Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

Institutional Review Boards: 

A Time for Reform 

JUNE GIBBS BROWN 

Inspecior General 

JUNE1998 

OEI-01-97-00193 
EXECUTIVE SUMMARY 

PURPOSE 

To summarize the challenges facing institutional review boards and to make 

recommendations for Federal oversight. 

BACKGROUND 

Role of Institutional Review Boards 

Institutional review boards (IRE3s) play vital roles in protecting human research subjects. 

They review initial research plans to make certain that the plans provide subjects with 

adequate opportunity to provide informed consent and do not expose subjects to 

unreasonable risks. They also conduct continuing review of approved research to ensure 

that human-subject protections remain in force. They carry out their initial and 

continuing review functions in accord with Federal regulations first established in the 

1970s and applicable to all research funded by the U.S. Department of Health and Human 

Services or carried out on products regulated by the Food and Drug Administration. 

This Summary Report 

This is a synthesis report. It draws on our broad inquiry of 1-s and on findings we 

presented in three parallel reports. Its overarching conclusion is that the long-established 

system for protecting human research subjects has vulnerabilities that threaten its 

effectiveness. In the report we highlight the major elements leading to this conclusion 

and offer recommendations for improvement. The recommendations are especially 

important in view of current Federal plans to increase significantly the numbers of human 

subjects participating in clinical trials, and proposals to give IRE& increased responsibility 

in the areas of genetics and confidentiality. 

With this report, we offer a warning signal and a framework for a concerted response to 

it. We do not document, nor do we suggest that widespread harm is being done to human 

subjects. We recognize the strengths of the current system and seek to build on them to 

enhance human-subject protections. 

Methodology 

Given our focus on the overall system of protections, we did not carry out audits of IRBs 

or investigations of particular cases. To help us understand the big picture, we conducted 

an extensive review of Federal records and pertinent literature; held interviews and group 

discussions with many Federal officials and with representatives of about 75 IRBs; 

visited IRE3sat 6 academic health centers where extensive clinical research is taking 

place; attended IRE3meetings; and accompanied FDA inspectors on IRB site visits. 

i OEI-Ol-97-00193 IRBS: A Time For Reform 
FINDINGS 

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 pressurecooker 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 hardpressed 

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 

revenue from industry sponsors exerts similar possibilities for conflict. 

They Provide Little Training for Investigators and Board Members. The RI3 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 

-w deficiency that is especially detrimental to nonscientific and noninstitutional members. 

ii OEI-Ol-97-00193 IRBS: A Time For Reform 
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 Offrce for Protection from Research Risks, in the National 1 

Institutes of Health, focuses almost entirely on upfront assurances. The Food and Drug 

Administration relies on compliance-focused inspections. 

RECOMMENDATIONS 

With the above findings, we do not claim that there are widespread abuses of human 

research subjects. The current system of protections is supported by many conscientious 

research investigators committed to protecting human subjects and by many dedicated 

IRB members and staff doing their best under trying circumstances. A reviewer of this 

system can not help but be impressed by the contributions of these individuals, and the 

important function that IRBs have fulfilled over the past quarter of a century. 

But our findings present an important warning signal. The capacity of IRBs to 

accomplish all that is expected of them is strained. In the years ahead, this difficult 

situation could become even worse in view of Federal plans to increase significantly the 

numbers of subjects in clinical trials and various proposals to give IRBs added 

responsibility in the areas of genetics and confidentiality. It is time, we believe, for 

reform. 

Our recommendations offer a framework for such a response. We direct them jointly to 

the two HHS agencies responsible for IRB oversight: the Office of Protection from 

Research Risks (OPRR), which is located within the National Institutes of Health (NIH), 

and the Food and Drug Administration (FDA). These agencies oversee IRBs with 

different jurisdictions and operational approaches. It is essential, therefore, for them to 

collaborate closely if HHS as a whole is to respond effectively to the serious concerns 

that emerge from our inquiry. Below we present our general recommendations for the 

two agencies. In the text, we offer more explicit elaborations directed, as appropriate, to 

the particular agencies. 

Recast Federal IRB Requirements So That They Grant IRBs Greater Flexibility and Hold 

Them More Accountable for Results. 

t Eliminate or lessen some of the procedural requirements directed to IRBs. 

t Require that IRBs undergo regular performance-focused evaluations. 

Strengthen Continuing Protections for Human Subjects-Participating in Research. 

b Require Data Safety Monitoring Boards for some multi-site trials. 

. . . 111 OEI-Ol-9740193 IRBS: A Time For Reform 
b Provide IRESswith feedback on developments concerning multi-site trials. 

b Routinely provide IRE&swith feedback about FDA actions against investigators. 

b Require sponsors and investigators to notify IRBs of prior reviews of research plans. 

b Call for increased IRE3 awareness of on-site research practices. 

Enact Federal Requirements That Help Ensure That Investigators and IRB Members Are 

Adequately Educated About and Sensitized to Human-Subject Protections. 

b Require that research institutions have a program for educating its investigators on 

human-subject protections. 

. Require that investigators provide a written attestation of their familiarity with and 

commitment to human-subject protections. 

b Require that IRBs have an educational program for board members. 

Help Insulate IRBs from Conflicts That Can Compromise Their Mission in Protecting 

Human Subjects. 

b Require more representation on Irks of nonscientific and noninstitutional members. 

b Reinforce to IRE3 institutions the importance of IRBs having sufficient independence. 

b Prohibit IRE! equity owners from participating in the IRE3review process. 

Recognize the Seriousness of the Workload Pressures That Many IRBs Face and Take 

Actions That Aim to Moderate Them. 

b Require that IREJshave access to adequate resources. 

