Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

JUNE GIBBS BROWN 

Inspector General 

APRIL 2000 

OEI-01-97-00197 

Protecting Human Research Subjects 

Status of Recommendations 
OFFICE OF INSPECTOR GENERAL 

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, is to 

protect the integrity of the Department of Health and Human Services programs as well as the 

health and welfare of beneficiaries served by them. This statutory mission is carried out through a 

nationwide program of audits, investigations, inspections, sanctions, and fraud alerts. The 

Inspector General informs the Secretary of program and management problems and recommends 

legislative, regulatory, and operational approaches to correct them. 

Office of Evaluation and Inspections 

The Office of Evaluation and Inspections (OEI) is one of several components of the Office of 

Inspector General. It conducts short-term management and program evaluations (called 

inspections) that focus on issues of concern to the Department, the Congress, and the public. The 

inspection reports provide findings and recommendations on the efficiency, vulnerability, and 

effectiveness of departmental programs. 

OEI's Boston regional office prepared this report under the direction of Mark R. Yessian, Ph.D., 

Regional Inspector General. Principal OEI staff included: 

REGION HEADQUARTERS 

Nancy London, Lead Analyst Elise Stein, Program Specialist

Aimee Kasenga, Program Analyst

Laura McBride, Program Analyst

Nicola Pinson, Program Analyst

To obtain copies of this report, please call the Boston Regional Office at (617) 565-1050. 

Reports are also available on the World Wide Web at our home page address: 

http://www.dhhs.gov/progorg/oei 
EXECUTIVE SUMMARY 

PURPOSE 

To provide an update of National Institutes of Health (NIH) and Food and Drug 

Administration (FDA) responses to recommendations we directed to them in a June 1998 

report entitled, Institutional Review Boards: A Time for Reform. 

BACKGROUND 

Our June 1998 Report on Institutional Review Boards 

Institutional review boards (IRBs) play a central role in providing human-subject 

protections. In our June 1998 report, we warned that the effectiveness of these boards 

was in jeopardy and presented numerous recommendations to NIH, its Office for 

Protection from Research Risks (OPRR), and FDA. In our call for widespread reform, we 

conveyed a sense of urgency, one that was reinforced by one of our prior inquiries. In that 

inquiry we discovered disturbing inadequacies in IRB oversight of clinical trials involving 

investigational medical devices. 

Subsequent Actions 

Since the issuance of our report, human subject protections have received considerable 

attention within the Department and at the national level. Congress has held two hearings 

addressing how the effectiveness of IRBs can be improved. The National Bioethics 

Advisory Commission (NBAC) has continued its deliberations on what reforms should be 

undertaken. The Secretary of Health and Human Services (HHS) has decided to relocate 

OPRR to the Office of the Secretary and to establish an advisory committee to provide 

scientific and ethical guidance to OPRR. Both NIH and FDA have been engaged in 

multiple efforts to address how human subject protections can be enhanced. With the 

death of a teenager participating in a gene transfer clinical trial funded by NIH, they have 

given particular attention to ways of improving the oversight of such trials. 

This Follow-up Report 

In this report, we provide an accounting of how fully our prior recommendations have 

been enacted. We do that because they have attracted substantial attention and because 

we believe they remain timely. In providing this update, we draw on information obtained 

over the past two years from HHS officials and from pertinent HHS documents. This 

report is deliberately limited in scope. It does not represent a further examination of the 

adequacy of the Federal oversight of human subject protections or of the protections 

themselves. It accepts as a starting point our prior recommendations and seeks to provide 

an accounting of how fully they have been carried out. 

Protecting Subjects: Status of Recommendations 1 OEI-01-97-00197 
UPDATE 

Since June 1998, there has been a substantial increase in the enforcement of 

Federal human-subject protection requirements. 

Investigations. Between April 1997 and May 1998, NIH/OPRR had conducted an onsite investigation at only 1 institution. Between June 1998 and March 2000, it conducted 

on-site investigations at 10 institutions. FDA’s number of routine on-site investigations of 

IRBs increased from 213 in Fiscal Year 1997, to 253 in FY 1998, and 336 in FY 1999. 

Sentinel Effect. OPRR’s reviews, which have occurred at major medical centers and 

have resulted in the suspension of federally funded research at 7 institutions, have been 

particularly influential in drawing attention of the national research community to the 

adequacy of IRB oversight and human-subject protections. 

Several promising steps have been taken. 

NIH and FDA have enacted two of our recommendations. NIH now requires data and 

safety monitoring boards to share summary information with IRBs and FDA now informs 

sponsors and IRBs about its findings of clinical investigator misconduct. 

In addition, both agencies have ongoing initiatives, particularly in the area of education. 

NIH and FDA continue to be active in educational outreach and programs, conducting 

numerous training presentations and seminars. OPRR hired a full-time educational staff 

person and is in the process of further expanding its educational staff. FDA convened a 

national meeting addressing current issues in human subject protections and has had 

numerous workgroups examining specific issues. NIH, also, has constructed a website 

containing bioethics resources. 

But overall, few of our recommended reforms have been enacted. 

Flexibility and Accountability. Minimal progress had been made in recasting Federal 

IRB requirements so that they grant IRBs greater flexibility and hold them more 

accountable for results. Too much IRB attention now focuses on review responsibilities 

of questionable protective value. 

Oversight and Protections. Minimal progress has been made in strengthening continuing 

protections for human subjects participating in research. Continuing IRB review of 

research after it has been initially reviewed is a low priority at many IRBs. IRBs know 

little of what actually occurs during the consent and research processes. 

Education. No educational requirements have been enacted for investigators or IRB 

members. The most important continuing protection for human subjects is the presence of 

well-trained and sensitized investigators and IRB members. 

Protecting Subjects: Status of Recommendations 2 OEI-01-97-00197 
Conflicts of Interest. There has been no progress in insulating IRBs from conflicts that 

can compromise their mission in protecting human subjects. The increased 

commercialization of research and the growing importance of research revenues for 

institutions heightens the potential for conflicts of interest in clinical research. 

Workload. Minimal progress has been made in moderating workload pressures of IRBs. 

IRBs are inundated with protocols and adverse event reports. With limited personnel and 

few resources, many IRBs are hard-pressed to give each review sufficient attention. 

Federal Oversight. Minimal progress has been made in reengineering the Federal 

oversight process. Federal oversight of IRBs is not equipped to respond effectively to the 

changing pressures and needs of the current system of protections. 

For a complete accounting of our prior recommendations and any Federal responses to 

them, see text beginning on page 9 and appendix C. 

The Common Rule represents a significant barrier to HHS progress in 

implementing many of our recommendations. 

In 1991, the HHS core regulations concerning IRBs and human-subject protections 

became the basis of a common Federal policy on human-subject protections. Known as 

the Common Rule, this policy is adhered to by HHS and 16 other Federal agencies. Any 

changes to the Rule call for the concurrence of all 17 agencies. 

Many of our recommendations call for changes in the Common Rule. NIH has 

emphasized to us that it cannot make those changes without the consent of the other 

agencies and that such a process is a long, complex one with uncertain results. We have 

to recognize that its observation is well-based. 

