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Ethical and

Policy Issues 

in International

Research:

Clinical Trials 

in Developing

Countries

VOLUME I

Report and 

Recommendations of 

the National Bioethics 

Advisory Commission

Bethesda, Maryland

April 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

Cover photo, top right, courtesy of James V. Lavery

ISBN 1-931022-13-5
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Ethical and

Policy Issues 

in International

Research:

Clinical Trials 

in Developing

Countries

VOLUME I

Report and 

Recommendations 

of the National Bioethics 

Advisory Commission

Bethesda, Maryland

April 2001
Table of Contents

Letter of Transmittal to the President

National Bioethics Advisory Commission

National Bioethics Advisory Commission Staff and Consultants

Executive Summary i

Chapter 1: Ethical Issues in International Research—

Setting the Stage 1

Introduction 1

Issues Prompting This Report 3

Scope and Limits of This Analysis 4

Themes and Premises of This Report 5

Conclusions 15

Notes 15

References 16

Chapter 2: Ethical Considerations in the Design and 

Conduct of International Clinical Trials 19

Introduction 19

Ethical Issues in Clinical Trial Design 20

Involvement of the Community and Study Participants 

in the Design of Research 30

Other Issues in Research Design 31

Conclusions 32

Notes 32

References 33

Chapter 3: Voluntary Informed Consent 35

Introduction 35

The Ethical Standard of Informed Consent 36

Cultural Barriers Relating to Disclosure Requirements 38

Other Cultural Issues Relating to the Informed Consent Process 40

Voluntary Participation in Research 45

Documentation of Informed Consent 48

Conclusions 50

Notes 51

References 52

Chapter 4: When Research Is Concluded—

Access to the Benefits of Research by 

Participants, Communities, and Countries 55

Introduction 55

What Should Be Provided to Communities and Countries? 61

Who Should Provide Post-Trial Benefits? 64

Prior Agreements 66

Conclusions and Recommendations 74

Notes 75

References 75

Chapter 5: Ensuring the Protection of Research 

Participants in International Clinical Trials 77

Introduction 77

U.S. Procedures for Ensuring the Protection of 

Human Participants 78

Building Host Country Capacity to Review and 

Conduct Clinical Trials 89

Conclusions 94

Notes 94

References 96

Appendices

Appendix A: Acknowledgments 97

Appendix B: Comparative Analysis of International 

Documents Addressing the Protection 

of Research Participants 99

Appendix C: Prior Agreements 103

Appendix D: Public Comments on NBAC’s 

September 29, 2000, Draft 111

Appendix E: Public and Expert Testimony 115

Appendix F: Commissioned Papers and Staff Analysis 117

Index 119
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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 Medical Ethics

Schools of Law and Medicine

The 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

The 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

The 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

The 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

The 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 and 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

Harold T. Shapiro, Ph.D., Chair

President

Princeton University

Princeton, New Jersey
National Bioethics Advisory 

Commission Staff and Consultants

Executive Director

Eric M. Meslin, 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 Gadbois, Ph.D., Senior Policy Analyst

Stu Kim, J.D., Program Analyst (until October 2000)

Kerry Jo Lee, Program Analyst

Anne Drapkin Lyerly, M.D., Greenwall Fellow

(June–August 2000)

Ayodeji Marquis, Intern (until July 2000)

Debra McCurry, M.S., Information Specialist

Alice K. Page, J.D., M.P.H., Project Manager/

Senior Policy Analyst

Robert S. Tanner, J.D., Research Analyst (until February 2000)

Consultants

Burness Communications, Communications Consultant

Sara Davidson, M.A., Editor

Liza Dawson, Ph.D., Research Consultant

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

Tamara Lee, Graphic Designer

Ruth Macklin, Ph.D., Senior Consultant (until July 2000)

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
Executive Summary

Introduction

I

n recent years, the increasingly global nature of health

research, and in particular the conduct of clinical trials

involving human participants,1 has highlighted a number

of ethical issues, especially in those situations in which

researchers or research sponsors from one country wish

to conduct research in another country. The studies in

question might simply be one way of helping the host

country address a public health problem, or they might

reflect a research sponsor’s assessment that the foreign

location is a more convenient, efficient, or less troublesome site for conducting a particular clinical trial. They

might also represent a joint effort to address an important

health concern faced by both parties.

As the pace and scope of international collaborative

biomedical research have increased during the past

decade, long-standing questions about the ethics of

designing, conducting, and following up on international

clinical trials have re-emerged. Some of these issues have

begun to take center stage because of the concern that

research conducted by scientists from more prosperous

countries in poorer nations that are more heavily 

burdened by disease may, at times, be seen as imposing

ethically inappropriate burdens on the host country 

and on those who participate in the research trials. The

potential for such exploitation is cause for a concerted

effort to ensure that protections are in place for all 

persons who participate in international clinical trials. 

As with other National Bioethics Advisory

Commission (NBAC) reports, several issues and activities

prompted the Commission’s decision to address this

topic. First, several members of the public suggested that

NBAC’s mandate to examine the protection of the rights

and welfare of human participants in research extends 

to international research conducted or sponsored by 

U.S. interests. In this respect, one particular dimension 

of research conducted internationally has attracted a

great deal of attention, namely whether the existing rules

and regulations that normally govern the conduct of 

U.S. investigators or others subject to U.S. regulations

remain appropriate in the context of international

research, or whether they unnecessarily complicate or

frustrate otherwise worthy and ethically sound research

projects.

A second circumstance—the changing landscape of

international research—also is relevant. Increasingly, 

scientists from developing countries are becoming more

involved as collaborators in research, as many of the

countries from which these investigators come have

developed their capacity for technical contributions to

research projects and for appropriate ethical review of

research protocols. Although the source of funding for

such collaborative research is likely to continue to be the

wealthier, developed countries, collaborators from developing countries are seeking—justifiably—to become

fuller and more equal partners in the research enterprise.

Finally, the current landscape of international research

also reflects the growing importance of clinical trials conducted by pharmaceutical, biotechnology, and medical

device companies. Some observers believe that market

forces have pressured private companies to become more

efficient in the conduct of research, which may—absent

vigilance—compromise the protection of research participants. Although the extent, relevance, and force of these

pressures are widely debated, it is clear that such pressures can exist regardless of the funding source.

i
ii

Executive Summary

Scope of This Report

This report discusses the ethical issues that arise

when research that is subject to U.S. regulation is sponsored or conducted in developing countries, where local

technical skills and other key resources are in relatively

scarce supply. Within this context, the Commission’s

attention was focused on the conduct of clinical trials

involving competent adults, in particular those trials—

such as Phase III drug studies—that can lead to the

development of effective new treatments. Complex and

important ethical concerns are likely to be more pressing

in clinical trials than in many other types of research

investigations; thus, the focus of this report has been limited accordingly. Although much of the discussion in this

report is relevant to other types of research, the particular characteristics of research endeavors other than clinical trials probably merit their own ethical assessment.

This report centers on the principal ethical requirements surrounding the conduct of clinical trials conducted by U.S. interests abroad, and in particular the

need for such trials to be directly relevant to the health

needs of the host country. Other major topics addressed

include ethical issues surrounding the choice of research

designs, especially in situations where a placebo control

is proposed when an established effective treatment is

known to exist; issues arising in the informed consent

process in cultures whose norms of behavior differ from

those in the United States; what benefits should be provided to research participants and by whom after their

participation in a trial has ended; and what benefits, if

any, should be made available to others in the host community or country. Finally, it makes recommendations

about the need for developed countries to assist developing countries in building the capacity to become fuller

partners in international research. Until this goal can be

met, however, recommendations are made regarding how

the United States should proceed in settings in which systems for protecting human participants equivalent to

those of the United States have not yet been established.

Essential Requirements for the 

Ethical Conduct of Clinical Trials

Many of the ethical concerns regarding the treatment of

human participants in international research are similar

to those raised in conjunction with research conducted in

the United States.2 They include, among others, choosing

the appropriate research question and design; ensuring

prior scientific and ethical review of the proposed protocol; selecting participants equitably; obtaining voluntary

informed consent; and providing appropriate treatment

to participants during and after the trial. These concerns

are consistent with principles endorsed in many international research ethics documents.

NBAC believes that two types of ethical requirements—

substantive and procedural—must be carefully considered

and distinguished when human research is conducted,

regardless of the location. The principles embodied in the

Belmont Report: Ethical Principles and Guidelines for the

Protection of Human Subjects of Research serve as a foundation for the substantive ethical requirements incorporated into the system of protection of human participants

in the United States. The Belmont Report sets forth three

basic ethical principles, which provide an analytical

framework for understanding many of the ethical issues

arising from research involving human participants:

respect for persons, beneficence, and justice. NBAC

believes that in order to be ethically sound, research 

conducted with human beings must, at a minimum, be

consistent with the ethical principles underlying the

Belmont Report. In addition, ethically sound research

must satisfy a number of important procedural requirements, including prior ethical review by a body that is

competent to assess compliance with these substantive

ethical principles. U.S. research regulations also set forth

more specific rules to guide ethics review committees3

(and researchers) in their work. NBAC believes that when

conducting clinical trials abroad, U.S. researchers and

sponsors should comply with these substantive ethical

requirements for the protection of human research

participants.

Recommendation 1.1 lists protections that should be

provided for individuals participating in U.S. government-sponsored clinical trials, whether conducted

domestically or abroad.4 Although existing U.S. law and

regulations impose limits on the extent to which nonfederally funded research is subject to oversight, the

Commission believes that these requirements should

extend to all clinical trials, regardless of who sponsors or

conducts them.
National Bioethics Advisory Commission

iii

Recommendation 1.1: The U.S. government should

not sponsor or conduct clinical trials that do not, 

at a minimum, provide the following ethical 

protections:

a) prior review of research by an ethics review

committee(s);

b) minimization of risk to research participants; 

c) risks of harm that are reasonable in relation to

potential benefits; 

d) adequate care of and compensation to participants for injuries directly sustained during

research; 

e) individual informed consent from all competent

adult participants in research;

f) equal regard for all participants; and 

g) equitable distribution of the burdens and benefits

of research.

Recommendation 1.2: The Food and Drug

Administration should not accept data obtained

from clinical trials that do not provide the 

substantive ethical protections outlined in

Recommendation 1.1. 

Responsiveness of the Research to 

the Health Needs of the Population

Sponsoring or conducting research in developing countries often poses special challenges arising from the combined effects of distinctive histories, cultures, politics,

judicial systems, and economic situations. In addition, in

countries in which extreme poverty afflicts so many, primary health care services generally are inadequate, and a

majority of the population is unable to gain access to the

most basic and essential health products and services. As

a result of these difficult conditions, the people in these

countries are often more vulnerable in situations (such as

clinical trials) in which the promise of better health

seems to be within reach. 

Whether the research sponsor is the U.S. government

or a private sector organization, some justification is

needed for conducting research abroad other than a less

stringent or troublesome set of regulatory or ethical

requirements. Moreover, when the United States (or any

developed country) proposes to sponsor or conduct

research in another country when the same research

could not be conducted ethically in the sponsoring 

country, the ethical concerns are more profound, and the

research accordingly requires a more rigorous justification.

To meet the ethical principle of beneficence, the risks

involved in any research with human beings must be 

reasonable in relation to the potential benefits. Plainly,

the central focus of any assessment of risk is the potential

harm to research participants themselves (in terms of

probability and magnitude), although risks to others also

are relevant. The potential benefits that are weighed

against such risks may include those that will flow to the

fund of human knowledge as well as to those now and in

the future whose lives may be improved because of the

research. In addition, some of the benefits must also

accrue to the group from which the research participants

are selected. NBAC understands the principle of justice

to require that a population, especially a vulnerable one,

should not be the focus of research unless some of the

potential benefits of the research will accrue to that group

after the trial. Thus, in the context of international

research—and particularly when the population of a

developing country has been sought as a source of

research participants—U.S. and international research

ethics require not merely that research risks are reasonable in relation to potential benefits, but also that they

respond to the health needs of the population being

studied. This is because, according to the principles of

beneficence and justice, only research that is responsive

to these needs can offer relevant benefits to the population.

Recommendation 1.3: Clinical trials conducted in

developing countries should be limited to those

studies that are responsive to the health needs of

the host country.

Choosing a Research Design and the

Relevance of Routine Care

Making a determination about the appropriate design for

a clinical trial depends on various contextual considerations, so that what might be an ethically acceptable

design in one situation could be problematic in another.

For example, it might be unethical to conduct a clinical

trial for a health condition in a country in which that
iv

Executive Summary

condition is unlikely to be found. In comparison, the

same trial might be quite appropriately conducted where

the trial results could be important to the local population. A more challenging question is whether a research

design that could not be ethically implemented in the

sponsoring country can be ethically justified in a host

country when the health problem being addressed is

common to both nations.

In this report, NBAC is especially interested in exploring the following question: Can a research design that could

not be ethically implemented in the sponsoring, developed

country be ethically justified in the country in which the

research is conducted? In all cases, there is an ethical

requirement to choose a design that minimizes the risk of

harm to human participants in clinical trials and that

does not exploit them. Because the choice of a study

design for any particular trial will depend on these 

and other factors, it would be inappropriate—indeed

wrong—to prescribe any particular study design as 

ethical for all research situations. Nevertheless, under

certain, specified conditions, one or another design can

be held to be ethically preferable.

Recommendation 2.1: Researchers should provide

ethics review committees with a thorough justification of the research design to be used, including

the procedures to be used to minimize risks to

participants.

Providing Established Effective Treatment as

the Control

From the perspective of the protection of human participants in research, one of the most critical issues in

clinical trial design concerns the use and treatment of

control groups, which often are an essential component

in methodologies used to guard against bias. Although

placebos are a frequently used control for clinical trials, it

is increasingly commonplace to compare an experimental

intervention to an existing established effective treatment.

These types of studies are called active-control (or positive

control) studies, which are often extremely useful in cases

in which it would not be ethical to give participants a

placebo because doing so would pose undue risk to their

health or well-being. 

Within the context of active treatment concurrent

controls, it is useful to consider whether, and if so under

what circumstances, researchers and sponsors have an

obligation to provide an established effective treatment 

to the control group even if it is not available in the 

host country. This report adopts the phrase an established 

effective treatment to refer to a treatment that is established

(it has achieved widespread acceptance by the global

medical profession) and effective (it is as successful as any

in treating the disease or condition). It does not mean

that the treatment is currently available in that country.

Investigators must carefully explain and ethics review

committees must cautiously scrutinize the justification

for the selection of the research design, including the

level of care provided to the control group. If in a proposed clinical trial the control group will receive less care

than would be available under ideal circumstances, the

burden on the investigator to justify the design should be

heavier. Furthermore, representatives of the host country,

including scientists, public officials, and persons with the

condition under study, should have a strong voice in

determining whether a proposed trial is appropriate. 

Recommendation 2.2: Researchers and sponsors

should design clinical trials that provide members

of any control group with an established effective

treatment, whether or not such treatment is available in the host country. Any study that would not

provide the control group with an established 

effective treatment should include a justification 

for using an alternative design. Ethics review 

committees must assess the justification provided,

including the risks to participants, and the overall

ethical acceptability of the research design.

Community Involvement in Research Design

and Implementation

Over the past three decades, researchers increasingly

have deliberately involved communities in the design of

research. In addition, research participants, health advocates, and other members of the communities from

which participants are recruited have requested, and in

some cases demanded, involvement in the design of clinical trials. By consulting with the community, researchers

often gain insight about whether the research question 

is relevant and responsive to health needs of the community involved. In addition, community consultation

can improve the informed consent process and resolve
National Bioethics Advisory Commission

v

problems that arise in this process because of the use of

difficult or unfamiliar concepts. Such discussions can

provide insight into whether the balance of benefits and

harms in the study is considered acceptable and whether

the interventions and follow-up procedures are satisfactory. Community consultation is particularly important

when the researcher does not share the culture or customs of the population from which research participants

will be recruited.

Recommendation 2.3: Researchers and sponsors

should involve representatives of the community

of potential participants throughout the design

and implementation of research projects.

Researchers should describe in their proposed

protocol how this will be done, and ethics review

committees should review the appropriateness of

this process. When community representatives

will not be involved, the protocol presented to 

the ethics committee should justify why such

involvement was not possible or relevant.

Fair and Respectful Treatment of

Participants

The requirement to obtain voluntary informed consent

from human participants before they are enrolled in

research is a fundamental tenet of research ethics. It was

the first requirement proclaimed in the Nuremberg Code

in 1947, and it has appeared in all subsequent published

national and international codes, regulations, and guidelines pertaining to research ethics, including those in

many developing countries. 

Nevertheless, discussion is ongoing about the value

and importance of particular procedural approaches to

informed consent in other countries. Problems involving

the interpretation and application of the requirement to

obtain voluntary informed consent—and its underlying

ethical principles—arise for researchers, ethics review

committees, and others. In some countries, the methods

used in U.S.-based studies for identifying appropriate

groups for study, enrolling individuals from those groups

in a protocol, and obtaining informed voluntary consent

might not succeed because of different cultural or social

norms. Meeting the challenge of developing alternative

methodologies requires careful attention to the ethical

issues involved in recruiting research participants and

obtaining their consent, which is necessary in order to

ensure justice in the conduct of research and to avoid the

risk of exploitation.

Recommendation 3.1: Research should not deviate

from the substantive ethical standard of voluntary

informed consent. Researchers should not propose,

sponsors should not support, and ethics review

committees should not approve research that 

deviates from this substantive ethical standard.

Disclosure Requirements

The basic disclosure requirements for satisfying the

informed consent provisions in U.S. research regulations

focus on the information needed by a potential participant in order to decide whether or not to participate in a

study. Requirements for disclosure of information in the

research setting usually exceed those for disclosure in

clinical contexts. Indeed, the extent of disclosure of medical information to patients in clinical settings differs

among cultures and can influence judgments about the

amount and kind of information that should be disclosed

in research settings. In the United States, the requirements

for disclosure of information to potential participants in

research are specific and detailed (45 CFR 46.116). The

Commission has found some evidence that disclosures

relating to diagnosis and risk, research design, and possible

post-trial benefits are not always clearly presented in clinical trials conducted in developing countries, even though

the current U.S. regulations include such requirements.

For example, one disclosure requirement in the U.S. regulations focuses on potential benefits: “a description of any

benefits to the subject or to others which may reasonably

be expected from the research” (45 CFR 46.116(a)(1)).

Traditionally, such a disclosure has been required to ensure

that potential participants understand whether there is any

possibility that the intervention itself might benefit them

while they are enrolled in the study. There is, however, no

specific mention of any possible post-trial benefits in current

U.S. regulations. The Commission believes that, because

this information is relevant to participants’ decisions to

participate in the trial, prospective participants should be

informed of the potential benefits, if any, that they might

receive after the trial is over.
vi

Executive Summary

Recommendation 3.2: Researchers should develop

culturally appropriate ways to disclose information that is necessary for adherence to the substantive ethical standard of informed consent,

with particular attention to disclosures relating to

diagnosis and risk, research design, and possible

post-trial benefits. Researchers should describe 

in their protocols and justify to the ethics review

committee(s) the procedures they plan to use 

for disclosing such information to participants.

Recommendation 3.3: Ethics review committees

should require that researchers include in the

informed consent process and consent documents

information about what benefits, if any, will be

available to research participants when their 

participation in the study in question has ended.

Ensuring Comprehension

In some cultures, the belief system of potential

research participants does not explain health and disease

using the concepts and terms of modern medical science

and technology. However, despite this potential barrier to

adequate understanding, if they are willing to devote the

time and effort to do so, researchers often are often able

to devise creative measures to overcome this barrier.

Despite the acknowledged difficulties of administering

tests of understanding, NBAC supports the idea of incorporating these tests into research protocols.

Recommendation 3.4: Researchers should develop

procedures to ensure that potential participants 

do, in fact, understand the information provided 

in the consent process and should describe those

procedures in their research protocols.

Recommendation 3.5: Researchers should consult

with community representatives to develop 

innovative and effective means to communicate

all necessary information in a manner that is

understandable to potential participants. When

community representatives will not be involved,

the protocol presented to the ethics review 

committee should justify why such involvement

is not possible or relevant.

Recognizing the Role of Others in the Consent

Process

In some cultures, investigators must obtain permission from a community leader or village council before

approaching potential research participants. Yet, it is

important to distinguish between obtaining permission

to enter a community for the purpose of conducting

research and for obtaining individual informed consent.

In their reports, NBAC consultants all noted that the role

of community leaders or elders is an integral part of the

process of recruiting research participants. Although

these reports typically use the terminology of consent to

refer to the community’s permission or a leader’s authorization for the researchers to approach individuals,

NBAC will use this term to refer to the permission or

authorization given by the individual being recruited as a

research participant. 

The need to obtain permission from a community

leader before approaching individuals does not need to

compromise the ethical standard requiring the individual’s voluntary informed consent to participate in

research. Gaining permission from a community leader is

no different, in many circumstances, from the common

requirement in this country of obtaining permission from

a school principal before involving pupils in research

or from a nursing home director before approaching

individual residents. An ethical problem arises only when

the community leader exerts pressure on the community

in a way that compromises the voluntariness of individual consent. In NBAC’s view, if the political system in a

country or the local situation makes it impossible for

individuals’ consent to be voluntary and that fact is

known in advance, then, because U.S. researchers cannot

adhere to the substantive ethical standard of informed

consent, it would be inappropriate for them to choose

such settings. 

Recommendation 3.6: Where culture or custom

requires that permission of a community representative be granted before researchers may approach

potential research participants, researchers should

be sensitive to such local requirements. However,

in no case may permission from a community representative or council replace the requirement of a

competent individual’s voluntary informed consent.
National Bioethics Advisory Commission

vii

Recommendation 3.7: Researchers should strive 

to ensure that individuals agree to participate in

research without coercion or undue inducements

from community leaders or representatives.

Family Members

It is customary although not required in some societies

for other members of a potential research participant’s

family to be involved in the informed consent process.

For example, in cultures in which men are expected to

speak for their unmarried adult daughters and husbands

are expected to speak for their wives, a woman may not

be permitted to consent on her own behalf to participate

in research. In most instances, the need to involve the

family is not intended as a substitute for individual consent, but rather as an additional step in the process. In

many cases, family members may be approached before

an individual is asked directly to participate in a research

project. However, seeking permission from family members without engaging the potential research participants

at all clearly departs from the ethical standard of

informed consent. On the other hand, potential participants might also choose to involve others, such as family

members, in the consent process. Indeed, involving family or community members in the informed consent

process need not diminish, and might even enhance, the

individual’s ability to make his or her own choices and to

give informed consent (or refusal).

It is often possible to obtain individual informed consent, which may require and indeed benefit from the

involvement of family or community members, while at

the same time preserving cultural norms. Such involvement ranges from providing written information sheets

for potential participants to take home and discuss with

family members to holding community meetings during

which information is presented about the research and

community consensus is obtained. When the potential

participant wishes to involve family members in the consent discussion, the researcher should take appropriate

steps to accommodate this desire.

Recommendation 3.8: When a potential research

participant wishes to involve family members in 

the consent process, the researcher should take

appropriate steps to accommodate this wish. In no

case, however, may a family member’s permission

replace the requirement of a competent individual’s voluntary informed consent.

Consent by Women

A strict requirement that a husband must first grant

permission before researchers may enroll his wife in

research treats the woman as subordinate to her husband

and as less than fully autonomous. In reality, it may be

impossible to conduct some research on common, serious health problems that affect only women without

involving the husband in the consent procedures. In such

cases, a likely consequence would be a lack of knowledge

on which to base health care decisions for women in that

country. The prospect of denying such a substantial 

benefit to all women in a particular culture or country

calls for a narrow exception to the requirement that

researchers use the same procedures in the consent

process for women as for men, one that would allow for

obtaining the permission of a man in addition to the

woman’s own consent. 

Recommendation 3.9: Researchers should use the

same procedures in the informed consent process

for women and men. However, ethics review 

committees may accept a consent process in

which a woman’s individual consent to participate

in research is supplemented by permission from 

a man if all of the following conditions are met: 

a) it would be impossible to conduct the research

without obtaining such supplemental permission; and 

b) failure to conduct this research could deny its

potential benefits to women in the host country;

and 

c) measures to respect the woman’s autonomy to

consent to research are undertaken to the

greatest extent possible. 

In no case may a competent adult woman be

enrolled in research solely upon the consent of

another person; her individual consent is always

required. 

Minimizing the Therapeutic

Misconception

One barrier to understanding the relevant, important

aspects of any proposed research is what has been called

the therapeutic misconception. This term refers to the belief

that the purpose of a clinical trial is to benefit the 
viii

Executive Summary

individual patient rather than to gather data for the purpose of contributing to scientific knowledge. The therapeutic misconception has been documented in a wide

range of developing and developed countries.

It is important to distinguish the confusion that arises

from the therapeutic misconception from a related consideration. In the research setting, participants often

receive beneficial clinical care. In some developing countries, the type and level of clinical care provided to

research participants may not be available to those 

individuals outside the research context. It is not a 

misconception to believe that participants probably will

receive good clinical care during research. But it is a 

misconception to believe that the purpose of clinical 

trials is to administer treatment rather than to conduct

research. Researchers should make clear to research participants, in the initial consent process and throughout

the study, which activities are elements of research and

which are elements of clinical care. 

Recommendation 3.10: Researchers working in

developing countries should indicate in their

research protocols how they would minimize the

likelihood that potential participants will believe

mistakenly that the purpose of the research is

solely to administer treatment rather than to 

contribute to scientific knowledge (see also

Recommendation 3.2).

Addressing Procedural Requirements in

the Consent Process

A number of issues may arise during the process of

obtaining informed consent that require careful scrutiny

before determining whether voluntary informed consent

can be obtained. These include, for example, determining when it is necessary to obtain written consent and

when oral consent should be permitted; when, if ever, 

it is appropriate to withhold important and relevant 

information from potential participants; the need in some

cultures to obtain a community leader’s or a family member’s permission before seeking an individual’s consent;

and standards of disclosure for research participants in

cultures in which people lack basic information about

modern science or reject scientific explanations of disease

in favor of traditional nonscientific beliefs. 

In light of the cultural variation that might arise in

international clinical trials, the Commission was especially interested in problems that may arise from expecting researchers in developing countries to adhere strictly

to the substantive and procedural imperatives of the 

U.S. requirements for informed consent. NBAC was particularly interested in exploring ways of dealing with the

situation that arises when cultural differences between

the United States and other countries make it difficult or

impossible to adhere strictly to the U.S. regulations that

stipulate particular procedures for obtaining informed

consent from individual participants. In general, it is

important to distinguish procedural difficulties from

those that reflect substantive differences in ethical 

standards. Clearly, more research is needed in this area.

Recommendation 3.11: U.S. research regulations

should be amended to permit ethics review committees to waive the requirements for written and

signed consent documents in accordance with

local cultural norms. Ethics review committees

should grant such waivers only if the research

protocol specifies how the researchers and others

could verify that research participants have given

their voluntary informed consent.

Recommendation 3.12: The National Institutes 

of Health, the Centers for Disease Control and

Prevention, and other U.S. departments and 

agencies should support research that addresses

specifically the informed consent process in various

cultural settings. In addition, those U.S. departments and agencies that conduct international

research should sponsor workshops and conferences

during which international researchers can share

their knowledge of the informed consent process. 

Access to Post-Trial Benefits

Discussions of the ethics of research with human beings

usually center on issues regarding research design and

approval and how individuals’ rights and welfare are protected when they are enrolled in research protocols. The

same has been true of the U.S. regulations, which only

tangentially address what happens after a research project has ended by requiring that research participants

must be informed in advance about what compensation,
National Bioethics Advisory Commission

ix

if any, will be provided if they are injured during the

course of the research. Other questions about what

should happen after a trial is completed are left unaddressed by U.S. guidelines.

Thus, central questions in the context of international

research include the following: What benefits (in the form

of a proven, effective medical intervention) should be provided

to research participants, and by whom, after their participation in a trial has ended, and what, if anything, should be

made available to others in the host community or country?

Although these questions are relevant in terms of the 

ethical assessment of research—regardless of where the

research is conducted—they are being posed with special

force, especially regarding serious diseases that affect

large numbers of people in developing countries.

Therefore, the question of what benefits, if any, research

sponsors should make available to participants or others

in the host country at the conclusion of a clinical trial is

particularly significant for those who live in developing

countries in which neither the government nor the vast

majority of the citizenry can afford the intervention resulting from the research. Of course, this is especially germane

when a drug is proven to be effective in a clinical trial.

An ethically relevant feature that distinguishes most

developing from developed countries is the lack of access

to adequate health care by a large majority of the population. Many developed countries have long provided

universal access to primary health care through a national

health service or government-based insurance system.

However, in the developing world, especially in the 

poorest countries in Africa and Asia, substantially fewer

health care services are available (if any), and where they

are available, access is severely limited. Access to health

care is an important issue in research ethics, because an

ethically appropriate clinical trial design requires an

assessment of the level and nature of care or treatment

available outside the research context, as well as any 

possible future health benefits that might arise from the

research. 

Recognizing that it is sometimes difficult to distinguish research from treatment when routine health care

is inadequate or nonexistent, it cannot be denied that it

may be difficult for participants, whose health status 

may be altered by their participation in a clinical trial, to

distinguish between participating in research and receiving clinical care. Consequently, if all interventions by the

research team cease at the end of a trial, participants may

experience a loss and feel that the researchers in their

clinical role have abandoned them. This sense of loss can

take several forms, the starkest of which arises when participants are left worse off at the conclusion of the trial

than they were before the clinical trial began. Being worse

off does not mean that they were harmed by the research.

It can simply mean that their medical condition has 

deteriorated because they were in what turned out to 

be the less advantageous arm of the protocol. Such an

outcome—particularly when participants are worse off

than they would have been had they received standard

treatment or if they had been in the other arm of 

the trial—underlines the extent to which any research

project can depart from the Hippocratic goal of “first, do

no harm,” despite the best intentions and efforts of all

concerned. When such a result occurs, efforts to restore

participants at least to their pretrial status could be

regarded as attempts to reverse a result that would otherwise be at odds with the ethical principles of nonmaleficence and beneficence.

Ironically, people who have benefited from an experimental intervention may also experience a loss if the

intervention is discontinued when the project ends. It

might be said that this is a risk the participant accepted

by enrolling in the trial. But participants who are ill when

they enter the research protocol may not be able to

appreciate fully how they will feel when they face a 

deterioration in their medical condition (once the trial is

completed) after having first experienced an improvement, even if the net result is a return to the status quo

ante. One of the ways to mediate or reduce the burden of

such an existential loss (the experience of loss as perceived

by the research participant) and to sustain an appropriate

level of trust between potential participants and the

research enterprise is to continue to provide to research

participants an intervention that has been shown to be

efficacious in the clinical trial if they still need it once the

trial is over.

Recommendation 4.1: Researchers and sponsors in

clinical trials should make reasonable, good faith

efforts before the initiation of a trial to secure, at
x

Executive Summary

its conclusion, continued access for all participants

to needed experimental interventions that have

been proven effective for the participants. Although

the details of the arrangements will depend on a

number of factors (including but not limited to the

results of a trial), research protocols should typically describe the duration, extent, and financing 

of such continued access. When no arrangements

have been negotiated, the researcher should justify

to the ethics review committee why this is the case.

Providing Benefits to Others

Once it is recognized that research projects should

sometimes arrange to provide post-trial benefits to participants, a question arises about the justice of differentiating between former trial participants and others in the

host community who need similar medical treatments. 

Is the distinction between former research participants and

those who were not merely arbitrary? Applying a competing

concept of justice, typically referred to as the principle of

fairness—treat like cases alike, and treat different cases 

differently—to this situation requires a consideration of

whether family members (or others) who suffer from the

same illness as the participants should be treated as “like

cases” with respect to receiving an effective treatment.

Similarly, are the claims to treatment of people who were

eligible for and willing to participate in a clinical trial but

who for any number of reasons were not selected comparable to the claims of those who were selected? Or are

such cases not sufficiently similar because participants

undertook the risks and experienced the inconveniences

of the research?

In NBAC’s view, the relevant distinction between

research participants and these other groups of individuals

is that research participants are exposed to the risks 

and inconveniences of the study. Moreover, a special 

relationship exists between participants and researchers

that does not exist for others. These are the ethical considerations that support the argument to provide effective

interventions to research participants after a trial is 

completed.

On what basis then can one justify an ethical obligation to make otherwise unaffordable (or undeliverable)

effective interventions available to members of the

broader community or host country? Given that global

inequities in wealth and resources are so vast, expecting

governmental or industrial research sponsors to seek to

redress this particular global inequity is unfair and unrealistic, especially when no such requirement exists in

other spheres of international relationships. Typically, it is

not the primary purpose of clinical trials to seek to

redress these inequities.

Recommendation 4.2: Research proposals submitted to ethics review committees should include

an explanation of how new interventions that

are proven to be effective from the research will

become available to some or all of the host country population beyond the research participants

themselves. Where applicable, the investigator

should describe any pre-research negotiations

among sponsors, host country officials, and other

appropriate parties aimed at making such interventions available. In cases in which investigators

do not believe that successful interventions will

become available to the host country population,

they should explain to the relevant ethics review

committee(s) why the research is nonetheless

responsive to the health needs of the country and

presents a reasonable risk/benefit ratio.

These concerns prompt the question of whether

research sponsors should consider implementing

arrangements, such as prior agreements (arrangements

made before a clinical trial begins that address the posttrial availability of effective interventions to the host community and/or country after the study has been

completed), that would allow some of the fruits of

research to be available in the host country when the

research is over. Such arrangements would be responsive

to the health needs of the host country. The parties to

these agreements usually include some combination of

producers, sponsors, and potential users of research

products. Although only a limited number of prior agreements, either formal (legally binding) or informal, are in

place in international collaborative research today, it is

useful to consider what role such agreements should play

in the future.

Recommendation 4.3: Wherever possible, preceding

the start of research, agreements should be negotiated by the relevant parties to make the effective

intervention or other research benefits available to

the host country after the study is completed.
National Bioethics Advisory Commission

xi

Mechanisms to Ensure the Protection 

of Research Participants in International

Clinical Trials

The two principal approaches used to ensure the protection of human participants in international clinical trials

are 1) relying on assurance processes and reviews by U.S.

Institutional Review Boards (IRBs) to supplement and

enhance local measures or determining that a host country or host country institution has a system of protections

in place that is at least equivalent to that of the United

States and 2) helping host countries build the capacity 

to independently conduct clinical trials and to conduct

their own scientific and ethical review. In addition, a 

regulatory provision permits the substitution of foreign

procedures that afford protections to research participants that are “at least equivalent” to those provided in

the Common Rule. Clarification of the scope and limits

of these mechanisms and their use would increase public

confidence that a valid system of protections is in place

for participants in clinical trials conducted abroad.

Negotiating Assurances of Compliance

U.S. researchers or sponsors and their collaborators

often encounter difficulties with some of the procedural

and administrative aspects of the U.S. research regulations or their implementation and at times perceive U.S.

regulations as unnecessarily rigid. Among the many concerns NBAC heard were those relating to the process of

negotiating assurances. An assurance is a document that

commits an institution to conduct research ethically and

in accordance with U.S. federal regulations. An approved

assurance is a prerequisite to federally conducted or

sponsored research. 

In December 2000, the U.S. Office of Human Research

Protections (OHRP) launched a new Federalwide

Assurance (FWA) and IRB registration process. The

process for filing institutional assurances with OHRP 

for protecting human research participants has been simplified by replacing Single, Multiple, and Cooperative

Project Assurances with the FWA, one for domestic

research and one for international research. Each legally

separate institution must obtain its own FWA, and assurances approved under this process would cover all of the

institution’s federally supported human research. The

proposed system eliminates the assurance documents

now in place and replaces them with either a Federalwide

Domestic Assurance or a Federalwide International

Assurance, covering all federally supported human

research.

NBAC was encouraged that OHRP is taking these

steps to revise and simplify the current assurance process.

It is not clear at this writing, however, whether the new

FWA process will eliminate the problems and inconsistencies that exist among agencies such as the Department

of Health and Human Services (DHHS), the Agency for

International Development, and the Food and Drug

Administration (FDA), or the difficulties expressed by

researchers who are familiar with the previous assurance

system. Moreover, it should be noted that the assurance

process itself does not provide a failsafe system of protections. Because weaknesses in this system have been noted

in failures at U.S. research institutions, care should be

taken not to rely too heavily on this single mechanism to

achieve protections abroad, especially when it is not clear

that OHRP will provide a visible presence in the host

country (through, for example, site visits). However, it will be

important to evaluate the success of these new initiatives.

Recommendation 5.1: After a suitable period of

time, an independent body should comprehensively evaluate the new assurance process being

implemented by the Office for Human Research

Protections.

Ethics Review

It is now widely accepted that research involving

human participants should be conducted only after an

appropriate ethics review has occurred. When research is

sponsored or conducted in accordance with U.S. research

regulations (and within the boundaries of these regulations), an appropriately constituted and designated IRB is

empowered to make these assessments. However,

spokespersons from developing countries have maintained that those who live in the countries in which the

research is to be conducted are in the best position to

decide what is appropriate, rather than those who may be

unfamiliar with local health needs and culture. It is

argued that committees that are familiar with the

researchers, institutions, potential participants, and other
factors associated with a study are likely to provide a

more careful and fully informed review than a committee

or other group that is geographically displaced or distant

and that only local committees can exercise the kind of

balanced and reasoned judgment required to review

research protocols. The concept of local review has been

a cornerstone of the U.S. system for protecting human

participants. Whether this standard can or should be

applied to research sponsored or conducted abroad was

a focus of Commission deliberations.

NBAC found that the requirement for local review is

occasionally tested and sometimes weakened when

research is conducted in developing countries. In some

cases, review by a local committee raises the potential for

conflict of interest—or at least a heightened interest in

approving research—when it means that valuable

research funds would flow to a local institution.

Although several developing countries have instituted

national research ethics guidelines, and in some countries, ethics review is becoming more established, many

difficulties and challenges to local review remain, including lack of experience with and expertise in ethics review

principles and processes; conflict of interest among committee members; lack of resources for maintaining the

committees; the length of time it can take to obtain

approvals; and problems involved with interpreting and

complying with U.S. regulations.

In NBAC’s view, efforts to enhance collaboration in

research must take into account the capacity of ethics

review committees in developing countries to review

research and the need for U.S. researchers and sponsors

to ensure that their research projects, at the very least, are

conducted according to the same ethical standards and

requirements applied to research conducted in the

United States. This has led NBAC to conclude that when

clinical trials involve U.S. and foreign interests, these 

protocols must still be reviewed and approved by a U.S.

IRB and by an ethics review committee in the host country, unless the host country or host country institution

has in place a system of equivalent substantive ethical 

protections. 

Ideally, equivalent (although not necessarily identical)

systems for providing protections to research participants

in developing countries would exist at both the national

and institutional levels. In countries in which a system

equivalent to the U.S. system exists at the national level,

some institutions may be incapable of conducting

research in accordance with that system. However, it is

difficult to conceive of institutional systems being

declared equivalent in the absence of an equivalent

national system, although it may be possible in a few

extremely rare cases. When multiple sponsors are participating in research, possibly all from developed countries, determining which ethics review committees (and

how many) are required poses additional complexities.

Because there may be legitimate reasons to question the

capacity of host countries to support and conduct prior

ethics review, NBAC believes that with respect to research

sponsored and conducted by the United States, it will be

necessary for an ethics review committee from the host

country and a U.S. IRB to conduct a review. The FDA’s

regulatory provisions for accepting foreign studies not

conducted under an investigational new drug application

or an investigational device exemption do not address

whether the foreign nation’s system must meet U.S. 

ethical standards. 

Recommendation 5.2: The U.S. government should

not sponsor or conduct clinical trials in developing

countries unless such trials have received prior

approval by an ethics review committee in the host

country and by a U.S. Institutional Review Board.

However, if the human participants protection 

system of the host country or a particular host

country institution has been determined by the

U.S. government to achieve all the substantive ethical protections outlined in Recommendation 1.1,

then review by a host country ethics review committee alone is sufficient.

Recommendation 5.3: The Food and Drug Administration should not accept data from clinical trials

conducted in developing countries unless those 

trials have been approved by a host country ethics

review committee and a U.S. Institutional Review

Board. However, if the human participants protection system of the host country or a particular

host country institution has been determined by

the U.S. government to achieve all the substantive 

ethical protections outlined in Recommendation 1.1,

then review by a host country ethics review 

committee alone is sufficient.

xii

Executive Summary
National Bioethics Advisory Commission

xiii

Lack of Resources as a Barrier to 

Ethics Review

Ethics review committees in developing countries

may have difficulty complying with U.S. regulations

because they lack the funds necessary to carry out their

responsibilities. In previous reports, NBAC has recognized that there are costs to providing protection to

human participants in research, and researchers and

institutions should not be put in the position of having to

choose between conducting research and protecting participants. Therefore, an additional means of enhancing

international collaborative research is to make the necessary resources available for conducting ethics reviews. 

Recommendation 5.4: Federal agencies and others

that sponsor international research in developing

countries should provide financial support for 

the administrative and operational costs of host

country compliance with requirements for oversight of research involving human participants.

Equivalent Protections

Although many countries have promulgated extensive regulations or have officially adopted international

ethical guidelines invoking high standards for research

involving human participants, the former Office for

Protection from Research Risks (OPRR) never determined

that any guidelines or rules from other countries—even

countries such as Australia and Canada, where research

ethics requirements closely parallel (and to some extent

exceed) those of the United States—afford protections

equal to those provided by U.S. regulations. If these variations cannot be mediated by joint efforts, difficulties may

arise in international research that will prevent important

and ethically sound research from going forward.

In June 2000, OHRP became the agency responsible

for making determinations of equivalent protections for

DHHS. However, to date, OHRP has not provided criteria

for determining what constitutes equivalent protections

or made any such determinations about other countries’

guidelines. In lieu of having developed a process for

making equivalent protections determinations, in the

past OPRR relied on its usual process for negotiating

assurances with foreign institutions to ensure the adequate protection of human participants.

Because the number of U.S.-sponsored studies undertaken in collaboration with other countries is increasing

(including many studies that have different procedural

requirements), there is a need to enhance the efficiency of

those efforts through increased harmonization and

understanding, without compromising the protection of

research participants. A way must be found to adhere to

widely accepted substantive ethical principles while at

the same time avoiding the undue imposition of regulatory procedures that are peculiar to the United States. 

Recommendation 5.5: The U.S. government 

should identify procedural criteria and a process

for determining whether the human participants 

protection system of a host country or a particular

host country institution has achieved all the 

substantive ethical protections outlined in

Recommendation 1.1.

Building Host Country Capacity to Review and

Conduct Clinical Trials

A unique feature of international collaborative

research is the degree to which economically more prosperous countries can enhance and encourage further 

collaboration by leaving the host community or country

better off as a result. The kinds of benefits that could be

realized as a result of the collaboration would depend on

local health conditions, the state of economic development, and the scientific capabilities of the particular host

country. The provision of post-trial benefits to participants or others in the form of effective interventions is

one option. The appropriateness of providing a benefit

other than the intervention will depend on the nature of

the benefit and on the economic and technological state

of development of the host country. In most cases, offering assistance to help build local research capacity is

another viable option. These two options are not, of

course, mutually exclusive. But no matter what form the

benefit takes, the ultimate goal of providing it is to

improve the welfare of those in the host country.

Approaches to capacity building are related to, but

not fully dependent on, the clarification and improvement of current U.S. procedures for ensuring the protection of research participants in international clinical

trials. Progress can and should occur simultaneously in
xiv

Executive Summary

both realms. Capacity building to conduct research could

include activities undertaken by investigators or sponsors

during a clinical trial to enhance the ability of host 

country researchers to conduct research (e.g., training

and education) or to provide research infrastructure

(e.g., equipment) so that future studies might proceed.

Building capacity to conduct scientific and ethics review

of studies, on the other hand, is primarily a matter of providing training and helping to establish systems designed

to review proposed protocols and sustain mutually beneficial partnerships with other more experienced review

bodies, including U.S. IRBs. 

To enhance research collaborations between developing and developed nations, it is important to increase the

capacity of resource-poor countries to become even more

meaningful partners in international collaborative

research. Making the necessary resources available for

improving the technical capacity to conduct and sponsor

research, as well as the ability to carry out prior ethics

review, is one way to move forward in this effort. 

Recommendation 5.6: Where applicable, U.S. 

sponsors and researchers should develop and

implement strategies that assist in building local

capacity for designing, reviewing, and conducting

clinical trials in developing countries. Projects

should specify plans for including or identifying

funds or other resources necessary for building

such capacity.

Recommendation 5.7: Where applicable, U.S. 

sponsors and researchers should assist in building

the capacity of ethics review committees in developing countries to conduct scientific and ethical

review of international collaborative research.

Conclusions

The ethical standards that NBAC is recommending for

conducting research in other countries are minimum

standards. Host countries might find it worthwhile to

adopt human research participant protections that go

beyond the protections that are currently provided under

the U.S. system if these higher standards further promote

the rights, dignity, and safety of research participants as

well as the credibility of research results. 

Ethical behaviors and commitments are not barriers

to the research enterprise. Indeed, ethical behavior is not

only an essential ingredient in sustaining public support

for research, it is an integral part of the process of planning, designing, implementing, and monitoring research

involving human beings. Just as good science requires

appropriate research design, consideration of statistical

factors, and a plan for data analysis, it must also be based

on sound ethical principles. Only then can research 

succeed in being efficient and cost-effective, while at the

same time embodying appropriate protections for the

rights and welfare of human participants. Researchers

and sponsors should strive to conduct research in the

United States and abroad in a way that furthers these

aspirations, even though, regrettably, financial, logistical,

and public policy obstacles often stand in the way of

immediately achieving this goal.

Although the recommendations in this report focus

principally on clinical trials conducted by U.S.

researchers or sponsors in developing countries, it will be

important to consider their application to other areas of

research. However, even though many ethical issues that

arise in clinical trials also arise in other types of research,

the relevance, scope, and implications of NBAC’s recommendations in other types of studies may be very different. Similarly, many of the issues and recommendations

discussed in this report may equally apply to research

conducted in the United States.

The relationships and, ultimately, the level of trust

established among individuals, institutions, communities, and countries are determined by complex and often

contradictory social, cultural, political, economic, and

historical factors. It is essential, therefore, that sponsors,

the countries from which they come, and researchers

work together to enhance these collaborations by creating

an atmosphere that is based on trust and respect. Finally,

because attention will continue to focus on the ethical

and policy issues that arise in international research in

general and regarding clinical trials in particular, this

report provides another opportunity for ongoing public

dialogue about how to provide appropriate protection to

all research participants. 
National Bioethics Advisory Commission

xv

Notes

1 In past reports, the Commission has used the term human 

subject to describe an individual enrolled in research. This term 

is widely used and is found in the Federal Policy for the Protection

of Human Subjects (45 CFR 46). For many, however, the term 

subject carries a negative image, implying a diminished position 

of those enrolled in research in relation to the researcher. NBAC

recognizes that merely changing terminology cannot achieve the

desired goal of true participation by individuals who volunteer 

for research, and NBAC does not imply that a truly participatory

role is always the case. Nevertheless, for purposes of simplicity 

and from a desire to encourage a more equal role for research 

volunteers, in this report the term participants is adopted to

describe those who are enrolled in research.

2 An upcoming NBAC report on the oversight of research conducted with human participants in the United States will address

the implications of the findings and conclusions of this report in

the context of domestic research. 

3 In the United States, committees that review the ethics of human

research protocols are referred to in regulation and practice as

Institutional Review Boards (IRBs). In other countries, different

names might be used, such as research ethics committees or ethics

review committees. In this report, references and recommendations

that are specific to the United States will refer to these committees

as IRBs. References and recommendations that refer to such 

committees generally regardless of their geographic location will

call them ethics review committees.

4 Although these protections are generally meant to apply to all

research involving more than minimal risk, there are exceptions in

certain guidelines for informed consent to be waived in research

involving minimal risk.
Introduction

Collaboration among peoples from different nations,

whether in the form of engaging in trade, providing

material assistance, or participating in cultural interchange, can substantially benefit all parties involved.

However, these kinds of collaborations do not always

proceed smoothly, particularly when controversy

emerges regarding the nature of the collaboration and/or

the distribution of benefits. Such controversies are perhaps more likely to occur when the nations involved 

do not share the same cultural, economic, political, and

ethical perspectives, or when they are at different stages

of development.

In recent years, the increasingly global nature of

health research, and in particular the conduct of clinical

trials involving human participants,1 has highlighted a

number of new ethical issues. This often happens when

researchers or research sponsors from one country wish

to conduct research in another country. The research in

question might simply be one way of helping the host

country address a public health problem, or it might

reflect a research sponsor’s assessment that the foreign

location is a more convenient or efficient—or less 

troublesome—site for conducting a particular clinical

trial. It might also represent a joint effort to address an

important health concern faced by both parties. In any

case, as the pace and scope of international collaborative

biomedical research have increased during the past

decade, long-standing questions about the ethics of

designing, conducting, and following up on clinical trials

have re-emerged. Some of these issues have begun to take

center stage because of the concern that research conducted by scientists from more prosperous countries in

poorer nations that are more affected by disease may, at

times, be seen as imposing ethically inappropriate burdens on the host country and on those who participate in

the research trials. For example, some commentators

have denounced as unethical clinical trials to test drugs

that might reduce perinatal transmission of HIV that

were conducted in Africa, Asia, and the Caribbean and

sponsored by parties from resource-rich countries

(Angell 1997; Lurie and Wolfe 1997). (See Exhibit 1.1.) 

In this case, concerns focused on two areas. First,

using placebo-controlled trials when an effective treatment exists means that individuals in the control group

are being treated differently than those in control groups

in developed nations (where the control is an established

effective treatment). This may imply that they are not

considered equally worthy or worthy of equal concern.

Second, some have claimed that an alternative research

design could have addressed the health needs of those in

the host country without using a placebo control.

The example of the AIDS trials is only one of the better-known cases of international research that has heightened ethical concerns. Recently, accounts have appeared

in the popular media of troubling cases of drug testing

conducted overseas in which participants allegedly were

exposed to risky research—often without their voluntary

informed consent—in studies of questionable value to

the citizens in the host country (DeYoung and Nelson

2000; Flaherty et al. 2000; LaFraniere et al. 2000;

Pomfret and Nelson 2000; Rothman 2000; Stephens

2000). The specter of exploitation raised by these allegations is cause for a concerted effort to ensure that protections are in place for individuals participating in

international clinical trials.

1

Ethical Issues in 

International Research— Setting the Stage

Chapter One 1
2

Chapter 1: Ethical Issues in International Research—Setting the Stage

Exhibit 1.1: Placebos—A Recent Ethical Controversy in International Research

In 1997, controversy arose over a series of placebo-controlled trials aimed at finding an affordable and implementable treatment to lower the rate of maternal-to-infant transmission of HIV in developing countries. The 

controversial studies followed an earlier National Institutes of Health (NIH)-sponsored study conducted in the United

States (called “ACTG 076,” after the number of the NIH protocol), which demonstrated that maternal-to-infant 

transmission of HIV could be reduced by two-thirds when AZT is administered continuously to women 

as early as the 14th week of pregnancy. 

Although this treatment became the standard of care in the United States and other industrialized countries, 

several factors made it impossible to follow the regimen in developing countries, primarily cost and the lack of a

health care infrastructure to administer the regimen. As a result, some of the clinical trials conducted in Thailand and

Africa were designed to test a lower dose of AZT in HIV-positive women, which was much less expensive than the

standard dose, in a placebo-controlled trial. In addition, these studies initiated the treatment much later in pregnancy,

since women in these countries do not receive early prenatal care, and the AZT was administered orally rather than

intravenously, in line with the availability of medical facilities. Moreover, newborns did not receive full treatment, if any.

These departures from the proven ACTG 076 regimen aimed to establish a course of treatment that could 

reasonably be implemented for HIV-positive pregnant women in resource-poor countries.

For ethical reasons, placebo-controlled trials testing this experimental treatment regimen could not have been

conducted in the United States and other developed countries once the efficacy of the ACGT 076 regimen had been

established. In other words, it would be considered unethical to withhold from women in a research study an effective treatment that they could obtain as part of their routine medical care. The justification for conducting the research

in developing countries was that it compared a new regimen with the existing level of care in those countries.

Critics of the study argued that it is wrong for researchers who come from a country where an effective treatment

is used to withhold that treatment from any study participant and that infants in the study, who could be prevented

from acquiring HIV, would become infected and die unnecessarily. These critics argued for the use of a different study

design to compare the experimental treatment with the standard treatment rather than with the placebo, thereby

avoiding these unnecessary deaths (Lurie and Wolfe 1997). Subsequently, such a study design was adopted in

another NIH-sponsored study in another location in Thailand at the same time that the placebo-controlled trials were

being carried out elsewhere in the same country.2

Defenders of the placebo-controlled studies replied with four arguments: 

1) The “standard of care” for HIV-positive women in these developing countries is no treatment at all, so they are left

no worse off as a result of participating in the study;

2) A placebo-controlled trial can be conducted with fewer participants and completed in a much shorter time than an

AZT-controlled study, so useful information and effective interventions pertinent to this population will be available

much sooner; 

3) The ACTG 076 treatment regimen that has become standard in the West is not now, and will not in the foreseeable future, be available to this population because of its prohibitive costs. Therefore, use of this active control

would render the results of very little relevance to the health needs of the developing country (Levine 1999; Wilfert

et al. 1999); and 

4) If it is proven to be effective, the less expensive and more appropriate regimen can be made available by 

governments to all HIV-positive pregnant women in these countries (Varmus and Satcher 1997). 

These placebo-controlled trials (which have long since been completed, although follow-up is still occurring) did 

succeed in showing that the cheaper, short-course AZT regimen was significantly better than a placebo. Yet, the 

controversy surrounding the ethical principles relevant to such research has not abated.
National Bioethics Advisory Commission

3

Issues Prompting This Report

As with other National Bioethics Advisory Commission

(NBAC) reports, several issues and activities prompted

the Commission’s decision to address this topic. First,

several members of the public suggested that NBAC’s

mandate to examine the protection of the rights and 

welfare of human participants in research extends to

international research conducted or sponsored by U.S.

interests.

A second circumstance—the changing landscape of

international research—also prompted the decision to

prepare this report. Increasingly, scientists from developing countries are achieving more equal status as collaborators in research, as many of these countries have built

their capacity for technical contributions to research

projects and for appropriate ethical review of research

protocols. Although the source of funding for such 

collaborative research is likely to continue to be wealthier,

developed countries with experience conducting

research outside their own borders (such as Canada,

France, Germany, Japan, the Netherlands, the

Scandinavian countries, the United Kingdom, and the

United States), collaborators from developing countries

are seeking—justifiably—to become more equal as 

partners in the research enterprise.

The current landscape of international research also

reflects the growing importance of clinical trials conducted by pharmaceutical, biotechnology, and medical

device companies. Over the last 40 years, U.S. funding of

all research and development has seen a dramatic shift in

its primary source from the public to the private sector.

Although the U.S. government has continued to increase

its investment in biomedical research, private industry

funding has increased much more rapidly (AAAS 2000;

PhRMA 2000).

Some observers believe that market forces have 

pressured private organizations to become more efficient

in the conduct of research, which may—absent 

vigilance—compromise the protection of research 

participants (DeYoung and Nelson 2000; Flaherty et al.

2000; LaFraniere et al. 2000; Pomfret and Nelson 2000;

Stephens 2000). Although the extent, relevance, and

force of these pressures are widely debated, it is clear that

such pressures can exist regardless of the funding source.

Third, NBAC also heard concerns from researchers,

Institutional Review Board (IRB) members, and federal

regulators about how U.S. regulations are “exported” to

other countries and interpreted by researchers and institutions abroad. In other words, the U.S. government

bundles its research regulations (and the ethical principles and commitments that underlie them) into research

projects it conducts in other countries. In particular,

most research sponsored by the U.S. government or 

regulated by the Food and Drug Administration (FDA)

must comply with the Federal Policy for the Protection 

of Human Subjects (45 Part 46 of the Code of Federal

Regulations [CFR], Subpart A, also known as the

Common Rule) and/or parallel FDA regulations (21 CFR

Parts 50 and 56). In previous reports, NBAC has noted

that even for domestic researchers, the U.S. regulations

are at times difficult to interpret and require clarification

(NBAC 1998; NBAC 1999), so it is not surprising that

understanding and interpreting U.S. research regulations in

other settings could pose even more profound difficulties.

Thus, another dimension to research conducted internationally deserves serious attention—whether the existing

rules and regulations that govern the conduct of U.S.

investigators or others subject to U.S. regulations are

appropriate in the context of international research efforts,

or whether they in fact unnecessarily complicate or frustrate

otherwise worthy and ethically sound research projects.

Fourth, the Commission recognizes the importance

of ongoing and vigorous international discussion concerning the most appropriate mechanisms for facilitating

important and necessary international research, while at

the same time ensuring the protection of the participants

of research. In this regard, discussions already are under

way in other countries (Nuffield Council on Bioethics

1999) within the context of an emerging international

effort to harmonize regulations governing clinical trials

under the auspices of the International Conference on

Harmonisation (ICH 1996). Similarly, recent efforts by

the World Medical Association (WMA), the Council for

International Organizations of Medical Sciences

(CIOMS), and the World Health Organization to revise

and develop guidelines on international research ethics

are a welcome contribution to this effort.

Finally, because attention will continue to focus on

the ethical and policy issues that arise in international
4

Chapter 1: Ethical Issues in International Research—Setting the Stage

research in general (Angell 1997; Angell 2000; Benatar

2000; Benatar and Singer 2000; Bloom 1998; Clarke et

al. 1998; Levine 1999; Lurie and Wolfe 1997; Nuffield

Council 1999; Tan-Torres Edejer 1999; Varmus and

Satcher 1997) and regarding clinical trials in particular,

this report provides another opportunity for ongoing

public dialogue about how to provide appropriate 

protection to all research participants. 

