Department of Health and Human Services 
OFFICE OF 
INSPECTOR GENERAL 
Protecting Human Research Subjects 
Status of Recommendations 
JUNE GIBBS BROWN 
Inspector General 
APRIL 2000 
OEI-01-97-00197  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  E X E C U T I V E   S U M M A R Y  
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. 
1 
Protecting Subjects: Status of Recommendations  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 on-
site investigation at only 1 institution.  Between June 1998 and March 2000, it conducted 
on-site investigations at 10 institutions.  FDAs 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.  OPRRs 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. 
2 
Protecting Subjects: Status of Recommendations  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 publics 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 
3 
Protecting Subjects: Status of Recommendations  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 human-
subject 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. 
4 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  T A B L E  O F  C O N T E N T S  
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

5 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  I N T R O D U C T I O N  
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 
Departments 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 
6 
Protecting Subjects: Status of Recommendations  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. 
7 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  HHS Oversight Roles and Competencies 
Delineation of HHS Authority and Activity 
Agency  Purview  Primary Body  Oversight Conducted 
for Protections 
NIH/OPRR  research supported or otherwise  IRBs  assurance, inspections of IRBs 
subject to regulation by HHS 
FDA  research conducted on products  IRBs  inspections of investigators, 
subject to FDA approval  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. 

OPRRs 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 institutions 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. 

8 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  U P D A T E  
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 protocols 
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 
<  FDAs 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. 
FDAs 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. 
FDAs presence in reviewing IRB practices remains much more direct and extensive than 
9 
Protecting Subjects: Status of Recommendations  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. 
OPRRs oversight activities have been particularly influential in drawing attention 
to the adequacy of IRB oversight and human-subject protections throughout the 
research community. 
With OPRRs 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 OPRRs recent actions, the fact that many major medical 
journals and newspapers gave prominent attention to OPRRs enforcement actions [see 
box] suggests that these actions are being widely noted. 
Some recent 
professional  NIH/OPRR Puts the Research Community on Notice 
conferences also 
A virtually unknown federal agency with only 31 employees is 
reflected a growing 
sending shock waves through the nations billion-dollar clinical-
sense that Federal 
research community. Physicians Weekly, July 19, 1999 
enforcement activities 
are being taken  OPRR has put every federally funded U.S. research institution on 
seriously by research  notice that its right to conduct clinical research could be summarily 
yanked. Science, May 21, 1999 
institutions, 
investigators, and 
But even as business goes back to normal at the prestigious medical 
IRBs.  The 1999 
center...new questions arose about the safety of human subjects at other 
annual meeting of  institutions around the country. The Washington Post, May 5, 1999 
Public Responsibility 
Across the country, university administrators and researchers are 
in Medicine and 
worried, even panicked that the same thing could happen at their 
Research (PRIM&R) 
institutions with millions of dollars of research funds from the National 
drew 1,300 attendees 
Institutes of Health and pharmaceutical companies at stake. 
compared with about  Chronicle of Higher Education, February 4, 2000 
900 the year before, 
and its first panel  OPRR is moving with new aggressiveness to monitor IRB 
performance. New York Times, May 25, 1999 
session included a 
presentation by the 
Recent suspensions indicate to some that NIH/OPRR is more 
director of research 
aggressively enforcing the federal protections for human subjects 
affairs from Rush- American Medical News, November 1, 1999 
Presbyterian Medical 
Center, an institution 
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? 
10 
Protecting Subjects: Status of Recommendations  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. 
11 
Protecting Subjects: Status of Recommendations  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 IRBs capacity to 
assess the ongoing safety of a trial. 
< Alert IRBs to corrective actions taken against investigators under the boards 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 
12 
Protecting Subjects: Status of Recommendations  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 Presidents 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 whats 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 IRBs 
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.  FDAs 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. 
13 
Protecting Subjects: Status of Recommendations  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. 
14 
Protecting Subjects: Status of Recommendations  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 IRBs ability to oversee research. 
Update:  OPRRs 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 institutionsand 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. 
15 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  Minimal progress in reengineering the Federal oversight process. 
Prior Recommendations: 
< Revamp the NIH/OPRR assurance process. NIH/OPRRs oversight process has been concentrated on 
reviewing up-front assurances aimed at obtaining an institutions 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: OPRRs and FDAs 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 foreven 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 
16 
Protecting Subjects: Status of Recommendations  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 forfor instance, more extensive representation on IRBs of nonscientific 
and noninstitutional members or stronger requirements on IRBs having sufficient 
independencecould 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.  NIHs 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. 
17 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197  L o o k i n g  A h e a d  
Gene Transfer Research as a Catalyst 
The untimely death of the subject in a gene transfer trial has raised the publics 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. 
18 
Protecting Subjects: Status of Recommendations  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. 
19 
Protecting Subjects: Status of Recommendations  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 
20 
Protecting Subjects: Status of Recommendations  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/OPRRs 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 institutions 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 
FDAs 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). 
21 
Protecting Subjects: Status of Recommendations  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 
22 
Protecting Subjects: Status of Recommendations  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 membersa 
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. 
23 
Protecting Subjects: Status of Recommendations  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  1a. Eliminate or lessen some of the procedural  < FDA and OPRR issued more expedited review categories (11/98) 
Federal  requirements  < OPRR/NCI proposed demonstration project using a central IRB to 
Requirements  streamline processes 
1b. Require IRBs undergo regular  < No action 
performance-based evaluations  < Private accreditation movement initiated 
2. Strengthen  2a. Require Data Safety Monitoring Boards  < NIH reasserts policy on appropriate monitoring of its trials (5/98) 
Continuing  (DSMBs) for certain trials  < No other action 
Protections 
2b. Require DSMBs to provide summary  < NIH requires its DSMBs to share summary info. with IRBs (6/99) 
information to IRBs  < No other action 
2c. Alert IRBs to corrective actions taken  < FDA now notifies IRBs and sponsors of actual and potential 
against investigators under their purview  misconduct by clinical investigators 
2d. Require sponsors and investigators to  < No action 
notify IRBs of any prior review 
2e. Call for increased IRB awareness of on- < No action 
site research practices 
3. Enact  3a. Require institutions to establish an  < NIH has launched a number of initiatives and OPRR has required 
Educational  education program for investigators in  the establishment of education programs as a result of investigations 
Requirements  human-subj. protections  < No action towards a requirement 
3b. Require investigators provide a written  < No action 
attestation to uphold human-subj. protections 
3c. Require IRBs to educate their members  < No action 
about human-subj. protections  < FDA and NIH/OPRR have required the establishment of educ. 
programs as a result of investigations and are active in outreach 
4. Help Insulate  4a. Require more extensive representation of  < No action 
IRBs from  nonscientific and noninstitutional members 
Conflicts That 
Threaten Their  4b. Reinforce the importance of IRBs  < No action 
Independence  maintaining sufficient independence 
4c. Prohibit equity owners from participating  < No action 
in the IRB review process 
5. Recognize  5. Require that IRBs have the resources to  < No action 
Workload  adequately carry out their duties 
Pressures 
6.Reengineer  6a. Revamp NIH/OPRR assurance process  < NIH has initiated a proposal to streamline the assurance process 
Federal 
Oversight 
6b. Revamp FDA on-site inspection process  < FDA has increased its on-site presence, but no other action 
Process 
6c. Require IRBs register with the Federal  < FDA set working group for registration process, but no action yet 
gov. 
24 
Protecting Subjects: Status of Recommendations  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 
25 
Protecting Subjects: Status of Recommendations  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. 
26 
Protecting Subjects: Status of Recommendations  OEI-01-97-00197