The goal of a common Federal rule is an important one. It can foster a level of 

consistency in protecting human subjects and make it easier for researchers and sponsors 

to understand and comply with regulations. Yet, we must acknowledge that the reality of 

gaining concurrence among 17 Federal agencies inhibits a timely response to many of our 

recommendations and to the rapidly changing developments in the clinical research 

environment. In view of this reality, legislative change may well be necessary to achieve a 

timely implementation of many of our recommendations. 

LOOKING AHEAD 

Gene Transfer as a Catalyst 

The recent national attention given to gene transfer trials has raised the public’s awareness 

of the risks that can be associated with clinical research and has prompted several 

important initiatives by NIH and FDA. One is a new requirement calling for study 

Protecting Subjects: Status of Recommendations 3 OEI-01-97-00197 
sponsors to submit to FDA monitoring plans for gene transfer trials; another is a series of 

symposia that will be held on the directions and safety of such trials. 

These initiatives may prove to be quite helpful, but they apply only to gene transfer 

research trials. We urge that these initiatives serve as a catalyst for improving humansubject protections for the broad universe of clinical trials, particularly those in which 

patients face significant risks. 

Our prior inquiry convinced us that often too much is expected of IRBs and that IRBs 

alone can not provide a sufficient degree of protection. That is why we gave so much 

attention to Federal actions that could be taken to help educate investigators about 

human-subject protections. It is why we have called in a subsequent report for the 

development of stronger guidelines on human-subject recruitment practices. And, it is 

why we drew attention to the vital roles that, for example, the Data and Safety Monitoring 

Boards can play particularly for trials that pose significant risks to patients. 

New Opportunity for Leadership 

Once OPRR is located in the Office of the Secretary and a new advisory committee on 

protection from research risks is established, as the HHS Secretary has called for, HHS 

will have a significant new opportunity to exert Federal leadership in protecting human 

subjects. 

We urge that the new office give significant attention to our prior recommendations and to 

those that will be forthcoming from NBAC. We also urge that it continue the important 

enforcement efforts undertaken by OPRR over the past 2 years. In increasingly 

commercialized research environments where IRBs are facing heightened pressures to 

conduct quicker reviews, the NIH/OPRR efforts have served as a reminder to research 

institutions, sponsors, individual investigators, and IRBs that the reviews must still be 

substantive ones that ensure adequate protections for human subjects. They must not only 

protect subjects from unnecessary physical harm, but must ensure that the informed 

consent process is one that fosters understanding and voluntary participation. 

Protecting Subjects: Status of Recommendations 4 OEI-01-97-00197 
TABLE OF CONTENTS 

Page

EXECUTIVE SUMMARY .................................................... 1

INTRODUCTION .......................................................... 6

Primer on HHS Oversight Roles and Competencies ........................... 8

UPDATE 

Increased enforcement of subject protections ................................. 9

Promising steps, but few recommendations enacted ........................... 11

The Common Rule is a barrier to progress .................................. 17

LOOKING AHEAD ........................................................ 18

APPENDICES 

A: Institutional Review Boards: The Basics ................................. 20

B: Findings from Institutional Review Boards: A Time for Reform ............... 22

C: Current Status of FDA and NIH/OPRR Response ......................... 24

D: Endnotes ........................................................ 25

Protecting Subjects: Status of Recommendations 5 OEI-01-97-00197 
INTRODUCTION 

PURPOSE 

To provide an update of National Institutes of Health (NIH) and Food and Drug 

Administration (FDA) responses to recommendations we directed to them in a June 1998 

report entitled, Institutional Review Boards: A Time for Reform. 

BACKGROUND 

Our June 1998 Report on Institutional Review Boards 

Institutional review boards (IRBs) play central roles in protecting human subjects enrolled 

in clinical research. In a June 1998 report, which was based on more than a year of 

extensive inquiry, we found that the effectiveness of IRBs was in jeopardy. While we did 

not claim there were widespread abuses of human research subjects, we did warn that the 

capacity of IRBs to accomplish all that is expected of them is strained. We conveyed a 

sense of urgency that was buttressed by earlier findings by a Presidential advisory body, by 

the General Accounting Office, and by one of our own prior inquiries.1 In that inquiry we 

examined clinical trials involving four investigational medical devices and in each case 

discovered disturbing inadequacies related to IRB oversight. 

In our June 1998 report, we presented six sets of recommendations. We directed them 

jointly to the two entities within the Department of Health and Human Services (HHS) 

that are responsible for IRB oversight: NIH, through its Office of Protections from 

Research Risks (OPRR), and the FDA (for a primer on HHS oversight roles, see page 8). 

In the formal comments they offered on our recommendations, both NIH and FDA 

expressed a number of reservations. But overall their reactions were quite positive. NIH 

responded as follows: “Twenty-four years after the initial promulgation of our 

Department’s rules for protection of human subjects, your summary of the challenges 

today facing IRBs, and your recommendations for DHHS oversight, form important 

additions to the evolving body of analysis of our system of protecting human subjects in 

research.” Similarly, FDA indicated that the reports “highlight and add support to a 

number of areas where we believe change may be needed.” 

Subsequent Actions 

In response to the substantial interest in the report, we have discussed its findings and 

recommendations in many different settings. We testified at two congressional hearings 

on IRBs, one held just as the report was issued in June 1998 and the other in December 

1999.2 We gave a presentation before the committee responsible for the uniform 

implementation of the common human subject protection regulations across 17 Federal 

Protecting Subjects: Status of Recommendations 6 OEI-01-97-00197 
agencies (including HHS) and gave speeches and participated in panel discussions at the

meetings of many professional associations.3

During the period from June 1998 to the present, the topic of protecting research subjects

gained considerable prominence within the Department. Of particular note was the July

1999 decision by the HHS Secretary to relocate OPRR from NIH to the 

Office of the Secretary and to establish a new advisory committee on protection from

research risks to provide scientific and ethical guidance to the office. These actions, not

yet completed, were taken to strengthen the stature and effectiveness of OPRR in its

oversight role.

At the same time, both NIH and FDA have been actively addressing human subject

protections. NIH has been giving particular attention to ways of reducing the regulatory

burden for IRBs and research institutions. FDA, in March 1999, convened a national

meeting addressing current issues in human subject protections and has had numerous

workgroups examining specific issues. Both NIH and FDA officials have been

participating in private sector efforts intended to develop mechanisms for accrediting

human subject protection programs. With the September 1999 death of an 18-year-old

participating in a gene transfer trial, both agencies have also been examining ways in which

they might improve their oversight of such trials.

This Follow-up Report 

In this report, we provide an update on the implementation of the recommendations we 

offered in our June 1998 report. We do that because 2 years have passed since we first 

made the recommendations, because they have drawn considerable interest in 

congressional hearings and many other forums, and because they remain relevant to 

current, heightened concerns about human subject protections. In appendix C, we list all 

of the recommendations we made in June 1998 and indicate their state of implementation. 

This report is deliberately limited in scope. It does not represent a further examination of 

the adequacy of the Federal oversight of human subject protections or of the protections 

themselves. It accepts as a starting point our prior recommendations and seeks to provide 

an accounting of how fully they have been carried out. In that context, it does address 

some related actions that have been taken, but does not purport to be a full accounting of 

all HHS actions that are relevant to human subject protections. We recognize that our 

recommendations address complex issues which can take some time to implement. But in 

this brief report, we seek to simply and clearly address what has and has not changed. 

