regulations, and the implementation of the 

regulations, which they and the Secretary prescribe.

Department of Health and Human Services

42 USC 289 Institutional review boards; ethics guidance program.

(a) The Secretary shall by regulation require that each entity which applies for a grant, contract, or cooperative 

agreement under this chapter for any project or program which involves the conduct of biomedical or behavioral

research involving human subjects submit in or with its application for such grant, contract, or cooperative 

agreement assurances satisfactory to the Secretary that it has established (in accordance with regulations which 

the Secretary shall prescribe) a board (to be known as an “Institutional Review Board”) to review biomedical and
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Appendix G: Statutory Authority for Agency Human Subjects Protection Regulations (Common Rule)

behavioral research involving human subjects conducted at or supported by such entity in order to protect the

rights of the human subjects of such research. 

(b)(1) The Secretary shall establish a program within the Department of Health and Human Services under which

requests for clarification and guidance with respect to ethical issues raised in connection with biomedical or behavioral research involving human subjects are responded to promptly and appropriately.

(2) The Secretary shall establish a process for the prompt and appropriate response to information provided to the

Director of NIH respecting incidences of violations of the rights of human subjects of research for which funds

have been made available under this chapter. The process shall include procedures for the receiving of reports of

such information from recipients of funds under this chapter and taking appropriate action with respect to such

violations.

Related Human Subjects Protection Regulations (Not Common Rule) and Statutory Authority Cited 

Department of Justice

Bureau of Prisons

28 CFR 512 Research

5 USC 301 Departmental regulations.

18 USC 3621 Imprisonment of a convicted person.

18 USC 3622 Temporary release of a prisoner. 

18 USC 3624 Release of a prisoner.

18 USC 4001 Limitation on detention; control of prisons.

18 USC 4042 Duties of Bureau of Prisons.

18 USC 4081 Classification and treatment of prisoners.

18 USC 4082 Commitment to Attorney General; residential treatment centers; extension of limits of

confinement; work furlough (repealed in part as to offenses committed on or after

November 1, 1987).

18 USC 5006 - 5024 Chapter 402 of Part IV Correction of youthful offenders (Repealed October 12, 1984 

as to offenses committed after that date).

18 USC 5039 Commitment (of youthful offenders).

28 USC 509 Functions of the Attorney General.

28 USC 510 Delegation of authority.

Department of Education

34 CFR 97, Subpart D Additional ED protections for children who are subjects in research

5 USC 301 Departmental regulations.

20 USC 1221e-3 General authority of Secretary.

20 USC 3474 Rules and regulations.

42 USC 300v-1(b) Duties of Commission.
National Bioethics Advisory Commission

209

34 CFR 98 Student rights in research, experimental programs, and testing.

20 USC 1221e-3 General authority of Secretary.

20 USC 1232h Protection of pupil rights (a) Inspection of instructional materials by parents or guardians.

20 USC 1232h Protection of pupil rights (b) Limits on survey, analysis, or evaluations.

20 USC 3474 Rules and regulations.

34 CFR 99 Family educational rights and privacy.

20 USC 1232g Family educational and privacy rights.

Office of Special Education and Rehabilitative Services

34 CFR 350.4(c) What regulations apply?

29 USC 761a Authorization of appropriations.

29 USC 762 National Institute on Disability and Rehabilitation Research.

42 USC 300v-1(b) Duties of Commission.

34 CFR 356.3(c) Disability and rehabilitation research: Research fellowships.

29 USC 761a Authorization of appropriations.

42 USC 300v-1(b) Duties of Commission.

Department of Veterans Affairs

38 CFR 17.85 Treatment of research-related injuries to human subjects.

38 USC 501 Rules and regulations.

38 USC 7303 Functions of Veterans Health Administration: research programs.

Department of Health and Human Services

45 CFR 46 Subpart B Additional Protections Pertaining to Research, Development, and Related Activities Involving

Fetuses, Pregnant Women, and Human In Vitro Fertilization.

5 USC 301 Departmental regulations.

42 USC 289 Institutional review boards; ethics guidance program.

42 USC 300v-1(b) Duties of Commission.

45 CFR 46 Subpart C Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners

as Subjects

5 USC 301 Departmental regulations.

42 USC 289 Institutional review boards; ethics guidance program.

42 USC 300v-1(b) Duties of Commission.

45 CFR 46 Subpart D Additional protections for children involved as subjects in research

5 USC 301 Departmental regulations.

42 USC 289 Institutional review boards; ethics guidance program.

42 USC 300v-1(b) Duties of Commission.
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Appendix G: Statutory Authority for Agency Human Subjects Protection Regulations (Common Rule)

Food and Drug Administration

21 CFR 50 Protection of human subjects

21 USC § 321 Definitions; generally.

21 USC § 346 Tolerances for poisonous or deleterious substances in food; regulations. 

21 USC § 346a Tolerances and exemptions for pesticide chemical residues.

21 USC § 348 Food additives.

21 USC § 352 Misbranded drugs and devices.

21 USC § 353 Exemptions and consideration for certain drugs, devices, and biological products.

21 USC § 355 New drugs.

21 USC § 360 Registration of producers of drugs or devices.

21 USC § 360c Classification of devices intended for human use.

21 USC § 360d Performance standards.

21 USC § 360e Premarket approval.

21 USC § 360f Banned devices.

21 USC § 360h Notification and other remedies.

21 USC § 360i Records and reports on devices.

21 USC § 360j General provisions respecting control of devices intended for human use.

21 USC § 371 Regulations and hearings.

21 USC § 379e Listing and certification of color additives for foods, drugs, devices, and cosmetics.

21 USC § 381 Imports and exports.

42 USC § 216 Regulations.

42 USC § 241 Research and investigations generally.

42 USC § 262 Regulation of biological products.

42 USC § 263b Certification of mammography facilities.

21 CFR 56 Institutional review boards

21 USC § 321. Definitions; generally.

21 USC § 346 Tolerances for poisonous or deleterious substances in food; regulations. 

21 USC § 346a Tolerances and exemptions for pesticide chemical residues.

21 USC § 348 Food additives.

21 USC § 351 Adulterated drugs and devices.

21 USC § 352 Misbranded drugs and devices.

21 USC § 353 Exemptions and consideration for certain drugs, devices, and biological products.

21 USC § 355 New drugs.

21 USC § 360 Registration of producers of drugs or devices.

21 USC § 360c Classification of devices intended for human use.

21 USC § 360d Performance standards.
National Bioethics Advisory Commission

211

21 USC § 360e Premarket approval.

21 USC § 360f Banned devices.

21 USC § 360h Notification and other remedies.

21 USC § 360i Records and reports on devices.

21 USC § 360j General provisions respecting control of devices intended for human use.

21 USC § 371 Regulations and hearings.

21 USC § 379e Listing and certification of color additives for foods, drugs, devices, and cosmetics.

21 USC § 381 Imports and exports.

42 USC § 216 Regulations.

42 USC § 241 Research and investigations generally.

42 USC § 262 Regulation of biological products.

42 USC § 263b Certification of mammography facilities.

The regulations containing provisions related to adverse

event reporting include:

21 CFR Part 56 Institutional Review Boards

21 CFR Part 310 New Drugs

21 CFR Part 312 Investigational New Drug 

Application

21 CFR Part 314 Applications for FDA Approval 

to Market a New Drug

21 CFR Part 600 Biological Products: General

21 CFR Part 803 Medical Device Reporting

21 CFR Part 812 Investigational Device Exemptions

Regulatory Text 1

Investigator Regulatory Reporting

Requirements

Investigator Reporting to Sponsor

21 CFR 312.64 Investigator Reports.

(b) Safety reports. An investigator shall promptly report to

the sponsor any adverse effect that may reasonably be

regarded as caused by, or probably caused by, the drug. If

the adverse effect is alarming, the investigator shall report

the effect immediately.

[312.64(b) requires the investigator to report certain

adverse effect to the sponsor. Life-threatening adverse

drug experience, serious adverse drug experience and

unexpected adverse drug experience are defined in

312.32(a), but adverse effect is not defined in Part

312. Therefore, the reporting requirement is openended.]

[The investigator is required to notify the sponsor of

only probably drug-caused adverse effects. However,

most sponsors require the investigator to report all

adverse effects to the sponsor, no matter what the

cause. This is probably because 21 CFR 312.32(b)

and 21 CFR 812.3(s) appear to require the sponsor to

know about all events that happen anywhere in the

world both to people on study or just taking the drug.

Recent FDA enforcement actions have reinforced this

view.]

21 CFR 812.150 Reports.

(a) Investigator reports. An investigator shall prepare and

submit he following complete, accurate, and timely

reports:

(1) Unanticipated adverse device effects. An investigator

shall submit to the sponsor and to the reviewing IRB a

report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no

event later than 10 working days after the investigator

first learns of the effect.

[Investigator informs the sponsor and his/her IRB, 

not all of the IRBs of a multi-site study. The Part 312

regulations do not include a time limit.]

21 CFR 812.3 Definitions.

(s) Unanticipated adverse device effect means any serious

adverse effect on health or safety or any life-threatening

problem or death caused by, or associated with, a device,

if that effect, problem, or death was not previously 

identified in nature, severity, or degree of incidence in 

the investigational plan or application (including a 

supplementary plan or application), or any other unanticipated serious problem associated with a device that

relates to the rights, safety, or welfare of subjects.

213

Food and Drug Administration

Regulations Requiring

Reporting of Adverse Events

Appendix H

1 Annotations provided by P. Goebel, Office for Human Research

Protections.
214

Appendix H: Food and Drug Administration Regulations Requiring Reporting of Adverse Events

[The unanticipated adverse device effect definition

(21 CFR 812.3(s)) requires reporting of certain unexpected effects.]

Investigator Reporting to IRB

21 CFR 312.66 Assurance of IRB review.

An investigator shall assure that an IRB that complies

with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of

the proposed clinical study. The investigator shall also

assure that he or she will promptly report to the IRB all

changes in the research activity [this wording is identical

to 21 CFR 56.108(a)(3)] and all unanticipated problems

involving risk to human subjects or others, [This wording is identical to 21 CFR 56.108(b)(1), which follows]

and that he or she will not make any changes in the

research without IRB approval, except where necessary to

eliminate apparent immediate hazards to human subjects.

21 CFR 56.108 IRB functions and operations.

In order to fulfill the requirements of these regulations,

each IRB shall:

(b) Follow written procedures for ensuring prompt

reporting to the IRB, appropriate institutional officials,

and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human subjects or

others; (2) any instance of serious or continuing noncompliance with these regulations or the requirements 

or determinations of the IRB; or (3) any suspension or

termination of IRB approval.

[Any unanticipated problem is all-inclusive. It includes

adverse events that occur at the investigator’s study

site, and adverse events that occur at all other institutions that are reported to the investigator by the sponsor. This section seems to require the investigator to

notify the IRB of all unanticipated problems that

occurred anyplace in the world.]

21 CFR 812.150 Reports.

(a) Investigator reports. An investigator shall prepare and

submit the following complete, accurate, and timely

reports:

(1) Unanticipated adverse device effects. An investigator

shall submit to the sponsor and to the reviewing IRB a

report of any unanticipated adverse device effect occurring

during an investigation as soon as possible, but in no

event later than 10 working days after the investigator

first learns of the effect.

Sponsor Evaluation of Adverse Event Reports

Requirements [Annotated]

21 CFR 312.32 IND safety reports.

(b) Review of safety information. The sponsor shall

promptly review all information relevant to the safety of

the drug obtained or otherwise received by the sponsor

from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing

experience, reports in the scientific literature, and

unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been

previously reported to the agency by the sponsor.

[This review requirement is not limited to “serious

and unexpected” or to “adverse events that may be

caused by the drug,” but includes “all information

relevant to the safety of the drug....” Also, the requirement to review information “from any source” is

interpreted by sponsors to mean they are required to

aggressively search worldwide for any event that may

remotely be related to use of the drug.]

21 CFR 312.32 IND safety reports.

d) Followup. (1) The sponsor shall promptly investigate

all safety information received by it.

(2) Followup information to a safety report shall be submitted as soon as the relevant information is available.

(3) If the results of a sponsor’s investigation show that an

adverse drug experience not initially determined to be

reportable under paragraph (c) of this section is so

reportable, the sponsor shall report such experience in a

written safety report as soon as possible, but in no event

later than 15 calendar days after the determination is made.

(4) Results of a sponsor’s investigation of other safety

information shall be submitted, as appropriate, in an

information amendment or annual report.

21 CFR 812.46 Monitoring investigations.

(b) Unanticipated adverse device effects (1) A sponsor shall

immediately evaluate any unanticipated adverse device

effect.
National Bioethics Advisory Commission

215

Sponsor Reporting Requirements [Annotated]

Sponsor Reporting to Investigators

21 CFR 312.32 IND safety reports.

(c) IND safety reports. (1) Written reports - (i) The sponsor

shall notify FDA and all participating investigators in a

written IND safety report of:

(A) Any adverse experience associated with the use of the

drug that is both serious and unexpected; or

(B) Any finding from tests in laboratory animals that 

suggests a significant risk for human subjects including

reports of mutagenicity, teratogenicity, or carcinogenicity.

Each notification shall be made as soon as possible and

in no event later than 15 calendar days after the sponsor’s

initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a 

narrative format (foreign events may be submitted either

on an FDA Form 3500A or, if preferred, on a CIOMS I

form; reports from animal or epidemiological studies

shall be submitted in a narrative format) and shall bear

prominent identification of its contents, i.e., “IND Safety

Report.” Each written notification to FDA shall be transmitted to the FDA new drug review division in the

Center for Drug Evaluation and Research or the product

review division in the Center for Biologics Evaluation and

Research that has responsibility for review of the IND. If

FDA determines that additional data are needed, the

agency may require further data to be submitted.

[The regulations require the sponsor to notify all

investigators within 15 days. This may not allow time

for the sponsor to analyze the significance of the

adverse event. The adverse event report would be of

greater value to the clinical investigator and the IRB if

it included a judgement as to whether a change in the

protocol or the informed consent should be made.]

(ii) In each written IND safety report, the sponsor shall

identify all safety reports previously filed with the IND

concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of

the previous, similar reports.

[The adverse event reports that sponsors presently send

to investigators and IRBs do not include an evaluation

or if they do, the evaluation is so general as to be of little use to the IRBs in attempting to determine whether

changes in the study or consent should be made.]

21 CFR 312.55 Informing Investigators.

(b) The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of

new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse

effects and safe use. Such information may be distributed

to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or

letters to clinical investigators, or other appropriate

means. Important safety information is required to be

relayed to investigators in accordance with Sec. 312.32.

[This section requires sponsors to notify all investigators in a multi-site study of all adverse events or “new

observations.” New observations is a very general allinclusive term.]

21 CFR 812.150 Reports (b) Sponsor reports.

(1) Unanticipated adverse device effects. A sponsor who

conducts an evaluation of a unanticipated adverse device

effect under 21 CFR 812.46(b) shall report the results to

FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first

receives notice of the effect. Thereafter the sponsor shall

submit such additional reports concerning the effect as

FDA requests.

Sponsor Reporting to IRBs

21 CFR 812.150 Reports (b) Sponsor reports.

(1) Unanticipated adverse device effects. A sponsor who

conducts an evaluation of a unanticipated adverse device

effect under 21 CFR 812.46(b) shall report the results to

FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first

receives notice of the effect. Thereafter the sponsor shall

submit such additional reports concerning the effect as

FDA requests.

Sponsor Reporting to FDA

21 CFR 312.32 IND safety reports (c) IND safety

reports. (1) Written reports - (i) The sponsor shall notify

FDA and all participating investigators in a written IND

safety report of:

(A) Any adverse experience associated with the use of the

drug that is both serious and unexpected; or
216

Appendix H: Food and Drug Administration Regulations Requiring Reporting of Adverse Events

(B) Any finding from tests in laboratory animals that 

suggests a significant risk for human subjects including

reports of mutagenicity, teratogenicity, or carcinogenicity.

Each notification shall be made as soon as possible and

in no event later than 15 calendar days after the sponsor’s

initial receipt of the information. Each written notification may be submitted on FDA Form 3500A or in a 

narrative format (foreign events may be submitted either

on an FDA Form 3500A or, if preferred, on a CIOMS I

form; reports from animal or epidemiological studies

shall be submitted in a narrative format) and shall bear

prominent identification of its contents, i.e., “IND Safety

Report.” Each written notification to FDA shall be transmitted to the FDA new drug review division in the

Center for Drug Evaluation and Research or the product

review division in the Center for Biologics Evaluation and

Research that has responsibility for review of the IND. If

FDA determines that additional data are needed, the

agency may require further data to be submitted.

[The regulations require the sponsor to notify all

investigators within 15 days. This may not allow time

for the sponsor to analyze the significance of the

adverse event. The adverse event report would be of

greater value to the clinical investigator and the IRB if

it included a judgement as to whether a change in the

protocol or the informed consent should be made.]

(ii) In each written IND safety report, the sponsor shall

identify all safety reports previously filed with the IND

concerning a similar adverse experience, and shall analyze the significance of the adverse experience in light of

the previous, similar reports.