Scope and Limits of This Analysis

This report discusses the ethical issues that arise when

research that is subject to U.S. regulation is sponsored or

conducted in developing countries, where local technical

skills and other key resources are in relatively scarce 

supply. Within this context, NBAC’s attention primarily is

focused on the conduct of clinical trials involving competent adults—in particular those trials, such as Phase III

drug studies, that can lead to the development of 

effective interventions. Clinical trials are conducted to

test and evaluate in human populations the safety and

therapeutic efficacy of drugs, biologics, devices, and 

various other health-related interventions. Appropriately

designed and conducted trials provide one of the most

definitive and powerful techniques for evaluating existing

clinical practices and developing innovative methods 

of diagnosis, treatment, and prevention. In addition,

because complex and important ethical concerns are

likely to be more pressing in clinical trials than in many

other types of research investigations, the focus of this

report has been limited accordingly.

However, limiting the scope of the report in this way

precludes discussion of a wide range of analyses of other

types of important international collaborative research

initiatives subject to U.S. regulation, including observational and case-control studies, health services research,

educational research, and various demonstration projects. Notably, this report does not focus on the important

area of public health research. Although much of the 

discussion in this report is relevant to these other types of

research, the particular characteristics of research

endeavors other than clinical trials probably merit their

own ethical assessment.

NBAC commissioned three separate research projects

to provide empirical data to inform its deliberations.3

One of the most ambitious of these reports, a survey 

of researchers involved in international research, was 

prepared by researchers at Johns Hopkins University.

(See Exhibit 1.2.) In addition, NBAC heard testimony

from a number of experts regarding scientific, cultural,

and ethical aspects of international research. Finally, after

the release of a draft version of this report in September

2000, NBAC received comments from 183 U.S. and

international researchers and health experts, as well as

from members of the public.

Exhibit 1.2: Survey of Researchers in

Developing Countries and the United

States

The largest empirical study commissioned by NBAC

for this report was a survey of investigators who conduct biomedical research in developing countries.

The study consisted of two parts: a survey of U.S.

investigators directed by Nancy Kass and a survey of

developing country investigators directed by Adnan

Hyder, both of Johns Hopkins University. Both arms

of the study used a written questionnaire and focus

groups and involved questions about researchers’

experiences with ethical issues in their research, ethical review in the United States and the host country,

informed consent, and recommendations for change

in U.S. and international guidelines for research in

developing countries.

Two versions of the questionnaire were used—

one for researchers from the United States and one

for developing country researchers. The two versions

differed only in the wording of some questions so that

they would be compatible with the different 

locations of researchers. Similar focus group guides

were used for each arm of the study as well. Data

collection took place from December 1998 to

September 2000.

More than 500 researchers completed the survey,

including more than 200 from developing countries.

Seventy-nine focus group respondents participated:

43 from the United States and 36 from developing

countries. The results of the study (available in

Volume II of this report) consist of quantitative data

(from the survey questionnaire) and qualitative 

data (from the focus groups). Methods, results, and

discussion are presented separately for each study

component (U.S. and developing country respondents), and additional sections of the report compare

the findings from the two groups and offer recommendations for policies concerning developing 

country research based on the overall study results.
National Bioethics Advisory Commission

5

Themes and Premises of This Report

The chapters in this report are organized to illustrate the

ethical issues that arise in the design, review, and follow-up

of clinical trials conducted abroad. In this chapter, NBAC

makes recommendations that apply to all research sponsored or regulated by U.S. institutions and conducted in

developing countries. The remaining sections of this chapter present general recommendations regarding research

conducted by U.S. interests in developing countries and

present an overview of issues raised in subsequent 

chapters. Chapter 2 focuses on ethical issues that arise in

choosing a research question and appropriate study

design of clinical trials and makes several recommendations in this area. Chapter 3 addresses the ethical issues

pertinent to recruiting participants and obtaining voluntary informed consent and makes a number of recommendations toward improving these processes. Chapter 4

examines the difficult issue of the obligations of sponsors

or others to provide post-study benefits to participants

and host communities and countries and recommends

approaches to providing such benefits once a trial is 

concluded. Chapter 5 recommends ways to enhance

research collaboration between developing and developed countries, with a particular focus on ethics review,

the processes of granting assurances and determining

equivalency, and capacity building. 

Essential Requirements for the Ethical Conduct

of Clinical Trials

Many of the ethical concerns regarding the treatment

of human participants in international research are 

similar to those raised in conjunction with research conducted in the United States.4 They include, among others,

choosing the appropriate research question and design;

ensuring prior scientific and ethical review of the proposed protocol; selecting participants equitably; obtaining

voluntary informed consent; and providing treatment to

participants during and after the trial. These concerns are

consistent with principles embraced in many international documents, such as the Declaration of Helsinki:

Ethical Principles for Medical Research Involving Human

Subjects (WMA 1964, as amended in 2000) and the

International Ethical Guidelines for Biomedical Research

Involving Human Subjects (CIOMS 1993), both widely

acknowledged sources on the ethics of international

research. 

NBAC believes that two types of ethical requirements—substantive and procedural—must be carefully

considered when human research is conducted, regardless of the location. The principles embodied in the

Belmont Report: Ethical Principles and Guidelines for the

Protection of Human Subjects of Research (National

Commission 1979) serve as a foundation for our national

substantive ethical requirements under the system of 

protection of human participants in the United States.

The Belmont Report sets forth the following three basic

ethical principles, which provide an analytical framework

for understanding many of the ethical issues arising from

research involving human participants: respect for 

persons, beneficence, and justice. Respect for persons

encompasses two ethical notions. First, “individuals should

be treated as autonomous agents” and their decisions

should be respected; and second, “persons with diminished autonomy are entitled to protection” (National

Commission 1979, 4). The principle of beneficence, the

obligations of which affect both investigators and society

at large, incorporates the rules of “do no harm” and

“maximize possible benefits and minimize possible

harms” (National Commission 1979, 6). Justice refers to

a fair and equitable distribution of benefits and burdens,

taking into consideration what is deserved or due and the

fair selection of participants, as well as the idea that

equals should be treated equally (National Commission

1979, 8–10). NBAC believes that in order to be ethically

sound, research conducted with human beings in a foreign country must, at a minimum, be consistent with the 

ethical principles underlying the Belmont Report. 

In addition, ethically sound research must comply

with an important procedural requirement—prior ethical

review by a body that is competent to assess compliance

with these substantive ethical principles. U.S. regulations, which are designed to implement the substantive

ethical principles embodied within the Belmont Report,

also set forth more specific rules to guide ethics review

committees (and researchers) in their work. 

NBAC believes that when conducting clinical trials

abroad, U.S. researchers and sponsors should comply

with these substantive ethical requirements for the 
6

Chapter 1: Ethical Issues in International Research—Setting the Stage

protection of human research participants. Although the 

ethical standards that this report is recommending for

conducting research in other countries are minimum

standards, host countries are encouraged to adopt

human research participant protections that go beyond

those that are currently provided under the U.S. system.

This will help to further promote the rights, dignity, and

safety of research participants as well as the credibility of

research results. Furthermore, explicitly stipulating these

ethical requirements will facilitate efforts to harmonize

international protections for human participants.

Already, many national and international guidelines

describe such protections, providing models for U.S.

consideration. (See Appendix B.) 

NBAC recognizes that the nature and understanding

of these broad requirements might not be the same in all

countries and regions. For example, although recognition

of the importance of obtaining informed consent is

increasing (Ijsselmuiden and Faden 1992), questions

have been raised about whether voluntary informed 

consent as procedurally implemented in the United

States is advisable or possible in some countries

(Bankowski 1992; Karim et al. 1998). In addition, the

need to provide compensation to individuals who have

been injured as a result of research is an issue that has

been discussed in many national and international guidelines and is the source of continuing discussion in the

United States.5 Many international guidelines require

approval by a local ethics review committee and by an

ethics review committee at the investigators’ or sponsors’

home institutions.6 Because, in order to approve a study,

U.S. IRBs must be satisfied that all U.S. regulatory

requirements are met, it is appropriate to consider how

these requirements should be understood and applied 

in the context of research conducted in developing 

countries.

The following protections, listed in Recommendation

1.1, are requirements of ethical research, whether conducted domestically or abroad.7 Throughout the report,

the Commission discusses the importance of context and

describes, where appropriate, ethically acceptable levels

of flexibility in the interpretation of the basic requirements outlined in this recommendation.

Recommendation 1.1: The U.S. government 

should not sponsor or conduct clinical trials that 

do not, at a minimum, provide the following 

ethical protections:

a) prior review of research by an ethics review

committee(s);

b) minimization of risk to research participants; 

c) risks of harm that are reasonable in relation to

potential benefits; 

d) adequate care of and compensation to participants for injuries directly sustained during

research; 

e) individual informed consent from all competent

adult participants in research;

f) equal regard for all participants; and 

g) equitable distribution of the burdens and benefits

of research.

These requirements should extend to the private 

sector, which often has contact with U.S. regulations only

through interaction with the FDA, for example, when

seeking approval to license or market a drug in the

United States. 

Recommendation 1.2: The Food and Drug

Administration should not accept data obtained

from clinical trials that do not provide the 

substantive ethical protections outlined in

Recommendation 1.1.

Choosing a Foreign Setting in Which to Answer

a Research Question

Identifying the research question and the methodology

necessary to answer that question is central to research

design (Meinert and Tonascia 1986; Sackett 1983;

Spilker 1991). (See Chapter 2.) In addition, when clinical

trials are conducted in a developing country, it is ethically

and scientifically important to justify why such a location

has been chosen as the research site.

Sponsoring or conducting research in developing

countries often poses special challenges arising from 

the combined effects of distinctive histories, cultures,

politics, judicial systems, and economic situations

(London et al. 1997). In countries in which extreme
National Bioethics Advisory Commission

7

poverty afflicts so many, primary health care services are

generally inadequate, resulting from the collective effects

of insufficient personnel (ranging from physicians to

pharmacists), transportation and communication problems, and various logistical challenges, including the lack

of basic medical supplies, the dearth of health facilities,

and the inability of the population to pay for products

and services. In addition, unsanitary living conditions

and water supplies can make some medical therapies

inappropriate or unproductive, and the high price of

drugs often places them out of reach of both individuals

and developing country governments.

Whether the research sponsor is the U.S. government—

through such agencies as NIH, the Centers for Disease

Control and Prevention, or the Agency for International

Development—or a private sector organization (e.g., a

nongovernmental organization [NGO] or private company), some justification is needed for conducting

research abroad other than its less stringent or complex

regulatory or ethical requirements, such as those regarding the speed with which ethics review occurs before 

initiating a study. Moreover, when the United States (or

any developed country) proposes to sponsor or conduct

research in another country when the same research

could not be conducted ethically in the sponsoring

country, the ethical concerns are more profound, and 

the research accordingly requires a more rigorous

justification.

Typically, developed countries sponsor or conduct

research in developing countries for some combination of

the following four reasons. First, the host country might

desire information about effective and affordable interventions for an indigenous health problem. For example,

researchers from many other countries have collaborated

with U.S. researchers and received NIH support for

investigations of malaria or dengue, diseases that rarely

occur in the United States, as well as for treatment 

of infectious diseases (e.g., tuberculosis, HIV/AIDS) or 

cancer, which are common in the United States. 

Second, in order to be marketed in some developing

countries, drugs and biologicals—even if already tested

and approved in other countries—must be approved by

national regulatory authorities. In some countries, this

may require domestic testing. Third, it is more efficient to

conduct research in a country in which the condition

being studied is more prevalent. Certain diseases associated with particular environmental conditions—such as a

tropical climate—can only be studied in locations where

those conditions exist. Fourth, it might be less expensive

and faster to conduct research in developing countries.

Enrollment of participants, for example, can occur more

quickly, or procedural requirements can be less burdensome (and protections for participants may not be as

comprehensive).

Whatever the reason or combination of reasons for

conducting research in developing countries, sponsors

and researchers must ensure that these activities are conducted ethically and that they do not exploit either the

participants or the population of the host country. When

assessing justification for conducting research in a developing country, it is particularly important to determine

whether the research is responsive to the health needs of

the population of that country. 

Responsiveness of the Research to the Health

Needs of the Population

To meet the ethical principle of beneficence, the risks

involved in any research involving human beings must

be reasonable in relation to the potential benefits. Plainly,

the central focus of any assessment of risk is the potential

harm that may occur to research participants themselves

(in terms of probability and magnitude), although risks

to others also are relevant. The potential benefits that are

weighed against such risks may include benefits that will

flow to the fund of human knowledge as well as to those

now and in the future whose lives may be improved

because of the research. In addition, some of the benefits

must also accrue to the group from which the research

participants are selected. NBAC understands the principle of justice to require that a vulnerable population

should not be the focus of research unless the potential

benefits of the research will accrue to that group after the

trial. Thus, in the context of international research—and

particularly when the population of a developing country

has been sought as a source of research participants—

U.S. and international research ethics require not merely

that research risks are reasonable in relation to potential 

benefits, but also that they respond to the health needs of
8

Chapter 1: Ethical Issues in International Research—Setting the Stage

the population being studied. This is because, according

to the principles of beneficence and justice, only research

that is responsive to these needs can offer relevant benefits to the population.

Versions of this “responsive-to-needs” requirement

appear in many international guidelines. For example,

the influential CIOMS International Ethical Guidelines

document states that “[b]efore undertaking research

involving subjects in underdeveloped communities,

whether in developed or developing countries, the investigator must ensure that the research is responsive to 

the health needs and the priorities of the community in

which it is to be carried out” (CIOMS 1993, 25

[Guideline 8]). This requirement is echoed in Ethical

Considerations in HIV Preventive Vaccine Research: UNAIDS

Guidance Document, recently issued by the Joint United

Nations Programme on HIV/AIDS (UNAIDS): “HIV vaccine development should ensure that the vaccines are

appropriate for use among such populations, among

which it will be necessary to conduct trials” (UNAIDS

2000, 12). The UNAIDS document carries the basic

premise of the responsive-to-needs argument to the next

level by insisting that when HIV vaccines are developed,

“they should be made available and affordable to such

populations” (UNAIDS 2000, 12).

Many researchers concur with this ethical premise.

One scientist told NBAC that “research should only be

conducted in a country if the results will potentially

directly benefit the population. [Trials] should be conducted in a given country because the investigators have

good reason for testing the intervention in the population

and it is expected that the intervention will be used in

that population.”8 The dean of a leading school of public

health keenly stated his own pragmatic rule before

undertaking a proposed study in the form of a question:

“If this trial turns out positive, is there a reasonable likelihood that this will change governmental policy?

Because if there is, that is the only real reason for doing

the trial.” 9

Recommendation 1.3: Clinical trials conducted in

developing countries should be limited to those

studies that are responsive to the health needs of

the host country.

Choosing a Research Design and the

Relevance of Routine Care

It is generally accepted that the selection of an ethically appropriate research design when using clinical 

trials as a tool to evaluate an experimental intervention is

critical. In this report, NBAC is especially interested in

the following question: Can a research design that could not

be ethically implemented in the sponsoring, developed country

be ethically justified in the country in which the research is

conducted? In addition, the Commission is interested in

exploring whether offering potential participants better

care or treatment than they could obtain outside the

study would be an undue inducement to potential participants to enroll in a clinical trial. As a general rule,

NBAC does not believe this to be the case, but the

Commission recognizes that determining the level of

treatment that should be provided to participants

(including those in a control group, who are not receiving the experimental intervention) is a research design

issue with ethical implications that must be addressed. A

key question is, if the condition of an individual is

improved as a result of participation in a study (whether

due to the experimental intervention or overall improved

medical care) is there some obligation on the part of

sponsors and/or researchers to work toward maintaining

that improved status after the study is completed? 

The ensuing debate that arose following studies of

maternal-to-infant transmission of HIV in developing

countries (see Exhibit 1.1) set in motion efforts to revise

the Declaration of Helsinki, first issued by the WMA in

1964 and amended several times (most recently in

2000), and the 1993 CIOMS Guidelines, the revision of

which is currently under way. The revised Declaration of

Helsinki calls for experimental interventions to be tested

against the best current method, when one exists, and

not against a placebo or any alternative intervention

(WMA 1964, as amended in 2000). Principle 29 states

that “the benefits, risks, burdens and effectiveness of a

new method should be tested against those of the best

current prophylactic, diagnostic, and therapeutic methods.

This does not exclude the use of placebo, or no treatment,

in studies where no proven prophylactic, diagnostic or

therapeutic method exists” (WMA 1964, as amended 

in 2000).
National Bioethics Advisory Commission

9

The CIOMS Guidelines document states that the 

ethical standards of the sponsoring agency’s country

should prevail when research is conducted in another

country and that the ethical standards employed should

be no less exacting than those in the sponsoring agency’s

country (CIOMS 1993, 43). Does this mean that every

procedure stipulated in the U.S. regulations must be

identical in the country collaborating in the research?

Interpreting “ethical standards” in this way leads to the

patently absurd conclusion that a country would somehow be applying a different ethical standard if its rules for

prior independent review of research stipulated, for

example, a different composition of research ethics committees than that required for U.S. research. Regarding

informed consent, as noted below, Chapter 3 distinguishes between fundamental principles, specific ethical

standards, and procedures mandated by U.S. regulations.

It is important that each ethical issue be examined in

light of the distinction between procedures and fundamental principles. Procedural requirements for informed

consent, while important, are simply methodologies for

implementing the ethical standards and are not themselves fundamental ethical principles.

Standard of Care

In many clinical trials, the standard of care for a given

intervention often constitutes the control arm of the

study. This report, for the most part, avoids the phrase

standard of care in describing the interventions that people in a community or country normally obtain in the

clinical setting. Instead, it refers in Chapter 2 to treatment

that is routinely available, which is meant to apply to the

majority of the population in that country. Standard 

of care is a concept borrowed from the medical-legal context that denotes the level of conduct against which a

physician’s or health provider’s treatment of a patient will

be judged in determining whether certain conduct constitutes negligence. It generally means, “what a reasonably prudent physician (or specialist) would do in the

same or similar circumstances” (Annas 1993, 4). Defined

in this way, it can meaningfully describe the types or level

of treatments provided to patients in the clinical setting,

but it might not serve as a justification for what should be

provided to participants in research. Moreover, when

most people in a country or a region routinely receive no

care, that situation amounts to an absence of care rather

than a standard of care.

Further, an ambiguity can be found in the term 

standard, which sometimes means, “what is normally

done,” or “standard practice.” However, in some countries, a standard practice, such as reusing syringes or

other disposable equipment, would not be acceptable to

U.S. researchers and would not constitute a justification

to employ the local unsafe practice. But a standard can

also refer to a level that must be attained, as in “a standard for admission to medical school” or “the standard

for maintaining hygienic practice in treatment and

research.” In this sense, U.S. researchers would be bound

by the proper medical standard that prohibits the reuse

of disposable equipment, even if reuse is standard practice in some countries. Other commentators have found

similar discrepancies in the use of this term, including

one group that has proposed an expanded concept that

attempts to resolve some of these difficulties (Benatar and

Singer 2000). Nevertheless, NBAC prefers where necessary to use the more cumbersome phrase, treatment that

is routinely available, although, as noted below, even this

phrase has certain limitations.

Established Effective Treatment

Before its most recent revision in October 2000, the

Declaration of Helsinki required that “every patient—

including those of a control group, if any—should be

assured of the best proven diagnostic and therapeutic

method” (WMA 1964, as amended in 1996). There has

been much debate about the appropriateness of this

requirement, particularly regarding the definition of the

word proven and the expectation that anything less than

providing the best treatment to patients (and by implication, research participants) will amount to treating them

unjustly. 

NBAC uses the phrase an established effective treatment

to refer to a treatment that is established (it has achieved

universal acceptance by the global medical profession)

and effective (it is as successful as any in treating the 

disease or condition). Established effective treatments are

not limited to what is routinely available in the country

in which the research is being conducted, and NBAC
10

Chapter 1: Ethical Issues in International Research—Setting the Stage

does not intend this phrase to refer to a single best

treatment, since agreement may be lacking about what

treatment is best. Although any phrase requires some

interpretation, NBAC believes that the proposed phrase is

reasonably clear and defines a concept that is useful in

developing recommendations in this area. In particular,

NBAC believes that it best conveys what is owed to

research participants during a study, a topic discussed at

length in Chapter 2.

This language is close to, but still somewhat different

from, that found in the October 2000 revision of the

Declaration of Helsinki, which states that “[t]he benefits,

risks, burdens and effectiveness of a new method should

be tested against those of the best current prophylactic,

diagnostic, and therapeutic methods” (WMA 1964, as

amended in 2000). It is close to that found in Helsinki

because NBAC also refers to providing a high quality of

care. However, it differs in some respects, because it does

not imply that there is only one best treatment. Indeed,

NBAC recognizes that there are often many effective

treatments for a given condition and that some controversy exists over which may be considered “best.”

Without question, it can be difficult to determine

whether an intervention constitutes an established effective treatment. Scientists may disagree regarding whether

an intervention shown to be effective in one population

is likely to be as effective in another that differs in significant ways (e.g., patients’ age, patterns of susceptibility or

resistance to drugs, or other medical conditions; stage of

disease; or locally available medical or social resources

needed for a successful intervention). Examples can be

found in both the developing and developed world, such

as differing drug susceptibilities of the parasite that

causes falciparum malaria in Haiti as compared to East

Africa and the differences among Canada, Europe, and

the United States in guidelines for coronary artery bypass

surgery and for chemotherapy in the treatment of solid

tumors. 

Fair and Respectful Treatment of Participants

Although many of the ethical issues that arise in international clinical trials also pose challenges to research

conducted in the United States, some issues are particularly noteworthy in the international setting. Two such

issues are the selection, recruitment, and enrollment of

participants for research and the duty to obtain their voluntary informed consent to participate. (See Chapter 3

for a more extensive discussion and recommendations.)

In some countries, the methods used in U.S.-based

studies for identifying appropriate groups for study and

enrolling them in a protocol may not succeed because of

different cultural or social norms. Meeting the challenge

of developing alternative methodologies requires careful

attention to the ethical issues involved in the recruitment

of research participants, which is necessary in order to

ensure justice in the conduct of research and to avoid the

risk of exploitation. These are ethical concerns that echo

an observation made by the National Commission for the

Protection of Human Subjects of Biomedical and

Behavioral Research in the Belmont Report more than 

20 years ago: 

[T]he selection of research subjects needs to be scrutinized in order to determine whether some

classes...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

(National Commission 1979, 9–10).

As noted, researchers, ethics review committees, and

relevant national and international guidelines agree

broadly about the importance of satisfying certain substantive and procedural requirements for enrolling

human participants in research. Although it is true that

much international research sponsored by the U.S. government and private industry has conformed to these

requirements, concern is ever present—both in the

United States and abroad—that human participants not

be exploited. In addition, exploitation may be more

likely to occur when wealthy or powerful individuals or

agencies take advantage of the poverty, powerlessness, 

or dependency of others to serve their own ends, without

a sufficient benefit for the less advantaged individuals or

group. Exploitation in any form can be construed as a

human rights violation by virtue of its failure to recognize

the inherent dignity of every human being, a precept

embodied in the Universal Declaration of Human Rights.

10

It follows that all parties have a fundamental obligation to
National Bioethics Advisory Commission

11

avoid exploitation when conducting research, especially

in poorer, less advantaged countries. In any case,

exploitation is a serious moral wrong, and a fundamental

obligation exists to refrain from behavior that constitutes

or promotes it.

However, the circumstances in which exploitation

occurs or might occur are not always apparent within the

context of international research. One document that

addresses international research in the context of

HIV/AIDS identifies several factors that render countries

or communities potentially vulnerable to exploitation in

the conduct of research (UNAIDS 2000). These include:

■ the level of the proposed community’s economic

capacity;

■ limited experience with or understanding of scientific

research in the country as a whole;

■ limited local infrastructure, personnel, and technical

capacity for providing health care and treatment

options;

■ limited experience and capacity for conducting 

ethical and scientific review; and

■ an uncertain ability of individuals in the community

to provide informed consent, for example, as a result

of class, gender, or other social patterns (UNAIDS

2000, 8).

It is important to note, moreover, that these same concerns

can and do arise in the context of research conducted in

developed countries.

The requirement to obtain voluntary informed consent

from human participants before they are enrolled in

research is a fundamental tenet of research ethics and was

the first requirement proclaimed in the Nuremberg Code

(Nuremberg Code 1947). It has appeared in all subsequent published national and international codes, regulations, and guidelines pertaining to research ethics,

including those in developing countries, such as India,

Thailand, and Uganda. Nevertheless, there is an ongoing

discussion about the value and importance of particular

approaches to informed consent in other countries

(Benatar and Benatar 1998; Edi-Osagie et al. 1998;

Preziosi et al. 1997). Problems involving the interpretation and application of the requirement to obtain voluntary

informed consent—and its underlying ethical principles—

arise for researchers, ethics review committees, and others.

For example, the CIOMS Guidelines specifically address

the practical difficulties in dealing with informed consent

as follows:

Some [individuals] may be relatively incapable of

informed consent because they are illiterate, unfamiliar with the concepts of medicine held by the investigators, or living in communities in which the

procedures typical of informed-consent discussions

are unfamiliar or alien to the ethos of the community

(CIOMS 1993, 25). 

In addition, in cultures in which men are expected to

speak for their unmarried adult daughters and husbands

are expected to speak for their wives, a woman may not

be permitted to consent on her own behalf to participate

in research. And, in many rural settings in developing

countries, permission from a village leader is required

before researchers may approach individuals to recruit

them as volunteers.

In light of such cultural variation, the Commission

was especially interested in problems that may arise from

expecting researchers in developing countries to adhere

strictly to the substantive and procedural imperatives of

the U.S. requirements for informed consent. NBAC was

particularly interested in exploring ways to deal with the

situation that arises when cultural differences between

the United States and other countries make it difficult or

impossible to adhere strictly to the U.S. regulations that

stipulate particular procedures for obtaining informed

consent from individual participants. In general, it is

important to distinguish procedural difficulties from

those that reflect substantive differences in ethical standards. A number of procedural issues may arise during

research, including variations (requiring written consent

and permitting oral consent); substantive ethical considerations (withholding important and relevant information from potential participants); the need in some

cultures to obtain a community leader’s or a family member’s permission before seeking an individual’s consent;

and standards of disclosure to research participants in

cultures in which people lack basic information about

modern science or reject scientific explanations of disease

in favor of traditional nonscientific beliefs. Chapter 3
12

Chapter 1: Ethical Issues in International Research—Setting the Stage

includes a series of recommendations that address these

issues.

Access to Post-Trial Benefits

Among the many important issues that continue to be

discussed in research ethics has been the concern about

what is owed to research participants during a clinical

trial. However, another question merits careful attention:

What products or services should be made available, and on

what terms, to research participants and to others in the host

country after completion of the research? Although this

question is relevant in ethical assessments of research

regardless of where the research is conducted, it is being

posed with special force, especially regarding serious 

diseases that affect large numbers of people in developing

countries. Therefore, the question of what benefits

research sponsors should make available to participants

or others in the host country at the conclusion of a clinical trial is particularly significant for those developing

countries in which neither the government nor the vast

majority of the citizenry can afford the intervention

resulting from the research. This question is discussed at

length in Chapter 4.

A feature that distinguishes most developing from

developed countries is the lack of access on the part of a

large majority of the population to adequate health care.

Many developed countries have long provided universal

access to primary health care through a national health

service or government-based insurance system. Although

the United States is among a small number of developed

countries that do not provide universal access to health

care, most people who live in this country have access to

an adequate basic level of medical services. Nevertheless,

a sizable minority in the United States has only limited

access to comprehensive health care services, and some

have virtually no access, due to the complexities of U.S.

health insurance coverage, the geographical distribution

of health care resources, and the persistence of poverty

and near-poverty conditions in some parts of the country.

In the developing world, especially in the poorest countries in Africa and Asia, substantially fewer health care

services are available (if any), and where they are available, access is severely limited. Despite some similarities,

the conditions that limit access to health care in the

United States and in developing countries are not comparable. In the United States, lack of access to adequate

health care results from the decisions of policymakers,

who have chosen not to use available resources to provide universal health coverage. In poor countries, most

citizens lack access to health care because the resources

simply are not available.

Access to health care is an important issue to consider

in research ethics, because an ethically appropriate clinical trial design requires an assessment of the level and

nature of care or treatment available outside the research

context, as well as any possible future health benefits that

might arise from the research. For example, if an effective

treatment for a disease is generally available to patients

outside the research context, it is not ethically acceptable

to withhold it when studying a new treatment, because

following the research trial, the participants would be left

worse off than they otherwise would have been. In contrast, a research design that tests an experimental treatment against a placebo could perhaps be implemented in

a developing country without participants becoming

worse off, since those who receive the placebo would not

otherwise receive an effective treatment for their condition. Whether it is sufficient from an ethical perspective

merely to avoid making participants worse off than they

would otherwise have been remains a matter of debate.

This issue is addressed in Chapter 2.

These concerns also prompt the question of whether

research sponsors should consider arrangements that

would allow some of the fruits of research to be available

in the host country when the research is concluded. Such

arrangements would be responsive to the health needs of

the host country. In this context, this report discusses the

use of “prior agreements”—documents that refer generally to arrangements made before a clinical trial begins—

that address the post-trial availability of effective

interventions to the host community and/or country after

the study has been completed. The parties to these agreements usually include some combination of producers,

sponsors, and potential users of research products,

including U.S. and international research organizations

and development agencies, NGOs, and private corporations. Although only a limited number of prior agreements, either formal (legally binding) or informal, are in
National Bioethics Advisory Commission

13

place in international collaborative research today, it is

useful to consider what role such agreements should play

in the future.

Ensuring the Protection of Research

Participants in International Clinical Trials

The two principal approaches to improving the protections of human participants in international clinical

trials are 1) relying on reviews by U.S. IRBs and assurance

processes to supplement and enhance local measures or

determining that a host country or host country institution has a system of protections at least equivalent to that

of the United States and 2) helping host countries build

the capacity to independently conduct clinical trials and

to carry out their own scientific and ethical review.

Chapter 5 is devoted to exploring these approaches.

Ethics Review

It is now widely accepted that research involving

human participants should be conducted only after an

appropriate ethics review committee (a body that is independent of the investigators and sponsors of the

research) has determined that several ethical issues have

been addressed, including the following: 1) voluntary

informed consent will be solicited; 2) risks will be

assessed as reasonable in relation to potential benefits;

and 3) evidence of a fair distribution of the benefits and

the burdens of the research is present. When research is

sponsored or conducted in accordance with U.S. research

regulations (and within the boundaries of these regulations), an appropriately constituted and designated IRB 

is empowered to make these assessments. However,

spokespersons from developing countries have maintained that people who live in the countries in which the

research is to be conducted are in the best position to

decide what is appropriate, rather than those who may 

be unfamiliar with local health needs and culture. These

spokespersons state that committees that are familiar

with the researchers, the institutions, potential participants, and other factors are more likely to provide a more

effective and fully informed review than a geographically

displaced or distant group. Only local committees, they

argue, can exercise the kind of balanced and reasoned

judgment required to review research protocols. In fact,

the concept of local review is a cornerstone of the U.S.

system for protecting human participants. Whether this

standard can or should be applied to U.S. research conducted abroad was a focus of Commission deliberations.

NBAC found that the requirement for local review is

occasionally tested and sometimes weakened when

research is conducted in developing countries (something that can also happen within U.S. borders). In some

cases, review by a local committee raises the potential for

conflict of interest—or at least a heightened interest in

approving research—when it means that valuable

research funds would flow to the institution. Although

several developing countries have instituted national

research ethics guidelines, and ethics review in some

countries is becoming more established, many difficulties

and challenges to local review remain, including lack of

experience with and expertise in ethics review principles

and processes; conflict of interest among committee

members; lack of resources for maintaining the committees; length of time it can take to obtain approvals; and

problems involved with interpreting and complying with

U.S. regulations.

In NBAC’s view, efforts to enhance collaboration in

research must take into account the status and capacity of

ethics review committees in developing countries to

review research and the need for U.S. researchers and

sponsors to ensure that their research projects, at the very

least, are conducted according to the same ethical standards and requirements applied to research conducted in

the United States. This has led NBAC to conclude that

when clinical trials involve U.S. and foreign interests,

these protocols must still be reviewed and approved by a

U.S. IRB and by an ethics review committee in the host

country, unless the host country or host country institution has in place a system of equivalent substantive 

ethical protections. (See Chapter 5.)

Because U.S.-sponsored research undertaken in collaboration with other countries is increasing (including

many studies that have different procedural requirements), there is a need to enhance the efficiency of those

efforts through increased harmonization and understanding, without compromising the protection of research

participants. We must find a way to adhere to widely

accepted substantive ethical principles while at the same

time avoiding the undue imposition of regulatory procedures that are peculiar to the United States. 
14

Chapter 1: Ethical Issues in International Research—Setting the Stage

Policy and Regulatory Issues

U.S. researchers or sponsors and their collaborators

often encounter difficulties with procedural and administrative aspects of the U.S. research regulations or their

implementation by the Office for Human Research

Protections (OHRP) in the Department of Health and

Human Services (DHHS).11 U.S. and host country

researchers at times perceive U.S. regulations as unnecessarily rigid. Among the many concerns NBAC heard were

those relating to the process of negotiating assurances 

(45 CFR 46.103). The assurance document can be

described as a commitment by the institution to conduct

research ethically and in accordance with U.S. federal

regulations; an approved assurance is a prerequisite to

federally conducted or sponsored research. Some within

the United States and abroad, however, view this as an

excessively and unnecessarily paternalistic requirement.

A second important question concerns the nature of

the variation in national and international ethical guidelines. Although many countries have promulgated extensive regulations or have officially adopted international

ethical guidelines invoking high standards for research

involving human participants, the former Office for

Protection from Research Risks (OPRR) never has determined formally that guidelines or rules from any other

countries afford protections equal to those provided by

U.S. regulations—even those from countries such as

Australia and Canada, where research ethics requirements closely parallel (and to some extent exceed) those

of the United States.12 Since its constitution in June 2000,

OHRP has not done so either. The result is that

researchers across the globe who are collaborating with

U.S.-sponsored researchers must adhere to U.S. research

regulations and obtain an assurance. 

In its effort to more fully understand existing provisions for international collaborative research, NBAC

reviewed 25 sets of guidelines, codes, and regulations

from 14 countries and 7 organizations.13 NBAC’s analysis

identified substantive ethical requirements of other countries that are absent from the U.S. regulations governing

research. In contrast, NBAC found that all of the substantive ethical provisions in the U.S. regulations appear

in other national or international rules. If these variations

cannot be mediated by joint efforts, difficulties may arise

in international research that will prevent important and

ethically sound research from going forward.

Unfortunately, some incompatibility remains, even

within the U.S. regulations, both between the Common

Rule and the FDA regulations and among the Common

Rule agencies. FDA regulations are congruent with the

Common Rule in most respects, but there are some differences stemming from the FDA’s particular statutory

authorities and regulatory mission. In contrast to the

DHHS regulatory focus on institutions receiving DHHS

funds, FDA regulations focus on the sponsors that

develop the products, the investigators who perform the

research studies, and the IRBs that review the research. In

addition, in the international research context, the FDA

does not make determinations of equivalent protection.

Addressing these inconsistencies should be a goal of

U.S. regulatory policy. As discussed in Chapter 5, some

actions can be taken at this time to make progress in this

area, without the need for new regulations, such as developing policy guidance for determining whether the

research policies of other nations provide protections

equivalent to those provided in the United States.

Building Host Country Capacity to Review and

Conduct Clinical Trials

Many international ethical guidelines, such as the

1993 CIOMS International Ethical Guidelines (CIOMS

1993) and UNAIDS’ Ethical Considerations in HIV

Preventive Vaccine Research (UNAIDS 2000), recommend

that when developed countries sponsor research in

developing countries, the sponsors have a responsibility

to help build local and national capacity for designing

and conducting trials and for the scientific and ethical

review of proposed research projects. To enhance

research collaborations between developing and developed nations, the capacity of resource-poor countries to

become even more meaningful partners in international

collaborative research must be increased. Making the

necessary resources available for improving the technical

capacity to conduct and sponsor research, as well as the

ability to carry out prior ethical review, is one way to

move forward in this effort. These issues are further

addressed in Chapter 5.
National Bioethics Advisory Commission

15

Conclusions

The aim of this report is not to revisit past wrongs or to

uncover a litany of examples in which participants in

international research have been harmed or have had

their rights violated. The intent, rather, is to examine the

circumstances that make clinical trials that are conducted

in developing countries ethically sound and to make 

recommendations to researchers, governmental and

industrial sponsors, and other interested groups, where

appropriate.

Ethical behaviors and commitments are not barriers

to the research enterprise. Indeed, ethical behavior is not

only an essential ingredient in sustaining public support

for research, it is an integral part of the process of planning, designing, implementing, and monitoring research

involving human beings. Just as good science requires

sound research design, consideration of statistical factors,

and a plan for data analysis, it must also be based on

sound ethical principles. Only then can research succeed

in being efficient and cost-effective, while at the same

time embodying appropriate protections for the rights

and welfare of human participants.

Most people believe that a world in which all have

access to good medical care would be preferable to one

in which many lack such access. Furthermore, most

would agree that one should volunteer to participate in

clinical research primarily for altruistic reasons and only

secondarily for personal gain. In addition, it is widely

believed that those who volunteer to be research participants should receive society’s respect and gratitude, as

manifested (at least in part) by ensuring they are treated

fairly and respectfully and can enjoy the benefits of the

research in which they participated. Researchers and

sponsors should strive to conduct research in the United

States and abroad in a way that furthers these aspirations,

even though, regrettably, financial, logistical, and public

policy obstacles often stand in the way of immediately

achieving this goal.

This report makes recommendations for a beginning—a series of first steps toward achieving the aims

discussed in this report. The Commission believes that

the recommendations presented in this report are

grounded in moral ideals, are tempered by reality, and are

consistent with minimal ethical norms for distributive

justice and respect for persons. However, abiding by these

recommendations should not end efforts to improve the

treatment of participants in research and the access of all

peoples to the fruits of medical research. They provide a

floor, not a ceiling, for ethical requirements.

Moreover, although the recommendations in this

report focus principally on clinical trials conducted by

U.S. researchers or sponsors in developing countries, it

will be important to consider their application to other

areas of research. Although many ethical issues that arise

in clinical trials also arise in other types of research, the

relevance, scope, and implications of NBAC’s recommendations in other types of studies may be very different.

Similarly, many of the issues and recommendations 

discussed in this report may equally apply to research

conducted in the United States.

Notes

1 In past reports, the Commission has used the term human subject

to describe an individual enrolled in research. This term is widely

used and is found in the Federal Policy for the Protection of

Human Subjects (45 CFR 46). For many, however, the term subject

carries a negative image, implying a diminished position of those

enrolled in research in relation to the researcher. NBAC recognizes

that by merely changing terminology the desired goal of true 

participation by individuals who volunteer for research cannot 

be achieved, and the Commission does not imply that a truly 

participatory role is always the case. Nevertheless, for purposes 

of simplicity and from a desire to encourage a more equal role for

research volunteers, in this report the term participants is adopted

to describe those who are enrolled in research.

2 Varmus, H., Testimony before the Subcommittee on Human

Resources, Committee on Government Reform and Oversight, 

U.S. House of Representatives. May 8, 1997. Washington, D.C.

3 See Kass, N., and A. Hyder, “Attitudes and Experiences of 

U.S. and Developing Country Investigators Regarding U.S. Human

Subjects Regulations”; Marshall, P., “The Relevance of Culture 

for Informed Consent in U.S.-Funded International Health

Research”; and Sugarman, J., B. Popkin, F. Fortney, and R. Rivera,

“International Perspectives on Protecting Human Research

Subjects.” These background papers were prepared for NBAC 

and are available in Volume II of this report. 

4 An upcoming NBAC report on the oversight of research 

conducted with human participants in the United States will

address the implications of the findings and conclusions of this

report in the context of domestic research. 
16

Chapter 1: Ethical Issues in International Research—Setting the Stage

5 In an upcoming NBAC report, the issue of compensation for

injury is addressed in more detail.

6 In the United States, committees that review the ethics of human

research protocols are referred to in regulation and practice as

IRBs. In other countries, different names might be used, such as

research ethics committees or ethics review committees. In this

report, references and recommendations that are specific to the

United States will refer to these committees as IRBs. References 

and recommendations that refer to such committees generally

regardless of their geographic location will call them ethics review

committees.

7 Although these protections are generally meant to apply to all

research involving more than minimal risk, there are exceptions in

certain guidelines for informed consent to be waived in research

involving minimal risk.

8 Dickersin, K., Testimony before NBAC. December 2, 1999.

Baltimore, Maryland. Meeting transcript, 138–139.

9 Sommer, A., Testimony before NBAC. September 16, 1999.

Arlington, Virginia. Meeting transcript, 168.

10 Andreopolis, G.J., Testimony before NBAC. May 4, 2000.

Madison, Wisconsin. 

11 Until June 2000, the Office for Protection from Research Risks

(OPRR) was the federal agency responsible for implementing U.S.

regulations pertaining to protection of human research participants

in other countries.

12 Letter from J. Thomas Puglisi, OPRR, to Eric M. Meslin, NBAC,

December 16, 1999.

13 NBAC, “Comparative Analysis of International Documents

Addressing the Protection of Research Participants.” This analysis

was prepared by NBAC staff and is available in Volume II of this

report.

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Human Subjects of Research. Washington, D.C.: Department of

Health, Education, and Welfare.

Nuffield Council on Bioethics. 1999. The Ethics of Clinical Research

in Developing Countries: A Discussion Paper. London: Nuffield

Council on Bioethics.

The Nuremberg Code. 1947. From Trials of War Criminals Before 

the Nuremberg Military Tribunals Under Control Council Law No. 10.

Nuremberg, October 1946–April 1949. Washington D.C.: U.S.

Government Printing Office, 1949–1953. 

Pharmaceutical Research and Manufacturers of America (PhRMA).

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

PhRMA.

Pomfret, J., and D. Nelson. 2000. “In Rural China, a Genetic

Mother Lode.” Washington Post 20 December, A-1.

Preziosi, M.P., A. Yam, M. Ndiaye, A. Simaga, F. Simondon, 

and S.G.F. Wassilak. 1997. “Practical Experiences in Obtaining

Informed Consent for a Vaccine Trial in Rural Africa.” New England

Journal of Medicine 336(5):370–373. 

Rothman, D.J. 2000. “The Shame of Medical Research.” New York

Book Review 30 November, 60–64.

Sackett, D.L. 1983. On Some Prerequisites for a Successful Clinical

Trial. In Clinical Trials: Issues and Approaches, eds. S.H. Shapiro and

T.A. Louis, 65–79. New York: Marcel Dekker.

Spilker, B. 1991. Guide to Clinical Trials. New York: Raven Press.

Stephens, J. 2000. “The Body Hunters: As Drug Testing Spreads,

Profits and Lives Hang in Balance.” Washington Post 17 December, A-1.

Tan-Torres Edejer, T. 1999. “North-South Research Partnerships:

The Ethics of Carrying Out Research in Developing Countries.”

British Medical Journal 319:438–441.

Varmus, H., and D. Satcher. 1997. “Ethical Complexities of

Conducting Research in Developing Countries.” New England

Journal of Medicine 337(14):1003.

Wilfert, C.M., A. Ammann, R. Bayer, J.W. Curran, C. del Rio, 

R.R. Faden, M.B. Feinberg, P.D. Karlin, R.J. Levine, C. Luo, and 

K. Sessions. 1999. “Consensus Statement: Science, Ethics, and the

Future of Research into Maternal Infant Transmission of HIV-1.”

The Lancet 353(9155):832–835.

World Medical Association (WMA). Declaration of Helsinki: Ethical

Principles for Medical Research Involving Human Subjects (adopted

18th WMA General Assembly, Helsinki, Finland, June 1964;

amended: 29th WMA General Assembly, Tokyo, Japan, October

1975; 35th WMA General Assembly, Venice, Italy, October 1983;

41st WMA General Assembly, Hong Kong, September 1989; 48th

WMA General Assembly, Somerset West, Republic of South Africa,

October 1996; and 52nd WMA General Assembly, Edinburgh,

Scotland, October 2000). Ferney-Voltaire, France: WMA. Available at

www.wma.net/e/policy/17-c_e.html. Last accessed January 12, 2001.
A

Introduction

s we stand poised on the frontiers of biomedical

science, populations worldwide face a broad range

of health concerns as well as many different issues related

to the conduct of clinical trials in international health

research. The multiple contexts within which biomedical

research proceeds call for an array of research designs in

order to forge scientific developments and advance clinical knowledge and treatment approaches. Any of a number of research designs may be appropriate for a clinical

trial, depending on the context and circumstances of the

research; however, every clinical trial must be scientifically sound and must incorporate important ethical principles regarding the treatment of research participants.

With respect to the ethical treatment of research 

participants, current U.S. regulations require that

Institutional Review Boards (IRBs) determine that a

research design is such that “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” (45 CFR 46.111(a)(2)).

However, although the federal regulations do not require

IRBs to review the scientific merit of a research design,

research with a scientifically flawed methodology will not

generate valid or reliable data or produce generalizable

and beneficial knowledge. In such cases, it is the participants in the research who will incur the risks, inconveniences, or discomforts that might be involved. Because it

would be wrong to put people at risk or even to inconvenience or discomfort them through participation in 

a poorly designed study, the scientific merit of research

becomes an ethical issue (OPRR 1993). Therefore, 

the National Bioethics Advisory Commission (NBAC)

believes that IRBs should assure themselves of both the

ethical and scientific merits of the protocols they review.

The Commission is not proposing that IRBs become

responsible for conducting scientific peer review (as they

may lack specific expertise, and in most instances the

proposed studies of research sponsors must undergo

independent scientific review)—but only that IRBs have

confidence that a study has scientific merit.1

Even when a clinical trial uses a scientifically sound

research design and addresses important questions, conducting the proposed research might be unethical if it

would result in the violation of certain ethical principles.

However, because determining the appropriate design for

a clinical trial depends on various contextual considerations, what might be an ethically acceptable design in one

situation could be problematic in another. For example,

it might be unethical to conduct a clinical trial for a

health condition in a country where that condition is

unlikely to be found, but the same trial might be appropriately conducted where the results could be important

to the local population. A more challenging question is

whether a research design that could not be ethically

implemented in the sponsoring country could be ethically

justified in a host country when the health problem that

the research is addressing is common to both countries.

It may be useful to classify international collaborative

research projects in developed and developing countries

on a continuum. At one end of the continuum is research

that has no practical relevance to the health needs of the

host country, but is important to the foreign sponsor or

researcher. At the other end of the spectrum is research

that is directly relevant to the health concerns of the host

country, but not to sponsors or researchers. These two

19

Ethical Considerations in 

the Design and Conduct of

International Clinical Trials 

Chapter Two 2
20

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

extremes illustrate how situations can differ starkly, particularly regarding the potential for exploiting research

participants in the host country. An assessment of the

ethical appropriateness of a particular study’s design

should include an evaluation of where it lies along this

continuum. It is worth noting that in an NBAC survey of

U.S. researchers, 40 percent of those surveyed said that

the research priorities of their funding agencies were

incongruent with the top priorities of the developing

country in which they were conducting research. Indeed,

the relevance of the proposed research to the host country was questioned by U.S. IRBs in 30 percent of the cases

reported and by host country ethics review committees

in 23 percent of the cases. At the same time, a majority

(73 percent) of U.S. researchers surveyed said that their

interest in addressing global inequalities in health motivated them to work in a developing country.2

This chapter focuses on the ethical requirement of

choosing a research design that minimizes the risk of

harm to human participants in clinical trials and that

does not exploit them (which raises the question of the

obligations of sponsors and researchers to the research

participants during the trial). Chapter 4 discusses the

broader question of what obligation, if any, sponsors and

researchers have to the participants and others in a host

country after a research trial is completed. Following are

some of the chief considerations with respect to both

research design and ethical obligations owed to research

participants:

■ whether the research is responsive to the health needs

of the host country;

■ whether a study design is appropriate for answering

the primary research question; 

■ whether an effective treatment already exists for the

condition that is the focus of the study; 

■ whether the condition for which a new intervention

is sought is severe or life threatening;

■ the probability and magnitude of any harm that might

come to participants in both the experimental and

control arms of a given study; 

■ the probability and magnitude of benefits that may

accrue to the study participants; 

■ the balance of the risks to the participants and the

probable benefits to the participants and to others;

and

■ the future availability of the experimental intervention, if proven effective, to participants and others in

the host country after the trial.

Because the choice of a study design for any particular

trial depends on these and other factors, it would be

inappropriate—indeed, wrong—to designate any one

particular study design as ethical for all research situations. Nevertheless, under certain specified conditions, a

particular design can be considered ethically preferable.

Recommendation 2.1: Researchers should provide

ethics review committees with a thorough justification of the research design to be used, including

the procedures to be used to minimize risks to 

participants.

Ethical Issues in Clinical Trial Design

Important and distinct scientific and ethical issues and

challenges can arise at different stages of drug development, during the development of other medical interventions, and in the use of various study designs used for

clinical trials. The development of a new drug is a long

and complex process that includes drug discovery, 

preclinical testing, and, finally, an ordered program of

clinical trials. The development of other medical interventions—such as new vaccines, gene transfer technology,

and medical devices—follows a similar process. Exhibit

2.1 summarizes the phases of drug development that

typically form the basis of U.S. efforts. Exhibit 2.2

describes the principal types of trial designs used in testing clinical interventions. 

Carefully designed and properly conducted clinical

trials are recognized as the principal mechanism for testing new clinical interventions, and, given the rapid

advance of biomedical science in recent years, the number of clinical trials is steadily increasing. The results of

any clinical trial must be free of bias, which can be

caused by flaws in the study design. Bias in clinical trials

refers to the tendency of any aspect of the methodology

or the interpretation of data to lead to conclusions about
National Bioethics Advisory Commission

21

the effects of an intervention that are systematically 

different from the truth (FDA 1999). Ensuring that the

chosen study design avoids various forms of bias and

generates data that can answer the scientific questions

being asked can be difficult. Fortunately, a significant 

literature has been developed to address this challenge

(Meinert and Tonascia 1986; Sackett 1983; Spilker

1991).

From the perspective of the protection of human 

participants in research, one of the most critical issues in

clinical trial design concerns the use and treatment of

control groups, which are often an essential component

in methodologies used to guard against bias. The main

purpose of a control group is to permit investigators to

determine whether an observed effect truly is caused by

the experimental intervention being tested or whether it

Exhibit 2.1: Phases of Drug Development 

The first step in the development process of a new drug, biologic (e.g., a vaccine, a gene transfer agent, a proteinbased therapy), or medical device is called discovery. During the drug discovery process, chemical compounds are

identified and/or synthesized and tested for biological activity. Of 5,000 to 10,000 chemical compounds tested for biological activity, approximately 250 eventually enter the next stage of drug development, called preclinical testing

(PhRMA 1999).

Preclinical studies are experiments that are carried out in the laboratory and in animals to provide preliminary evidence that the experimental intervention will be safe and effective in humans. Safety information from preclinical testing is used to support a request to the Food and Drug Administration (FDA) to begin testing the experimental

intervention in humans. Preclinical testing usually takes three to six years, and only 2 percent of compounds evaluated in preclinical testing are eventually tested in humans (Mann 1999; PhRMA 1999).

In the United States, an investigational new drug (IND) application or an investigational device exemption (IDE)

must be submitted to the FDA before a drug, biologic, or device can be studied in humans. Once the FDA allows an

IND or IDE to proceed, testing of an experimental intervention in a clinical trial can begin. For studies conducted outside the United States, an IND is not required, unless data from the study are intended to be used to support the

licensing of a drug in the United States. Clinical trials usually are classified into the following four phases: Phase I

trials, the earliest-stage clinical trials for studying an experimental intervention in humans, are small (typically fewer

than 100 participants) and aim to determine the toxicity and maximum safe dose of a new drug. Phase I trials 

commonly are conducted with normal volunteers (rather than patients with the condition in question). However,

Phase I trials that involve potent and potentially toxic chemicals (e.g., for cancer or HIV/AIDS) are often performed

in participants with advanced disease who have not responded to all other standard treatments. 

Phase II trials usually involve 100 to 300 participants and are designed to determine whether a drug produces any

clinically significant effects in those with the targeted disease. If the results of these trials are promising, then 

a larger Phase III trial, aimed at establishing efficacy, may be conducted. Phase III trials are large, frequently 

multi-institution studies, and typically involve from a hundred to thousands of participants. Approximately 25 percent

of all drugs tested in clinical trials successfully complete Phase III testing (Mann 1999).

Some Phase II and Phase III trials are designed to be pivotal trials (sometimes also called confirmatory trials). The

goal of a pivotal trial is to eliminate systematic biases and increase statistical power and to establish the intervention’s safety and efficacy. By providing firm evidence of safety and efficacy, pivotal trials are designed to produce data

that will be accepted by the FDA as adequate for supporting a New Drug Application (NDA). On average, it takes

almost seven years to complete the required clinical trials (Phases I through III) and to gather the data 

necessary to establish the safety and efficacy of an experimental intervention (PhRMA 1999).

Once sufficient evidence exists regarding the safety and efficacy of an experimental intervention from studies conducted inside and/or outside the United States, an NDA is submitted to the FDA for approval of a new drug; a Biologic

License Application is submitted for approval of a new vaccine or other biologic; or a Product License Application is

submitted for approval of a new device. Occasionally, the FDA requires Phase IV trials, which are usually performed

after the intervention has been approved. Such post-marketing surveillance aims to obtain additional information

about the risks, benefits, and optimal use of the intervention by observing the results of the intervention in a large

number of patients. Phase IV trials enable the long-term effects of an intervention to be assessed and sometimes

reveal rare, but serious, side effects.
22

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

is caused by other factors, such as the natural progression

of the disease, observer or participant expectations, differences in the baseline condition of subjects, or other

treatment (FDA 1999). The experience of an appropriately selected control group lets the investigator know

what would have happened to study participants had

they not received the test intervention or what would

have happened had they received a different treatment

that is known to be effective (FDA 1999). (A description

of and additional discussion regarding the use of control

groups is provided below.)

This chapter will discuss the following ethical issues

involved in evaluating any proposed clinical trial:

equipoise; randomization; the nature and treatment of

control groups; the distinction between efficacy and

effectiveness studies; and the selection of the participant

population and sample size.

Equipoise

Among the most important ethical and scientific justifications for beginning a clinical trial is the uncertainty

about whether the experimental intervention is better

than the status quo (which may be an existing treatment

or no treatment at all). This state of uncertainty is known

as equipoise, and it is a requirement for the ethical conduct of a clinical trial. Equipoise has been defined as the

point at which a rational, informed person would have

no preference between two (or more) available treatments (Lilford and Jackson 1995). It is a state in which

honest professional disagreement exists among experts

regarding whether the study intervention or the control

is preferred. In the clinical context, the belief that one

intervention is superior to others ethically compels the

clinician to recommend the superior intervention.

Clinicians are justified in recommending different treatments based on their assessment of what will be effective

for a particular patient. Often, the preferences of a clinician regarding an intervention and those of the patient

are similar in this regard. However, in the research context,

individual preferences are replaced by the collective

uncertainty of the clinical community. According to this

concept of clinical equipoise, a trial is ethical if there is

“genuine uncertainty within the expert medical community about the preferred treatment” (Freedman 1987).

Exhibit 2.2: Clinical Trial Designs 

Clinical trials are research studies that evaluate new

ways to prevent, detect, diagnose, or treat disease in

human beings. The key to clinical trial design is

choosing an approach that addresses the scientific

question being asked, the intervention being tested,

and the group of participants involved, while at the

same time considering the risks and benefits to the

participants. Several commonly used research

designs include the following:

Add-on design: A placebo-controlled trial of an

experimental intervention is tested in people who are

already receiving an established effective treatment.

Crossover design: Each participant is randomized 

to a sequence of two or more treatments and 

hence acts as his/her own control for treatment 

comparisons.

Equivalence trials: 1) compare the efficacy of an

experimental treatment to that of an established

effective treatment (also called noninferiority trials)

and 2) compare bioequivalence (to show that two

drugs have the same potency and tissue availability).

Factorial design: Two or more treatments are 

evaluated simultaneously in the same participant

population through the use of varying combinations

of the treatments (e.g., in a 2 x 2 factorial design, 

participants are randomly allocated to one of the 

four possible combinations of two treatments: 

A alone, B alone, both A and B, neither A nor B).

Group sequential design: Allows the trial to be

monitored at specific time intervals so that a treatment arm, or the entire trial, may be stopped early if

there is clear evidence of efficacy or of unacceptable

adverse effects.

Parallel group design: Participants are randomized

to one of two or more arms, and each arm is 

allocated a different treatment.

Randomized withdrawal design: Participants who

respond positively to an experimental intervention

are randomized either to continue receiving the intervention or to receive a placebo.

Superiority trials: Trials designed to determine

whether an experimental intervention is more efficacious than an established effective treatment.
National Bioethics Advisory Commission

23

It should be emphasized that often there is a considerable lack of clarity in the scientific community about

the state of equipoise for a particular set of interventions.

There may be no consensus about how many studies

must be completed to show the efficacy of a new intervention or about how strong the evidence must be to

change medical practice. In addition, there may be disagreement or concern about the applicability of research

findings in, for example, different populations with different genetic backgrounds, different co-morbidities, or

different environmental and social factors.3 However, disagreements about these issues, although important, are

distinct from those regarding equipoise. At the end of a

clinical trial, if it is determined that an experimental

intervention is superior—or inferior—to the control

intervention, the state of clinical equipoise may have

been eliminated or evidence may have been accumulated

that could lead to such a conclusion. Therefore, although

a clinical trial starts in a state of equipoise, investigators

hope that the analysis of the data collected during the

trial will remove or reduce the level of uncertainty.

Randomization

Randomization is the process by which participants

in a clinical trial are assigned to different interventions in

a study. Through randomization, each person has a specified chance of being assigned to one or another group.