In providing this update, we have drawn on information obtained over the past two years 

from pertinent HHS documents, from interviews with NIH, FDA, and other HHS officials, 

and data reported to us by NIH and FDA. We have also drawn on their comments on a 

prior working draft of this report. We have sought to make our accounting as 

straightforward, accurate, and nonjudgmental as possible. But we recognize that others 

may offer different interpretations of the significance of actual actions and of the state of 

progress in implementing our recommendations. 

Protecting Subjects: Status of Recommendations 7 OEI-01-97-00197 
HHS Oversight Roles and Competencies 

Delineation of HHS Authority and Activity 

Agency Purview Primary Body 

for Protections 

Oversight Conducted 

NIH/OPRR research supported or otherwise 

subject to regulation by HHS 

IRBs assurance, inspections of IRBs 

FDA research conducted on products 

subject to FDA approval 

IRBs inspections of investigators, 

IRBs, and research sponsors 

The Office for Protection from Research Risks (OPRR) within the NIH, acts as the primary 

body for human-subjects research oversight and guidance for the Department. HHS/NIH 

regulations were established in 1974 and in 1991 became the basis for the Common Rule for 

17 Federal Departments and agencies. The FDA established another set of regulations in 1981 

which were later harmonized, to the largest extent possible, to conform to the Common Rule in 

1991. The two sets of regulations are distinct, but very similar. The most significant 

distinction between the agencies is their purview. 

Delegation of Responsibility 

The focus of both regulations is to require the review of human research by an institutional 

review board. Institutional review boards (IRBs) are committees of scientists and lay people, 

independent of the research being conducted, who review and approve the research. As part of 

their review, boards approve the research before it can begin, provide ongoing review of 

amendments and adverse event reports, and conduct continuing reviews at least annually. 

IRBs seek to ensure adequate protections are in place and that subjects are given the 

opportunity for informed consent. For further explanation of the roles and responsibilities of 

IRBs, see appendix A. 

Oversight 

Despite the primary role of IRBs, both FDA and OPRR are responsible for subject protections

and IRB oversight. 

OPRR’s primary mechanism of oversight is the assurance process. Institutions wishing to

conduct human-subjects research under OPRR jurisdiction must appoint an IRB of record by

applying for and receiving an assurance from OPRR. The assurance is a document that states

the institution’s commitment to uphold human-subject protection regulations and their policies

and procedures for meeting the regulations. Institutions must renew their assurance every 5

years, after an initial period of 3 years. OPRR also conducts a limited number of IRB

inspections. Their reviews are primarily based on complaints or concerns about compliance. 

Spontaneous reviews are rare. 

FDA conducts inspections of clinical investigators, research sponsors, and IRBs. FDA

generally inspects investigators through its bioresearch monitoring program when the

investigators’ research is associated with a product approval application. FDA also inspects

investigators during the conduct of research when a for-cause inspection is warranted. 

Protecting Subjects: Status of Recommendations 8 OEI-01-97-00197 
<

UPDATE 

Since June 1998, there has been a substantial increase in the 

enforcement of Federal human-subject protection 

requirements. 

Within HHS, the increase in enforcement activity is the most significant action that has 

been taken to foster human-subject protections since the issuance of our report. The 

increased enforcement responds to the sense of urgency that we presented in our prior 

report and more specifically responds to our call for a greater on-site focus addressing the 

performance of IRBs. 

OPRR and FDA have stepped up their on-site presence at research institutions. 

< Between April 1997 and May 1998, OPRR had conducted an on-site investigation 

at only 1 institution. Between June 1998 and March 2000, it conducted on-site 

investigations at 10 institutions. 

Since June 1998, OPRR also conducted off-site investigations (document reviews) at 

more than 140 additional institutions. It found performance problems at a number of 

institutions it investigated and has required 7 of them to suspend some or all of their 

federally funded research. 

In letters to research institutions where OPRR found weaknesses in the institutions’ 

systems of protections, it cited institutions for substantive, broad-based deficiencies— 

ones that have direct consequences on the rights and safety of research subjects. For 

instance, in one case OPRR found that the IRB failed to review a research protocol’s 

recruitment procedures, including a document that discussed how to persuade reluctant 

potential subjects to enroll in the study. Some of the potential subjects from this study 

were recontacted so many times after refusing to participate that they filed a complaint, 

which led to the OPRR investigation 

< FDA’s number of routine on-site investigations of IRBs increased from 213 in 

Fiscal Year 1997, to 253 in FY 1998, and 336 in FY 1999. 

FDA’s Center for Devices and Radiological Health, for example, issued eight warning 

letters to IRBs during FY 1999, compared to zero in FY 1998. The Center for Drug 

Evaluation and Research took administrative action against eight IRBs during FY 1998 

and 1999. 

FDA’s presence in reviewing IRB practices remains much more direct and extensive than 

Protecting Subjects: Status of Recommendations 9 OEI-01-97-00197 
that of NIH/OPRR. The strong enforcement capability of FDA is especially important as 

FDA is the primary Federal on-site presence at most research sites outside of academic 

medical centers, where an increasing proportion of research takes place. 

OPRR’s oversight activities have been particularly influential in drawing attention 

to the adequacy of IRB oversight and human-subject protections throughout the 

research community. 

With OPRR’s reviews occurring at major medical centers and in 7 cases actually resulting 

in a temporary suspension of federally funded research those centers, they have had the 

strongest sentinel effect. Although we can not determine precisely how fully the research 

community has responded to OPRR’s recent actions, the fact that many major medical 

journals and newspapers gave prominent attention to OPRR’s enforcement actions [see 

box] suggests that these actions are being widely noted. 

Some recent 

professional 

conferences also 

reflected a growing 

sense that Federal 

enforcement activities 

are being taken 

seriously by research 

institutions, 

investigators, and 

IRBs. The 1999 

annual meeting of 

Public Responsibility 

in Medicine and 

Research (PRIM&R) 

drew 1,300 attendees 

compared with about 

900 the year before, 

and its first panel 

session included a 

presentation by the 

director of research 

affairs from RushPresbyterian Medical 

Center, an institution 

NIH/OPRR Puts the Research Community on Notice 

“A virtually unknown federal agency with only 31 employees is 

sending shock waves through the nation’s billion-dollar clinicalresearch community.” Physician’s Weekly, July 19, 1999 

“OPRR has put every federally funded U.S. research institution on 

notice that its right to conduct clinical research could be summarily 

yanked.” Science, May 21, 1999 

“But even as business goes back to normal at the prestigious medical 

center...new questions arose about the safety of human subjects at other 

institutions around the country.” The Washington Post, May 5, 1999 

“Across the country, university administrators and researchers are 

worried, even panicked that the same thing could happen at their 

institutions with millions of dollars of research funds from the National 

Institutes of Health and pharmaceutical companies at stake.” 