[The adverse event reports that sponsors presently

send to investigators and IRBs do not include an evaluation or if they do, the evaluation is so general as to

be of little use to the IRBs in attempting to determine

whether changes in the study or consent should be

made.]

21 CFR 312.32 IND safety reports (c) IND safety 

reports. 

(2) Telephone and facsimile transmission safety reports.

The sponsor shall also notify FDA by telephone or 

by facsimile transmission of any unexpected fatal or 

life-threatening experience associated with the use of the

drug as soon as possible but in no event later than 7 calendar days after the sponsor’s initial receipt of the information. Each telephone call or facsimile transmission to

FDA shall be transmitted to the FDA new drug review

division in the Center for Drug Evaluation and Research

or the product review division in the Center for Biologics

Evaluation and Research that has responsibility for

review of the IND.

[Inconsistency: No requirement to notify each investigator of the 7 day reports, but each investigator

must get a copy of the 15 day report. The 7 day report

is for reporting more alarming situations.]

21 CFR 312.33 Annual reports.

(b) Summary information. Information obtained during

the previous year’s clinical and nonclinical investigations,

including:

(1) A narrative or tabular summary showing the most 

frequent and most serious adverse experiences by body

system.

(2) A summary of all IND safety reports submitted during

the past year.

(3) A list of subjects who died during participation in the

investigation, with the cause of death for each subject.

(4) A list of subjects who dropped out during the course

of the investigation in association with any adverse experience, whether or not thought to be drug related.

21 CFR 812.150 Reports (b) Sponsor reports.

(1) Unanticipated adverse device effects. A sponsor who

conducts an evaluation of a unanticipated adverse device

effect under 21 CFR 812.46(b) shall report the results to

FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first

receives notice of the effect. Thereafter the sponsor shall

submit such additional reports concerning the effect as

FDA requests.

[Sponsors are required to send unanticipated adverse

device effects directly to the IRBs, and to the investigators. The 10 working day time frame is inconsistent

with the IND requirement of 15 calendar days.]
Public Comments on NBAC’s

December 19, 2000, Draft

Appendix I

217

Alaska Division of Public Health

(Juneau, AK)

Albany Medical College (Albany, NY)

Alzheimer’s Association 

(Washington, D.C.)

American Anthropological Association

(Arlington, VA)

American Association of Physical

Anthropologists (Chapel Hill, NC)

American College of Obstetricians and

Gynecologists (Washington, D.C.)

American Geriatrics Society 

(New York, NY)

American Medical Association

(Chicago, IL)

American Medical Directors

Association (Columbia, MD)

American Political Science

Organization (Washington, D.C.)

American Psychiatric Association

(Washington, D.C.)

American Psychological Association

(Washington, D.C.)

American Red Cross, Jerome H.

Holland Laboratory (Rockville, MD)

American Sociological Association

(Washington, D.C.)

American Thoracic Society 

(New York, NY)

Appalachian State University 

(Boone, NC)

Applied Research Ethics National

Association (Boston, MA)

Mark H. Ashcraft, Cleveland State

University Institutional Review Board

(Cleveland, OH)

Association of American Medical

Colleges (Washington, D.C.)

Association of Independent Research

Institutes (Westminster, MD)

John A. Balint, Albany Medical College

(Albany, NY)

Deborah R. Barnbaum, Kent State

University (Kent, OH)

Jonathan Baron, University of

Pennsylvania (Philadelphia, PA)

Paul Batalden, Center for the

Evaluative Clinical Sciences,

Dartmouth College (Hanover, NH)

Lisa Bellantoni, Quincy University

(Quincy, IL)

Daniel O. Benson, “Eye Care”

(Klamath Falls, OR)

Malcolm P. Berger, Armstrong County

Memorial Hospital (Kittanning, PA)

Don Berwick, University of

Pennsylvania (Philadelphia, PA)

Bethany College (Bethany, WV)

Biotechnology Industry Organization

(Washington, D.C.)

Gretchen Birbeck, Michigan State

University (East Lansing, MI)

Michael Birnbaum, California State

University at Fullerton (Fullerton, CA)

Paula A. Bistak, Newark Beth Israel

Medical Center (Newark, NJ)

Melissa Bottrell, New York University

Division of Nursing (New York, NY)

S. Gaylen Bradley, Penn State College

of Medicine (Hershey, PA)

Mark L. Brenner, Indiana University

Purdue University-Indianapolis

(Indianapolis, IN)

Bristol-Myers Squibb Pharmaceutical

Research Institute (Princeton, NJ)

Kerwin Brook, San Francisco State

University (San Francisco, CA)

Bill Burman, Denver Health Authority

(Denver, CO)

Corrinne Caldwell, Temple University

(Philadelphia, PA)

Case Western Reserve University

(Cleveland, OH)

David Cassaratt, University of

Pennsylvania (Philadelphia, PA)

Oswaldo Castro, Victor R. Gordeuk,

and Fitzroy W. Dawkins, Howard

University (Washington, D.C.)

Centers for Disease Control and

Prevention (Atlanta, GA)

Center for Regulatory Effectiveness

(Washington, D.C.)

Chicago State University (Chicago, IL)
218

Appendix I: Public Comments on NBAC’s December 19, 2000, Draft

Citizens for Responsible Care &

Research (New York, NY)

Thomas Coggins, University of South

Carolina (Columbia, SC)

Consortium of Social Science

Associations (Washington, D.C.)

Consumer Product Safety Commission

(Bethesda, MD)

Council of State and Territorial

Epidemiologists (CSTE) (Atlanta, GA)

Shan Cretin, RAND Health 

(Santa Monica, CA)

Richard D. Culbertson (Fort Worth, TX)

Virginia Dato, University of Pittsburgh,

Graduate School of Pubic Health

(Pittsburgh, PA)

Robyn M. Dawes, Carnegie Mellon

University (Pittsburgh, PA)

Linda Degh, Indiana University,

Folklore Institute (Bloomington, IN)

Department of Agriculture,

Agricultural Research Service

(Washington, D.C.)

Department of Commerce, National

Institutes of Standards and Technology

(Gaithersburg, MD)

Department of Education 

(Washington, D.C.)

Department of Energy 

(Germantown, MD)

Department of Veterans Affairs, 

Office of Research and Development

(Washington, D.C.)

Department of Veterans Affairs,

Veterans Health Administration

National Center for Ethics

(Washington, D.C.)

Department of Veterans Affairs,

Veterans Health Administration Office

of Research Compliance and Assurance

(Washington, D.C.)

Evan G. DeRenzo, Washington

Hospital Center (Washington, D.C.)

Rebecca Dresser, Washington

University (St. Louis, MO)

Nancy Dubler, Montefiore Medical

Center (Bronx, NY)

East Carolina University, University

and Medical Center Institutional

Review Board (Greenville, NC)

The Endocrine Society (Bethesda, MD)

Environmental Protection Agency

(Washington, D.C.)

Katherine Ewing and Linda K. George,

Duke University (Durham, NC)

Federation of American Societies for

Experimental Biology (Bethesda, MD)

Sandra Finestone, 

Hoag Memorial Hospital Presbyterian

(Newport Beach, CA)

John C. Fletcher, University of 

Virginia School of Medicine

(Charlottesville, VA)

Food and Drug Administration

(Rockville, MD)

Elmar H. Frangenberg, Finger Lakes

DDSO, MDC Medical Clinic

(Rochester, NY)

Edward F. Gabriele (Germantown, MD)

Leonard H. Glantz, George Annas, and

Michael Grodin, Boston University

School of Public Health (Boston, MA)

Jacquelyn Gnuse, Deaconess College of

Nursing (St. Louis, MO)

Goodwyn Institutional Review Board

(Cincinnati, OH)

Robert M. Hauser, Wisconsin

University (Madison, WI)

Harvard University, Committee on the

Use of Human Subjects in Research

(Boston, MA)

Health Privacy Project, Institute for

Health Care Research, Georgetown

University (Washington, D.C.)

Sherri Heitner-Margalit 

(New York, NY)

Hellenic National Bioethics

Commission (Athens, Greece)

Shirley Y. Hill, University of Pittsburgh

School of Medicine (Pittsburgh, PA)

Søren Holm, University of Manchester

(Manchester, United Kingdom)

Frank C. Hood, Battelle Columbus

Operations (Columbus, OH)

Human Factors and Ergonomics

Society (Santa Monica, CA)

Illinois Department of Public Health

(Springfield, IL)

Indiana University at Bloomington

(Bloomington, IN)

David Introcaso, Center for Clinical

Bioethics at Georgetown University

(Washington, D.C.)

Anne Janin, Hopital Saint Louis 

(Paris, France)

Bruce Jennings, The Hastings Center

(Garrison, NY)

Timothy Jones, Tennessee Department

of Health (Nashville, TN)

Eric T. Juengst, Case Western Reserve

University (Cleveland, OH)

Neil Jumonville, Florida State

University (Tallahassee, FL)

Juvenile Diabetes Research Foundation

International (New York, NY)

Jonathan Kaplan, U.S. Army Research

Institute for Behavioral and Social

Sciences (Alexandria, VA)

Jason H. T. Karlawish, University of

Pennsylvania (Philadelphia, PA)

Kenneth Kipnis, University of Hawaii

at Manoa (Honolulu, HI)

Donald S. Kornfeld, Columbia

Presbyterian Medical Center 

(New York, NY)

Michael Kubovy, University of Virginia

(Charlottesville, VA)
National Bioethics Advisory Commission

219

David Leder, Crystalion Publishing

(Las Vegas, NV)

Lewis and Clark College 

(Portland, OR)

Fernando Lolas, Pan American 

Health Organization, Regional Program

on Bioethics (Santiago, Chile)

Aurolyn Luykx, Universidad Mayor de

San Simón (Cochabamba, Bolivia)

Joanne Lynn, RAND Center to Improve

Care of the Dying (Washington, D.C.)

Howard Mann, Intermountain Health

Care (Salt Lake City, UT)

Peter J. Marshall, Cleveland VAMC

(Cleveland, OH)

Dennis J. Mazur, Department 

of Veterans Affairs Medical Center

Institutional Review Board 

(Portland, OR)

A. Thomas McLellan, Treatment

Research Institute (Philadelphia, PA)

Elizabeth S. Menkin (San Jose, CA)

Merck & Co., Inc. 

(Whitehouse Station, NJ)

Minnesota Center for Health Care

Ethics (Minneapolis, MN)

Ethel Mitty, New York University

Division of Nursing (New York, NY)

Naomi Modeste, Loma Linda

University (Loma Linda, CA)

Torin Monahan, Rensselaer Polytechnic

Institute (Troy, NY)

Jane Mostoller, Florida State University

(Tallahassee, FL)

Roxanne D. Mountford, University of

Arizona (Tucson, AZ)

Cynthia F. Mulliken, Pikeville College

(Pikeville, KY)

Frances M. Murphy, Office for Under

Secretary for Health Veterans Affairs

(Washington, D.C.)

National Aeronautics and Space

Administration (Washington, D.C.)

National Association of School

Psychologists (Bethesda, MD)

National Breast Cancer Coalition

(Washington, D.C.)

National Institutes of Health 

(Bethesda, MD)

National Organization for Rare

Disorders, Inc. (New Fairfield, CT)

National Science Foundation

(Arlington, VA)

National Society of Genetic Counselors

(Wallingford, PA)

Karl M. Nelson, Aultman Health

Foundation (Canton, OH)

Robert M. Nelson, The Children’s

Hospital of Philadelphia 

(Philadelphia, PA)

Newark Beth Israel Medical 

Center Institutional Review Board

(Newark, NJ)

North Dakota State University 

(Fargo, ND)

John Nurnberger, Indiana University

School of Medicine (Indianapolis, IN)

John O’Shea

OSF Healthcare (Peoria, IL)

Malcolm I. Page, University 

Hospital Institutional Review Board

(Augusta, GA)

Pediatric Pharmacology Research

Network (PPRU) (Rockville, MD)

Pennsylvania State University, College

of Medicine, Milton S. Hershey

Medical Center (Hershey, PA)

Pharmaceutical Research and

Manufacturers of America

(Washington, D.C.)

Kenneth W. Phifer, First Unitarian

Universalist Church of Ann Arbor,

University of Michigan IRBMED 

(Ann Arbor, MI)

Rexann G. Pickering, Methodist

Healthcare Institutional Review Board

(Memphis, TN)

Donald Pinkel

Public Citizen (Washington, D.C.)

David Quadagno, Florida State

University (Tallahassee, FL)

Quintiles Transnational Corp.

(Research Triangle Park, NC)

Gary E. Raskob, University of

Oklahoma Health Sciences Center

(Oklahoma City, OH)

Research Foundation for Mental

Hygiene, Inc. (Albany, NY)

Robert Richardson, Kaiser-Permanente

North West (Portland, OR)

Jennifer L. Rosato, Brooklyn Law

School (Brooklyn, NY)

Adam A. Rosenberg, University 

of Colorado School of Medicine

(Denver, CO)

Nancy Sander, Allergy and Asthma

Network, Mothers of Asthmatics, Inc.

(Fairfax, VA)

Naomi Scheman, University of

Minnesota (Minneapolis, MN)

Karen L. Schmidt, University of

Pittsburgh (Pittsburgh, PA)

George S. Schuster, Medical College of

Georgia Human Assurance Committee

(Augusta, GA)

Larry D. Scott, University of Texas at

Houston, Health Science Center, Texas

Medical Center (Houston, TX) 

Jeanne M. Sears, University 

of California at San Francisco 

(San Francisco, CA)

Lauren S. Seifert, Malone College

(Canton, OH)

Shannon Health System, Human

Subjects Committee (San Angelo, TX)
220

Appendix I: Public Comments on NBAC’s December 19, 2000, Draft

James Shelton, U.S. Agency 

for International Development

(Washington, D.C.)

Richard C. Shelton, Vanderbilt

University Medical Center 

(Nashville, TN)

Linda Shopes, Pennsylvania 

Historical & Museum Commission

(Harrisburg, PA)

Wayne Silverman (Holmdel, NJ)

John Simmons

Social Security Administration

(Washington, D.C.)

Southern Polytechnic State University

(Marietta, GA)

Southern University at New Orleans

(New Orleans, LA)

Stuart Spicker, Massachusetts College

of Pharmacy and Health Sciences

(Boston, MA)

State University of New York at

Fredonia (Fredonia, NY)

Kenneth A. Suarez, Midwestern

University (Downers Grove, IL)

Dennis M. Sullivan, Cedarville

University (Cedarville, OH)

Syracuse University (Syracuse, NY)

Leon Thal, University of California at

San Diego (San Diego, CA)

Cecilia Tiller, Abilene Intercollegiate

School of Nursing (Abilene, TX)

James A. Tulsky, VA Medical Center

and Duke University (Durham, NC) 

University of California (Oakland, CA)

University of California at Santa

Barbara (Santa Barbara, CA)

University of California at 

San Diego, Human Subjects Program

(San Diego, CA)

University of Colorado at Boulder

(Boulder, CO)

University of Iowa (Iowa City, IA)

University of Maryland, Baltimore

County (Baltimore, MD)

University of Southern California 

(Los Angeles, CA)

University of Texas at El Paso, Office 

of Research and Sponsored Projects 

(El Paso, TX)

University of Texas at Houston, Health

Science Center Institutional Review

Board (Houston, TX)

Valdosta State University Institutional

Review Board (Valdosta, GA)

Stephen Vanderslice, Christus St.

Frances Cabrini Hospital Institutional

Review Board (Alexandria, LA)

Washington State Department of

Health (Olympia, WA)

Stanley Way, Myasthenia Gravis

Foundation of America 

(Rockville, MD)

David Webb, Kutztown University

(Kutztown, PA)

Jan Weber, Huron University 

(Huron, SD)

Charles Weijer, Dalhousie University

(Halifax, Canada)

Dorothy C. Wertz, University of

Massachusetts Medical School, 

Eunice Kennedy Shriver Center

(Worcester, MA)

Shelia L. White, Office of Clinical

Trials Compliance, Medical College of

Georgia (Augusta, GA)

Anne M. Wilkinson, RAND

(Washington, D.C.)

Tina Wininger, University of Nevada at

Las Vegas (Las Vegas, NV)

Wisconsin Preventive Medicine Society

(Madison, WI)

Beverly Woodward, Brandeis

University (Waltham, MA)

World Health Organization,

Communicable Diseases 

(Geneva, Switzerland)

Shirley J. Wright, University of Dayton

(Dayton, OH)

Peter Zilgalvis, Council of Europe

(Strasbourg, France)

Listed below are those who 

provided comments after the

public comment deadline. These

comments were not included in

the analysis.

American Academy of Pediatrics 

(Elk Grove Village, IL)

Marie-Christine Bercot

United Nations Educational, 

Scientific and Cultural Organization

Devision of Human Sciences,

Philosophy and the Ethics of Science

and Technology

(Paris, France)

Marisela Vargas Cortes, 

Ministry of Health, Epidemiologia

(Mexico City, Mexico)

Department of Justice 

(Washington, D.C.)