Randomization differs from systematic assignment, in

which individuals are assigned to a particular arm of a

study for a specific clinical, scientific, or perhaps demographic reason (e.g., medical history, presence of a

genetic marker, age). Rather, it is a process used to minimize any inherent differences among participants in the

various arms of a trial by distributing people with particular characteristics randomly to the intervention and

control arms, and it is the only way to equalize all factors,

known and unknown, between study groups (Fletcher 

et al. 1982). The consensus among clinical investigators

is that nonrandomized controls can create severe bias and

therefore may result in unreliable trial results. Along with

the use of placebos (defined as an intervention that

although physically resembling the intervention being

tested is inert and not expected to have any pharmacological effect on the condition being treated) or other

controls as well as double blinding (in which neither the

investigator nor the participant knows which intervention, if any, the participant is receiving), randomization of

a study is essential in evaluating new interventions. At

times, however, randomized trials are not practical, such

as when an insufficient number of participants is available to provide the statistical power needed for drawing

conclusions.4

Types of Control Groups

The first documented example of a controlled clinical

trial was James Lind’s experiment in 1747 with 12 sailors

with scurvy aboard the H.M.S. Salisbury (Lind 1753).

Lind divided the sailors into six groups of two each and

compared the effects of providing different nutritional

supplements to each group. The two men who ate

oranges and lemons recovered immediately. Lind concluded that something in the citrus fruit was counteracting the cause of the scurvy, so he gave citrus fruit to all

the other men and observed that they too were cured of

the disease. Lind’s experiment laid the initial groundwork

that established the controlled clinical trial as the best

method for determining the effects of new therapies.

The FDA classifies clinical trial control groups into

five types: placebo concurrent control, active treatment

concurrent control, no treatment concurrent control,

dose-comparison concurrent control, and external control

(FDA 1999). Each type has strengths and weaknesses,

depending on the scientific question being asked, the

intervention being tested, and the group of participants

involved. Therefore, because no one type of control

group is ideal in all situations, researchers should choose

the one that best answers the scientific question to be

addressed and presents the least risk to the participants.

Because of their importance, placebo concurrent control

and active treatment concurrent control trials are

described more fully below.

Placebo Concurrent Control

A placebo is an intervention that physically resembles

the intervention being tested, but is inert and not

expected to have any pharmacological effect on the condition being treated. Placebo-controlled trials control not

only for the placebo effect (changes in a person’s physical
24

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

or mental condition that result from his or her belief that

the study is providing an active treatment), but also for

changes that arise due to the natural course of the disease;

participant or investigator expectations; the use of other

therapies; and the subjective elements of a diagnosis or

assessment (FDA 1999). By including a placebo group in

a clinical trial, the action of the experimental intervention

can be distinguished from other confounding factors and

from changes that can be attributed purely to the physical

or socioeconomic environment.

For some clinical trials, the decision regarding the

appropriateness of using a placebo is not problematic. It

is generally accepted that when no established intervention exists to treat or prevent the condition being studied,

it is ethically acceptable to give the control group a

placebo. This is because in such trials, there is no treatment against which to compare the experimental intervention. Another argument in favor of the use of placebo

controls has been made in the context of research conducted in a developing country. Many researchers have

contended that the research question must be defined

differently in a setting in which health care resources are

limited and participants do not have access to established

effective treatments outside of the research context. Some

have advocated that in these cases, the measurement of

absolute efficacy of a new and potentially more affordable

and available intervention is a more relevant research

question for the host country than the comparison of a

new intervention to an established effective treatment

already available elsewhere (Levine 1999; Perinatal HIV

Intervention Research in Developing Countries

Workshop Participants 1999).

On the other hand, virtually all experts believe that 

a placebo-controlled trial would not be ethical if an 

established effective treatment that is known to prevent

serious harm—such as death or irreversible injury—is

available and can be provided. NBAC agrees with the

consensus that it is not ethically acceptable to perform

placebo-controlled clinical trials when established effective treatments exist (such as in the cases of new thrombolytics [blood clot-dissolving agents], beta blockers,

aspirin, or angiotensin-converting enzyme inhibitors to

improve survival after heart attacks, or new chemotherapeutics for leukemia or testicular cancer).5 Even under

these circumstances, however, exceptions may exist if an

established effective treatment does not work in certain

populations or has such serious side effects that some

patients refuse treatment. 

In the United States, there is substantial agreement 

in the research community that the use of placebos in

studies involving severe or life-threatening illnesses when

existing treatment could prevent them or delay their 

progression is ethically suspect.6 The American Medical

Association’s (AMA’s) guidance for the use of placebos

states that “protocols that involve conditions causing

death or irreversible damage cannot ethically employ a

placebo control if alternative treatment would prevent or

slow the illness progression....In general, the more severe

the consequences and symptoms of the illness under

study, the more difficult it will be to justify the use of a

placebo control when alternative therapy exists” (AMA

1999). In contrast, most experts agree that the use of a

placebo is acceptable if it does not harm the participants

and only results in discomfort (Temple 1996). Similarly,

guidance from the International Conference on

Harmonisation (ICH) indicated that with informed 

consent and appropriate review by an IRB, research 

participants could be asked to participate in placebocontrolled trials, even if an existing treatment is available,

when the only risk from not receiving treatment is discomfort (ICH 1996). In such cases, it is necessary to

ensure that the setting is not coercive and that the participants are fully informed about other available therapies

and the consequences of delaying treatment (FDA 1999).

Ethics review committees will rightfully exercise their

judgment in assessing research designs that employ a

placebo control. However, the Commission believes that

there are some studies for which the presumption in

favor of active controls simply cannot be overcome.

Although NBAC did not review the protocol, it appears

that a recently reported case may serve as example of

such a study (see Exhibit 2.3). In addition, as reflected in

the recommendations in this report, the study discussed

in the exhibit would be unacceptable because it intends

to use developing country citizens as research participants while its primary purpose is to develop a drug 

for market in the United States and other developed

countries.
National Bioethics Advisory Commission

25

Yet, there are some who criticize the use of placebo

controls even in cases in which risks to participants are

low. One argument against the use of placebos is often

grounded in the Declaration of Helsinki: Ethical Principles

for Medical Research Involving Human Subjects, which states

that “[i]n any medical study every patient—including

those of a control group, if any—should be assured of the

best proven diagnostic and therapeutic method” (WMA

1964, as amended in 1989). Giving research participants

a placebo in place of an established effective treatment

deprives them of the “best proven diagnostic and therapeutic method” (WMA 1964, as amended in 1989).

Moreover, some critics argue that 1) research participants

should not face unnecessary pain or disease resulting

from a medical experiment (Rothman and Michels

1994); 2) using a placebo instead of an established

effective treatment knowingly breaches researchers’ duty

to minimize harm (Levine 1998); and 3) it is unethical

for individual investigators to enroll patients in a study in

which some participants are expected to do even slightly

worse than others (Barinaga 1988).

Indeed, although the placebo-controlled, randomized,

double-blind clinical trial is an authoritative and widely

accepted standard for new drug evaluation, some have

argued that it is not always ethical to use this trial design

(Freedman et al. 1996). In situations in which the best

scientific design is not ethically acceptable, it may be 

necessary to reconsider the primary research question

and to choose one for which an ethically acceptable

design can be proposed (Levine 1998), or it may be 

necessary to accept the fact that ethical constraints can

create limitations to obtaining scientific knowledge.7

Exhibit 2.3: Placebo Versus Established Effective Treatment (Active Control)

In early 2001, a proposal was submitted to the FDA by a U.S. biotechnology company for approval of a three-arm

study of a new surfactant drug in as many as four Latin American countries. In the study, a control group of premature newborn infants with Respiratory Distress Syndrome (RDS)—a potentially fatal condition—would be treated with

placebos, rather than a life-saving and already FDA-approved surfactant drug (Flaherty and Stephens 2001; Lurie et

al. 2001). The apparent justification for conducting these studies is to decrease the time needed to develop the drug,

which is intended for market in the United States. The company also plans to conduct a similar study 

on newborns in Europe, where no placebo controls will be used. Instead, all newborns will receive either the experimental intervention or another already approved surfactant.

Concerns have been voiced about whether the proposed study is ethical, mainly because the study design

involves the use of a placebo control when an established effective treatment exists (Flaherty and Stephens 2001;

Lurie et al. 2001). Thus, approval is being sought to conduct research in a developing country that could not be 

ethically justified in a developed country. Indeed, internal FDA documents state that “conduct of a placebo controlled

surfactant trial for premature infants with RDS is considered unethical in the USA” (Lurie et al. 2001). The company,

however, contends that because infants in Latin America with RDS who do not have access to established drugs

would not be left worse off by placebo treatment, the proposed study is ethically justifiable in the hospitals where surfactant drugs are not available (Flaherty and Stephens 2001; Lurie et al. 2001). It is widely accepted, though, that in

cases such as RDS that involve a life-threatening condition, a placebo control should not be employed when an

established effective treatment exists against which the experimental intervention can be tested. 

The other ethical concern that has been raised about the proposed study is that poor Latin American newborns

would be participating in testing an intervention, which, if proven effective, would be too expensive for their families

or others in the host country (Flaherty and Stephens 2001; Lurie et al. 2001). The company has indicated that, to

some extent, it will provide the drug at a reduced cost to the host countries if it is proven effective (Flaherty and

Stephens 2001; Lurie et al. 2001). Nevertheless, the lack of care available in a developing country cannot provide

the principal ethical justification for using such a research design, especially when the benefits of the study are

intended primarily for the developed world.

In studies of this kind—in which the disease is life threatening, an established effective treatment is available,

patients in developed countries will be the primary beneficiaries of the results of the clinical trial, and it is not 

clear that the clinical trial is responsive to the health needs of the host country—a placebo control would not be 

permissible under the rules recommended in this report.
26

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

The recent revision of the Declaration of Helsinki

attempts to resolve the debate about placebos by recommending that “[t]he benefits, risks, burdens and effectiveness of a new method should be tested against those

of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of

placebo, or no treatment, in studies where no proven

prophylactic, diagnostic or therapeutic method exists”

(WMA 1964, as amended in 2000). Certain criticisms

about this provision remain—principally that it makes 

it very difficult, if not impossible, to conduct placebocontrolled trials when such trials may be the only method

of addressing the health needs of a particular population

(Enserink 2000). 

Active Treatment Concurrent Control

Although placebos are a frequently used control for

clinical trials, it is increasingly commonplace to compare

an experimental intervention to an existing established

effective treatment. These types of studies are called

active-control (or positive control) studies, which can take

two forms—a superiority trial, in which the question is

whether the new drug will be superior to the active control, and an equivalence (noninferiority) trial, in which the

question is whether the new drug will be equivalent to

but not inferior to the active control (Hauck and

Anderson 1999). Active-controlled trials are often

extremely useful in cases in which it would be unethical

to give participants a placebo because doing so would

pose undue risk to their health or well-being. 

In an active-control study, participants are randomly

assigned to the experimental intervention or to an activecontrol treatment. Such trials are often double blinded,

but this is not always possible. Many oncology studies are

considered impossible to blind because of the variable

regimens, different routes of administration, and range of

toxicities involved. In a study in which an active control

is used, it may be difficult to determine whether the

active control or the experimental intervention had an

effect unless the effects of the treatments are obvious or a

placebo control is included. For example, because the

natural history of depression varies from patient to

patient and it is often difficult to prove that a standard

treatment has had an effect, studies of anti-depressants

usually include both an active control and a placebo 

control.8

Treatment of Control Groups

Within the context of active treatment concurrent

controls, it is useful to consider whether, and if so under

what circumstances, researchers and sponsors are obligated to provide an established effective treatment to the

control group, even if that treatment is not available in

the host country. In the survey conducted by Nancy Kass

and Adnan Hyder, more than half (52 percent) of the surveyed U.S. researchers conducting studies with control

groups in developing countries thought that the standard

of care in the host country was lower than that in the

funding country. This created ethical difficulties in establishing appropriate procedures for the control group. A

strong majority (78 percent) of these researchers believed

that the level of medical care provided to control groups

should be decided on a case-by-case basis.9

One view pertinent to this dilemma was expressed to

the Commission in the following way: It is unethical to

provide members of a control group with an established

effective treatment if that treatment is unavailable in the

country where the research is conducted. This is because

the opportunity to obtain this treatment would render

the choice to enroll in the study irresistible, as those

receiving the treatment are unlikely to be able to get it

once the trial is over.10 The Commission does not agree

with this proposition, because cases exist in which trials

using the established effective treatment as a control

would generate valuable information that is responsive to

the health needs of the host country. 

Some might argue that researchers and sponsors are

under no ethical obligation to provide members of a control group with an established effective treatment if 

that treatment is unavailable in the country in which 

the research is conducted. This position maintains that

the researchers’ and sponsors’ obligations to participants

do not go beyond providing treatments that are routinely

available to the majority of people in the host country. 

Still others might contend that researchers and sponsors have an obligation to provide members of a control

group with an established effective treatment even if that

treatment is unavailable in the host country. Supporters
National Bioethics Advisory Commission

27

of this view assert that a special relationship is created

when sponsors and investigators from a developed country enter a developing country to conduct research. For

many, these obligations arise regardless of the prevailing

situation in a particular location or country. 

A description of the obligations that arise from these

situations can be found in the basic principles of research

ethics presented in the Belmont Report: Ethical Principles

and Guidelines for the Protection of Human Subjects of

Research (National Commission 1979) and many other

national and international guidelines. For example, the

most straightforward interpretation of the principle of

beneficence—to “maximize possible benefits and minimize possible harms”—is that sponsors and investigators

should make an established effective treatment available

whether or not it is routinely available, because providing the treatment to the control group would maximize

possible benefits and minimize possible harms to that

group. Therefore, assuming that the sponsoring agency

or organization can provide an established effective treatment and that the host country’s collaborators, ethics

review committee, and ministry of health or other appropriate authority are willing to accept the established

effective treatment as part of a randomized controlled

trial, a presumption should exist to provide members of

a control group with an established effective treatment

whether or not that treatment is available in the host

country.

A tension exists, however, between this version of the

principle of beneficence and the need for a research

design that is relevant to real health concerns facing the

population of the host country. These concerns may not

be the relative efficacy of the new intervention (compared

to the established treatment available in the developed

countries), but rather the absolute efficacy of the intervention compared with the absence of any treatment or

the level of care routinely available. Researchers in the

Kass/Hyder survey described the tension between

researchers’ desire to benefit the larger population of the

host country and their concern for the well-being of

study participants. One researcher described a dramatic

example of a vaccine designed to prevent children from

dying from a particular tropical disease. To determine if

the experimental vaccine was effective—using mortality

as an endpoint—the research design entailed administering either the vaccine or a placebo to groups of children

and subsequently withholding a feasible effective treatment from sick children. The researcher who described

this study thought that it was imperative to develop a

vaccine for this illness, but was troubled by withholding

treatment that could save lives.11

Resolving this tension is central to the assessment

conducted by ethics review committees, whose responsibilities include evaluating the ethical appropriateness of

study designs. Thus, for example, in assessing a given

study design, ethics review committees should consider

the potential harm that may occur to participants who do

not receive an established effective treatment for their

condition, the strength of the evidence that a new intervention will be useful and affordable to the host country,

and the feasibility of implementing an existing established treatment during the course of the study. If

researchers make an acceptable case to the ethics review

committee that comparing the new intervention to an

established effective intervention is not a relevant

research question for the host country, then the control

group may receive the best care available that enables the

researcher to answer a useful question. 

Determining the most useful and ethical research

design depends on several factors particular to the circumstances, and one can expect a certain amount of disagreement in this area. Perhaps the best answer for now

is to say that investigators must carefully explain and

ethics review committees must carefully scrutinize the

justification for the selection of the research design,

including the level of care provided to the control group.

If in a proposed clinical trial the control group will

receive less care than would be available under ideal 

circumstances, the burden on the investigator to justify

the design should be heavier. Furthermore, representatives of the host country, including scientists, public 

officials, and persons with the condition under study,

should have a strong voice in determining whether a 

proposed trial is appropriate. This view is reflected in 

certain national and international guidelines (see

Appendix B) and has been advocated by others as well

(Benatar and Singer 2000).
28

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

Established Effective Treatment and Best 

Current Methods

Chapter 1 provided NBAC’s rationale for adopting the

term an established effective treatment and indicated that

this phrase refers to a treatment or a group of treatments

that has achieved widespread acceptance by the medical

profession (established) and that is as successful as any 

in treating the disease or condition anywhere in the

world (effective). The treatment is not limited to what is

routinely available in the host country. The Commission

concluded that the standard of an established effective

treatment best conveys what is owed to research participants during a trial. 

NBAC recognizes that although it can be difficult to

determine whether an intervention constitutes an established effective treatment, this term has certain advantages.

Among the difficulties noted, however, was the possible

disagreement of some scientists about whether an intervention shown to be effective in one population is likely

to be as effective in another population that differs in 

significant ways. By choosing the term an established 

effective treatment and avoiding the qualifier best, NBAC

proposes, simply, that the selection of an established

effective treatment in a clinical trial conducted in a developing country must be made on a case-by-case basis. 

The Commission also believes that this approach

would satisfy those who have criticized the best proven

method standard, or the established effective treatment

standard proposed here, by arguing that the use of complex and very expensive medical care (such as surgery or

catheterization for cardiovascular disease) in a developing country often is not feasible, even within the context

of most research studies, and that such care is not sustainable after the research is complete. These commentators allege that if complex and costly medical care is used

as the control against which new interventions are measured, research studies will generate data that potentially

will be irrelevant to the host country—an argument analogous to that used to defend placebo use. 

As noted in the discussion of placebo use, three factors must be considered by researchers when designing a

study and by ethics review committees when reviewing

protocols if they are to assess the level of medical care

that should be provided to participants: 1) the well-being

of the study participants; 2) the relevance of the research

question to the host country; and 3) the feasibility of

implementing a given type of medical care in the host

country setting. In the case of medical treatments that

involve a huge medical infrastructure or that are

extremely costly to implement, feasibility may be the

determining factor. In addition to feasibility, the ethical

assessment of what level of care to provide often will

depend on balancing the concern for the well-being of

study participants with concern for the relevance of the

research question to the host country. NBAC believes that

researchers and ethics committees must find a balance

between these important ethical demands in each

research project. 

Recommendation 2.2: Researchers and sponsors

should design clinical trials that provide members

of any control group with an established effective

treatment, whether or not such treatment is available in the host country. Any study that would 

not provide the control group with an established 

effective treatment should include a justification 

for using an alternative design. Ethics review 

committees must assess the justification provided,

including the risks to participants, and the overall

ethical acceptability of the research design.

Distinguishing Between Efficacy and

Effectiveness Studies

Efficacy clinical trials are sometimes considered 

optimal care studies in which the research question is

whether the experimental treatment works under ideal

conditions. In contrast, effectiveness clinical trials ask

whether the experimental treatment works under ordinary circumstances. Often, there are legitimate differences of opinion regarding whether an efficacy trial or an

effectiveness trial is more scientifically and ethically

appropriate in a given situation. On the one hand, efficacy

trials ignore problems of access to care, generalizability

from a highly selective sample of patients and physicians,

and adherence to regimens, for example. If an efficacy

trial is negative, it is hard to imagine that an effectiveness

trial would show a benefit; therefore, effectiveness trials

might have limited usefulness in developing countries. If

an efficacy trial is productive, the question regarding
National Bioethics Advisory Commission

29

whether the intervention will be effective when used by a

broader range of doctors and patients, who may not find

it affordable, accessible, or acceptable, is still open. On

the other hand, a problem with effectiveness trials is that

if they produce a negative result, it is unclear whether the

experimental intervention would fail under any circumstances, or only because patients and doctors lacked

access to it, or because the doctors were unskilled or the

patients poorly adherent.

In an efficacy trial, the control group should receive

the best established treatment. However, in an effectiveness trial, the research question cannot always be

answered by giving the control group the best established

treatment. No consensus has emerged that the research

questions posed in efficacy trials would be as pertinent to

the needs of a host country as would the research questions posed in effectiveness trials. To provide the best

established treatment would be to ask a completely 

different research question, one that may not be relevant

to the clinical needs of the population being studied. 

Another consideration in the context of developing

country research is that a new intervention’s degree of

effectiveness may be critically important in terms of allocating scarce resources. Although a new intervention may

be shown to be significantly better than existing or no

treatment, policymakers may want to determine exactly

how much benefit can be derived from the new intervention before deciding to allocate funds to implement it,

particularly when there are competing health priorities in

the host country.12

Selection of the Participant Population and

Sample Size

Another important study design issue is the selection

of the population to be studied. In the early phases of

drug development, for example, research participants are

selected from a small subgroup of the patient population

in which the drug eventually may be used (CPMP 1995).

This is done to maximize the opportunity to observe 

specific clinical effects of interest. By the time the experimental intervention enters pivotal Phase III trials, the

participants should more closely mirror the intended

users. Therefore, in these trials the criteria for selecting

participants usually are relaxed as much as possible,

without jeopardizing the possibility of conducting a 

successful trial. However, even a Phase III clinical trial

usually is not completely representative of future users,

because of several factors, including the geographical

location of the trial, when it is conducted, and the medical practices of the investigators and clinics involved

(CPMP 1995). Multicenter trials help to reduce the influence of such factors; however, if a multicenter trial is not

feasible, every effort should be made to reduce the variations that can be caused by these factors.

Determining the sample size is another important

component of clinical trial planning. Appropriate sample

size depends on the design of the trial and its primary

objective. Many methods and statistical models have

been developed to calculate appropriate sample size.

However, the number of participants in a clinical trial

always should be large enough (but no larger than necessary) to provide a reliable answer to the questions posed.

The issue of sample size has been raised in the debate

over placebo-controlled trials and equivalence trials.

Most equivalence trials require more participants than

placebo-controlled trials, an argument that has been used

against them. Because placebo-controlled trials involve

fewer subjects, they tend to be completed more quickly,

and any resulting treatment is made available sooner

(Levine 1998). The sooner a new treatment is introduced, the more people stand to benefit from its use.

Others argue that in a well-designed trial and with the

use of appropriate statistical methods, the required sample sizes for equivalence trials are often similar to those

needed for placebo-controlled trials.13

Each of these issues in the choice of research design—

equipoise, randomization, the nature and treatment of

control groups, the distinction between efficacy and

effectiveness studies, and the selection of the participant

population and sample size—involves scientific questions that have ethical relevance (Freedman 1987; Levine

1986; Sutherland et al. 1994) and are therefore properly

the concern of ethics review committees. One additional

issue, which has been identified recently as important 

in the design of clinical trials and which has particular

relevance to international collaborative research, is the

involvement of the community and study participants in

the design of research.
30

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

Involvement of the Community and

Study Participants in the Design of

Research

Over the past three decades, researchers increasingly

have deliberately involved communities in the design of

research (Arole and Arole 1994; CDC 1997; Taylor 1970;

Taylor 1983; Taylor 1984). In addition, research participants, health advocates, and other members of the communities from which participants are recruited have

requested, and in some cases demanded, involvement in

the design of clinical trials. These trends are noteworthy.

By consulting with the community, researchers often gain

insight about whether the research question is relevant

and responsive to the health needs of the community

involved. In addition, community consultation can

improve the informed consent process and resolve problems that arise during this process because of the use of

difficult or unfamiliar concepts. Such discussions can

provide insight into whether the balance of benefits and

harms in the study is considered acceptable and whether

the interventions and follow-up procedures are satisfactory. Community consultation also can reveal the best

methods for recruiting participants. (See Chapter 3 for a

more extensive discussion of community involvement in

the recruitment of participants and the informed consent

process.)

The Joint United Nations Programme on HIV/AIDS

(UNAIDS), for example, has since its inception in the

mid-1990s promoted the involvement of local communities and prospective research participants in the design

and implementation of research studies. UNAIDS has 

an Ethical Review Committee—the duties of which

include the basic IRB function of ethical review of

research protocols—and this committee’s standard

assessment form includes a section entitled “Community

Involvement and Impact.” The following questions are

included in this section:

■ Is there a process of community consensus-building

prior to initiating the research, i.e., consultation/discussion of impact of study and its relevance to (a)

potential beneficiaries, (b) participants’ communities?

If not, why?14

and 

■ To the degree possible, are (a) potential participants;

(b) beneficiaries; (c) other community members; 

(d) local researchers, involved in: (i) the design; 

(ii) evaluation; (iii) analysis; (iv) publication and/or

dissemination of the proposal; (v) implementation of

results? If not, why?15

Researchers submitting proposals to UNAIDS receive a

copy of the assessment form used by the Ethical Review

Committee and are made aware of the need to address

the issue of community involvement in the preparation

of a research proposal for submission to UNAIDS.

In anticipation of the initiation of an increasing 

number of HIV/AIDS preventive vaccine trials, UNAIDS

issued a guidance document in February 2000, in which

Guidance Point 5 recommends the following:

To ensure the ethical and scientific quality of proposed research, its relevance to the affected community, and its acceptance by the affected community,

community representatives should be involved in an

early and sustained manner in the design, development, implementation, and distribution of results of

HIV vaccine research (UNAIDS 2000, 19).

However, it is frequently difficult to define the relevant community of participants, no matter where the

research is conducted. In cases in which no traditional

community structure exists, local organizations or nongovernmental organizations often can assist in representing the interests of participants in the research process. A

research project might involve participants from widely

scattered communities—sometimes in several nations—

and it might be logistically difficult to reach representatives of every location from which participants are drawn.

In addition, in some communities social hierarchies or

corrupt elements exist that might impede the consideration of research participants’ interests; therefore, in each

research setting, it is necessary to determine the most

appropriate way to involve local representatives who can

provide a voice for research participants.

Recommendation 2.3: Researchers and sponsors

should involve representatives of the community

of potential participants throughout the design

and implementation of research projects.

Researchers should describe in their proposed
National Bioethics Advisory Commission

31

protocol how this will be done, and ethics review

committees should review the appropriateness of

this process. When community representatives

will not be involved, the protocol presented to 

the ethics committee should justify why such

involvement is not possible or relevant.

Other Issues in Research Design

Although this chapter has focused primarily on the 

ethical issues that arise in the design of clinical trials, two

additional issues warrant mention—monitoring the

interim results of a study and repeating a study. 

Monitoring the Interim Results of a Study

Randomized clinical trials begin at a point of

equipoise regarding the relative risks and benefits of the

intervention being evaluated. As the study proceeds,

however, cumulative data or recent findings from other

research efforts may provide strong evidence in favor of

one of the interventions being tested, thus overturning

the equipoise and suggesting that the study should be

stopped. Responsibility for the review of interim data is

often given to an independent group, such as a Data and

Safety Monitoring Board (DSMB), with expertise in the

clinical problem, biostatistics, and bioethics. DSMBs have

confidential access to interim results, which are not 

available to investigators or sponsors. Unblinding investigators and sponsors would introduce bias into the trial

and undermine its integrity. The goal of interim analysis

is to stop the trial early if the superiority or inferiority of

the experimental intervention being tested has been

clearly established, if it is evident that the experimental

intervention has no efficacy, or if unacceptable adverse

effects are occurring (CPMP 1995; DeMets et al. 1999). 

In addition to examining the evolving results of the

trial, groups that are conducting interim analysis should

be aware of advances in the field and assess whether

study designs remain ethically and scientifically valid.

This is especially important for studies that involve diseases for which rapid progress in the development of

effective therapies has occurred. For example, trials in

which the control group receives an established effective

treatment may be deemed unethical because a new treatment has been found that is clearly more effective. In

addition, trials may no longer be considered ethical

because they have no reasonable hope of leading to an

unequivocal result, or they have already demonstrated a

statistically definitive and clinically significant difference

between the control group and the experimental arm.

Trials that are deemed to be unethical should be terminated to protect the research participants, even if continuation of the research would be of interest to the medical

and scientific communities. Because clinical trials often

require several years to complete, it is important to monitor them regularly to safeguard the best interests of the

participants.

Repeating a Study

A different situation arises when a treatment has been

shown to be effective in a developed country and

researchers propose to repeat the study in a developing

country. What could justify repeating a study using the

same research design? Several who provided comments

to NBAC remarked that generally, an accumulation of

evidence from many studies is needed in order to establish a new intervention as efficacious and to warrant

changes in health policy or medical practice. Whether

several studies of the same intervention constitute repetition or whether conditions or protocols among studies

are different enough that genuinely new evidence is being

collected may not be known until all of the data are

examined. Dispute frequently occurs, even in the United

States, about whether differences in study populations—

such as race, sex, stage of disease, presence of other conditions, or environmental conditions—constitute

scientific differences that necessitate further empirical

research because they might have a material effect on the

effectiveness of an intervention.16 In principle, if there is

no scientific reason to question the effectiveness of the

new treatment in the developing country population, it

would be ethically problematic to repeat the study.

However, in practice, as mentioned above, it may be difficult to determine when valid reasons to repeat a study

exist. In some cases, because different biological, social,

and environmental conditions are found in different

developing countries, new interventions must be studied

in those countries to determine their effectiveness in

those settings. In other cases it may be reasonable to presume that treatments that are recognized to be effective
32

Chapter 2: Ethical Considerations in the Design and Conduct of International Clinical Trials

based on data from the United States or other developed

countries do not need to be studied in every country in

which they are used.

Another possible reason to repeat a study is that 

policymakers in many countries will not accept the

results of trials conducted elsewhere.17 This reluctance

can stem from legal or regulatory considerations or from

the existence of a policy that requires a determination of

the adequacy of other countries’ scientific, technical, or

ethical review procedures. However, a reluctance to

accept data from studies conducted in other countries

also may represent a political stance on the part of a 

ministry of health or legislative body—that is, a refusal to

recognize the relevance of research results from other

countries because of national pride or political rivalries or

an unwillingness to accept the results of studies that 

are not conducted by local authorities. Although these

reasons cannot alone serve as ethical justifications for

conducting a study that has already been successfully

conducted, the urgent health needs of a host country

may lead developed country sponsors to decide that it

would be unethical not to carry out the necessary

research if the established effective treatment could not

otherwise be made available to the population.

Conclusions

This chapter has focused on a specific set of ethical issues

related to choosing research designs for clinical trials.

The discussion of some alternative designs is intended to

demonstrate that no single design is appropriate for

answering all research questions. In addition, the very act

of choosing a research question has ethical implications.

NBAC does not try to draw a conclusion about the 

precise circumstances under which, for example, the use

of a placebo is acceptable in a particular clinical trial.

Rather, this chapter has identified a set of ethically and

scientifically relevant considerations that must be taken

into account from the earliest stages of research design

and of which potential investigators, ethics review committees, research participants, and research sponsors

must be aware.

NBAC recognizes that some will disagree with the

position that, in general, researchers and sponsors should

make every effort to design clinical trials that provide

control group members with an established effective

treatment. In taking this position NBAC seeks to apply

the same ethical standard to research conducted in developing countries that is applied in countries where established effective treatments are available to the general

population. To do otherwise would leave the door open

to conducting research in a developing country that

could not be conducted in a wealthier country, while still

allowing the benefits to flow to the wealthier country. If

one accepts the fundamental premise articulated in

Chapter 1—that research should be responsive to the

health needs of the host country—then the logical next

step should be choosing an appropriate research design,

one that does not exploit the populations of countries

with few resources while permitting those countries to be

the sites of research that could benefit their populations. 

Notes

1 NBAC made recommendations in this area in two previous

reports (NBAC 1998; NBAC 1999) that are just as relevant to the

current discussion. 

2 See Kass, N., and A. Hyder, “Attitudes and Experiences of U.S.

and Developing Country Investigators Regarding U.S. Human

Subjects Regulations,” 49–50. This background paper was prepared for NBAC and is available in Volume II of this report.

3 Goodman, S., Public comment submitted to NBAC. November

13, 2000.

4 Dickersin, K., Testimony before NBAC. December 2, 1999.

Baltimore, Maryland. 

5 Temple, R., Testimony before NBAC. September 18, 1997.

Bethesda, Maryland. Meeting transcript, 7–8.

6 AMA, Public comment submitted to NBAC. Received November

15, 2000; FDA, Public comment submitted to NBAC. Received

November 9, 2000; Temple, R., Public comment submitted to

NBAC. Received November 13, 2000.

7 Temple, R., Public comment submitted to NBAC. Received

November 13, 2000.

8 Temple, R., Testimony before NBAC. September 18, 1997.

Bethesda, Maryland. 

9 See Kass and Hyder, 53.

10 Sommer, A., Testimony before NBAC. September 16, 1999.

Arlington, Virginia. Meeting transcript, 189.

11 See Kass and Hyder, 53. 
National Bioethics Advisory Commission

33

12 Goodman, S., Public comment submitted to NBAC. 

November 13, 2000.

13 Lurie, P., and S.M. Wolfe, Testimony before the Committee 

on Government Reform and Oversight. U.S. House of

Representatives. April 22, 1998. Washington, D.C. Available at

www.house.gov/reform/hearings/healthcare/fda498/index.htm. 

Last accessed January 9, 2001.

14 UNAIDS, Ethical Review Committee. Assessment Form for

Committee Review. Question 9.

15 Ibid., Question 10.

16 Bennish, M., Public comment submitted to NBAC. Received

November 12, 2000; Goodman, S., Public comment submitted to

NBAC. Received November 13, 2000.

17 Sommer, A., Testimony before NBAC. September 16, 1999.

Arlington, Virginia. Meeting transcript, 179–180, 188–189,

215–218.

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Research into Maternal Infant Transmission of HIV-1.” The Lancet

353:832–835.

Pharmaceutical Research and Manufacturers of America (PhRMA).

1999. 1999 Pharmaceutical Industry Profile. Washington, D.C.:

PhRMA.

Rothman, K.J., and K.B. Michels. 1994. “Sounding Board: The

Continuing Unethical Use of Placebo Controls.” The New England

Journal of Medicine 331(6):394–398.

Sackett, D.L. 1983. “On Some Prerequisites for a Successful

Clinical Trial.” In Clinical Trials: Issues and Approaches, eds. 

S.H. Shapiro and T.A. Louis, 65–79. New York: Marcel Dekker.

Spilker, B. 1991. Guide to Clinical Trials. New York: Raven Press.

Sutherland, H.J., E.M. Meslin, and J.E. Till. 1994. “What’s 

Missing from Current Clinical Trial Guidelines? A Framework 

for Integrating Ethics, Science and Community Context.” Journal 

of Clinical Ethics 5(4):297–303.

Taylor, C.E. 1970. “Public Health Research.” In Medical Research:

Priorities and Responsibilities. Proceedings of a Round Table

Conference Organized by the Council for International

Organizations of Medical Sciences (CIOMS). Geneva: CIOMS.

———. 1983. “Health Systems Research: How Can It Be Used?”

World Health Forum 4:328–335.

———. 1984. The Uses of Health Systems Research. Public Health

Paper No. 78. Geneva: World Health Organization.

Temple, R. 1996. “Problems in Interpreting Active Control

Equivalence Trials.” Accountability in Research 4:267–275.

World Medical Association (WMA). Declaration of Helsinki: Ethical

Principles for Medical Research Involving Human Subjects (adopted

18th WMA General Assembly, Helsinki, Finland, June 1964;

amended: 29th WMA General Assembly, Tokyo, Japan, October

1975; 35th WMA General Assembly, Venice, Italy, October 1983;

41st WMA General Assembly, Hong Kong, September 1989; 48th

WMA General Assembly, Somerset West, Republic of South Africa,

October 1996; and 52nd WMA General Assembly, Edinburgh,

Scotland, October 2000). Ferney-Voltaire, France: WMA. Available

at www.wma.net/e/policy/17-c_e.html. Last accessed January 12,

2001.
Introduction

The requirement to obtain voluntary informed consent from individuals before they are enrolled in a

research trial is a fundamental principle of research

ethics. This requirement is reflected in all published

national and international codes, regulations, and guidelines pertaining to research ethics, including those in

many developing countries, such as India, Thailand, and

Uganda. It also appears in a major international human

rights instrument—the International Covenant on Civil

and Political Rights—to which the United States is a

party. Article 7 of this covenant provides that “no one

shall be subjected without his free consent to medical or

scientific experimentation” (United Nations 1996).

The requirement for freely given and informed 

consent to participate in research reflects important substantive ethical principles, including respect for persons,

human dignity, and autonomy. However, it is possible to

respect persons and their dignity or autonomy and

affirm the requirement to obtain voluntary informed

consent and at the same time allow for the modification

of the procedures that are involved in obtaining consent,

such as those stipulated in the Federal Policy for the

Protection of Human Subjects, known as the Common

Rule (45 CFR 46.117(c)).2

Despite the ethical centrality of voluntary informed

consent and its underlying principles, problems of interpretation and application exist for researchers and ethics

review committees in both developed and developing

countries. Some problems regarding informed consent

are particularly difficult when the host country has little

experience with clinical trials and has markedly different

cultural values and ethical commitments than the United

States. It is important, therefore, for U.S. sponsors of

international research to address pressing issues concerning the application of U.S. research regulations for

informed consent in settings with different cultures and

customs. 

This chapter addresses a number of related topics,

including the following:

■ whether cultural factors create a barrier to complying

with the substantive ethical standard of informed

consent and whether it is permissible to depart from

that standard if the research could not otherwise be

carried out;

■ how investigators obtain voluntary informed consent

in settings in which the belief system of potential

research participants does not explain health and disease using the concepts and terms of modern medical

science and technology;

■ how voluntary participation can be ensured in settings in which community leaders may exert pressure

on the entire community to enroll in a proposed 

clinical trial;

■ how cultural differences can be addressed between

the United States and other countries that make it 

difficult or impossible for other countries to adhere 

to U.S. federal regulations stipulating specific procedures for obtaining voluntary informed consent; and

■ the means by which the United States could modify

its informed consent regulations to adapt to various

cultural circumstances in other countries without

compromising the substantive ethical standard of

informed consent.

Although individual voluntary informed consent by

competent adults is a widely accepted standard in most

research environments, it is not universally embraced.

35

Voluntary Informed Consent

3

1

Chapter Three
36

Chapter 3: Voluntary Informed Consent

Nonetheless, the National Bioethics Advisory Commission

(NBAC) remains convinced that U.S. sponsors of

research in developing countries should adhere to internationally agreed-upon ethical standards of voluntary

informed consent for research, even in the face of cultural

diversity. Obtaining adequately informed voluntary consent from individual research participants is a necessary

requirement in preventing exploitation, and it should 

be possible to remain sensitive to cultural differences

without departing from these standards. 

The justification for the need for obtaining informed

voluntary consent is simple: The use of human beings as

a means to the ends of others without their knowledge

and freely granted permission constitutes exploitation

and is therefore unethical. NBAC recognizes, however,

that disagreement still exists about this claim. One commentator has argued that “[i]t is ‘ethical imperialism’ at its

worst to assume that the informed consent requirement,

which does indeed serve one (only one) moral principle

in the Western setting, is in itself such a universal ethical

standard” (Newton 1990, 11). This same commentator

contends that growing doubt surrounds the values of

individualism and individual rights, so “the investigator

might better stick to the research, and accept the local

assessment as to adequate protection of individual rights”

(Newton 1990, 11).

Two other commentators, Ijsselmuiden and Faden,

take an opposing view: “Appeals to cultural sensitivity...

are no substitute for careful moral analysis. We see no

convincing arguments for a general policy of dispensing

with, or substantially modifying, the researcher’s obligation to obtain first-person consent in biomedical research

conducted in Africa” (1992, 833). They add that

defenders of such a policy “have relied on limited and

often dated anthropologic literature that does not reflect

the rapid cultural changes brought about by colonialism

and independence, warfare, and urbanization” (1992, 833).

The recommendations developed in this chapter

focus on three traditional elements of informed consent

(Faden and Beauchamp 1986): 1) disclosing information

to potential research participants (see Exhibit 3.1); 

2) ascertaining their understanding of what has been 

disclosed; and 3) ensuring that their agreement to participate in research is voluntary. The basic elements of 

disclosure in the informed consent process as presented

in the Federal Policy for the Protection of Human Subjects

are listed in Exhibit 3.1. References in this chapter to the

basic elements of disclosure in informed consent are to

these eight requirements.

The Ethical Standard of Informed

Consent

Various descriptions of the process and nature of informed

consent can be found in the Common Rule (45 CFR 46.116

and 46.117), Food and Drug Administration (FDA) 

regulations (21 CFR 56), the Council for International

Organizations of Medical Sciences (CIOMS) International

Ethical Guidelines for Biomedical Research Involving Human

Subjects (CIOMS 1993), the International Conference on

Harmonisation (ICH) ICH Harmonised Tripartite Guideline,

Guideline for Good Clinical Practice (GCP) (ICH 1996),

and the World Medical Association’s (WMA) Declaration

of Helsinki: Ethical Principles for Medical Research Involving

Human Subjects (WMA 1964, as amended in 1996 and

again in 2000). Principle 9 of the 1996 revision of the

Declaration of Helsinki states that “[i]n any research on

human beings, each potential subject must be adequately

informed of the aims, methods, anticipated benefits and

potential hazards of the study and the discomfort it may

entail. He or she should be informed that he or she is at

liberty to abstain from participation in the study and that

he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the

subject’s freely given informed consent, preferably in

writing” (WMA 1964, as amended in 1996). In the

October 2000 revised Declaration of Helsinki, Principle 22

addresses the informed consent process, stating that:

[I]n any research on human beings, each potential

subject must be adequately informed of the aims,

methods, sources of funding, any possible conflicts of

interest, institutional affiliations of the researcher, the

anticipated benefits and potential risks of the study

and the discomfort it may entail. The subject should

be informed of the right to abstain from participation

in the study or to withdraw consent to participate at

any time without reprisal. After ensuring that the subject has understood the information, the physician
National Bioethics Advisory Commission

37

should then obtain the subject’s freely given informed

consent, preferably in writing. If the consent cannot

be obtained in writing, the non-written consent must

be formally documented and witnessed (WMA 1964,

as amended in 2000). 

Substantive changes between the 1996 and 2000 revisions of the Declaration include 1) informing each potential subject about any possible conflicts of interest and the

institutional affiliations of the researcher; 2) ensuring that

research participants have understood the information

presented to them; and 3) requiring that if the consent

cannot be obtained in writing, the nonwritten consent

must be formally documented and witnessed.

For this report, NBAC adopts, as the clearest and

most appropriate guides for discussion, the following

definitions of informed consent and the substantive standard of informed consent: Informed consent is a process

by which an individual voluntarily expresses his or her 

willingness to participate in a particular trial, after having

been informed of all aspects of the trial that are relevant

to the decision to participate. This definition is adopted

from the ICH Guideline for Good Clinical Practice, GCP

Guideline 1.28 (ICH 1996). An important feature of this

definition is that it focuses on the process of obtaining

consent rather than on the documentation of that process

using, for example, a written, signed, and dated form. 

In an ethically sound consent process, a member of

the research team provides information to the potential

participant, determines that the individual understands

the information provided, and ensures that the individual voluntarily agrees to participate. Although consent

traditionally has been documented by the signing of a

consent form, other methods of documentation often are

acceptable or even preferable, such as oral consent with

a witness signature. In many settings, it is also required

that the person obtaining the consent sign the consent

form or other related documents and that a witness (or

person designated by the participant) attests to the

process. It is always essential to make a distinction

between the consent document and the consent process and

to not allow the document itself to constitute the process.

The phrase substantive standard of informed consent

refers to the requirement to obtain voluntary informed

consent and reflects the principle that competent 

individuals are entitled to choose freely whether to 

Exhibit 3.1: Disclosure Requirements in

the U.S. Common Rule

The disclosure requirements found in the Federal

Policy for the Protection of Human Subjects at 

45 CFR 46.116(a), under the heading of “basic 

elements of informed consent,” are as follows: 

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 (as

defined in 45 CFR 46.102(i)), 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 (45 CFR 46.116(a)).

It should be noted that these requirements could

be modified or waived by an Institutional Review

Board (IRB) under certain circumstances. In addition

to the basic information listed above, the U.S. regulations require that participants be given other information that may affect their participation in research,

depending on the nature of the project itself. The 

U.S. regulations list six such additional disclosures

(45 CFR 46.116(b)).
38

Chapter 3: Voluntary Informed Consent

participate in research. This definition was adopted 

from the CIOMS International Ethical Guidelines for

Biomedical Research Involving Human Subjects, Guideline 1,

Commentary, para. 2 (CIOMS 1993, 13). In general, 

voluntary informed consent protects the individual’s freedom of choice, respects his or her personhood, dignity,

and autonomy, and reduces the chances of exploitation. 

Objections to this substantive ethical standard are

rarely, if ever, voiced, even in parts of the world in which

less cultural emphasis is placed on individual rights and

freedom of choice than is common in Western and most

developed countries. However, various objections often

arise about the need for certain procedures for obtaining

and documenting informed consent, including those

stipulated in U.S. research regulations and other documents, such as the ICH Guideline for Good Clinical Practice.

As noted, it is important to distinguish substantive ethical

principles and standards from the procedures that implement them. Although procedures are important, they

often can be modified without compromising ethical

principles or standards. Examples of procedural aspects

of the informed consent process and its documentation

include the following requirements: the informed consent documents should be in writing and signed by the

research participant; the consent form should be signed

by the person obtaining consent or by the principal

investigator; and there should be a witness to the signing

of consent forms. Other examples of procedures that are

not always central to meeting the substantive ethical

principles and standards of voluntary informed consent

are involving family members in the consent process or

obtaining a community leader’s permission before

approaching individuals in the community. Although it is

necessary—and not always easy—to determine which

procedural aspects are ethically required and which

might be altered or waived altogether, procedural

requirements should be viewed as less fundamental than

matters of substantive ethical standards or principles.

Recommendation 3.1: Research should not deviate

from the substantive ethical standard of voluntary

informed consent. Researchers should not propose,

sponsors should not support, and ethics review

committees should not approve research that

deviates from this substantive ethical standard.

Cultural Barriers Relating to Disclosure

Requirements

Requirements for disclosing information in research settings usually exceed those for disclosing information in

clinical contexts. In the United States, the requirements

for disclosure of information to potential participants in

research are specific and detailed. (See Exhibit 3.1.) The

extent of medical information that is disclosed to patients

in clinical settings differs among cultures and can influence judgments about the amount and kind of information that should be disclosed in research settings. Three

principal types of disclosure are central to the process of

informed consent in the research setting: 1) disclosure of

diagnosis and risk; 2) disclosure of the use of placebos

and randomization; and 3) disclosure of alternative treatments. In addition, NBAC considers a fourth type of disclosure—that of the possibility of access to any post-trial

benefits—a central issue discussed in Chapter 4.

Disclosure of Diagnosis and Risk

In some parts of the world, it is still customary for

physicians to withhold certain information from

patients.3 Clinicians often provide diagnoses (as well as

prognoses) of cancer or other serious conditions to 

family members, but they withhold such information

from patients. As a result, the patient’s consent to certain

procedures, if sought, may not be fully informed. Jeremy

Sugarman and his colleagues noted in their report to

NBAC that “[i]n one country, complete information

about medical diagnoses and prognoses are withheld

routinely from patients with certain diseases, such as

cancer. Consequently, valid informed consent (for either

treatment or research participation) can be difficult or

impossible.” 4

Nancy Kass and Adnan Hyder describe a similar situation in their study for NBAC: “...in some developing

country settings, a diagnosis of cancer would never be

revealed directly to the patient but rather to members of

the patient’s family.” 5 Although this observation was

made in reference to clinical care, these cultural practices

are relevant to research participants, who may have similar

expectations. Similarly, different cultures have different

attitudes toward the disclosure of risks in the clinical context,
National Bioethics Advisory Commission

39

and some researchers believe that it is not always appropriate to disclose to patients the full ramifications of their

situation. 

In another study conducted for NBAC, Nigerian

researchers indicated that consent documents attached to

certain research protocols included information that

potential participants might find extraneous, irrelevant,

or culturally inappropriate. These researchers called particular attention to the emphasis placed on explaining the

potential risks to study participants, noting that in the

United States, there is much greater interest in communicating the possibility of harm to research participants

than there is in Nigeria. One physician noted that, given

Nigerian cultural norms, disclosing all possible risks

would unnecessarily alarm potential research participants associated with the research.6 Based on such 

observations, some people believe that, at least in some

cultures, it would be impossible to enroll research participants by adhering to the basic elements of disclosure as

presented in 45 CFR 46.116(a). 

NBAC believes that cultural standards regarding the

inappropriateness of providing diagnoses and prognoses

to patients or research participants do not justify deviation from the substantive ethical standard of informed

consent in research. Even if the custom of routinely 

withholding complete information about diagnoses and 

prognoses from patients with certain diseases could be

defended in ordinary medical practice, it poses a severe

challenge to the need to adhere to the substantive ethical

standard of disclosure required for research involving

human participants. Those who lack information about

their diagnosis and prognosis cannot be expected to

understand the purpose of the research, any potential

direct benefits, the risks of not participating, or the alternatives to participation. Similarly, potential participants

cannot make an informed decision to participate without

knowing that they may not receive a proven treatment

that could be beneficial. Enrolling individuals in research

who are not given the opportunity to understand such

important information represents a deviation from the

substantive ethical standard of disclosure required for

adequate informed consent and should not be permitted.

Diversity in the practice of disclosing information in the

clinical context does not alter the requirements for such

disclosure in the research context. 

These matters must be studied in more detail to learn

about how cultural variations affect the meaning and

effectiveness of the consent process and the use of particular consent documents. It is critical that we find innovative and culturally responsive ways to disclose

information to potential participants. NBAC heard testimony from U.S. and developing country researchers who

have succeeded in adhering to this standard,7 even

though doing so often takes more time and effort than

researchers typically expend in the informed consent

process. Even in cultures in which a diagnosis of serious

illness is not normally revealed in the treatment context,

researchers often can find ways to overcome this barrier

to disclosure in the research setting. 

Disclosure About Control Interventions and

Randomization

In some cultural contexts, questions also arise regarding the appropriateness of requiring information to be

disclosed about the use of a placebo in one arm of a 

clinical trial, the randomization of participants, and any

uncertainty that may exist regarding the efficacy of an

experimental intervention. Sugarman and his colleagues

reported on “local perceptions concerning cultural 

barriers to randomization and the use of placebos.”

Indeed, investigators sometimes struggled with these

barriers, responding in different ways. For example, in

one case, investigators who believed that it would be

impossible to obtain valid informed consent for a randomized trial abandoned the use of randomization in

their research. However, in another case, investigators

used placebos, even though they did not believe that the

research participants understood the implications of

doing so.8 Despite these barriers, cultural differences do

not provide adequate justification for foregoing the

requirement to disclose key elements of the nature of the

clinical trial, such as the use of a placebo or the randomization of participants into different trial arms.

Disclosure of Alternative Therapies

An example from the literature illustrates a particular

disclosure problem. Love and Fost (1997) describe a

struggle that occurred in one U.S. IRB that reviewed a

proposal for a randomized clinical trial of adjuvant treatment for breast cancer to be conducted in Vietnam. The
40

Chapter 3: Voluntary Informed Consent

investigator “found himself uncertain about the application of American standards of informed consent in the

Vietnamese setting.” After consultation with experts on

Vietnam and Vietnamese culture, he concluded that

“American standards would not be acceptable to

Vietnamese physicians, political leaders in Vietnam, or

the vast majority of Vietnamese patients” (Love and Fost

1997, 424). The investigator argued that in medical 

practice in Vietnam, patients do not participate in their

medical decisions. Thus, the researcher contended that

participants in the clinical trial should not receive any

information that would convey the treating doctor’s

uncertainty—specifically, information about alternative

therapies and the use of randomization to determine the

subject’s proposed treatment (Love and Fost 1997).

Although the Commission recognizes the challenges

raised by these cultural differences in practicing medicine

and obtaining consent, it does not believe that these 

challenges provide adequate justification for foregoing

the requirement to make disclosures about alternative

therapies that are available to potential participants

should they choose not to enter a clinical trial.

Recommendation 3.2: Researchers should develop

culturally appropriate ways to disclose information that is necessary for adherence to the substantive ethical standard of informed consent,

with particular attention to disclosures relating to

diagnosis and risk, research design, and possible

post-trial benefits. Researchers should describe 

in their protocols and justify to the ethics review

committee(s) the procedures they plan to use for

disclosing such information to participants.

Disclosure About Possible Post-Trial Benefits

The basic disclosure requirements for satisfying the

informed consent provisions in U.S. research regulations

(see Exhibit 3.1) focus on information needed by a

potential participant to decide whether or not to participate in a study. Of the eight basic disclosure requirements,

one focuses on potential benefits: “a description of any

benefits to the subject or to others which may reasonably

be expected from the research” (45 CFR 46.116(a)(1)).

Traditionally, such a disclosure has been required to

ensure that potential participants understand whether

there is any possibility that the intervention itself might

benefit them while they are enrolled in the study. There

is, however, no specific mention of any post-trial benefits.

In any case, those who may participate in studies should

be informed of the potential benefits, if any, that they

might receive by doing so. Because this information is

relevant to participants’ decisions to participate in the

research, ethics review committees should require investigators to make these disclosures.

Recommendation 3.3: Ethics review committees

should require that researchers include in the

informed consent process and consent documents

information about what benefits, if any, will be

available to research participants when their 

participation in the study in question has ended.

Other Cultural Issues Relating to the

Informed Consent Process

Additional issues in the informed consent process

include the ability of potential participants to understand

the scientific and technical aspects of research protocols—

given the culture and belief systems within which they

live—and the influence and involvement of others in the

consent process.

Innovative Ways of Presenting Information 

to Participants

In some cultures, the belief system of potential

research participants does not explain health and disease

using the concepts and terms of modern medical science

and technology. This is significant, because when people

do not understand or accept scientific explanations of

health and disease, the challenge of obtaining informed

consent can be daunting.9 Patricia Marshall’s report to

NBAC quotes one physician as follows: “...[W]hat I

worry about is whether we are really informing them. We

are talking to a society that does not believe in the germ

theory of disease so it’s difficult to explain.” The

researcher provided an example of the pervasive belief

that a person’s death is a result of sorcery rather than a

lethal infection.10 In noting that he had encountered a

cultural belief that spirits cause epilepsy, Alfred Sommer,

Dean of the Johns Hopkins University School of Hygiene
National Bioethics Advisory Commission

41

and Public Health, told NBAC that “we do not want to

fight a belief system. We simply say we have this pill. We

believe it is safe. We think it may reduce the recurrence

of the following thing. We would like you to take it.” 11

Despite this potential barrier to adequate understanding, if they are willing to devote the time and effort to do

so, researchers often are able to devise creative measures

for overcoming these barriers. An example appears in 

the Kass/Hyder report for NBAC: “...the concept of

immunology, an immune response, that there’s something in your blood that’s going to attack bacteria and

viruses which you also don’t have a concept for....[H]ow

much can someone really focus on the consent form

when they have this whole new idea that there’s this 

battle going on in their bloodstream?...When we go and

translate, we try to use, for example, immune cells, we

talk about people who guard houses...it’s a particular

kind of watchman. So you have a particular kind of

watchman in your blood....” 12 Even in countries with

very low literacy rates (e.g., 30 percent for men and 

10 percent for women in Senegal), one group found that

“widespread illiteracy is not a barrier to comprehension,

especially since informed consent is more an interactive

process than one that depends on reading” (Preziosi et al.

1997, 372). However, the authors of this study concluded that understanding abstract scientific concepts,

such as double blinding and randomization, could be

difficult. To help explain these complex issues,

researchers used terms and concepts that were understandable to the community involved: “To illustrate the

principle of randomization and the possibility that one of

the vaccines might fail, the presenters used a familiar

agricultural example: the evaluation of fertilizers or of

seed varieties on randomized plots, a procedure familiar

to farmers in the area” (Preziosi et al. 1997, 370).

Another illustration emphasizes the importance of

educating individuals and the community about the

study and its specific purpose and procedures.

Investigators and research assistants interviewed by

Marshall noted that education should begin at the community level. “You approach some person as a contact

person...you often start with the local governance...we

need to obtain permission from them and we need their

help to get to community leaders...they need to work

with community leaders...we spend time discussing [the

study]...you have to explain [it] fully.” 13 Researchers may

find, for example, that, in circumstances where they do

not speak the local language, the use of intermediaries

can be an effective means of ensuring adequate understanding among potential participants. 

In some countries, a process of community education

acts as a precursor to the process of obtaining individual

consent. For example, one study reported that in

Senegal, the field staff and physicians held meetings in

each village to provide information about a study of a

new pertussis vaccine and to obtain consensus about its

use. A physician then provided additional information

and sought individual informed consent at the monthly

vaccination session. A clinical trial for vaccination against

Haemophilus influenzae type b in The Gambia was preceded by an intensive publicity campaign involving

radio, newspapers, and discussions with village leaders

(Leach et al. 1999). When mothers attended the first

child health clinic, they received an information sheet

about the clinical trial to take home for discussion with

their families. When a mother returned for the first vaccination, the trial worker explained the study again, and,

if the mother gave oral consent, the trial worker signed

the information sheet.

Translation and back translation of a written consent

form may be one way of ensuring that information is 

correctly disclosed; however, this may not always be

effective. Jean Pape, a researcher from Haiti, who is also on

the Cornell University faculty, described the complexity

of this process.14 In preparing to begin HIV vaccine trials

in Haiti, his research group needed approval from its own

IRB in Haiti, as well as from the IRB at Vanderbilt

University—one of the collaborators—and from the IRB

at Cornell University Medical School. To be understandable to participants, the consent form had to be in the

Creole language. Yet, the document also had to be in

French, the language of the Haitian researchers. Because

the consent form had to be reviewed by the Cornell IRB,

a translation in English was also required. Pape said that

the back translation of a consent form “does not guarantee that volunteers have really understood the objective

of the study, the risks and advantages, and their voluntary participation,” 15 a difficulty reported in another

study in Nigeria.16
42

Chapter 3: Voluntary Informed Consent

NBAC also heard about the desirability of testing

research participants to understand whether and how

much they understood regarding the informed consent

process.17 Pape described the process he regularly undertakes to ensure understanding. This process includes a

person who counsels potential participants about all

aspects of the project, helps to develop a test questionnaire that all potential participants must pass before

being given the actual consent form, and is available to

address participants’ concerns and questions. The period

before obtaining ethical clearance from the various

review committees is used to counsel and inform potential volunteers, who should pass this test of understanding before receiving a simpler informed consent form.18

These mechanisms—the counseling sessions and test

questionnaires—illustrate some of the ways in which

informed consent can and should be a process that takes

place over time and that is much more than the mere

signing of a document that may be imperfectly comprehended. Despite the acknowledged difficulties of administering tests of understanding, NBAC supports the idea

of incorporating these tests into research protocols.

Recommendation 3.4: Researchers should develop

procedures to ensure that potential participants 

do, in fact, understand the information provided 

in the consent process and should describe those

procedures in their research protocols.