Reengineer the Federal Oversight Process. 

b Revamp the NIWOPRR assurance process. 

b Revamp the FDA on-site inspection process. 

t Require the registration of 1-s. 

iv 031-01-97-00193 IRRS: A Time For Reform 
COMMENTS ON THE DRAFT REPORTS 

Within the Department of Health and Human Services (HHS), we received comments on 

our four draft reports from the National Institutes of Health (NIH), the Food and Drug 

Administration (FDA), and jointly from the Assistant Secretary for Planning and 

Evaluation (ASPE) and the Assistant Secretary for Health (ASH). We also solicited and 

received comments from the following external organizations: the Applied Research 

Ethics National Association (ARENA), the American Association of Medical Colleges 

(AAMC), the Consortium of Independent Review Boards (CIRB), and Public Citizen’s 

Health Research Group. We include the detailed text of their comments and our 

responses to them in appendix D. Below we summarize the major thrust of both their 

comments and our responses. We made a number of changes in the final reports. Most 

were technical in nature. Their comments sought to clarify certain findings and a few 

involved clarifications and elaborations concerning the recommendations. 

NIH, FDA, and ASPE/ASH Comments 

The HHS parties viewed the reports as raising important issues and recommendations 

warranting widespread discussion. They suggested various ways this could be 

accomplished. The NIH expressed particular support for our recommendation calling for 

the assurance process to be revamped so that it rests essentially on an institutional 

attestation to conform to IRB requirements and thereby enables OPRR to focus more on 

performance assessment and education. The FDA expressed reservations about 

refocusing its compliance-oriented inspection process, which it regards as having “great 

value,” to one that is more performance-oriented. The FDA also raised concerns about 

the resource implications of some of our recommendations. 

We will support efforts to engage broadly-based dialogue on our findings and 

recommendations. At the same time, we underscore the importance ofpractical nearterm actions that can be taken to address the vulnerabilities we point out. We 

particularly urge that FDA and NIH incorporate into their oversight spectfic lines of 

inquiry to determine how well IRBs are actually protecting human subjects. This would 

call for examining such matters as how the processes of recruiting, selecting, and gaining 

informed consent@om human subj*ects actually work. It would also call for addressing 

vertftcation efforts to make sure that protocols are in fact submittedfor review and that 

approvedprotocols do not stray offcourse. On the matter of resources, we agree that this 

is an important issue warranting serious attention in the research andpolicy 

communities, particularly in view of added responsibilities IRBs may well face in the 

years ahead. 

External Organizations’ Comments 

While the external parties supported many of our findings and recommendations, they 

also raised some strong concerns. Basically, these involved differences of substance and 

objections to the use of certain terms and language. In regard to the former, Public 

V OEI-Ol-97-00193 IRBS: A Time For Reform 
Citizen, in expressing considerable alarm over our findings, felt that we should have gone 

further with our investigations and recommendations. On the other hand, ARENA and 

AAMC had reservations about our call for performance-focused evaluations and for more 

outside representation on IRBs. They were also concerned that a more active IRB role in 

conducting continuing review could undermine the trust that has existed between IRBs 

and the research community. With respect to the language we used, ARENA, AAMC, 

and CIRE3 called for a more precise use of a number of terms. The ARENA indicated that 

our use of the term “IRE3 oversight” was particularly misleading. The ARENA and 

AAMC both indicated that some of our wording was unduly alarmist and more 

encompassing than our methodology warranted. 

To facilitate a serious examination of the matters of substance we raise, we changed 

some of the language we used in the draft reports. Most notably, instead of referring to 

“IRB oversight, ” we focused on IRB responsibilities and authorities to conduct 

“continuing review, ” as spectfied in Federal regulations. But, this and various other 

such textual modifications we made in no way lessen our assessment that the effectiveness 

of the IRB system is in jeopardy. Our wide ranging and in-depth inquiry offers us ample 

basis to sound that warning. With respect to concerns raised that focus more strictly on 

matters of substance, we must underscore that if IRBs are to meet the significant 

challenges they face in the years ahead they must become more fully accountable to the 

public. Trust in the investigators performing research is vitally important, but in itself is 

insuf$cient. The IRBs and Federal oversight agencies mustfind more effective and open 

ways of verifying that the consumer protection mission of IRBs is in fact being 

accomplished. This is especially important as the research environment in which IRBs 

function becomes increasingly commercialized. 

vi OEI-Ol-9740193 IRRS: A Time For Reform 
PAGE 

EXECUTIVE SUMMARY 

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..l 

IRBs:THEBASICS............................................................3 

FINDINGS: The Effectiveness of IRBs is in Jeopardy 

They Face Major Changes in the Research Environment ........................ .4 

They Review Too Much, Too Quickly, with Too Little Expertise ................. .5 

They Conduct Minimal Continuing Review of Approved Research ................ .6 

They Face Conflicts that Threaten Their Independence ......................... .7 

They Provide Little Training for Investigators and Board Members ................. 8 

Neither They Nor HHS Devote Much Emphasis to Evaluating Effectiveness ......... 8 

RECOMMENDATIONS.......................................................lO 

COMMENTS ON THE DRAFT REPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22 

APPENDICES 

A: Advertising to Recruit Human Subjects ................................. A-l 

B: Federal Requirements on IRB Continuing Review .......................... B-l 

C: Federal Oversight of IRBs ............................................. C-l 

D: Comments on the Draft Reports ....................................... D-l 

E:Endnotes ........................................................ ..E- 1 

OEI-Ol-97-00193 IRBS: A Time For Reform 
INTRODUCTION 

PURPOSE 

To summarize the challenges facing institutional review boards and to make 

recommendations for Federal oversight. 

BACKGROUND 

On page three we offer a primer on IRBs: why they were established, what roles they 

perform, how they are organized, where they are located, and how they are overseen by 

the Department of Health and Human Services. 