Antonio M. Gotto, Cornell University

(New York, NY)

Henry Harpending

University of Utah, Department of

Anthropology

(Salt Lake City, UT)

Melvin M. Mathias, U.S. Department

of Agriculture (Washington, D.C.)

John S. Meyer, St. Luke’s Hospital

(Chesterfield, MO)

National Association of State 

Mental Health Program Directors

(Alexandria, VA)

Donald Pasquale

Stratton Veterans Affairs Medical

Center Institutional Review Board

(Albany, NY)

Julie Simpson, University of New

Hampshire (Durham, NH)

State University of New York College

at Old Westbury (Old Westbury, NY)

Rubye Prigmore Torrey, 

Tennessee Technological University

(Cookeville, TN)

Virginia State University 

(Petersburg, VA)

Joe E. Winstead, Southern Arkansas

University (Magnolia, AK)
Public and Expert Testimony

Appendix J

221

October 4, 1996 (Bethesda, Maryland)

Public:

Gwendon Plair, Task Force on Radiation and Human Rights

Jeffrey Cossman, College of American Pathologists and 

Georgetown University Medical Center

Charles MacKay

Suzanne Thomlinson, Biotechnology Industry Association

Acie Byrd, Atomic Veterans

Robert McMurrough, Centers for Disease Control and Prevention,

HIV/AIDS Prevention and Community Planning

Expert:

John H. Gibbons, Assistant to the President for Science and

Technology

Aaron Meinkoff, Legislative Assistant, Senator Mark O. Hatfield, 

U.S. Senate

Leonard Weiss, Minority Staff Director, U.S. Senate Committee on

Governmental Affairs

Francis S. Collins, National Human Genome Research Institute

Gary B. Ellis, Office for Protection from Research Risks

November 21, 1996 (San Francisco, California)

Public:

John Cavanaugh O’Keefe, American Life League

December 16, 1996 (Bethesda, Maryland)

Public:

Joan Rachlin, Public Responsibility in Medicine and Research

Susan Rose, Department of Energy

Expert:

Gary B. Ellis, Office for Protection from Research Risks

J. Thomas Puglisi, Office for Protection from Research Risks 

Sandy Titus, Food and Drug Administration

Allison Wichman, National Institutes of Health

Janice Stoklosa, National Aeronautics and Space Administration

Amanda Norton, Food and Drug Administration

Ronald Wilson, Food and Drug Administration

Joan Rachlin, Public Responsibility in Medicine and Research

January 9–10, 1997 (Washington, D.C.)

Public:

Chris Kline, Minority Staff Member, U.S. Senate Committee on

Governmental Affairs

February 24, 1997 (Bethesda, Maryland)

Public:

James Shelton, Joint United Nations Programme on HIV/AIDS

Expert:

Charles McKay, National Institutes of Health

April 12–13, 1997 (Arlington, Virginia)

Expert:

Ruth Faden, Advisory Committee on Human Radiation Experiments

Helen McGough, Applied Research Ethics National Association 

November 23, 1997 (Bethesda, Maryland)

Expert:

Charles R. McCarthy, Georgetown University

John C. Fletcher, University of Virginia

Joan Porter, Presidential Advisory Committee on Gulf War 

Veterans Illnesses

December 9, 1997 (Arlington, Virginia)

Public:

Mark Sobel, National Cancer Institute

Expert:

Debra Saslow, National Action Plan for Breast Cancer

January 6–8, 1998 (Arlington, Virginia)

Expert:

John C. Fletcher, University of Virginia

C.K. Gunsalus, University of Illinois

Joan Porter, Office of Science and Technology Policy

Gary B. Ellis, Office for Protection from Research Risks

February 5–6, 1998 (Los Angeles, California)

Public:

Art Ablin, University of California, San Francisco

Robert Aller, Patients Rights Network

Con Hopper, University of California System

Expert:

Rachel Levinson, Office of Science and Technology Policy
222

Appendix J: Public and Expert Testimony

May 19–20, 1998 (Cleveland, Ohio)

Public:

Tillman Bauknight

July 14–15, 1998 (Portland, Oregon)

Public:

Karen Hansen, Public Responsibility in Medicine and Research 

Expert:

Albert R. Jonsen, University of Washington

January 19–20, 1999 (Miami, Florida)

Public:

John Price

May 11–12, 1999 (Northbrook, Illinois)

Public:

Peggy Connelly

June 28–29, 1999 (Washington, D.C.)

Expert:

Roger Cortesi, Environmental Protection Agency

Timothy Gerrity, Department of Veterans Affairs

Barbara C. Levin, National Institute on Standards and Technology

Beth McCormick, National Aeronautics and Space Administration

Stuart Plattner, National Science Foundation

Blanca Rosa Rodriguez, Department of Education

James D. Shelton, U.S. Agency for International Development

Lana Skirboll, National Institutes of Health

Marjorie Speers, Centers for Disease Control and Prevention

Nancy Dubler, Albert Einstein College of Medicine 

Renee M. Landers, Ropes & Gray

Jonathan D. Moreno, University of Virginia

October 21–22, 1999 (Washington, D.C.)

Expert:

Neal F. Lane, Assistant to the President for Science and 

Technology Policy

December 2–3, 1999 (Baltimore, Maryland)

Expert: 

Jonathan D. Moreno, University of Virginia

January 13–14, 2000 (Washington, D.C.)

Expert:

Robert J. Levine, Yale University School of Medicine

Dixie E. Snider, Centers for Disease Control and Prevention

Duane Alexander, National Institute of Child Health and 

Human Development

Paul W. Goebel, Jr., Food and Drug Administration

Douglas Forcino, Department of Defense

Ed Lane, Department of Defense

Helene Deramond, Department of Education

Peter Wathen-Dunn, Department of Education

James Burris, Department of Veterans Affairs 

Joan Porter, Department of Veterans Affairs

Ellen Fox, Department of Veterans Affairs

February 29–March 1, 2000 (Herndon, Virginia)

Expert: 

Claudia Mickelson, Recombination DNA Advisory Committee

Lana Skirboll, National Institutes of Health

Kathryn C. Zoon, Food and Drug Administration

Michele Russell-Einhorn, Office for Protection from Research Risks

J. Thomas Puglisi, Office for Protection from Research Risks

Gary B. Ellis, Office for Protection from Research Risks

Diane Flack, Nuclear Regulatory Commission

Jane Ley, Office of Government Ethics

Andrew Nelson, Health Partners and HMO Research Network

Mary Durham, Kaiser Foundation Hospitals

Paul T. Kim, Counsel, Congressman Henry A. Waxman, 

U.S. House of Representatives

Souheila Al-Jadda, Legislative Aide, Congressman Dennis J.Kucinich,

U.S. House of Representatives

April 6–7, 2000 (Washington, D.C.)

Expert:

Shirley Fry, Oak Ridge Associate Universities, Oak Ridge National

Laboratory IRB

John Eisenberg, Agency for Health Care and Research Quality

Norman M. Bradburn, National Science Foundation

Murray Wax, Washington University

John M. Abowd, Cornell University

Joan E. Sieber, California State University, Hayward

Linda Shopes, Organization of American Historians and American

Historical Society

Bert A. Spilker, Pharmaceutical Research and Manufacturers of

America

R. Sebastian Wanless, Bristol-Myers Squibb Company

Rose G. Snipes, Glaxo Wellcome, Inc.

Bernice R. Welles, Genentech, Inc.

Thomas W. McKenna, Westat

James G. Ross, Macro International, Inc.

Inderjit Kaul, Abt Associates, Inc.

Anne Coletti, Abt Associates, Inc.

May 4–5, 2000 (Madison, Wisconsin)

Expert: 

Bernard M. Dickens, University of Toronto

June 5–6, 2000 (San Francisco, California)

Expert:

Jeffrey Kahn, University of Minnesota

Richard Schreck, General Motors Corporation

Henry B. Chin, National Food Processors Association

Donald Chalmers, University of Tasmania

Erica Heath, Independent Review Consulting, Inc.

Harold Y. Vanderpool, University of Texas Medical Branch at

Galveston

Jonathan D. Moreno, University of Virginia

Donald Magnus, University of Pennsylvania
National Bioethics Advisory Commission

223

July 10–11, 2000 (Bethesda, Maryland)

Public:

Jim Tozzi, Center for Regulatory Effectiveness

Expert:

Vincent T. Francisco, University of Kansas

Edison J. Trickett, University of Maryland

Timmeca Wilson

Susan May

Linda Smith

Kenneth Kipnis, University of Hawaii at Manoa

Ernest D. Prentice, University of Nebraska Medical Center

Daniel K. Nelson, University of North Carolina at Chapel Hill

Moira A. Keene, University of Minnesota Health Center

E. Ray Stinson, Wayne State University

Robert M. Nelson, The Children’s Hospital of Philadelphia

Sharon B. Murphy, Northwestern University School of Medicine

William Burman, Denver Department of Public Health

Monica M. Farley, Emory University School of Medicine, 

Atlanta VA Medical Center

Samuel A. Wells, Jr., American College of Surgeons

September 12–13, 2000 (Washington, D.C.)

Public:

Lee Zwanziger, Institute of Medicine, National Academy of Sciences 

Expert:

Joan E. Sieber, California State University, Hayward

Janlori Goldman, Georgetown University

Greg Koski, Office for Human Research Protections

David Lepay, Food and Drug Administration

Daniel P. Schuster, Washington University in St. Louis

Steven Peckman, University of California, Los Angeles

Søren Holm, University of Manchester, England

Michael S. Hamm, Michael Hamm & Associates

October 24–25, 2000 (Salt Lake City, Utah)

Public:

Howard Mann, Intermountain Health Care 

Colin Thomson, Australian Health Ethics Committee

Kateri Harnetiaux

December 7–8, 2000 (Washington, D.C.)

Public:

Vera Hassner Sharav, Citizens for Responsible Care in Research

January 18–19, 2001 (Washington, D.C.)

Public:

Kate Louise Gottfried, National Human Research Protections

Advisory Committee

Mary Faith Marshall, National Human Research Protections 

Advisory Committee

March 15–16, 2001 (Atlanta, Georgia)

Public:

Erica Frank, Emory University School of Medicine

225

Commissioned Papers 

and Staff Analysis

Appendix K

Research Ethics in Australia

Donald Chalmers

University of Tasmania

Location of the Office for Protection from Research Risks Within the National

Institutes of Health: Problems of Status and Independent Authority 

John C. Fletcher

University of Virginia

Privacy and Confidentiality in Health Research 

Janlori Goldman and Angela Choy

Georgetown University

An Examination of Issues Presented by Proposals to Unify and Expand

Federal Oversight of Human Subject Research

C.K. Gunsalus

University of Illinois at Urbana-Champaign

The History, Function, and Future of Independent Institutional Review Boards

Erica Heath

Independent Review Consulting, Inc.

The Danish Research Ethics Committee System—Overview and Critical

Assessment

Søren Holm

University of Manchester

Vulnerability in Research Subjects: A Bioethical Taxonomy

Kenneth Kipnis

University of Hawaii at Manoa

Reflections on the Organizational Locus of the Office for Protection from

Research Risks

Charles R. McCarthy
226

Appendix K: Commissioned Papers and Staff Analysis

Protectionism in Research Involving Human Subjects

Jonathan D. Moreno

University of Virginia

Federal Agency Survey on Policies and Procedures for the Protection of

Human Subjects in Research

National Bioethics Advisory Commission

Local Institutional Review Boards

Steven Peckman

University of California-Los Angeles

Institutional Review Board Assessment of Risks and Benefits Associated 

with Research 

Ernest D. Prentice and Bruce G. Gordon

University of Nebraska Medical Center

Oversight of Human Subject Research: The Role of the States

Jack Schwartz

Office of the Maryland Attorney General

Privacy and Confidentiality: As Related to Human Research in Social and

Behavioral Science

Joan E. Sieber

California State University, Hayward 

Unfulfilled Promise: How the Belmont Report Can Amend the Code of 

Federal Regulations Title 45 Part 46—Protection of Human Subjects

Harold Y. Vanderpool

University of Texas Medical Branch, Galveston

The Ethical Analysis of Risks and Potential Benefits in Human Subjects

Research: History, Theory, and Implications for U.S. Regulation

Charles Weijer

Dalhousie University

Protecting Communities in Research: Philosophical and Pragmatic Challenges

Charles Weijer

Dalhousie University
Index

A

AAALAC. See Association for Assessment and Accreditation of

Laboratory Animal Care (AAALAC)

AAAS. See American Association for the Advancement of Science

(AAAS)

AAHRPP. See Association for the Accreditation of Human Research

Protection Programs (AAHRPP)

AAMC. See Association of American Medical Colleges (AAMC)

Accountability

public, of human participants research, oversight system 

proposal for, xii, 26

Accreditation

organizations, for human participants research, oversight

responsibilities of, 27

research ethics competence of institutions/IRBs, measures for

demonstrating, vii, xiv, 49–50

ACHRE. See Advisory Committee on Human Radiation

Experiments (ACHRE)

ADAMHA. See Alcohol, Drug Abuse and Mental Health

Administration (ADAMHA)

Adaptability

human participants research and, oversight issues, 11–12

Administration for Children and Families, 11, 132

See also Department of Health and Human Services (DHHS)

Administration on Aging, 11

See also Department of Health and Human Services (DHHS)

Adverse reactions

research, FDA reporting requirements for, 113–114, 115, 116

research, FDA reporting requirements for, regulatory text,

213–216

research, reporting requirements for local institutions/IRBs,

xix–xx, 113–114, 115–117

research, review requirements for local institutions/IRBs, 114,

115–116

See also Drugs and drug testing

Advisory Committee on Human Radiation Experiments (ACHRE),

45, 46, 99, 124, 156

Final Report, 124

human participants research, recommendations of, 158

Advocacy

organizations, for human participants research, oversight

responsibilities of, 27

Africa

vaccine death rates in, 85

African Americans

Tuskegee Syphilis Study, 46, 153, 164

Agency for Healthcare Research and Quality, 11, 132

See also Department of Health and Human Services (DHHS)

Agency for International Development (USAID), 11, 132, 205

HIV/AIDS and Pre-Adolescent Awareness Programs in Africa, 5

human participants research, regulations of, 157

Alabama. See Macon County, Alabama; Tuskegee, Alabama;

University of Alabama at Birmingham

Alcohol, Drug Abuse and Mental Health Administration

(ADAMHA), 155

AMA. See American Medical Association (AMA)

American Association for the Advancement of Science (AAAS), 47

American Medical Association (AMA), 151

American Psychological Association, 33

Applied Research Ethics National Association, 15, 33

Armed Forces Epidemiological Board, 153

Association for Assessment and Accreditation of Laboratory Animal

Care (AAALAC), 49

Association for the Accreditation of Human Research Protection

Programs (AAHRPP), 49

Association of American Medical Colleges (AAMC), 15, 46, 60

Association of American Universities, 15

Association of American University Professors, 13

Assurances of compliance

federal agencies practices regarding, listing by agency, 51

research standards compliance by institutions/IRBs, 

mechanisms for, xiv, 50–51, 52

See also Compliance; Cooperative Project Assurance (CPA);

Federalwide Assurance (FWA); Multiple Project Assurances

(MPAs); Single Project Assurances (SPAs)

Audits

institutional, for research standards compliance of

institutions/IRBs, xiv, 53

Auschwitz, Germany

interview, face-to-face, risks/potential benefits analysis 

example, 81

Australia

human participants research, terminology for, 33

research-related injuries, compensation for, 123

Autonomy

human participants research and, ethical principles, 162 

227
228

Index

B

Backlar, Patricia, 33

Balanced Budget Act of 1997, 4

Beecher, Henry, 153

Behavior

psychological experiment on, risk/potential benefits analysis, 82

state law effects on, study of, risks/potential benefits analysis, 81

Behavioral research

prisoners as subjects, protections for, 45 CFR 46, Subpart C, in

entirety, 182–184

See also Research

Belmont Report: Ethical Principles and Guidelines for the Protection of

Human Subjects of Research, ii, v, 35, 69, 97, 98, 154

applications of principles, 164–167

beneficence, relevance for, 162–163, 165–167

discussion of principles, 162–164

informed consent for, considerations, 164–165

justice, relevance for, 163–164, 167

research subject selection for, considerations, 167

research v. practice, distinction between, 161–162

respect for persons, relevance for, 162, 164–165

risks/benefits assessment for, considerations, 165–167

text, in entirety, 161–167

See also National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research (National

Commission)

Beneficence, 71

See also Ethics

Benefits

research, potential, from Belmont Report, 162–163, 165–167

research, potential, to others, 74

research, potential, to participants, 73–74

research, potential, to society, 73

research, potential, types, 73–74

research, potential, v. risks, analysis in IRB review process, 

ii–iv, 79

research, potential, v. risks, analysis of, new technologies effects

on, 7

research, potential, v. risks, analysis of, xvi–xvii, 69–85, 93

research, potential, v. risks, assessment of, ethical guidelines 

for, 165–167 

research, potential, v. risks, balance between, assessment 

procedure, 78–80

research, potential, v. risks, component-based framework for

analysis, 76–77, 78, 81–82

research, potential, v. risks, historical perspective, 75–76

research, potential, v. risks, relationship, assessment of, 74–75

Bernard, Claude, 163

Bioethics Commission. See National Bioethics Advisory

Commission (NBAC)