Recommendation 3.5: Researchers should consult

with community representatives to develop 

innovative and effective means to communicate 

all necessary information in a manner that is

understandable to potential participants. When

community representatives will not be involved,

the protocol presented to the ethics review committee should justify why such involvement is not

possible or relevant.

Involvement of Others in the Informed 

Consent Process

In some cultures, several barriers might arise to

ensuring free and individual choice to participate in

research. Among those identified by Kass and Hyder were

deference to physician/health personnel; low economic

status of potential participants; low level of awareness or

education of potential participants; limited decisionmaking power for women; community leaders’ disapproval;

family disapproval; and cultural customs that prohibit

“refusing a guest” (rules of traditional hospitality).19 A

subset of these barriers is discussed in this section—

barriers that pertain to the involvement of community

leaders and family members in the consent process.

Community Leaders

In some cultures, investigators must obtain permission from a community leader or village council before

approaching potential research participants. Yet, it is

important to distinguish between obtaining permission

to enter a community for the purpose of conducting

research and for obtaining individual informed consent.

In their reports, NBAC consultants all noted that the role

of community leaders or elders is an integral part of the

process of recruiting research participants. Although

these reports typically use the terminology of consent to

refer to the community’s permission or a leader’s authorization for the researchers to approach individuals,

NBAC will use this term to refer to the permission or

authorization given by the individual being recruited as a

research participant. 

The need to obtain permission from a community

leader before approaching individuals does not need to

compromise the ethical standard requiring an individual’s

voluntary informed consent to participate in research.

Gaining permission from a community leader is no different, in many circumstances, from the common

requirement in this country of obtaining permission from

a school principal before involving pupils in research,

from a nursing home director before approaching individual residents, or from a workplace supervisor before

initiating an experimental screening program. An ethical

problem arises only when the community leader exerts

pressure on the community in a way that compromises

the voluntariness of individual consent. The reports commissioned by NBAC describe a number of situations in

which community leaders have been involved in the

informed consent process. (See Exhibit 3.2.) 

Nevertheless, recruitment procedures in some cultures involve community leaders whose authority does

not allow individual members of the community to

refuse to participate in research for which the leader has
National Bioethics Advisory Commission

43

granted permission. Also, in some settings, authoritarian

governments may limit autonomous decisionmaking by

their citizens, which may affect their participation in

research.27 The question then arises regarding whether

there are some countries in which U.S. researchers

should not engage in international collaborative research.

In NBAC’s view, if a country’s political system or a local

situation makes it impossible for individuals’ consent to

be voluntary and that fact is known in advance, then,

because U.S. researchers cannot adhere to the substantive

ethical standard of informed consent, it would be inappropriate for them to choose such settings.

Recommendation 3.6: Where culture or custom

requires that permission of a community representative be granted before researchers may approach

potential research participants, researchers should

be sensitive to such local requirements. However,

in no case may permission from a community representative or council replace the requirement of a

competent individual’s voluntary informed consent.

Exhibit 3.2: Involvement of Community Leaders in Informed Consent

During the course of its deliberations, NBAC sponsored a survey in which researchers who conducted international

research were asked about the process of obtaining informed consent in different cultural settings.20 The following

excerpts highlight some of the issues raised when cultural practices require the involvement of community leadership in the informed consent process.

■ “There are very positive informed consent stories where you would never go first to the individual. You can

approach the individual after you have explained the research to the chief or local leader. Then they explain the

informed consent process to their people without exerting the pressure. The best evidence of the effectiveness

of this approach is when people refuse to participate. That’s a good sign. They are able to refuse.” 21

■ In contrast, in some settings, the head of the village or a group of elders makes a collective decision for the 

village. “If they make the decision in favor of participating in the trial, virtually everyone will participate. The people in the community are then extremely reluctant to withdraw from the trial because of the collective nature of

community activities.” 22

■ In other settings, there is authorization by a community leader that is compatible with individuals’ right to refuse

and authorization in a context in which the Chief’s word is law. One physician described “two levels” of consent

or permission: “One is community and the other is individual....When you leave [the Chief], the Chief is expected

to open households so there is really another level of consent [in between]...the Chief and council, the household head, then the individual.” 23 In answer to the question, “then how will the community respond?” the physician said that most of the time the members agree to participate. At the same time, there is some uncertainty on

the part of the physicians interviewed about the extent to which individual agreement to participate is voluntary.24

■ “Regarding whether the community leaders should be asked to approve the study depends on 1) whether you

are working in a healthy community, and 2) the level of corruption of the community leaders. I have been conducting a study in an African city since 1987. There, we have ‘laid low,’ trying to avoid the gaze of the community leaders and state or national politics. Had we been noticed there, the tremendous corruption would have

destroyed the study. However, working in an African village would be an entirely different matter. In that situation,

a study could not be conducted without the approval and active support of the community leaders.” 25

■ An American researcher conducting malaria studies in Mali and in Malawi noted the difference between the two

settings. In Mali, the study was conducted in a remote rural area in which community leaders were heavily

involved. In contrast, the Malawi study took place in a large city with an established health care system and a

more educated population. In this latter setting, community consent at the national or institutional level is removed

from individuals and the local community, and it seems likely that consent by community leaders would not have

an undue impact on the decisions of individuals. In addition, in an urban context, it is more difficult to identify

appropriate spokespersons for the larger community, especially as individuals in urban areas tend to associate

themselves with many different kinds of communities.26
44

Chapter 3: Voluntary Informed Consent

Recommendation 3.7: Researchers should strive 

to ensure that individuals agree to participate in

research without coercion or undue inducements

from community leaders or representatives.

Family Members

It is customary although not required in some societies for other members of a potential research participant’s family to be involved in the informed consent

process. In most instances, the need to involve the family

is not intended as a substitute for individual consent, but

rather as an additional step in the process.28 An example

of a multistep process involving the family is described

by Loue and colleagues (Loue and Okello 2000) in their

report on a workshop in Uganda that addressed the

problem of acquiescence by another family member in

order for an individual to participate in research. (See

Exhibit 3.3.)

Researchers in other countries also have reported on

their efforts to involve the family in the informed consent

process in ways that do not undermine the standard of

individual consent. Marshall reported, for example, that

in Nigeria in areas where traditional cultural norms are

strong, the permission of a woman’s husband might be

required before she can enroll in research. A Nigerian

physician involved in a breast cancer study noted that

cancer patients often need the approval of their husbands

to participate in research. However, the physician also

emphasized that in such cases, the woman’s individual

consent is still essential. Indeed, most investigators have

developed strategies that accommodate and encourage

discussion regarding study participation with family

members.29

NBAC recognizes that this situation does not apply in

cases in which a family member lacks the capacity to give

informed consent. Indeed, there is consensus that having

the capacity to decide is an important precondition (or

threshold element) for informed consent (Beauchamp

and Childress 1994; NBAC 1998).

In many cases, family members may be approached

before asking an individual directly to participate in a

research project. However, seeking permission from family members without engaging the potential research participants at all clearly departs from the ethical standard of

informed consent. On the other hand, potential participants might also choose to involve others, such as family

members, in the consent process. Indeed, involving 

family or community members in the informed consent

process need not diminish, and might even enhance, the

Exhibit 3.3: New Ugandan Guidelines for

Informed Consent 

Uganda has a new constitution that specifically 

recognizes the rights of women and minorities, which

had not been recognized in that country.30 A more

specific development regarding research was the

adoption of guidelines protecting the individual rights

of research participants. In July 1997, the representatives of the National Consensus Conference on

Bioethics and Health Research in Uganda voted

unanimously to adopt the Guidelines for the Conduct

of Health Research Involving Human Subjects in

Uganda (National Consensus Conference 1997).

Participants in the consensus conference came from

a wide range of governmental and nongovernmental

agencies. 

The Ugandan guidelines for research specifically

prohibit an investigator from relying on the permission

of a community leader for the participation of community members in research. The development and

adoption of this requirement of individual consent

necessitated a reexamination of various aspects of

Ugandan customary laws, which traditionally have

demanded the subordination of an individual’s wishes

to those of a specified family leader, usually the father

or husband. An individual’s wishes could be further

subordinated to those of the community or the tribe.

Although these guidelines clearly require individual

consent, it is not known whether this provision is

always adhered to in practice. The process that led to

adoption of these guidelines was informed by

Uganda’s own recognition of its history, including its

experience with tyranny, torture, and the elimination

of targeted groups. 

The Ugandan guidelines for research reflect

efforts to achieve some balance between the older

traditions and the ethical standard of voluntary and

informed individual consent. The guidelines include a

provision that allows potential participants sufficient

and adequate time to confer with anyone else of their

own choosing to discuss the particular features of the

research and to minimize the possibility that they may

be subjected to undue influence or coercion.31
National Bioethics Advisory Commission

45

individual’s ability to make his or her choices and to give

informed consent (or refusal). 

These examples show that it is often possible to

obtain individual informed consent, which may require

and indeed benefit from the involvement of family or

community members, while at the same time preserving

cultural norms. Such involvement ranges from providing

written information sheets for potential participants to

take home and discuss with family members to holding

community meetings during which information is presented about the research and community consensus is

obtained. When the potential participant wishes to

involve family members in the consent discussion, the

researcher should take appropriate steps to accommodate

this desire.

Recommendation 3.8: When a potential research

participant wishes to involve family members in 

the consent process, the researcher should take

appropriate steps to accommodate this wish. In no

case, however, may a family member’s permission

replace the requirement of a competent individual’s voluntary informed consent.

Consent by Women

Some cultures customarily require the permission of

a woman’s husband, if she is married, or her father, if she

is unmarried, before she can enroll in a research protocol.

A strict requirement that a husband must first grant permission before researchers may enroll his wife in research

treats the woman as subordinate to her husband and as

less than fully autonomous. If the requirement of spousal

authorization, in addition to individual informed consent, were applied equally to enrollment of men and

women as research participants, it would at least constitute gender equity. But in cultures in which spousal

authorization for participation in research is customary, 

it appears always to be the woman who must obtain her

husband’s permission. If women wish to consult with

their husbands or to seek voluntarily to obtain their 

husbands’ permission before deciding to enroll in

research, this is not only ethically permissible, but in

some contexts highly desirable. However, a strict

requirement of spousal authorization violates the substantive respect for persons principle, which mandates

that equal respect be accorded to women as persons.

Much research is directed at conditions that affect

both women and men. Yet, it is important not to neglect

research on diseases or conditions that affect only

women. In reality, without involving the husband in the

consent procedures, it may be impossible to conduct

some research on common and serious health problems

that affect only women. In such cases, a likely consequence would be a lack of knowledge on which to base

health care decisions for women in that country. The

prospect of denying such a substantial benefit to all

women in a particular culture or country calls for a narrow exception to the requirement that researchers use the

same procedures in the consent process for women as for

men, one that would allow for obtaining the permission

of a man in addition to the woman’s consent. 

Recommendation 3.9: Researchers should use the

same procedures in the informed consent process

for women and men. However, ethics review 

committees may accept a consent process in

which a woman’s individual consent to participate

in research is supplemented by permission from a 

man if all of the following conditions are met:

a) it would be impossible to conduct the research

without obtaining such supplemental permission; and 

b) failure to conduct this research could deny 

its potential benefits to women in the host

country; and 

c) measures to respect the woman’s autonomy 

to consent to research are undertaken to the

greatest extent possible. 

In no case may a competent adult woman be

enrolled in research solely upon the consent of

another person; her individual consent is always

required. 

Voluntary Participation in Research

A fundamental principle of research ethics is the requirement that participation be voluntary—that is, “free of

coercion and undue influence” (National Commission

1979). However, among the most difficult requirements

to ensure is the voluntariness with which participants

consent to enroll in a study. Pressure from a community
46

Chapter 3: Voluntary Informed Consent

leader, the power and authority of the medical professionals who serve as investigators, and the fear of loss of

health benefits that people would normally expect to

receive may compromise individuals’ freedom to refuse

to participate in research. The provision of medical care

and treatment during a study may constitute an incentive

for individuals to enroll in a study, but it should not be

construed as a coercive offer that would unduly compromise the voluntariness of participation.

Undue Inducement

It is likely to be difficult to decide when a study

design constitutes an undue influence. One definition

states that “undue influence...occurs through an offer of

an excessive, unwarranted, inappropriate or improper

reward or other overture in order to obtain compliance”

(National Commission 1979, 14). There are many circumstances that can cause undue inducements to participate in clinical trials, including offers of medical care not

otherwise available or offers of money. Discussions in the

literature traditionally have focused on monetary payments to research participants and address the question

of whether any amount of money is an acceptable

inducement, and, if so, at what point the acceptable

inducement becomes undue (Dickert and Grady 1999;

Macklin 1981; Macklin 1982).

Other aspects of research design that may pose a

problem of undue influence have received considerably

less attention. As the CIOMS Guidelines document

acknowledges: “It may be difficult to distinguish between

suitable recompense and undue influence to participate

in research....Someone without access to medical care

may be unduly influenced to participate in research 

simply to receive such care” (CIOMS 1993, 19). This situation is likely to exist in developing countries in which

large numbers of people have little or no access to medical

care and treatment even for ordinary illnesses, a concern

expressed to NBAC in testimony.32

It is necessary, then, to answer the threshold question

of whether the very offer to participate in research constitutes an undue inducement to citizens of developing

countries who have little or no access to medical care and

treatment (Bernstein 1999). Even a placebo-controlled

trial offers such individuals a 50 percent likelihood (in a

two-arm trial) of receiving an intervention that, although

unproven, may be beneficial. If the solution to this fundamental problem is to forgo research entirely in such

places, it might make those populations worse off than

they would be if research goes forward. This consideration requires the review of the ethical consequences of not

conducting research and the determination of whether

those consequences outweigh the ethical problems

alleged to exist in the conduct of the research. But the

need to attempt such a balance can be avoided if a proper

distinction can be made between acceptable inducements

and those that constitute undue influence or coercion. 

No hard-and-fast criterion can be stipulated for making this distinction. However, one approach would be to

consider the possible motivations for participating in

research, according to the following schema. People may,

for example:

a) Act out of self-interest, when there is a potential 

benefit to them. 

b) Act out of rational or enlightened self-interest, when

there is potential benefit to others as well as to 

themselves, and some risk to themselves.

c) Act out of pure altruism, when they expect no 

benefit to themselves but expect benefit to others, and

accept some risk to themselves. 

d) Refuse to act because of perceived high risk or great

inconvenience, only agreeing to undergo the risk

when offered considerable material reward.

e) Act out of fear of the consequences of refusing to 

participate.

All of these situations apply to some extent in

research. Situation (b) is the standard presupposition in

Phase II or III clinical trials. Prospective participants

weigh the risks and potential benefits, recognizing that

there may be some risk to themselves but also some possible benefit and that the research as a whole may provide

benefits to others. Situation (c) is the standard for

research not designed to provide direct benefit to participants, but, for example, to determine the safety of drugs

in Phase I studies, to discover basic physiological mechanisms, or to arrive at baseline data. Situation (d) captures the idea of undue inducement when people make a

rational refusal based on perceived risk, but then agree to
National Bioethics Advisory Commission

47

accept the risk only when provided with a considerable

material reward. Situation (e), by definition, is the paradigm of coercion: In hierarchical groups, in coercive settings, or under threat, individuals agree to participate in

research because they fear the consequences of refusal. In

this situation, their participation is coerced, not voluntary. Situation (e), therefore, is ethically prohibited.

In principle, there is no difference between the sort of

motivation that prompts people anywhere to volunteer

for research—situation (b)—and what may induce people in developing countries to agree to participate. The

more difficult challenge lies in situation (d): Does the

prospect of receiving medical care as a benefit during (or

possibly after) the research prompt people in developing

countries to undertake serious risks they would otherwise refuse to accept? There can be no general answer 

to this question, which can be determined only on a 

case-by-case basis. In studies with the usual range of

risks, the provision of medical care may be an inducement to participate, but there is little reason to believe it is

an undue inducement. Recalling the definition of undue

influence cited earlier—“an excessive, unwarranted, inappropriate or improper reward”—it is reasonable to conclude that providing medical care to research participants

is warranted, appropriate, and proper. 

One might object that this definition is embedded in

a document created in the United States—a wealthy,

industrialized country—and therefore is irrelevant to

resource-poor countries. The reply to this objection is

twofold. First, poor people exist in every country, and

participation in a clinical trial often is the only way that

uninsured individuals in the United States can gain

access to some medical care. Yet, no one could reasonably maintain that the poor or uninsured should be

excluded from participation in research or that it would

be ethically acceptable to deny them medical benefits

that they could not otherwise obtain.

Second, the problem may not lie in the idea that an

offer to possibly receive medical care is an inducement,

but rather in the difficulty of determining when such an

offer—admittedly an inducement—becomes undue.

Those who argue that participation in research constitutes an undue inducement for poor people in developing countries would have to maintain that offering

high-quality medical care and treatment that participants

would not otherwise receive is unwarranted and inappropriate. However, the provision of medical care or

treatment that would not otherwise be available to

research participants should not, in principle, be construed as an undue influence to participate. This conclusion is supported by developing country researchers

surveyed by Kass and Hyder: 64 percent stated that 

participants joined research projects in order to obtain

benefits.33 Many researchers interviewed in focus groups

for this same study seemed to believe that this was

acceptable, given the overall risk/benefit ratio of the

research; some focus group respondents remarked that

providing significant benefits essentially left potential

participants with no reasonable choice except to participate, but they did not specifically refer to this as undue

inducement.34 NBAC concludes that although the potential benefits of participation in research may be an

inducement for those in developing countries who lack

access to medical care to participate in research, this does

not sufficiently diminish the voluntariness of their decision in a way that would make their consent ethically

invalid.

Somewhat more problematic are clinical trials studying a new intervention in which members of a control

group receive an established effective treatment that is

unavailable outside the trial. Does provision of the established effective treatment constitute an undue inducement to participate?

This situation can be cast in the form of a dilemma. If

providing treatment otherwise unavailable to members 

of a control group is an undue inducement and hence

ethically unacceptable, then the only ethically acceptable

research design in such situations would be that of a

placebo control or some other substandard treatment

that is available. However, as discussed in Chapter 2,

placebo-controlled trials may be ethically unacceptable in

cases in which the disease is life threatening or permanently disabling and established effective treatments exist

for the condition. The dilemma arises because of the 

tension between the potential loss of full voluntariness 

on the part of participants and the probability of harm

befalling those in the control arm who receive the

placebo instead of an established effective treatment. 
48

Chapter 3: Voluntary Informed Consent

As in any ethical dilemma, this one requires that

moral considerations be weighed in order to determine

which alternative is more acceptable. An appeal to certain

ethical principles offers some insight. The well-accepted

principle of nonmaleficence (Beauchamp and Childress

1994; National Commission 1979) requires that harm to

participants be minimized;35 however, it could never be

used to justify coercion of research participants, which

would entirely preclude their voluntary participation.

NBAC concludes that in this situation, it is more acceptable to allow the possibility of somewhat diminished

voluntariness of participation than to risk harm 

to participants in the control arm, who are denied an

established effective treatment. This is a position consistent with other guidelines, such as those of the 

Medical Research Council of the United Kingdom 

(MRC-UK 1999). 

Minimizing the Therapeutic Misconception

One barrier to understanding the relevant, important

aspects of any proposed research is what has been called

the therapeutic misconception (Appelbaum et al. 1982;

Churchill et al. 1998; King 1995). This term refers to the

belief that the purpose of a clinical trial is to benefit the

individual patient rather than to gather data for the purpose of contributing to scientific knowledge. The trust

that patients have in their physicians in the clinical setting depends on an important element of the physicianpatient relationship—that physicians should choose the

most appropriate treatment for their individual patients.

To apply that same concept to the research setting is to

fall prey to the therapeutic misconception, which surfaces even when participants have received complete

information (ACHRE 1996). In short, the therapeutic

misconception rests on confusion between the aims of

research and those of individualized medical treatment.

The therapeutic misconception has been documented

in a wide range of developing and developed countries.

For example, in a study conducted in a clinic in Brazil, 

all of the women who were interviewed said that 

they entered the study because they “thought that the

contraceptive being offered would be good for them”

(Hardy et al. 1998). In some parts of the world, a different kind of complication arises from the language itself.

One American respondent to the study conducted by

Kass and Hyder stated the following: “In many African

languages, there is no word for ‘research’ or ‘science.’

The word used is generally the same as the word for

‘medicine.’ There is no concept of an experiment, placebos, etc., and despite the best translation of the most 

simply worded consent form, many adult subjects still

have no understanding of the difference between being a

research subject and receiving medical treatment.” 36 The

researcher went on to say that “[t]his should not be a 

reason to exclude these people from research; in fact they

are often the population who will benefit most from the

research and the only population in whom the studies

can be done, e.g., persons at risk of naturally acquired

malaria or other tropical diseases.” 37

It is important to distinguish the confusion that arises

from the therapeutic misconception from a related consideration. In the research setting, participants often

receive beneficial clinical care. In some developing 

countries, the type and level of clinical care provided to

research participants may not be available to those 

individuals outside the research context. It is not a 

misconception to believe that participants probably will

receive good clinical care during research. But it is a 

misconception to believe that the purpose of clinical 

trials is to administer treatment rather than to conduct

research. Researchers should make clear to research 

participants, in the initial consent process and throughout the study, which activities are elements of research

and which are elements of clinical care. 

Recommendation 3.10: Researchers working in

developing countries should indicate in their

research protocols how they would minimize the

likelihood that potential participants will believe

mistakenly that the purpose of the research is

solely to administer treatment rather than to 

contribute to scientific knowledge (see also

Recommendation 3.2).

Documentation of Informed Consent

Distinguishing between the substantive need to obtain

informed consent and the particular process by which

consent is documented is critical. The U.S. requirements

for documentation of informed consent (45 CFR 46.117)

can pose unnecessary barriers to research that conforms
National Bioethics Advisory Commission

49

to the substantive ethical standard for informed consent.

Problems arise, for example, from the need for written,

signed consent forms and from the amount of information that is typically provided on U.S. consent forms for

a complex clinical trial. In some developing countries,

the requirement of documenting informed consent on a

written form signed by the research participants is

thought to be inappropriate. One obvious circumstance

is that of illiterate participants, who may be able to

understand information presented orally, but who find a

written form on which they are required to make their

mark useless. Moreover, in some cultures, people distrust

any signing process. This distrust is common even in

countries with a high literacy rate, such as Argentina and

other Latin American countries, where people have lived

under oppressive regimes and fear that signing a document could place them in jeopardy. Several examples that

illustrate these situations are provided in Exhibit 3.4.

At the same time, there is some evidence that

researchers can overcome many of the obstacles to 

participants’ understanding of lengthy complicated

consent forms by devoting more time and effort to the

consent process. Several empirical studies of informed

consent carried out in developed countries describe a

fairly elaborate, multistage consent process aimed at

overcoming these barriers. Studies conducted in Chile,

the Netherlands, and Switzerland found that researchers

could overcome these barriers with three separate

Exhibit 3.4: Examples of Documentation of Informed Consent Requirements

■ Sugarman and colleagues provided two examples in which requiring a signed informed consent document was

especially problematic: “...in one project involving many illiterate subjects, although thumbprints might be considered to be an appropriate means of documenting individual informed consent, local investigators did not use such

an approach because it too closely related to past police tactics and [was] believed to frighten potential research

participants. In another setting, where guerilla warfare was ongoing, the use of written informed consent posed a

risk to participants because these documents linked them to particular institutions.” 38

■ The Ugandan document Guidelines for the Conduct of Health Research Involving Human Subjects in Uganda

rejects a requirement for written informed consent. This rejection stems from Uganda’s past experience of torture

and persecution of individuals found to be associated with particular enterprises and recognizes the sensitivity to

individuals’ reluctance to sign a piece of paper that attaches their name to an enterprise. Individuals who do not

wish to sign may put an “X” in place of a signature.39 This is a good example of how procedural requirements can

be made sufficiently flexible to reflect social and cultural sensitivities. 

■ Jean Pape, a Haitian researcher, discussed the complexity of the consent forms. He said that the forms are clearly

too lengthy and that over the past 22 years, he has found them to be increasingly complicated. He stated that

“[t]hey appear to be more concerned about legal implications for sponsor agencies than...with the welfare of the

volunteers. We cannot read them to volunteers because the only time a volunteer had a document like this read

to him was when he was in a court of law and had to sign some kind of papers. So this is changing the trust relationship that we have with our participants and, therefore, we have to explain it step by step.” 40

■ Grace Malenga said of consent forms used in Malawi that providing too much information is likely to scare

patients. “You start asking questions or telling them to sign...some papers and immediately...they will look at

them, some of them have actually withdrawn.” Some people were willing to participate until they were asked to

sign a piece of paper.41

■ Nigerian researchers pointed to the length and complexity of informed consent documents and the need for written consent as obstacles for those attempting to obtain consent from potential study participants.42 In Marshall’s

study for NBAC, investigators agreed that individuals may have some anxiety about writing their signature or placing their thumbprint on a formal document because of uncertainties about whether the document could be used

against them. One investigator noted the following: “Even if they use a thumbprint, they [can] get suspicious. They

can’t read so they wonder why [you need their thumbprint]. It’s a big fear...the issue [has to do with] government

documents. [It’s threatening] because they don’t know what they are signing or what they might be ‘giving away.’” 43
50

Chapter 3: Voluntary Informed Consent

preparatory sessions conducted with potential participants (Rodenhuis et al. 1984; Sánchez et al. 1998;

Tomamichel et al. 1995). For example, in approving protocols, IRBs may waive documentation of informed consent through a signature or a thumbprint, provided that

the researchers provide adequate justification for the

waiver and ensure adherence to the substantive ethical

standard of informed consent. It is NBAC’s view that in

such cases, the justification, while important, also must

pass public scrutiny, and we would encourage a process

by which these waivers were audited by a competent

body. Commentators to NBAC remarked that waivers 

of written consent documentation should include 

safeguards to ensure that individual consent is obtained.

The FDA requires that clinical trial data entail some 

form of documentation of the consent process 

(21 CFR 312.62(b) and 21 CFR 812.140(a)(3)(i)), which

means that an alternative form of documentation is

needed for those trials submitted to the FDA that do 

not use individual signed consent forms. At the same

time, more information is needed to determine the extent

and magnitude of cultural differences in the informed

consent process. 

Recommendation 3.11: U.S. research regulations

should be amended to permit ethics review committees to waive the requirements for written and

signed consent documents in accordance with

local cultural norms. Ethics review committees

should grant such waivers only if the research

protocol specifies how the researchers and others

could verify that research participants have given

their voluntary informed consent.

Recommendation 3.12: The National Institutes 

of Health, the Centers for Disease Control and

Prevention, and other U.S. departments and 

agencies should support research that addresses

specifically the informed consent process in 

various cultural settings. In addition, those 

U.S. departments and agencies that conduct 

international research should sponsor workshops

and conferences during which international

researchers can share their knowledge of the

informed consent process.

Conclusions

In many countries, cultural barriers can prevent the

informed consent process from being conducted in

precisely the same way stipulated by U.S. research regulations. Investigators can, however, for the most part

overcome these barriers without violating the substantive

ethical standard that requires them to obtain individual

and voluntary informed consent from competent

research participants. One mechanism for addressing

problems in a culturally sensitive way—without compromising ethical standards for obtaining voluntary

informed consent—is to work collaboratively with the

community in which the research will be carried out.

Informing and educating the local community before the

research begins can be helpful in recruiting volunteers

and ensuring that this recruitment is noncoercive.

Community education and consultation are important in

protecting the rights of potential participants during

recruitment, in promoting their understanding of the

research, and in providing additional information about

the study when relevant and necessary.

During the course of its deliberations, NBAC found

that there is a great deal of support in developing countries for the requirement of voluntary, individual

informed consent. The surveys conducted by Kass and

Hyder lend considerable support to the view that both

developed and developing country researchers view the

requirement to obtain voluntary informed consent as a

critical ethical standard. Adherence to this standard

requires that researchers disclose relevant information,

take steps to determine that potential participants understand what they have been told, and ensure that each

individual’s consent is voluntary. Nevertheless, for some

customs and traditions, some of the specific procedures

related to the process and documentation of informed

consent as stipulated in the U.S. regulations must be

modified. These procedures should be sufficiently flexible to be adapted for use in various developing countries.

The requirements of written consent and the participant’s

signature, mark, or thumbprint on consent forms are

procedures that ethics review committees should be

allowed to waive when researchers provide adequate 

justification for such waivers.
National Bioethics Advisory Commission

51

Every competent adult should be able to decide freely

whether to participate in research, a position adopted in

previous NBAC reports (NBAC 1998; NBAC 1999).

Those who wish to cede that decision to another should

be able to do so, but the initial choice is still theirs. Often,

personal and local circumstances complicate this choice,

and many obstacles remain to achieving an ideal process.

Nevertheless, adherence to a country’s customs and 

traditions need not compromise the ethical standard of

informed consent. In some circumstances, researchers

should have greater flexibility in determining how they

inform participants about the research and in the methods they use to document consent. In addition, potential

participants may wish to involve family members in their

decision to participate, and researchers may need to

obtain a community leader’s permission before approaching individuals in the recruitment process. NBAC

believes that these recommendations represent only the

first steps toward eventually reaching a point at which

every competent individual, based on adequate information, can voluntarily make his or her own decision about

participating in research.

Notes

1 The material in this chapter benefited from reports prepared by

several NBAC consultants, articles published in the literature, and

two unpublished studies provided to NBAC by researchers from

South America (Hardy et al. 1998; Sánchez et al. 1998). The consultants’ reports are as follows: Kass, N., and A. Hyder, “Attitudes

and Experiences of U.S. and Developing Country Investigators

Regarding U.S. Human Subjects Regulations,” Marshall, P., “The

Relevance of Culture for Informed Consent in U.S.-Funded

International Health Research,” and Sugarman, J., B. Popkin, 

F. Fortney, and R. Rivera, “International Perspectives on Protecting

Human Research Subjects.” These background papers were 

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

2 We acknowledge that the principle of respect for persons also

permits the foregoing of voluntary informed consent in certain situations, such as research involving those who lack the capacity to

give consent, research involving only minimal risk, or emergency

research. These areas pose their own unique issues, which will not

be addressed in this report.

3 See Kass and Hyder; Marshall; and Sugarman et al. 

4 See Sugarman et al., 10. 

5 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 9. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

6 See Marshall, 18. 

7 Plowe, C., Testimony before NBAC. February 29, 2000. Herndon,

Virginia; Pape, J.P., Testimony before NBAC. February 29, 2000.

Herndon, Virginia.

8 See Sugarman et al., 17. 

9 See Kass and Hyder. 

10 See Marshall, 34. 

11 Sommer, A., Testimony before NBAC. September 16, 1999.

Arlington, Virginia. Meeting transcript, 214. 

12 See Kass and Hyder, 6. 

13 See Marshall, 17. 

14 Pape, J.P., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. 

15 Ibid., 32.

16 See Marshall, 15. 

17 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 151.

18 Pape, J.P., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. 

19 See Kass and Hyder.

20 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

21 See Kass and Hyder, 43. 

22 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 8. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

23 See Marshall, 34. 

24 Ibid., 22.

25 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 1. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

26 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia.

27 See Kass and Hyder, 43. 

28 Sugarman and colleagues state that “investigators in one country repeatedly noted that patients who might be asked to enroll 

in a medical study would be skeptical of an investigator who 

did not involve the family in the decision making process.”

See Sugarman et al., 9.
52

Chapter 3: Voluntary Informed Consent

29 See Marshall, 28.

30 The Constitution of the Republic of Uganda. Available at

www.federo.com/Pages/Uganda_Constitution_1995.htm. Last

accessed January 12, 2001.

31 Loue, S., Testimony before NBAC. October 21, 1999.

Washington, D.C. 

32 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 106.

33 See Kass and Hyder, 56. 

34 Ibid., 57.

35 This same principle is implicit in 45 CFR 46.111(a)(1), stating

that in reviewing research, IRBs must determine that risks to subjects are minimized.

36 See Kass and Hyder, 41. 

37 Ibid.

38 See Sugarman et al., 11.

39 Loue, S., Testimony before NBAC. October 21, 1999.

Washington, D.C. Meeting transcript, 28–29, 40.

40 Pape, J.P., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 32.

41 Malenga, G., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 61.

42 See Marshall, 24.

43 Ibid., 26.

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Experiments. Washington, D.C.: U.S. Government Printing Office. 

Appelbaum, P.S., L.H. Roth, and C.W. Lidz. 1982. “The

Therapeutic Misconception: Informed Consent in Psychiatric

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5(3–4):319–329. 

Beauchamp, T.L., and J.F. Childress. 1994. Principles of Biomedical

Ethics, 4th ed. New York: Oxford University Press.

Bernstein, N. 1999. “For Subjects in Haiti Study, Free AIDS Care

Has a Price.” New York Times 6 June, A-1.

Churchill, L.R., M.L. Collins, N.M.P. King, S.G. Pemberton, and

K.A. Wailoo. 1998. “Genetic Research as Therapy: Implications of

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Council for International Organizations of Medical Sciences

(CIOMS). 1993. International Ethical Guidelines for Biomedical

Research Involving Human Subjects. Geneva: CIOMS. 

Dickert, N., and C. Grady. 1999. “What’s the Price of a Research

Subject? Approaches to Payment for Research Participation.” New

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

Informed Consent. New York: Oxford University Press.

Hardy, E., M.J.D. Osis, S.F. Bento, A.L. Jiménez, and C.R.

Carnevalli. 1998. Informed Consent and Fertility Regulation in Brazil.

Final Report. Campinas, São Paulo, Brazil. Unpublished.

Ijsselmuiden, C.B., and R.R. Faden. 1992. “Research and Informed

Consent in Africa—Another Look.” New England Journal of Medicine

326(12):830–844. 

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. 

King, N.M.P. 1995. “Experimental Treatment: Oxymoron or

Aspiration?” Hastings Center Report 25(4):6–15.

Leach, A., S. Hilton, B.M. Greenwood, E. Manneh, B. Dibba, A.

Wilkins, and E.K. Mulholland. 1999. “An Evaluation of the

Informed Consent Procedure Used During a Trial of a Haemophilus

influenzae type b Conjugate Vaccine Undertaken in The Gambia,

West Africa.” Social Science and Medicine 48:139–148.

Loue, S., and D. Okello. 2000. “Research Bioethics in the Ugandan

Context II: Procedural and Substantive Reform.” Law, Medicine, and

Ethics 28(2):165–173.

Love, R.R., and N.C. Fost. 1997. “Ethical and Regulatory

Challenges in a Randomized Control Trial of Adjuvant Treatment

for Breast Cancer in Vietnam.” Journal of Investigative Medicine

45(8):423–431.

Macklin, R. 1981. “‘Due’ and ‘Undue’ Inducements: On Paying

Money to Research Subjects.” IRB: A Review of Human Subjects

Research 3(5):1–6.

———. 1982. “Beyond Paternalism.” IRB: A Review of Human

Subjects Research 4(3):6–7.

Medical Research Council of the United Kingdom (MRC-UK).

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in Developing Societies: Ethical Guidelines for MRC-Sponsored Studies.

London: MRC.

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

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

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National Commission for the Protection of Human Subjects of

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in Uganda (National Consensus Conference). 1997. Guidelines for

the Conduct of Health Research Involving Human Subjects in Uganda.

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Newton, L. 1990. “Ethical Imperialism and Informed Consent.”

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Preziosi, M.P., A. Yam, M. Ndiaye, A. Simaga, G. Simondon, 

and S.G.F. Wassilak. 1997. “Practical Experiences in Obtaining

Informed Consent for a Vaccine Trial in Rural Africa.” New England

Journal of Medicine 336(5):370–373.

Rodenhuis, S., W.J.A. Van den Heuvel, A.A. Annyas, H.S. Koops,

D.T. Sleijfer, and N.H. Mulder. 1984. “Patient Motivation and

Informed Consent in a Phase I Study of an Anticancer Agent.”

European Journal of Cancer and Clinical Oncology 20(4):457–462.

Sánchez, S., G. Salazar, and M. Tijero. 1998. Final Report of the

Project Decisions and Perspectives of Women Who Participate in

Contraceptive Clinical Trials. Instituto Chileno de Medicina

Reproductiva. Santiago, Chile. Unpublished. 

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Y. Willems, and F. Cavalli. 1995. “Informed Consent for Phase I

Studies: Evaluation of Quantity and Quality of Information

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Last accessed January 12, 2001.
Introduction

Discussions of the ethics of research involving human

beings usually center on issues regarding research

design and approval and how individuals’ rights and 

welfare are protected when they are enrolled in research

protocols. The same has been true of the application of

the Common Rule, which addresses only tangentially

what happens after a research project has ended by

requiring that research participants must be informed in

advance about what benefits (in the form of a proven

effective medical intervention), if any, will be provided if

they are injured during the course of the research. (At the

risk of creating semantic confusion, post-trial medical

interventions are conventionally—and frequently in this

report—described generically as “benefits.”) Other questions about what should happen after a trial is completed

are left unaddressed by U.S. guidelines. In the context of

domestic research, this oversight is understandable.

Although ethical issues certainly arise when many have

no guarantee of access to an adequate level of health care

services (which is true today for an estimated 44 million

Americans, who lack public or private health insurance,

to say nothing of the millions more whose insurance

plans [including Medicare] do not adequately cover the

cost of drugs and medical devices), these issues are usually related to access to health care services, not the ethics

of health research.

In recent years, however, as research sponsored by

government agencies, foundations, and private companies in developed countries increasingly has been conducted in developing countries, officials in some of these

countries—as well as leaders of international bodies concerned with research ethics—have begun to insist that

the ethics of research address what happens when a

study ends. The questions raised—such as what should be

provided to research participants, and by whom, after their

participation in a trial has ended, and what, if anything,

should be made available to others in the host community or

country?—have obvious implications for domestic

research as well, especially when such research is carried

out among members of economically disadvantaged

and/or socially or geographically isolated groups. But the

questions of post-trial obligations have been raised first,

and most urgently, in the context addressed by this

report—that is, clinical trials conducted in developing

countries by researchers and sponsors from the United

States and other developed countries. 

This concern springs from the stark reality that in

many developing countries, a large portion of the population lives in poverty and cannot pay for needed health

care services, and the government cannot provide for

their health care needs. Consequently, the governments

of and most people who live in the developing countries

where new medical interventions have been tested cannot afford them. Indeed, a survey commissioned by the

National Bioethics Advisory Commission (NBAC) of

researchers from the United States and abroad conducted

by Nancy Kass and Adnan Hyder revealed that 33 percent of the U.S. researchers and 48 percent of researchers

abroad believe that the interventions being tested in their

research are unlikely to be available to most host country

residents in the foreseeable future.1 Furthermore, data

55

When Research Is Concluded— Access to the Benefits of

Research by Participants,

Communities, and Countries

Chapter Four 4
56

Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

provided by clinical trials in poor nations are sometimes

important for the development and approval of new

drugs, biologics, and devices in wealthy nations whose

citizens therefore derive benefits that remain unavailable

to those who live in the very nations where the trials were

conducted. A researcher from a developing country who

participated in an NBAC survey summarized the deeply

problematic nature of this situation by saying that 

“[i]t should be made a requirement that [if developing

country] research involving testing of drugs and other

interventions [is] found efficacious, the participating

populations should be among the first ones to benefit, at

affordable costs.”2

In addressing the topic of post-trial obligations,

NBAC realizes that any changes in government policy

should take into account a host of specific contextual 

factors, such as the following: 

■ Who is entitled to receive what benefits? 

■ What benefits should be provided to participants

after the trial is completed—the intervention being

tested, another intervention for the same condition,

or some unrelated medical or nonmedical good 

that is relevant to a significant problem in the host

country? 

■ How is what should be provided to participants

affected by the outcome of the clinical trial?

Specifically, is the obligation to provide post-trial 

benefits stronger when a pivotal clinical trial shows a

statistically and clinically significant superiority of

outcomes in the intervention group than when the

evidence of benefit and safety is weaker? 

■ What is the cost of providing continued access to the

intervention, and who is responsible for providing it? 

■ What mechanisms should be used to implement this

responsibility, and how might these differ, depending

on whether the research sponsor is an international

pharmaceutical company eager to develop a new

product for the world market, a government agency

or nonprofit foundation responding to a request 

for funds from a group of investigators, the host

country itself, or some combination of these or other

sponsors?

Whether the concern is continuing a research intervention for participants after a trial has ended or making

an intervention more widely available within the host

country, certain issues must be addressed. For example,

deciding when a particular trial has demonstrated a new

intervention’s effectiveness will seldom be a simple 

matter, and those who are trying to provide access to

post-trial benefits must confront a number of economic

and practical barriers in many developing countries. But

in other respects, the issues regarding continuing benefits

for research participants differ sufficiently from those

regarding ensuring access for others in the host country

that they require separate treatment.

Obligations to Research Participants

The obligations of sponsors and investigators to research

participants have always been of central importance in

research ethics. Over the years, these obligations—such

as ensuring equitable selection of participants, minimizing risks and ensuring that they are reasonable in relation

to potential benefits, and obtaining voluntary informed

consent—have been formalized in government regulations and in international and professional guidelines. In

a previous report, NBAC explored the issue of post-trial

obligations to a particular group of patients involved in

research studies and concluded that medical follow-up is

warranted for research participants with mental disorders

(NBAC 1998). 

Should this position be generalized to other research

participants, especially in developing countries? In recent

years, a number of international organizations and

national research regulators have moved in this direction.

For example, in November 2000, the World Medical

Association (WMA) adopted the latest revision of the

Declaration of Helsinki: Ethical Principles for Medical

Research Involving Human Subjects, which for the past

three decades has been the most widely recognized statement of ethical principles for research involving human

beings. For the first time, the Declaration contains a 

provision concerning the need for some benefits to

accrue to research participants. Principle 30 states that

“[a]t the conclusion of the study, every patient entered

into the study should be assured of access to the best

proven prophylactic, diagnostic, and therapeutic methods

identified by the study” (WMA 1964, as amended in 2000).

National guidelines on research have also recently

begun to address the post-trial obligations of sponsors and

researchers to participants. The requirements promulgated
National Bioethics Advisory Commission

57

thus far by developed nations have been modest, simply

indicating that access issues should be dealt with before

the start of research rather than imposing an affirmative

obligation to make interventions available. In the United

Kingdom, the Medical Research Council’s (MRC’s) Interim

Guidelines for Research Involving Human Participants in

Developing Societies: Ethical Guidelines for MRC-Sponsored

Studies states that “[i]n anticipation of any beneficial

results of therapeutic research, there should normally 

be discussion in advance with relevant parties in the

developing society...about subsequent availability of the

relevant product to local inhabitants” (MRC-UK 1999,

Specific Consideration 9). Canada’s Tri-Council Policy

Statement: Ethical Conduct for Research Involving Humans

provides that the research ethics board should examine

“the issue of continuing access after the trial” (MRC-CA,

NSERC, and SSHRC 1998, Commentary to Article 7.2).

Similarly, the guidelines issued by some nations that host

research have begun to address such post-trial obligations. For example, South African guidelines refer directly

to the availability of treatment to research participants

after a trial is completed:

The arrangements, if any, for continuing to supply the

superior treatment, if any, after the end of the study

should be known at the beginning of the study and

declared to all potential participants. Any special

arrangements should be honored. Participants do not

have the right to claim ongoing treatment with a new

unlicensed medicine unless special arrangements

have been made at the time of the trial (MRC-SA

1993, Sect. 10). 

Guidelines from other developing nations have taken

the next step; they do not merely insist that the issue be

addressed, but they impose affirmative obligations to

provide effective interventions to research participants

and in some cases to the general population as well. For

example, the Ugandan document Guidelines for the

Conduct of Health Research Involving Human Subjects in

Uganda obliges investigators to “make every effort to

ensure its [an effective intervention, if available] provision, without charge, to participants in the trial following

the conclusion of the trial” (National Consensus

Conference 1997, Sect. V. Part D. 4). In Brazil, the

National Health Council (NHC) approved a resolution

that “research involving human subjects...must...ensure

the research subjects the benefits resulting from the

research project, in terms of social return, access to procedures, products or research agents” (NHC 1996,

III.3(p)). The resolution also provides that “in case of

research conducted abroad or with external cooperation”

evidence “of commitments and advantages to the

research subjects and to Brazil, which will result from the

implementation of the research” must be submitted

(NHC 1996). Another resolution states that “...access to

the medicine being tested must be assured by the sponsor or by the institution, researcher, or promoter...in the

event its superiority to the conventional treatment is

proven” (NHC 1997, IV.1(m)).

In addition to the Declaration of Helsinki, other international documents make recommendations that would

impose post-trial obligations. The Joint United Nations

Programme on HIV/AIDS (UNAIDS) was the first organization to make recommendations that explicitly focus on

resolving drug access problems as part of international

collaborative research. Not only does the UNAIDS document Ethical Considerations in HIV Preventive Vaccine

Research endorse the notion that planning for the availability of the proven intervention must begin before the

start of the research, it also identifies in general terms the

parties that should be part of that process and the issues

that need to be addressed. Guidance Point 2 states that

“[a]ny HIV preventive vaccine demonstrated to be safe

and effective...should be made available as soon as possible to all participants in the trials in which it was

tested....Plans should be developed at the initial stages of

HIV vaccine development to ensure such availability.”

The document further explains that “[a]t a minimum, the

parties directly concerned should begin this discussion

before the trials commence” (UNAIDS 2000, 13–14).

What are some other reasons to recognize the obligation to care for research participants after a clinical trial

has been completed? One source of support for doing 

so comes from researchers themselves. The Kass/Hyder

survey revealed that a substantial percentage of the

researchers surveyed had plans to distribute interventions that were proven effective to some participants 

at the conclusion of the research; 43 percent of 

U.S. researchers surveyed and 32 percent of developing

country researchers surveyed planned to distribute the
58

Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

intervention to the entire study population at the conclusion of the study. About a third of the researchers surveyed planned to provide the intervention to participants

for two to five years, and another third for more than 

five years.3 One U.S. researcher described plans made 

by the research team to provide medication to study 

participants:

I would feel uncomfortable if I thought there was no

chance what we were doing would be of benefit to

that country. It doesn’t have to be a benefit to that

country the day the study ends. The day the study

ends, though, I do think that all the participants 

in the trial should have the benefit of whatever 

was found to be the best therapy....We had made

provisions for them not to just get [experimental

treatment], but to get the [existing treatment] they

were going to be placed on...indefinitely. 4

Besides the examples of other nations and the beliefs

of researchers, a number of reasons have been offered to

justify the claim that participants should receive needed

interventions that have been proven effective as a result

of their research participation. Two prominent perspectives involve the nature of the special relationship that

exists between researchers and research participants and

the application of the concept of justice as reciprocity.

The Researcher-Participant Relationship

Ethicists have struggled to distinguish the researcherparticipant relationship from the physician-patient relationship, because of concern regarding researchers’

competing obligations to sponsors, institutions, and science that may affect the care they can offer participants.

Indeed, such conflicts provide much of the rationale for

the development of the federal regulations that are

designed to protect human research participants.

Furthermore, commentators have noted that problems

arise when research participants in protocols that concern diseases or conditions that affect them directly think

of themselves as the recipients of health care services

rather than as research subjects. The trust that potential

participants place in the medical profession undoubtedly

affects their willingness to participate. Recognizing the

resulting complications for the informed consent process,

Chapter 3 of this report—and other work being undertaken by the Commission—suggests some mechanisms

for minimizing the therapeutic misconception. 

Although these efforts to distinguish research from

treatment are appropriate, it is clear that participation in

a clinical trial resembles treatment because the health status of participants may be altered by their participation.

Consequently, if all intervention by the research team

ends when the trial is over, participants may experience

a loss and feel that the researchers in their clinical role

have abandoned them. This sense of loss can take several

forms. The starkest form arises when participants in a

clinical trial are worse off at the conclusion of the trial

than they were before it began. Being worse off does not

mean that they were harmed by the research. It can simply mean that their medical condition has deteriorated

because they were in the less advantageous arm of the

protocol. Such an outcome—particularly when participants are worse off than they would have been had they

received standard treatment or if they had been in the

other arm of the trial—underlines the extent to which

any research project can depart from the Hippocratic goal

of “do no harm,” despite the best intentions and efforts of

all concerned. When such a result occurs, efforts to

restore participants to at least their pretrial status could

be regarded as attempts to reverse a result that would

otherwise be at odds with the ethical principles of nonmaleficence and beneficence.

Ironically, people who have benefited from an experimental intervention may also experience a loss if the

intervention is discontinued when the project ends. It

might be said that this is a risk the participants accept by

enrolling in the trial. But participants who are ill when

they enter the research protocol may not be able to

appreciate fully how they will feel when they face a deterioration in their medical condition (once the trial is

completed) after having first experienced an improvement, even if the net result is a return to the status quo

ante. One way to mediate or reduce the burden of such

an existential loss (the experience of loss as perceived by

the research participant) and to sustain an appropriate

level of trust between potential participants and the

research enterprise is to continue to provide to research

participants an intervention that has been shown to be
National Bioethics Advisory Commission

59

efficacious in the clinical trial if they still need it when the

trial is over.

Although the need to respond to the sorts of losses

experienced by participants provides one justification for

recognizing an obligation to continue to care for participants after a trial ends, many questions remain regarding

the scope of the obligation as well as the circumstances in

which it applies. For example, considerations of how

effective an intervention is shown to be or the seriousness

and clinical trajectory of the underlying condition clearly

are pertinent factors. It seems reasonable to conclude that

the greater and clearer the health benefit to participants,

the stronger the obligation. Another issue is whether the

relationship with the researcher, rather than the provision of the intervention, should continue. There is considerable evidence that a major benefit of being in a

clinical trial derives from the quality of general care provided by the research team, not just the experimental

intervention. Yet, it is doubtful that merely recognizing

the value of the clinical activities that are inherent in the

researcher-participant relationship is compelling enough

to generate an open-ended obligation to provide all medical care—regardless of its relevance to the research—to

participants indefinitely. 

Justice as Reciprocity

Another perspective that is said to provide a justification for the provision of post-trial medical interventions

to research participants arises from considerations of justice. Justice is a broad concept, encompassing several

more specific concepts. Broadly, questions of justice ask,

“What does this individual or group deserve?” One familiar conception of justice is distributive justice, which deals

with the fair allocation of society’s benefits and burdens.

In the research context, distributive justice requires that

no group or social class be disproportionately exposed to

the risks and inconveniences of serving as participants in

research that aims to develop medical interventions to

benefit the entire population.

Justice as reciprocity, on the other hand, is concerned

with what people deserve as a function of what they have

contributed to an enterprise or to society. In the context

of clinical trials, justice as reciprocity could mean that

something is owed to research participants even after

their participation in a trial has ended, because it is only

through their acceptance of risk and inconvenience that

researchers are able to generate findings necessary to

advance knowledge and develop new medical interventions. Of course, the sense that they have made a contribution is especially strong at the completion of a

successful trial—that is, one that establishes the efficacy

and safety of an intervention. Yet, negative results also

can be important in research, and the case for obligations

of reciprocity may actually be stronger for those who participate in a trial in which the intervention has not been

proven effective, because these participants are less likely

to have benefited from their involvement.

Several problems are involved in the application of

justice as reciprocity to clinical trials in developing countries. First, when post-trial treatment has not been promised to individuals, the fact that the trial has produced a

success does not itself generate an obligation to go

beyond the terms accepted by the participants when they

enrolled. Although a sense of gratitude to participants

under such circumstances would be understandable, this

is not the same as an obligation to continue to provide

the intervention when the study is over. Because the

argument for reciprocity rests on the willingness of

research participants to sacrifice their time (and even

their well-being) to help advance knowledge, what is

owed them can be no greater than what is owed those

who made the same gift to a research project that may not

have proved a particular medical innovation to be successful. Thus, if there is an argument in favor of “repaying” participants in a successful trial (one that resulted in

an effective intervention) by continuing to provide the

intervention after the trial is over, while not doing the

same for participants in earlier trials, which, although

unsuccessful, contributed to the eventual development of

the effective intervention, it would appear to be a practical one. Difficulties in identifying participants in earlier

unsuccessful trials and delivering the intervention to

them, perhaps years after a trial is completed, might 

present obstacles that cannot reasonably be overcome.

A different problem would arise if applying the principle of reciprocity led to the inclusion of post-trial interventions in the initial design of the project. Indeed, great

care must be exercised in this regard. On the one hand,
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

making a commitment to provide interventions to those

who participated in establishing their value would overcome the argument that participants’ initial consent

negates the claim that they deserve a reciprocal gift from

the researcher: If post-trial benefits are part of the inducement to participate, they would, of course, need to be

provided. (Although this provision would in the first

instance simply honor the contract between researcher

and participant, in a deeper sense, including the posttrial benefit in the research plan could be said to reflect

the need to reciprocate for what the participants are giving to the research.) On the other hand, the promise to

continue to provide a successful intervention after the

trial may exacerbate the therapeutic misconception and,

in certain instances, even amount to an undue inducement to potential participants to enroll in the research.

Indeed, in its examination of the general rules for

research, NBAC has taken the position that in comparing

the expected risks and benefits of research protocols,

ethics review committees should exclude any potential

post-trial interventions from the category of benefits.

If the cautions about the therapeutic misconception

lead researchers to omit any mention of post-trial benefits from the informed consent process (which is not

inconsistent with discussing the possibility of such benefits with research sponsors, the ethics review committee,

and representatives of the host country), is there any

room to apply the concept of justice as reciprocity when,

in fact, a research project has established the value of 

an intervention? As with the effect of the researcherparticipant relationship, where it seems reasonable to

conclude that at the outset of research, participants cannot fully anticipate the loss they might experience when

all interventions cease at the end of the trial, it also may

be difficult in advance for either participants or

researchers to fully appreciate the sense of injustice that

would arise if participants were left in need while others

(the researchers as well as patients who will receive the

newly proven intervention) benefited from the success to

which the participants had made such an essential contribution. In such circumstances, a narrow reading of the

relevant obligations would surely be met with the question, “Don’t they deserve better treatment than this?”

That question is likely to become even more powerful in

cases in which participants in a poor country already face

many hardships and the beneficiaries of the research are

patients, scientists, and companies in a wealthy country,

such as the United States. It is unjust to deny them 

benefits based on the argument of justice as reciprocity.

But it is also unjust because participants in these studies

(especially studies that are shown to produce a benefit

retrospectively) may be disadvantaged by the unequal

relationship that exists between themselves and others

(e.g., their own country’s officials who approved the 

project, the foreign sponsors, the researchers). 

Thus, although the strength of the obligation depends

on the specific circumstances of a clinical trial, situations

will arise in which a fair reading of justice as reciprocity

would lead to the conclusion that participants are due

some benefit at the end of the trial commensurate with

what they have contributed. Yet, recognizing the justification for such an obligation is not the same as specifying the nature of the benefit itself. Some commentators

have argued that it is particularly appropriate that the

benefit should relate directly to the interventions studied

in the research project. Making the benefit responsive to

the health needs of the participants provides an additional way to ensure that research participants are not

exploited. But given the considerable variations in local

context, the presumption in favor of this form of compensation probably should not be mandatory and might

be overridden if those who can speak with moral authority for the host community present good reasons why

alternative forms of compensation would provide a more

appropriate benefit. The notion that there should be

some intrinsic connection between what people have

contributed by participating in the research and what is

returned to them opens the door to the provision, for

example, of other health care services of comparable

value to the newly proven intervention, while not allowing some other good—such as a new soccer stadium—to

be regarded as appropriate.

The difference between justifying post-trial obligations to participants based on the moral nature of the

researcher-participant relationship and justifying such

obligations based on justice as reciprocity is illuminated

by comparing what is owed to participants in a control

group who did not receive the experimental intervention

and what is owed to those who did receive the intervention. Although justice as reciprocity would lead to treating
National Bioethics Advisory Commission

61

the two groups similarly because both suffer from the 

illness and undertook the risks of research, what is owed

the two groups from the perspective of the researcherparticipant relationship could differ. This is because only

the participants who actually benefited would experience

a loss if the intervention were discontinued. Of course, if

the experimental intervention turns out to be ineffective,

and a control group in the study received an established

effective treatment, then those in the control group

would experience loss at the end of the trial. This leads

to the question of whether those in the experimental

group should be provided with the established effective

treatment that benefited the control group. Responding

to these dilemmas—for which there are no easy solutions—depends on the context of each research project.

At the very least, it would be highly desirable if collaborating parties in international research negotiated and

reached agreements in advance on this and similar issues.

Because potential participants are most affected by the

research and its aftermath, researchers should consider

including representatives from the community being

studied in these negotiations and agreements.

What Should Be Provided to

Communities and Countries?

Once it is recognized that research projects should sometimes arrange to provide post-trial benefits to participants, a question arises about the justice of differentiating

between former trial participants and others in the host

community who need similar medical treatments. A

competing concept of justice—typically referred to as the

principle of fairness—is to treat like cases alike, and treat

different cases differently. To implement this concept, the

equivalence of persons or situations must be determined.

For example, should family members (or others) who

suffer from the same illness as participants be treated as

like cases with respect to receiving an effective treatment?

Similarly, are the claims to treatment of people who were

eligible for and willing to participant in a clinical trial but

who for any number of reasons were not selected comparable to the claims of those who were selected? Or are

such cases not sufficiently similar because participants

undertook the risks and experienced the inconveniences

of the research?

In NBAC’s view, the relevant distinction between

research participants and these other groups of individuals is that research participants are exposed to the risks

and inconveniences of the study. Moreover, a relationship

grounded in trust and care exists between participants

and researchers that does not exist for others. The concept of justice as reciprocity addresses what people

deserve as a function of what they have contributed to an

enterprise or to society and the related risks that they

undertook. These ethical considerations support the

argument for providing effective interventions to research

participants after a trial is completed.

On what basis then can one justify an ethical obligation to make otherwise unaffordable (or undeliverable)

effective interventions available to members of the

broader community or host country? Given that global

inequities in wealth and resources are so vast, expecting

governmental or industrial research sponsors to seek to

redress this particular global inequity is unfair and unrealistic, especially when no such requirement exists in

other spheres of international relationships. Typically, it is

not the primary purpose of clinical trials to seek to

redress these inequities.