Prior Inquiries 

For about a quarter of a century, IRELshave been playing an important role in protecting 

human subjects enrolled in research projects. Almost from the start, however, prominent 

studies have drawn attention to some of their limitations. A 1983 Presidential 

commission report raised concerns about the adequacy of the review procedures of some 

Irks, about how well some of the members of these boards understood their roles, and 

about the commitment of some of the institutions to their 1RBs.r Twelve years later, in 

1995, a Presidential advisory committee raised even stronger concerns about the 

adequacy of the IRB review process, especially for research involving greater than 

minimal risks, and about the effectiveness of Federal oversight strategies.* In the 

following year, the General Accounting Office issued a report reinforcing these points 

and identifying numerous factors inhibiting IRB performance.3 

In a recent inquiry of our own, we raised concerns about the continuing review effort of 

Irks. In examining clinical trials involving four investigational medical devices, we 

discovered inadequacies related to IRB oversight in each case. These inadequacies 

concerned serious matters such as the implantation of a device in three times the number 

of human subjects specified in the IRB-approved research protocol, the initiation of a 

research effort without the changes called for in the informed consent document, and the 

continuation of a research project for six weeks beyond when the IRB had suspended it.4 

The concerns about human-subject protections become even more significant in view of 

current developments. These include current Federal plans to raise the level of funding 

for the National Institutes of Health (NIH), which would significantly increase the 

number of human subjects participating in clinical trials, and proposals to give Irks 

increased responsibility in the areas of genetic testing and confidentiality.’ 

1 OEMl-9740193 IRBS: A Time For Reform 
This Inquiry and Report 

This inquiry builds on the prior reviews and, we hope, will contribute to the deliberations 

of the currently active Presidential advisory body examining the protections available to 

human subjects.6 This report is one of four that has resulted from our total inquiry. It is a 

summary report that draws on our overall review and on findings presented in the three 

companion reports. It presents a picture of IRE& under considerable stress. It houses our 

recommendations for improving the current system of human-subject protections. 

A second report, Institutional Review Boards: Their Role in Reviewing Approved 

Research, finds that continuing review of approved research is of vital importance but 

that IREJsare devoting little attention to this part of their mission. It also identifies key 

obstacles to effective continuing review. A third report, Institutional Review Boards: 

Promising Approaches, presents innovative strategies that IRE& have developed in six 

key areas of responsibility. These include promising approaches to managing the 

expanding workload and providing education to investigators and members. A fourth 

report, Institutional Review Boards: The Emergence of Independent Boards, finds that 

independent IRBs are becoming a significant force and addresses the advantages and 

disadvantages they present. 

The inquiry that supports each of these reports draws on a rich variety of sources. These 

included analyses of Federal records; reviews of government documents and national 

commission reports produced over the past 25 years; articles and books addressing 

human-subject protections; site visits to IRE& in 6 academic health centers 7; additional 

IRE3 site visits accompanying FDA inspectors; attendance at IRE3 meetings; a survey on 

the electronic e-mail forum for those associated with IRE3s; and the systematic gathering 

of data from representatives of about 75 IRE& of varying sizes and auspices.8 At the 

academic health centers, which are among the most heavily funded biomedical research 

centers in the cour~try,~ we interviewed not only IRB administrators and members, but 

also many others in the parent institutions who had a bearing on IRB performance. These 

included medical school deans; hospital vice presidents; heads of pertinent academic, 

administrative, and clinical committees or departments; attorneys; ethicists; and many 

others. 

The thrust of our information gathering for this and the other reports was to gain a better 

understanding of the big picture involving IRE3s. We focused on the IRB system as a 

whole and on the environment in which they function. We did not conduct an audit of 

their operations, nor did we carry out an investigation of specific IRE& or of specific 

research plans reviewed by IRE3.s. 

We conducted this inspection in accordance with the Quality Standards for Inspections 

issued by the President’s Council on Integrity and Efficiency. 

2 OEI-Ol-97-00193 IRRS: A Time For Reform 
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 researchplan before the researchis carried out. This review 

encompassesthe researchprotocol, the informed consent document to be signed by subjects,any 

advertisementsto be used in recruiting subjects,and other relevant documents. In carrying out this review, 

the boards seekto ensurethat any risks subjectsmay incur are warranted in relation to the anticipated 

benefits, that informed consentdocuments clearly convey the risks and the true nature of research,that 

advertisementsare not misleading, and that the selection of subjectsis equitable andjustified. IRBs focus 

much attention on the informed consent document becauseit is the vehicle for providing information to 

potential researchsubjects. 

Continuing Review: The continuing review processis multifaceted and includes required reviews “at an 

interval appropriate to the degreeof risk but not lessthan once per year.” In addition to this continuing 

review, study amendmentsand reports of unexpectedadverseexperiencesby subjectsare received 

periodically and reviewed to ensurethat the risk-benefit ratio of the researchhasnot changedandremains 

acceptable. 

Why Were They Established? 

As public awarenessand concern about the treatment of human subjectsin researchincreased,the needfor 

additional review mechanismswas evident. Theseconcerns grew from stories of the abuseof subjectsduring 

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 patientsat a 

hospital in New York, and others. A 1966 article by Henry Beecherbrought prominent attention to human 

researchabusesin medical schoolsand hospitals citing 22 casesinvolving highly questionableethics. The 

formal requirements for the establishmentof IRBs were outlined in regulations stemming from the National 

ResearchAct of 1974 and in FDA regulations issued in 1981. 

Where Are They Located? 

An estimated3,000-5,000 IRBs can be found acrossthe country. They are most commonly associatedwith 

hospitals and academiccenters. Boards also exist in managedcare organizations, government agencies(such 

asthe National Institutes of Health, the Centersfor DiseaseControl, and Stategovernments),or asfor-profit 

entities that are independentof the institutions in which the researchtakes place. 

How Are They Organized? 

Federalregulations require that boardshave at least five memberswith varying backgrounds. At leastone 

membermust have primarily scientific interests,one must have primarily nonscientific interests,and one must 

be otherwise unaffiliated with the institution in which the IREJresides. A quorum, with at leastonemember 

whose interestsare primarily nonscientific present, is neededfor voting. 