Biomedical research

prisoners as subjects, protections for, 45 CFR 46, Subpart C, 

in entirety, 182–184

See also Research

Brazil

compensation for research-related injuries, 123

Brooklyn Jewish Chronic Disease Hospital, 152

Bureau of Census, 5, 10, 39

Disclosure Review Board, 10

Policy Office, 10

C

California, 3

See also Los Angeles, California; University of California, Irvine;

University of California, Los Angeles; University of California,

San Diego; University of California, San Francisco

Capron, Alexander M., 33

Cassell, Eric J., 33

CCIP. See Council for Certification of IRB Professionals (CCIP)

CDC. See Centers for Disease Control and Prevention (CDC)

Census Bureau. See Bureau of Census

Center for Molecular Medicine and Immunology

research compliance investigations resulting in

restrictions/actions, 55

Centers for Disease Control and Prevention (CDC), 5, 11, 36, 39,

105, 107, 132

research compliance investigations resulting in

restrictions/actions, 55

See also Department of Health and Human Services (DHHS)

Central Intelligence Agency (CIA), 9, 11, 85, 132, 156

Certificate of Confidentiality, 106, 107

Certification

organizations, for human participants research, oversight

responsibilities of, 27

research ethics competence of individuals, measures for 

demonstrating, vii, xiv, 48–49

21 CFR 50. See Code of Federal Regulations, Title 21, Part 50 

(21 CFR 50)

21 CFR 56. See Code of Federal Regulations, Title 21, Part 56 

(21 CFR 56)

45 CFR 46. See Code of Federal Regulations, Title 45, Part 46 

(45 CFR 46)

Chicago, Illinois. See University of Illinois at Chicago

Children

research involving human participants, possible exemptions

from oversight, 39

research participants with vulnerabilities targeted, listing by

sponsoring agency, 86

research use of, protections for, 45 CFR 46, Subpart D, 

in entirety, 184–186
National Bioethics Advisory Commission

229

Children’s Research Act of 2000, 156

China

human research participants protection, regulations of, 157

research-related injuries, compensation for, 123

CIA. See Central Intelligence Agency (CIA)

CIOMS. See Council for International Organizations of Medical

Sciences (CIOMS)

City University of New York

research compliance investigations resulting in

restrictions/actions, 55

Clinical trials

drug efficacy, risks/potential benefits analysis example, 82

vaccine safety/immunogenicity, risk/potential benefits analysis

example, 82

See also Research

Cloning Human Beings, vii

Code of Federal Regulations, Title 21, Part 50 (21 CFR 50), 28,

98, 100

human research participants protection, agency regulations,

statutory authority for, 205–208

human research participants protection, regulations of, 157

Subpart A: General Provisions, for human subjects protection,

in entirety, 187–189

Subpart B: Informed Consent of Human Subjects, in entirety,

189–195

See also Federal regulation

Code of Federal Regulations, Title 21, Part 56 (21 CFR 56), 28,

53, 87, 98

human research participants protection, regulations of, 157

Subpart A: General Provisions, for IRBs, in entirety, 195–198

Subpart B: Organization and Personnel, for IRBs, in entirety,

198

Subpart C: IRB Functions and Operations, in entirety, 198–201

Subpart D: Records and Reports, for IRBs, in entirety, 201

Subpart E: Administrative Actions for Noncompliance, for IRBs,

in entirety, 201–203

See also Federal regulation

Code of Federal Regulations, Title 45, Part 46 (45 CFR 46), 2, 11,

28, 35, 87, 98, 100

human research participants protection, Common Rule and

agency-specific regulations, 157

Subpart A: Federal Policy for Protection of Human Subjects, in

entirety, 169–179

Subpart B: Additional DHHS Protections Pertaining to Research,

Development, and Related Activities Involving Fetuses,

Pregnant Women, and Human In Vitro Fertilization, in entirety,

179–182

Subpart C: Additional DHHS Protections Pertaining to

Biomedical and Behavioral Research Involving Prisoners as

Subjects, in entirety, 182–184

Subpart D: Additional DHHS Protections for Children Involved

as Subjects in Research, in entirety, 184–186

See also Federal regulation

Coercion

human participants research, requirements for, 45 CFR 46,

Subpart A, 176–178

voluntariness of, ethical guidelines from Belmont Report, 165

vulnerability in human participants research, definition of,

NBAC recommendation, xvii, 92

vulnerable individuals protection in human participants

research and, iv–v, xvii, 9, 11, 85–93

Cognitive ability

psychological experiment on, risk/potential benefits analysis

example, 82

vulnerability, capacity- and situation-related, in research 

participants, ethical considerations, 88

Colleges. See Universities and colleges

Comments. See Public comments

Commission. See National Bioethics Advisory Commission (NBAC)

Commissioned papers. See Papers commissioned

Common Rule. See Code of Federal Regulations, Title 45, Part 46

(45 CFR 46); Federal Policy for the Protection of Human Subjects

(Federal Policy)

Communication

vulnerability, in research participants, ethical considerations, 88

Communities

research involving human participants, consideration of, 7–8

Compensating for Research Injuries, 124

See also President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research

(President’s Commission)

Compensation

research-related harm and, current regulatory requirements,

123–124

research-related harm and, current situation, 125

research-related harm and, NBAC recommendations, xx, 126

research-related harm and, need for, v, 125–126

research-related harm and, previous recommendations for 

program, 124–125

research-related harm and, role of local institutions, xx,

123–126

Competence

research ethics, accreditation for institutions/IRBs, vii, xiv,

49–50

research ethics, certification of individuals, vii, xiv, 48–49

research ethics, measures for demonstrating, xiv, 48–50

Compliance

research oversight enforcement weaknesses, 12–13

research oversight investigations resulting in

restrictions/actions, listing by institution, 54–56

research standards and, by institutions/IRBs/investigators,

mechanisms for ensuring, xiv, 50–58

research standards and, institutional audits for, xiv, 53

research standards and, site inspections by FDA for, xiv, 52–53
230

research standards and, site inspections by other than FDA for,

xiv, 53

See also Assurances of compliance; Cooperative Project

Assurance (CPA); Federalwide Assurance (FWA); Multiple

Project Assurances (MPAs); Single Project Assurances (SPAs)

Comprehensive Alcohol Abuse and Alcoholism Prevention,

Treatment, Rehabilitation Act of 1970, 207

Confidentiality

definition for human participants research, proposed by NBAC,

107

research involving human participants, current regulations on,

104–105

research involving human participants, issues for, xviii,

106–107

research risk/potential benefit analysis, new technologies effects

on, 7 

See also Privacy

Conflict of interest

IRB as institutional body and, protection of research 

participants, xv, 61–63, 64

IRB composition issues for, protection of research participants,

63–64

IRB membership and, protection of research participants,

xv–xvi, 60–61, 63–64

research institutions/investigators/IRBs and, managing, NBAC

recommendations, xv–xvi, 64

research investigators/IRBs and protection of human participants,

measures for managing, xiv–xv, 58–60

See also Ethics

Congress, U.S. See U.S. Congress

Consent. See Informed consent

Consent forms. See Documentation; Informed consent

Consent process. See Informed consent 

Consumer Product Safety Commission, 11, 132, 205

human participants research, regulations of, 157

Contract research organizations (CROs), 6, 23, 25

Cook County Hospital Hektoen Institute for Medical Research

research compliance investigations resulting in

restrictions/actions, 55

Cooperative Project Assurance (CPA), 52

See also Assurances of compliance; Compliance; Office for

Human Research Protections (OHRP)

Cooperative research

human participants research, and IRB multi-site research 

studies, 14

range of, summary, 117

review of, by IRBs, foreign models of, 121–122

review of, by local IRBs, considerations, 118–122

review of, current requirements and problems, xx, 118

See also Research

Cornell University Medical Center

research compliance investigations resulting in

restrictions/actions, 55

Council for Certification of IRB Professionals (CCIP), 48

Council for International Organizations of Medical Sciences

(CIOMS), 123, 215, 216

Council of Europe, 123

CPA. See Cooperative Project Assurance (CPA)

CROs. See Contract research organizations (CROs)

Current Population Survey, 1988, 81

D

Data

existing, research risks/potential benefits analysis of, example, 81

Data and Safety Monitoring Board (DSMB), 25, 54, 134

research adverse events reporting requirements for, xix–xx, 113,

115–116, 117

Death

research involving deceased individuals, possible exemptions

from oversight, 39–40

Deception research

informed consent requirements for human participants in, 101

Decisionmaking capacity

mentally impaired research participants and, informed consent

and limitations on, 101

Denmark

cooperative research, IRB review models in, 121

Department of Commerce, 11, 132, 205

human participants research, regulations of, 157

Department of Defense (DOD), 5, 11, 132, 190, 191, 192, 205

human participants research, regulations of, 157

Secretary, 151

Top Secret policy, 151–152

Department of Education, 9, 11, 39, 85, 104, 107, 132

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 206, 208–209

Secretary, 206

site inspections to ensure compliance with research standards, 53

Department of Energy (DOE), 5, 11, 12, 132

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 206

Secretary, 206

site inspections to ensure compliance with research standards, 53

See also Nuclear Regulatory Commission (NRC)

Department of Health and Human Services (DHHS), vi, xiv, 2, 4,

8, 9, 10, 11, 12, 15, 28, 29, 30, 31–32, 37, 39, 50, 51, 55, 56, 71,

75, 76, 83, 85, 87, 88, 91, 105, 106, 116, 124, 131, 132, 152,

154, 155, 156

children as research subjects, protections for, 45 CFR 46,

Subpart D, in entirety, 184–186

Ethics Advisory Board, 155

Index
National Bioethics Advisory Commission

231

human participants research, 45 CFR 46, Subpart A, in entirety,

169–179

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 207–208, 209

Office of Inspector General (OIG), 8, 57, 112, 116, 131

Office of the Secretary, 15, 30

pregnant women, fetuses, and in vitro fertilization in research,

protections for, 45 CFR 46, Subpart B, in entirety, 179–182

prisoners in biomedical/behavioral research, protections for, 45

CFR 46, Subpart C, in entirety, 182–184

Secretary, 152, 154, 155, 179, 180, 182, 183, 185, 207, 208

“Standards for Privacy of Individually Identifiable Health

Information,” 105

See also Administration for Children and Families;

Administration on Aging; Agency for Healthcare Research and

Quality; Centers for Disease Control and Prevention (CDC);

Department of Health, Education, and Welfare (DHEW), Food

and Drug Administration (FDA); Health Care Financing

Administration; Health Resources and Services Administration

(HRSA); Indian Health Service; National Institutes of Health

(NIH); Substance Abuse and Mental Health Services

Administration 

Department of Health, Education, and Welfare (DHEW), 124, 

153, 154

Ethics Advisory Board, 124

Medical Malpractice Commission, 124

Secretary, 124

Secretary’s Task Force on the Compensation of Injured Research

Subjects, 124

“Yellow Book,” 153

See also Department of Health and Human Services (DHHS)

Department of Housing and Urban Development, 11, 132

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 206

Secretary, 206

Department of Justice, 9, 11, 39, 85, 105, 132

Attorney General, 206

Bureau of Prisons, 9, 208

Federal Prison Industries, Inc., 206

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 206, 208

Department of Labor, 171

Department of Transportation, 11, 85, 132, 205

Federal Highway Administration, Human Factors Laboratory, 5

human participants research, regulations of, 157

U.S. Coast Guard, 5

Department of Veterans Affairs (VA), 5, 10, 11, 16, 49, 126, 132

Comprehensive Research Integrity Program, 53

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 205, 207, 209

Multi-Assessment Program, 53

Office of Research Compliance and Assurance, 53

Secretary, 207

site inspections to ensure compliance with research standards, 53

Special Inquiry Force Teams, 53

DHEW. See Department of Health, Education, and Welfare

(DHEW)

DHHS. See Department of Health and Human Services (DHHS)

Disclosure of information

conflict of interest for investigators/IRBs, measures for 

managing, 59–60

human participants research and, ethical guidelines from

Belmont Report, 164–165

human participants research, requirements for, emphasis on,

issues, iv, xvii, 98–100

human participants research, requirements for, listing, 99

See also Information; Informed consent

Diseases and disorders

illness, serious, as vulnerability in research participants, ethical

considerations, 89–90 

See also Mental diseases and disorders; Syphilis 

Documentation

informed consent requirements for human participants

research, discussion of, xviii, 103–104

DOD. See Department of Defense (DOD)

DOE. See Department of Energy (DOE)

Drug Abuse Office and Treatment Act of 1972, 207

Drugs and drug testing

efficacy of, clinical trial on, risks/potential benefits analysis

example, 82

vaccine, clinical trial on, risk/potential benefits analysis 

example, 82

research adverse events, FDA reporting requirements for,

113–114, 115, 116

See also Adverse reactions; Clinical trials; Vaccines and 

vaccination

DSMB. See Data and Safety Monitoring Board (DSMB)

Duke University, 133

research compliance investigations resulting in

restrictions/actions, 56

Medical Center, research compliance investigations resulting in

restrictions/actions, 56

E

Economics. See Investment; Personal finance

Edgar, H., 9

Editors

scientific, oversight system proposed for human participants

research, responsibilities of, 27

Education

disadvantaged persons targeted for research, listing by 

sponsoring agency, 86
232

research involving human participants, and IRB needs, 15

research involving human participants, measures needed for,

vi–vii, xiii, 45–48

research involving human participants, oversight system 

proposal for, xii, 23

Eisenberg, J.M., 36

Ellis, Gary, 119

Embryos and embryonic materials

research involving human participants, possible exemptions

from oversight, 39

See also Fetus and fetal tissue; Pregnancy

Enforcement

research involving human participants, protection of, oversight

system proposal for, xii, 25–26

research involving human participants, protection of, oversight

weaknesses, 12–13

Environmental Protection Agency (EPA), 5, 11, 132, 170, 197, 205

human participants research, regulations of, 157

EPA. See Environmental Protection Agency (EPA)

Equipoise

research, explanation of, 77, 78

See also Clinical trials

Equivalent protections. See Protections for human participants

Ethical Advisory Board, 182

research involving pregnant women, fetuses, and in vitro

fertilization, requirements for, 45 CFR 46, Subpart B, 180

Ethical and Policy Issues in International Research: Clinical Trials in

Developing Countries, vii 

Ethics

accreditation of competence of research institutions/IRBs for,

xiv, 49–50

benefits, potential, of research to others, 74

benefits, potential, of research to participants, 73–74

benefits, potential, of research to society, 73

benefits, potential, of research, types, 73–74

certification of competence of research individuals for, xiv, 46,

48–49

competence for research, measures for demonstrating, xiv,

48–50

compliance with research standards by institutions/IRBs/

investigators, mechanisms for ensuring, xiv, 50–58

research equipoise, explanation, 77, 78

risks of harms from research to nonparticipants, 72–73

risks of harms from research, types of, 71–73

risks, research, minimizing, 73

risks, research, v. potential benefits, analysis of, xvi–xvii, 

69–85, 93

risks, research, v. potential benefits, balance between, 

assessment procedure, 78–80

risks, research, v. potential benefits, component-based 

framework for analysis, 76–77, 78, 81–82

risks, research, v. potential benefits, historical perspective,

75–76

risks, research, v. potential benefits, relationship, assessment of,

74–75

See also Beneficence; Conflict of interest; Ethics review and

review committees; Justice; Protections for human participants;

Respect for persons

Ethics review and review committees

adverse events and, local institutions/IRBs responsibilities, 114,

115–116

conflict of interest and IRB institutional role, measures for managing, xv, 61–63, 64

conflict of interest and IRB membership/composition, xv–xvi,

60–61, 63–64

continuing for ongoing research, local institutions responsibilities, xix, 111–112, 117

cooperative research, by IRBs, foreign models of, 121–122

cooperative research, by local IRBs, alternatives to, 120–122

cooperative research, by local IRBs, considerations, 118–120

cooperative research, current requirements and problems, xx,

118

cooperative research, role of local IRBs/institutions, xx, 122

human participants research, and IRB multi-site research 

studies, 14

human participants research, IRB burdens, 13–15

human participants research, oversight system proposal, xii,

23–24, 28, 30

independent IRBs, emergence of, 6

levels of, oversight system proposal for, vii–viii, xiii, 41–42

risk, minimal, research classification, use as sorting mechanism

for, 84

risks v. potential benefits of human participants research, 

analysis in, ii–iv, 79

risks v. potential benefits, analysis in IRB process, 79

risks v. potential benefits, balance between, assessment 

procedure, 78–80

risks v. potential benefits, component-based framework for

analysis, 76–77, 78, 81–82

risks v. potential benefits, component-based framework for

analysis, examples, 81–82 

See also Ethics; Evaluation; Institutional Review Boards (IRBs)