Some have urged, however, that those who sponsor

and conduct research are obligated to provide effective

interventions after a study is completed to the population

from which the research participants were drawn. One

group of commentators offers the following rationale for

this position:

Research is, by definition, designed to create generalizable knowledge, and is legitimate in a developing

country only if its purpose is to create generalizable

knowledge that will benefit the citizens of that country. If the research only has the potential to benefit the

limited number of individuals who participate in the

study, it cannot offer the benefit to the underdeveloped country that legitimizes the use of its citizens as

research subjects. It should be emphasized that

research whose goal is to prevent or treat large populations is fundamentally public health research, and

public health research makes no sense (and thus

should not be done) if its benefits are limited to the

small population of research subjects (Glantz et al.

1998, 41). 
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

Grace Malenga, a researcher from Malawi, testified

before NBAC about clinical trials conducted in her country in which mefloquine was found to be more effective

against malaria than either quinine or chloroquine; however, 20 years after the study was completed, mefloquine

has yet to be used there.5 Christopher Plowe, a malaria

researcher from the United States, expressed a similar

view. When asked if he thought whether there is an ethical obligation to provide some benefit to the country in

which the research is conducted, Plowe testified that he

would have questions about conducting a mefloquine

study in Malawi, knowing that it would remain very

expensive and thus inaccessible in that country. 6 In contrast, a more cost-effective and efficacious anti-malarial

study involving sulfadoxine-pyrimethamine was completed in Malawi in early 1992. This study regimen has

been implemented as national policy by the Malawi

Ministry of Health (Schultz et al. 1996).

A number of international and national guidelines

recognize post-trial obligations to host communities and

countries. The commentaries under the Council for

International Organizations of Medical Sciences

(CIOMS) International Ethical Guidelines for Biomedical

Research Involving Human Subjects, Guideline 8, “Research

Involving Subjects in Underdeveloped Communities,”

and Guideline 15, “Obligations of Sponsoring and Host

Countries,” provide support for the obligation of sponsors to make the products of research available. The language used in the two commentaries is similar. Although

they both provide that, as a general rule, effective interventions developed through research should be made

“reasonably available,” the guidelines are inconsistent in

specifying who should be the recipients of such products.

Commentary from Guideline 8 refers to “inhabitants of

the underdeveloped community in which the research

was carried out” (CIOMS 1993, 26), while Guideline 15

refers to “the inhabitants of the host community or country” (CIOMS 1993, 45). Both guidelines also indicate that

the agreement to provide effective interventions after

completion of the study (or to make exceptions to the

general rule) should be reached in advance of the

research (CIOMS 1993). Later, this chapter will address

in more detail the issue of prior agreements. Regarding

the “reasonable availability” clause, although considerable discussion has occurred about its meaning and how

it should be applied, to date no consensus has been

reached.

Another international document, the World Health

Organization’s (WHO’s) Operational Guidelines for Ethics

Committees That Review Biomedical Research, refers to the

consideration of the availability of successful interventions in the host community in the ethics review process.

The document states that “a description of the availability and affordability of any successful study product to

the concerned communities following the research”

should be considered as part of the ethical review process

(WHO 2000, para. 6.2.6.6). The UNAIDS Guidance

Document provides that effective HIV vaccines should be

made available not only to research participants, but also

“to other populations at high risk of HIV infection”

(UNAIDS 2000, 12). 

Finally, the recently revised Declaration of Helsinki

contains a new provision concerning the need for the

accrual of some potential benefit to the population in

which the research is conducted. Principle 19 states that

“[m]edical research is only justified if there is a reasonable likelihood that the populations in which the

research is carried out stand to benefit from the results of

the research” as well (WMA 1964, as amended in 2000).

As noted earlier, the document Guidelines for the

Conduct of Health Research Involving Human Subjects in

Uganda makes a distinction between the post-trial obligations owed by investigators to research participants

and to the host community. In contrast to the investigator’s charge to make “every effort to ensure its provision”

to participants following the conclusion of the trial, in the

case of the local community in which the research

occurred, “the investigator shall make a reasonable effort

to secure the product’s availability” (National Consensus

Conference 1997, Sect. V. Part D.4).

Several provisions from Brazil addressing access to

benefits by participants and others were discussed earlier

in this chapter. However, there is another provision in the

1996 resolution that states that research should “guarantee the individuals and communities where the research

was undertaken a return on the benefits obtained in the

research” (NHC 1996, III.3 (n)). 

This discussion about documents that support the

idea of post-trial obligations to the host community or

country also should include the Belmont Report: Ethical
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63

Principles and Guidelines for the Protection of Human

Subjects of Research of the National Commission for the

Protection of Human Subjects of Biomedical and

Behavioral Research (National Commission 1979) and the

Statement on Benefit Sharing of the Ethics Committee of 

the Human Genome Organisation (HUGO 2000) (the

international organization of scientists involved in the

Human Genome Project—the global initiative to map and

sequence the human genome). Chapter 1 of the Belmont

Report sets forth the “responsive-to-needs” requirement

as a manifestation of the core ethical principles of beneficence and respect for persons. The justification for requiring that research be responsive to the health needs of the

population involved in it also rests on a concept of justice

that was articulated by the National Commission as the

third basic tenet of research ethics. In conjunction with its

discussion of justice and the distribution of the benefits

and burdens of research, the Belmont Report touches indirectly on the issue of making effective interventions available to those populations upon which they were tested:

[W]henever 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 (National

Commission 1979, 10).

The Belmont Report’s concept of justice encompasses

the prospect of making effective interventions available 

to a population that is larger than that of the research 

participants, whether the population is a poor group

within a wealthy society or one that lives in a developing

country and is participating in a study sponsored and/or

conducted by a developed country. 

The Ethics Committee of HUGO in April 2000 issued

a Statement on Benefit Sharing, which recommends that

“all humanity,” not just research participants, share in the

benefits of genetic research. The statement resulted from

the recognition that “expenditures by private industry for

genetic research now exceed the contributions of governments” (HUGO 2000, Section A). The Ethics Committee

recommended prior discussion with individuals and

communities about benefit sharing, including “consideration of affordability and accessibility of eventual therapy,

and preventive and diagnostic products of research”

(HUGO 2000, Section G). It further recommended that

for-profit entities engaging in genetic research donate a

percentage of their annual net profit “to the health care

infrastructure or for vaccines, tests, drugs, and treatments,

or to local, national, and international humanitarian

efforts” (HUGO 2000, Section G). 

NBAC believes that an ethical obligation to make

effective interventions available to the developing host

country arises from the concept of distributive justice,

which refers to a fair and equitable distribution of social

benefits and burdens. In the research context, distributive justice demands that no one group or class of persons assumes the risks and inconveniences of research if

that group or class is unlikely to benefit from the fruits of

that research. When research is conducted in the developing world, the huge power disparity between rich and

poor nations manifests itself in two ways. In most cases,

the developed world sets the research agenda and carries

out the research. The involvement of developing countries in these activities is generally still limited (although

it is gradually changing), and in only a few instances do

they function as full and equal partners in either respect.

Moreover, although it assumes very few of the burdens 

of research, the developed world receives the great

majority—and in some cases, all—of its benefits because

it can afford to buy the interventions that are proven to

be effective. The burdens of research, in contrast, are

borne by developing countries whose poorest inhabitants

serve as research participants, but these countries rarely

share the benefits, because many interventions are

beyond the economic reach of both the research participants and their governments. Under these circumstances,

the concept of distributive justice supports a fair and

equitable distribution of research benefits to the host

community or country. However, crafting practical and

economically feasible solutions that support distributive

justice in research conducted in the developing world is

one of the most difficult challenges in international

research. 

Data suggest that in international research, post-trial

benefits are being provided to developing countries. In
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

the Kass/Hyder survey of U.S. and developing country

researchers, 29 percent of U.S. and 22 percent of developing country respondents stated that the intervention

being tested in their study would be available to the

entire host country at the conclusion of the research.7

Researchers listed a variety of parties to these agreements

for making the interventions available as well as different

sources of funds, including those from U.S. and international funding agencies as well as host country governments. Clearly, in some cases, plans for providing

effective interventions to host countries can be negotiated

before the research ends; however, further work in this

area is needed to implement and expand successful

strategies.

Who Should Provide Post-Trial

Benefits?

Determining who should be responsible for providing

post-trial benefits to research participants and host communities or countries is an especially difficult problem.

This report has referred generally to the obligations of

researchers or sponsors. But it is evident that these categories cover a diverse set of individuals and entities, with

different resources, roles, and responsibilities in the

research process. These differences will influence the

nature of the obligations that each party should shoulder. 

Obligations of Researchers

Although individual researchers do not usually have

either the resources or the authority to directly provide

post-trial benefits to participants or host countries, they

can play an important role in helping to ensure that such

arrangements are in place. As described earlier, the

researcher-participant relationship gives rise to certain

obligations regarding how participants are treated before

and during a clinical trial, but these obligations generally

do not extend to the post-trial distribution of resources

and the economic, social, and health policy implications

of such activities. 

In NBAC’s view, however, the post-trial obligations of

researchers do extend to some kind of an advocacy role.

The researcher’s basic and generally accepted responsibility

is to respect the participants (and the community they

represent) by informing them about the research and

their role in it, obtaining meaningful consent, enrolling

participants in clinical trials only when there is a reasonable balance between risk and potential benefits, and

designing the study in such a way that it addresses a

pressing health problem.

Researchers can further fulfill their ethical obligation

to participants and host countries by ensuring that the

issue of access to effective interventions and other posttrial benefits is considered at each stage of the research

process, especially the planning and design stages. This

means discussing with relevant parties the potential for

making effective interventions available and serving as an

advocate, assuming that the trial results are positive. This

does not mean that researchers must negotiate directly

with host country governments or international agencies,

although they may make recommendations and serve as

consultants. This advocacy role follows from the

researcher’s specialized knowledge and expertise about

the diseases being studied, his or her understanding of

who might benefit from or be harmed by particular interventions, and his or her commitment to the participants

and to the research process. Consideration, therefore,

should be given to including researchers as parties in the

process of negotiating post-trial benefits. 

Obligations of Public and Private Research

Sponsors and Others 

Given that most researchers are not able themselves

to ensure that research participants and others in the host

community obtain post-trial benefits, consideration

should be given to whether that burden would fall most

appropriately on research sponsors. There are many

types of research sponsors—ministries of health in the

host country, federal research agencies, nonprofit organizations, and private corporations—each of which supports research in different ways and for different reasons.

Thus, it is important to consider what motivates sponsors. Government sponsors are accountable to their 

citizens for the use of public funds for research. Often

they are motivated by a desire to advance and promote

the public’s health. In addition, they may wish to assist

other countries in addressing their health concerns. Their

ability to commit support for future benefits may be 
National Bioethics Advisory Commission

65

constrained, however, by their annual cycle of legislative

appropriations or other factors. Charities and philanthropies also are motivated by a desire to advance and protect

the public’s health, but these organizations may not wish

to or be able to assume future obligations to provide

post-trial benefits. Private sponsors, and industry in particular, are driven by an interest in maximizing benefits

to their shareholders, customers, or clients, and these

organizations may not feel any obligation or be able to

provide post-trial benefits. In addition, the types and

numbers of sponsors vary greatly across clinical trials.

Many trials involve multiple sponsors—some U.S. government sponsors and others private companies. Still

other studies involve multiple sponsors from different

countries, in which the distinction between public and

private sponsors is not made in the same way as it is in

the United States. In still other clinical trials, the sponsor’s involvement is limited to providing funds directly to

the project rather than to an institution. 

Despite these variations, general support exists for the

proposition that the obligation should be placed on the

sponsors and/or researchers to make effective interventions available to a host country or community after a

study is completed. If one accepts NBAC’s justification

for conducting research in developing countries—that

the research will offer some prospect of direct benefit to

the population from which research participants will be

drawn—then that justification provides a strong basis for

also accepting the claim that researchers and sponsors

should play a significant role in making arrangements to

provide post-trial benefits to the host country. 

International researchers participating in focus

groups conducted for NBAC expressed a strong belief

that effective interventions should be implemented in the

host countries and that U.S. or other foreign sponsors

have an obligation to give something back to their host

countries. Yet, U.S. researchers surveyed for this report

worried that, over time, an absolute requirement to provide effective interventions to host countries would act 

as an impediment to finding sponsors that are willing 

to support research and thus might harm developing

countries by delaying or preventing beneficial research.8

One U.S. researcher suggested that an assessment should

always be made about the economic feasibility of implementing a particular intervention:

There is the issue of scope, in both place and time—

for how long should the intervention be implemented

with outside assistance? Should it cover the original

study population, the whole country, or what? I feel

strongly that only interventions which have a hope of

being replicable in the prevailing conditions should

be tried in the first place—that’s where the economic

work should come in, and at the very beginning, not

as an add-on. No research funding agency would

accept funding with a blank check for implementation of the intervention at the end.9

It has been pointed out that expecting industrial

sponsors to provide expensive drugs free of charge after

a trial is over might curtail interest among companies 

in developing interventions specifically for diseases

prevalent in developing countries (Nuffield Council on

Bioethics 1999, 19). If companies do not anticipate a fair

return on their investment, either from the market or

from government subsidies, they might be less likely to

embark on such research. 

The obligation of researchers and sponsors to provide

post-trial benefits cannot be absolute. This is because the

availability of effective interventions will depend on

many factors that are often beyond the control of

researchers and sponsors, who, under these circumstances, should make good faith efforts to secure the continued benefit of effective interventions by ensuring that

the issue of their availability is discussed during trial

planning. The result of these negotiations should be

included in the protocol submitted for Institutional

Review Board (IRB) review, and potential participants in

the trial should be told during the consent process what

arrangements have been made for making effective interventions available after the trial is completed and that

availability of the intervention will cease when it becomes

available as standard care in the host country. In some situations, researchers and others involved in negotiating

post-trial benefits may conclude that there is no plausible

scenario in which an effective intervention would

become available to the participants in the trial or to the

population from which potential participants are drawn.

Under these circumstances, the parties need to reconsider whether the study should be carried out at all.
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

Prior Agreements

The discussion regarding post-trial benefits leads to the

following questions: What is the process that should be 

used for determining what benefits, if any, should be made

available following completion of research, and who should

shoulder this obligation? Although there are no single or

simple answers to these questions, ethically appropriate

conclusions can be reached through negotiations on a

case-by-case basis, supported by a principled justification.

Kass and Hyder recommend a number of innovative

mechanisms for encouraging researchers to engage

donors, aid agencies, or health care delivery organizations in discussions about realistic strategies before a

study is initiated:

Possible mechanisms might include: requiring discussion in a grant proposal about prospects for future

implementation; including a professional from a

donor agency on study sections for international

health research; encouraging IRBs to incorporate

questions related to future access in their review; or

offering continuation grants for implementation and

infrastructure creation to support research interventions shown to be successful. This does not mean that

studies cannot go forward without guarantees of

future access; however, it does mean that studies 

cannot go forward where researchers have given no

thought to how realistic future implementation is.

While researchers do not need to shoulder this

responsibility alone, it is still not appropriate for 

funders to support research where no one is taking

responsibility for holding discussions about the 

feasibility of future access to effective health

interventions.10 

In recent years, efforts have been made to define the

arrangements for making proven interventions available

when a successful clinical trial has ended. These arrangements are generally referred to as prior agreements. The

parties to these agreements usually include some combination of producers, sponsors, and potential users of

research interventions. Industry, academia, and various

other organizations are frequently producers and sponsors in these arrangements, while developing country

governments and not-for-profit health organizations are

most likely to be users. The use of the term agreement

generally is not meant to have any legal connotation in

the international research context, and, although some of

these agreements will be legally binding instruments,

others will not. 

Furthermore, only a limited number of prior agreements are in place in international collaborative research

today. Four entities that have used prior agreements are

WHO, the world’s leading international health organization; the International Aids Vaccine Initiative (IAVI), an

international scientific nonprofit organization founded in

1996; VaxGen, a small California-based biotechnology

company; and UNAIDS. WHO collaborates with industry

to promote the development of health-related products

and technologies pursuant to agreements designed to

ensure that final therapeutic interventions will be made

widely available at low cost to developing countries.

Likewise, IAVI has secured unique pricing and intellectual property agreements with its industrial partners

aimed at increasing global access to AIDS vaccines developed with IAVI support. VaxGen is working directly with

the government of Thailand to test an AIDS vaccine it

developed for use in that country. As part of this collaboration, the company has agreed to help build research

capacity in Thailand by transferring knowledge and technology. It has also provided a letter of intent to assist the

Thai government in producing the vaccine for use in

Thailand, should it prove effective. In two instances,

UNAIDS and product manufacturers have entered into

preferential pricing agreements for developing countries

prior to the commencement of research. (See Appendix C.)

Prior agreements also can be used in a number of

ways to provide the benefits of the proposed research to

the population from which the research participants are

drawn. One way is to design prior agreements so that the

experimental intervention that is being tested will be

made available to research participants and their communities at a cost the developing country can afford. This

could be accomplished, for example, by continuing to

provide a proven intervention to the class of individuals

represented by the participants in a clinical trial for a

specified period and at a specified cost. Exactly what this

would mean in a given situation would depend on a

number of factors, particularly the health problem that
National Bioethics Advisory Commission

67

the intervention is intended to address. Or, if a country’s

need for a particular drug can be adequately quantified

and the shelf life of a drug and other factors made it

appropriate to do so, the country could make bulk purchases of the drug, perhaps at a subsidized price.

Prior agreements also can be designed to provide a

benefit derived from research other than the research

intervention itself. An example of such a benefit is technology transfer. In such a case, a pharmaceutical company could agree to grant to a developing country

government a free or low-cost license to manufacture a

drug in exchange for a commitment from that government to manufacture the drug and distribute it to its population. Another potential benefit of this type, discussed

in Chapter 5, is helping to build research capacity in the

host country. 

The kind of benefit that is negotiated will depend on

the conditions in and the capabilities of the host country.

The suitability of providing a benefit other than the

research intervention will depend on the nature of the

benefit and the economic and technological state of

development of the host country. Technology transfer

may be an especially useful benefit for countries in the

process of developing strong local pharmaceutical industries. On the other hand, assistance in building research

capacity is applicable to most, if not all, developing countries involved in international research. 

Some have argued that, in order to be ethically

acceptable, research sponsored by developed countries

and conducted in developing countries must “offer the

potential of actual benefit to the inhabitants” (Glantz et

al. 1998, 39) of that country by providing affordable

access to the intervention to those communities where

the intervention has been tested. Even if the intervention

being tested is provided to the participants in a trial,

without a guarantee of affordable access to the intervention by the population from which the participants are

drawn, the developing country receives little benefit. If

the knowledge gained from the research is used primarily

for the benefit of the developed world, the research may

be rightly characterized as exploitative and therefore

unethical (del Rio 1998; Glantz et al. 1998).

Some observers believe this argument can be taken

even further. Glantz and his co-authors write that, ethically,

it is not enough to make a proven intervention available

to a developing country by removing the financial barrier

to access if there is no means of getting the intervention

to the population that needs it. A realistic plan for distribution must be provided as part of the study review

process in order to determine that there will be sufficient

potential benefit to justify conducting the research.

“Where the infrastructure is so undeveloped that it

would be impossible to deliver the intervention even if it

were free, research would be unjustified in the absence 

of a plan to improve the country’s health care delivery

capabilities” (Glantz et al. 1998, 41).

Some Critiques (and Responses) Concerning

Prior Agreements

Most stakeholders in the research enterprise probably

would agree that, at least in principle, prior agreements

are an ethically desirable idea and that their use should be

encouraged in international collaborative research. When

research is to be conducted expressly for the purpose of

responding to public health needs in developing countries, prior agreements can assist researchers, sponsors,

ethics review committees, developing country governments, and other involved parties to focus on whether

the proposed research will truly benefit those countries.

Plans that are devised for the funding, distribution, and

use of successful interventions before research begins can

help to overcome some of the major barriers to making

interventions widely available in the countries in which

they are tested. An agreed-upon plan for funding may

help solve the problem of affordability, to which poverty

and high prices contribute, while a plan for distribution can

help address obstacles to availability and inappropriate

drug use, such as a weak health care infrastructure or

overprescription of drugs by providers.

However, others believe that it is not feasible to use

prior agreements that are negotiated as a condition of

research approval to ensure the availability of a proven

intervention or other health benefit. Following are some

of the criticisms that have been made of requiring the use

of prior agreements in international collaborative

research. They appear in order of NBAC’s determination

of the most to the least valid: 

■ Prior agreements would serve only to delay or prevent

new drug research in developing countries.
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

■ Prior agreements are substantively, procedurally, and

logistically problematic.

■ The use of prior agreements is not the prevailing

international standard.

■ The use of prior agreements would go far beyond the

influence one can reasonably expect sponsors or

researchers to have concerning changes in a country’s

health policy.

■ The use of prior agreements would create a double

standard.

■ Prior agreements can always be breached.

Delay or Prevention of Research

One criticism of imposing a requirement to negotiate

prior agreements as a condition of research approval is

that it will serve only to delay or prevent new drug

research in developing countries (Glantz et al. 1998; Lie

2000). Others respond that, even if this is true, the population has lost nothing, because the benefits of the

research would not be available to them anyway (Glantz

et al. 1998). Furthermore, the fact that the research is not

conducted serves to protect the country’s inhabitants

against exploitation as participants in research from

which only developed countries are likely to benefit. 

NBAC has already expressed the view that any obligation to provide effective interventions to host countries

would be borne principally by research sponsors rather

than by, for example, researchers. However, as several 

public commentators have noted, for a variety of reasons,

research sponsors may be reluctant to make financial

commitments to provide effective interventions as part 

of the prior agreement process, which, in turn, might

ultimately affect their willingness to sponsor research in

developing countries. Nonetheless, the use of prior

agreements and the advancement of research that is 

beneficial to developing countries are not mutually

exclusive goals.

First, it is erroneous to assume that all, or even most,

effective interventions simply will be distributed to developing countries free of charge. Although in many cases

effective interventions will be purchased by developing

countries, the ability to do so will vary greatly. Some

countries cannot afford to buy interventions, even at a

reduced cost, while many others are able to buy them as

long as they are not expected to do so at developed-world

prices. Still others can be licensed to produce the intervention themselves. Over time, interventions should

become more accessible to developing countries as their

economic and technological capabilities improve.

Second, although in many situations research sponsors will play a primary role in providing effective interventions, this will not always be the case. Public agencies

that sponsor research are often too constrained financially to provide post-trial interventions. When such an

obligation arises, the public agency becomes responsible

for locating another funding source for the intervention

(such as an organization involved with promoting health

or development). Similar creative funding arrangements

also may be needed for private industry in order to 

provide incentives for undertaking research on neglected

diseases that occur primarily in the developing world.

Thus, the actual or perceived barrier to research imposed

by prior agreements might be removed (or at least 

lowered) through the use of creative partnerships and

arrangements designed to more widely distribute any

financial burdens of fulfilling the obligation to provide

effective interventions to developing countries. Muchneeded research can move forward while, at the same

time, these countries are protected from exploitation

through arrangements designed to ensure that they

receive the benefits of research.

Substantive, Procedural, and Logistical Problems 

A second criticism of requiring the use of prior agreements in international collaborative research is that in

practice, many substantive, procedural, and logistical

aspects of prior agreements can be extremely problematic.

Affordability, availability, and appropriate product use

must all be considered before the research is conducted.

The UNAIDS Guidance Document identifies specific issues

that need to be addressed in order to ensure product

availability, including “payments, royalties, subsidies,

technology and intellectual property, as well as distribution costs, channels and modalities, including vaccination strategies, target populations, and number of doses.”

The text surrounding Guidance Point 2 expressly states

that it is necessary for these discussions to “consider

financial assistance regarding making vaccines available”
National Bioethics Advisory Commission

69

and to “help build the capacity of host governments and

communities to negotiate for and implement distribution

plans” (UNAIDS 2000, 14).

It is easy for some to dismiss the use of prior agreements because of problems that arise for which there are,

as yet, no solutions. However, resolving critical health

problems always requires grappling with complex and

challenging issues, and collaborators in international

research acknowledge that the concerted efforts and talents of multiple partners from diverse environments and

disciplines are needed. Collaborative efforts are routinely

employed to address problems arising from the funding

or distribution of drugs in developing countries in a 

nonresearch context, including situations involving purchases made by nongovernmental organizations (NGOs)

or donations made by pharmaceutical companies. In

both cases, decisions must be made about to whom

drugs will be distributed and how. If drugs are purchased

by an NGO, a determination must be made regarding

whether the proven intervention will be distributed free

of charge or the developing country will be responsible

for paying a minimal charge. Thus, there is no good 

reason to believe that these same kinds of problems in

international collaborative research cannot be resolved in

a similar fashion. 

The process of negotiating a prior agreement requires

focusing on the expected benefits of the proposed

research by developing a detailed and concrete plan for

funding and distributing the proven intervention. There

may be cases in which, at the time the protocol is being

reviewed, it is known (or should be known) that the 

proposed intervention will not be widely available in the

host country after the trial. The process of developing a

funding and distribution plan would make this apparent

and help the parties focus on and deal with the issue of

availability. Or, it may become apparent in the course of

developing this plan that availability cannot realistically

be addressed. This situation may call for re-evaluating the

ethics of conducting the research. One commentator

encouraged 

...the creation of a multidisciplinary partnership for a

given study, or for a program of research, consisting of

investigators, study sponsors, host country authorities,

international assistance organizations, representatives

of the prospective research participants’ communities,

and other relevant parties. This group would assume

the responsibility for post-trial implementation and

develop approaches to negotiating that would remain

responsive to changes over time as the study data

mature, and as other related evidence unfolds. This

group would begin work at the earliest possible stages

of planning and design of the study and would

remain in place to address any developments,

research-related or otherwise, as they arose through

the course of the study and for post-trial implementation. To the extent possible in any given context, its

proceedings would be open to general scrutiny.11

If these issues are not addressed, the new proven

intervention may not be made available to the host country. For example, if a drug that requires refrigeration is

being developed for use in a country that cannot provide

refrigeration, a plan for ensuring that the drug will be

properly stored must be devised. There is no reason to

believe that such issues cannot be addressed effectively

before the research begins or that it is somehow easier to

address them after the study is completed. Ultimately, the

parties involved must reach an understanding about how

the country will benefit from the proposed research

before it begins. This does not mean that the entire population must benefit immediately, but rather that the 

parties involved should be convinced that sufficient

numbers will benefit over a reasonable period, demonstrating that a meaningful contribution to the country’s

overall welfare will occur.

Finally, the debate concerning the definition of reasonable availability has continued, and arriving at a definition that would satisfy all parties remains a formidable

challenge. However, developing an internationally

acceptable standard is a highly desirable goal that should

continue to be the subject of discussion. Meanwhile, the

use of prior agreements might enable effective interventions to be made available to communities and countries

on a case-by-case basis without the need to first reach a

consensus on this difficult and divisive issue. The use of

prior agreements may even facilitate this process by providing specific examples of the effectiveness or ineffectiveness of various types of arrangements for making

effective interventions available.
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Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

Not the Prevailing International Standard

A third criticism of requiring prior agreements in

international collaborative research is that an ethical obligation to make proven interventions available to communities or countries where research is conducted is not

the prevailing international standard. It is far from being

universally accepted by researchers, ethicists, public

health officials, politicians, industry, and other stakeholders in new drug development, and there is little support for such an obligation in existing ethical guidelines. 

Many believe strongly that a plan to make interventions available should be adopted based on the premise

that the host community or country, and not just the

research participants, should benefit from the research if

it is to be ethically sound and not exploitative. Even

though it is not the prevailing international standard,

support for making interventions available after the

research has ended is found in a number of important

documents, including the CIOMS International Ethical

Guidelines for Biomedical Research Involving Human

Subjects (CIOMS 1993); the WHO Operational Guidelines

for Ethics Committees That Review Biomedical Research

(WHO 2000); the guidelines of a few industrialized and

developing countries, including the United Kingdom

(MRC-UK 1999), Canada (MRC-CA, NHERC, and

SSHRC 1998), Uganda (National Consensus Conference

1997), and Brazil (NHC 1996; NHC 1997); the UNAIDS

Guidance Document (UNAIDS 2000); the Human

Genome Organisation Ethics Committee Statement on

Benefit Sharing (HUGO 2000); and the most recent 

revision of the Declaration of Helsinki (WMA 1964, as

amended in 2000). Such support has manifested itself in

two ways. First, all of these documents encompass the

notion that the ethical acceptability of the proposed

research, including issues related to product availability,

should be determined before it is under way. Second, a

more limited number of them (CIOMS 1993; National

Consensus Conference 1997; NHC 1996; NHC 1997;

UNAIDS 2000; WHO 2000; WMA 1964, as amended 

in 2000) impose an affirmative obligation to provide 

successful interventions to research participants and to

the host community.

To consider as part of the protocol review whether a

proven intervention will be made available after the trial

forces researchers and their sponsors to be realistic about

the reasons they want to conduct the research. Is the proposed research to be conducted in a developing country

for the express purpose of addressing a particular health

need of that country? What is the likelihood of implementing the proven intervention in the host country, and

how will implementation occur? 

Even though making effective interventions available

to the host country after a trial is over is not the prevailing international practice, it is still a standard to which

ethical researchers and sponsors should aspire. Little

attention has been given in international research ethics

to the question of what should be provided to communities and countries in which research is conducted. As

these issues begin to receive the benefit of public debate

and scholarly discourse, our collective ethical conscience

will be raised and our ways of thinking about obligations

will change accordingly. One might reasonably expect to

see increasing numbers of international and national 

ethical guidelines address these considerations in the

future. NBAC welcomes and encourages this development.

Unrealistic Influence on Health Policy

A fourth criticism of requiring prior agreements in

international collaborative research is that it “would go

far beyond the influence one can reasonably expect

researchers to have concerning changes in a country’s

health policy” (Lie 2000). In other words, a question

arises regarding the likelihood that government policy in

a developing country will change as a result of conducting a study so that those who need an intervention will

receive it.12 Researchers contend that they are powerless

to ensure that interventions will actually be made available once a study is over, even when the interventions are

supplied to developing countries. 

The problem, in most instances, is not that

researchers cannot influence national health policy or

that developing countries are being told that they must

accept unwanted prior agreements. Rather, it is that

access to successful interventions, which goes far beyond

affordability, is an issue that researchers, sponsors, IRBs,

and/or developing countries have either failed to address

altogether or have simply neglected to address in sufficiently explicit and realistic terms. As one public commentator noted, there is a need to “integrate the new
National Bioethics Advisory Commission

71

intervention into the priorities and complex politics of an

existing health care system”13 in developing countries

with limited funds. It is important that issues, such as

health care financing and delivery, infrastructure development, and appropriate use of products, are considered

during pretrial negotiations regarding making products

reasonably available. Also, product availability cannot be

the sole province of researchers. It is crucial to involve

sponsors, host country governments, the community,

international aid agencies, and other interested parties in

this process. 

There may be circumstances under which one or

more of these parties is not willing to make a firm commitment to making a particular product available until

after the conclusion of a pivotal clinical trial that clarifies

the probability and magnitude of beneficial effect, safety,

and the effectiveness of alternatives. As one international

health researcher testified, “...in a vaccine study in

another African country...the Health Ministry resented

the requirement that some commitment be made up

front feeling that that was a patronizing requirement and

that they would be able to make a commitment when

they saw the results of the study and could do an appropriate analysis of cost and benefit. And that gets to some

of the perceived paternalism and rigidity of the current

guidelines.”14 Moreover, the results of the trial may

strengthen the position of the host country in negotiating

with sponsors, manufacturers, and private philanthropies.

In the complex and uncertain environment in which

research products are to be made reasonably available, a

commitment to a continuing process of discussion and

negotiation about post-trial benefits undertaken by the

parties before research begins is the first step. During

their initial discussions about proposed research, developing country governments should make known to

researchers their positions concerning the availability of

the intervention once the research is completed.

Assuming that the host country wants to move toward

ensuring that a proven intervention will be made available to its population after the research is completed, the

use of a prior agreement can assist in this effort through

the development of an implementation plan.

Creation of a Double Standard

A fifth criticism of prior agreements is that adopting a

requirement for negotiating prior agreements in conjunction with research conducted in developing countries

when it does not currently exist for research conducted

in the United States creates a double standard. It has been

suggested that without prior agreements, the benefits of

successful research will not be generally available in

developing countries (as it would be in the United

States): “The reality in the United States is that regardless

of the very significant gaps in insurance and Medicaid

coverage and the health care discrepancies between the

rich and poor, medical interventions are relatively widely

available, especially when compared to developing countries” (Glantz et al. 1998, 41).

However, others disagree. Evidence suggests that

access to proven interventions is an issue for some 

people in this country. For example, one study concluded that food, housing, and other subsistence needs 

of HIV-infected individuals in the United States are 

just as important to quality of life as access to health 

care (Cunningham et al. 1999). Some would respond

that, even so, in contrast to developing country research,

government-sponsored research in the United States

would never be considered ethical if only the poor were

recruited as research participants and the resulting intervention would not be made generally available to them

(Glantz et al. 1998).

NBAC does not seek to determine whether a double

standard would, in fact, be created if prior agreements

were required for research conducted in developing

countries. However, the fact that the use of prior agreements is not the current ethical standard for research

conducted in the United States does not justify the lack

of adherence to such a standard elsewhere. Perhaps we

should set the goal of reaching agreements before

research starts in this country to ensure that effective

interventions are made available to those who need

them here.

From a number of ethical perspectives, NBAC

believes that those enrolled in clinical trials should have

access to treatments that a trial proves effective. This

report focuses on trials conducted in developing countries, where the discrepancies in access are greatest.
72

Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

However, it is also ethically unacceptable if those

enrolled in clinical trials in the United States have little

likelihood of gaining access to the treatments studied

after the trial ends. Whenever researchers carry out 

clinical trials in populations with poor access to health

care, they should consider in advance the question of

access to treatments that are proven effective after the

trial and should seek prior agreements in order to make

treatments accessible.

Potential for Breach of Obligations

A final criticism of prior agreements is that

researchers, sponsors, and others (such as host country

governments, agencies that provide aid, and NGOs)

might breach their prior agreement obligations to make

proven interventions available (Glantz et al. 1998).

Because most of these agreements are not legally binding,

developing countries are left without a reliable remedy,

and they might be reluctant to enter into such agreements. However, although a party’s failure to honor an

agreement is always a possibility, this does not provide

sufficient justification for rejecting the use of prior agreements. A suitable analogy can be made to promise keeping. People make promises and then break them. In

doing so, a moral rather than a legal wrong is committed,

one for which there is no remedy. However, this is not a

reason to forego the institution of promise keeping as a

means of establishing legitimate expectations in a given

situation. Furthermore, the threat of debarment from

future research and ostracism by the international

research community would in many cases serve as effective deterrents to an unjustified breach of a prior agreement (Glantz et al. 1998). Finally, depending on whether

there is general compliance with nonbinding prior agreements, parties may in the future insist on legally binding

documents with enforceable remedies.

Economic globalization and the AIDS epidemic have

made the developed world more acutely aware of the

magnitude of health problems in developing countries

and the imbalances in the global burden of disease. These

factors have impressed upon us the need for moral

progress and reforms to liberate countries from poor

health and poverty and have led to a new awareness that

unique and untested approaches must be considered for

narrowing the gap between the developed and the developing worlds. In 2000, substantial commitments made

by President Clinton, the U.S. Congress, private industry,

foundations, and NGOs to combat AIDS indicate an

increasing recognition by the developed world that developing countries may be unable to successfully address

their health needs without its help. (See Exhibit 4.1.)

Exhibit 4.1: Vaccine Initiatives 

Timeline 2000–2001

January 24, 2000: Representative Jim Leach 

introduces H.R. 3519, the World Bank AIDS

Prevention Trust Fund Act. Senator John Kerry 

introduces companion legislation, S. 2033, on

February 3. The legislation requires that the

Secretary of the Treasury negotiate with the World

Bank to create a trust fund to address the AIDS 

epidemic in eligible countries. 

January 27, 2000: In his State of the Union

address, President Clinton proposes the Millennium

Vaccine Initiative. The initiative includes a $50 million contribution to the Global Alliance for Vaccines

and Immunization, an increase in federal funding for

basic research on diseases that affect developing

nations, and a tax credit for sales of vaccines for

infectious diseases to accelerate invention and 

production. 

March 1, 2000: Senator Kerry and Representative Nancy Pelosi introduce S. 2132/H.R. 3812,

Vaccines for the New Millennium Act of 2000. The

legislation includes a tax credit for medical research

and a sales credit for vaccine purchases by foreign

governments and nonprofit organizations for distribution in developing countries. The bills authorize

contributions to the Global Alliance for Vaccines and

Immunization and the IAVI. The bills also establish a

vaccine purchase fund, through which the Secretary

of the Treasury is authorized to purchase vaccines

for distribution to developing countries. In addition,

the President is authorized to negotiate with foreign

governments and other parties to establish a similar

international vaccine purchase fund. 

March 2, 2000: In a White House event, President

Clinton meets with leaders of pharmaceutical and

biotechnology companies, who endorse the

Millennium Vaccine Initiative and pledge to donate

more than $150 million in vaccines to developing

countries. Merck pledges to donate doses of its 

hepatitis B vaccine and commits to developing
National Bioethics Advisory Commission

73

Exhibit 4.1 continued

vaccines for worldwide HIV strains, American Home

Products pledges to donate doses of its Haemophilus

influenza type b (Hib) vaccine, Glaxo SmithKline

Beecham pledges to expand its malaria vaccine 

program and donate funds to eliminate elephantiasis,

and Aventis Pharma pledges to donate doses of polio

vaccine to Africa.

May 15, 2000: H.R. 3519 passes the U.S. House of

Representatives. On July 26, the legislation passes

the U.S. Senate. On August 19, President Clinton

signs the Global AIDS and Tuberculosis Relief Act of

2000, Public Law 106-264. In its final form, the act provides for a World Bank AIDS Trust Fund for prevention

and treatment of individuals with HIV/AIDS and health

care and education for AIDS orphans. The law also

authorizes appropriations to the Global Alliance for

Vaccines and Immunizations and the IAVI.

September 2000: The Presidential Advisory Council

on HIV/AIDS recommends the creation of a global

plan for HIV vaccine development. The council recommends that the administration boost research funding,

create tax credits for vaccine research and development, and establish international purchase funds.

November 6, 2000: The FY 2001 Foreign Operations

Appropriations, Public Law 106-429, is signed into law.

The law allows for up to a $50 million contribution to

the Global Fund for Children’s Vaccines of the Global

Alliance for Vaccines and Immunization, up to $10 million to the IAVI, and up to $20 million for the World

Bank AIDS Trust Fund. The statute also appropriates

up to $435 million for Heavily Indebted Poor Countries

debt relief.

HIV/AIDS Drug Cost Reduction Initiatives

May 10, 2000: President Clinton issues Executive

Order (EO) 13155, Access to HIV/AIDS Pharmaceuticals and Medical Technologies. The EO is designed to

make HIV/AIDS drugs available at lower costs in subSaharan Africa. It declares that the United States will

not seek revocation or revision of intellectual property

law or policy in sub-Saharan African nations that 

promotes access to HIV/AIDS drugs or technologies,

as long as the law or policy is consistent with the

Agreement on Trade-Related Aspects of Intellectual

Property Rights. This allows countries to license local

companies to manufacture generic versions of drugs

or to import the drugs from other countries where they

are available at a lower cost. The EO also notes that

the United States shall encourage “policies that provide an incentive for public and private research on,

and development of, vaccines and other medical innovations that will combat the HIV/AIDS epidemic in

Africa.”

May 11, 2000: Five pharmaceutical companies

announce that they will reduce the cost of HIV/AIDS

drugs for African and other developing nations. Merck,

Glaxo Wellcome, Boehringer Ingelheim, Bristol-Myers

Squibb, and Roche announce that they will work with

UNAIDS, WHO, the World Bank, the United Nations

Children’s Fund, and the United Nations Population

Fund to improve access to HIV/AIDS care and treatment.

Bill and Melinda Gates Foundation 

Research Initiatives 

July 10, 2000: Together with Merck, the Bill and

Melinda Gates Foundation announces a donation of

$50 million to Botswana for HIV/AIDS prevention,

health care access, patient management, and treatment of HIV. The Gates Foundation will focus on

improving the health care system, and Merck will handle the management and delivery of pharmaceuticals.

July 12, 2000: The Gates Foundation announces a

$15 million grant to the Elizabeth Glaser Pediatric

AIDS Foundation. The gift will support the Glaser

Foundation’s Call to Action project in Africa and

Thailand, which provides for community training, HIV

testing and counseling, treatment, and education to

prevent mother-to-child transmission. 

July 30, 2000: The Gates Foundation awards a $40

million grant to the London School of Hygiene and

Tropical Medicine to strengthen the public health infrastructure and research capacity for nations heavily

affected by malaria. The work is in collaboration with

WHO, Wellcome Trust Research Laboratories, and

the National Institute for Medical Research in

Tanzania. The program involves developing centers of

excellence in Africa, which could eventually receive

money directly from the Gates Foundation. 

December 18, 2000: The Gates Foundation awards a

$15.1 million grant to an international consortium of

researchers to develop new drugs to fight African

sleeping sickness and leishmaniasis. The team will 

be led by a researcher at the University of North

Carolina at Chapel Hill and includes the Kenya

Trypanosomiasis Research Institute and Immtech

International, Inc., an Illinois-based company. 

January 27, 2001: IAVI receives a $100 million 

challenge grant from the Bill and Melinda Gates

Foundation to mobilize global support toward the

development and delivery of a preventive AIDS 

vaccine.
74

Chapter 4: When Research Is Concluded—Access to the Benefits of Research by Participants, Communities, and Countries

Increasingly, efforts are being undertaken before

research begins to make proven interventions and other

research benefits widely available in host communities

and countries. Two organizations have successfully used

prior agreements to make proven interventions available

to developing countries, while other initiatives are newly

developed and untested.

Many opportunities and challenges remain in pursuing

the use of prior agreements in international collaborative

research. Some agreements, such as those employed by

WHO and UNAIDS, have proved successful. Agreements

forged by other entities, such as IAVI and VaxGen (see

Appendix C), remain untested, and whether their experimental interventions will actually be made available to

the developing countries in which they are studied is not

yet known. Nevertheless, the use of prior agreements in

international collaborative research shows great promise

as a means of helping to ensure that proven interventions

and other research benefits will be made widely available

to the developing countries in which they are tested and

thereby prevent the exploitation of those countries and

the individuals who serve as research participants. 

The prior agreements described in Appendix C all

have been negotiated with the aim of making successful

interventions available to host communities and countries. In addition, international documents such as the

CIOMS Guidelines, the UNAIDS Guidance Document, and

the revised Declaration of Helsinki urge that successful

products should be made available not just to the

research participants themselves, but also to a wider 

segment of the population. 

Conclusions and Recommendations

This chapter has considered the question of what benefits, if any, sponsors and researchers should provide to

participants after their participation in a trial has ended,

and what benefits, if any, should be made available to

others (i.e., nonparticipants) in the host country at the

conclusion of a study. NBAC concludes that at the end of

a clinical trial that results in an effective intervention,

research participants should be provided with this intervention. In addition, NBAC concludes that before initiating a research project, researchers or sponsors should

consider how they might make benefits, if any, available

to others in the host country, with the understanding 

that appropriate host country decisionmakers must be

meaningful and essential participants in making such

arrangements. 

Recommendation 4.1: Researchers and sponsors in

clinical trials should make reasonable, good faith

efforts before the initiation of a trial to secure, at

its conclusion, continued access for all participants to needed experimental interventions that

have been proven effective for the participants.

Although the details of the arrangements will

depend on a number of factors (including but not

limited to the results of a trial), research protocols

should typically describe the duration, extent, and

financing of such continued access. When no

arrangements have been negotiated, the researcher

should justify to the ethics review committee why

this is the case.

Recommendation 4.2: Research proposals submitted to ethics review committees should include 

an explanation of how new interventions that 

are proven to be effective from the research will

become available to some or all of the host country population beyond the research participants

themselves. Where applicable, the investigator

should describe any pre-research negotiations

among sponsors, host country officials, and other

appropriate parties aimed at making such interventions available. In cases in which investigators

do not believe that successful interventions will

become available to the host country population,

they should explain to the relevant ethics review

committee(s) why the research is nonetheless

responsive to the health needs of the country 

and presents a reasonable risk/benefit ratio.

Recommendation 4.3: Whenever possible, preceding the start of research, agreements should be

negotiated by the relevant parties to make the

effective intervention or other research benefits

available to the host country after the study is

completed.
National Bioethics Advisory Commission

75

Notes

1 See Kass, N., and A. Hyder, “Attitudes and Experiences of U.S.

and Developing Country Investigators Regarding U.S. Human

Subjects Regulations,” 141. This background paper was prepared

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

2 Ibid., 98. 

3 Ibid., 39–40.

4 Ibid., 43.

5 Malenga, G., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. 

6 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia.

7 See Kass and Hyder, 39–40. 

8 Ibid., 40–41.

9 Ibid., 41.

10 Ibid., 155.

11 National Institutes of Health (NIH), Public comment submitted

to NBAC. Received November 13, 2000.

12 Sommer, A., Testimony before NBAC. September 16, 1999.

Arlington, Virginia.

13 NIH, Public comment submitted to NBAC. Received 

November 13, 2000.

14 Killen, J., Testimony before NBAC. September 16, 1999.

Arlington, Virginia. Meeting transcript, 120.

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Guidelines on Ethics for Medical Research. South Africa: MRC.

Medical Research Council of the United Kingdom (MRC-UK).

1999. Interim Guidelines for Research Involving Human Participants in

Developing Societies: Ethical Guidelines for MRC-Sponsored Studies.

London: MRC. 

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.

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.: Department of

Health, Education and Welfare.

National Consensus Conference on Bioethics and Health Research

in Uganda (National Consensus Conference). 1997. Guidelines for

the Conduct of Health Research Involving Human Subjects in Uganda.

Kampala, Uganda: National Consensus Conference.

National Health Council (NHC). 1996. Resolution No. 196/96 on

Research Involving Human Subjects. Brazil: NHC. Addition: 1997.

Resolution No. 251. Addition: 1999. Resolution No. 292. Brazil: NHC.

Nuffield Council on Bioethics. 1999. The Ethics of Clinical Research

in Developing Countries: A Discussion Paper. London: Nuffield

Council on Bioethics.

Schultz, L.J., R.W. Steketee, L. Chitsulo, A. Macheso, P. Kazembe,

and J.J. Wirima. 1996. “Evaluation of Maternal Practices, Efficacy,

and Cost-Effectiveness of Alternative Antimalarial Regimens for

Use in Pregnancy: Chloroquine and Sulfadoxine-Pyrimethamine.”

American Journal of Tropical Medicine 55(1):87–94.

World Health Organization (WHO). 2000. Operational Guidelines

for Ethics Committees That Review Biomedical Research. Geneva: WHO.

World Medical Association (WMA). Declaration of Helsinki: Ethical

Principles for Medical Research Involving Human Subjects (adopted

18th WMA General Assembly, Helsinki, Finland, June 1964;

amended: 29th WMA General Assembly, Tokyo, Japan, October

1975; 35th WMA General Assembly, Venice, Italy, October 1983;

41st WMA General Assembly, Hong Kong, September 1989; 48th

WMA General Assembly, Somerset West, Republic of South Africa,

October 1996; and 52nd WMA General Assembly, Edinburgh,

Scotland, October 2000). Ferney-Voltaire, France: WMA. Available at

www.wma.net/e/policy/17-c_e.html. Last accessed January 12, 2001.
Introduction

I

n previous chapters of this report, the National

Bioethics Advisory Commission (NBAC) has made

recommendations regarding the ethical design and conduct of clinical trials sponsored by U.S. organizations and

subject to U.S. regulations that are carried out in developing countries. For the most part, these recommendations have focused on issues that arise during and after the

trials themselves. The Commission has expressed the

view not only that research participants should be left no

worse off as a result of their participation in clinical trials

conducted in a developing country, but that there is an

ethical obligation to provide participants (and perhaps

others) with the benefits that follow from a successful

trial once it has ended. In the most general terms, it is

important that sponsors or investigators from developed

nations who are conducting clinical trials in developing

countries take steps to ensure that participants are not

exploited. Likewise, because there is always a possibility

that exploitation might occur when a large disparity in

power and wealth exists between the parties involved, it

is important to ensure that the host country itself is not

exploited and that the rich and powerful do not appropriate an unfair share of the fruits of the research. In

addition, when the disparity between the resources of

the sponsoring and host countries is large, the sponsoring country has an ethical obligation to ensure that the

host country receives an adequate share of the research

benefits.

It is important to consider the overall nature of the

ethical obligation, if any, of richer nations to transfer

resources to poorer nations (known as distributive justice).

For some observers, such an ethical obligation arises

either out of a desire to relieve poverty and distress or

because of a belief that the wealth of the richer countries

is unearned and, therefore, undeserved. This report does

not address issues, as important as they are, related to the

general obligations of rich nations in the context of international distributive justice. However, NBAC acknowledges these issues in order to ensure that in considering

the ethical concerns that accompany the interactions of

nations engaged in biomedical research, discussions are

not complicated by conflating more general ethical obligations to improve the well-being of poorer countries

with the ethical obligations that arise specifically within

the context of biomedical research. 

A unique feature of international collaborative

research is the degree to which economically more prosperous countries can enhance and encourage further 

collaboration by leaving the host community or country

better off as a result. The kinds of benefits that could be

realized as a result of the collaboration would depend on

local health conditions, the state of economic development, and the scientific capabilities of the particular host

country. As discussed in Chapter 4, the provision of 

post-trial benefits to participants or others in the form of

effective interventions is one option. The appropriateness

of providing a benefit other than the intervention will

depend on the nature of the benefit and on the economic

and technological state of development of the host country. In most cases, offering assistance to help build local

research capacity is another viable option. These two

options are not, of course, mutually exclusive. But no

matter what form the benefit takes, the ultimate goal of

providing it is to improve the welfare of those in the host

country.

77

Ensuring the Protection of 

Research Participants in

International Clinical Trials

Chapter Five 5
78

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials

Although NBAC has not been persuaded that there is

an absolute obligation to provide a proven intervention

to all citizens of a country who need it (as opposed 

to those who participated in the clinical trial), the

Commission believes that serious efforts should be made

to ensure that some post-trial benefits flow to the host

community or country and that negotiations and the use

of prior agreements should be considered as vehicles for

such efforts. (See below and Appendix C.) Additional

opportunities to provide long-lasting benefits to communities and countries may be available by taking steps that

would enhance future or ongoing international research

collaboration.

This chapter discusses measures to enhance the ethical

soundness of collaborative international research by

focusing on the following issues: 1) clarification of the

substantive and procedural requirements for ensuring

the protection of those who participate in research and 

2) assistance in building host country capacity to conduct clinical trials and undertake the necessary scientific

and ethical review of these studies.

In considering these topics, NBAC attempts to clarify

the current U.S. regulatory procedures regarding research

conducted or sponsored by U.S. interests in developing

countries, and, when appropriate, make suggestions for

revisions. Currently, there is some uncertainty about the

scope of existing U.S. regulations, particularly with

respect to the determination of whether other countries

(and their research institutions) have systems to ensure

that the substantive ethical protections the Commission

described in Chapter 1 are achieved. Other considerations include the role of U.S. Institutional Review Boards

(IRBs) in the review of research conducted abroad and

the process used by the U.S. government for issuing

assurances of compliance to institutions located abroad. 

Approaches to capacity building are related to, but do

not fully depend on, the clarification and improvement of

current U.S. procedures for ensuring the protection of

research participants in international clinical trials.

Progress can and should occur simultaneously in both

realms. Capacity building to conduct research could

include activities undertaken by investigators or sponsors

during a clinical trial to enhance the ability of host country researchers to conduct research (e.g., training and

education), or to provide research infrastructure (e.g.,

example, equipment) so that future studies might proceed. Building capacity to conduct scientific and ethics

review of studies, on the other hand, is primarily a matter

of providing training and helping to establish systems

designed to review proposed protocols and sustain mutually beneficial partnerships with other more experienced

review bodies, including U.S. IRBs. 

U.S. Procedures for Ensuring the

Protection of Human Participants

Two principal regulatory mechanisms are used under the

U.S. system for ensuring the protection of human participants in research: assurances and ethics review. In addition, a regulatory provision permits the substitution of

foreign procedures that afford protections to research

participants that are “at least equivalent” to those provided in the Federal Policy for the Protection of Human

Subjects (45 CFR 46, Subpart A), also known as the

Common Rule. Clarification of the scope and limits of

these mechanisms and their use would increase public

confidence that a valid system of protections is in place

for participants in clinical trials conducted abroad.

Assurances

An assurance is “[a] legally binding written document

that commits a public or private entity to compliance

with applicable federal minimum standards for the 

protection of human subjects prior to engagement in

department or agency conducted or supported

research.”1 The assurance document can be described as

a pledge or commitment by the institution to conduct

research ethically and in accordance with the Common

Rule. An approved assurance is a prerequisite to research

conducted or sponsored by federal agencies that are signatories to the Common Rule. It is important to note that

assurances are required regardless of the type of federal

sponsorship.2 For example, if a federal employee collaborates in research, even though no federal funds are provided, this constitutes agency support sufficient to bring

the institution under the agency’s jurisdiction, which in

some cases renders it subject to the Common Rule. In

cooperative research projects, each institution engaged in
National Bioethics Advisory Commission

79

research, whether domestic or foreign, must have a valid

assurance. 

The current assurance practice of the Office for

Human Research Protections (OHRP) applies to institutions conducting research with human participants that

is subject to the Common Rule, whether the research site

is in the United States or abroad. Institutions engaged 

in research may be any public or private entity or any

federal or state agency (45 CFR 46.102(b)). Under this

definition, for example, the U.S. Centers for Disease

Control and Prevention, a drug company, or a nongovernmental organization may constitute an institution.

Each institution involved in a cooperative research 

project (a project involving more than one institution) is

responsible for safeguarding the rights and welfare of

human participants and for complying with the

Common Rule (45 CFR 46.114).

Until recently, OHRP has used two main types of

assurances: Multiple Project Assurances (MPAs) and

Single Project Assurances (SPAs). A third type of assurance, the Cooperative Project Assurance (CPA), also was

used for research conducted under the Cooperative

Protocol Research Program, which involves multiple sites

and multiple protocols where the studies are similar 

(e.g., oncology trials) and under joint institutional sponsorship. A variation of the CPA, the International

Cooperative Project Assurance, often was used for

research conducted in other countries. Finally, the regulations authorized the Department of Health and Human

Services (DHHS) to approve an institution’s assurance for

use across federal agencies. When DHHS approved such

an assurance, all other Common Rule signatory agencies

had to accept the assurance if it is “appropriate for the

research in question” (45 CFR 46.103(a)). If another

department accepted the DHHS assurance for such use,

the institution had to provide any reports required under

the regulations to the former Office for Protection from

Research Risks (OPRR) and the supporting agency. 

Criticisms of the SPA Process

Many researchers working in developing countries

have found the SPA process to be burdensome, irrational

in its structure, and of questionable merit in achieving

the goal of protecting research participants.3 One concern

is that because separate assurances are required for each

source of funds involved in a research protocol rather

than for the individual research protocol itself,

researchers may need to obtain several SPAs for a single

protocol with multiple funding sources. Moreover, when

a funding source changes for the same protocol,

researchers must obtain a new SPA, which imposes what

may be the unnecessary burden of multiple reviews on

the U.S. researchers and their collaborators in other

countries, who often question the need to review a study

more than once.4

Some have criticized OPRR/OHRP’s assurance

process, principally because it requires foreign institutions to rigidly abide by U.S. procedures. For example,

according to a 1997 survey of international researchers

using SPAs, “there needs to be an increased acceptance by

OPRR of ethical guidance and standards of practice in

other countries” (Wichman et al. 1997, 5). Other comments from researchers about how to improve the 

current process for protecting research participants in

international collaborative research almost uniformly

suggest the need for greater flexibility by the United

States in the application of its regulations. One individual

urged that other countries’ institutions should choose the

composition of the IRB. Another asked, “Why is it that

the country’s or institution’s IRB must be approved on

every occasion? It is stupid and embarrassing to have to

demand this. Approve the Board and let them get on with

the job” (Wichman et al. 1997, 4). Still another

researcher said, “My single experience has been very 

negative—to the point where my collaborators almost

pulled out” (Wichman et al. 1997, 4). Wichman and her

colleagues observed that:

[i]n requiring conformity by foreign sites with all U.S.

regulatory requirements, the current process may not

be the best way to promote the ethical principles

underlying the obligation to protect human research

subjects. If...the assurance process is based on trust,

then a major goal should be to assure that the rights

and welfare of human subjects will be protected in

accordance with commonly held ethical principles

and standards of practice, not necessarily those of the

United States (Wichman et al. 1997, 6).
80

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials

In addition, in their study prepared for NBAC, Nancy

Kass and Adnan Hyder reported that 77 percent of U.S.

and 85 percent of developing country researchers surveyed recommended the use of international guidelines

instead of U.S. regulations to cover joint projects.5

An alternative mechanism proposed to NBAC would

allow for the certification of foreign ethics review committees. Under this mechanism, once a foreign ethics

review mechanism achieves certification, it would be

allowed to review and approve protocols in the same

manner as institutions that have received an MPA.6

A particular feature of the SPA process is the requirement by OHRP that foreign research ethics committees

be constituted in precisely the way stipulated by the 

U.S. regulations. Several researchers commented that this

procedural requirement is unduly rigid. In the

Kass/Hyder report, 83 percent of U.S. researchers and 

92 percent of international researchers surveyed commented that U.S. regulations should not dictate the 

composition of host country ethics review committees.7

OHRP’s Proposed Revisions to the Assurance

System

In December 2000, OHRP launched a new Federalwide

Assurance (FWA) and IRB registration process. The process

for filing institutional assurances with OHRP for protecting

human research participants has been simplified by

replacing SPAs, MPAs, and CPAs with the FWA, one for

domestic research and one for international research.

Each legally separate institution must obtain its own

FWA, and assurances approved under this process would

cover all of the institution’s federally supported human

research. The proposed system eliminates the assurance

documents now in place and replaces them with either a

Federalwide Domestic Assurance or a Federalwide

International Assurance, covering all federally supported

human research. 