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

Two agencieswithin HHS shareresponsibility for IRB oversight: the Office for Protection from Research 

Risks (OPRR) in NIH and the FDA. The OPRR’s main tool for oversight is the assurancedocument. Any 

institution that intends to conduct HHS-funded researchmust have an assuranceon file with OPRR. The 

assuranceis a written statementof an institution’s requirements for its IRB and human-subjectprotections. 

Institutions consistently conducting multiple HHS-supported studies are eligible for a multiple project 

assurance(MPA) which can be renewed every five years. Institutions with smaller HHS-funded workloads, 

however, usea single project assurance(SPA) for each such project it conducts. The OPRRalso conductsa 

small number of site visits. The FDA’s main mechanism for IRB oversight is the inspection process. The 

FDA also inspectsresearchsponsorsand scientists (known as researchinvestigators). A more detailed 

t- explanation of the agencies’ oversight processescan be found in appendix C. 

3 OEI-Ol-97-00193 IRRS: A Time For Reform 
FINDINGS 

The Effectiveness of IRBs Is in Jeopardy. 

As they have for about 25 years, IRBs continue to provide vital protections for human 

subjects. But our inquiry leads us to the troubling central conclusion that the system of 

protections, that has been so carefully developed over the years, is in jeopardy. A recent 

review, published in The Journal of the American Medical Association, offered a similar 

conclusion: “Never before has such a pressure-cooker atmosphere prevailed within the 

IRB system, leading government officials, university administrators, research sponsors, 

and IRB members to wonder whether the IRB system will crack or reform.“” 

This vulnerability becomes especially significant in view of emerging.budgetary 

developments that could add significantly to the number of human subjects taking part in 

clinical trials and proposals to give IRBs increased responsibility in the areas of genetic 

testing and confidentiality. It is crucial, therefore, to understand the major factors that 

jeopardize IRB effectiveness and then to take strong corrective actions. In our three other 

reports we identify and explain a number of such factors. Below, we highlight six that 

are particularly compelling and that buttress the case for reform at a national level. 

IRBs Face Major Changes in the Research Environment. 

Federal IRB regulations were formulated during the 1970s and early 1980s at a time when 

most research involving human subjects took place under government funding in a 

university teaching hospital with established research-related controls.” Clinical trials 

typically involved a small cohort of subjects and were generally conducted by a single 

investigator at a single institution.‘2 In the wake of the Tuskegee experiments and other 

research abuses of human subjects, there was considerable awareness of the risks that 

research could pose for human subjects.13 IRB workloads were, for the most part, limited 

enough to allow IRBs ample opportunity to deliberate about the research proposals before 

them.r4 

The environment in which IRBs operate has changed significantly in the past two 

decades. The chart on the next page identifies six major developments contributing to 

this change and outlines some of the key implications for IRBs. 

One of the more visible reflections of this new environment is the widespread advertising 

that sponsors and investigators often rely upon to recruit human subjects. Such 

advertisements are prominently displayed in buses and subways, newspapers, university 

bulletin boards, and other places. Typically, they stress the personal benefits (including 

cash payments) that one may receive by signing up as a research subject and make no 

mention of attendant risks (see appendix A). _ 

4 031-01-97-00193 IRIS: A Time For Reform 
-- 

A CHANGING ENVIRONMENT FOR IRBs 

CHANGE EXPLANATION 

Expansion of Emphasison cost control 

Managed Care and competition. Squeeze 

on researchsupport for 

academichealth centers. 

Increased Heightened industry role 

Commercialization in sponsoring research. 

of Research Sponsoremphasison rapid 

product development. 

Proliferation of Proliferation of trials 

Multi-Center spreadacrosshundreds of 

Trials sites, even acrossthe 

world. 

New Types of Advances in biomedical 

Research researchin the areasof 

genetesting and gene 

therapy; increasedresearch 

on mental health issues. 

IncreasedNumber Intensified efforts to 

of Proposals obtain government funding 

and to develop new 

products. 

Rise of Patient Increasedconsumer 

Consumerism demand for accessto 

research. 

KEY IMPLICATIONSFOR IRBs 

*Pressuresto accommodateresearchsponsorswho can 

provide research-relatedrevenuesfor the parent institution. 

*Increaseddifficulty in obtaining staff and other resources. 

*More pressureon staff physiciansto generateincome, 

with lesstime available for voluntary commitmentsto IRBs. 

l Institutional and sponsorpressuresfor quick reviews. 

*Sponsorshopping for customer-focusedIRBs. 

*Added complexity on issuesinvolving liability, academic 

freedom, and patient disclosure. 

*Diminished influence of “local” review. 

*Flood of adverse-eventreportsto review. 

*Lack of accessto significant information concerning the 

statusof ongoing research. 

*Need for new, highly specializedareasof expertise. 

*Emergenceof thorny ethical issuesinvolving informed 

consentand appropriate research. 

-Increased importance of having noninstitutional board 

members. 

*Significant increasein workloads. 

*Without sufficient increasesin staff and/or efficiency, less 

time is available to review initial protocols and to conduct 

continuing reviews of approvedresearch. 

*Presentsmajor challengesin: 

Ensuring equitable recruitment of subjects. 

Ascertaining local attitudes and values. 

Maintaining distinctions betweentherapy and research. 

IRBs Review Too Much, Too Quickly, with Too Little Expertise. 

IRBs across the country are inundated with protocols. Our study sites reported average 

increases of 42 percent in initial reviews during the past 5 years, with the result that some 

of them are now reviewing more than 2,000 protocols. At the same time, these IRBs are 

being deluged with adverse-event reports from the multi-center trials they oversee. One 

IRB we visited had received several boxes of adverse-event reports within the past few 

weeks. Another indicated that it was receiving an average of 200 such reports a month. 