Chronicle of Higher Education, February 4, 2000 

“OPRR is moving with new aggressiveness to monitor IRB 

performance.” New York Times, May 25, 1999 

“Recent suspensions indicate to some that NIH/OPRR is more 

aggressively enforcing the federal protections for human subjects” 

American Medical News, November 1, 1999 

that OPRR had visited. The presentation was entitled: “Learning from Recent Compliance 

Hot Spots: The Top Ten Compliance Problems and How to Avoid Them.” The 1999 

annual meeting of the Applied Research Ethics National Association, which immediately 

preceded the PRIM&R meeting, featured a presentation by an ethicist from Duke entitled, 

“The Duke University Experience: What Lessons Can IRBs Learn?” 

Protecting Subjects: Status of Recommendations 10 OEI-01-97-00197 
Finally, the opening panel of a recent national conference on legal issues affecting 

academic medical centers, sponsored by the American Health Lawyers Association, was 

entitled, “Clinical Research: Staying Out of Trouble With the Regulators.” 

Several promising steps have been taken. But overall, few of 

our recommended reforms have been enacted. 

In the following text, we provide a brief synopsis of our prior six recommendations and a 

more detailed description of Federal actions taken, if any, since the release of the report. 

Minimal progress in recasting Federal IRB requirements so that they grant IRBs 

greater flexibility and hold them more accountable for results. 

Prior Recommendations: 

< Eliminate or lessen specific procedural requirements that are of questionable value. Our aim was to 

provide overburdened IRBs with greater discretion that would enable them to develop more innovative and 

strategic approaches to their reviews. There are requirements, for example, that limit what IRBs can 

accomplish in conducting protocol reviews outside of convened board meetings. In addition, we 

highlighted requirements that call for IRBs to conduct full, annual reviews of approved protocols and that 

call for complete reviews of Federal funding applications prior to funding decisions. 

< Require that IRBs undergo regular performance-focused evaluations that are carried out in accordance 

with Federal guidelines. In our review, we were struck by how little attention Federal oversight bodies and 

IRBs themselves gave to evaluating how successful IRBs were in protecting human subjects. It is time, we 

concluded, for the Federal government to mandate self-evaluations or, better yet, evaluations conducted by 

independent, outside parties. We also urged that the results of such evaluations be made public. 

Update: While some deliberations have been taking place, there have been few enacted 

reforms along the lines we recommended. The most tangible action was a November 1998 

Federal Register notice issued jointly by FDA and NIH/OPRR that expands the categories 

of research that may be reviewed by IRBs through an expedited review procedure.4 This 

change, already in process before our report was issued, does help minimize IRB 

workload, but is only one small step toward that end. 

The NIH established the Regulatory Burden Advisory Group to identify burdensome 

procedural requirements and make recommendations on steps to help streamline the 

regulatory processes for grantee institutions. Among its recommendations, the group 

proposed a change to the requirement that IRBs review all protocols before funding 

decisions are made, an improvement we suggested. NIH indicates this change is about to 

be implemented. Also, NIH/OPRR has been working with the National Cancer Institute 

to develop a pilot project to establish a central IRB that for certain trials would take on 

the review functions previously carried out by separate IRBs and streamline the process. 

Protecting Subjects: Status of Recommendations 11 OEI-01-97-00197 
We identified no significant movement in the Federal sector in response to our call for 

performance evaluations. The most notable development in this regard is in the private 

sector, where some momentum has been established in developing a system for 

accreditation of human research protection programs. PRIM&R, a private group devoted 

to the ethical conduct of research, is working to develop performance standards and apply 

them as part of an accreditation process. Both NIH/OPRR and FDA are participating in 

these discussions. We believe that this movement toward accreditation and certification 

has significant potential for improving human subject protections and urge both 

NIH/OPRR and FDA to pay particular attention to how it might best complement their 

continuing oversight responsibilities. 

Minimal progress in strengthening continuing protections for human subjects 

participating in research. 

Prior Recommendations: 

< Require Data Safety Monitoring Boards (DSMBs) for certain high-risk and multi-site trials. DSMBs are 

independent assessment bodies that provide medical, scientific and other expertise that typically is not 

available on IRBs, thereby serving an invaluable function in protecting human subjects. We recommended 

that NIH and FDA take the lead in seeing that DSMBs become more firmly established as oversight 

mechanisms and become more clearly accountable. 

< Require DSMBs to provide summary information to IRBs. We urged that DSMBs provide their 

summary assessments of adverse event reports to IRBs. IRBs are swamped with individual adverse event 

reports from multi-site trials, but these reports lack the essential context to confer meaning about the 

relative safety of the trial. DSMBs can provide this context and thereby enhance the IRB’s capacity to 

assess the ongoing safety of a trial. 

< Alert IRBs to corrective actions taken against investigators under the board’s purview. Although FDA 

provides information on its website about corrective actions that result from investigator inspections, the 

Agency does not routinely inform the respective IRBs of such actions. We recommended that FDA inform 

individual IRBs when it takes corrective action against an investigator who is conducting research 

reviewed by the IRB. 

< Require sponsors and investigators to notify IRBs of any prior IRB review of a research plan. 

Sometimes sponsors shop around for an IRB that will give their protocol a favorable review. We pointed 

out that such action can undermine the IRB review process and, accordingly, urged that this requirement 

be enacted. 

< Call for increased IRB awareness of on-site research practices involving human subjects. IRBs are 

rarely aware of what actually takes place between investigator and subject. We called for IRBs to move 

beyond their focus on the informed consent document and periodically check for themselves how the actual 

consent process is working. For particularly sensitive or risky projects, we suggested they might call for 

the participation of counselors, ombudsmen, or other third parties that could be available to make certain 

that the consent process functions in the interest of human subjects. 

Update: For the most part, little has been done to strengthen continuing protections of 

clinical research subjects. Neither NIH nor FDA has issued requirements for sponsors to 

notify IRBs of prior reviews, nor have they issued guidance to IRBs to increase their 

attention to on-site research practices. FDA has not set forth regulations mandating 

Protecting Subjects: Status of Recommendations 12 OEI-01-97-00197 
DSMBs in trials, beyond those for emergency research, or setting standards for the 

composition of DSMBs, nor has it required that existing DSMBs provide their 

assessments to the respective IRBs.5 Ongoing concern about continuing protections was 

recently reinforced by the Chairman of the President’s National Bioethics Advisory 

Commission (NBAC). Upon hearing testimony of NIH and FDA witnesses at a NBAC 

hearing, he responded, “One problem we have heard again and again is that, once an 

experiment is approved, there is a failure to follow what’s going on with the patients. I 

think there is a growing consensus that something must be done.”6 

Some promising action has been taken. When FDA finds evidence of misconduct on the 

part of clinical investigators, as of October 1998, FDA now informs the sponsors and 

IRBs associated with that investigator. In June 1998, NIH reaffirmed its policy that all 

NIH-supported or -conducted trials “should have a system for the appropriate oversight 

and monitoring of the conduct of clinical trials.”7 For example, phase III trials are 

required to have DSMBs and most involve site monitoring as part of the quality assurance 

program of the funding Institute or Center. More directly related to our 

recommendations, in June 1999, NIH issued a policy stating that all DSMBs associated 

with NIH trials are expected to forward summary reports of adverse events to IRBs.8 

This is a significant development because this summary information is key to an IRB’s 

ability to ensure the continued safety of subjects. 