Other features of the new assurance system would

permit a U.S. institution to keep or establish its own

IRB(s), rely on the IRB of another institution, or use an

independent IRB. Foreign institutions would be permitted to abide by the ethical principles of the World

Medical Association’s Declaration of Helsinki: Ethical

Principles for Medical Research Involving Human Subjects,

the National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research’s Belmont

Report: Ethical Principles and Guidelines for the Protection 

of Human Subjects of Research (1979), or other relevant

international research guidelines as an alternative to 

the U.S. research regulations. Under all assurances, 

institutional personnel (assurance signatory official, senior

IRB/ethics review committee administrator or contact

person, IRB/ethics review committee chairperson and

members, and research investigators) are required to

complete training on guidelines or regulations pertaining

to the protection of human research participants. OHRP

will provide a basic education module through its website to facilitate such training. To ensure that institutions

are in compliance with the assurance, OHRP plans to

expand educational activities, review institutional procedures for protecting human participants, increase the

number of announced and unannounced site visits, and

develop a website and a telephone information service.

NBAC is encouraged that OHRP is taking these steps

to revise and simplify the current assurance process. It is

not clear at this time, however, whether the new FWA

process will eliminate the problems and inconsistencies

that exist among agencies such as DHHS, the Agency for

International Development (USAID), and the Food 

and Drug Administration (FDA) or the difficulties

expressed by researchers who are familiar with the previous assurance system. Moreover, it should be noted that

the assurance process itself does not provide a failsafe

system of protections. Because weaknesses in this system

have been noted in failures at U.S. research institutions,

care should be taken not to rely too heavily on this single

mechanism to achieve protections abroad, especially

when it is not clear that OHRP will provide a visible 

presence in the host country (through, for example, site

visits). However, it will be important to evaluate the 

success of these new initiatives.

Recommendation 5.1: After a suitable period of

time, an independent body should comprehensively evaluate the new assurance process being

implemented by the Office for Human Research

Protections.
National Bioethics Advisory Commission

81

Ethics Review

NBAC has argued that individuals enrolled as

research participants in clinical trials in developing countries should be guaranteed the substantive ethical protections outlined in Recommendation 1.1 and based on the

ethical standards currently embodied in the U.S. system

for the protection of human participants. Nevertheless, it

is appropriate to allow for procedural variations in order

to accommodate circumstances that are common in some

developing countries. NBAC also has argued that in the

absence of these protections, clinical trials in developing

countries should not be conducted or sponsored by the

U.S. government and that federal regulatory agencies

should not approve drugs, devices, or biologics for sale in

the United States based on such trials. (See Chapter 1,

Recommendation 1.2.) As stated in Recommendation

1.1, prior review by ethics review committees is one of

the most important ethical and procedural requirements

for research.

Ethics review and the assurance process are closely

connected. Each institution provides an assurance to

DHHS that research involving human participants will be

reviewed, approved, and provided continuing review by

the IRB identified in its assurance (45 CFR 46.103(b)).

The Common Rule establishes detailed requirements

regarding the form and substance of IRBs, including

membership (45 CFR 46.107), functions and operations

(45 CFR 46.108), requirements for review of research

(45 CFR 46.109), criteria for approval of research (45

CFR 46.111), authority to suspend or terminate research

(45 CFR 46.113), record-keeping obligations (45 CFR

46.115), and the authority of the institution within

which an IRB resides to approve or disapprove research

(45 CFR 112). This means that all foreign institutions

engaged in DHHS-sponsored research must comply with

these requirements.

The FDA, although an agency of DHHS, operates

under separate human participant protection regulations

(21 CFR Parts 50 and 56) promulgated pursuant to the

Federal Food, Drug, and Cosmetic Act8 and the Public

Health Service Act.9 The FDA regulates all human research

involving human drugs, biologics, and medical devices

that is submitted in support of U.S. marketing approval

for such products (21 CFR Parts 312 and 812). All of the

limited amount of research involving human participants

that the FDA sponsors and conducts is subject to the

DHHS regulations. In addition, DHHS-funded research

studying FDA-regulated products is subject to both

DHHS and FDA regulations.

Like DHHS, USAID is a federal agency that subscribes

to the Common Rule. However, its interpretation and

implementation of the Common Rule differ markedly

from those of DHHS in several respects and can be problematic for both U.S. researchers and their host country

collaborators. USAID sponsors research in the United

States and in other countries, but the agency does not

conduct any research of its own. It has codified the

Common Rule to set standards for USAID-supported

research conducted in the United States or in other countries (22 CFR 225). The regulations are oriented primarily toward biomedical research, but they cover other

types of research in which the principal issue generally “is

protection of privacy rather than direct physical harm”

(USAID 1996, 6(a)).

Safeguarding the rights and welfare of human

research participants is the primary responsibility of the

organizations to which USAID provides support. Its 

regulations and procedures emphasize “practicality, flexibility, and common sense” (USAID 1996). USAID recognizes three essential “pillars of protection”: 1) review by a

properly constituted ethics review committee or IRB; 2) a

meaningful assessment of risk/benefit by the IRB or ethics

review committee; and 3) a meaningful informed consent

procedure. USAID “recognizes that foreign countries may

often present special situations” (USAID 1996, 2(c)). 

Multicenter cooperative research projects present special problems for ethics review because the ethics review

committee of each participating institution must review

the same research protocol. In addition to duplication of

effort, time, and resources (which are particularly scarce

in many developing countries), multiple reviews always

present the possibility of different review outcomes.

Although the DHHS regulations provide that, with the

approval of the department or agency head, an institution

participating in a cooperative research project may enter

into a joint review arrangement and rely on the review of

another qualified IRB or “make similar arrangements for

avoiding duplication of effort” (45 CFR 46.114), NBAC is
82

not aware that this provision has been used in conjunction with cooperative research projects.10

In contrast, in a situation in which USAID provides

support to a U.S.-based institution conducting research

in another country, only the U.S. institution is required to

review the research. The foreign institution is encouraged

to review the research as well, but USAID does not

require it. The FDA regulation also differs slightly from

the DHHS regulation in that the FDA does not require

approval of institutional agreements regarding whether

one or multiple IRBs meeting regulatory requirements

will review the research (21 CFR 56.114). NBAC also recognizes that the FDA clinical investigation and product

approval regulations are not congruent with the

Common Rule regarding IRB review of foreign clinical

studies. The FDA expressly requires review by an IRB

when an investigational new drug (IND) application or

an investigational device exemption (IDE) has been filed

(312.23 (a)(1)(iv), 812.42). In cases in which a foreign

clinical study of a drug or biologic is not conducted

under an IND, the FDA requires that “[f]oreign clinical

research is required to have been conducted in accordance with the ethical principles stated in the

‘Declaration of Helsinki’ or the laws and regulations of

the country in which the research was conducted,

whichever represents the greater protection of the individual” (312.120(c)(1)). Similar language is used in the

medical device approval regulations (21 CFR 814.15(b)). 

Current Challenges to Host Country Ethics Review

The concept of local review—that is, review conducted by committees located in the community or institution in which the research will occur—enjoys

considerable support in the international research ethics

community and is one of the cornerstones of the U.S.

system for protecting human participants. It is argued

that committees that are familiar with the particular

researchers, institutions, potential participants, and other

factors associated with a study are likely to provide a

more careful and considered review than a committee or

other group that is geographically displaced or distant.

According to this perspective, only local committees can

exercise the kind of balanced and reasoned judgment

required for reviewing protocols, and review cannot be

accomplished from a distance. 

Although ethics review committees are widely used

throughout the international research community to

ensure the protection of human participants, differences

still remain in the level and quality of review. Data from

the Kass/Hyder study provide some insight into the

review and oversight of research in developing countries.

For example, nearly all (91 to 96 percent) of the studies

described by U.S. respondents were reviewed by a U.S.

IRB, and these respondents reported that 87 percent of

studies also were reviewed by an ethics review committee

in the host country. In 29 percent of studies reported by

U.S. researchers, the host country ethics review committee

was established because of U.S. regulations.11 In general,

however, ethics review committees in developing countries were less likely to raise either procedural or substantive issues for a given study, compared to U.S.

boards.12 Survey respondents also remarked that host

country ethics boards may be likely to have conflicts of

interest regarding study approval, because research generates desperately needed resources that often provide an

incentive to host country governments, ethics committees, and local researchers to accept such projects.13 These

findings provide a useful reminder of the difference

between the existence of an ethics review committee and

the capacity of the committee to conduct ethics reviews.

Nevertheless, most respondents (85 percent of the host

country researchers and 77 percent of U.S. researchers

surveyed) believed that local review should be required

for all studies conducted in developing countries.14

The Need for Multiple Ethics Reviews

Any research project in which a U.S. institution

receives federal funds from an agency or department that

is a signatory to the Common Rule (regardless of the

number and location of other sponsors or research sites)

must be submitted to and approved by a U.S. IRB of an

institution with which the researcher is affiliated. Some

commentators view this requirement as an imposition by

the United States on other countries. Despite the fact that

some countries—such as Australia, Canada, Denmark,

India, the United Kingdom, and New Zealand—have

well-established systems of oversight (with detailed

guidelines and policies), NBAC believes it is essential to

our system of oversight that studies conducted with funds

from U.S. interests also comply with U.S. regulations.

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials
National Bioethics Advisory Commission

83

For these countries, a different type of problem exists:

Institutions in those countries must find ways to comply

with their own guidelines as well as with those of the

United States. Institutions in these countries would be

unlikely to delegate ethics approval of studies to U.S.

IRBs, even though local review processes and principles

are similar to those under the U.S. regulations.15

As a result, some researchers surveyed for this report

expressed a preference for using guidelines from the host

countries rather than those of the United States:

National guidelines in developing countries should

take precedence over U.S. regulations when the study

is initiated by researchers in the developing country

and the role of U.S. researchers is merely to provide

technical assistance and expertise as in the collection

and analyses of samples....Alternatively, international

guidelines should be instituted based on international

consensus. Having international guidelines would

expedite the IRB approval process since researchers in

all countries would be operating under the same set

of rules.16

In contrast, expert testimony provided to NBAC, as

well as data collected by Kass and Hyder from researchers

from both the U.S. and developing countries, indicated

that host country ethics committees are not always well

equipped to address substantive ethical issues. One

researcher working in a developing country told Kass

and Hyder that “[i]n [African country] there was no

ethics or research committee by the time I got there

and...there were a lot of researchers coming from abroad

and calling themselves researchers who just came to the

country and they did what they wanted to do and left. It

took awhile for us to push the government to the point

[of addressing the situation].”17

Similar sentiments were expressed to Kass and Hyder

by U.S. researchers. One said, “Some of the [developing

country IRBs] do really quite a decent job, just as you

would want them to be. And there are others that are

completely rubber stamps, and nothing else....Yes,

there’s an IRB, [but] I don’t have any faith that there was

any real review.”18 Another U.S. researcher added, “In

some cases, the developing country ethical review is

actually a process of seeking permission to conduct

research, and no ethical questions are raised at all.

Developing country review boards are often more concerned about the financial aspects of the study than

about ethics.”19 Efforts are needed, therefore, to enable

the systems for protecting human research participants—

including their ethics review committees—of some other

countries to become more fully committed to the ethical

standards outlined in Chapter 1. 

Ideally, equivalent (although not necessarily identical)

systems for providing protections to research participants

in developing countries would exist at both the national

and institutional levels. In countries where a system

equivalent to the U.S. system exists at the national level,

some institutions may be incapable of conducting

research in accordance with that system. However, it is

difficult to conceive of institutional systems being

declared equivalent in the absence of an equivalent

national system, although it may be possible in a few

extremely rare cases. When multiple sponsors are participating in the research, possibly all from developed countries, determining which ethics review committees (and

how many) are required poses additional complexities.

Because there are legitimate reasons to question the

capacity of host countries to support and conduct prior

ethics review, NBAC believes that with respect to research

sponsored and conducted by the United States, it will be

necessary for an ethics review committee from the host

country and a U.S. IRB to conduct a review. The FDA’s

regulatory provisions for accepting foreign studies that

are not conducted under an IND or IDE do not address

whether a foreign nation’s system must meet U.S. ethical

standards. 

Recommendation 5.2: The U.S. government 

should not sponsor or conduct clinical trials in

developing countries unless such trials have

received prior approval by an ethics review 

committee in the host country and by a U.S.

Institutional Review Board. However, if the

human participants protection system of the host

country or a particular host country institution

has been determined by the U.S. government to

achieve all the substantive ethical protections 

outlined in Recommendation 1.1, then review by 

a host country ethics review committee alone is

sufficient.
84

Recommendation 5.3: The Food and Drug

Administration should not accept data from 

clinical trials conducted in developing countries

unless those trials have been approved by a host

country ethics review committee and a U.S.

Institutional Review Board. However, if the human

participants protection system of the host country

or a particular host country institution has been

determined by the U.S. government to achieve all

the substantive ethical protections outlined in

Recommendation 1.1, then review by a host 

country ethics review committee alone is sufficient.

Challenges of Multiple Review

Some U.S. researchers who work in other countries

and their host country collaborators have expressed concern about the excessive rigidity of certain U.S. regulations and the perceived inflexibility with which the

former OPRR had interpreted and implemented these

regulations.20 These researchers noted inordinate delays

in being able to start their work and requirements that

are procedurally burdensome, sometimes either financially or administratively impossible for many developing

countries to fulfill, and, in any case, ethically unnecessary.

It may be problematic for ethics review committees in

other sponsoring or collaborating countries to conform

to U.S. regulations. Patricia Marshall’s report to NBAC

cites the comments of a physician-researcher from Lagos,

Nigeria. In addition to having to “fight with Washington”

to change the consent form, this investigator was frustrated with the administrative aspects of the process,

including paperwork and committee negotiations.21 After

making the required changes in consent forms, several

physicians expressed concerns about the possibility of

overlooking some of the suggested modifications for consent forms because of the need to route them back and

forth between U.S. and host researchers and their ethics

review committees, as well as to the U.S. funding agency. 

Haitian researcher Jean Pape testified about the 

complexity of the IRB process, which he noted as the 

area where collaboration has been the most difficult. He

described the barriers he has faced:

...for any given project there are multiple IRB clearances. Each IRB meets once a month at different times.

Each IRB uses different presentations and consent

forms. Each IRB has a different set of rules. Some

accept oral consent. Others written consent. Others

written consent with witnesses, without witnesses.

And depending on who the witnesses are, each IRB

responds with different comments that must be

addressed, a different time period for approval and,

therefore, different time for yearly renewal.22

The need to seek approval of a protocol and informed

consent documents from multiple ethics review committees raises the question of what should be done when

ethics review committees disagree. Currently, some

argue, there is no mechanism for resolving such conflicts

and no understanding on the part of one ethics review

committee of how the other committee operates.23 Ethics

review committees’ lack of familiarity with the situations

in host countries was noted by many researchers, who

stated that U.S. IRBs essentially have no experience with

the conditions and realities of life, medical care, and

research in developing countries.24

Regardless of these concerns, it is clear to the

Commission that ethics review in the host country is

important, because the host country is best able to represent the interests of prospective participants. Although

some developing countries currently may not have mechanisms in place to conduct ethics review, they should be

encouraged to engage in this process as a step toward full

collaboration with the visiting research team. NBAC

heard a number of useful suggestions for addressing

these issues, both from researchers who provided testimony and from respondents to NBAC-commissioned

surveys. These suggestions included the following:

■ Seek ways to increase communication among multiple ethics review committees responsible for review of

U.S.-sponsored research conducted in other countries, perhaps through an annual meeting between the

chairs of the ethics review committees/IRBs from collaborating countries or through visits between the

chairs of each ethics review committee/IRB. 

■ Develop a system of coordination among investigators

and local IRBs/ethics review committees. 

■ Seek input from host country ethics review committees or community members in the host country in

designing the consent process before review by a U.S.

IRB. The U.S. IRB should be flexible and receptive to

such proposals. 

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■ Have local investigators design consent forms in the

host country, followed by approval by the local ethics

review committee, rather than having the documents

and their approval come from the United States. 

■ On U.S. IRBs that review developing country protocols, include members who have experience working

or living in developing countries.

These suggestions for reducing the burden of 

multiple ethics reviews have not yet been assessed comprehensively, but they are worth pursuing. Clearly, in

cases in which clinical trials are supported by multiple

sponsors (including several sponsors from the United

States or other countries), ethics review may be conducted in accordance with the guidelines and procedures

already established in those settings. In such cases, coordination and communication between and among review

committees as described above should be fostered. This

is particularly important when more than one U.S. sponsor or institution is involved, in which case it might be

important to designate a lead U.S. IRB in order to achieve

timely review. 

Lack of Resources as a Barrier to Ethics Review

Ethics review committees in developing countries

may have difficulty complying with U.S. regulations

because they lack the funds necessary to carry out their

responsibilities. In some cases, local IRBs have requested

overhead or operational costs for studies conducted in

collaboration with U.S. researchers. Some investigators

interviewed by Marshall suggested that U.S. regulatory

agencies should make a greater investment in the ethics

review committees of host countries through training

members and providing materials and resources.25 This

suggestion raises concerns about the intermingling of

ethics and finances, a situation that can be problematic,

because protocols could be delayed for financial reasons

rather than as a result of ethical concerns. Because the

National Institutes of Health (NIH) does not provide

financial support to subcontracting institutions in other

countries, and the World Health Organization (WHO)

pays no overhead, “what you end up doing is trying to

bargain by offering to train personnel, provide equipment, provide services, or trying to somehow imbed the

equivalent of overhead in your budget and deal with it

that way.”26

One researcher noted that ethics review committees

in developing countries have no budget and asked why

these committees should use their time to meet U.S. regulations when no funds are provided for salary, secretarial assistance, courier service, office maintenance, or

other necessities.27 Indeed, 20 percent of U.S. researchers

surveyed by Kass and Hyder mentioned that host country ethics board members had complained of lack of

resources, and 70 percent believed that U.S. funding

agencies should help to support the work of these committees.28 Two researchers commented that support for

host country ethics review should come in the form of a

percentage of each research grant, which would be

donated to host country ethics systems. This would help

avoid a situation in which an individual research grant

pays to convene a specific IRB.29

NBAC is persuaded that funding issues are often

problematic for researchers and ethics review committees

in other countries. Indeed, in previous reports (NBAC

1998; NBAC 1999a; NBAC 1999b), the Commission has

recognized that there are costs to providing protection to

human participants in research and that researchers and

institutions should not be placed in the position of 

having to choose between conducting research and protecting participants. Therefore, an additional means of

enhancing international collaborative research would be

to make the necessary resources available for conducting

ethics reviews. 

Recommendation 5.4: Federal agencies and others

that sponsor international research in developing

countries should provide financial support for 

the administrative and operational costs of host

country compliance with requirements for oversight of research involving human participants.

Equivalent Protections

DHHS and its lead agency, NIH, conduct or sponsor

more research involving human participants in the

United States and abroad than any other federal agency.

OHRP is responsible for interpreting and implementing

the DHHS regulations that provide protections for

human research participants. The cornerstone of the

DHHS regulatory framework is the Common Rule, which

“applies...to federally funded [human participants]
86

research that is supported or conducted by a signatory

agency or department, either internally by its own staff

and in its own facilities, or externally through grants and

contracts with investigators at universities or other

research facilities.” It includes such research “conducted,

supported, or otherwise subject to regulation by the

Federal Government outside the United States” (45 CFR

46.101(a)). 

The same regulations that apply to research conducted in the United States apply to U.S.-sponsored

research conducted in foreign countries. The only 

provision in the DHHS regulations unique to research

conducted in foreign countries is one that permits the

substitution of foreign procedures that afford protections

to research participants that are “at least equivalent” to

those provided in the Common Rule (45 CFR

46.101(h)). This means that instead of adhering to the

particular procedures of the Common Rule, the regulations allow foreign researchers to follow procedures

adopted by their own country if these procedures provide

protections for research participants that are “at least

equivalent” to those protections provided in the U.S. 

regulations. For purposes of international research, the

“equivalent protections” provision is one of the most

important provisions of the Common Rule, because if

another ethics review system were to be declared equivalent to those procedures in the Common Rule, a foreign

institution following that system would not be required

to negotiate an assurance with a U.S. agency. 

Earlier in this chapter, NBAC examined some of the

difficulties that U.S. and foreign researchers who must

adhere to the provisions of the Common Rule encounter

when participating in DHHS-conducted or sponsored

research in developing countries. These requirements can

be problematic in two respects. First, they may present

unnecessary difficulties for the foreign researchers and

developing country researchers in particular who must

implement them. For example, as noted above, the regulations that govern the assurance process and ethics

review are viewed by some as tedious and often require

researchers in other countries to duplicate their efforts

and spend scarce resources on administrative requirements that have little to do with the actual protection of

human research participants. Second, by “exporting” its

regulations to foreign countries as a way of ensuring that

human research participants involved in U.S.-sponsored

research in those countries are sufficiently protected, the

United States may appear to be exhibiting a lack of

respect for the countries and their researchers and

research institutions. For example, some researchers

expressed the view that there is a perception that U.S.

regulations are being “imposed” on other countries. A

U.S. researcher who participated in the Kass/Hyder 

survey for NBAC invoked the distinction between ethical

principles and specific procedures with the following

comment: “The principles of U.S. ethical review should

be applied overseas but not the specifics.”30 Others

expressed a preference for using international guidelines

instead of U.S. rules. One U.S. researcher said that “[I]t

would be good to have international standards that at

least match the extent of the U.S. requirements, since

these would be more appropriate to the international 

setting.”31

The regulations themselves may provide the framework for a possible solution to these problems. As 

mentioned earlier, a provision in the regulations permits

a foreign institution to deviate from the specific procedures for protecting human participants delineated in 

45 CFR 46 as long as the procedures with which it agrees

to comply provide “at least equivalent” protections 

(45 CFR 46.101(h)). That provision states that: 

When research covered by this policy takes place in

foreign countries, procedures normally followed in

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...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 institutions afford protections that are

at least equivalent to those provided in this policy, the

Department or Agency head might approve the 

substitution of the foreign procedures in lieu of the

procedural requirements provided in this policy.

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Starting in June 2000, OHRP became the agency

responsible for making determinations of equivalent 

protections for DHHS. However, to date, OHRP has not

provided criteria for determining what constitutes equivalent protections or made any such determinations about

other countries’ guidelines. In lieu of having developed a

process for making equivalent protections determinations, OPRR in the past relied on its usual process for

negotiating assurances with foreign institutions to ensure

that human participants are adequately protected. In

response to questions from NBAC, an OPRR official

wrote that “[t]here is no established process by which

requests for ‘equivalent protections’ determinations are

made. Requests to OPRR to accept an institution’s procedures for protecting human subjects are generally made

by investigators which, in turn, are invariably addressed

in the process of negotiating an assurance.”32 The same

official testified before NBAC that “[t]ypically what happens is that we very delicately negotiate an assurance that

spells out those protections without actually citing the

U.S. regulations. In other words, what we have done is

negotiate an assurance on a case-by-case basis that incorporates those national protections without a formal 

declaration of equivalence.”33

OHRP, however, has taken steps in the direction of

recognizing the protections described in three guidelines:

the Canadian Tri-Council Policy Statement: Ethical Conduct

for Research Involving Humans (1998), the recently issued

Ethical Guidelines on Biomedical Research Involving 

Human Subjects of the Indian Council of Medical 

Research (2000), and the International Conference on

Harmonisation (ICH) ICH Harmonised Tripartite Guideline,

Guideline for Good Clinical Practice (1996). The FDA is a

signatory to the ICH and has adopted the ICH document

as FDA guidance. In doing so, OHRP has permitted institutions in Canada and India to follow their own guidelines as part of negotiating assurances under the new

FWA, which permits investigators to follow ethical codes

with which they are more familiar and comfortable.

OHRP has not, however, declared these guidelines to

provide equivalent protections pursuant to 45 CFR

46.101(h). To do so would obviate the need for assurances, and, as a result, OHRP would have to relinquish

its oversight authority.

USAID, a signatory to the Common Rule, also has the

authority to make determinations of equivalent protections. USAID will accept foreign procedural systems as

long as they are determined to provide protection to

human participants “at least equivalent” to its policy

(USAID 1996). Substantive application of the three

essential pillars of protection described earlier in the

chapter—ethics committee review, risk/benefit assessment, and meaningful informed consent—will generally

satisfy this requirement. “At least equivalent” determinations can be made by USAID in two ways. First, the

agency has determined that “research supported through

or adhering to the standards established by United

Nations agencies” is considered to afford “at least equivalent” protections (USAID 1996, 4(a)). In theory, this

mechanism is based on USAID’s familiarity with the

United Nations’ agency standards and review processes

and its trust in those agencies to protect human research

participants.

In addition to its authority as a signatory to the

Common Rule, USAID has developed a procedure for

making its own “at least equivalent” protections determinations through its recognition of the three essential 

pillars of protection, which generally satisfies the “at least

equivalent” protections requirement. USAID procedural

guidelines state that “[i]n assessing equivalency, the 

general concept should be whether protection under the

system is for all practical purposes the same when viewed

in toto [meaning under all the circumstances or when

viewed in totality] and not whether any specific component (e.g., the precise make-up of the IRB equivalent) 

is identical.” A justification memorandum must be prepared that describes how the alternative system provides

the three pillars of protection (USAID 1996). The in toto

standard used by USAID differs significantly from what

OHRP generally would require under the same circumstances (i.e., full compliance with U.S. regulations).

Although the in toto standard has never been invoked by

USAID, the USAID standards provide a solid foundation

on which to build, and NBAC encourages USAID to

adopt the substantive ethical standards described in this

report in determining equivalency.

The FDA regulations do not contain the equivalent

protections provisions set forth in the DHHS and USAID
88

regulations. The FDA does not specify the location of the

IRB or ethics review committee conducting the assessment and does not require institutions to negotiate assurances. However, in requiring that research be conducted

in accordance with international ethical principles (such

as the Declaration of Helsinki), which mandate ethics

review, and in its adoption of the standards of the ICH,

the FDA regulations do address many of the central

issues involved in determining equivalent protections.

NBAC recognizes that, from the perspective of

researchers in other countries who wish to collaborate

with U.S. colleagues, the potential exists for confusion

regarding the different sets of U.S. regulatory requirements—those of the FDA and those of the Common Rule

agencies (which may differ as well). A step toward reducing this confusion would be for the FDA to amend its

regulations to conform with the recommendations in this

report regarding equivalent protections and review by

multiple ethics committees when studies involve multiple countries.

It appears that U.S. agencies that sponsor or conduct

research in other countries have the authority to determine whether foreign laws, regulations, or guidelines

provide protections to human participants equivalent 

to those provided in the U.S. regulations; however, no

criteria exist for agencies to implement this authority, nor

does there appear to be any incentive to do so. Indeed, as

Bernard Dickens observed in a paper commissioned by

NBAC for this report:

Accordingly, it may be an act of faith for a Department

or Agency head to determine that institutional procedures in some foreign countries ‘afford protections

that are at least equivalent to those provided in this

policy’ as required by 45 CFR 46.101(h). Ultimately,

confidence may have to be placed in foreign institutions’ conformity with substantive rules of ethical

conduct for protection of human subjects of research,

and not on the procedures that they use.34

Given the breadth of experience within U.S. agencies—

particularly DHHS and USAID—this situation could be

remedied quickly. It is appropriate for OHRP to both

coordinate this activity and be responsible for developing

further guidance in conjunction with FDA, USAID, and

other U.S. agencies.

The Need for Uniformity in Application

As noted above, the equivalent protections provision

of the DHHS regulations has never been explicitly 

used by OHRP (or OPRR), nor has OHRP developed 

any criteria by which to make such determinations. 

The regulations do not specify what is meant by equivalent protections, and, furthermore, the language of 

45 CFR 46.101(h) is confusing. For example, it speaks 

of “procedures normally followed in the foreign countries

to protect human subjects” and “a foreign institution

which complies with guidelines consistent with

the...Declaration of Helsinki,” but also of “procedures

prescribed by the institution [that] afford protections that

are at least equivalent to those provided in this policy.”

Just how the language of this section should be interpreted is unclear. Dickens addresses this issue as follows: 

This intention to accommodate studies the policy

covers that are conducted in a foreign country therefore depends on a determination that ‘the procedures

prescribed by the institution’ afford human subjects

at least equivalent protections to those provided in

the policy. The reference to ‘procedures’ repeats the

policy’s recognition that ‘procedures normally followed’ in foreign countries ‘may differ from those set

forth in this policy.’ This raises the issue of whether

equivalent protection is focused only on matters of

institutional review procedures, where the equivalent

structure and functioning of an IRB are required, or

whether equivalence must extend beyond the process

of review to include the substance of the proposal to

be reviewed....

35

The issue Dickens raises is significant and supports

the distinction emphasized earlier in this report that substantive ethical principles or standards are more fundamental and, therefore, much less subject to negotiation

than are matters of procedure. Any given set of substantive ethical standards and principles may give rise to

more than one set of appropriate procedures to implement these standards. As long as a particular procedure

(e.g., obtaining informed consent without documenting

signatures) is consistent with the ethical standard, it

should be seen as less consequential. In contrast, disagreements or tensions regarding a substantive ethical

principle or standard can cause problems for which no

mere procedural solution would be adequate.

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Assuming that a host country’s substantive guidelines

are determined to provide equivalent protections, how

do we ensure that a particular ethics review committee in

that country is able to comply with those guidelines? In

the United States, OHRP assures that local institutions

comply with federal regulations. Similarly, ethics review

committees in another country, whether they exist at the

national, regional, local, or institutional level, would be

established by the appropriate authorities in that country

and would be equivalent in stature to a U.S. IRB. Such a

process would have the same effect as the committee 

having obtained an MPA or an FWA from a U.S. agency.

NBAC believes that equivalent protections should

mean that a process should be established to determine

whether the system of protection of human participants

in another country meets the three basic ethical principles of respect for persons, beneficence, and justice, and

has adopted the substantive ethical standards outlined in

Recommendation 1.1. Developed and developing countries might aspire to go even further to promote the

rights, dignity, and safety of research participants in other

ways. 

Consistent with the substantive ethical standards and

procedural requirements set forth above, OHRP should

take affirmative steps, in conjunction with other U.S.

agencies, to develop uniform and detailed criteria for

determining whether the system of protection of human

participants in a host country and/or host institution is

fully equivalent to the U.S. system. Once these criteria

are developed, OHRP should begin to use them to identify those countries whose guidelines are deemed to provide equivalent protections. Although it has never been

invoked in this way, the approach that has been adopted

by USAID in setting standards for equivalent protections

determinations under the Common Rule is useful. This

approach is to ask whether the protection afforded to

human research participants under the system being

assessed, for all practical purposes, is the same when

viewed in toto, and it stands in sharp contrast to the

approach of asking whether the individual components

of that system are identical (e.g., the precise make-up 

of the ethics review committee or what constitutes a 

quorum).

Recommendation 5.5: The U.S. government should

identify procedural criteria and a process for 

determining whether the human participants 

protection system of a host country or a particular

host country institution has achieved all the 

substantive ethical protections outlined in

Recommendation 1.1.

At the same time, the move toward equivalent protections is one that needs to be made carefully and with

much thought regarding substantive criteria and process.

NBAC recognizes that this recommendation may be an

aspiration that will only be attained after efforts are made

that will take a great deal of time. The Commission hopes

that in the near future at least some, if not many, of the

difficulties and frustrations currently experienced by U.S.

and foreign researchers conducting research in developing countries will be alleviated through determinations

that the laws, regulations, or guidelines of those countries

provide equivalent protections. Such a process would

also accord to those countries, their researchers, and

research institutions an appropriate level of respect for

their research systems and capabilities. Nevertheless, it

appears that at least some of the problems associated

with the assurance process described above could be

avoided if determinations of equivalent protections were,

in fact, made by DHHS and other agencies. 

Building Host Country Capacity to

Review and Conduct Clinical Trials

NBAC heard repeated testimony about the need to build

capacity in international research. For example, one

expert noted that training and capacity building help to

provide mechanisms for strengthening relationships with

local collaborators as well as for leaving behind lasting

benefits in the host communities.36 Researchers suggested

various approaches to building capacity, including training local personnel who will remain at the end of a trial

in clinical areas and research methodology; involving

host country scientists in writing grants as well as in 

analyzing data and preparing manuscripts; and at the

conclusion of a trial, leaving behind equipment that can

continue to serve local needs. Similarly, scientists who

responded to the Kass/Hyder survey agreed that capacity

building should be an integral part of any study. Kass and
90

Hyder characterized this sentiment as follows:

“Researchers should conceive of their role as facilitating

host countries’ capacity to eventually conduct most of

their research independently, and should aim for such

capacity development to be one of the most significant

benefits a study can provide.”37

In addition, many survey respondents remarked that

the participation of local researchers was essential to conducting well-designed studies in developing countries

and provided examples of long-term collaborations

between U.S. and host country research institutions.38

Developing country scientists commented that effective

collaboration entails involving host country researchers

in the early stages of research design and including them

as partners throughout the research process. Such collaboration results in additional benefits that flow in two

directions: The host country researchers may gain from

the expertise and material resources of the U.S. team, and

the U.S. researchers benefit from the knowledge and

experiences of the local team, whose input into the

research process often is essential to reaching the most

appropriate and relevant research design.

The guidelines and other policy statements of several

national and international bodies emphasize capacity

building. These documents include provisions that pertain to the responsibilities of developed country research

sponsors in developing countries, including providing

assistance in building local and national capacity for

designing and conducting trials, and for their scientific

and ethical review, and for implementing the results of

the research following a trial. The provisions of some

developing countries’ guidelines directly address these

issues. For example, Section III.3.s of Brazil’s Resolution

No. 196/96 on Research Involving Human Subjects states

that “...[s]tudies sponsored by external organizations

must also respond to training needs in Brazil” (NHC

1996). The South African Guidelines on Ethics for Medical

Research states that “[w]hile studies are in progress...the

opportunity should be taken to train local health 

workers in skills and techniques that can be used to

improve health services....When the study team departs

it leaves something of value, such as the ability to monitor diseases or mortality rates” (MRC-SA 1993, Sec. 18).

In addition, both the 1993 CIOMS International Ethical

Guidelines for Biomedical Research Involving Human

Subjects (CIOMS 1993) and the UNAIDS Guidance

Document for Preventive HIV/AIDS Vaccine Trials (UNAIDS

2000) address this topic.

In a departure from the way research in developing

countries has been conducted in the past, a consensus

has emerged that a fuller and more genuine partnership

should be forged, rather than an approach in which

developed country sponsors dictate the terms of the

research. For example, UNAIDS has developed a list of

mechanisms for capacity building in the context of HIV

vaccine research that may be adapted to other areas of

international research, including the following: 

■ scientific exchange and knowledge and skills transfer

between sponsor countries and institutions, host

countries, and communities;

■ capacity-building programs in the science and ethics

of vaccine development;

■ development of national and local ethics review

capacity; 

■ information and education program support to

affected communities from which research participants are drawn; and

■ early involvement of affected communities in the

design and implementation of research protocols

(UNAIDS 2000, 16). 

A number of organizations are involved in the type of

capacity-building activities suggested by UNAIDS (see

Exhibit 5.1).

As acknowledged in Chapter 4, a potential problem

exists in maintaining the quality of health care that has

been established during the course of a clinical trial. This

point has been made by other entities, such as the

Nuffield Council on Bioethics, whose discussion paper

notes that “[o]ften, large-scale trials of interventions in

developing countries are associated with improvements

in community healthcare during the period of the trial

due to better staffing and facilities. The support required

for the improvement will not ordinarily continue after

the trial is over” (Nuffield Council on Bioethics 1999, 5).

Although sponsors should not be expected—once the

trial is over—to continue to provide staffing and equipment indefinitely, they could nevertheless undertake

efforts to train personnel in the host country in providing

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials
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91

adequate medical care and maintaining equipment and

facilities. The goal of capacity building is to enable host

country researchers to develop fuller partnerships with

developed country researchers or sponsors. However, the

particular needs that capacity-building activities could

address may depend on the local circumstances. 

Recommendation 5.6: Where applicable, U.S. sponsors

and researchers should develop and implement

strategies that assist in building local capacity for

designing, reviewing, and conducting clinical trials

in developing countries. Projects should specify

plans for including or identifying funds or other

resources necessary for building such capacity.

Of particular importance to the concerns addressed in

this report is the adequacy of procedures in host countries for conducting prior scientific and ethical review of

clinical trials. Ultimately, increased capacity for conducting these reviews contributes to more effective collaborations in international research. Chapters 2, 3, and 4 offer

recommendations that address specific aspects of ethics

review that are relevant to the assessment and approval of

clinical trial protocols. This chapter focuses on enhancing

the capacity of developing countries to conduct scientific

and ethical reviews independently. 

Exhibit 5.1: Examples of Building Research Capacity

■ The Fogarty International Center (FIC) at NIH sponsors international research and training programs aimed at

building research capacity in the poorest nations of the world where the need is the greatest. These grants allow

institutions in the United States to work in partnership with colleagues in the developing world to conduct research

and, in the process, build a cadre of young foreign investigators positioned to address the scientific challenges

in the most crucial areas, including HIV/AIDS, emerging infectious diseases, bioethics, medical informatics, population and health, environmental and occupational health, maternal and child health, and others.39 The center’s

activities follow from the many activities of “international cooperation” described in the U.S. Public Health Service

Act (Sec. 307 [242] (a)). Recently, the FIC announced the funding of five initial awards and three planning grants

to institutions in developing countries under the new International Bioethics Education and Career Development

Award Program. Support for the program will total $1.4 million over three years.40

■ The International AIDS Vaccine Initiative (IAVI) has formed several wide-ranging partnerships to accelerate the

development and testing of preventive AIDS vaccines that would be appropriate for use in various parts of the

developing world. (See also Appendix C.) One of these partnerships is with the Ugandan Ministry of Health.

Ugandan scientists will be collaborating with IAVI on the development and testing of an orally administered AIDS

vaccine under development at the University of Maryland Biotechnology Institute. The vaccine’s development is

being funded by IAVI. The Ministry of Health in Uganda and IAVI also intend to work together to support ongoing

efforts in Uganda to build clinical trial infrastructure and prepare sites for trials of a range of preventive AIDS vaccines. Both organizations also are committed to strengthening the capacity of Ugandan scientists to play an

active role in vaccine research and development and to collaborate with other U.S. and European groups working on vaccine development in Uganda.

■ The Rockefeller Foundation created the International Clinical Epidemiology Network (INCLEN) in 1980 to

improve the health of populations by bringing the science of public health epidemiology to bear on the practice

of medicine. INCLEN identifies medical schools in the developing world to train mid-level faculty in the disciplines

of clinical epidemiology, biostatistics, health social science, and clinical economics and supports those faculty

members (and the Clinical Epidemiology Units [CEUs] that they formed) through mentorship, continuing education, logistical support, and ongoing linkages with colleagues around their regions and the world. INCLEN helps

those who have been trained establish themselves as productive and influential teachers and researchers, 

as well as clinicians, administrators, and policymakers. INCLEN has trained nearly 500 faculty members at the

master’s level since 1980, and 83 percent remain affiliated with 56 CEUs, located in 24 countries.41
92

Variation in National and International

Guidelines

In developing recommendations for enhancing 

international collaborative research and to more fully

understand what provisions currently exist regarding

international collaborative research, NBAC has prepared

a detailed comparison of 25 documents that contain 

the international laws, regulations, and guidelines from

15 countries and 7 international organizations. (A summary of the analysis appears in Appendix B, and the

complete analysis is available in Volume II of this report.)

The seven documents developed by international

organizations describe general principles and guidelines

for the ethical conduct of research, while the national

documents set forth the laws, regulations, or guidelines

specific to particular countries. These documents were

selected from developed and developing countries and

represent a breadth of geographical and cultural diversity.

The analysis focused on identifying features of U.S.

research regulations that might be absent from other

national and international documents, and conversely,

determining whether issues that are dealt with in certain

international documents are not found in the U.S. regulations. Exhibit 5.2 lists the 25 documents.

It is evident that although the importance of prior 

scientific and ethical review is well established in many

developed countries and agencies that sponsor international collaborative research, the associated procedures

necessary to effectively implement the relevant principles

are at different stages of evolution. In addition, many

developing countries have not yet promulgated national

ethics guidelines related to the protection of human 

participants, including those necessary to support and

implement review and monitoring of research. In certain

countries where international collaborative research is

conducted, ethics review committees are not well established. At the very least, these differences begin to explain

why researchers who are from different countries collaborating on the same research project may encounter misunderstandings regarding which ethical standards and

procedures must be satisfied. At worst, it may indicate

that if the lack of consistency among guidelines and practices is not addressed, the implementation of a coherent

and sufficient set of guidelines may pose serious and

unnecessary difficulties in international research, possibly preventing important and ethically sound research

from going forward.

Although researchers sometimes complained about

delays of more than two years, which undermined effective collaboration with local scientists,42 good reasons for

delays in the review process may exist, including, most

obviously, some countries’—and the research institutions

within them—lack of capacity to establish and maintain

a system of ethical review. This is why, for example, the

UNAIDS Guidance Document (2000) and the WHO

Operational Guidelines for Ethics Committees That Review

Biomedical Research (2000) recommend that collaboration between sponsors and host countries and among

other international organizations and experts can

enhance the capacity for developing countries to provide

independent and competent review.

Researchers in the Kass/Hyder survey commented

that host country ethics review committees were variable

in their level of experience and expertise and noted that,

in some cases, researchers felt that the host country committees should be given more authority. They also raised

issues about local culture and the ability of U.S. IRBs to

effectively recognize local concerns. Others pointed to

deficiencies in local review committees and remarked

that different countries and locales were at different

stages of evolution in the development of ethics review

processes. In fact, survey data indicate that lower levels of

overall development in host countries are associated with

difficulties in ethics review, including greater delays in

obtaining ethics clearance and greater likelihood that

researchers would abandon a research project because of

a lack of host country ethics clearance.43 Several individuals responding to NBAC’s request for comments noted

that collaborative ethics training projects are needed in

their countries, and survey respondents made similar

proposals.

Even where published guidelines or regulations exist,

they cannot serve as adequate protection for research

participants unless they are properly implemented and

enforced. For example, researcher Sana Loue testified

that there is no infrastructure in Uganda that has oversight and enforcement authority over the operation of

research ethics committees at the institutional and

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials
national levels. In the Ugandan context, the situation is

further complicated by a controversy between the

National Drug Authority, the Uganda National Council of

Science and Technology, and the Ministry of Justice

regarding exactly who should assume responsibility for

the oversight of ethics committees. Although the consequences of violating the Ugandan guidelines for the 

protection of research participants include a prohibition

against ever again conducting research in Uganda, the

termination of a specific research project, or the temporary suspension of a research project pending further

investigation, mechanisms for monitoring and enforcing

these guidelines have not yet been put into place. 

Nonetheless, because some mechanism must be 

available to provide ethics review before research is 

conducted in another country, it is in the interests of all

Exhibit 5.2: National and International Guidelines Reviewed by NBAC

■ Australia – National Statement on Ethical Conduct 

in Research Involving Humans (NHMRC 1999)

■ Brazil – Resolutions No. 196/1996, 251/1997, and

292/1999 (NHC 1996; NHC 1997; NHC 1999)

■ Canada – Tri-Council Policy Statement: Ethical

Conduct for Research Involving Humans (MRC-CA,

NSERC, SSHRC 1998)

■ China – Guidelines on Ethical Review of Medical

Research (Committee on Research Involving

Human Subjects 1998)

■ Council for International Organizations of Medical

Sciences – International Guidelines for Ethical

Review of Epidemiological Studies (CIOMS 1991)

■ Council for International Organizations of Medical

Sciences – International Ethical Guidelines for

Biomedical Research Involving Human Subjects

(CIOMS 1993)

■ Council of Europe – Convention for the Protection

of Human Rights and Dignity of the Human Being

with Regard to the Application of Biology and

Medicine (Council of Europe 1997)

■ Declaration of Helsinki: Ethical Principles for

Medical Research Involving Human Subjects

(WMA 1964, as amended in 2000)

■ Denmark – Act on a Scientific Ethical Committee

System and the Handling of Biomedical Research

Subjects44

■ Finland – Decrees 785/1992, 494/1998 and 986/1999

■ France – Law 88-1138 Regarding the Protection of

Persons Agreeing to Biomedical Research45

■ India – Indian Council of Medical Research. Ethical

Guidelines on Biomedical Research Involving

Human Subjects (ICMR 2000)

■ International Conference on Harmonisation –

ICH Harmonised Tripartite Guideline. Guideline 

for Good Clinical Practice (ICH 1996)

■ Joint United Nations Programme on HIV/AIDS –

Ethical Considerations in HIV Preventive Vaccine

Research: UNAIDS Guidance Document (UNAIDS

2000)

■ Netherlands – Law Regarding Medical-Scientific

Research on Humans46

■ New Zealand – HRC Guidelines on Ethics in

Health Research (HRC 1997)

■ The Nuremberg Code (Nuremberg Code 1947)

■ South Africa – Guidelines on Ethics for Medical

Research (MRC-SA 1993)

■ Thailand – Rule of the Medical Council on the

Observance of Medical Ethics (MOPH 1995)

■ Uganda – Guidelines for the Conduct of Health

Research Involving Human Subjects in Uganda

(National Consensus Conference 1997)

■ United Kingdom – Guidelines for Good Clinical

Practice in Clinical Trials (MRC-UK 1998)

■ United Kingdom – Interim Guidelines for Research

Involving Human Participants in Developing

Societies: Ethical Guidelines for MRC-Sponsored

Studies (MRC-UK 1999)

■ United States – Food and Drug Administration 

(21 CFR 50; 21 CFR 56; 21 CFR 312) 

■ United States – The Common Rule (45 CFR 46)

■ United States – Agency for International

Development (22 CFR 225)

National Bioethics Advisory Commission

93
94

parties to develop such a capacity in the host country.

And because the number of U.S.-sponsored research

studies conducted in collaboration with and situated

within developing countries is increasing, self-interest

dictates a need to have effective local review mechanisms

in place so that the efficiency of these efforts may be

enhanced without compromising the protection of

research participants. Although, ideally, local ethics

review will enhance the protection of human participants

in clinical trials—regardless of the country in which the

research occurs—NBAC recognizes that it will take time

for all countries to develop the infrastructure needed to

conduct such review. 

Recommendation 5.7: Where applicable, U.S. sponsors and researchers should assist in building the

capacity of ethics review committees in developing countries to conduct scientific and ethical

review of international collaborative research.

Conclusions

This chapter has identified ways in which U.S. regulations might be improved to accommodate some of the

barriers to successful international research collaboration

without lowering the substantive ethical standards

embodied in the U.S. regulations. It has focused in particular on the assurance process and on the abilities of

U.S. federal agencies to adopt a common set of criteria for

making determinations of equivalent protection. In addition, this chapter has identified two ways that additional

benefits can flow to the developing countries in which

clinical trials have been conducted—through building

capacity to conduct research and through building capacity to conduct scientific and ethics review. In addition,

NBAC discussed some of the current challenges faced by

ethics review committees and reiterated the need for

ethics review in the host country as well as by a U.S. IRB.

NBAC recognizes, however, that establishing the

means to enhance international collaborative research

must go beyond regulations (King et al. 1999). Chapter 4

describes the relationship between researchers and 

participants as unique. Although it is necessary to ensure

that research is conducted in an ethically defensible

manner, this issue is infrequently discussed in the context of traditional research ethics or in relationship to the

cross-cultural environment in which international collaborative research is conducted. Trust is not subject to laws

or regulations. Rather, it is the foundation for the creation

of relationships between individuals involved in research

and for the connections and interactions that flow from

them. An international collaboration may consist of

researchers from many countries and sponsors from

varying disciplines, institutions, communities, and countries, all of whom bring different viewpoints and perspectives to the table. The relationships and, ultimately,

the level of trust established among individuals, institutions, communities, and countries are determined by

complex and often contradictory social, cultural, political, economic, and historical factors. It is essential, therefore, for sponsors, the countries from which they come,

and researchers to work together to enhance these collaborations by creating an atmosphere that is based on

trust and respect.

Notes

1 Available at http://ohrp.osophs.dhhs.gov/humansubjects/

assurance/assurancepurps.htm. Last accessed January 5, 2001.

2 USAID and other federal agencies that are signatories to the

Common Rule also have the authority to negotiate assurances.

When USAID provides support to a U.S.-based institution conducting research in another country, a DHHS-approved assurance

may be applied to USAID-sponsored research. If not, the institution must obtain an assurance from USAID. In this type of situation,

USAID trusts and relies heavily on the judgment of the U.S.-based

IRB to protect human research participants. Although USAID may

be familiar with the institution’s assurance, it does not examine

each new project or protocol. The foreign institution can then rely

on review by the IRB of its U.S. partner holding the assurance.

USAID encourages, but does not require, that a host country IRB

also review the research. When USAID supports research in other

countries, the recipient organization, institution, or country can

agree to be bound by a USAID assurance. USAID, however, may

ensure that requirements for protecting research participants are

met through determinations of equivalent protections, discussed

later in this chapter.

3 From data collected by Kass, N., and L. Dawson 1999,

Preliminary Focus Group Report, 31. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.” This

background paper was prepared for NBAC and is available in

Volume II of this report. 

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials
National Bioethics Advisory Commission

95

4 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 102.

5 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 30. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

6 Ibid., 115–117.

7 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 31. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

8 Public Law 717, 75th Congress.

9 Public Law 184, 78th Congress.

10 On January 24, 2001, OHRP announced the establishment of

an Office of International Activities. The proposed office would

provide an independent body to provide additional review and

input for U.S.-sponsored research involving foreign populations.

11 See Kass and Hyder, 76. 

12 Ibid., 77.

13 Ibid., 159.

14 Ibid., 209.

15 See Dickens, B.M., “The Challenge of Equivalent Protection,” 26.

This background paper was prepared for NBAC and is available in

Volume II of this report.

16 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 30. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

17 Ibid., 159.

18 See Kass and Hyder, 51. 

19 Ibid.

20 Ibid.

21 See Marshall, P., “The Relevance of Culture for Informed

Consent in U.S.-Funded International Health Research,” 31. This

background paper was prepared for NBAC and is available in

Volume II of this report.

22 Pape, J.P., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 30.

23 Ibid.

24 See Kass and Hyder, 147–149. 

25 See Marshall, 32. 

26 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia. Meeting transcript, 103–104.

27 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 30. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

28 Ibid., 13, 210.

29 Garcia, H., Public comment submitted to NBAC. Received

November 9, 2000; Wikler, D., Public comment submitted to

NBAC. Received November 13, 2000.

30 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 32. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

31 Ibid., 30.

32 Letter from J. Thomas Puglisi, OPRR, to Eric M. Meslin, NBAC.

December 16, 1999. 

33 Puglisi, J.T., Testimony before NBAC. March 3, 1998. Tysons

Corner, Virginia. Meeting transcript, 9.

34 See Dickens, 6.

35 Ibid., 3.

36 Plowe, C., Testimony before NBAC. February 29, 2000.

Herndon, Virginia.

37 See Kass and Hyder, 222. 

38 Ibid., 67.

39 Keusch, G.T., Letter of Welcome, Fogarty International Center.

Available at www.nih.gov/fic/about/welcome.html. Last accessed

January 4, 2001.

40 Fogarty International Center. International Research Ethics

Initiatives. Available at www.nih.gov/fic/news/bioethics.html. 

Last accessed January 12, 2001.

41 Global Forum for Health Research website. Available at

www.global forumhealth.org/default2.htm. Last accessed

September 2, 2000.

42 From data collected by Kass, N., and L. Dawson, 1999,

Preliminary Focus Group Report, 30. For Kass, N., and A. Hyder,

“Attitudes and Experiences of U.S. and Developing Country

Investigators Regarding U.S. Human Subjects Regulations.”

43 See Kass and Hyder, 209–210.

44 Act No. 503 of 24 June 1993.

45 Law 88-1138 of December 20, 1988, regarding the protection

of persons agreeing to biomedical research, J.O. December 22,

1988, at 16032.

46 Law of 26 February 1998, containing regulations with regard 

to medical-scientific research on humans, Staatblad (Official Law

Gazette of the Netherlands), 161.
96

References

Committee on Research Involving Human Subjects. 1998.

Guidelines on Ethical Review of Medical Research. China: Ministry 

of Public Health.

Council of Europe. 1997. Convention for the Protection of 

Human Rights and Dignity of the Human Being with Regard to 

the Application of Biology and Medicine. Strasbourg, France: 

Council of Europe Publishing.

Council for International Organizations of Medical Sciences

(CIOMS). 1991. International Guidelines for Ethical Review of

Epidemiological Studies. Geneva: CIOMS.

———. 1993. International Ethical Guidelines for Biomedical

Research Involving Human Subjects. Geneva: CIOMS. 

Health Research Council of New Zealand (HRC). 1997. 

HRC Guidelines on Ethics in Health Research. Auckland, 

New Zealand: HRC.

Indian Council of Medical Research (ICMR). 2000. Ethical

Guidelines on Biomedical Research Involving Human Subjects. 

New Dehli: ICMR.

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.

Ethical Considerations in HIV Preventive Vaccine Research: UNAIDS

Guidance Document. Geneva: UNAIDS.

King, N.M.P., G.E. Henderson, and J. Stein.1999. Beyond

Regulations: Ethics in Human Subjects Research. Chapel Hill:

University of North Carolina Press.

Medical Research Council of Canada (MRC-CA); Natural Sciences

and Engineering Research Council of Canada (NSERC); Social

Sciences and Humanities Research Council of Canada (SSHRC).

1998. Tri-Council Policy Statement: Ethical Conduct for Research

Involving Humans. Ottawa: Public Works and Government Services.

Medical Research Council of South Africa (MRC-SA). 1993.

Guidelines on Ethics for Medical Research. South Africa: MRC.

Medical Research Council of the United Kingdom (MRC-UK).

1998. Guidelines for Good Clinical Practice in Clinical Trials. 

London: MRC. 

———. 1999. Interim Guidelines for Research Involving Human

Participants in Developing Societies: Ethical Guidelines for MRCSponsored Studies. London: MRC.

Ministry of Public Health (MOPH). Ethics Committee. 1995. Rule

of the Medical Council on the Observance of Medical Ethics. Thailand:

MOPH.

National Bioethics Advisory Commission. 1998. Research Involving

Persons with Mental Disorders That May Affect Decisionmaking

Capacity. 2 vols. Rockville, Maryland: U.S. Government Printing

Office. 

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

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

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

Ethical Issues and Policy Guidance. 2 vols. Rockville, Maryland: 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.: Department of

Health, Education, and Welfare.

National Consensus Conference on Bioethics and Health Research

in Uganda (National Consensus Conference). 1997. Guidelines for

the Conduct of Health Research Involving Human Subjects in Uganda.

Kampala, Uganda: National Consensus Conference.

National Health Council (NHC). 1996. Resolution No. 196/96 on

Research Involving Human Subjects. Brazil: NHC. Addition: 1997.

Resolution No. 251. Addition: 1999. Resolution No. 292. Brazil: NHC.

National Health and Medical Research Council (NHMRC). 1999.

National Statement on Ethical Conduct in Research Involving Humans.

Australia: NHMRC.

Nuffield Council on Bioethics. 1999. The Ethics of Clinical Research

in Developing Countries: A Discussion Paper. London: Nuffield

Council on Bioethics.

The Nuremberg Code. 1947. From Trials of War Criminals Before 

the Nuremberg Military Tribunals Under Control Council Law No. 10.

Nuremberg, October 1946–April 1949. Washington D.C.: U.S.

Government Printing Office, 1949–1953. 

U.S. Agency for International Development (USAID). 1996.

Procedures. Washington, D.C.: USAID.

Wichman, A., J. Smith, D. Mills, and A.L. Sandler. 1997.

“Collaborative Research Involving Human Subjects: A Survey 

of Researchers Using International Single Project Assurances.”

IRB: A Review of Human Subjects Research 19(1):1–6.

World Health Organization (WHO). 2000. Operational 

Guidelines for Ethics Committees That Review Biomedical Research.

Geneva: WHO. Document TDR/PRD/ETHICS/2000.I.

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Principles for Medical Research Involving Human Subjects (adopted

18th WMA General Assembly, Helsinki, Finland, June 1964;

amended: 29th WMA General Assembly, Tokyo, Japan, October

1975; 35th WMA General Assembly, Venice, Italy, October 1983;

41st WMA General Assembly, Hong Kong, September 1989; 48th

WMA General Assembly, Somerset West, Republic of South Africa,

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at www.wma.net/e/policy/17-c_e.html. Last accessed January 12, 2001.

Chapter 5: Ensuring the Protection of Research Participants in International Clinical Trials
Acknowledgments

Appendix A

The Commission benefited from the input of manyindividuals who agreed to review portions of the report

for scientific, legal, and regulatory accuracy. The comments

provided by these individuals improved the quality of

the report and are greatly appreciated.

■ Seth Berkley (International AIDS Vaccine 

Initiative-IAVI)

■ Ken Bridbord (Fogarty International Center,

National Institutes of Health) 

■ Gary Chase (Henry Ford Health Science Center)

■ Marlene Chernow (VaxGen) 

■ Francis Crawley (European Forum for Good Clinical

Practice)

■ Gary Ellis (formerly, Office for Protection from

Research Risks, National Institutes of Health)

■ Imogen Evans (Medical Research Council-UK)

■ Julian Fleet (Joint United Nations Programme on

HIV/AIDS)

■ Sev Fluss (Council for International Organizations 

of Medical Sciences)

■ Leonard Glantz (Boston University)

■ P. David Griffin (World Health Organization)

■ Karen Hofman (Fogarty International Center,

National Institutes of Health)

■ SØren Holm (University of Manchester)

■ Jack Killen (National Institute of Allergy and

Infectious Diseases, National Institutes of Health)

■ Andre Knottnerus (Health Council of the

Netherlands)

■ Richard Laing (Boston University)

■ Bonnie Lee (Food and Drug Administration)

■ Steven Legakos (Harvard University)

■ David Lepay (Food and Drug Administration)

■ Marguerite Pappaioanou (Centers for Disease

Control and Prevention)

■ Francis Rolleston (formerly, Medical Research

Council of Canada)

■ Alan Sager (Boston University)

■ James Shelton (United States Agency for

International Development)

■ Didier Sicard (Comité Consultatif National

d’Ethique-France)

■ Alfred Sommer (Johns Hopkins University School 

of Public Health)

■ Robert Temple (Food and Drug Administration)

■ Chris Whalen (Case Western Reserve University

School of Medicine)

■ Peter Zilgalvis (Council of Europe)

97
Comparative Analysis of

International Documents

Addressing the Protection 

of Research Participants 

Appendix B

99
100

1 ● indicates that the document or country makes mention of a topic. For a more complete presentation of the actual provisions contained in a particular document, see Volume II of this report.