Evaluation

health services research and, determining oversight coverage,

36–37

See also Ethics review and review committees 

Expert testimony. See Testimony and speakers

F

Family Education Rights and Privacy Act of 1974, 104

FDA. See Food and Drug Administration (FDA)

Federal Coordinators Council for Science, Engineering, and

Technology, 154

Federal departments and agencies

assurances of compliance, practices regarding, listing by 

agency, 51

human participants research, Common Rule and agencyspecific regulations, 157

Index
National Bioethics Advisory Commission

233

human participants research, inconsistencies among, 9, 10

human participants research, independent oversight office 

proposal for, vi, xii, 28, 30–32

human participants research, percent exempt, listing by agency,

11 

human participants research, regulations of, statutory authority

for, 205–211

human participants research, support for FY 1999, listing by

agency, 132

human participants research, supported by, size and scope of, 5

vulnerability and human participants targeted in research, 

listing by agency/vulnerability, 86

See also Federal government; Federal regulation; specific 

departments and agencies

Federal Food, Drug, and Cosmetic Act, 29, 187, 190, 195

Kefauver-Harris amendments, 152, 153

Federal funding for research

oversight system for, resources for, viii, xx–xxi, 131, 133

research investment trends, changes in, 4

research involving human participants supported by, size and

scope of, 5

research involving human participants, resources for, xx–xxi,

131, 133

research involving human participants, support for FY 1999,

listing by agency, 132

See also Federal government; Research funding

Federal government

human research participants protection, activities of, 156

See also Federal departments and agencies; Federal funding for

research; Federal legislation; Federal regulation; Public policy;

U.S. Congress

Federal legislation

human research participants protection, agency regulations and,

statutory authority for, 205–211

See also Federal government; Federal regulation; specific 

legislation; U.S. Congress

Federal oversight. See Federal regulation; Oversight

Federal policy. See Federal government; Federal regulation; Public

policy

Federal Policy for the Protection of Human Subjects (Common

Rule), 2, 3, 5, 9, 11–12, 24, 26, 28, 29, 31, 35, 38, 51, 52, 70–71,

76, 113, 118, 135, 155–156

Common Rule definition, 154

Common Rule signatories, 159

human participants research, Common Rule and agencyspecific regulations, 157

human participants research, inconsistencies among federal

agencies, 10

See also Code of Federal Regulations, Title 45, Part 46 

(45 CFR 46)

Federal Register, 10, 39, 154, 170, 174, 179, 182, 183, 184, 191,

199, 202, 205, 206

Federal regulation

accreditation of competence of research institutions/IRBs, vii,

xiv, 49–50

adverse research events, FDA reporting requirements, 113–114,

115, 116, 213–216

adverse research events, reporting requirements for local institutions, xix–xx, 113–117

certification of competence of research individuals, vii, xiv,

48–49

compliance with research standards by institutions/IRBs/

investigators, mechanisms for ensuring, xiv, 50–58

conflict of interest for research IRBs, measures for managing,

60–63

cooperative research review, current requirements and problems, xx, 118

cooperative research review, requirements for IRBs, 122

education on human participants protection, measures needed

for, vi–vii, xiii, 45–48

educational programs for human participants research, 

oversight system proposal for, xii, 23

human participants research, Common Rule and agencyspecific regulations, 157

human participants research, consequences of flawed system, 16

human participants research, current oversight system, 

challenges for, 8–16

human participants research, current protection of, 29

human participants research, defining for oversight coverage

determination, xii–xiii, 34–42

human participants research, description of, 154, 155–156, 157

human participants research, enforcement weaknesses, 12–13

human participants research, ethical issues for, future research

on, xxi, 134

human participants research, history of, 151–154

human participants research, inconsistencies among agencies, 

9, 10

human participants research, IRB burdens in, 13–15

human participants research, lack of adaptability in, 11–12

human participants research, limited scope of, 12

human participants research, oversight independent office 

proposed for, vi, xii, 28, 30–32

human participants research, oversight possible exemptions,

37–41

human participants research, oversight system proposal for,

xi–xiii, 21–42

human participants research, oversight system for, purpose of,

i–ii, xi, 2–4, 21–22

human participants research, oversight system for, resources for,

viii, xx–xxi, 131, 133

human participants research, oversight system proposal for

enforcement of, xii, 25–26

human participants research, oversight system proposal for 

ethical review of research, xii, 23–24

human participants research, oversight system proposal for

monitoring, xii, 24–25

human participants research, oversight system proposal for

National Office for Human Research Oversight for, xii, 28,

30–32
234

human participants research, oversight system proposal for 

policy development through, xii, 23

human participants research, oversight system proposal for

public accountability, xii, 26

human participants research, oversight system proposal for 

unified/comprehensive policy for, v–vi, xii, 28, 30–32 

human participants research, oversight system proposal for, as

dynamic/responsive structure, 134–135

human participants research, oversight system proposal for,

scope and structure, xii, 26–32

human participants research, oversight system proposed for,

functions and responsibilities of, xi–xii, 23–27 

human participants research, percent exempt from, listing by

agency, 11 

human participants research, procedural v. ethical emphasis, 13

human participants research, protection for, ACHRE 

recommendations, 158

human participants research, recent government interest in,

156

human participants research, recent initiatives for, 15–16

human participants research, report implications for IRBs/

investigators/institutions, 136–137

human participants research, report implications for 

participants, 137

human participants research, report recommendations for, 

general themes in, 135

informed consent requirements for research participants, 

deficiencies in, 98

informed consent requirements for research participants,

scope/structure of, iv, xvii, 97–104

privacy and confidentiality protection for research participants,

104–105

research approval by IRBs, current regulations for, 69–71

research protocol changes and unanticipated problems, local

institutions responsibilities, xix, 112–113, 117

research, ongoing, monitoring responsibilities of local 

institutions, xix, 117

research-related injuries, compensation for, current 

requirements, v, 123–124

review, continuing, of ongoing research, IRBs responsibilities,

xix, 117

review, levels of, for human participants research, oversight 

system proposal for, vii–viii, xiii, 41–42

risk, minimal, research classification, definition in, xvi, 80,

83–84

risks, research, v. potential benefits, analysis in IRB review

process, ii–iv, 79

vulnerability of research participants, current protections for,

85–92

vulnerable individuals protection in human participants

research, oversight issues, iv–v, 9, 11

See also Federal departments and agencies; Federal government;

Federal legislation; Public policy

Federalwide Assurance (FWA), 52

See also Assurances of compliance; Compliance

Fetus and fetal tissue 

research activities on, protections for, 45 CFR 46, Subpart B, in

entirety, 179–182

research involving human participants, possible exemptions

from oversight, 39

research targeting participants with vulnerabilities, listing by

sponsoring agency, 86

See also Embryos and embryonic materials; Pregnancy

Finance. See Investments; Personal finance

Florida. See Florida State University; University of Florida;

University of South Florida

Florida State University

research compliance investigations resulting in

restrictions/actions, 54

Food and Drug Administration (FDA), v, xiv, 2, 3, 4, 7, 9, 10, 11,

12, 15, 25, 26, 27, 28, 29, 32, 38, 50, 57, 59, 71, 98, 106, 120,

121, 126, 132, 152, 153, 154, 156, 170, 171, 187, 188, 191, 192,

193, 194, 203

Bioresearch Monitoring Program, 52, 53

Center for Biologics Evaluation and Research, 215, 216

Center for Drug Evaluation and Research, 215, 216

Commissioner, 202

human participants research, regulations of, 157

human participants research, regulations of, statutory authority

for, 210–211

IRB functions/operations and, 21 CFR 56, Subpart C, in

entirety, 198–201

IRB noncompliance with federal regulations and, administrative

actions for, 21 CFR 56, Subpart E, in entirety, 201–203

IRB records/reports and, 21 CFR 56, Subpart D, in entirety, 201

IRBs and, general provisions for, 21 CFR 56, Subpart A, in

entirety, 195–198

Office of Clinical Science, 15

research adverse events reporting requirements of, 113–114,

115, 116

research adverse events reporting requirements of, regulatory

text, 213–216

site inspections by, to ensure IRBs compliance with research

standards, xiv, 52–53

See also Department of Health and Human Services (DHHS)

Food, Drug, and Cosmetic Act. See Federal Food, Drug, and

Cosmetic Act

Fordham University

research compliance investigations resulting in

restrictions/actions, 56

Foreign countries

cooperative research, IRB review models in, 121–122

See also specific countries

France

research involving human participants, terminology for, 33

research-related injuries, compensation for, 123

Francis, Leslie, 61

Index
National Bioethics Advisory Commission

235

Friends Research Institute

research compliance investigations resulting in

restrictions/actions, 56

FWA. See Federalwide Assurance (FWA)

G

Gelsinger, Jesse, 3

General Accounting Office, 8

Germany. See Auschwitz, Germany

Government funding for research. See Federal funding for research

Great Britain

human research participants, studies on abuses of, 153

See also United Kingdom

Groups

research involving human participants, consideration of, 7–8

H

Harms

research involving human participants, oversight of, need 

for, 2–4

research participants vulnerability, current regulatory 

protections for, 85–92

research risks of, for nonparticipants, 72–73

research risks of, minimizing, 73

research risks of, types of, 71–73

research risks/potential benefits, analysis in IRB review 

process, 79

research risks/potential benefits, balance between, assessment

procedure, 78–80

research risks/potential benefits, component-based framework

for analysis, 76–77, 78, 81–82

research risks/potential benefits, historical perspective, 75–76

research risks/potential benefits, relationship, assessment 

of, 74–75

research-related, compensation for, current regulatory 

requirements, 123–124

research-related, compensation for, current situation, 125

research-related, compensation for, need for, v, 125–126

research-related, compensation for, previous recommendations

for program, 124–125

research-related, compensation for, role of local institutions, 

xx, 123–126

Health and Human Services Department. See Department of Health

and Human Services (DHHS)

Health and illness. See Diseases and disorders

Health care

research v. practice of, distinction between, 161–162

research v. practice of, distinction between for determining

oversight coverage, 34–37

See Diseases and disorders; Public health

Health Care Financing Administration, 5, 11, 132

See also Department of Health and Human Services (DHHS)

Health Education and Welfare Task Force, 71

Health Insurance Portability and Accountability Act of 1996, 105

Health Resources and Services Administration (HRSA), 10, 11, 132

Human Subjects Committee, 10

See also Department of Health and Human Services (DHHS)

Health services research

oversight system coverage determination, 36–37

See also Research

Hippocratic oath, 163

Holm, Søren, 121

Hospitals. See Medical centers 

HRSA. See Health Resources and Services Administration (HRSA)

Human participants. See Protections for human participants

Human Radiation Interagency Working Group, 158

Human Subjects Research Subcommittee, 154

I

ICH. See International Conference on Harmonization (ICH)

IDE. See Investigational device exemption (IDE)

Illinois. See University of Illinois at Chicago

Illness. See Diseases and disorders

Immunogenicity

vaccine safety clinical trial, risk/potential benefits analysis

example, 82

Implementing Human Research Regulations, 155

See also President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research

(President’s Commission)

IND. See Investigational new drug application (IND)

Independent bodies

IRBs, emergence of, 6 

human participants research, oversight office proposed for, vi,

xii, 28, 30–32 

India

research-related injuries, compensation for, 123

Indian Health Service, 11, 132

See also Department of Health and Human Services (DHHS)

Inducement. See Coercion

Influence. See Coercion

Information

revelation of, about others, research involving human 

participants, 39

See also Disclosure of information; Informed consent

Informed consent

comprehension for, ethical guidelines from Belmont Report, 165

deficiencies in current requirements for, 98

documentation requirements for, discussion of, xviii, 103–104

human participants research and, ethical guidelines from

Belmont Report, 164–165
236

human participants research, requirements for, 21 CFR 50,

Subpart B, in entirety, 189–195

human participants research, requirements for, 45 CFR 46,

Subpart A, 176–178

mentally impaired research participants and, requirements 

for, 101

process, emphasis on, discussion of, iv, xvii, 98–101

processes for various research settings, 100–101

recommendations of NBAC on, xvii, xviii, 98, 101, 102, 

103, 104

voluntariness of, ethical guidelines from Belmont Report, 165

voluntary, requirements for research participants, scope/

structure of, 97–104

waiver of requirements for, discussion, xvii–xviii, 101–103

See also Disclosure of information; Information

Injuries. See Harms

Inspections. See Site inspections

Institute of Medicine (IOM), 36, 49, 107

Institutional Review Boards (IRBs), xi, xvi, xvii, xviii, 1, 10, 13, 22,

31, 32, 37, 39, 53, 58, 59, 71, 72, 73, 80, 83, 85, 87, 90, 91, 92,

97, 98, 99, 100, 101, 104, 105, 106, 107, 155, 158

accreditation of competence for research ethics, measures for

demonstrating, vii, xiv, 49–50

adverse events reporting requirements for, xx, 117 

adverse events review, requirements for, xix, xx, 114, 115–116,

117

adverse events, FDA reporting requirements for, regulatory text,

213–216

assurances of compliance for research standards by, xiv, 50–51, 52

audits, institutional, for research standards compliance by, xiv, 53

children as research subjects, protections for, requirements for,

45 CFR 46, Subpart D, 184

competence in research ethics, measures for demonstrating, xiv,

48–50

compliance oversight investigations resulting in

restrictions/actions to MPAs, listing by institution, 54–56

compliance with research standards by, mechanisms for 

ensuring, xiv, 50–53

compliance with research standards of, by investigators, 

monitoring for verification, xiv, 57–58

composition of and conflict of interest, issues for, 63–64

conflict of interest and institutional role of, measures for 

managing, xv, 61–63, 64

conflict of interest and, measures for managing, xv–xvi, 64

cooperative research local review by, alternatives to, 120–122

cooperative research local review by, pros/cons, 118–119,

119–120

cooperative research review by, foreign models of, 121–122

cooperative research review role of, xx, 122

cooperative research review, current requirements and 

problems, xx, 118

education on human participants protection, measures needed

for, vi–vii, xiii, 45–48

educational needs on human participants research, 15

functions/operations of, requirements for, 21 CFR 56, Subpart

C, in entirety, 198–201

human participants research, current oversight burdens of,

13–15

human participants research, general provisions for, 21 CFR 56,

Subpart A, in entirety, 195–198

human participants research, proposed oversight system, and

ethical review, xii, 23–24

human participants research, proposed oversight system, and

enforcement of requirements, xii, 25–26

human participants research, proposed oversight system, and

functions/responsibilities of, xi–xii, 23–27

human participants research, proposed oversight system, and

monitoring, xii, 24–25

human participants research, report implications for, 136–137

human participants research, requirements for, 45 CFR 46,

Subpart A, 173–176

human participants research, resources for, 131, 133

human participants research, responsibilities of, issues 

concerning, xix–xx, 111–126

human participants research, revised oversight system, as

dynamic/responsive structure, 134–135

independent, emergence of, 6

informed consent documentation requirements of, xviii, 104

informed consent requirements of, waiver of, xviii, 102, 103

membership and conflict of interest, measures for managing,

xv–xvi, 60–61, 64

monitoring of ongoing research, responsibilities of, xix–xx,

111–117

multi-site research studies, and human participants, 14

noncompliance with federal regulations by, administrative

actions for, 21 CFR 56, Subpart E, in entirety, 201–203

organization/personnel of, requirements for, 21 CFR 56,

Subpart B, in entirety, 198

pregnant women, fetuses, and in vitro fertilization, research 

protections for, requirements for, 45 CFR 46, Subpart B, 180

prisoners in biomedical/behavioral research, protections for,

requirements for, 45 CFR 46, Subpart C, 182–183

protocol changes and unanticipated problems, local institutions

responsibilities, xix, 112–113, 117

records/reports of, requirements for, 21 CFR 56, Subpart D, in

entirety, 201

research approval by, current regulations for, 69–71

research risks v. potential benefits analysis, xvi–xvii, 69–85, 93

research risks v. potential benefits, component-based framework

for analysis, 76–77, 78, 81–82

research risks v. potential benefits, component-based framework

for analysis, examples, 81–82 

research risks v. potential benefits, relationship, assessment of,

74–75

review process for research of, 79

review, continuing, of ongoing research, responsibilities of, 

xix, 117

review, levels of, for human participants research, oversight 

system proposal for, xiii, 41–42

Index
National Bioethics Advisory Commission

237

risk, minimal, for human research participants, review of, 

oversight proposal, 24

risk, minimal, research classification, use as sorting mechanism

for review, 84

risks v. potential benefits of human participants research, 

analysis in review process, ii–iv, 79

site inspections by FDA to ensure compliance with research

standards, xiv, 52–53

vulnerability of research participants, evaluation of, xvii, 85–93

See also Ethics review and review committees

Internal Revenue Service (IRS), 34, 40

International Conference on Harmonization (ICH), 123

Internet, 7

Interventions. See Health care

Interviews

face-to-face, research risks/potential benefits analysis example, 81

Investigational device exemption (IDE), 193 

Investigational new drug application (IND), 190, 191, 193

adverse research events, FDA reporting requirements for, 

regulatory text, 213–216

Investigators

accreditation for competence of, measures for demonstrating,

xiv, 49–50

certification of competence of research individuals, vii, xiv,

48–49

compliance with research standards by, monitoring for 

verification, xiv, 57–58

conflict of interest for, measures for managing, xiv–xv, 58–60

education on human participants research, measures needed

for, vi–vii, xiii, 45–48

human participants research, report implications for IRBs/

investigators/institutions, 136–137

monitoring of ongoing research, local institutions responsibilities,

xix, 117

oversight system, proposed, functions and responsibilities of, 26

oversight system, proposed, monitoring, xii, 24–25

oversight system, proposed, enforcement of requirements, xii,

25–26

recommendations of NBAC for, xiv, xv–xvi, xiii, xix, 47–48, 50,

64, 117

See also Research

Investment

research, changes in trends in, 4

In Vitro fertilization (IVF)

research activities involving, protections for, 45 CFR 46,

Subpart B, in entirety, 179–182

IOM. See Institute of Medicine (IOM)