Although the large academic health centers are hit hardest by mounting workloads, small 

IRE!s are suffering as well. Several small IRE3 representatives told us that while the 

number of proposals they review is substantially fewer than at the large institutions, they 

often have only one staff member who is responsible for coordinating all IRE3 activities. 

5 OEI-Ol-9740193 IRBS: A Time For Reform 
Despite the increase in workload, staffing 

many IRE3s. At the same time, 

managed care cost pressures have 

constrained the time that IRE3members 

have to devote to reviewing protocols. 

In an effort to cope, many rely on preassigned reviewers to examine and 

summarize research plans for the entire 

IRB. In some IRBs, unless one of the 

assigned reviewers raises a question or 

concern about the research, the IRE3 

engages in little or no discussion at its 

meeting.15 While some IRE& have been 

able to increase the length of their 

meetings, others squeeze more reviews 

levels and budgets have remained the same at 

IRBs Under Pressure 

The agendasof the IRB review meetingsat 

academichealth centerswhere most of the HHSsponsoredresearchoccurs arepacked, leaving 

busy reviewers little time to reflect on and debate 

issuesraised by researchprotocols. As an 

illustration, at the siteswe visited, their most 

recent meetings typically lastedabout 2 % hours 

and included an averageof 18 initial reviews, 9 

expedited reviews, 43 protocol amendments,and 

2 1 adverse-eventreports. 

into a fixed block of time. With limited personnel and few resources, IRBs are hard 

pressed to give each review sufficient attention. A 1996 GAO report stated that some 

Irks may spend only one to two minutes of review per study.16 

Many IRBs find that they lack sufficient scientific expertise on their boards or staffs to 

adequately assess protocols. For example, protocols involving advanced biomedical 

techniques--such as gene testing--raise scientific issues, as well as moral and ethical 

questions, that might not be apparent to the untrained eye. From time to time, IRBs will 

use consultants to fill the gap, but this can be costly and can bog down an already 

overburdened review process. 

IRBs Conduct Minimal Continuing Review of Approved Research. 

Continuing review has become a low priority at many IRBs, often relegated to the last 

few minutes of a meeting. For example, at one IRE3 meeting we observed, several annual 

reviews and amendments were approved within the last 15 minutes of the 2 ‘%hour 

meeting. At another site, several members were visibly hurried to end the almost 6 hour 

meeting and the board relied mainly on the assessment of the primary reviewer for the 

annual re-reviews. One IRE3member told us that he reviews the continuing review 

summaries during the board meeting to see if a patient has died. If no patient has died, 

then he generally will not raise questions. 

Continuing review is a paper-based activity at many IRE3s. At the six academic medical 

centers we visited, officials reported that during the past year they seldom visited the 

research site. Five of the 11 independent boards we interviewed reported that they have 

no routine policy for visiting the research sites under their purview. Although many IRBs 

would like to, very few oversee the consent process or solicit feedback from subjects. 

According to one IRB chair, the lack of resources has forced IRE&sto rely on the 

willingness of investigators to provide timely, accurate reports to the IRK Many 

6 OEI-Ol-97-00193 IRBS: A Time For Reform 
members are uncomfortable with this degree of reliance on self-reported data and would 

like to devote more attention to continuing review. 

Continuing review is further limited by the inadequate information IRBs receive from 

outside sources. There is little communication between the Data Safety Monitoring 

Boards, which are established by sponsors to oversee many of the large-scale trials, and 

the IRB. The adverse-event reports that the IRBs receive from sponsors arrive without 

sufficient contextual information to make them meaningful. When FDA issues a warning 

letter to a clinical investigator, it typically does not inform the IRB.‘7 And, when a 

sponsor or investigator submits a research plan to the IRB, it may not inform the RI3 of 

any prior review of that plan by another IRB. ’* 

In an effort to improve continuing review, the OPRR and FDA have issued interpretations 

of Federal requirements in the forms of Dear Colleague letters and Information Sheets.lg 

Many of these are outlined in appendix B. From the perspective of the IRBs, some of 

these have served to reduce IRE3flexibility and add to their burdens. Of particular note is 

the OPRR issuance reinforcing the Federal intent that IRBs conduct substantive and 

meaningful annual reviews of active protocols. This issuance, some conclude, has had a 

particularly disruptive and demoralizing effect on many IRBs.~’ 

IRBs Face Conflicts that Threaten Their Independence. 

Clinical research is an important revenue source for most academic health centers. For 

example, at one of our sites, about 25 percent of the operating budget (nearly $200 

million) derives from research activities. For decades, under the fee-for-service system, 

research expenditures were subsidized by patient-care revenues; under managed care, 

however, traditional financial support for research activities has been diminishing. In the 

process, commercial sponsorship has become increasingly important. At the academic 

health centers we visited, commercial sponsorship accounted for as much as 50 percent of 

the research funding. 

Commercial sponsorship of research has heightened the potential for conflicts of interest. 

We found several examples of hospital IRBs that are housed in offices of grants and 

contracts or in clinical research programs, the very offices geared to bringing in research 

dollars. Such organizational placements, while not necessarily representing a conflict, 

certainly can accentuate pressures on IRBs to accommodate institutional financial 

interests. Independent IRBs, which primarily review commercially sponsored research, 

are subject to similar pressures. This may be particularly so for those independent IRBs 

that are owned by contract research organizations:’ and those that allow equity owners to 

participate in the review process. The NIH policy for HHS-funded research reviews by 

for-profit IRBs is to prohibit IRB equity owners from participating in the review process, 

but there is no such policy for industry-sponsored studies submitted to FDA. 

..- The phenomenon of IRB shopping, in which research sponsors seek out the IRB they 

choose to work with, places considerable pressure on IRBs and their institutions. 