2 This category includes many different obligations to research participants covering topics such as treatment, stopping trials, provision of post-trial interventions, etc. Note that some provisions focus only

on obligations during a trial, while others focus on post-trial obligations.

3 Although this document does not have the force and effect of law, there are related provisions concerning judicial protections and sanctions.

4 Although this document does not have the force and effect of law, there are related provisions concerning sanctions and noncompliance.5 The Canadian document mentions an obligation to engage in discussions about post-trial access, but it does not impose an affirmative obligation to make interventions available.6 The Danish Council of Ethics has a separate report entitled Protection of Personal Sensitive Information.

Comparative Analysis of International Documents Addressing the Protection of Research Participants1

Obligations Interventions Harmonize Coversto Participants Made Standards: Privately

Document/Country Privacy and Prior Compensation During/After Available Countries/ Force Funded

of Origin Consent Confidentiality Review for Injury the Trial2 to Countries Documents of Law ResearchNuremberg Code (1947) ●● ●Declaration of Helsinki (2000) ●● ● ● ● ● ●Council of Europe (1997) ● ● ●● ● ● 3 ●Council for International Organizations of Medical ● ● ●● ● ● ● 4 ●Sciences (1993)International Conference In someon Harmonisation (1996) ● ● ●● ● ●● cases UNAIDS (2000) ● ●● ● ● ●Australia (1999) ● ● ● ● ● ● ●●Brazil (1996–1999) ● ● ● ● ● ● ● ●●Canada (1998) ●● ● ●5 ● ●●China (1998) ● ● ●● ●Denmark (1992) ● 6 ● ●●Finland (1992–1999) ● ● ● ● ● ●●France (1988) ● ●● ●
101

Obligations Interventions Harmonize Coversto Participants Made Standards: Privately

Document/Country Privacy and Prior Compensation During/After Available Countries/ Force Funded

of Origin Consent Confidentiality Review for Injury the Trial to Countries Documents of Law ResearchIndia (2000) ● ● ●● ● ●●Netherlands (1998) ● ● ● ● ● ●●New Zealand (1997) ● ● ●● ●South Africa (1993) ● ● ●● ●Thailand (1995) ● ● ● ●●Uganda (1997) ● ● ● ● ● ● ● ●●United Kingdom (1999) ● ● ●● ● ●7 ●United States (FDA) (2000) ● ● ● ● ● ● ● ●●United States In some(Common Rule) (2000) ● ● ●● ● ●● cases

United States (USAID) In some

(2000) ● ● ●● ● ●● cases

7 The Interim Guidelines for Research Involving Human Participants in Developing Societies: Ethical Guidelines for MRC-Sponsored Studies from the United Kingdom mentions an obligation to engage in discussions about post-trial access but does not impose an affirmative obligation to make interventions available.
Prior Agreements

Appendix C

The World Health Organization

The World Health Organization (WHO) is an intergovernmental, technical unit of the United Nations

system consisting of 191 Member States. In conjunction

with its role “of harnessing support from among a variety

of players to meet its health development agenda” (WHO

1999b, 2), WHO collaborates with industry to promote

the research and development of new health-related

products and technologies for the prevention, diagnosis,

control, and treatment of diseases that are of priority to

WHO. It is also committed to improving access to products in its study populations. The types of products that

are developed through social science research, biomedical research, operations/service research, and epidemiological research include information, drugs and devices,

changed practices, and improved services.1 An essential

element of these collaborations is the negotiation of agreements prior to the commencement of work to ensure that

final products will be made widely available to developing countries at low cost. WHO’s collaborative partners

include pharmaceutical and biotechnology companies as

well as manufacturers of health-related instruments and

equipment. It is estimated that WHO has employed well

over a dozen such agreements.2

WHO requires that any commercial enterprise with

which it collaborates “be a suitable partner” (WHO

1999b, 3). In determining the suitability of a potential

collaborator, WHO considers three factors: first, whether

the major products or services of the industry are beneficial to health; second, whether the industry engages on 

a large scale in practices that are negative to health; 

and third, whether the likely public health benefit will

outweigh any possible harmful practices, products, or

services (WHO 1999b).

Generally, WHO collaborates with industry in two

ways. First, it may design, conduct, and fund studies, trials,

and other development work on proprietary industry

products in which WHO expresses an interest and/or is

invited to collaborate. Second, it may license certain

intellectual property that WHO owns to industry for 

further development into a final product. Industry also

licenses and manufactures such products. Intellectual

property is usually acquired by WHO through research

performed by institutions that it funds. However, such

property is of little direct benefit to the organization

because it lacks the facilities, resources, and know-how

to further utilize it. This type of effort may include the

provision by WHO of technical and financial support. 

Prior agreements between WHO and its industrial

partners are mindful of the organization’s interest in

ensuring that successful products are made available to

the public sector, and to developing countries in particular, on preferential terms and of industry’s interest in

obtaining a reasonable return on its investment (WHO

1985). The agreements follow standard principles set

forth in WHO’s Policy on Patents: Information Paper on

WHO Patents Policy (1985) and its Guidelines on Interaction

with Commercial Enterprises (1999b) and are negotiated

on a case-by-case basis. As a result, their final terms and

conditions may differ depending on a variety of factors,

such as the ownership of the intellectual property rights

in question, the stage of the product’s development at the

time of negotiations, and the past and expected future

contributions to the collaboration by the parties. The

negotiations are then memorialized in a document called

a Memorandum of Understanding (MOU) (WHO

1999a).

103
104

Appendix C: Prior Agreements

In all of its collaborations, WHO seeks to ensure that

its public sector objectives are achieved by requiring that

prior agreements provide that products and technologies

developed with WHO support will be made generally

available to both the public and to public sector agencies.

The MOU defines a public sector agency as “a government, or a department or agency thereof, or a recognized

non-profit organization or entity, including WHO and

any other organization within the United Nations system” (WHO 1999a, 6). Agreements usually provide that

the product will be made available to the public either by

the industry partner or through a license to WHO, if the

industry partner decides to abandon the project. In addition, the industry partner must agree to make the product available to public sector agencies for use in the

public sector of developing countries “in sufficient quantities to meet the needs of such agencies” for distribution

in such countries (WHO 1999a, 3).

In addition to commitments relative to quantity, commitments are also sought relative to pricing. Pricing 

commitments obtained from industry partners by WHO

on behalf of public sector agencies may differ depending

on whether the product will be distributed through the

private sector. If it is to be distributed through both 

the private and public sectors, the price at which the

product is made available to public sector agencies “shall

be (i) preferential compared to the Private Sector price,

and (ii) set at the lowest possible level permitting a commercially reasonable return on combined worldwide

sales of the Compound for Distribution in both Public

and Private Sectors” (WHO 1999a, 3). The product can

be sold in the private sector at whatever price the industry partner chooses. Pricing commitments from industry

partners can also take the form of “cost, plus a modest

mark-up” or of a maximum price, depending on the circumstances.3 “Cost, plus a modest mark-up” can be used

at any stage of the collaboration, provided the terms can

be defined and agreed upon. In contrast, a maximum

price commitment can only be used if the development

work is at such a point that the parties are able to determine what it will “cost to make a product.”4 If the product will not be distributed through the private sector,

availability to public sector agencies shall be “at the 

lowest possible, commercially reasonable price” (WHO

1999a, 3). Bulk purchase is another mechanism used to

ensure availability of products at the lowest cost possible.5 To a much lesser degree, WHO may receive royalties

that are invested in the public interest either to offset the

cost of products or to fund further research to meet 

the needs of developing countries.6

In addition to quantity and pricing commitments, a

final item that is negotiated in each case is the period of

years during which product availability is ensured.

Although there is no fixed time, “at the end of the agreed

period of time the company concerned must agree to

provide technology transfer to enable the country or

countries concerned to continue either to manufacture

the product themselves or through a sublicensing agreement to have somebody else manufacture it for them.”7

Over the years, WHO and the private sector have successfully collaborated on a variety of projects in many

areas, of which tropical diseases and reproductive health

are just two examples. Drugs to combat malaria, schistosomiasis, and onchocerciasis have been developed in this

way. So have new and improved contraceptives, including emergency contraception, injectable hormonal preparations for men and women, vaginal rings, and

immunocontraceptives.8

The International AIDS Vaccine Initiative

The International AIDS Vaccine Initiative (IAVI) is an

international scientific nonprofit organization founded in

1996 with the single aim of accelerating the development

of safe, effective, and accessible HIV vaccines for global

use. IAVI’s research focus is on vaccines for developing

countries. Through the investment of what it calls “social

venture capital,” IAVI’s goal is to develop vaccines that

“would be inexpensive to manufacture, easy to transport

and administer, stable under field conditions and require

few inoculations” (Zonana 1999, 5). IAVI’s work is driven

by the belief that a vaccine represents the world’s best

hope to end the AIDS epidemic. 

In June 1998, IAVI issued a Scientific Blueprint for

AIDS Vaccine Development (IAVI 1998) that links promising vaccine approaches with countries in which to test

them. It seeks to accelerate product development and

clinical trials through public/private partnerships among
National Bioethics Advisory Commission

105

vaccine developers, manufacturers, and those who will

test the vaccines. Because it is in developing countries

where the epidemic is the most severe and the need for a

vaccine is greatest, most of IAVI’s efforts are focused

there. These collaborations seek to ensure that people 

in developing countries for whom particular vaccines 

are designed benefit from those vaccines once they are

developed.

To date, IAVI has invested about $15 million to create

four North-South vaccine development partnerships. It

also contributes expertise “as needed, in areas ranging

from project management to regulatory affairs and infrastructure for clinical trials.”9 The first is an academic partnership with the University of Oxford and the University

of Nairobi to develop for East Africa two separate vaccine

constructs to be used in combination. Phase I clinical 

trials began in Oxford in August 2000, and the Kenyan

government has approved Phase I clinical trials, which

have begun in Nairobi.

The second is an industry/academic/developing

country government collaboration, which involves

Alphavax Human Vaccines, Inc., a small North Carolina

biotechnology firm, and three institutions in South

Africa: the University of Capetown, the National Institute

of Virology, and the Medical Research Council. The goal

of this collaboration is to develop a vaccine to be tested

in South Africa (AVAC 1999).10

In February 2000, IAVI entered into a third partnership with Targeted Genetics Corporation (TGC), of

Seattle, Washington, and the Children’s Research

Institute on the campus of Children’s Hospital, in

Columbus, Ohio, to develop a vaccine for Southern and

Eastern Africa that will utilize a vector technology developed by TGC to deliver HIV genes as a form of genetic

immunization. TGC’s manufacturing process is based on

a cell line originally developed by a researcher at the

Children’s Research Institute, which holds the patent to

the technology. The vaccine being developed has the

characteristic of giving long-standing protection from a

single dose and, therefore, may be particularly appropriate for areas where vaccine delivery is difficult. Finally, in

May 2000, IAVI entered into a fourth partnership with

the Institute of Human Virology. The vaccine under

development in partnership with Uganda will be

designed to use genetically modified Salmonella bacteria

as an oral delivery system for DNA. The ease of use and

extremely low cost make this a very promising vaccine

for large-scale field use. IAVI expects to launch more

partnerships later this year.

IAVI’s focus on encouraging industrial participation 

in AIDS vaccine development is based on the belief that

private sector involvement and ingenuity in this process

are crucial. A successful AIDS vaccine will necessarily

rely on technologies covered by new and existing patents.

Realistically, however, prospects for the development of

an AIDS vaccine by the pharmaceutical and biotechnology industries alone are unlikely for four reasons. First,

the development costs of a vaccine are high; second, a

very large percentage of the potential vaccine market

probably will be in developing countries without the

resources to buy the vaccine; third, because there is a difference in the predominant viral strains in developed and

developing countries, the vaccine that is developed may

have to be region specific (Nchinda 1999); and fourth,

the highly charged political environment for HIV/AIDS is

becoming a disincentive for vaccine development.

IAVI has been instrumental in structuring prior agreements with industry partners to facilitate developing

country access to vaccines developed with IAVI resources

at reasonable prices. According to Seth Berkley, IAVI’s

president, “[d]ealing with the access issue at the start of

the process represents a wholly new approach to vaccine

development that will ultimately benefit both industrialized and developing countries” (Zonana 1999, 5).

IAVI’s prior agreements with its industrial partners

call for reasonable pricing policies for the public sector in

developing countries. The public sector is considered the

governments and not-for-profit organizations serving

developing countries. In return for financing the early

vaccine development, companies agree to make the vaccine available to the public sector in developing countries

in quantities reasonable to demand and at a cost of manufacturing plus a reasonable profit, which is defined. If

companies do not do so, IAVI has the right to transfer the

intellectual property and background technology to

another manufacturer. If the costs of manufacture seem

unreasonable, IAVI is permitted under the terms of the

agreement to obtain alternative bids for manufacture. If a
106

Appendix C: Prior Agreements

third party can produce the vaccine for less, the company

must match that price or contract the manufacturing

from the third party. The vaccine can be sold at the price

the market will bear in the developed world and in 

private markets in the developing world. If its partner is

unable to meet its overall obligations under the agreements, IAVI retains the right to choose from several

options to ensure global accessibility. 

Investment in industry is not the only component of

IAVI’s strategy for making vaccines available in developing countries. IAVI is also working on the creation of 

vaccine purchase funds along with the World Bank in 

an effort to provide additional financial incentives for

industry to engage in vaccine development. Vaccine purchase funds are “mechanisms that can create a market in

the developing world to purchase these vaccines and to

distribute them. The idea would be that...before the vaccine is ever made [we] would have a mechanism in place

to have the vaccines purchased.”11 The creation of these

funds is based on the notion that although companies

should not lose money on the vaccines they produce, the

financial return that companies can expect to receive

(and must be willing to accept) will differ according to

the market in question. The profit margin in the developing world would be next to nothing; however, companies that are willing to deal in those markets receive other

important benefits, such as economies of scale and entrée

into those markets.12

To help ensure that sufficient quantities of successful

vaccines are available to the developing world, IAVI is

investigating other mechanisms for vaccine production.

It is helping to launch national vaccine development programs in several developing countries with a significant

AIDS problem. These countries, which include South

Africa, India, and China, not only have large markets, but

they also have large vaccine industries and therefore the

potential capability to produce vaccines locally. 

In addition to the involvement of industry, IAVI

believes that international funding from governments is

critical to creating the global consortium necessary to

ensure that a safe and effective vaccine is developed that

will be accessible to the developing country poor. Thus

far, IAVI has received financial support from Canada, the

United Kingdom, and the Netherlands. The United States

is the fourth country to provide support for IAVI’s 

work through the FY 2001 Foreign Operations

Appropriations.13 (See Exhibit 4.1.)

When asked if the types of agreements that IAVI has

forged will work in other contexts for other diseases with

different partners, Seth Berkley explained that he sees

IAVI’s quest for an AIDS vaccine “as a chance to begin to

develop the mechanisms that make sense, that can be

used across the whole range of different products. When

we sit down and compare the issues on malaria to HIV,

they are not that different.”14

IAVI has updated its 1998 Blueprint in Scientific

Blueprint 2000: Accelerating Global Efforts in AIDS Vaccine

Development (IAVI 2000c), which is designed to continue

to accelerate the development of AIDS vaccines for use

throughout the world. The 2000 Blueprint calls for the

establishment of four to eight new Vaccine Development

Partnerships with the goal of initiating efficacy trials of

three of the most promising AIDS vaccines within five to

seven years. IAVI has created yet another blueprint, AIDS

Vaccines for the World: Preparing Now to Assure Access (IAVI

2000a), which “presents a strategy for addressing the

many economic, political, and logistical obstacles to

immediate and widescale access in the developing world”

and seeks to avoid “the typical ten to twenty year delay 

in introducing new vaccines to poor countries”

(IAVI 2000b, 9). 

VaxGen

VaxGen, a California-based biotechnology company,

developed an AIDS vaccine known as “AIDSVAX.”

AIDSVAX is the first vaccine candidate in the world to

enter Phase III efficacy studies. The company raised

money to finance its own trials in an effort to get the 

vaccine tested as quickly as possible (AVAC 1999). Two

trials are being conducted on two different vaccines. Each

vaccine is designed to prevent a particular strain of the

virus prevalent in the country in which it is being tested.

The first trial is being conducted in the United States.

Between June 1998 and October 1999, more than 5,400

participants were recruited, mostly men who have sex

with men. Thailand is the site of the second trial, also

currently ongoing. Recruitment of 2,500 participants, all
National Bioethics Advisory Commission

107

intravenous drug users at high risk of becoming HIV

infected, began in March 1999 and concluded in 

August 2000. 

The Thai government, the Bangkok municipal government, and Mahidol University have been proactive in

working with VaxGen in testing the potential vaccine

candidate on the Thai population. Despite the implementation of other interventions, Thailand has one of the

fastest growing rates of HIV infection in the world, and

the government has made the development of an AIDS

vaccine a health priority. Thailand was chosen as a study

site for several reasons. One reason is the strong professional relationship that has developed between key individuals at VaxGen and Thai researchers. Another reason

is that the two predominant strains of the HIV virus present in Thailand are similar, making it easier to test the

vaccine. Finally, WHO and the Joint United Nations

Programme on HIV/AIDS (UNAIDS) selected and supported the building of infrastructure to conduct vaccine

trials, and UNAIDS and the Centers for Disease Control

and Prevention (CDC) have supported cohort development over a number of years. The CDC has developed a

cohort of injecting drug users from methadone clinics

run by the Bangkok Metropolitan Association, which is

now being recruited for the vaccine trial.15

As a condition of participating in this study, the Thai

government required first that any vaccine tested in

Thailand have a reasonable likelihood of preventing

infection by the particular strains of the virus most prevalent in the country. AIDSVAX B/E was developed specifically to prevent further infections by the two subtypes, 

B and E, that are prominent in those infected through

sexual exposure and in the injecting drug user population. The Thai government also required that the country

receive research benefits in two forms—the product itself

and capacity building. 

In its discussions with the Thai Ministry of Public

Health, VaxGen offered an informal agreement that

should there be a licensed product, the country would

receive special treatment from the company in making

the product available in Thailand.16 VaxGen has agreed to

make a concerted effort to decrease the cost of the vaccine for the country. Or, if feasible, because Thailand has

a strong local pharmaceutical industry, arrangements

could be made for a bulk shipment of the product with

filling and finishing in Thailand.17 This arrangement was

described by one Thai AIDS researcher as a “letter of

intent” and the first of its kind in any vaccine trial in the

world (IAVI 1999, 7). Discussions about ways of making

the product available after completion of the study are

ongoing between the parties. Although there is a formal

agreement governing the conduct of the Phase III study

in Thailand, nothing beyond the letter of intent has been

requested by the Thai government. 

Many of the benefits that will accrue to Thailand as a

result of participating in the study take the form of capacity building. The Thais view the transfer of such knowledge and technology as extremely important. Capacity

building is occurring in three ways. First, VaxGen is

transferring its data management capabilities to Thailand.

A complete data center has been established so that the

Thais have state-of-the-art hardware and software.

VaxGen is teaching the Thai data management unit how

to collect, monitor, and validate data to comply with

international clinical research guidelines. Second, the

company has developed a repository of laboratory specimens. Technical know-how is being provided to the

Thais about how to store, track, locate, and connect data

to specimens. Third, VaxGen is training the Thais in clinical research and good clinical practices relative to conducting Phase III trials. The Thais’ experience has been

previously limited to Phase I and II trials. By having the

Thais engage in these types of capacity-building activities, the goal is to provide them with the necessary skills

and knowledge to enable them to function independently and conduct Phase III clinical trials on their own.

Capacity building is occurring as the result of a verbal

commitment between VaxGen and the Thais. It is not

part of the letter of intent.18

The prior agreement negotiated between VaxGen and

the Thai government was portrayed in a far less flattering

light in the last of a six-part series, “The Body Hunters,”

that ran in the Washington Post in late December 2000

(Flaherty and Struck 2000). The article made several allegations concerning post-trial benefits sought by the Thais

for either research participants or the country itself that

VaxGen would not agree to provide. First, VaxGen

refused to pledge care for research participants who
108

Appendix C: Prior Agreements

became HIV infected during the trial. Thai health authorities finally agreed to provide the best local treatment,

described as “years behind what an American could

expect.” Second, VaxGen refused to guarantee that the

vaccine, if proven effective, would be sold to the Thais 

at a reduced price. Flaherty and Struck noted that “[a]

‘gentlemen’s agreement’ the company wrote in 1998 to

Thai health officials suggested that if the Thais helped

with packaging the vaccine, VaxGen might be able to

reduce the country’s costs for the vaccine.” But, according

to the company president, VaxGen “can’t give vaccine

away and bankrupt the company.” Finally, VaxGen

rejected the Thai requests for profit-sharing or a manufacturing plant to be located in the country. Said one Thai

representative who reviewed the study and is now a

member of the Thai Senate, “We were making test subjects available and we were agreeable to that. But on the

other hand, we did not have that much bargaining

power. Our situation was desperate.” VaxGen has

invested almost $600,000 in equipment and facilities

that will remain in Bangkok when the study is over

(Flaherty and Struck 2000). 

UNAIDS

UNAIDS has employed prior agreements in two

instances. One agreement was made with the manufacturers of the female condom before the research began.

That agreement stipulates that the product should be

made available to the public sector in developing countries at a preferential price. The price at which the product is sold in Brazil, Lesotho, South Africa, Thailand,

Zambia, Zimbabwe, and other developing countries is

U.S. $0.61. The manufacturers’ price in industrialized

countries is reported to be significantly higher. Thus far,

the manufacturers of the female condom have complied

with the agreement.

UNAIDS also entered into a preferential pricing

agreement with Columbia Laboratories prior to the commencement of UNAIDS-funded microbicide trials in

Côte d’Ivoire, South Africa, Benin, and Thailand. It is

expected that the product, if proven successful, will be

made available by Columbia Laboratories, its manufacturer, to all trial participants at no cost until it is registered in the markets in the countries where the research

is conducted. After that time, it will be available at a

reduced price in the private sector of all developing

countries.19
National Bioethics Advisory Commission

109

Notes

1 Griffin, P.D., Testimony before the National Bioethics Advisory

Commission (NBAC). January 13, 2000. Washington, D.C. 

2 E-mail communication between P. David Griffin, WHO, and

Alice Page, NBAC. July 18, 2000.

3 E-mail communication between P. David Griffin, WHO, and

Alice Page, NBAC. February 11, 2000.

4 E-mail communication between P. David Griffin, WHO, and

Alice Page, NBAC. July 18, 2000.

5 Griffin, P.D., Testimony before NBAC. January 13, 2000.

Washington, D.C. 

6 Ibid.

7 Ibid., Meeting transcript, 144.

8 Ibid.

9 Available at www.iavi.org/programs_z_science_4-1-7.html. 

Last accessed February 2, 2001.

10 Available at www.iavi.org. Last accessed January 9, 2001.

11 Berkley, S., Testimony before NBAC. January 13, 2000.

Washington, D.C. Meeting transcript, 303.

12 Ibid.

13 Public Law 106-429.

14 Berkley, S., Testimony before NBAC. January 13, 2000.

Washington, D.C. Meeting transcript, 308.

15 E-mail communication from Marlene Chernow, VaxGen, to

Alice Page, NBAC. May 1, 2000.

16 E-mail communication from Donald Francis, VaxGen, to Alice

Page, NBAC. November 17, 1999.

17 Ibid.

18 E-mail communication from Marlene Chernow, VaxGen, to

Alice Page, NBAC. May 1, 2000.

19 E-mail communication from Julian Fleet, UNAIDS, to Alice

Page, NBAC. May 17, 2000.

References

AIDS Vaccine Advocacy Coalition (AVAC). 1999. HIV Vaccine

Handbook: Community Perspectives on Participating in Research,

Advocacy, and Progress. Washington, D.C.: AVAC.

Flaherty, M.P., and D. Struck. 2000. “Life by Luck of the Draw.”

Washington Post, 22 December, A-1.

International AIDS Vaccine Initiative (IAVI). 1998. Scientific

Blueprint for AIDS Vaccine Development. New York: IAVI.

———. 1999. “From ‘Guinea Pig’ Fears to Phase III Trial: An

Interview with Natth Bhamarapravati.” IAVI Report 4(4):6–7.

———. 2000a. AIDS Vaccines for the World: Preparing Now to Assure

Access. New York: IAVI.

———. 2000b. “IAVI Releases Blueprints for Speeding Vaccine

Development.” IAVI Report 5(4):9. 

———. 2000c. Scientific Blueprint 2000: Accelerating Global Efforts

in AIDS Vaccine Development. New York: IAVI.

Nchinda, T.C. 1999. Initiatives in Health Research. In The 10/90

Report on Health Research 1999, ed. S. Davey, 99–124. Geneva:

Global Forum for Health Research.

World Health Organization (WHO). 1985. Policy on Patents:

Information Paper on WHO Patents Policy. Geneva: WHO.

———. 1999a. Draft Memorandum of Understanding. Geneva: WHO.

———. 1999b. WHO Guidelines on Interaction with Commercial

Enterprises (preliminary version). Geneva: WHO.

Zonana, V. 1999. “Commonwealth Leaders Urge Greater Support

for AIDS Vaccines.” IAVI Report 4(5):5.
Public Comments on NBAC’s

September 29, 2000, Draft

Appendix D

Mubina Agboatwalla, Health 

Oriented Preventive Education

(Karachi, Pakistan)

Cirle Alcantara, University of Virginia 

(Charlottesville, VA)

E. Ratcliffe Anderson, Jr., American

Medical Association (Chicago, IL)

Sandra Arnold, Population Council 

(Washington, DC)

Alison Bateman, Johns Hopkins

Bioethics Institute (Baltimore, MD)

Barry J. Beaty, Colorado State

University, College of Veterinary

Medicine and Biomedical Sciences

(Fort Collins, CO)

Hasna Begum, University of Dhaka

(Dhaka, Bangladesh)

Solomon R. Benatar, University 

of Cape Town (Western Cape, 

South Africa)

Michael Bennish, Africa Centre 

for Health and Population Studies

(Mtubatuba, South Africa)

Kamma Bertelsen, Odense University

Hospital (Odense, Denmark)

Bob Bollinger, Johns Hopkins Medical

Institute (Baltimore, MD)

David A. Borasky, Jr., Roberto Rivera,

and Willard Cates, Jr., Family Health

International (Durham, NC)

A. David Brandling-Bennett, Pan

American Health Organization

Regional Office (Washington, DC)

Kerry Breen, Australian Health Ethics

Committee (Canberra, Australia)

Mark L. Brenner, Indiana UniversityPurdue University at Indianapolis

(Indianapolis, IN)

Carmen Hooker Buell and Keith

Bragman, Quintiles Transnational

Corp. (Research Triangle Park, NC)

Susan Bull, Nuffield Council on

Bioethics (London, England)

Christine Burnswick, National Breast

Cancer Coalition (Washington, DC)

Christian Burri, Swiss Tropical

Institute, Swiss Center for

International Health (Basel,

Switzerland)

Stephen Calderwood, Harvard

Medical School (Boston, MA)

Juame Canela-Solen, University of

Barcelona (Barcelona, Spain)

Richard Cash, Harvard School of

Public Health (Boston, MA)

Gary Chase, Henry Ford Health

Sciences Center (Detroit, MI)

Gabriel Chavez, Universidad

Autonoma de Guadalajara, School of

Medicine (Guadalajara, Mexico)

Jordan J. Cohen, Association of

American Medical Colleges

(Washington, DC)

H.M. Coovadia, University of Natal

(Durban, South Africa)

James J. Corrigan, Tulane University

(New Orleans, LA)

Chandice Covington, Wayne State

University (Detroit, MI)

H.C. Crain, University of 

Wisconsin-Milwaukee School of

Nursing (Milwaukee, WI)

Haile T. Debas, University 

of Southern California, San 

Francisco School of Medicine 

(San Francisco, CA)

Peter Deckers and Zita Lazzarini,

University of Connecticut School 

of Medicine (Farmington, CT)

Maurice A.M. de Wachter (Brussels,

Belgium)

Carter Diggs, USAID Malaria 

Vaccine Development Program

(Washington, DC)

Sambia Diop, University of Montréal

(Montréal, Canada)

Anita and Michael Dohn, South

American Missionary Society of the

Episcopal Church (San Pedro de

Macorís, Dominican Republic)

111
112

Appendix D: Public Comments on NBAC’s September 29, 2000, Draft

Regis M. Dunne, Mater Medical

Research Institute (South Brisbane,

Australia)

Javier Luna Orosco Eduardo,

Bioethical Impeller Committee 

(La Paz, Bolivia)

Javier Elizari, Instituto Superior de

Ciencias Morales (Madrid, Spain)

José Esparza, WHO-UNAIDS HIV

Vaccine Initiative, Health Technology

and Pharmaceuticals, World Health

Organization (Geneva, Switzerland)

Dora Feliciangeli, Bioethics

Commission of the Venezuelan

National Research Council (Maracay,

Venezuela)

John H. Fielder, Villanova University

(Villanova, PA)

Harvey V. Fineberg, Harvard

University (Boston, MA)

Neil Flynn, University of California at

Davis (Davis, CA)

Doug Forcino, Department of

Defense (Washington, DC)

Robert W. Frenck, Jr., F. Edward

Hébert School of Medicine,

Uniformed Services University of the

Health Sciences (Bethesda, MD)

Edward F. Gabriele 

(Germantown, MD)

Maria Graciela M. GarayblasGonzaga, University of Santo Tomas

(Manila, Philippines)

Hector H. Garcia, Universidad

Peruana Cayetano Heredia 

(Lima, Peru)

Charles A. Gardner, U.S. Embassy

(New Dehli, India)

Leonard H. Glantz, Boston University

School of Public Health (Boston, MA) 

Steven Goodman, Johns Hopkins

University School of Medicine

(Baltimore, MD)

Dirceu B. Greco, University of Minas

Gerais (Belo Horizonte, Brazil)

Jeffrey K. Griffiths, Tufts University

School of Medicine (Boston, MA)

Fred Grinnell, University of Texas,

Southwestern Medical Center 

(Dallas, TX)

Laura Guay, Johns Hopkins

University School of Medicine

(Baltimore, MD)

Humberto Guerra, Universidad

Peruana Cayetano Heredia 

(Lima, Perú)

Richard L. Guerrant, University of

Virginia (Charlottesville, VA)

Harry Guess, Merck & Co., Inc.

(West Point, PA)

Ellen Hardy, Universidade Estadual

de Campinas (Campinas, Brazil)

Val G. Hemming, Uniformed Services

University of the Health Sciences

(Bethesda, MD)

David L. Heymann, Communicable

Diseases Cluster, World Health

Organization (Geneva, Switzerland)

Søren Holm, University of

Manchester (Manchester, UK)

John Horton

Adnan Hyder, Johns Hopkins

University School of Hygiene and

Public Health (Baltimore, MD)

Wang Jialiang, ChinaCLEN (Sichuan,

China)

Steven Joffe, Harvard University

(Cambridge, MA)

R.A. Kambaromi, University of

Zimbabwe (Harore, Zimbabwe)

M.M. Katjire, University of Namibia

(Windhoek, Namibia)

Aristotle Katsas (Greece)

James Kazura, Case-Western Reserve

University School of Medicine

(Cleveland, OH)

Charles King, Case-Western Reserve

University (Cleveland, OH)

C. Judson King, University of

California Office of the Vice Provost

and Senior Vice Provost 

(Oakland, CA)

Andrew Kitua, National Institute for

Medical Research (Tanzania)

Cristina Lammers, Latin American

Center for Perinatology and Human

Development (Montevideo, Uruguay)

Walter Landesman, Sindicato Medico

del Uruguay (Montevideo, Uruguay)

David Lepay, Food and Drug

Administration (Rockville, MD)

Zhu Li, Peking University Health

Science Center (Beijing, China)

Alex John London, Carnegie Mellon

University (Pittsburgh, PA)

Florencia Luna, University of Buenos

Aires (Buenos Aires, Argentina)

Peter Lurie and Sidney Wolfe, Public

Citizen (Washington, DC)

Kate MacQueen, Centers for Disease

Control and Prevention (Atlanta, GA) 

Partha Pratim Majumder, Indian

Statistical Institute (Calcutta, India)

Philip Makutsa, CARE Kenya’s

Nyanza Healthy Water Project (Homa

Bay, Kenya)

V. Manickavel (Nepal)
National Bioethics Advisory Commission

113

Sherri Margalit (New York, NY)

Elizabeth McPherson, Glaxo Wellcome

(Middlesex, United Kingdom)

Michael Merson, Yale University

(New Haven, CT)

Jens Mielke, University of Zimbabwe

(Harare, Zimbabwe)

John Mills, Macfarland Burnet Centre

for Medical Research (Melbourne,

Australia)

Achilleas Mitsos, European

Commission (Brussels, Belgium)

Kenrad Nelson, Johns Hopkins

School of Hygiene and Public Health

(Baltimore, MD)

N. Yasemin Oguz, Ankara University

(Ankara, Turkey)

Colin Ohrt, Walter Reed 

Army Institute of Research 

(Silver Spring, MD)

Yaman Örs, Ankara Medical Faculty,

Ankara University (Ankara, Turkey)

Ouémé Ethical Committee 

(Porto-Novo, Benin)

Ruicong Peng, Medical Ethics

Committee, Ministry of Public Health

(Thailand)

Mary Penny, Insituto de Investigacion

Nutricional (Lima, Perú)

William A. Petri, University of

Virginia (Charlottesville, VA)

Kate Phillips, Council on

Governmental Relations

(Washington, DC)

Christopher Plowe, American Society

of Tropical Medicine and Hygiene

(Northbrook, IL)

Peter N. Poon and John H. Mather,

Department of Veterans Affairs, 

Office of Research Compliance and

Assurance (Washington, DC)

Ivor Pritchard, Department of

Education (Washington, DC)

Ren-Zong Qui, Tsinghua University

(Beijing, China)

Norma Reyes, Ethical Committee of

the National Institute of Health

(Lima, Peru)

Udo Schuklenk, University of the

Witwatersrand (Johannesburg, 

South Africa)

Amos Shapira, Tel Aviv University

(Tel Aviv, Israel)

James Shelton, USAID 

(Washington, DC)

Nikita Shklovskiy-Kordi, 

National Center for Hematology

(Moscow, Russia)

Joram Siangla, Kenya Medical

Research Institute (Nairobi, Kenya)

Lana Skirboll, National Institutes of

Health, Office of Science Policy

(Bethesda, MD)

Dixie Snider, Centers for Disease

Control and Prevention (Atlanta, GA)

Alfred Sommer, Johns Hopkins

School of Hygiene and Public Health

(Baltimore, MD)

Bert Spilker, Pharmaceutical Research

and Manufacturers of America

(Washington, DC)

Richard W. Stektee, Centers for

Disease Control and Prevention

(Atlanta, GA)

Rebecca Stoltzfus, Johns Hopkins

School of Hygiene and Public Health

(Baltimore, MD)

Robert Temple, Center for Drug

Evaluation, Food and Drug

Administration (Rockville, MD)

Arvo Tikk, Estonian Council on

Bioethics (Tartu, Estonia)

Sten H. Vermund, University of

Alabama at Birmingham

(Birmingham, AL)

Angela Wasunna, The Hastings

Center (Garrison, NY)

Dorothy C. Wertz, Eunice Kennedy

Shriver Center (Waltham, MA)

Christopher Whalen, Case-Western

Reserve University School of

Medicine (Cleveland, OH)

Widiastuti, Diponegoro University

(Semarang, Indonesia)

Daniel Wikler, World Health

Organization (Geneva, Switzerland)

Catherine Wilfert and Kate Carr,

Elizabeth Glaser Pediatric AIDS

Foundation (Washington, DC)

Erin D. Williams, Foundation 

for Genetic Medicine, Inc. 

(Manassas, VA)

Wayne L. Wilson (Apex, NC)

Beverly Woodward, Brandeis

University (Waltham, MA)

Peter F. Wright, Vanderbilt University

Medical Center (Nashville, TN)

Dezhong Xu, Fourth Military Medical

School (Xi’n, China)

Boris Yudin, Russian National

Committee on Bioethics (Moscow,

Russia)

Stanley Zinberg, American College 

of Obstetricians and Gynecologists

(Washington, DC)

Shu-xian Zu, Anhui Medical

University (Anhui, China)
Public and Expert Testimony

Appendix E

September 16–17, 1999 (Arlington, Virginia)

Public:

Peter Lurie, Public Citizen

Expert:

Donald Burke, Johns Hopkins School of Hygiene and Public Health

Jack Killen, National Institutes of Health

Alfred Sommer, Johns Hopkins School of Hygiene and Public Health

Jeremy Sugarman, Duke University School of Medicine

Patricia Marshall, Loyola University-Chicago

Liza Dawson, Johns Hopkins School of Hygiene and Public Health

Noreen Teoh, Johns Hopkins School of Hygiene and Public Health

Elisa Eiseman, RAND Corporation

October 21–22, 1999 (Washington, DC)

Public:

Adnan Hyder, Johns Hopkins University

Susan Poland, Kennedy Institute of Ethics, Georgetown University

Expert:

Sam Avrett, AIDS Vaccine Advocacy Coalition

Sana Loue, Case-Western Reserve University

December 2–3, 1999 (Baltimore, Maryland)

Public:

Kohar Jones

Peter Lurie, Public Citizen

Steven Goodman, Johns Hopkins University School of Medicine

Expert:

Christopher Whalen, Case-Western Reserve University

Sidney Wolfe, Public Citizen

Stephen Legakos, Harvard University School of Public Health 

Dennis Dixon, National Institute of Allergy and Infectious Diseases

Kay Dickersin, Brown University

Gary Chase, Henry Ford Health Sciences Center

David Lepay, Food and Drug Administration

January 13–14, 2000 (Washington, DC)

Expert:

Robert Levine, Yale University School of Medicine

Ruth Faden, Johns Hopkins University

P. David Griffin, World Health Organization

Leonard Glantz, Boston University School of Public Health

Seth Berkley, International AIDS Vaccine Initiative

February 29–March 1, 2000 (Herndon, Virginia)

Expert:

Jean Pape, University of Haiti

Grace Malenga, University of Malawi College of Medicine

Christopher Plowe, American Society of Tropical Medicine and

Hygiene

April 6–7, 2000 (Washington, DC)

Expert:

Bert Spilker, Pharmaceutical Research and Manufacturers of America

R. Sebastian Wanless, Bristol-Myers Squibb

Rose Snipes, Glaxo Wellcome

Bernice Welles, Genentech, Inc.

May 4–5, 2000 (Madison, Wisconsin)

Expert:

Norman Fost, University of Wisconsin-Madison

Susan Nayfield, National Cancer Institute

Sofia Gruskin, Harvard University School of Public Health

George Andreapoulos, University of New York

Bernard Dickens, University of Toronto

June 5–6, 2000 (San Francisco, California)

Public:

Jerome Weinberg, Glendale Adventist Medical Center

September 12–13, 2000 (Washington, DC)

Public:

Francis Crawley, European Forum for Good Clinical Practice

Steven Peckman, University of California at Los Angeles

December 7–8, 2000 (Washington, DC)

Public:

Peter Lurie, Public Citizen

Sidney Wolfe, Public Citizen

Oluwole O. Odujinrin, Cell Therapeutics, Inc.

January 18–19, 2001 (Vienna, Virginia)

Public:

Sidney Wolfe, Public Citizen

115
Commissioned Papers 

and Staff Analysis

Appendix F

The following papers, prepared for the National Bioethics Advisory Commission, 

are available in Volume II of this report:

The Challenge of Equivalent Protection

Bernard M. Dickens

University of Toronto

Attitudes and Experiences of U.S. and Developing Country 

Investigators Regarding U.S. Human Subjects Regulations

Nancy Kass and Adnan A. Hyder

Johns Hopkins University 

The Relevance of Culture for Informed Consent in 

U.S.-Funded International Health Research 

Patricia A. Marshall

Loyola University-Chicago

Comparative Analysis of International Documents 

Addressing the Protection of Research Participants 

Staff Analysis

National Bioethics Advisory Commission

International Perspectives on Protecting Human 

Research Subjects 

Jeremy Sugarman, Benjamin Popkin, Judith Fortney, and Roberto Rivera

Duke University

117
Index

A

Access to HIV/AIDS Pharmaceuticals and Medical Technologies.

See Executive Order 13155

Acquired immune deficiency syndrome. See Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS)

Active treatment concurrent control

equivalence (noninferiority) trial, 26

explanation of, iv, 26

Latin America proposed study use, ethical concerns, 25

placebo control vs., ethical concerns, 25

superiority trial, 26

See also Clinical trials; Control groups; Health care

Africa

Eastern/Southern, AIDS vaccine development efforts, 105

established effective treatment, example of, 10

health care services, 12

HIV perinatal transmission, placebo-controlled trials in, 

controversy, 1, 2

informed consent in biomedical research in, 36

informed consent involvement of community leaders, 

issues for, 43

post-trial benefits in international research, prior agreements 

on, criticisms of, 71

review of clinical trials, 83

sub-Saharan, HIV/AIDS drugs for, Executive Order on, 73

vaccine initiatives for, 73

Agency for International Development (USAID), 7, 80

equal protection provision for international research, in toto

standard for, 87, 89

equal protection provision for international research, 

role of, 87–89

ethics review for protection of participants in international 

clinical trials, U.S. provisions for, 81, 82

host country capacity for international research, building,

national/international guidelines reviewed by NBAC, 93

Agreement on Trade-Related Aspects of Intellectual Property

Rights, 73

Agreements. See Agreement on Trade-Related Aspects of

Intellectual Property Rights; Prior agreements

AIDS/HIV. See Human immunodeficiency virus/acquired immune

deficiency syndrome (HIV/AIDS)

AIDSVAX, 106

Alphavax Human Vaccines, Inc., 105

AMA. See American Medical Association (AMA)

American Home Products, 73

American Medical Association (AMA), 24

Argentina

informed consent documentation requirements, issues, 49

Asia

health care services, 12

HIV perinatal transmission, placebo-controlled trials in, 

controversy, 1

Assurances of compliance

independent evaluation of procedures for protection of 

participants in international clinical trials, NBAC 

recommendations, xi, 80

protection of participants in international clinical trials, 

U.S. procedures for, xi, 14, 78–80

protection of participants in international clinical trials, 

U.S. procedures for, OHRP proposed revisions to, 80

See also Cooperative Project Assurance (CPA); Federalwide 

Assurance (FWA); International Cooperative Project 

Assurance; Multiple Project Assurances (MPAs); Single 

Project Assurances (SPAs)

Australia

ethics review for international clinical trials, 82

National Statement on Ethical Conduct in Research Involving

Humans, 93

protection of participants in international research, xiii, 14, 100

Aventis Pharma, 73

AZT, 2

B

Barriers. See Cultural barriers

Benefits

AIDS vaccines development, prior agreements on post-trial 

benefits, 66, 106–108

disclosure requirements for participants informed consent, in

international clinical trials, v–vi, 37 

equitable distribution for U.S. government-sponsored 

international clinical trials, NBAC recommendations, iii, 6

post-trial, and researcher-participant relationship in 

international research, ethical issues, 58–59

post-trial, disclosure requirements for informed consent in

international research, NBAC recommendations, vi, 40

post-trial, ethical issues for in international research, viii–x, 

12–13, 55–74

post-trial, for host country from international research, 

NBAC recommendations, x, 74

post-trial, for host country from international research, 

prior agreements on, NBAC recommendations, x, 74

post-trial, for others from international research, ethical 

issues, x, 12–13

post-trial, for participants in international research, justice as 

reciprocity and 59–61

119
120

Index

post-trial, for participants in international research, NBAC 

recommendations, x, 74

post-trial, IAVI prior agreements for international research, 

description, 66, 74, 104–106

post-trial, obligations of public/private research sponsors in 

international research, 64–65

post-trial, obligations of researchers in international research, 64

post-trial, obligations to host community/country in 

international research, ethical concerns, 61–64

post-trial, obligations to participants in international 

research, 56–58

post-trial, prior agreements for international research, and 

breach of obligations potential, 72, 74

post-trial, prior agreements for international research, and 

creation of double standard, issues, 71–72 

post-trial, prior agreements for international research, and 

delay/prevention of research, 68

post-trial, prior agreements for international research, and 

funding/distribution problems, 67–69

post-trial, prior agreements for international research, and 

health policy influence, issues, 70–71

post-trial, prior agreements for international research, and 

prevailing international standard, issues, 70

post-trial, UNAIDS prior agreements for international 

research, 66, 74, 108 

post-trial, VaxGen prior agreements for international 

research, 66, 74, 106–108

post-trial, WHO prior agreements for international 

research, 66, 74, 103–104

Thailand AIDS vaccine research, VaxGen prior agreements 

on post-trial benefits, description, 66, 106–108

Benin

post-trial benefits in, UNAIDS prior agreement for, 108 

Berkley, Seth, 105, 106

Bill and Melinda Gates Foundation

research initiatives of, timeline 2000–2001, 73

Bioethics Commission. See National Bioethics Advisory

Commission (NBAC)

“Body Hunters,” 107

Boehringer Ingelheim, 73

Botswana

HIV/AIDS prevention in, funding for, 73 

Brazil

National Health Council (NHC), 57

post-trial benefits in, UNAIDS prior agreement for, 108 

post-trial obligations to international research participants, 

provisions for, 57, 62, 70

protection of international research participants, documents 

concerning, comparative analysis of, 100

Resolution No 196/96 on Research Involving Human Subjects, 90, 93

Bristol-Myers Squibb, 73

C

California, 66, 106

Canada

AIDS vaccine development funding for IAVI, 106 

established effective treatment, example of, 10

ethics review for international clinical trials, 82

international research activities of, 3

post-trial obligations to international research participants, 

provisions concerning, 57, 70

protection of international research participants, xiii, 14, 100

Tri-Council Policy Statement: Ethical Conduct for Research 

Involving Humans, 57, 87, 93

Capacity

building, for design/review/conduct of international research 

by developing countries, strategies for, NBAC 

recommendations, xiv, 91

building, for ethics review of international clinical trials by

developing countries, assistance for, NBAC recommendations,

xiv, 94

building, for review/conduct of international clinical trials by

host country, necessity of, xiii–xiv, 14, 89–94

Caribbean

HIV perinatal transmission, placebo-controlled trials in, 

controversy, 1

CDC. See Centers for Disease Control and Prevention (CDC)

Centers for Disease Control and Prevention (CDC), 7, 50, 79, 107

informed consent process for international clinical trials, 

NBAC recommendations, viii, 50

CEUs. See Clinical Epidemiology Units (CEUs)

Chapel Hill, North Carolina, 73

See also North Carolina

Children’s Hospital

Children’s Research Institute, 105

Chile

informed consent documentation requirements, issues, 49–50

China

AIDS vaccine development efforts, 106

Committee on Research Involving Human Subjects, 93

Guidelines on Ethical Review of Medical Research, 93

protection of international research participants, documents 

concerning, comparative analysis of, 100

CIOMS. See Council for International Organizations of Medical

Sciences (CIOMS)

Clinical Epidemiology Units (CEUs), 91

Clinical trials

Add-on design for, description of, 22

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

alternative therapies disclosure requirements, cultural barriers 

to, 39–40

assurances of compliance, for protection of international 

research participants, xi, 14, 78–80
National Bioethics Advisory Commission

121

biomedical researchers in, ethical issues for, NBAC survey, 4

capacity building for host country, variation in U.S./

international guidelines for, 92, 93–94

capacity building for international research, need to, xiii–xiv,

14, 89–94

capacity building for international research, strategies for, 

NBAC recommendations, xiv, 91, 94 

control groups treatment in developing countries, ethical 

concerns for, 26–28

crossover design for, description of, 22

design for protection of participants in international research,

iii–iv, 8–10, 20–29

design/implementation, community involvement in, for 

international research, iv–v, 30–31

design issues for repeating trials, 31–32

designs of, descriptions of, 22

developing countries as setting for, reasons for, 6–7 

disclosure requirements for international research, cultural 

barriers to, 38–40

efficacy (optimal care) vs. effectiveness, distinction, 28–29

equivalence trials, description of, 22

equivalent protections for participants in, procedures 

for, xiii, 14, 85–89

established effective treatment for control groups in 

international research, iv, 9–10, 28

ethical concerns for international research, papers 

commissioned on, 117

ethical concerns for international research, public comments

on, 111–113

ethical concerns for international research, testimony,

public/expert on, 115

ethical conduct of, requirements for, NBAC recommendations

on, 5–6

ethical issues for developing countries as setting for, 3–4

ethics review by host country for international research, 

challenges to, 82

ethics review for protection of international research 

participants, requirements, xi–xii, 13–14, 81–85

factorial design, description of, 22

financial support for costs of ethical review of, requirements,

NBAC recommendations, xiii, 85

group sequential design, description of, 22

health needs of host country, responsiveness of international

research in developing countries to, iii, 7–8 

HIV perinatal transmission, placebo-controlled trials in 

developing countries for, controversy, 1, 2

inducement (undue) for enrollment in, definition/concerns,

46–47

informed consent disclosure requirements, for participants in

international research, NBAC recommendations, v–vi, 37, 40

informed consent in international research, ensuring 

comprehension, NBAC recommendations, vi, 42

informed consent process, cultural variations for international

research, NBAC recommendations, viii, 50

informed consent role of family members for international

research, vii, 44–45

informed consent role of others for international research,

NBAC recommendations, vi, 43

multiple ethics review for international research, issues, 82–85

parallel group design, description of, 22

participant population selection for, 29

participants fair/respectful treatment in international research,

v–vii, 10–12

participants in international research, ethical requirements 

for, 5–6

participants standard of care in international research, 9, 26–28

phases of, summary of, 21

pivotal (confirmatory) trials, description of, 21 

post-trial benefits for host country in international research,

NBAC recommendations, x, 74

post-trial benefits for host country, prior agreements for 

international research, NBAC recommendations, x, 74

post-trial benefits for others in international research, ethical

issues, x, 12–13

post-trial benefits for participants in international research,

NBAC recommendations, x, 74

post-trial benefits, and researcher-participant relationship, 

ethical issues, 58–59

post-trial benefits, disclosure in informed consent documents

for, NBAC recommendations, vi, 40

post-trial benefits, IAVI prior agreements for international

research, 66, 74, 104–106

post-trial benefits, in international research, ethical issues,

viii–x, 12–13, 55–74

post-trial benefits, obligations of public/private research 

sponsors, 64–65

post-trial benefits, obligations of researchers, 64

post-trial benefits, obligations to host country of international

research, ethical concerns, 61–64

post-trial benefits, obligations to participants in international

research, concerns, 56–58

post-trial benefits, prior agreements on international research,

discussion, 66–72, 74, 103–108

post-trial benefits, prior agreements on, and breach of 

obligations potential, 72, 74

post-trial benefits, prior agreements on, and creation of double

standard, issues, 71–72 

post-trial benefits, prior agreements on, and delay/prevention 

of research, 68

post-trial benefits, prior agreements on, and funding/distribution

problems, 67–69

post-trial benefits, prior agreements on, and health policy 

influence, issues, 70–71

post-trial benefits, prior agreements on, and prevailing 

international standard, issues, 70

post-trial benefits, UNAIDS prior agreements for international

research, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for international

research, 66, 74, 106–108

post-trial benefits, WHO prior agreements for international

research, 66, 74, 103–104

post-trial treatment for research participants, justice as 

reciprocity and, 59–61
122

Index

protection of participants in international research, ethical

requirements, ii–iii, 5–6

protection of participants in international research, mechanisms

for, xi–xiv, 13–14, 78–89

randomized withdrawal design, description of, 22

recruitment issues for international research, 10–12

repeating study, design issues, 31–32

resources (funding) support for ethics review of international

research, xiii, 85

risk disclosure requirements for, cultural barriers to, 38–39

sample size selection for, 29

Single Project Assurances for protection of research participants

in, criticisms of, 79–80

superiority trials, description of, 22

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

therapeutic misconception minimization, for participants in

international research, vii–viii, 48

voluntary consent process for international research, v–vii, 11,

36–38

voluntary consent process, role of others, for international

research, vi–vii, 42–45

voluntary informed consent, ethical issues, 35

voluntary participation and undue inducement for, involvement

of community leaders, NBAC recommendations, vi, 44

women’s informed consent, role of husband in international

research, vii, 45

See also Research

Clinton, William J., 72, 73

State of the Union address, 72

Code of Federal Regulations, Title 45, Part 46 (45 CRF 46), 3, 35,

36, 48, 55

assurances for protection of participants in international clinical

trials, 78, 79 

disclosure requirements for international research participants,

v–vi, 37 

equivalent protections for international research participants,

provision for, 85, 86, 87, 88, 89

ethics review for protection of international research participants,

81, 82

host country capacity building for international clinical trials,

U.S./international guidelines on, 93

protection of international research participants, U.S./

international policy/regulatory issues for, 14

protection of international research participants, U.S. procedures

for, 78, 79, 81, 82, 85, 86, 87, 88, 89

Coercion

community leaders role in participation in international clinical

trials, NBAC recommendations, vi, 44

inducement (undue) for enrollment in international research,

definition and concerns, 46–48

Columbia Laboratories, 108

Columbus, Ohio, 105

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)

Communities

design/implementation of international clinical trials, 

involvement in, iv–v, 30–31

education on scientific/technical aspects of research protocols,

innovative methods, 41

leaders, involvement in informed consent process for 

international clinical trials, issues for, 42–44

leaders, involvement in voluntary participation in international

clinical trials, NBAC recommendations, vi, 44

post-trial benefits of international research, access to, ethical

issues, 55–74

post-trial benefits of international research for host countries,

prior agreements on, x, 74

post-trial benefits of international research, obligations of 

public/private research sponsors, 64–65

post-trial benefits of international research, obligations of

researchers, 64

post-trial benefits of international research, obligations to host

community, ethical concerns, 61–64

Uganda, leaders involvement in informed consent guidelines 

for international research, 44

Compensation

participants in international clinical trials, ethical requirements

for, 6

participants in international research, documents concerning

protection of, comparative analysis of, 100–101

participants in U.S. government-sponsored clinical trials,

care/compensation for, NBAC recommendations, iii, 6

Confidentiality. See Privacy and confidentiality 

Congress, U.S. See U.S. Congress

Consent. See Informed consent

Consent forms. See Documentation; Informed consent

Consent process. See Informed consent 

Contraceptive devices

female condom, international research on, UNAIDS prior 

agreement for post-trial benefits in selected countries, 108 

Control groups

dose-comparison concurrent control, 23

established effective treatment in international clinical trials, 

iv, 9–10, 28 

established effective treatment vs. best current methods in

developing countries, standard definition, 28

external control, 23

interventions for, cultural barriers to disclosure requirements, 39

nature of, ethical design issues, 23–26

no treatment concurrent control, 23

randomization of, cultural barriers to disclosure requirements, 39

treatment of, ethical design issues, 22, 26–28
National Bioethics Advisory Commission

123

types of, summary, 23–26

See also Active treatment concurrent control; Clinical trials;

Placebo concurrent control

Cooperative Project Assurance (CPA), 79, 80

See also Assurances of compliance; International Cooperative

Project Assurance; Office for Human Research Protections

(OHRP)

Cooperative Protocol Research Program, 79

Cornell University

Medical School, 41

CÔte d’Ivoire

UNAIDS prior agreement for post-trial benefits in, 108 

Council for International Organizations of Medical Sciences

(CIOMS), 3

International Ethical Guidelines for Biomedical Research Involving

Human Subjects, 5, 8, 9, 11, 14, 36, 38, 46, 62, 70, 74, 90, 93

International Guidelines for Ethical Review of Epidemiological

Studies, 93

international research participants protection, documents 

concerning, comparative analysis of, 100

“Obligations of Sponsoring and Host Countries,” 62

“Research Involving Subjects in Underdeveloped 

Communities,” 62

Council of Europe

Convention for the Protection of Human Rights and Dignity of 

the Human Being with Regard to the Application of Biology and

Medicine, 93

international research participants protection, documents 

concerning, comparative analysis of, 100

CPA. See Cooperative Project Assurance (CPA)

Cultural barriers 

alternative therapies, disclosure requirements for international

clinical trials and, 39–40

control interventions, disclosure requirements for international

clinical trials and, 39

control randomization, disclosure requirements for international

clinical trials and, 39

diagnosis/prognoses, disclosure requirements for international

clinical trials and, 38–39

disclosure requirements for international clinical trials, and,

38–40

informed consent documentation for international clinical trials,

issues, 48–50

informed consent process for international clinical trials,

variations due to, viii, 50

informed consent process for women in international clinical

trials, issues, 45

informed consent process involvement of community leaders

for international clinical trials, issues, 43

informed consent process involvement of family members for

international clinical trials, issues, 44–45

informed consent process involvement of others for international

clinical trials, issues, 42–45

post-trial benefits, disclosure requirements for international

clinical trial and, 40

risk information, disclosure requirements for international 

clinical trials and, 38–39 

scientific/technical information explanation for informed 

consent for international research, innovative methods, 40–42

voluntary consent process, role of others, for international 

clinical trials, vi–vii, 42–45

D

Data and Safety Monitoring Board (DSMB), 31

Declaration of Helsinki: Ethical Principles for Medical Research

Involving Human Subjects, 5, 8, 9, 10, 25, 26, 36, 37, 56, 57, 

62, 70, 74, 80, 82, 88, 93, 100

See also World Medical Association (WMA)

Denmark

Act on a Scientific Ethical Committee System and the Handling of

Biomedical Research Subjects, 93

international clinical trials, ethics review for, 82

international research participants protection, documents 

concerning, comparative analysis of, 100

Department of Health and Human Services (DHHS)

international clinical trials, assurance regulations for protection

of participants, 79, 80

international clinical trials, ethics review regulations for 

protection of participants, 81, 82

international research participants, equal protection provision

for, xiii, 14, 85–89

Department of the Treasury

Secretary, 72

Design. See Research design

Developing countries. See Research involving developing countries

DHHS. See Department of Health and Human Services (DHHS)

Dickens, Bernard, 88

Disclosure of information

alternative therapies for international research and, cultural 

barriers to requirements, 39–40

community representatives involvement to ensure 

comprehension in international clinical trials, vi, 42

control interventions for international research and, cultural

barriers to requirements, 39

control randomization for international research and, cultural

barriers to requirements, 39

cultural barriers to clinical trial requirements, 38–40

diagnosis/prognoses for international research and, cultural 

barriers to requirements, 38–39

participants in international clinical trials, informed consent

requirements for, v–vi, 37, 40

post-trial benefits from international research, informed consent

requirements for, vi, 40

risk to participants of international clinical trials and, cultural

barriers to requirements, 38–39

scientific/technical information explanation for international

clinical trials, innovative methods, 40–42

See also Information; Informed consent
124

Index

Diseases and disorders

diagnosis disclosure requirements for international clinical 

trials, cultural barriers to, 38–39

disclosure requirements for participants in international clinical

trials, v–vi, 37, 40

See also Human immunodeficiency virus/acquired immune 

deficiency syndrome (HIV/AIDS); Respiratory Distress

Syndrome (RDS)

Documentation

Haiti informed consent requirements for international research, 49

informed consent process for international research, concerns

for, 48–50

informed consent requirements for international research,

examples of, 49

Malawi informed consent requirements for international

research, 49

Nigeria informed consent requirements for international

research, 49

Uganda informed consent requirements for international

research, 49

Double standards. See Standards

Drugs and drug testing

Biologic License Application, 21

development phases, summary of, 21

discovery process for, 21 

investigational device exemption (IDE), 21

investigational new drug (IND) application, 21

New Drug Application (NDA), 21

pivotal trials (confirmatory trials), 21

post-trial access and prior agreements for international research,

funding/distribution issues, 67–69 

preclinical testing, 21

Product License Application, 21

See also Clinical trials; Placebos; Vaccines and vaccination

DSMB. See Data and Safety Monitoring Board (DSMB)

E

Effectiveness studies. See Clinical trials

Efficacy studies. See Clinical trials

Elizabeth Glaser Pediatric AIDS Foundation

Call to Action project, 73

EO 13155. See Executive Order 13155

Equipoise

clinical trials and, requirement for, 22–23

definition of, 22

See also Clinical trials; Research design

Equivalent protections. See Protections for human participants

Established effective treatment. See Active treatment concurrent

control; Health care

Ethics

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

biomedical researchers in developing countries and U.S., issues

for, NBAC survey, 4

clinical trials in developing countries and, papers commissioned

on, 117

clinical trials in developing countries and, public comments on,

111–113

clinical trials in developing countries and, testimony,

public/expert on, 115

clinical trials in developing countries, issues for, 3–4

clinical trials participants, obligations owed to during, 20

control groups treatment in clinical trials in developing 

countries, concerns, 26–28

design/conduct of international clinical trials, concerns, 19–32

HIV perinatal transmission, placebo-controlled trials in 

developing countries, controversy, 1, 2

informed consent, standard of, definitions, 36–38

Latin America proposed placebo use in study, concerns, 25

participants in international clinical trials, fair/respectful 

treatment of, v–vii, 10–12

post-trial benefits for international research, issues, viii–x,

12–13, 55–74

post-trial benefits for others in international research, issues, 

x, 12–13

post-trial benefits, and researcher-participant relationship in

international research, issues, 58–59

post-trial benefits, IAVI prior agreements for international

research, 66, 74, 104–106

post-trial benefits, obligations of public/private research 

sponsors for international research, 64–65

post-trial benefits, obligations of researchers in international

research, 64

post-trial benefits, obligations to host community/country of

international research, concerns, 61–64

post-trial benefits, obligations to participants in international

clinical trials, concerns, 56–58

post-trial benefits, prior agreements for international research,

discussion, 66–72, 74

post-trial benefits, prior agreements for international research,

and health policy influence, issues, 70–71

post-trial benefits, prior agreements for international research,

and prevailing international standard, issues, 70

post-trial benefits, prior agreements for international research,

funding/distribution problems for, 67–69

post-trial benefits, UNAIDS prior agreements for international

research, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for international

research, 66, 74, 106–108

post-trial benefits, WHO prior agreements for international

research, 66, 74, 103–104

post-trial treatment for participants in international research,

justice as reciprocity and, 59–61

protection of participants in international clinical trials, 

requirements for, ii–iii, 5–6
National Bioethics Advisory Commission

125

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

protections for participants in U.S. government-sponsored

international clinical trials, NBAC recommendations, ii–iii, 6

recruitment for international clinical trials, issues, 10–12

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

voluntary informed consent, substantive standard of, 

recommendations, 38

See also Ethics review and review committees

Ethics review and review committees, 6

assurance process for protection of participants in international

research, U.S. procedures for, xi, 80

capacity building for developing countries, for international

clinical trials, strategies for, NBAC recommendations, xiv, 91

capacity building, for host country in international clinical 

trials, need to, xiii–xiv, 14, 89–94

capacity building, for host country in international clinical 

trials, U.S./international guidelines reviewed by NBAC on, 93

clinical trials involving human participants in developing 

countries, requirements for, xi–xii, 13–14, 81–85

design involvement of community and study participants, for

international clinical trials, v, 30–31

design justification to, for protection of participants in 

international clinical trials, iv, 20

equal protection provision, for participants in international 

clinical trials, role of, 88, 89

established effective treatment for control groups in developing

countries, concerns for, iv, 9–10, 28 

financial support for costs of, for research in developing 

countries, xiii, 85

informed consent for international clinical trials, ensuring 

comprehension for, vi, 42

informed consent for participants in international clinical trials,

disclosure for, NBAC recommendations, vi, 40

informed consent, procedural requirement for international

research, cultural barriers to, NBAC recommendations, viii, 50

multiple, for international clinical trials, considerations, 82–84

post-trial benefits for host country population, for international

research, NBAC recommendations, x, 74

post-trial benefits, in international research, disclosure in

informed consent documents, NBAC recommendations, vi, 40

post-trial treatment/benefits for participants in international

research, NBAC recommendations, x, 74

protection of international research participants, challenges to

host country review, 82

protection of international research participants, U.S. provisions

for, 81, 82, 83, 84, 85

U.S. government-sponsored clinical trials in developing 

countries, requirements for, NBAC recommendations, xii, 83, 84

voluntary informed consent for participants in international

clinical trials, NBAC recommendations, v, 38

women’s informed consent process, role of husband, in 

international clinical trials, vii, 45

See also Ethics; Institutional Review Boards (IRBs)

Europe

AIDS vaccine research, 91 

established effective treatment in international research, 

example of, 10

Evaluation

international research participants, assurance process for 

protection of, independent evaluation, NBAC recommendations,

xi, 80

See also Ethics review and review committees 

Executive Order 13155, 73

Expert testimony. See Testimony and speakers

F

Faden, R.R., 36

Families

husbands involvement in informed consent of women, for

international clinical trials, cultural issues, 45

informed consent process involvement of, for international 

clinical trials, vii, 44–45

Uganda informed consent guidelines for involvement, 44

See also Marriage

FDA. See Food and Drug Administration (FDA)

Federal departments and agencies

financial support for ethical review costs of research in 

developing countries, requirements, xiii, 85

informed consent documentation for international clinical trials,

and, recommendations, viii, 50

See also Agency for International Development (USAID);

Department of Health and Human Services (DHHS);

Department of the Treasury; Federal government; Federal 

regulation; Food and Drug Administration (FDA)

Federal Food, Drug, and Cosmetic Act, 81

Federal funding for research

ethics review of U.S. government-sponsored international 

clinical trials, NBAC recommendations, xii, 83, 84

financial support for costs of ethical review of research in 

developing countries, NBAC recommendations, xiii, 85

post-trial obligations of public sponsors, 64–65

protections for participants in U.S. government-sponsored

international clinical trials, NBAC recommendations, ii–iii, 6

See also Federal government; Research funding

Federal government

assurances for protection of participants in international clinical

trials, explanation, 78–80

ethics review of U.S. government-sponsored clinical trials in

developing countries, requirements, NBAC recommendations,

xii, 83

protection of participants in international research, documents

concerning, comparative analysis of, 101

protection of participants in U.S. government-sponsored 

international clinical trials, NBAC recommendations, ii–iii, 6

Single Project Assurances for protection of international

research participants, criticisms of, 79–80
126

Index

See also Federal departments and agencies; Federal funding for

research; Federal legislation; Federal regulation; Health policy;

Public policy; U.S. Congress

Federal legislation

Vaccines for the New Millennium Act of 2000 (S. 2132/H.R.