IRBs. See Institutional Review Boards (IRBs)

IRS. See Internal Revenue Service (IRS) 

J

Joint United Nations Programme on HIV/AIDS (UNAIDS), 33, 123

Jonas, Hans, i, ii

Justice

human research participants protection and, from Belmont

Report, 163–164

human research participants selection and relevance, from

Belmont Report, 167

individual, and human research participants selection, 167

social, and human research participants selection, 167

L

Languages

German, interview, face-to-face, risks/potential benefits analysis

example, 81

Hebrew, interview, face-to-face, risks/potential benefits analysis

example, 81

Levine, Robert J., 75

Local entities

adverse events reporting requirements for, xix–xx, 113–117

adverse events review, requirements for, 114, 115–116

compensation for research-related injuries, role of, xx, 123–126

cooperative research review, by, alternatives to, 120–122

cooperative research review, by, considerations, 118–120

cooperative research review, role of, 122

human participants research responsibilities of, issues 

concerning, xix–xx, 111–126

monitoring of ongoing research, responsibilities of, xix–xx,

111–117

Los Angeles, California, 119

See also California

M

Macon County, Alabama, 153

Massachusetts Eye and Ear Infirmary

research compliance investigations resulting in

restrictions/actions, 54

Maternity. See Pregnancy

Maryland, 56

See also University of Maryland, Baltimore

Medicaid, 5

Medical care. See Health care

Medical centers

academic, and research universities, stresses on, 4, 6

Medical devices

research adverse events, FDA reporting requirements, 114, 115

Medical interventions/treatment. See Health care 

Medical University of South Carolina

research compliance investigations resulting in

restrictions/actions, 54
238

Medicare, 5, 7

Memorial-Sloan Kettering Cancer Center

research compliance investigations resulting in

restrictions/actions, 54

Mental diseases and disorders

vulnerable persons targeted for research, listing by sponsoring

agency, 86

See Diseases and disorders

Milgram, S., 71

Minnesota. See University of Minnesota

Monitoring

human research participants protection, local institutions

responsibilities for, xix–xx, 111–117

human research participants protection, oversight enforcement

weaknesses, 12–13

human research participants protection, oversight proposal for,

xii, 24–25

research standards compliance by investigators, verification of,

xiv, 57–58

Moreno, Jonathan, 9, 22

MPAs. See Multiple Project Assurances (MPAs)

Mt. Sinai School of Medicine

research compliance investigations resulting in

restrictions/actions, 56

Multiple Project Assurances (MPAs), 8, 14, 46, 52, 118

compliance investigations by OPRR resulting in

restrictions/actions to, listing by institution, 54–56

See also Assurances of compliance; Compliance; Office for

Human Research Protections (OHRP)

Multi-site research. See Cooperative research

N

NAS. See National Academy of Sciences (NAS)

NASA. See National Aeronautics and Space Administration (NASA)

National Academy of Sciences (NAS), 47

National Aeronautics and Space Administration (NASA), 5, 11,

132, 205

human participants research, regulations of, 157

National Bioethics Advisory Commission (NBAC), ii, xi, xviii, 1, 5,

7, 16, 21, 22, 24, 26, 30, 31, 32, 33, 34, 35, 38, 39, 41, 45, 46,

47, 48, 52, 53, 60, 63, 71, 72, 75, 76, 84, 85, 92, 97, 99, 100,

101, 102, 103, 104, 106, 107, 116, 117, 119, 123, 125, 131, 133

accreditation of competence of research institutions/IRBs, 

recommendations, xiv, 50

adverse events reporting requirements for, recommendations,

xx, 117 

certification of competence of research individuals, 

recommendations, xiv, 48–49

compensation for research-related injuries, recommendations,

xx, 126

compliance with research standards by institutions/IRBs/

investigators, ensuring, recommendations, xiv, 58

confidentiality for research participants, proposed definition for,

107

confidentiality for research participants, recommendation, xviii,

107

conflict of interest and investigators/IRBs/institutions, 

recommendations, xv–xvi, 64

cooperative research review, requirements for, recommendations,

xx, 122

education on research ethics and human participants protection,

education on, recommendations, xiii, 47–48

human participants research, defining for oversight coverage

determination, recommendations, xii, 40

human participants research, ethical and policy issues in, 

recommendations summary, xi–xxi

human participants research, ethical issues for, future research

recommendations, xxi, 134

human participants research, report recommendations for, 

general themes in, 135

human participants research, resources for, recommendations,

xx–xxi, 133

human participants research, revised oversight system for,

scope/structure, recommendations, xii, 28, 30

human participants research, unified/comprehensive federal

policy for, recommendations, xii, 30

informed consent documentation requirements for human 

participants, recommendation, xviii, 104

informed consent requirements for human participants, previous

recommendations on, 98

informed consent requirements for human participants, process

emphasis, recommendations, xvii, 101

informed consent requirements for human participants, waiver

of, recommendations, xviii, 102, 103

IRB membership/composition and conflict of interest, 

recommendations, xv–xvi, 64

monitoring of ongoing research, local institutions responsibilities,

recommendations, xix, 117

National Office for Human Research Oversight creation, 

recommendations, xii, 28, 30

privacy for research participants, proposed definition for, 106

privacy for research participants, recommendation, xviii, 107

research protocol changes and unanticipated problems, local

institutions role, recommendations, xix, 117

research risks v. potential benefits, analysis of, recommendations,

xvi–xvii, 77, 85

review, continuing, of ongoing research, IRBs responsibilities,

recommendations, xix, 117

review, levels of, for human participants research, oversight 

proposal for, recommendations, xiii, 41–42

risk, minimal, of research, federal policy on, recommendation,

xvi–xvii, 85

vulnerability of research participants, definition of, 

recommendation, xvii, 92

National Cancer Institute (NCI), 121

National Center for Educational Statistics Confidentiality Statute,

105, 107

National Center for Health Statistics, 39

Index
National Bioethics Advisory Commission

239

National Commission. See National Commission for the Protection

of Human Subjects of Biomedical and Behavioral Research

(National Commission)

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (National Commission), i, 34,

35, 45, 50, 57, 58, 62, 83, 112, 118, 120, 124, 131, 153–154,

155, 161, 207

Institutional Review Boards, 76

Research Involving Children, 75

Research on the Fetus, 75

Research Involving Prisoners, 75

research risks/potential benefits, historical perspective, 75–76

See also Belmont Report: Ethical Principles and Guidelines for the

Protection of Human Subjects of Research

National Heart, Lung, and Blood Institute, 7–8

National Human Experimentation Board, 153

National Institutes of Health (NIH), 3, 7, 10, 11, 15, 28, 30, 46,

48, 113, 116, 118, 131, 132, 133, 151, 152, 153, 155, 170, 172,

174

Clinical Center, 34, 151, 152

Director, 152, 208

Division of Research Grants, 50, 152

Institutional Relations Branch, 152

Office of Extramural Research, 8

Reducing Regulatory Burden, 133

research compliance investigations by OPRR resulting in restrictions/actions to MPAs, 54

See also Department of Health and Human Services (DHHS);

Office for Protection from Research Risks (OPRR)

National Office for Human Research Oversight (NOHRO), 40, 84

advantages v. disadvantages of, 30–31

creation of, vi, xii, 28, 30–32

operating mode of, 31–32

private sector research, regulation of, 32 

National Research Act. See Public Law 93–348

National Science Foundation (NSF), 5, 11, 53, 132, 205

Directorate of Social, Behavioral and Economic Sciences, 5

human participants research, regulations of, 157

Office of Inspector General, 53

site inspections to ensure compliance with research standards, 53

Nazis, 34, 81, 151, 164

NBAC. See National Bioethics Advisory Commission (NBAC)

NCI. See National Cancer Institute (NCI)

Netherlands

research-related injuries, compensation for, 123

New York City, 3

See also City University of New York

New York State, 153

See also State University of New York

New York Times, 153

New Zealand

research-related injuries, compensation for, 123

NIH. See National Institutes of Health (NIH)

NOHRO. See National Office for Human Research Oversight

(NOHRO)

NRC. See Nuclear Regulatory Commission (NRC)

NSF. See National Science Foundation (NSF)

Nuclear Regulatory Commission (NRC), 31

See also Department of Energy (DOE)

Nuremberg Code, 151, 152, 161

Nuremberg Military Tribunal, 151

Nuremberg War Crime Trials, ii, 161

O

“Obedience to Authority” experiments, 71

Office for Human Research Protections (OHRP), 8, 9, 10, 12, 13,

15–16, 28, 30, 31–32, 49, 52, 58, 61, 62–63, 100, 121, 124, 133,

152

“Common Findings and Guidance,” 13

site inspections to ensure compliance with research standards, 53

See also Cooperative Project Assurance (CPA); Multiple Project

Assurances (MPAs); Office for Protection from Research Risks

(OPRR); Single Project Assurances (SPAs)

Office for Protection from Research Risks (OPRR), 3, 8, 10, 14, 15,

30, 46, 58, 83, 102, 119, 121, 133, 152, 154, 170, 172, 174

compliance investigations of, resulting in restrictions/actions to

MPAs, listing by institution, 54–56

IRB Guidebook, 70

OPRR Reports, 154

site inspections to ensure compliance with research standards, 53

See also National Institutes of Health (NIH); Office for Human

Research Protections (OHRP)

Office of Government Ethics (OGE), 31

See also Office of Personnel Management (OPM)

Office of Personnel Management (OPM), 31

See also Office of Government Ethics (OGE)

Office of Science and Technology Policy (OSTP), xi, 1, 155

human participants research, regulations of, 157

See also White House

Office of Special Education and Rehabilitative Services

human participants research, regulations of, statutory authority

for, 209

Office of the President

Committee on Science, National Science and Technology

Council, 154

See also President of the U.S.

OGE. See Office of Government Ethics (OGE)

Opinion. See Public opinion

OHRP. See Office for Human Research Protections (OHRP)
240

OPM. See Office of Personnel Management (OPM)

OPRR. See Office for Protection from Research Risks (OPRR)

OSTP. See Office of Science and Technology Policy (OSTP)

Oversight 

accreditation of competence of research institutions/IRBs, vii,

xiv, 49–50

adverse research events, FDA reporting requirements, 113–114,

115, 116, 213–216

adverse research events, reporting requirements for local institutions, xix–xx, 113–117

biomedical/behavioral research, prisoners in, and, 45 CFR 46,

Subpart C, in entirety, 182–184

certification of competence of research individuals, vii, xiv,

48–49

children as research subjects, 45 CFR 46, Subpart D, in entirety,

184–186

compliance with research standards by institutions/IRBs/

investigators, mechanisms for ensuring, xiv, 50–58

conflict of interest for research IRBs, measures for managing,

60–63

cooperative research review, current requirements and 

problems, xx, 118

cooperative research review, requirements for IRBs, 122

education on human participants protection, measures needed

for, vi–vii, xiii, 45–48

educational programs for human participants research, proposal

for, xii, 23

health services research/program evaluation, determining 

coverage, 36–37

human participants research, Common Rule and agencyspecific regulations, 157

human participants research, consequences of flawed system, 16

human participants research, current protection of, 29

human participants research, current system, challenges for,

8–16

human participants research, current system, description of,

154, 155–156, 157

human participants research, current system, enforcement

weaknesses, 12–13

human participants research, current system, IRB burdens,

13–15

human participants research, current system, lack of adaptability

of, 11–12

human participants research, current system, limited scope of, 12

human participants research, current system, procedural v. 

ethical emphasis of, 13

human participants research, defining for coverage determination,

xii–xiii, 34–42

human participants research, ethical issues for, future research

on, xxi, 134

human participants research, exemptions possible, 37–41

human participants research, federal agency regulations and,

statutory authority for, 205–211

human participants research, federal regulations on, 21 CFR 50,

Subpart A, in entirety, 187–189

human participants research, federal regulations on, 45 CFR 46,

Subpart A, in entirety, 169–179

human participants research, flawed, for, consequences, 16

human participants research, history of, 151–154

human participants research, inconsistencies among agencies, 

9, 10

human participants research, percent exempt from, listing by

agency, 11 

human participants research, possible exemptions from, 37–41

human participants research, proposal for, independent office,

vi, xii, 28, 30–32

human participants research, proposed system for, independent

office for, vi, xii, 28, 30–32

human participants research, proposed system,

functions/responsibilities of all parties, xi–xii, 23–27 

human participants research, proposed system, as

dynamic/responsive structure, 134–135

human participants research, proposed system, educational 

programs for all parties, xii, 23

human participants research, proposed system, enforcement of,

xii, 25–26

human participants research, proposed system, ethical review of

research, vii–viii, xii, 23–24

human participants research, proposed system, functions and

responsibilities of, xi–xii, 23–27 

human participants research, proposed system, monitoring for,

xii, 24–25

human participants research, proposed system, National Office

for Human Research Oversight for, xii, 28, 30–32

human participants research, proposed system, overview of,

xi–xiii, 21–42

human participants research, proposed system, policy 

development through regulations/guidance, xii, 23

human participants research, proposed system, public 

accountability of, xii, 26

human participants research, proposed system, recommendations

for, general themes in, 135

human participants research, proposed system, resources for,

viii, xx–xxi, 131, 133

human participants research, proposed system, scope and 

structure, vii, xii, 26–32

human participants research, proposed system, unified/

comprehensive policy for, v–vi, xii, 28, 30–32 

human participants research, protection for, ACHRE 

recommendations, 158

human participants research, purpose of, i–ii, xi, 2–4, 21–22

human participants research, recent government interest in,

156

human participants research, recent initiatives for, 15–16

human participants research, report implications for IRBs/

investigators/institutions, 136–137

human participants research, report implications for participants,

137

human participants research, report recommendations for, 

general themes in, 135

human participants research, resources for, viii, xx–xxi, 131, 133

Index
National Bioethics Advisory Commission

241

informed consent for human participants research, 21 CFR 50,

Subpart B, in entirety, 189–195

informed consent requirements for research participants, 

deficiencies in, 98

informed consent requirements for research participants,

scope/structure of, iv, xvii, 97–104

IRB approval for research, current regulations for, 69–71

IRB functions/operations for human participants research, 21

CFR 56, Subpart C, in entirety, 198–201

IRB noncompliance for human participants research, 21 CFR

56, Subpart E, in entirety, 201–203

IRB organization/personnel and human participants research,

21 CFR 56, Subpart B, in entirety, 198

IRB records/reports and human participants research, 21 CFR

56, Subpart D, in entirety, 201

IRBs and, general provisions for, 21 CFR 56, Subpart A, in

entirety, 195–198

medical practice v. research, distinction for determining 

coverage, 34–37

pregnant women, fetuses, and in vitro fertilization in research,

45 CFR 46, Subpart B, in entirety, 179–182

prisoners in biomedical/behavioral research and, 45 CFR 46,

Subpart C, in entirety, 182–184

privacy and confidentiality protection for research participants,

104–105

research protocol changes and unanticipated problems, local

institutions responsibilities, xix, 112–113, 117

research, ongoing, monitoring responsibilities of local 

institutions, xix, 117

research-related injuries, compensation for, current 

requirements, v, 123–124

review for, levels of, proposal for, vii–viii, xiii, 41–42

review, continuing, of ongoing research, IRBs responsibilities,

xix, 117

review, levels of, for human participants research, proposal for,

vii–viii, xiii, 41–42

risk, minimal, research classification, definition in, xvi, 80,

83–84

risks, research, v. potential benefits, analysis in IRB review

process, ii–iv, 79

vulnerability and human participants research, issues, iv–v, 9,

11

vulnerability of research participants, current protections for,

85–92

See also Federal regulation; Public policy 

P

Papers commissioned

human research participants protection, ethical and policy

issues, 225–226

Participants. See Protections for human participants

Peckman, Steven, 119

Pennsylvania. See University of Pennsylvania

Personal finance

disadvantaged persons targeted for research, listing by 

sponsoring agency, 86

vulnerability in research participants, considerations, 90

Personnel

human participants research, resources for, xx–xxi, 131, 133

human participants research, federal support for FY 1999, 

listing by agency, 132

Phillips, D.F., 9

PHS. See Public Health Service (PHS)