7 OEI-tIl-97-00193 IRBS: A Time For Reform 
Commercial sponsors seek quick turnaround reviews for their protocols and can be tough 

negotiators on publication rights, liability issues, and other matters. Many academic 

health centers are struggling to respond to this new environment. They find it especially 

difficult to be as timely in their reviews as the independent, typically for-profit IRBs that 

are a growing presence. While they rarely can conduct initial reviews within a month, the 

independent IRBs often do so in little more than a week.22 

Federal regulations calling for at least one IRB member whose concerns are primarily in 

nonscientific areas and orie member who is not otherwise affiliated with the institution 

aim to provide a counterbalance to the kind of pressures noted above. But, we found few 

such “outside” members on the boards. Few IRBs seem to seek or to be able, on a 

consistent basis, to recruit and maintain lay and/or nonaffiliated members who play an 

active, effective role in helping the IRBs stay focused on their mission of protecting 

human subjects. It is not unusual for an IRB of 15 to 20 or more members to include only 

one or two noninstitutional members. 

IRBs and Their Institutions Provide Little Training for Investigators and Board Members. 

The IRB officials that we spoke with fully recognize the significance of educational 

outreach to research investigators and board members. Many have been active in holding 

seminars and/or providing individualized assistance to help investigators become more 

informed about and sensitized to human-subject protections. But nationally, in the 

context of the numbers of investigators and the complexity of the issues, such efforts are 

minimal. Further, they face significant obstacles which include not only insufficient 

resources, but the reluctance of many investigators, especially experienced ones, to 

participate. 

For new RI3 members, their orientation to the role is seldom much more than a stack of 

materials to read and on-the-job learning. A 1995 survey of 172 university-based IRBs 

found that one-quarter offered no training at all to their members. At the vast majority of 

institutions, training was limited to less than four hours. 23 This limitation is especially 

detrimental to the “outside” members who tend to need grounding not only in the basics 

of the regulations but also, in many cases, in the basic concepts, approaches, and terms 

associated with scientific research. The lack of such training further impedes their ability 

to serve as an effective counterbalance to institutional and scientific interests. 

Neither IRBs nor HHS Devote Much Emphasis to Evaluating IRB Effectiveness. 

As we conducted our inquiry, we became increasingly aware of a striking reality: IRBs 

have little basis for knowing how well they are accomplishing their mission of protecting 

human subjects. The IRB and institutional officials we spoke with typically felt that their 

IRBs were quite successful. But when we asked them their bases for that judgment, they 

almost invariably pointed to the lack of serious problems or complaints that have come to 

their attention. Such factors are, of course, relevant to assessing effectiveness, but in 

themselves provide a weak foundation. Seldom, we found, do the IRBs seek out 

8 OEI-Ol-9740193 IRBS: A Time For Reform 

..” 
feedback from human subjects or their families, examine the few complaints that they do 

receive to determine if they reflect broader, systemic problems, or initiate probing 

inquiries--for example, to determine how the informed consent process is actually 

working. Even more seldom, it appears, do independent, outside parties conduct such 

evaluations. 

Federal oversight does not compensate for these deficiencies as it, too, is not geared to 

evaluating effectiveness (see appendix C). The OPRR’s oversight is limited almost 

entirely to upfront assurances aimed at obtaining an institution’s commitment to adhere to 

Federal requirements.24 The majority of IRB staff we spoke with viewed the assurance as 

a paperwork process having no impact on RI3 functioning. Only in instances of alleged 

breakdowns in RI3 protections has the OPRR conducted site visits. Some of these 

reviews represent the most probing and results-focused inquiries we have found of IRB 

performance, resulting in strong recommendations to the IRBs. But because of resource 

shortages, they are infrequent. Between April 1997 and May 1998 only one such visit 

was carried out. 

The FDA oversight involves a more frequent on-site presence. In 1997, they conducted a 

little under 200 site visits (see appendix C). These visits are carried out by FDA 

inspectors who often are also responsible for inspections focusing on food products, 

research sponsors, and clinical investigators. They focus almost entirely on IRB 

compliance with the procedural requirements set forth in Federal regulations--concerning 

matters such as attendance at review meetings, completeness of minutes, and a review of 

the informed consent document. Such matters can be important indicators of 

performance, but they offer FDA little direct feedback on the actual effectiveness of 

IRBs. For instance, in an information letter to IRBs, FDA calls for them to make certain 

that individuals understand what they are consenting to when they agree to participate in a 

research effort. Yet, FDA’s inspection process does not extend beyond determining that 

informed consent forms contain all the appropriate elements and that they have been 

reviewed by the IRB. For example, the FDA inspectors do not review the adequacy of 

the IRBs’ own bases for determining subject understanding. 

9 OEI-Ol-97-00193 IRBS: A Time For Reform 
The stress that so many IRBs now face compromises the protections that IRBs seek to 

provide to human research subjects. Federal leadership can be instrumental in addressing t 

this vulnerability and in shoring up the system of protections that is vital to the continued 

progress of biomedical and behavioral research. It is toward this end that we present our 

recommendations. We call for some strong and inevitably controversial actions. But, the 

recommendations also seek to minimize unnecessary Federal regulation. They reflect a 

respect for the largely collegial manner in which IRBs operate and aim to nourish the 

volunteer contributions that have provided the underpinning of IRB reviews. They also 

take into account the increasingly important role being played by independent IRBs. 

We direct most of our recommendations jointly to the Office of Protection from Research 

Risks (OPRR) which is located within the National Institutes of Health (N1I-I)~’ and to 

the Food and Drug Administration (FDA), since they are the two focal points for IRB 

oversight in the Department of Health and Human Services (HHS). In those instances 

where we direct a recommendation to one of the agencies, we specify the agency. 

In presenting our recommendations jointly to NIWOPRR and FDA, we fully recognize 

that they have different jurisdictions, mandates, and operational approaches. Yet they are 

bound by a common intent to protect human subjects and by what is, for the most part, a 

common set of regulations. If they are to respond effectively to the very serious warning 

signal that our findings present, then it is essential that they collaborate closely among 

themselves and with other pertinent HHS components. In that context, they might also 

address how the Department’s responsibilities for overseeing IRBs could be organized in 

a manner that is most effective and allows for the clearest possible Federal leadership. 