3812), 72

World Bank AIDS Prevention Trust Fund Act (S. 2033/H.R.

3519), 72 

See also Federal Food, Drug, and Cosmetic Act; Federal 

government; Federal regulation; Public Health Service Act;

Public Law 106-264; Public Law 106-429; U.S. Congress

Federal oversight. See Federal regulation

Federal policy. See Federal government; Federal regulation; Health

policy; Public policy

Federal Policy for the Protection of Human Subjects. See Code of

Federal Regulations, Title 45, Part 46 (45 CFR 46)

Federal regulation

assurances for protection of participants in international clinical

trials, explanation, 78–80

equal protection for participants in international research, 

provision of DHHS, explanation, xiii, 14, 85–89

ethics review for protection of participants in international 

clinical trials, U.S. procedures, 81–85

host country capacity for international research, variation in

U.S./international guidelines for, 92, 93–94

protection of participants in international clinical trials, U.S.

procedures for, 78–89

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

Single Project Assurances for protection of international

research participants, criticisms of, 79–80

See also Federal departments and agencies; Federal government;

Public policy

Federalwide Assurance (FWA), 87, 89

Federalwide Domestic Assurance, xi, 80

Federalwide International Assurance, xi, 80

international research participants protection, OHRP proposed

revisions to, 80

See also Assurances of compliance

FIC. See Fogarty International Center (FIC)

Finland

Decrees 785/1992, 494/1998, and 986/1999 on international

research guidelines, 93

international research participants protection, documents 

concerning, comparative analysis of, 100

Flaherty, M.P., 108

Fogarty International Center (FIC)

International Bioethics Education and Career Development

Award Program, 91

See also National Institutes of Health (NIH)

Food and Drug Administration (FDA), 3, 23, 25, 36, 50, 80, 87, 93

drug development phases and, 21

ethics review of international clinical trial, requirements of, xii,

81, 82, 83, 84

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

protection of participants in U.S. government-sponsored 

international clinical trials, requirements of, NBAC 

recommendations, iii, 6

Foreign countries. See Developing countries; International research 

Fost, N.C., 39

France

international research activities of, 3

Law 88-1138 Regarding the Protection of Persons Agreeing to

Biomedical Research, 93 

protection of international research participants, documents

concerning, comparative analysis of, 100

Freedom of choice

inducement (undue) for research enrollment, definition and

concerns, 46–48

informed consent process involvement of community leaders,

issues, 42–44

informed consent process involvement of family members,

issues, 44–45

informed consent process involvement of others, issues, 42–45

voluntary informed consent and, issues, 45–48

women’s voluntary informed consent, issues, 45

FWA. See Federalwide Assurance (FWA)

FY 2001 Foreign Operations Appropriations Act. See Public Law

106-429 

G

Gambia

clinical trial, community education for informed consent, 41

Gates Foundation. See Bill and Melinda Gates Foundation

Germany

international research activities of, 3

Glantz, L.H., 67

Glaser Foundation. See Elizabeth Glaser Pediatric AIDS Foundation

Glaxo SmithKline Beecham, 73

Glaxo Wellcome, 73

Global AIDS and Tuberculosis Relief Act of 2000. See Public Law

106-264

Global Alliance for Vaccines and Immunization, 72

Global Fund for Children’s Vaccines, 73

Government funding for research. See Federal funding for research

H

Haemophilus influenzae type b, 4, 73

Haiti

established effective treatment, example of, 10

ethics review process in international research, comments on, 84

HIV vaccine trials, scientific information explanation for

informed consent, 41

informed consent documentation requirements, 49
National Bioethics Advisory Commission

127

Health and Human Services Department. See Department of Health

and Human Services (DHHS)

Health care

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

control groups of U.S. researchers in developing countries, 

ethical concerns, 26–28

design and routine care, relevance for participants in 

international clinical trials, iii–iv, 8–10, 20–29

disclosure requirements for control interventions in 

international clinical trials, cultural barriers, 39–40

established effective treatment for control groups in 

international clinical trials, iv, 9–10, 28 

established effective treatment vs. best current methods, for

international clinical trials, 28

HIV perinatal transmission, placebo-controlled trials in 

developing countries, controversy, 1, 2

host country needs, responsiveness of clinical trials in 

developing countries to, iii, 7–8

post-trial benefits for host country population, for international

research, NBAC recommendations, x, 74

post-trial benefits for international clinical trials, ethical issues,

viii–x, 12–13, 55–74

post-trial benefits for participants in international clinical trials,

justice as reciprocity and, 59–61

post-trial benefits, IAVI prior agreements for international

research, 66, 74, 104–106

post-trial benefits, obligations of public/private research 

sponsors, 64–65

post-trial benefits, obligations of researchers, 64

post-trial benefits, obligations to host community/country, 

ethical concerns, 61–64

post-trial benefits, obligations to participants, ethical concerns,

56–58

post-trial benefits, prior agreements for international research,

and breach of obligations potential, 72, 74

post-trial benefits, prior agreements for international research,

and creation of double standard, issues, 71–72 

post-trial benefits, prior agreements for international research,

and delay/prevention of research, 68

post-trial benefits, prior agreements for international research,

and prevailing international standard, issues, 70

post-trial benefits, prior agreements for international research,

discussion, 66–72, 74

post-trial benefits, prior agreements for international research,

funding/distribution problems, 67–69

post-trial benefits, prior agreements for international research,

health policy influence of, issues, 70–71

post-trial benefits, UNAIDS prior agreements for international

research, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for international

research, 66, 74, 106–108

post-trial benefits, WHO prior agreements for international

research, 66, 74, 103–104

post-trial obligations, and researcher-participant relationship,

ethical issues for, 58–59

post-trial treatment/benefits for participants in international

research, NBAC recommendations, x, 74

protection of participants in international research, documents

concerning, comparative analysis of, 100–101

standard of, for participants in international clinical trials, 9,

26–28

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

therapeutic misconception minimization, for participants in

international clinical trials, vii–viii, 48

See also Active treatment concurrent control; Health care costs;

Health policy; Placebo concurrent control

Health care costs

post-trial benefits for international research, prior agreements

for, funding issues for, 68–69

See also Health care

Health policy

prior agreements on post-trial benefits in international research,

unrealistic influence on, 70–71 

See also Health care; Health care costs; Public policy

Heavily Indebted Poor Countries, 73

Helsinki, Finland. See Declaration of Helsinki: Ethical Principles for

Medical Research Involving Human Subjects; Finland

Hippocratic oath, 58

HIV/AIDS. See Human immunodeficiency virus/acquired immune

deficiency syndrome (HIV/AIDS)

H.M.S. Salisbury, 23

HUGO. See Human Genome Organization (HUGO)

Human Genome Organization (HUGO)

Ethics Committee, 63, 70

Human Genome Project, 63

post-trial benefits access for international research participants,

provisions for, 63, 70

Statement on Benefit Sharing, 63, 70

Human immunodeficiency virus/acquired immune deficiency 

syndrome (HIV/AIDS)

maternal-to-infant transmission of, placebo-controlled trials in

developing countries, controversy, 1, 2

Thailand vaccines testing, prior agreement on post-trial benefits,

66, 106–108

vaccine development, IAVI prior agreements on post-trial 

benefits, 66, 74, 104–106

vaccine development, VaxGen prior agreements on post-trial

benefits, 66, 74, 106–108

vaccine initiatives timeline 2000–2001, 72–73

vaccine trials, 30, 41

Human participants. See Participants; Protections for human 

participants

Husbands. See Families; Marriage

Hyder, Adnan, 26, 27, 38, 41, 42, 47, 48, 50, 55, 57, 64, 66, 80,

82, 83, 85, 86, 89–90, 92
128

Index

I

IAVI. See International AIDS Vaccine Initiative (IAVI)

ICH. See International Conference on Harmonisation (ICH)

IDE. See Investigational device exemption (IDE)

Ijsselmuiden, C.B., 36

Illinois, 73

Immtech International, Inc., 73

INCLEN. See International Clinical Epidemiology Network

(INCLEN)

IND. See Investigational new drug (IND) application

Independent bodies

international research participants, assurance process for 

protection of, evaluation by, NBAC recommendations, xi, 80

India

AIDS vaccine development efforts, 106

Ethical Guidelines on Biomedical Research Involving Human

Subjects, 87, 93

Indian Council of Medical Research, 87, 93

international clinical trials, ethics review for, 82

international research ethics and voluntary informed consent,

11, 35

international research participants protection, documents 

concerning, comparative analysis of, 101

Inducement. See Coercion

Infants

Latin America Respiratory Distress Syndrome proposed study, 25

See also Maternity

Influence. See Coercion

Information

scientific/technical, explanation for informed consent, innovative

methods, 40–42

See also Disclosure of information; Informed consent

Informed consent

biomedical researchers in developing countries and U.S., ethical

issues for, NBAC survey, 4

community leaders involvement in process, cultural issues,

42–44

comprehension of, ensuring, for international clinical trials, 

vi, 42

cultural issues relating to process of, 40–45

cultural variations to process, for international clinical trials,

NBAC recommendations, viii, 50

documentation requirement for, discussion, 37, 38, 48–50

documentation requirement for, examples, 49

documents concerning protection of international research 

participants, comparative analysis of, 100–101

ethical issues for international research by U.S. researchers,

35–51

ethical standard of, definitions of, 36–38

family members role in process for international clinical trials,

vii, 44–45

others involvement in process for international clinical trials, 

vi, 42–45

post-trial benefits from international research, disclosure for,

NBAC recommendations, vi, 40

process of, discussion, 36, 37, 38

recruitment issues for international clinical trials, 10–12

scientific/technical information explanation for, innovative

methods, 40–42

substantive standard of, definition, 37–38

therapeutic misconception minimization, for participants in

international clinical trials, vii–viii, 48

Uganda involvement of others, new guidelines for, 44

voluntary, for participants in international clinical trials, v–vii,

11, 36–38

voluntary, role of others, for international clinical trials, vi–vii,

42–45

women, role of husband in process for international clinical trials, vii, 45 

See also Disclosure of information; Information

Institute of Human Virology, 105

Institutional Review Boards (IRBs), xiv, 6, 13, 19, 20, 24, 39, 41,

50, 65, 66, 92, 94

disclosure requirements for international clinical trials, and, 37

equal protection provision, for research participants in 

international clinical trials, role of, 87, 88, 89

ethics review for international clinical trials, U.S. procedures

concerning, 81, 82, 83, 84, 85

ethics review of U.S. government-sponsored clinical trials in

developing countries, requirements, xii, 83, 84

protection of participants in international research participants,

U.S. procedures concerning, 78, 79

registration process, for assurances protection of international

research participants, and proposed revisions 80, 81

See also Ethics review and review committees

International AIDS Vaccine Initiative (IAVI)

AIDS vaccine development efforts, 72, 73, 104–106

AIDS Vaccines for the World: Preparing Now to Assure Access, 106

international research, prior agreements for post-trial benefits

from, 66, 74, 104–106

Scientific Blueprint 2000: Accelerating Global Efforts in AIDS

Vaccine Development, 106

Scientific Blueprint for AIDS Vaccine Development, 104–105

Uganda research capacity building, efforts of, 91

International Clinical Epidemiology Network (INCLEN), 91

See also Rockefeller Foundation

International Conference on Harmonisation (ICH), 3, 24

Harmonised Tripartite Guideline, Guideline for Good Clinical

Practice (GCP), 36, 37, 38, 87, 88, 93

international research participants protection, documents 

concerning, comparative analysis of, 100

International Cooperative Project Assurance, 79

See also Assurances of compliance; Cooperative Project

Assurance (CPA); Office for Human Research Protections

(OHRP)
National Bioethics Advisory Commission

129

International Covenant on Civil and Political Rights, 35

International regulation

equal protection for research participants in international

research, DHHS provision for, explanation, xiii, 14, 85–89 

host country capacity for international research, variation in

U.S./international guidelines for building, 92, 93–94

host country review for international research, challenges to, 82 

post-trial obligations to international research participants,

existing guidelines, 56–58

protection of participants in international clinical trials, 

comparative analysis of relative documents, 99–101

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

International research

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

alternative therapies disclosure requirements, cultural barriers

to, 39–40

assurances of compliance, for protection of participants, xi, 14,

78–80

biomedical researchers in, ethical issues for, NBAC survey, 4

capacity building for host country, variation in U.S. international

guidelines for, 92, 93–94

capacity building for, need to, xiii–xiv, 14, 89–94

capacity building for, strategies for, NBAC recommendations,

xiv, 91, 94 

clinical trials in developing countries, ethical issues for, 3–4

clinical trials in developing countries, reasons for, 6–7 

clinical trials in developing countries, recruitment issues, 10–12

control groups treatment in developing countries, ethical 

concerns for, 26–28 

design for protection of participants in, iii–iv, 8–10, 20–29

design issues for repeating trials, 31–32

design/implementation, community involvement in, for, iv–v,

30–31

disclosure requirements for, cultural barriers to, 38–40

efficacy (optimal care) vs. effectiveness, distinction, 28–29

equivalent protections for participants in, procedures for, xiii,

14, 85–89

established effective treatment for control groups in, iv, 

9–10, 28

ethical concerns for, papers commissioned on, 117

ethical concerns for, public comments on, 111–113

ethical concerns for, testimony, public/expert on, 115

ethical conduct of, requirements for, NBAC recommendations

on, 5–6

ethics review by host country for, challenges to, 82

ethics review for protection of participants, requirements,

xi–xii, 13–14, 81–85

financial support for costs of ethical review of, requirements,

NBAC recommendations, xiii, 85

health needs of host country, responsiveness of clinical trials in

developing countries to, iii, 7–8 

HIV perinatal transmission, placebo-controlled trials in 

developing countries, controversy, 1, 2

inducement (undue) for enrollment in, definition/concerns,

46–47

informed consent in, ensuring comprehension, NBAC 

recommendations, vi, 42

informed consent process, cultural variations for, NBAC 

recommendations, viii, 50

informed consent role of family members for, vii, 44–45

informed consent role of others for, NBAC recommendations,

vi, 43

informed consent, disclosure requirements for participants in,

NBAC recommendations, v–vi, 37, 40

multiple ethics review for international research, issues, 82–85 

participants fair/respectful treatment in, v–vii, 10–12

participants in, ethical requirements for, 5–6

participants standard of care in, 9, 26–28

post-trial benefits for host country in, NBAC recommendations,

x, 74

post-trial benefits for host country, prior agreements for, NBAC

recommendations, x, 74

post-trial benefits for others in, ethical issues, x, 12–13

post-trial benefits for participants in, NBAC recommendations,

x, 74

post-trial benefits, and researcher-participant relationship, 

ethical issues, 58–59

post-trial benefits, disclosure in informed consent documents

for, NBAC recommendations, vi, 40

post-trial benefits, IAVI prior agreements for, 66, 74, 104–106

post-trial benefits, in, ethical issues, viii–x, 12–13, 55–74

post-trial benefits, obligations of public/private research 

sponsors, 64–65

post-trial benefits, obligations of researchers, 64

post-trial benefits, obligations to host country of, ethical 

concerns, 61–64

post-trial benefits, obligations to participants in, concerns,

56–58

post-trial benefits, prior agreements on, and breach of 

obligations potential, 72, 74

post-trial benefits, prior agreements on, and creation of double

standard, issues, 71–72 

post-trial benefits, prior agreements on, and delay/prevention of

research, 68

post-trial benefits, prior agreements on, and funding/distribution problems, 67–69

post-trial benefits, prior agreements on, and health policy influence, issues, 70–71

post-trial benefits, prior agreements on, and prevailing international standard, issues, 70

post-trial benefits, prior agreements on, discussion of, 66–72,

74, 103–108

post-trial benefits, UNAIDS prior agreements for, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for, 66, 74,

106–108

post-trial benefits, WHO prior agreements for, 66, 74, 103–104

post-trial treatment for participants, justice as reciprocity and,

59–61

protection of participants in, ethical requirements, ii–iii, 5–6
130

Index

protection of participants in, mechanisms for, xi–xiv, 13–14,

78–89

resources (funding) support for ethics review of, xiii, 85

risk disclosure requirements for, cultural barriers to, 38–39 

Single Project Assurances for protection of participants in, 

criticisms of, 79–80

standard of care for participants in, 9, 26–28

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

therapeutic misconception minimization, for participants in,

vii–viii, 48

voluntary consent process for, role of others, vi–vii, 42–45

voluntary consent process for, v–vii, 11, 36–38

voluntary informed consent for, ethical issues, 35

voluntary participation and undue inducement for, involvement

of community leaders, NBAC recommendations, vi, 44

women’s informed consent for, role of husband in, vii, 45

See also Research

Interventions. See Health care

Investigational device exemption (IDE), 82, 83

Investigational new drug (IND) application, 82, 83

IRBs. See Institutional Review Boards (IRBs)

J

Japan

international research activities of, 3

Johns Hopkins University, 4

School of Hygiene and Public Health, 40–41

Joint United Nations Programme on HIV/AIDS (UNAIDS), 73, 107

Community Involvement and Impact, 30

Ethical Considerations in HIV Preventive Vaccine Research, 8, 14,

57, 93

Ethical Review Committee, 30

Guidance Document for Preventive HIV/AIDS Vaccine Trials, 

62, 68, 70, 74, 90, 92

HIV vaccine research in developing countries, capacity building

mechanisms for, listing, 90

post-trial benefits for international research, prior agreements

for, 66, 74, 108

protection of international research participants, documents

concerning, comparative analysis of, 100

See also United Nations (UN)

Justice

distributive, ethical obligation for international clinical trials,

summary, 77

fairness principle, and post-trial obligations to host community/

country, ethical concerns, 61–64

reciprocity principle in clinical trials, and participants post-trial

access to benefits, 59–61

K

Kass, Nancy, 26, 27, 38, 41, 42, 47, 48, 50, 55, 57, 64, 66, 80, 82,

83, 85, 86, 89–90, 92

Kenya

Nairobi, AIDS vaccine development efforts, 105

Trypanosomiasis Research Institute, 73

See also University of Nairobi

Kerry, John, 72

L

Languages

Creole, informed consent for international research, form in, 41

English, informed consent for international research, form in, 41

French, informed consent for international research, form in, 41

translation of scientific/technical aspects of research protocols

for informed consent, innovative methods, 41

Latin America

informed consent documentation requirements, issues, 49–50

placebo vs. established effective treatment in proposed study,

ethical concerns, 25

Leach, Jim, 72

Lesotho

UNAIDS prior agreement for post-trial benefits in, 108 

Lind, James, 23

London School of Hygiene and Tropical Medicine, 73 

See also United Kingdom

Loue, Sana, 44, 92

Love, R.R., 39

M

Mali

informed consent process involvement of community leaders,

issues for, 43

Malawi

informed consent documentation requirements, 49

informed consent process involvement of community leaders,

issues for, 43

malaria drugs clinical trials, 43, 49, 62

Ministry of Health, 62

Malenga, Grace, 49, 62

Maternity

HIV perinatal transmission, placebo-controlled trials in 

developing countries, controversy, 1, 2

See also Infants; Women

Marriage

husbands involvement in informed consent of women, for

international clinical trials, vii, 45

See also Families
National Bioethics Advisory Commission

131

Marshall, Patricia, 40, 41, 44, 49, 84, 85

Maryland. See University of Maryland

Medicaid, 71

Medical costs. See Health care costs

Medical interventions/treatment. See Health care 

Medicare, 55

Merck, 72, 73

Millennium Vaccine Initiative, 72

MPAs. See Multiple Project Assurances (MPAs)

Multiple Project Assurances (MPAs), 79, 80, 89

See also Assurances of compliance; Office for Human Research

Protections (OHRP)

N

National Bioethics Advisory Commission (NBAC), i, 3, 9, 10, 11,

13, 14, 15, 19, 24, 26, 32, 36, 37, 39, 41, 46, 47, 49, 51, 55, 56,

57, 60, 61, 62, 63, 64, 65, 67, 68, 70, 71, 77, 78, 81, 82, 86, 87,

88, 92

assurance process for protecting international research 

participants, recommendations, xi, 80

biomedical researchers in developing countries and U.S., 

ethical issues for, survey, 4

capacity building for design/review/conduct of clinical trials by

developing countries, strategies for, recommendations, xiv, 91

capacity building for international research, for ethics 

review committees in developing countries, assistance for, 

recommendations, xiv, 94

design/conduct of international clinical trials, ethical concerns,

recommendations, iv, 20, 28, 30–31

design/implementation of international clinical trials, 

involvement of community, recommendations, v, 30–31

equivalent protections for participants in international research,

determination of, recommendations, xiii, 89

established effective treatment for control groups in international

clinical trials, recommendations, iv, 28

ethics review of U.S. government-sponsored clinical trials in

developing countries, requirements, recommendations, xii, 83

financial support for costs of ethical review of research in 

developing countries, requirements, recommendations, xiii, 85

health needs of host country, responsiveness of clinical trials in

developing countries, iii, 8

host country capacity building, for international research,

review of U.S./international guidelines on, 93

inducement (undue) and voluntary participation in international clinical trials, involvement of community leaders, vi, 44

informed consent for participants in U.S. governmentsponsored international clinical trials, recommendations, iii, 6

informed consent process for international clinical trials, 

cultural variations for, recommendations, viii, 50

informed consent process for international clinical trials, 

disclosure requirements, recommendations, vi, 40

informed consent process for international clinical trials, 

ensuring comprehension for, recommendations, vi, 42

informed consent process for international clinical trials,

involvement of family members, recommendations, vii, 45

informed consent process for international clinical trials,

involvement of community leaders, recommendations, vi, 42,

43, 44

informed consent process for international clinical trials,

involvement of others, recommendations, vi, 43, 44, 45

post-trial benefits for host country from international research,

recommendations, x, 74

post-trial benefits for host country from international research,

prior agreements on, recommendations, x, 74

post-trial benefits from international research, disclosure in

informed consent documents, recommendations, vi, 40

post-trial benefits/treatment for participants in international

research, recommendations, x, 74

protections for participants in U.S. government-sponsored

international clinical trials, recommendations, ii–iii, 6

risk minimization, for participants in U.S. governmentsponsored international clinical trials, recommendations, iii, xii,

6, 84

scientific/technical aspects of research protocols, explanation for

informed consent, innovative methods, recommendations, 42

therapeutic misconception minimization, for participants in

international clinical trials, recommendations, viii, 48

voluntary informed consent for participants in international

clinical trials, recommendations, v, 38

women’s informed consent process for international clinical 

trials, role of husband, recommendations, vii, 45

National Commission. See National Commission for the Protection

of Human Subjects of Biomedical and Behavioral Research

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research, 63, 80

Belmont Report: Ethical Principles and Guidelines for the Protection

of Human Subjects of Research, ii, 5, 10, 27, 62–63, 80

National Consensus Conference on Bioethics and Health Research

in Uganda, 44

National Institutes of Health (NIH), viii, 2, 7, 50, 85, 91

See also Fogarty International Center (FIC)

NBAC. See National Bioethics Advisory Commission (NBAC)

Netherlands

AIDS vaccine development funding for IAVI, 106

informed consent documentation requirements, issues, 49–50

international research activities of, 3

protection of international research participants, documents

concerning, comparative analysis of, 101

Law Regarding Medical-Scientific Research on Humans, 93

New Zealand

HRC Guidelines on Ethics in Health Research, 93

international clinical trials, ethics review for, 82

international research participants protection, documents concerning, comparative analysis of, 101

NGOs. See Nongovernmental organizations (NGOs)

Nigeria

informed consent documentation requirements, 49

informed consent involvement of women’s husbands, issues 

for, 44
132

Index

Lagos, ethics review committees, comments on, 84

research disclosure requirements, cultural barriers to, 39 

scientific/technical information explanation for informed 

consent, translation for, 41

NIH. See National Institutes of Health (NIH)

Nongovernmental organizations (NGOs), 7, 69, 72

North Carolina, 105

See also Chapel Hill, North Carolina; University of North

Carolina

Nuffield Council on Bioethics, 90

Nuremberg Code, v, 11, 93

international research participants protection, documents 

concerning, comparative analysis of, 100

O

Obligations

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

clinical trial participants and, ethical considerations, 20

post-trial benefits for host community/country of international

research, ethical concerns, 61–64

post-trial benefits for international research participants, ethical

concerns, 55–74

post-trial benefits in international research, and researcherparticipant relationship, ethical concerns, 58–59

post-trial benefits in international research, prior agreements

for, and delay/prevention of research, 68

post-trial benefits in international research, prior agreements

for, and prevailing international standard, 70

post-trial benefits in international research, prior agreements

for, discussion of, 66–72, 74, 104–106

post-trial benefits in international research, prior agreements

for, double standard creation, 71–72 

post-trial benefits in international research, prior agreements

for, potential breach of, 72, 74

post-trial benefits in international research, prior agreements

for, health policy influence of, issues, 70–71

post-trial benefits in international research, prior agreements

for, funding/distribution problems for, 67–69

post-trial benefits in international research, public/private

research sponsors and, 64–65

post-trial benefits in international research, researchers and, 64

post-trial treatment for international research participants, 

justice as reciprocity and, 59–61

protection of participants in international research, comparison

of documents concerning, 100–101

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

Office for Human Research Protections (OHRP), 81

assurance system for protection of international research 

participants, current practices of, 79, 80

assurance system for protection of international research 

participants, proposed revisions of, 80

equal protection provision, for international research 

participants, implementation by, xiii, 14, 85, 87–89

See also Cooperative Project Assurance (CPA); International

Cooperative Project Assurance; Multiple Project Assurances

(MPAs); Office for Protection from Research Risks (OPRR);

Single Project Assurances (SPAs)

Office for Protection from Research Risks (OPRR), xiii, 14, 79, 84,

87, 88

See also National Institutes of Health (NIH); Office for Human

Research Protections (OHRP)

Ohio. See Columbus, Ohio

OHRP. See Office for Human Research Protections (OHRP)

Okello, D., 44

OPRR. See Office for Protection from Research Risks (OPRR)

Oversight. See Federal regulation; International regulation

Oxford University. See University of Oxford

P

Pape, Jean, 41, 42, 49, 84

Papers commissioned

international clinical trials, protection of participants, ethical

concerns, 117

Participants. See Protections for human participants

Pelosi, Nancy, 72

P.L. 106-264. See Public Law 106-264

P.L. 106-429. See Public Law 106-429

Placebo concurrent control

active treatment concurrent control vs., ethical concerns, 25

explanation of, 23–26

Latin America proposed study use, ethical concerns, 25

See also Clinical trials; Control groups; Placebos

Placebos

effect, explanation of, 23–24

HIV perinatal transmission, controversial trials in developing

countries, 1, 2

See also Drugs and drug testing; Placebo concurrent control

Plowe, Christopher, 62

Policy. See Health policy; Public policy

Positive control. See Active treatment concurrent control

Presidential Advisory Council on HIV/AIDS, 73

Prevailing standards. See Standards

Prior agreements

AIDS vaccines development, post-trial benefits and, 66

IAVI, for post-trial benefits in international research, 

description, 66, 74, 104–106

post-trial benefits access to others in international research, 

ethical issues, x, 12

post-trial benefits for host country population in international

research, and, NBAC recommendations, x, 74

post-trial benefits in international research and, discussion,

66–72, 74, 104–108
National Bioethics Advisory Commission

133

post-trial benefits in international research and, double 

standard creation, issues, 71–72 

post-trial benefits in international research and, funding/

distribution problems, 67–69

post-trial benefits in international research and, health policy

influence, issues, 70–71

post-trial benefits in international research and, potential

breach of obligations, 72, 74

post-trial benefits in international research and, prevailing 

international standard and, issues, 70

post-trial benefits in international research and, research

delay/prevention and, 68

Thailand AIDS vaccines testing, and post-trial benefits, 66,

106–108

UNAIDS, for post-trial benefits in international research,

description, 66, 74, 108 

VaxGen, for post-trial benefits in international research,

description, 66, 74, 106–108

WHO, for post-trial benefits in international research, 

description, 66, 74, 103–104

Privacy and confidentiality

protection of participants in international research, comparison

of documents concerning, 100–101

Private sector

post-trial obligations of international research sponsors from,

64–65

Protections for human participants

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

assurances of compliance, for international clinical trials, 

xi, 14, 78–80

biomedical researchers in, ethical issues for, NBAC survey, 4

clinical trials in developing countries and, mechanisms for,

xi–xiv, 13–14, 78–89

clinical trials in developing countries and, U.S./international

policy/regulatory issues, 14

clinical trials in developing countries sponsored by U.S. 

government, and, NBAC recommendations, ii–iii, 6

clinical trials in developing countries, ethical requirements for,

ii–iii, 5–6

clinical trials in developing countries, recruitment issues, 10–12

control groups treatment in developing countries, ethical 

concerns for, 26–28 

design and routine care for, in international clinical trials, iii–iv,

8–9, 20–29

design involvement of, for international clinical trials, 30–31

equivalent protections for, procedures for, xiii, 14, 85–89

ethical concerns for, papers commissioned on, 117

ethical concerns for, public comments on, 111–113

ethical concerns for, testimony, public/expert on, 115

ethics review by host country for, challenges to, 82

ethics review for protection of participants, requirements,

xi–xii, 13–14, 81–85

existential loss of, in international research, 58–59 

fair/respectful treatment of, in international clinical trials, 

v–vii, 10–12

HIV perinatal transmission, placebo-controlled trials in 

developing countries, controversy, 1, 2

inducement (undue) for enrollment in, definition/concerns,

46–47

informed consent process for international research, cultural

variations for, NBAC recommendations, viii, 50

informed consent process for international research, ensuring

comprehension, NBAC recommendations, vi, 42

informed consent process for international research, role of

family members for, vii, 44–45

informed consent process for international research, role of 

others for, NBAC recommendations, vi, 43

informed consent, disclosure requirements for international

research, cultural barriers to, 38–40

informed consent, disclosure requirements for international

research, NBAC recommendations, v–vi, 37, 40

international documents concerning, comparative analysis of,

99–101

multiple ethics review for international clinical trials, issues 

for, 82–85

post-trial benefits for host country in, NBAC recommendations,

x, 74

post-trial benefits for host country population, for international

research, NBAC recommendations, x, 74

post-trial benefits, IAVI prior agreements for, 66, 74, 104–106

post-trial benefits, in international research, ethical issues,

viii–x, 12–13, 55–74

post-trial benefits, obligations of public/private research 

sponsors, 64–65

post-trial benefits, obligations of researchers, 64

post-trial benefits, prior agreements for international research,

and breach of obligations potential, 72, 74

post-trial benefits, prior agreements for international research,

and creation of double standard, issues, 71–72 

post-trial benefits, prior agreements for international research,

and delay/prevention of research, 68

post-trial benefits, prior agreements for international research,

and funding/distribution problems, 67–69

post-trial benefits, prior agreements for international research,

and health policy influence, issues, 70–71

post-trial benefits, prior agreements for international research,

and prevailing international standard, issues, 70

post-trial benefits, prior agreements for international research,

discussion of, 66–72, 74, 103–108

post-trial benefits, UNAIDS prior agreements for, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for, 66, 74,

106–108

post-trial benefits, WHO prior agreements for, 66, 74, 103–104

post-trial obligations to, ethical concerns, 56–58

post-trial obligations to, relationship with researcher and, 

ethical issues, 58–59

post-trial treatment for participants, justice as reciprocity and,

59–61

post-trial treatment/benefits for participants in international

research, NBAC recommendations, x, 74

Single Project Assurances for, criticisms of for research in 

developing countries, 79–80
134

Index

standard of care for, in international clinical trials, 9, 26–28

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

therapeutic misconception minimization, for international 

clinical trials, vii–viii, 48

voluntary consent, concerns for, 45–48

voluntary informed consent for international clinical trials,

v–vii, 11, 36–38

voluntary participation and undue inducement for, involvement

of community leaders, NBAC recommendations, vi, 44

women’s informed consent for international clinical trials, role

of husband in, vii, 45 

See also Research

Public comments

international clinical trials, protection of participants, ethical

issues, 111–113

See also Testimony and speakers

Public Health Service Act, 81, 91

Public Law 106-264, 73

Public Law 106-429, 73, 106

Public policy

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

See also Federal government; Federal regulation; Health policy

Public testimony. See Testimony and speakers

R

Randomization

clinical trials, and, 22, 23

clinical trials, and disclosure requirements, cultural barriers to, 39

See also Clinical trials; Research design

RDS. See Respiratory Distress Syndrome (RDS)

Reciprocity

justice as, and participants access to post-trial treatment in

international research, 59–61

Recommendations

assurance process for protecting international research 

participants, xi, 80

capacity for international research, for ethics review committees

in developing countries, assistance for building, xiv, 94

capacity of developing countries to design/review/conduct 

clinical trials, strategies for building, xiv, 91

design/conduct of international clinical trials, ethical concerns,

iv, 20, 28, 30–31

design/implementation of international clinical trials, 

involvement of community, v, 30–31

disclosure for informed consent of participants in international

clinical trials, vi, 40

equivalent protections for participants in international research,

determination of, xiii, 89

established effective treatment for control groups in international

clinical trials, iv, 28

ethics review of U.S. government-sponsored clinical trials in

developing countries, requirements, xii, 83

financial support for costs of ethical review of research in 

developing countries, requirements, xiii, 85

health needs of host country, responsiveness of clinical trials in

developing countries, iii, 8

inducement (undue) and voluntary participation in international

clinical trials, involvement of community leaders, vi, 44

informed consent for participants in U.S. government-sponsored

international clinical trials, iii, 6

informed consent in international clinical trials, ensuring 

comprehension for, vi, 42

informed consent process for international clinical trials,

involvement of family members, vii, 45

informed consent process for international clinical trials,

involvement of community leaders, vi, 42, 43, 44

informed consent process for international clinical trials,

involvement of others, vi, 43, 44, 45

informed consent process, cultural variations for international

clinical trials, viii, 50

post-trial benefits for host country from international research,

x, 74

post-trial benefits for host country from international research,

prior agreements on, x, 74

post-trial benefits from international research, disclosure in

informed consent documents, vi, 40

post-trial benefits/treatment for participants in international

research, x, 74

protections for participants in U.S. government-sponsored

international clinical trials, ii–iii, 6

risk minimization, for participants in U.S. government-sponsored

international clinical trials, iii, xii, 6, 84

scientific/technical aspects of research protocols, explanation for

informed consent, innovative methods, 42

therapeutic misconception minimization, for participants in

international clinical trials, viii, 48

voluntary informed consent for participants in international

clinical trials, v, 38

women’s informed consent process for international clinical 

trials, role of others, 45

women’s informed consent process for international clinical 

trials, role of husband, vii, 45

Regulation. See Federal government; Federal regulation;

International regulation

Relationships. See Families; Marriage

Relatives. See Families; Marriage

Research

inducement (undue) for participation in, definition and 

concerns, 46–48

informed consent disclosure requirements, description, 37

therapeutic misconception of, minimization of, 48

voluntary participation in, concerns for, 45–48

See also Clinical trials; International research; Protections 

for human participants; Research design; Research funding;

Research involving developing countries; Research regulation;

Science and technology
National Bioethics Advisory Commission

135

Research design

capacity of developing countries to design/review/conduct clinical

trials, strategies for building, NBAC recommendations, xiv, 91

clinical trials, chief considerations for, 20

community involvement in, for international clinical trials, iv–v,

30–31

community/participants involvement in, for international 

clinical trials, v, 30–31

ethical concerns for international clinical trials, 19–32

host country health needs, responsiveness of clinical trials in

developing countries, NBAC recommendations, iii, 8

information disclosure for informed consent of participants in

international clinical trials, NBAC recommendations, vi, 40

medical treatment for participants in clinical trials in developing

countries, ethical concerns, 26–28

participants protection in international clinical trials, NBAC 

recommendations, iv, 20

participants routine care in international clinical trials, and,

iii–iv, 8–9, 20–29

repeating study in developing country, issues for international

research, 31–32

results (interim), monitoring issues for international research, 31

sample size determination for international critical trials, 29

See also Equipoise; Randomization; Research

Research funding

capacity of developing countries to design/review/conduct clinical

trials, strategies for building, NBAC recommendations, xiv, 91

post-trial obligations of public/private sponsors of international

clinical trials, 64–65

resources support for ethics review of international clinical 

trials, xiii, 85

See also Federal funding for research; Research

Research involving developing countries

AIDS vaccines development, prior agreements on post-trial 

benefits, 66

assurances of compliance, for protection of international

research participants, xi, 14, 78–80

biomedical researchers in, ethical issues for, NBAC survey, 4

capacity building for host country, for international clinical 

trials, variation in U.S./international guidelines for, 92, 93–94

capacity building for international clinical trials, need to,

xiii–xiv, 14, 89–94

capacity building for international clinical trials, strategies for,

NBAC recommendations, xiv, 91, 94 

clinical trials conducted in, reasons for, 6–7

control groups treatment in international clinical trials, ethical

concerns for, 26–28

design for protection of participants in international clinical 

trials, iii–iv, 8–9, 20–29

design issues for repeating clinical trials, 31–32

design/implementation, community involvement in, for 

international clinical trials, iv–v, 30–31

efficacy (optimal care) vs. effectiveness trials, distinction, 28–29

equivalent protections for research participants in, procedures

for, xiii, 14, 85–89

established effective treatment for control groups in international

clinical trials, iv, 9–10, 28

ethical concerns for, papers commissioned on, 117

ethical concerns for, public comments on, 111–113

ethical concerns for, testimony, public/expert on, 115

ethical issues for clinical trials conducted in, 3–4

ethics review by host country for international research, 

challenges to, 82

ethics review for protection of participants in international 

clinical trials, requirements, xi–xii, 13–14, 81–85

financial support for costs of ethical review of, requirements,

NBAC recommendations, xiii, 85

health needs of host country, responsiveness of international

clinical trials, iii, 7–8 

HIV perinatal transmission, placebo-controlled trials in, 

controversy, 1, 2

informed consent in international clinical trials, ensuring 

comprehension, NBAC recommendations, vi, 42

informed consent process, cultural variations for international

clinical trials, NBAC recommendations, viii, 50

informed consent role of family members for international 

clinical trials, vii, 44–45

informed consent role of others for international clinical trials,

NBAC recommendations, vi, 43

informed consent, disclosure requirements for participants in

international clinical trials, NBAC recommendations, v–vi, 37, 40

multiple ethics review for international clinical trials, issues,

82–85

participants fair/respectful treatment in international clinical 

trials, v–vii, 10–12

participants in international clinical trials, ethical requirements

for, 5–6

participants standard of care in international clinical trials, 

9, 26–28

post-trial benefits for host country in international research,

NBAC recommendations, x, 74

post-trial benefits for host country, prior agreements for 

international research, NBAC recommendations, x, 74

post-trial benefits for others in international research, ethical

issues, x, 12–13

post-trial benefits for participants in international research,

NBAC recommendations, x, 74

post-trial benefits, and researcher-participant relationship, 

ethical issues, 58–59

post-trial benefits, disclosure in informed consent documents

for, NBAC recommendations, vi, 40

post-trial benefits, IAVI prior agreements for international 

clinical trials, 66, 74, 104–106

post-trial benefits, in international research, ethical issues,

viii–x, 12–13, 55–74

post-trial benefits, obligations of public/private research 

sponsors, 64–65

post-trial benefits, obligations of researchers, 64

post-trial benefits, obligations to host country of international

clinical trials, ethical concerns, 61–64

post-trial benefits, obligations to participants in international

clinical trials, concerns, 56–58
136

Index

post-trial benefits, prior agreements for, summary of, 103–108

post-trial benefits, prior agreements on international research,

discussion, 66–72, 74

post-trial benefits, prior agreements on, and breach of obligations

potential, 72, 74

post-trial benefits, prior agreements on, and creation of double

standard, issues, 71–72 

post-trial benefits, prior agreements on, and delay/prevention of

research, 68

post-trial benefits, prior agreements on, and funding/distribution

problems, 67–69

post-trial benefits, prior agreements on, and health policy 

influence, issues, 70–71

post-trial benefits, prior agreements on, and prevailing 

international standard, issues, 70

post-trial benefits, UNAIDS prior agreements for international

clinical trials, 66, 74, 108 

post-trial benefits, VaxGen prior agreements for international

clinical trials, 66, 74, 106–108

post-trial benefits, WHO prior agreements for international

clinical trials, 66, 74, 103–104

post-trial treatment for research participants, justice as 

reciprocity and, 59–61

protection of participants in international clinical trials, ethical

requirements, ii–iii, 5–6

protection of participants in international clinical trials, 

mechanisms for, xi–xiv, 13–14, 78–89

recruitment issues for international clinical trials, 10–12

resources (funding) support for ethics review of international

clinical trials, xiii, 85

Single Project Assurances for protection of research participants

in, criticisms of, 79–80

Thailand AIDS vaccines testing, prior agreement on post-trial

benefits, 66

therapeutic misconception minimization, for participants in

international clinical trials, vii–viii, 48

voluntary consent process for international clinical trials, v–vii,

11, 36–38

voluntary consent process, role of others, for international 

clinical trials, vi–vii, 42–45

voluntary informed consent, ethical issues, 35

voluntary participation and undue inducement for, involvement

of community leaders, NBAC recommendations, vi, 44

women’s informed consent, role of husband in international

clinical trials, vii, 45

See also Research

Research regulations

equal protection for participants in international research, 

provision of DHHS, explanation, xiii, 14, 85–89

ethics review for protection of participants in international 

clinical trials, U.S. procedures, 81–85

host country capacity for international research, variation in

U.S./international guidelines for, 92, 93–94

protection of participants in international clinical trials, 

challenges to host country review, 82

protection of participants in international clinical trials,

U.S./international policy/regulatory issues, 14

protection of participants in international clinical trials, 

U.S. procedures for, 78–89

See also Research

Respiratory Distress Syndrome (RDS)

Latin America infants proposed study using placebo vs. 

established effective treatment, 25

See also Diseases and disorders

Review bodies. See Ethics review and review committees;

Institutional Review Boards (IRBs)

Risk

disclosure requirements for clinical trials, cultural barriers to,

38–39

disclosure requirements for participants informed consent, in

international clinical trials, v–vi, 37, 40

minimization of, for participants in U.S. government-sponsored

clinical trials, NBAC recommendations, iii, 6

Roche, 73

Rockefeller Foundation, 91

See also International Clinical Epidemiology Network (INCLEN)

S

Safeguards. See Protections for human participants

Salmonella bacteria, 105

Scandinavia

international research activities of, 3

Science and technology

information, explanation for informed consent in international

clinical trials, innovative methods, 40–42

Seattle, Washington, 105

Senegal

literacy rates, summary, 41

scientific/technical information explanation for research study, 41

Single Project Assurances (SPAs), 79, 80

criticisms of, for research in developing countries, 79–80

See also Assurances of compliance; Office for Human Research

Protections (OHRP)

Sommer, Alfred, 40–41

South Africa

AIDS vaccine development efforts, 105, 106

Guidelines on Ethics for Medical Research, 90, 93

Medical Research Council, 105

National Institute of Virology, 105

post-trial benefits access for international research participants,

guidelines for, 57

protection of participants in international research, comparative

analysis of documents concerning, 101

UNAIDS prior agreement for post-trial benefits in, 108 

See also University of Capetown

SPAs. See Single Project Assurances (SPAs)
National Bioethics Advisory Commission

137

Standards

double, prior agreements for post-trial benefits in international

research, and creation of, issues, 71–72

health care, for participants in international clinical trials,

explanation of, 9

prevailing, prior agreements for post-trial benefits in international

research, problems, 70–71

protection of participants in international research, documents

concerning, comparative analysis of, 100–101

Statistics. See Randomization

Struck, D., 108

Substantive standard of informed consent. See Informed consent

Sugarman, Jeremy, 38, 49

Surveys and questionnaires

biomedical researchers in developing countries and U.S., ethical

issues for, 4, 20, 26, 27, 55, 56, 57, 64, 80, 82, 83, 85, 86,

89–90, 92

Switzerland

informed consent documentation requirements for international

research, issues, 49–50

T

Tanzania

National Institute for Medical Research, 73

Targeted Genetics Corporation (TGC), 105

Technology. See Science and technology

Testimony and speakers

international clinical trials, protection of participants in, ethical

concerns, 115

See also Public comments

TGC. See Targeted Genetics Corporation (TGC)

Thailand

AIDS Call to Action project in, 73

AIDS vaccine research, prior agreements on post-trial benefits,

66, 106–108

Bangkok, 107, 108

Bangkok Metropolitan Association, 107

female condom research, UNAIDS prior agreement for post-trial

benefits, 108 

HIV perinatal transmission, placebo-controlled trials in, 

controversy, 1, 2

Mahidol University, 107

Ministry of Public Health, 107

protection of participants in international research, documents

concerning, comparative analysis of, 101

Rule of the Medical Council on the Observance of Medical Ethics, 93

Senate, 108

voluntary informed consent and international research ethics,

11, 35

Therapeutic misconception

minimization of, for participants in international clinical trials,

vii–viii, 48

Translation. See Languages

Treatment. See Active treatment concurrent control; Health care

Trials. See Clinical trials

U

Uganda

AIDS vaccine development efforts, 105

capacity building efforts for international research in, 91, 93

Guidelines for the Conduct of Health Research Involving Human

Subjects in Uganda, 44, 49, 57, 62, 93

informed consent documentation requirements, 49

informed consent process involvement of others, new guidelines

for, 44

Ministry of Health, 91

Ministry of Justice, 93

National Council of Science and Technology, 93

National Drug Authority, 93

post-trial obligations to international research participants,

guidelines for, 57, 70

protection of international research participants, documents

concerning, comparative analysis of, 101

voluntary informed consent and ethics in international research,

11, 35

UN. See United Nations (UN)

UNAIDS. See Joint United Nations Programme on HIV/AIDS

(UNAIDS)

Undue influence. See Coercion 

United Kingdom

AIDS vaccine development funding for IAVI, 106

Guidelines for Good Clinical Practice in Clinical Trials, 93

Interim Guidelines for Research Involving Human Participants 

in Developing Societies: Ethical Guidelines for MRC-Sponsored

Studies, 57, 93

international clinical trials, ethics review for, 82

international research activities of, 3

Medical Research Council (MRC), 48, 57

post-trial obligations to international research participants,

guidelines for, 57, 70

protection of international research participants, documents

concerning, comparative analysis of, 101

See also London School of Hygiene and Tropical Medicine;

University of Oxford

United Nations (UN), 103, 104

See also Joint United Nations Programme on HIV/AIDS

(UNAIDS); United Nations Children’s Fund; United Nations

Population Fund

United Nations Children’s Fund, 73

See also United Nations (UN)

United Nations Population Fund, 73

See also United Nations (UN)

United Nations Programme on HIV/AIDS. See Joint United Nations

Programme on HIV/AIDS (UNAIDS)
138

Index

Universal Declaration of Human Rights, 10

Universities

See also Cornell University; Johns Hopkins University; London

School of Hygiene and Tropical Medicine; University of

Capetown; University of Maryland; University of Nairobi;

University of North Carolina; University of Oxford; Vanderbilt

University

University of Capetown, 105

See also South Africa

University of Maryland

Biotechnology Institute, 91

University of Nairobi, 105

See also Kenya

University of North Carolina, 73

See also North Carolina

University of Oxford, 105

See also United Kingdom

USAID. See Agency for International Development (USAID)

U.S. Congress, 72

House of Representatives, 73

Senate, 73

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

Vaccines and vaccination

AIDS/HIV, development, and prior agreements on post-trial

benefits, 66, 74

AIDS/HIV, development, IAVI prior agreements on post-trial

benefits, 66, 74, 104–106

AIDS/HIV, development, VaxGen prior agreements on post-trial

benefits, 66, 74, 106–108

AIDS/HIV, trials for, 30, 41

Haemophilus influenzae type b, trial for, 41

initiatives timeline 2000–2001, 72–73

Thailand AIDS/HIV vaccine research, prior agreements on 

post-trial benefits, 66, 106–108

See also Drugs and drug testing

Vanderbilt University, 41

VaxGen

international research, and prior agreements for post-trial 

benefits, 66, 74, 106–108

Thailand AIDS/HIV vaccine research, prior agreements on 

post-trial benefits, 66, 74, 106–108

Vietnam

alternative therapies disclosure requirements for clinical trials,

cultural barriers to, 39–40

Voluntary consent. See Coercion; Informed consent

W

Washington. See Seattle, Washington; Washington, D.C.

Washington, D.C., 84

Washington Post, 107

Wellcome Trust Research Laboratories, 73

White House, 72

WHO. See World Health Organization (WHO)

WMA. See World Medical Association (WMA)

Women

condom (female), international research on, prior agreement

for, 108 

informed consent for international clinical trials, role of 

husband, vii, 45

informed consent for international clinical trials, role of others

in, cultural issues, 45

See also Maternity

World Bank, 72, 105

World Bank AIDS Trust Fund, 73

World Health Organization (WHO), 3, 73, 85, 107

Compound for Distribution in both Public and Private 

Sectors, 104

Guidelines on Interaction with Commercial Enterprises, 103

Memorandum of Understanding (MOU), 103–104

Operational Guidelines for Ethics Committees That Review

Biomedical Research, 62, 70, 92

Policy on Patents: Information Paper on WHO Patents Policy, 103

post-trial benefits for international research, prior agreements

for, 66, 74, 103–104

World Medical Assembly Declaration, 86

World Medical Association (WMA), 3, 8, 36, 56, 80

See also Declaration of Helsinki: Ethical Principles for Medical

Research Involving Human Subjects

Z

Zambia

international research, UNAIDS prior agreement for post-trial

benefits in, 108 

Zimbabwe

international research, UNAIDS prior agreement for post-trial

benefits in, 108 
ISBN 1-931022-13-5