In March 2000, FDA and NIH announced an initiative that could have important 

implications for the continuing review of gene transfer trials.9 Among other things, FDA 

will require sponsors of gene transfer trials to routinely submit their monitoring plans to 

FDA. FDA will review the plans, seek changes it deems necessary, and will perform 

surveillance and for-cause inspections of the trials to ensure that proper monitoring is 

taking place. This is an important response to the concerns that have been raised about 

the adequacy of the oversight of gene transfer trials. FDA’s Center for Devices and 

Radiological Health also requires sponsors of its trials to routinely submit monitoring 

plans. But both of these policies do not address a large majority of clinical trials, outside 

of gene transfer or device trials, in which patients can face significant risk. We continue to 

urge FDA and NIH take similar initiatives directed at other research areas. 

Protecting Subjects: Status of Recommendations 13 OEI-01-97-00197 
No educational requirements have been enacted for investigators or IRB 

members. 

Prior Recommendations: 

< Require institutions to establish an education program for investigators in human-subject protections. 

Such a requirement exists for research involving animal subjects. We found the case for education 

requirements no less compelling for research involving humans. The mandatory education we called for 

could be provided through media such as seminars, individual instruction, videos, or on-line tutorials. 

< Require investigators receiving funding under the Public Health Service Act for research involving 

human subjects to provide a written attestation indicating that they will uphold Federal policies 

concerning human-subject protections. We recommended such an attestation as a way of heightening 

investigators’ awareness of their responsibilities as investigators and interest in participating in educational 

programs addressing human-subject protections. 

< Require IRBs to educate their members about human-subject protections. In order for IRBs to 

adequately review research protocols to ensure human-subject protections, each board member must be 

educated in both applicable Federal regulations and ethical principles. We called for a specific mandate 

that IRBs and their parent institutions provide initial and continuing education. 

Update: These recommendations draw on similar ones made in 1995 by the Commission 

on Research Integrity and, in part, parallel existing NIH policy for institutional recipients 

of research training grants.10 No Federal regulations have been enacted requiring 

institutions to establish education programs for clinical investigators. Similarly, no Federal 

requirements have been enacted calling for education for IRB members. 

NIH intramural researchers are required to complete a web-based tutorial in order to 

conduct human-subjects research on campus.11 We urge NIH to consider expanding this 

policy to all extramural researchers, who conduct the majority of research funded by NIH. 

In responses to inspection findings, NIH/OPRR and FDA have called upon institutions to 

establish education programs for clinical investigators, IRB members, and IRB staff. 

Implicit in these actions is the recognition that an adequate system of protections requires 

the sensitivity and understanding of everyone involved in human-subject research. Also 

noteworthy is that a number of institutions have taken important initiatives of their own to 

strengthen educational efforts.12 

Both NIH and FDA have increased their activity in educational outreach, conducting 

numerous training presentations and seminars for IRBs and professional groups. NIH has 

constructed a website containing bioethics resources and has launched important new 

initiatives, through training grants, that seek to involve a wide array of investigators in 

education on human subjects issues and bioethics.13 FDA is in the process of updating its 

Information Sheets, an important source of IRB guidance. NIH/OPRR hired a full-time 

educational staff person in January 1999, and is in the process of further expanding this 

staff. 

Protecting Subjects: Status of Recommendations 14 OEI-01-97-00197 
No progress in insulating IRBs from conflicts that can compromise their mission 

in protecting human subjects. 

Prior Recommendations: 

< Require more extensive representation on IRBs of nonscientific and noninstitutional members. At 

present just one IRB member can wear both of these hats and satisfy the requirement. We found that to be 

an untenable situation, one that can deprive IRBs of a valuable counterbalance to internal, institutional 

pressures that can threaten their independence. 

< Reinforce to IRBs and their parent institutions the importance of IRBs maintaining sufficient 

independence. It is particularly important that IRBs not report to a part of an institution responsible for 

bringing in research funds. 

< Prohibit equity owners from participating in the IRB review process. Such a practice does not 

necessarily inhibit the independence of the review process, but it establishes a situation that can undermine 

a perception of impartiality. We recommended that it should be disallowed. 

Update: We did not identify any significant action in HHS that moves in the directions 

we called for above. We continue to regard this as a significant area warranting attention. 

In this increasingly commercialized research environment, the potential for conflicts within 

research institutions loom larger than ever. The gene transfer trials that have gained so 

much attention in recent months help reinforce the importance of such attention. In some 

of these trials, the investigators may also have financial investments in the products they 

are testing. This makes it ever more important that IRB reviews be sufficiently 

independent, both in reality and in appearance. 

Minimal progress in moderating workload pressures of IRBs. 

Prior Recommendations: 

< Require that IRBs have access to sufficient resources to adequately carry out their duties. Our 

recommendation was directed not only to staff and board member resources, but also to space, computers, 

and other essential elements. We urged OPRR to hold institutions accountable for the resource 

commitments they made in their assurances and for FDA to modify its site visit protocol so that it could 

more readily identify situations where resource shortages jeopardize an IRB’s ability to oversee research. 

Update: OPRR’s enforcement efforts have brought attention to IRB resource shortages 

at individual institutions and have led to additional support for IRB functions at a number 

of those institutions—and quite likely at others that have taken note of the OPRR efforts. 

However, no further action has been taken to develop indicators of adequate resource 

levels or to enable greater investments to support IRB functions. One approach that 

warrants more attention, and that NIH reports is under consideration, would be to allow 

an additional increment of grant funds to institutions to be used to provide necessary 

resources for IRBs. Such an approach could help reinforce to institutions and 

investigators that a well-supported IRB is a necessary cost of doing business. 

Protecting Subjects: Status of Recommendations 15 OEI-01-97-00197 
Minimal progress in reengineering the Federal oversight process. 

Prior Recommendations: 

< Revamp the NIH/OPRR assurance process. NIH/OPRR’s oversight process has been concentrated on 

reviewing up-front assurances aimed at obtaining an institution’s commitment to adhere to Federal 

requirements. We found that assurance process to be paperwork-laden with little effect on IRB 

functioning. We urged that NIH/OPRR reorient the assurance process so that it rests on an institutional 

attestation to conform to Federal requirements, and then devote more NIH/OPRR resources to periodic 

performance-based reviews of institutions and their IRBs. 

< Revamp the FDA on-site inspection process. We recognized that FDA has a much greater on-site 

presence than NIH/OPRR, but urged that FDA transform its site visit protocol from a narrow compliance 

orientation to one that is much more performance-based. Such an approach would pay particular attention 

to how individuals were actually being approached about participating as human subjects and to how IRBs 

were making risk-benefit trade-offs. 

< Require IRBs to register with the Federal government. We found that one of the major impediments to 

Federal oversight of human-subjects research is that there is no complete registry of the IRBs reviewing 

this research. Such a registry would be invaluable for FDA and NIH/OPRR as it would allow them to 

target their oversight and communicate more effectively with IRBs. 

Update: OPRR’s and FDA’s response, as we have already indicated, has been quite 

significant in one sense. Since issuing our report, both bodies, have increased their 

enforcement efforts and in so doing have fostered compliance with Federal regulations. 