P.L. 93–348. See Public Law 93–348

Policy. See Public policy

Postal service

questionnaire, mail, for study of state law effects on behavior,

risks/potential benefits analysis example, 81

Practice of health care/medicine. See Health care

Pregnancy

research activities on, protections for, 45 CFR 46, Subpart B, in

entirety, 179–182

vulnerable persons targeted for research, listing by sponsoring

agency, 86

See also Embryos and embryonic materials; Fetus and fetal 

tissue

President of the U.S., 190, 191

Memorandum of, 11

See also Office of the President

President’s Commission. See President’s Commission for the Study

of Ethical Problems in Medicine and Biomedical and Behavioral

Research (President’s Commission)

President’s Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research (President’s

Commission), i, v, xx, 45–46, 50–51, 52, 57–58, 112, 124, 

126, 154

See also Compensating for Research Injuries; Implementing Human

Research Regulations

PRIM&R. See Public Responsibility in Medicine and Research

(PRIM&R)

Prisoners

biomedical/behavioral research subjects, protections for, 

45 CFR 46, Subpart C, in entirety, 182–184

vulnerable persons targeted for research, listing by sponsoring

agency, 86

Privacy 

definition for human research participants proposed by NBAC,

106

research participants protection, current regulations on,

104–105

research participants protection, issues for, xviii, 106–107

research participants protection, NBAC recommendation, 

xviii, 107

See also Confidentiality 
242

Private sector

research involving human participants, recommendations of

President’s Commission, 155

research involving human participants sponsored by, proposed

regulation by NOHRO, 32

Professional societies

human participants research, proposed oversight system for,

responsibilities of, 27

research ethics and human participants research, programs in,

measures needed for, xiii, 48

Protection of Pupil Rights Amendment, 104–105

Protections for human participants

accreditation of competence for institutions/IRBs, vii, xiv, 49–50

adverse events FDA reporting requirements for, 113–114, 115,

213–216

adverse events reporting requirements for local institutions,

xix–xx, 113–117

adverse events review, requirements for local institutions/IRBs,

114, 115–116

beneficence, relevance for, from Belmont Report, 162–163,

165–167

benefits, potential, to others, 74

benefits, potential, to participants, 73–74

benefits, potential, to society, 73

benefits, potential, types, 73–74

biomedical/behavioral, prisoners in, and, 45 CFR 46, Subpart

C, in entirety, 182–184

certification of competence of individuals, vii, xiv, 48–49

children as subjects, 45 CFR 46, Subpart D, in entirety,

184–186

communities/groups and, consideration of, 7–8

compensation for research-related injuries, current situation,

123–125

compensation for research-related injuries, need for, v, 125–126

compensation for research-related injuries, previous 

recommendations for program, 124–125

compensation for research-related injuries, role of local 

institutions, xx, 123–126

competence for, measures for demonstrating, xiv, 48–50

compliance investigations by OPRR resulting in

restrictions/actions to MPAs, listing by institution, 54–56

compliance with standards by institutions/IRBs/investigators,

mechanisms for ensuring, xiv, 50–58

conflict of interest for investigators, measures for managing,

xiv–xv, 58–60

conflict of interest for IRBs, measures for managing, xv, 60–64

cooperative research review, by IRBs, foreign models of,

121–122

cooperative research review, by local IRBs, alternatives to,

120–122

cooperative research review, by local IRBs, considerations,

118–120

cooperative research review, current requirements and 

problems, xx, 118

cooperative research review, role of local IRBs/institutions, 122

defining for oversight coverage determination, xii–xiii, 34–42

education on, measures needed for, vi–vii, xiii, 45–48

ethical and policy issues for, papers commissioned on, 225–226

ethical and policy issues for, public comments on, 217–220

ethical and policy issues for, testimony, public/expert, on,

221–223

ethical issues for, future research on, xxi, 133–134

ethical principles/guidelines for, Belmont Report text in entirety,

161–167

federal agency regulations for, statutory authority for, 205–211

federal agency support for FY 1999, listing by agency, 132

federal protection for, 29

federal regulations of Common Rule and specific agencies, 157

federal regulations on, 21 CFR 50, Subpart A, in entirety,

187–189

federal regulations on, 45 CFR 46, Subpart A, in entirety,

169–179

federal regulations on, exemptions from, percent listing by

agency, 11 

federal regulations on, inconsistent interpretation/implementation by agencies, 9, 10

federally supported research, size and scope of, 5

government recent interest in, 156

health services research/program evaluation, determining 

oversight coverage, 36–37

informed consent disclosure requirements for, emphasis on,

issues, xvii, 98–100

informed consent disclosure requirements for, listing, 99

informed consent documentation requirements for, discussion

of, xviii, 103–104

informed consent for, 21 CFR 50, Subpart B, in entirety,

189–195

informed consent for, ethical considerations, from Belmont

Report, 164–165

informed consent process for, emphasis on, discussion of, iv,

xvii, 98–101

informed consent requirements for, deficiencies in, 98

informed consent requirements for, scope/structure of, 97–104

informed consent requirements for, waiver of, discussion,

xvii–xviii, 101–103

IRB functions/operations and, 21 CFR 56, Subpart C, in

entirety, 198–201

IRB noncompliance with regulations, actions for, 21 CFR 56,

Subpart E, in entirety, 201–203

IRB organization/personnel and, 21 CFR 56, Subpart B, in

entirety, 198

IRB records/reports and, 21 CFR 56, Subpart D, in entirety, 201

IRB research review process, 79

IRB research studies approval, current regulations for, 69–71

IRBs and, general provisions for, 21 CFR 56, Subpart A, in

entirety, 195–198

justice and participants selection, ethical guidelines from

Belmont Report, 167

justice, relevance for, from Belmont Report, 163–164, 167

local institutions and IRBs responsibilities for, issues for, xix–xx,

111–126

Index
National Bioethics Advisory Commission

243

medical practice v., distinction for determining oversight 

coverage, 34–37

mentally impaired research participants and informed consent,

requirements for, 101

moderate protectionism, explanation, 22

monitoring of ongoing research, local institutions responsibilities,

xix–xx, 111–117

oversight of, need for, i–ii, 2–4 

oversight office, independent, proposed for, vi, xii, 28, 30–32

oversight system for, purpose of, xi, 21–22

oversight system proposed for, as dynamic / responsive 

structure, 134–135

oversight system proposed for, educational programs for all 

parties, xii, 23

oversight system proposed for, enforcement of requirements,

xii, 25–26

oversight system proposed for, ethical review of research,

vii–viii, xii, 23–24

oversight system proposed for, functions/responsibilities of all

parties, xi–xii, 23–27 

oversight system proposed for, monitoring, xii, 24–25

oversight system proposed for, need for unified/comprehensive

federal policy for, v–vi, xii, 28, 30–32 

oversight system proposed for, overview of, xi–xiii, 21–42

oversight system proposed for, policy development through regulations/guidance, xii, 23

oversight system proposed for, public accountability for, xii, 26

oversight system proposed for, recommendations for, general

themes in, 135

oversight system proposed for, resources for, viii, xx–xxi, 131, 133

oversight system proposed for, scope and structure, vii, xii,

26–32

oversight system, current, challenges for, 8–16

oversight system, current, description, 154, 155–156, 157

oversight system, current, enforcement weaknesses of, 12–13

oversight system, current, IRB burdens, 13–15

oversight system, current, lack of adaptability of, 11–12

oversight system, current, limited scope of, 12

oversight system, current, procedural v. ethical emphasis of, 13

oversight system, exemptions possible, 37–41

oversight system, flawed, for, consequences, 16

oversight system, history of, 151–154

oversight system, recent initiatives for, 15–16

pregnant women, fetuses, and in vitro fertilization and, 45 CFR

46, Subpart B, in entirety, 179–182

prisoners in biomedical/behavioral research and, 45 CFR 46,

Subpart C, in entirety, 182–184

privacy and confidentiality for, current regulations on, 104–105

protocol changes and unanticipated problems, local institutions

responsibilities, xix, 112–113, 117

public perspectives about research participation, changes in,

6–7

recommendations of ACHRE for, 158

recommendations of NBAC for, xi–xxi, 28, 30, 40, 41–42,

47–49, 50, 64, 77, 85, 92, 98, 101, 102, 103, 104, 117, 122,

124–126, 133, 134

report implications for, 137

respect for persons, relevance for, from Belmont Report, ii, 162,

164–165

review for, levels of, oversight system proposal for, vii–viii, xiii,

41–42

review, continuing, IRBs responsibilities, xix, 117

risk, minimal, classification, definition in federal regulations,

xvi, 80, 83–84

risk, minimal, classification, use as sorting mechanism for IRB

review, 84

risk, minimizing, 73

risks of harms, to nonparticipants, 72–73

risks of harms, types of, 71–73

risks v. potential benefits analysis for, ethical considerations,

from Belmont Report, 165–167

risks v. potential benefits analysis for, new technologies effects

on, 7

risks v. potential benefits analysis for, xvi–xvii, 69–85, 93

risks v. potential benefits analysis in IRB review process, ii–iv,

79

risks v. potential benefits, balance between, assessment 

procedure, 78–80

risks v. potential benefits, component-based framework for

analysis, 76–77, 78, 81–82

risks v. potential benefits, component-based framework for

analysis, examples, 81–82 

risks v. potential benefits, historical perspective, 75–76

risks v. potential benefits, relationship, assessment of, 74–75

selection of, ethical considerations, from Belmont Report, 167

strong protectionism, explanation, 22

terminology for, 32–33

vulnerability and, current regulatory protections for, 85–92

vulnerability and, definition of, xvii, 92

vulnerability and, evaluation of, xvii, 85–93

vulnerability and, minimal risk and, 92

vulnerability and, oversight issues, iv–v, 9, 11

vulnerability, cognitive/communicative, and, considerations, 88

vulnerability, deferential, and, considerations, 89

vulnerability, economic, and, considerations, 90

vulnerability, institutional, and, considerations, 88–89

vulnerability, medical, and, considerations, 89–90

vulnerability, participants targeted in research, listing by 

sponsoring agency/vulnerability, 86

vulnerability, social, and, considerations, 90–91

weak protectionism, explanation, 22

See also Research

Psychology

experiment to study human cognition/behavior, risk/potential

benefits analysis example, 82

Public

accountability to, for research involving human participants,

oversight system proposal, xii, 26

See also Public comments; Public health; Public opinion; 

Public policy
244

Public comments

human participants research, ethical and policy issues, 217–220

See also Testimony and speakers

Public health

activities, v. research involving human participants, distinction

for determining oversight coverage, 35–36

See also Health care

Public Health Service (PHS), 124, 152

“Policy for Clinical Investigations with Human Subjects,” 152

See also Tuskegee Syphilis Study; Tuskegee Syphilis Study Ad

Hoc Advisory Panel

Public Health Service Act, 29, 105, 106, 187, 188, 189, 196, 197

Public Law 93–348, 153–154, 207

Public opinion

research participation and, changing perspectives, 6–7

Public policy

adverse research events, reporting requirements for, NBAC 

recommendations, xx, 117 

conflict of interest and IRB membership/composition, NBAC

recommendations, xv–xvi, 64

conflict of interest for research investigators/IRBs/institutions,

NBAC recommendations, xv–xvi, 64

education for human participants research, NBAC 

recommendations, xiii, 47–48

human participants research, defining for oversight coverage,

NBAC recommendations, xii, 40

human participants research, ethical principles/guidelines for,

Belmont Report text in entirety, 161–167

human participants research, issues for, NBAC recommendations

summary, xi–xxi

human participants research, issues for, papers commissioned

on, 225–226

human participants research, issues for, public comments on,

217–220

human participants research, issues for, testimony,

public/expert, on, 221–223

human participants research, oversight system proposed for,

development through regulations/guidance, xii, 23

human participants research, oversight system proposed for,

independent office for, vi, xii, 28, 30–32

human participants research, oversight system proposed for,

National Office for Human Research Oversight for, vi, xii, 28,

30–32

human participants research, oversight system proposed for,

scope/structure of, NBAC recommendations, xii, 28, 30

human participants research, oversight system proposed for,

unified/comprehensive policy for, v–vi, xii, 28, 30–32 

human participants research, report implications for IRBs/

investigators/institutions, 136–137

human participants research, report implications for 

participants, 137

review, continuing, of ongoing research, IRBs responsibilities,

NBAC recommendations, xix, 117

review, levels of, for human participants research, NBAC 

recommendations, xiii, 41–42

risk, minimal, of research, and, NBAC recommendation,

xvi–xvii, 85

risks, research, v. potential benefits, analysis of, NBAC 

recommendations, xvi–xvii, 77, 85

vulnerability of research participants, definition of, NBAC 

recommendation, xvii, 92

See also Federal government; Federal regulation

Public Responsibility in Medicine and Research (PRIM&R), 15, 33, 46

Public testimony. See Testimony and speakers

Publishers

scientific, and human participants research, oversight 

responsibilities proposed for, 27

Q

Questionnaires

mail, study of effects of state law on behavior, risks/potential

benefits analysis example, 81

R

Reactions. See Adverse reactions

Recommendations

accreditation of competence of research institutions/IRBs, 

measures for demonstrating, xiv, 50

adverse events reporting requirements for, xx, 117 

certification of competence of research individuals, measures 

for demonstrating, xiv, 48–49

compensation for research-related injuries, xx, 124–125, 126

compliance with research standards by institutions/IRBs/

investigators, mechanisms for ensuring, xiv, 58

confidentiality protection for research participants, xviii, 107

conflict of interest and investigators/IRBs/institutions, measures

for managing, xv–xvi, 64

cooperative research review, requirements for, xx, 122

education on research ethics and human participants, measures

needed for, xiii, 47–48

human participants research, ACHRE recommendations, 158

human participants research, defining for oversight coverage

determination, xii, 40

human participants research, ethical and policy issues in, 

summary of, xi–xxi

human participants research, ethical issues for, future research

on, xxi, 134

human participants research, general themes in, 135

human participants research, oversight proposal for

unified/comprehensive federal policy for, xii, 30

human participants research, oversight system proposal for,

scope and structure, xii, 28, 30

human participants research, proposal for National Office for

Human Research Oversight, xii, 28, 30

human participants research, resources for, xx–xxi, 133

informed consent documentation requirements for human 

participants, xviii, 104

informed consent requirements for human participants, waiver

of, xviii, 102, 103

Index
National Bioethics Advisory Commission

245

informed consent requirements for human participants, xvii,

98, 101

IRB membership/composition and conflict of interest, measures

for managing, xv–xvi, 64

monitoring of ongoing research, local institutions responsibilities,

xix, 117

privacy protection for research participants, xviii, 107

research protocol changes and unanticipated problems, local

institutions responsibilities, xix, 117

research risks, v. potential benefits, analysis of, xvi–xvii, 77, 85

review, continuing, of ongoing research, IRBs responsibilities,

xix, 117

review, levels of for human participants research, oversight 

system proposal for, xiii, 41–42

risk, minimal, of research, Federal policy on, xvi–xvii, 85

vulnerability of research participants, definition of, xvii, 92

Regulation. See Federal government; Federal regulation; Oversight;

Research regulations

Reporting requirements

adverse research events and, xix–xx, 113–117

adverse research events, FDA, 113–114, 115, 213–216

research protocol changes and unanticipated problems, local

institutions responsibilities, xix, 112–113, 117

Research

adverse events, FDA reporting requirements for, regulatory text,

213–216

assurances of compliance for institutions/IRBs, xiv, 50–51, 52

audits, institutional, for standards compliance by

institutions/IRBs, xiv, 53

benefits, potential, to others, 74

benefits, potential, to participants, 73–74

benefits, potential, to society, 73

benefits, potential, types, 73–74

communities/groups consideration for, 7–8

compliance with standards by institutions/IRBs/investigators,

mechanisms for ensuring, xiv, 50–58

conduct of, current factors influencing, 4, 6–8

equipoise of, explanation, 77, 78

ethical issues for, future research on, xxi, 133–134

informed consent processes for various settings, 100–101

injuries from, compensation for, current regulatory requirements,

123–124

injuries from, compensation for, current situation, 125

injuries from, compensation for, need for, v, 125–126

injuries from, compensation for, previous recommendations for

program, 124–125

injuries from, compensation for, role of local institutions, xx,

123–126

IRB approval for studies, current regulations for, 69–71

IRB review process, 79

observational study of effects of state law on behavior,

risks/potential benefits analysis example, 81

participation in, changing public perspectives about, 6–7

practice v., distinction between, from Belmont Report, 161–162

pregnant women, fetuses, and in vitro fertilization in, protections

for, 45 CFR 46, Subpart B, in entirety, 179–182

risk of harms to nonparticipants, 72–73

risk of harms, minimizing, 73

risk of harms, types of, 71–73

risks v. potential benefits, analysis in IRB review process, 79

risks v. potential benefits, balance between, assessment 

procedure, 78–80

risks v. potential benefits, component-based framework for

analysis, 76–77, 78, 81–82

risks v. potential benefits, component-based framework for

analysis, examples, 81–82 

risks v. potential benefits, historical perspective, 75–76

risks v. potential benefits, relationship, assessment of, 74–75

site inspections by FDA to ensure IRBs compliance with 

standards, xiv, 52–53

site inspections to ensure compliance with standards, xiv, 53

universities for, and academic medical centers, stresses on, 4, 6

value of, summary, 1–2 

See also Behavioral research; Biomedical research; Clinical trials;