In their deliberations on how to enhance human-subject protections, we also urge 

NIWOPRR and FDA to take the lead in finding ways to involve other non-HHS parties. 

This should include representatives of the research community, the institutions in which 

IRBs are located, and most of all IRBs themselves. Many of these individuals bring 

valuable front-line perspectives on how best to protect human subjects and can offer 

valuable insights into how the Federal government can provide effective leadership. 

Finally, we must emphasize that emerging developments add a sense of urgency to the 

reforms we propose. Most notably, these include Federal plans to increase substantially 

the Federal investment in cancer and other biomedical research. This expanded research 

holds forth great potential benefit to society and perhaps even to subjects participating in 

clinical trials, but at the same time it will add to the review burden of IRBs. So too, if 

enacted, could recent proposals to expand IRB responsibilities in overseeing genetic 

testing and in ensuring patient confidentiality. In considering these developments, it is 

particularly vital that sufficient financial provisions be made to buttress IRB and Federal 

efforts that aim to provide essential protections for research subjects. 

10 OEI-Ol-97-00193 IRRS: A Time For Reform 
1. Recast Federal IRB Requirements so that They Grant IRBs 

Greater Flexibility and Hold Them More Accountable for Results. 

Such a redirection is an essential starting point. We have found that RI3 members and 

staff tend to be strongly committed to human-subject protections and have many ideas 

about how to improve performance. Our report on promising approaches reveals many of 

the innovative efforts they are undertaking, even under current restraints?6 The 

NII-I/OPRR and FDA could help unleash further innovation by giving IRBs more 

flexibility in how they carry out their responsibilities. But, in doing so, a necessary quid 

pro quo, we believe, would be a greater accountability for results. 

What we call for here is in accordance with what is occurring generally in the field of 

health care quality assurance. For instance, in recently announcing major reforms in 

Federal conditions for hospitals’ participation in Medicare, HHS Secretary Shalala noted: 

“We are doing away with old requirements that focused on process rather than results, 

and instead we’re telling hospitals that they must monitor the quality of care they provide, 

improve that quality, and document that improvement.“27 

1 a. Eliminate or Lessen Some of the Procedural Requirements that Federal Regulations 

Impose on IRBs. 

The aim here should be to enable IRBs to be more strategic in how they use their limited 

time and resources and, in that context, to concentrate their attention on those research 

practices posing the greatest risks to human subjects. Too much of their attention now 

focuses on perfunctory review responsibilities yielding little protective value. 

The NIH/OPRR and FDA should work with IRBs and others in identifying the specific 

Federal requirements to be eliminated or modified. One especially strong candidate is the 

requirement that IRBs conduct full, annual reviews of approved protocols. On the basis 

of our review, this mandate generates substantial burdens on IRBs and does not have the 

intended effect. It compels IRBs to devote too much effort to routine, paperwork reviews 

at a time when the quantity of that paperwork is mounting. It impedes them from taking a 

more strategic approach--one that would enable them to concentrate on research 

involving substantial risks to human subjects, to conduct periodic reviews, and to visit 

research sites to determine how the informed consent process is actually working. 

Another candidate for consideration would be what some call the “unfunded mandate,” 

whereby IRBs must conduct complete reviews of Federal funding applications prior to the 

funding decisions. Other candidates would be those Federal requirements that limit what 

IRBs can accomplish in conducting protocol reviews outside of convened board 

meetings.28 

11 OEI-Ol-97-00193 IRBS: A Time For Reform 
1 b. Require that All IRBs Under the Purview of NIH/OPRR and FDA Undergo Regular 

Performance-Focused Evaluations that are Carried Out in Accord with Federal Guidelines. 

This is the direction called for by the Advisory Committee on Human Radiation 

Experiments. In its 1995 report, it concluded (as we have) that the Federal system for ’ 

overseeing IRE& is inadequate. An adequate system, it indicated, would require “that the 

system be subjected to regular, periodic evaluations that are based on an examination of 

outcomes and performance and that include the perspective and experiences of research 

as well as the research community.“2g 

Federal guidelines for IRB evaluations should call for the evaluation results to be 

available to the public (to foster accountability). The guidelines should be minimal and 

should stress assessments of IRB effectiveness. In this regard, they should be attuned to 

the Institute of Medicine’s recent recommendation that IRE3 systems be examined to 

determine how well they are functioning. Among the basic questions posed by the IOM 

that we believe warrant particular attention are the following: “1) Are IRE& successfully 

representing the interests of human subjects in research and not merely those of the 

sponsoring institution? and 2) Do IRE3sgenerally fulfill their goals?“3o We suggest that 

NIWOPRR and FDA convene symposia with IRE3sto discuss the type of performance 

measures and evaluations that would foster a system of accountability based more fully 

on results.31 

The federally mandated evaluations could be self-evaluations or, better yet, ones 

conducted by independent, outside parties. Their frequency should depend on the 

quantity of protocols being reviewed by an IRl3, but probably no less than every 5 years. 

To reinforce their importance, NIWOPRR could include an evaluation requirement as a 

component of the assurances it obtains from research institutions. 

2. Strengthen Continuing Protections for Human Subjects 

Participating in Research. 

In a prior study focusing on investigational medical devices, we found significant 

deviations from IRB-approved protocols and raised concerns about the adequacy of IRB 

oversight of such protocols.32 In this study, which was more broadly based, we found 

little basis for easing those concerns; in fact, they have been intensified. 

It is essential, we believe, for NIWOPRR and FDA to ensure more rigorous and 

accountable oversight of research approved by IRBs. As we have noted, the current 

regulatory infrastructure was established at a time when research was typically conducted 

by a principal investigator, working at one institution, with a local cohort of subjects?3 

Now, a significant portion of IRE3approved research is part of multi-site trials involving 

many investigators and subjects at sites across the nation and even the world?4 The 

Federal regulations should be updated to account more fully for these changed 

circumstances. 