But neither FDA nor NIH/OPRR have to date enacted any significant revamping of their 

oversight processes as we have called for—even though they can initiate such reform 

without the constraints of the Common Rule as explained below. This is unfortunate 

because stepped up enforcement without a more efficient, performance-oriented 

enforcement process will still leave us with an oversight system that falls well short of its 

potential. 

While FDA has substantially increased its IRB inspections since the issuance of our report, 

it has not yet engineered any significant changes in its approach to these inspections. The 

inspections remain narrow and focused on compliance. We recognize the importance of 

ensuring compliance, but we continue to believe that FDA is losing a major opportunity by 

not injecting a more results-oriented focus to its inspections. As we indicated in our June 

1998 report, such a focus would involve paying particular attention to how individuals are 

actually being approached about participating as human subjects and to how IRBs are 

making continuing assessments of risk-benefit trade-offs. It might also involve some 

probing on how often potential subjects actually turn down requests to participate in 

research or on how much time they are given to deliberate about participation. 

NIH/OPRR reports that it has been developing plans to streamline the assurance process 

as we called for in our June 1998 report and in accord with a congressional directive to 

lessen the regulatory burden associated with extramural scientific research. But no actual 

Protecting Subjects: Status of Recommendations 16 OEI-01-97-00197 
change has taken place to date. When and if such change occurs, we continue to urge 

NIH/OPRR to heed our recommendation that some of the Federal resources freed up by 

the reform should be directed to periodic performance-oriented reviews of IRBs 

Finally, it is important to note that FDA has formed a working group to establish an IRB 

registration system. The working group has agreed upon specifications for this registry 

that reflect many of our suggestions. However, nothing has been implemented yet. We 

encourage the group to follow through with this effort. 

The Common Rule represents a significant barrier to HHS 

progress in implementing many of our recommendations. 

In 1991, the HHS core regulations concerning IRBs and human-subject protections 

became the basis of a common Federal policy on human-subject protections. The Federal 

policy, known as the Common Rule, is adhered to by HHS and 16 other Federal agencies. 

Any changes to the Rule call for the concurrence of all 17 Federal agencies. 

Several of our recommendations can be carried out through administrative changes, for 

example through contract and grant language. Many others are incorporated in the 

Common Rule. In reacting to our June 1998 report and to an earlier version of this 

report, NIH emphasized that it cannot unilaterally implement any of those 

recommendations that concern the Common Rule. It reminded us that a number of the 

changes we call for—for instance, more extensive representation on IRBs of nonscientific 

and noninstitutional members or stronger requirements on IRBs having sufficient 

independence—could not be carried out without the agreement of the other 16 agencies. 

It also made it clear that this was a long and complex process. NIH’s point, we have to 

recognize, is well-taken. 

The intention of having a common Federal policy on human subject protections is an 

important one. One set of standards fosters a level of consistency in protections of human 

subjects in many different areas of research and is easier for researchers and sponsors to 

understand and comply with. At the same time, we must acknowledge that the reality of 

gaining concurrence among 17 Federal agencies inhibits a timely and effective HHS 

response to a number of our recommendations. With the clinical research environment 

changing rapidly, we believe it is essential for the Federal policy and regulatory actions to 

keep pace. The current cumbersome process associated with changing the Common Rule 

seems to preclude that. It suggests that legislative change may be necessary to achieve a 

timely implementation of many of our recommendations. 

Protecting Subjects: Status of Recommendations 17 OEI-01-97-00197 
Looking Ahead 

Gene Transfer Research as a Catalyst 

The untimely death of the subject in a gene transfer trial has raised the public’s awareness 

of the risks that can be associated with clinical research and has spurred some important 

initiatives by NIH and FDA. These include: (1) a new requirement calling for study 

sponsors to submit to FDA monitoring plans for gene transfer trials and (2) a series of 

gene transfer safety symposia that will bring together, in public forums, leading experts to 

discuss the conduct and potential of this important research.14 These initiatives may prove 

to be quite helpful. But, they apply only to gene transfer trials. It is essential, we believe, 

for similar attention to be directed to ensuring human-subject protections for a broader 

universe of clinical trials, particularly those in which patients face significant risks. 

The Need for Additional Sources of Expertise 

Our June 1998 report focused on IRBs, but concluded with recommendations on a broad 

range of Federal actions that must be taken to protect human subjects. That is because 

our inquiry convinced us that IRBs alone can not do the job and that in various subtle 

ways IRBs are expected to carry too much of the burden. We ought not to allow the 

reform agenda to focus strictly on what can be done to buttress IRBs. That is why we 

give so much attention to Federal actions that can help educate investigators, who, while 

they are in a position to do the most harm to patients, are also in a position to do the most 

good. It is why we have called in a recent report for developing stronger guidelines on 

human subject recruitment practices.15 It is also why we draw attention to the vital role 

that DSMBs can play, particularly for trials that pose significant risks to patients and 

multi-site trials. 

Our Recommendations as a Reference Point 

The recommendations we presented in our June 1998 report offer an important reference 

point for how the current effort to enhance protections for subjects can be extended. We 

continue to support the recommendations we made in our earlier report and call for a 

greater sense of urgency in carrying them out. They offer a balanced and practical set of 

actions that would strengthen human-subject protections without impeding the clinical 

research that has much potential for society and perhaps even for the individuals 

participating in the clinical trials. They reflect a respect for the largely collegial manner in 

which IRBs operate and seek to nourish the volunteer contributions that have provided the 

underpinning of IRB reviews. Yet they recognize that verification and accountability must 

also be important features of a system intended to protect human subjects. 

Protecting Subjects: Status of Recommendations 18 OEI-01-97-00197 
While our recommendations serve as an important framework for reform, we do not 

intend to suggest that they provide a complete blueprint for action. In the months ahead, 

we will be conducting further inquiry that more closely examines how HHS oversight can 

help enhance human subject protections. In that period, the National Bioethics Advisory 

Commission (NBAC) is also likely to offer further guidance on the kind of changes that 

need to be made in the Federal regulatory system. Its recommendations will offer 

valuable perspective and grounding for the reform agenda that we continue to call for with 

a sense of urgency. 

New Opportunity for Leadership 

Once OPRR is located in the Office of the Secretary and a new advisory committee on 

protection from research risks is established, as the HHS Secretary has called for, HHS 

will have a significant new opportunity to exert Federal leadership in protecting human 

subjects. 

We urge that the new office give significant attention to our prior recommendations and to 

those that will be forthcoming from NBAC. We also urge that it continue the important 

enforcement efforts undertaken by OPRR over the past 2 years. In increasingly 

commercialized research environments where IRBs are facing heightened pressures to 

conduct quicker reviews, the NIH/OPRR efforts have served as a reminder to research 

institutions, sponsors, individual investigators, and IRBs that the reviews must still be 

substantive ones that ensure adequate protections for human subjects. In the important 

quest to reduce regulatory burdens, it is important not to lose sight of this underlying 

protection function. 