Cooperative research; Health services research; Investigators;

Protections for human participants; Research documents;

Research funding; Research institutions; Research regulations;

Science and technology; Sponsors

Research design. See Equipoise; Research

Research documents

IRB records/reports requirements, 21 CFR 56, Subpart D, in

entirety, 201

See also Research

Researchers. See Investigators

Research funding

academic medical centers and research universities, stresses 

on, 4, 6

human participants protection, federal support for FY 1999,

listing by agency, 132

human participants protection, resources for, viii, xx–xxi, 

131, 133

investment trends for, changes in, 4

See also Federal funding for research; Research

Research institutions

accreditation for research ethics competence, measures for

demonstrating, vii, xiv, 49–50

adverse events FDA reporting requirements, 113–114, 115

adverse events reporting requirements for, xix–xx, 113–117

adverse events review, requirements for, 114, 115–116

assurances of compliance for research standards, xiv, 50–51, 52

audits, institutional, for research standards compliance by, xiv,

53

compensation for research-related injuries, role of, xx, 123–126

compliance oversight investigations resulting in

restrictions/actions to MPAs, listing by institution, 54–56

compliance with research standards by, mechanisms for 

ensuring, xiv, 50–53

conflict of interest for, measures for managing, xiv–xv, 58–64
246

Index

cooperative research review by local IRBs, alternatives to,

120–122

cooperative research review by local IRBs, considerations,

118–120

cooperative research review, current requirements and problems, xx, 118

cooperative research review, role of local IRBs/institutions, 122

education on human participants protection, measures needed

for, vi–vii, xiii, 45–48

human participants research responsibilities of local institutions, issues concerning, xix–xx, 111–126

human participants research, report implications for IRBs/

investigators/institutions, 136–137

monitoring of ongoing research, local institutions responsibilities, xix–xx, 111–117

oversight system, proposed, for human participants research,

functions and responsibilities of, 26–27

oversight system, proposed, for human participants research,

monitoring, xii, 24–25

oversight system, proposed, for human participants research,

enforcement of requirements, xii, 25–26

protocol changes and unanticipated problems, reporting

requirements for, xix, 112–113, 117

site inspections to ensure compliance with research standards,

xiv, 53

See also Research

Research Involving Persons with Mental Disorders That May Affect

Decisionmaking Capacity, vii

Research regulations

accreditation of competence of institutions/IRBs, vii, xiv, 49–50

adverse events, FDA reporting requirements, 113–114, 115,

116, 213–216

adverse events, reporting requirements for local institutions,

xix–xx, 113–117

biomedical/behavioral, prisoners in, and, 45 CFR 46, Subpart

C, in entirety, 182–184

certification of competence of individuals, vii, xiv, 48–49

children as subjects, 45 CFR 46, Subpart D, in entirety,

184–186

compliance with standards by institutions/IRBs/investigators,

mechanisms for ensuring, xiv, 50–58

conflict of interest for IRBs, measures for managing, 60–63

cooperative review, current requirements and problems, xx, 118

cooperative review, requirements for IRBs, 122

education on human participants protection, measures needed

for, vi–vii, xiii, 45–48

educational programs on human participants protection, 

oversight system proposal for, xii, 23

human participants, Common Rule and agency-specific 

regulations, 157

human participants, consequences of flawed system, 16

human participants, current oversight system, challenges for,

8–16

human participants, current protection of, 29

human participants, defining for oversight coverage 

determination, xii–xiii, 34–42

human participants, description of, 154, 155–156, 157

human participants, enforcement weaknesses, 12–13

human participants, ethical issues for, future research on, xxi, 134

human participants, federal regulations on, 21 CFR 50, 

Subpart A, in entirety, 187–189

human participants, federal regulations on, 45 CFR 46, 

Subpart A, in entirety, 169–179

human participants, history of, 151–154

human participants, inconsistencies among agencies, 9, 10

human participants, IRB burdens in, 13–15

human participants, lack of adaptability in, 11–12

human participants, limited scope of, 12

human participants, oversight independent office proposed for,

vi, xii, 28, 30–32

human participants, oversight possible exemptions, 37–41

human participants, oversight system proposal for, xi–xiii,

21–42

human participants, oversight system for, purpose of, i–ii, xi,

2–4, 21–22

human participants, oversight system for, resources for, viii,

xx–xxi, 131, 133

human participants, oversight system proposal for enforcement

of, xii, 25–26

human participants, oversight system proposal for ethical

review of research, xii, 23–24

human participants, oversight system proposal for monitoring,

xii, 24–25

human participants, oversight system proposal for National

Office for Human Research Oversight for, xii, 28, 30–32

human participants, oversight system proposal for policy 

development through, xii, 23

human participants, oversight system proposal for public

accountability, xii, 26

human participants, oversight system proposal for unified/

comprehensive policy for, v–vi, xii, 28, 30–32 

human participants, oversight system proposal for, as

dynamic/responsive structure, 134–135

human participants, oversight system proposal for, scope and

structure, xii, 26–32

human participants, oversight system proposed for, functions

and responsibilities of, xi–xii, 23–27 

human participants, percent exempt from, listing by agency, 11 

human participants, procedural v. ethical emphasis, 13

human participants, protection for, ACHRE recommendations,

158

human participants, recent government interest in, 156

human participants, recent initiatives for, 15–16

human participants, report implications for IRBs/investigators/

institutions, 136–137

human participants, report implications for participants, 137

human participants, report recommendations for, general

themes in, 135

informed consent for human participants, 21 CFR 50, 

Subpart B, in entirety, 189–195

informed consent requirements for participants, deficiencies 

in, 98
National Bioethics Advisory Commission

247

informed consent requirements for participants, scope/structure

of, iv, xvii, 97–104

injuries, compensation for, current requirements, v, 123–124

IRB approval, current regulations for, 69–71

IRB functions/operations for human participants, 21 CFR 56,

Subpart C, in entirety, 198–201

IRB noncompliance for human participants, actions for, 

21 CFR 56, Subpart E, in entirety, 201–203

IRB organization/personnel and human participants, 

21 CFR 56, Subpart B, in entirety, 198

IRB records/reports and human participants, 21 CFR 56,

Subpart D, in entirety, 201

IRBs and, general provisions for, 21 CFR 56, Subpart A, in

entirety, 195–198

ongoing, monitoring responsibilities of local institutions, xix, 117

pregnant women, fetuses, and in vitro fertilization and, 

45 CFR 46, Subpart B, in entirety, 179–182

prisoners in biomedical/behavioral research and, 45 CFR 46,

Subpart C, in entirety, 182–184

privacy and confidentiality protection for participants, 104–105

protocol changes and unanticipated problems, local institutions

responsibilities, xix, 112–113, 117

review, continuing, IRBs responsibilities, xix, 117

review, levels of, for human participants, oversight system 

proposal for, vii–viii, xiii, 41–42

risk, minimal, classification, definition in, xvi, 80, 83–84

risks v. potential benefits, analysis in IRB review process, ii–iv, 79

vulnerability of participants, current protections for, 85–92

vulnerable participants protection, oversight issues, iv–v, 9, 11

See also Research

Research review. See Ethics review and review committees;

Institutional Review Boards (IRBs)

Resources

human participants research, federal support for FY 1999, 

listing by agency, 132

human participants research oversight system and, viii, xx–xxi,

131, 133

Respect for persons

research participants informed consent and, ethical guidelines

from Belmont Report, 164–165

research participants protection and, from Belmont Report, ii,

162, 164–165

See also Ethics

Review bodies. See Ethics review and review committees;

Institutional Review Boards (IRBs)

Risks

informed consent requirements for research participants and,

xviii, 102, 103

levels of, review for, oversight system proposal for, vii–viii, xiii,

41–42

minimal, of research, Federal policy on, NBAC recommendation,

xvi–xvii, 85

minimal, research classification, definition in federal regulations,

xvi, 80, 83–84

minimal, research classification, use as sorting mechanism for

IRB review, 84

minimal, research involving no more than for human participants,

IRB review of, oversight proposal, 24

minimal, use related to vulnerability of research participants, 92

research, for nonparticipants, 72–73

research, for participants, minimizing, 73

research, for participants, types of, 71–73

research, v. potential benefits, analysis in IRB review process,

ii–iv, 79

research, v. potential benefits, analysis of, new technologies

effects on, 7

research, v. potential benefits, analysis of, xvi–xvii, 69–85, 93 

research, v. potential benefits, assessment for protection of 

participants, ethical guidelines, 165–167

research, v. potential benefits, balance between, assessment 

procedure, 78–80

research, v. potential benefits, component-based framework for

analysis, 76–77, 78, 81–82

research, v. potential benefits, component-based framework for

analysis, examples, 81–82 

research, v. potential benefits, historical perspective, 75–76

research, v. potential benefits, relationship, assessment of,

74–75

Rothman, D.J., 9

Rush Presbyterian St. Lukes Medical Center

research compliance investigations resulting in

restrictions/actions, 56

S

Safeguards. See Protections for human participants

Sanctions

administrative action, for IRB noncompliance, 21 CFR 56,

Subpart E, in entirety, 201–203

human research participants protection, oversight enforcement

weaknesses, 12–13

research compliance investigations resulting in

restrictions/actions to MPAs, listing by institution, 54–56

Science and technology

IRB scientists membership and conflict of interest, measures for

managing, xv, 62–63, 64

technologies, new, challenges to research risk/potential benefit

analysis, 7

See also Research

Scripps Clinic and Research Foundation, Scripps Research Institute

research compliance investigations resulting in

restrictions/actions, 56

Senate Committee on Governmental Affairs, 8

Senate Labor and Public Welfare Committee, 153

Shannon, James, 152

Single Project Assurances (SPAs), 14, 52, 55, 56

See also Assurances of compliance; Compliance; Office for

Human Research Protections (OHRP)
248

Index

Site inspections

compliance investigations by OPRR resulting in

restrictions/actions to MPAs, listing by institution, 54–56

compliance with research standards by IRBs, FDA, xiv, 52–53

compliance with research standards, site inspections to ensure,

xiv, 53

directed (for cause), of FDA, 53

surveillance (routine), of FDA, 53

Site Management Organizations (SMOs), 6

SMOs. See Site Management Organizations (SMOs)

Social position

vulnerability of research participants, considerations, 90–91

Social Security Act, 10

Social Security Administration (SSA), 9, 10, 11, 85, 132, 156

human participants research, regulations of, 157

South Africa

research-related injuries, compensation for, 123

South Carolina. See Medical University of South Carolina

SPAs. See Single Project Assurances (SPAs)

Sponsors

accreditation of competence in research ethics, NBAC 

recommendations, xiv, 50

education on research ethics and human participants protection,

NBAC recommendations, xiii, 47–48

human participants research, proposed oversight system, 

functions and responsibilities of, 27

human participants research, proposed oversight system, 

monitoring, xii, 24–25

research conflict of interest for institutions/IRBs/investigators,

NBAC recommendations, xv, 64

research, ongoing, monitoring of, local institutions responsibilities,

NBAC recommendations, xix, 117

vulnerability, participants targeted in research, listing by 

sponsoring agency, 86

See also Research

SSA. See Social Security Administration (SSA)

State Children’s Health Insurance Program, 5

State laws

behavior effects of state law, observational study of, risks/

potential benefits analysis example, 81

State regulation

human participants research, oversight system proposed for,

responsibilities of, 27

State University of New York

College of Optometry, research compliance investigations

resulting in restrictions/actions, 54

St. Jude Children’s Research Hospital

research compliance investigations resulting in

restrictions/actions, 56

Subordination

deferential vulnerability in research participants, considerations,

89

institutional vulnerability in research participants, considerations,

88–89

Substance Abuse and Mental Health Services Administration, 5,

11, 132

See also Department of Health and Human Services (DHHS)

Substantive standard of informed consent. See Informed consent

Syphilis, 46, 153, 164

T

Technology. See Science and technology

Terminology

research involving human participants, discussion, 32–33

Testimony and speakers

human research participants protection, issues for, testimony,

public/expert, on, 221–223

See also Public comments

Translation. See Languages

Treatment. See Health care

Trials. See Clinical trials

Tuskegee, Alabama, 153, 164

Tuskegee Syphilis Study, 46, 153, 164

Tuskegee Syphilis Study Ad Hoc Advisory Panel, 125, 153

Final Report, 124

See also Public Health Service (PHS)

U

Uganda

human participants research, terminology for, 33

research-related injuries, compensation for, 123

UNAIDS. See Joint United Nations Programme on HIV/AIDS

(UNAIDS)

Undue influence. See Coercion 

United Kingdom

cooperative research, IRB review models in, 121

human participants research, terminology for, 33

research-related injuries, compensation for, 123

See also Great Britain

United Nations (UN). See Joint United Nations Programme on

HIV/AIDS (UNAIDS)

United Nations Programme on HIV/AIDS. See Joint United Nations

Programme on HIV/AIDS (UNAIDS)

Universities and colleges

research, and academic medical centers, stresses on, 4, 6

research ethics and human participants protection, programs in,

measures needed for, xiii, 48

See also specific universities and colleges
National Bioethics Advisory Commission

249

University of Alabama at Birmingham

research compliance investigations resulting in

restrictions/actions, 56

University of California, Irvine

research compliance investigations resulting in

restrictions/actions, 55

University of California, Los Angeles

research compliance investigations resulting in

restrictions/actions, 54, 55

University of California, San Diego

research compliance investigations resulting in

restrictions/actions, 54

University of California, San Francisco

research compliance investigations resulting in

restrictions/actions, 54

University of Florida

research compliance investigations resulting in

restrictions/actions, 54

University of Illinois at Chicago

research compliance investigations resulting in

restrictions/actions, 56

University of Maryland, Baltimore

research compliance investigations resulting in

restrictions/actions, 55

University of Minnesota

Department of Surgery, research compliance investigations

resulting in restrictions/actions, 54

University of Pennsylvania, 3

University of Rochester, 3

research compliance investigations resulting in

restrictions/actions, 55

University of South Florida, 3–4

University of Virginia

research compliance investigations resulting in

restrictions/actions, 55

USAID. See Agency for International Development (USAID)

U.S. Congress, 7, 27, 31, 42, 52, 125, 134, 155, 156

human participants research, interest in, 156

human participants research, oversight system proposed for,

responsibilities of, 27

U.S. Department of Agriculture (USDA), 205

Food Safety and Inspection Service, 170, 197

human participants research, regulations of, 157

U.S. district courts, 11

U.S. government. See Federal government; Federal regulation;

Public policy; U.S. Congress

U.S. Public Health Service Act. See Public Health Service Act

V

VA. See Department of Veterans Affairs (VA)

Vaccines and vaccination

safety/immunogenicity, clinical trial on, risks/potential benefits

analysis example, 82

See also Drugs and drug testing

Vanderpool, Harold, Y., 22, 97

Verification

compliance with research standards by investigators, monitoring

for, xiv, 57–58

Veterans Affairs, Greater Los Angeles Health Care System

research compliance investigations resulting in

restrictions/actions, 56

See also Veterans Affairs Medical Center, West Los Angeles

Veterans Affairs Medical Center, West Los Angeles

research compliance investigations resulting in

restrictions/actions, 55

See also Veterans Affairs, Greater Los Angeles Health Care

System

Virginia. See University of Virginia; Virginia Commonwealth

University

Virginia Commonwealth University

research compliance investigations resulting in

restrictions/actions, 56

Voluntary consent. See Coercion; Informed consent

Vulnerability

cognitive/communicative, in research participants, 

considerations, 88

deferential, in research participants, considerations, 89 

economic, in research participants, considerations, 90

institutional, in research participants, considerations, 88–89

medical, in research participants, considerations, 89–90

research participants protection and, current regulatory 

protections for, 85–92

research participants protection and, definition of, NBAC 

recommendation, xvii, 92

research participants protection and, evaluation of, xvii, 85–93

research participants protection and, oversight issues for, iv–v,

9, 11

research participants protection and, use of minimal risk and,

92

research participants targeted for, listing by sponsoring

agency/vulnerability, 86

research participants, aligning protections with, considerations,

91–92

social, in research participants, considerations, 90–91
250

Index

W

Waivers

informed consent requirements and, discussion, xvii–xviii,

101–103

informed consent requirements and, NBAC previous 

recommendations, 102

informed consent requirements and, NBAC recommendation,

xviii, 103

Wayne State University

research compliance investigations resulting in

restrictions/actions, 55

Weijer, Charles, 76

Western Carolina Center

research compliance investigations resulting in

restrictions/actions, 55

West Virginia University

research compliance investigations resulting in

restrictions/actions, 54

White House, xi, 1, 154

See also Office of Science and Technology Policy (OSTP)

Willowbrook State School for the Retarded, 153

Wilson, Charles, 151

Women. See Pregnancy

World Medical Assembly Declaration, 170

World War II, 161



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