Continued Significance of FDA and NIH Roles 

At the same time, we continue to call for stronger FDA and NIH responses to our 

recommendations. Even with the establishment of the new office, both agencies retain 

significant statutory and operational responsibilities for protecting human subjects. With 

FDA conducting about 300 on-site inspections of IRBs each year, it still has the most 

visible on-site presence and thus is in the best position to identify shortcomings and 

opportunities for improvement. We recognize that FDA must operate with limited 

resources, but much could be accomplished through a revamping of its on-site inspection 

process in the performance-oriented direction we spelled out. FDA can make better use 

of the opportunities its site visits offer as catalysts for positive change. In addition, we 

continue to urge FDA to expedite its efforts to require registration of IRBs. 

As a major funder of clinical research and as a major link with the research community, 

NIH retains significant roles in ensuring human-subject protections despite the relocation 

of OPRR. We urge particular attention to our recommendations calling for Federal 

requirements to ensure that investigators are adequately educated about and sensitized to 

human-subject protections. It is vital, we continue to believe, for NIH to exert stronger, 

more directed leadership in this educational arena. 

Protecting Subjects: Status of Recommendations 19 OEI-01-97-00197 
APPENDIX A 

Institutional Review Boards: The Basics 

What Do They Do? 

The responsibilities of IRBs fall into two main categories: initial review and continuing 

review of research involving human subjects. 

Initial Review. IRBs review and approve a research plan before the research is carried 

out. This review encompasses the research protocol, the informed consent document to 

be signed by subjects, any advertisements to be used in recruiting subjects, and other 

relevant documents. In carrying out this review, the boards seek to ensure that any risks 

subjects may incur are warranted in relation to the anticipated benefits, that informed 

consent documents clearly convey the risks and the true nature of research, that 

advertisements are not misleading, and that the selection of subjects is equitable and 

justified. IRBs focus much attention on the informed consent document because it is the 

vehicle for providing information to potential research subjects. 

Continuing Review. The continuing review process is multifaceted and includes required 

reviews at an interval appropriate to the degree of risk but not less than once per year. In 

addition to this continuing review, IRBs receive periodically and review amendments and 

reports of subjects’ unexpected adverse experiences. This review seeks to ensure that the 

risk-benefit ratio of the research remains acceptable. 

Why Were They Established? 

As public awareness and concern about the treatment of human subjects in research 

increased, the need for additional review mechanisms was evident. These concerns grew 

from stories of the abuse of subjects during the World War II trials at Nuremberg, the 

promotional distribution of thalidomide resulting in numerous children born with birth 

defects, the administration of cancer cells to chronically ill and senile patients at a hospital 

in New York, and others. In 1966, Henry Beecher brought prominent attention to human 

research abuses in medical schools and hospitals, citing 22 cases involving highly 

questionable ethics. The formal requirements for the establishment of IRBs were outlined 

in regulations stemming from the National Research Act of 1974 and in FDA regulations 

issued in 1981. 

Where Are They Located? 

An estimated 3,000-5,000 IRBs can be found across the country. They are most 

commonly associated with hospitals and academic centers. Boards also exist in managed 

care organizations, government agencies (such as the NIH, FDA, the Centers for Disease 

Protecting Subjects: Status of Recommendations 20 OEI-01-97-00197 
Control and Prevention, and State governments), or as independent for-profit entities. 

How Are They Organized? 

Federal regulations require that boards have at least five members with varying 

backgrounds. At least one member must have primarily scientific interests, one must have 

primarily nonscientific interests, and one must be otherwise unaffiliated with the institution 

in which the IRB resides. A quorum, with at least one member whose interests are 

primarily nonscientific present, is needed for voting. 

How Does the Department of Health and Human Services (HHS) Oversee Them? 

Two agencies within HHS share responsibility for IRB oversight: NIH, through its Office 

for Protection from Research Risks (NIH/OPRR), and the FDA. The NIH/OPRR’s main 

tool for oversight is the assurance document. Any institution that intends to conduct 

HHS-funded research must have an assurance on file with NIH/OPRR. The assurance is a 

written statement of an institution’s requirements for its IRB and human-subject 

protections. Institutions consistently conducting multiple HHS-supported studies are 

eligible for a multiple project assurance which can be renewed every 5 years. Institutions 

with smaller HHS-funded workloads, however, use a single project assurance for each 

such project it conducts. The NIH/OPRR also conducts a small number of site visits. The 

FDA’s main mechanism for IRB oversight is the inspection process. FDA becomes aware 

of IRBs when they are listed by a clinical investigator in a statement that the investigator 

will comply with all pertinent regulations. The FDA also inspects research sponsors and 

scientists (also known as research investigators). 

Protecting Subjects: Status of Recommendations 21 OEI-01-97-00197 
APPENDIX B 

FINDINGS

Institutional Review Boards: A Time for Reform 

(OEI-01-97-00193), June 1998 

What follows are the findings taken from the Executive Summary of our June 1998 report, 

Institutional Review Boards: A Time For Reform: 

The Effectiveness of IRBs Is in Jeopardy. 

They Face Major Changes in the Research Environment. The current framework of 

IRB practices was shaped in the 1970s in an environment where research typically was 

carried out by a single investigator working under government funding with a small cohort 

of human subjects in a university teaching hospital. In recent years, that environment has 

been changing dramatically as a result of the expansion of managed care, the increased 

commercialization of research, the proliferation of multi-site trials, new types of research, 

the increased number of research proposals, and the rise of patient consumerism. Each of 

these developments has presented major disruptions and challenges for IRBs. “Never 

before,” concluded one recent review, “has such a pressure-cooker atmosphere prevailed 

within the IRB system.” 

They Review Too Much, Too Quickly, with Too Little Expertise. This is especially 

apparent in many of the larger institutions. Expanded workloads, resource constraints, 

and extensive Federal mandates contribute to a rushed atmosphere where sufficient 

deliberation often is not possible. At the same time, the IRBs frequently are hard-pressed 

to gain access to the scientific expertise they need to reach informed judgments about the 

research taking place under their jurisdiction. 

They Conduct Minimal Continuing Review of Approved Research. In the 

environment described above, continuing review often loses out. Even where there is the 

will, there often is not the time to go beyond the perfunctory obligations. A lack of 

feedback from other entities that oversee multi-site trials contributes to the problem. The 

result is that IRBs have all too little information about how the informed consent process 

really works and about how well the interests of subjects are being protected during the 

course of research. 

They Face Conflicts That Threaten Their Independence. Clinical research provides 

revenue and prestige to the institutions to which many IRBs belong. The institutions 

expect IRBs to support these interests at the same time that they protect human subjects. 

The resulting tension can lessen the IRBs’ focus on their basic mission. The minimal 

“outside” representation that typically exists on IRBs deprives them of an important 

counterbalance to the institutional interests. For independent IRBs, the dependence on 

Protecting Subjects: Status of Recommendations 22 OEI-01-97-00197 
revenue from industry sponsors exerts similar possibilities for conflict. 

They Provide Little Training for Investigators and Board Members. The IRB system 

depends heavily on research investigators’ commitment to uphold human-subject 

protections. But as that system now operates, it offers little educational outreach to 

investigators to help them become informed and sensitized about these protections. 

Similarly, it provides minimal orientation and continuing education for IRB members—a 

deficiency that is especially detrimental to nonscientific and noninstitutional members. 

Neither IRBs Nor HHS Devote Much Attention to Evaluating IRB Effectiveness. 

IRBs rarely conduct inquiries to determine how well they are accomplishing their mission; 

their judgments of effectiveness rely mainly on the number of protection lapses or 

complaints that are brought to their attention. The HHS agencies conducting oversight 

seldom go any further. The Office for Protection from Research Risks, in the National 

Institutes of Health, focuses almost entirely on up-front assurances. The Food and Drug 

Administration relies on compliance-focused inspections. 

Protecting Subjects: Status of Recommendations 23 OEI-01-97-00197 
APPENDIX C 

Current Status of FDA and NIH/NIH/OPRR Response to Recommendations 

Institutional Review Boards: A Time for Reform (OEI-01-97-00193), June 1998 

Recommendation Status 

1. Recast 

Federal 

Requirements 

1a. Eliminate or lessen some of the procedural 

requirements 

< FDA and OPRR issued more expedited review categories (11/98) 

< OPRR/NCI proposed demonstration project using a central IRB to 

streamline processes 

1b. Require IRBs undergo regular 

performance-based evaluations 

< No action 

< Private accreditation movement initiated 

2. Strengthen 

Continuing 

Protections 

2a. Require Data Safety Monitoring Boards 

(DSMBs) for certain trials 

< NIH reasserts policy on appropriate monitoring of its trials (5/98) 

< No other action 

2b. Require DSMBs to provide summary 

information to IRBs 

< NIH requires its DSMBs to share summary info. with IRBs (6/99) 

< No other action 

2c. Alert IRBs to corrective actions taken 

against investigators under their purview 

< FDA now notifies IRBs and sponsors of actual and potential 

misconduct by clinical investigators 

2d. Require sponsors and investigators to 

notify IRBs of any prior review 

< No action 

2e. Call for increased IRB awareness of onsite research practices 

< No action 

3. Enact 

Educational 

Requirements 

3a. Require institutions to establish an 

education program for investigators in 

human-subj. protections 

< NIH has launched a number of initiatives and OPRR has required 

the establishment of education programs as a result of investigations 

< No action towards a requirement 

3b. Require investigators provide a written 

attestation to uphold human-subj. protections 

< No action 

3c. Require IRBs to educate their members 

about human-subj. protections 

< No action 

< FDA and NIH/OPRR have required the establishment of educ. 

programs as a result of investigations and are active in outreach 

4. Help Insulate 

IRBs from 

Conflicts That 

Threaten Their 

Independence 

4a. Require more extensive representation of 

nonscientific and noninstitutional members 

< No action 

4b. Reinforce the importance of IRBs 

maintaining sufficient independence 

< No action 

4c. Prohibit equity owners from participating 

in the IRB review process 

< No action 

5. Recognize 

Workload 

Pressures 

5. Require that IRBs have the resources to 

adequately carry out their duties 

< No action 

6.Reengineer 

Federal 

Oversight 

Process 

6a. Revamp NIH/OPRR assurance process < NIH has initiated a proposal to streamline the assurance process 

6b. Revamp FDA on-site inspection process < FDA has increased its on-site presence, but no other action 

6c. Require IRBs register with the Federal 

gov. 

< FDA set working group for registration process, but no action yet 

Protecting Subjects: Status of Recommendations 24 OEI-01-97-00197 
APPENDIX D 

Endnotes

1. (1) Advisory Committee on Human Radiation Experiments, Final Report, (Washington DC: 

U.S. Government Printing Office, 1995). (2)U.S. General Accounting Office, Scientific 

Research: Continued Vigilance Critical to Protecting Human Subjects, GAO/HEHS-96-72, 

March 1996. (3) Department of Health and Human Services, Office of Inspector General, 

Investigational Devices: Four Case Studies (OEI-05-94-00100), April 1995. 

2. (1) Institutional Review Boards: A System in Jeopardy?: Before the House Comm. on 

Government Reform and Oversight, 105th Cong., June 11, 1998. (2) Do Current Federal 

Regulations Adequately Protect People Who Participate in Medical Research?: Before the 

Subcomm. on Criminal Justice, Drug Policy, and Human Resources of the House Comm. on 

Government Reform, 106th Cong., December 9, 1999. 

3. These groups include, but are not limited to, Public Responsibility in Medicine and Research, 

Applied Research Ethics National Association, the Society of Administrative Managers of General 

Clinical Research Centers, the American Health Lawyers Association, and the Food and Drug 

Law Institute. 

4. 63 Fed. Reg. 60,364-60,367 (November 9, 1998). 

5. FDA does require DSMBs for trials in emergency circumstances in which informed consent is 

waived. (21 C.F.R. 50.24) 

6. Phillip Hilts, “Panel Seeks Better Monitoring of Experiments Using People,” New York Times, 

March 2, 2000. 

7. “NIH Policy for Data and Safety Monitoring,” National Institutes of Health, June 10, 1998. 

[http://www.nih.gov/grants/guide/notice-files/not98-084.html, accessed 4/1/99] 

8. “Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-supported 

Multicenter Clinical Trials,” National Institutes of Health, June 11, 1999. 

[http://grants.nih.gov/grants/guide/notice-files/not99-107.html, accessed 3/00] 

9. “New Initiatives to Protect Participants in Gene Therapy Trials,” National Institutes of Health, 

March 7, 2000. [http://www.nih.gov/news/pr/mar2000/od-07.htm, accessed 3/00] 

10. The Commission on Research Integrity, Integrity and Misconduct in Research, (Washington, 

DC: U.S. Government Printing Office, November 1995). 

11. The web-based tutorial is available on the internet at [http://helix.nih.gov:8001/ohsr/newcbt/] 

12. Of particular note is the effort at the University of Rochester. After the death of a healthy 

subject participating in a trial, University administration formed a committee to recommend 

needed reforms. The Committee recommended, “that all investigators at the University be 

informed adequately, and on a continuing basis, of the fundamental requirements, responsibilities 

and ethical issues related to the conduct of human subject research.” In addition, it recommended 

Protecting Subjects: Status of Recommendations 25 OEI-01-97-00197 
“that this be accomplished in the setting of a formalized educational program and that a 

reasonable effort be made to assess the understanding of the information conveyed.” As a result, 

all investigators must follow a self-study training program and pass a brief exam before their 

projects will be reviewed by the IRB and, thus, before they may conduct clinical research at the 

university. (Further information, see [http://www.urmc.rochester.edu/urmc/rsrb/hspp.htm, accessed 3/00]) 

13. The website can be found at [www.nih.gov/sigs/bioethics/]. The training initiatives include a 

short-term training program in bioethics, for which 15 awards have been given to date, a clinical 

program in 35 academic health centers which addresses clinical research more generally but also 

includes bioethics issues, and a mentored scientist award that supports scientists who want to 

specialize in training in bioethics. 

14. “New Initiatives to Protect Participants in Gene Therapy Trials,” National Institutes of 

Health, March 7, 2000. [http://www.nih.gov/news/pr/mar2000/od-07.htm, accessed 3/00] 

15. Department of Health and Human Services, Office of Inspector General, Recruiting Subjects 

for Industry-Sponsored Clinical Research (OEI-01-97-00196), in draft. 

Protecting Subjects: Status of Recommendations 26 OEI-01-97-00197