12 031-01-97-00193 IRBS: A Time For Reform 
2 a. Require Data Safety Monitoring Boards for Multi-Site Trials that are Under 

NIWOPRR and FDA Purview and that Meet Specified Conditions Warranting Such a 

Safeguard. 

Data Safety Monitoring Boards (DSMBs) are independent review bodies that review 

ongoing research to assess the efficacy of the data, the adherence of the research to the 

approved protocols, and the continued safety of the subjects. These boards include 

medical, scientific, and other expertise that typically is not available on IRBs. The NIH 

institutes do require DSMBs for many of the cooperative group projects they fund. But, 

there are no Federal regulations calling for the routine establishment of DSMBs?5 The 

NIWOPRR and FDA should take the lead in seeing that DSMBs become more firmly 

established as oversight mechanisms and be made more clearly accountable in that 

regard. ‘Among their designated responsibilities should be those of assessing, 

summarizing, and determining when and how to follow up on adverse-event reports 

submitted by sponsors/investigators. 

The NIWOPRR and FDA should define the types of trials for which DSMBs would be 

required. These could include trials that involve many subjects, that include control 

groups not having access to the research interventions, and/or that involve new drugs, 

devices or procedures that present significant risks to human subjects. In addition, the 

NIWOPRR and FDA should set forth requirements for the composition of DSMBs. 

2 b. Provide IRBs with Regular Feedback on Developments Concerning Multi-Site Trials. 

As we have noted, a substantial portion of the research that many IRBs now oversee 

involves local research investigators and local subjects participating in national or 

international multi-site trials bound by a common research protocol. To provide adequate 

continuing review in these situations, IRBs must be informed about key developments 

concerning the trial as a whole. For instance, if an IRB receives a report about an 

unexpected adverse outcome experienced by a local subject, it will be hard pressed to 

assess the significance of that information unless it knows how many such outcomes have 

occurred for the overall trial. During the course of our inquiry, we identified two key 

sources of information of this kind that should regularly be shared with IRBs. 

First, and probably most important, is information from DSMBs. Instead of receiving 

large quantities of individual adverse-event reports submitted by sponsors and 

investigators, IRBs should receive compilations and assessments of those reports 

prepared by DSMBs. At present, most IRBs receive little if any feedback from DSMBS?~ 

Routine, substantive feedback from DSMBs would allow the IRB to concentrate its time 

and resources on reviewing that which it knows best--the continued suitability of the local 

environment to the research project in question. Regular feedback from the DSMB will 

serve to increase the effectiveness and thoroughness of IRB reviews, as well as its 

efficiency. 

13 OELOI-97-00193 IRRS: A Time For Reform 
-- 

A second important, external source of information is that which federally funded 

cooperative research groups obtain from their monitoring visits to research sites that are 

part of a single protocol.37 This is valuable information collected and analyzed by 

individuals expert in the research being conducted. The reports incorporating this 

information are sent to the research investigators, but rarely are shared with the NBS!* 

The IRBs should receive these reports routinely and thus have the opportunity to draw 

upon them as a complement to their own reviews. 

2 c. Routinely Provide IRBs with Feedback on FDA Actions Taken Against Investigators 

Under their Jurisdiction. 

The FDA inspections of research investigators can result in a variety of actions, from 

warning letters to a disqualification from participating in pre-market research. Officials 

at FDA indicate that legal restrictions under the Privacy Act preclude FDA from 

disclosing all investigator-related correspondence to Irks and sponsors on a routine 

basis. Certain information, however, is available to the public on an FDA web site or 

through the Freedom of Information Act. But many IRBs do not have the time to 

regularly scan the FDA website and might not know when to request information from 

the FDA about one of their investigators. The FDA is in the process of seeking approval 

to modify the relevant Privacy Act systems notice so that the sharing of this information 

with IRBs and sponsors will be made easier. We think this is important as the lack of 

information sharing puts IRBs in an untenable position if they are to be held accountable 

for protecting the interests of human subjects. 

2 d. Require Sponsors and Investigators to Notify IRBs of any Prior IRB Review of a 

Research Plan. 

We heard of a few situations where sponsors and/or research investigators who were 

unhappy with one IRB’s reviews switched to another without the new IRB being aware of 

the other’s prior involvement. This kind of IRB shopping deprives the new IRB of 

information that it should have and that can be important in protecting human subjects. 

The ground rules should be changed so that the sponsors and investigators have the clear 

obligation to inform an IRB of any prior reviews. 3g The obligation should be applied to 

all those conducting research funded by HHS or carried out on FDA-regulated products. 

It will have particular importance for those sponsors and investigators working with 

independent IRBs. 

2 e. Call for Increased IRB Awareness of On-Site Research Practices Involving Human 

Subjects. 

To some readers, this recommendation might represent a violation of the long established 

ethic of trust that has guided IRBs’ relationships with the research community. It might 

be interpreted as “surveillance” and “policing” that could compromise the research 

enterprise. But given the scope and type of research now under the purview of IRBs, the 

risks that much of this research presents to human subjects, the widespread blurring of 

14 OEI-OI-9740193 IRBS: A Time For Reform 
research and therapy, and, the kinds of violations we identified in our previous OIG 

report, trust alone does not provide sufficient continuing protection. The credibility of the 

IRB process in protecting human subjects requires more. While trust must remain an 

important part of the system, it should be accompanied by a greater readiness to verify 

that IRE3sare accomplishing their consumer protection mission. Such verification is 

allowable under current Federal regulations and, in fact, consistent with the intent of the 

National Commission that laid the groundwork for those regulations!o 

Increased awareness of actual practice is consistent with our earlier call for a greater 

focus on results and can be carried out, we believe, in a manner that does not shatter the 

foundation of trust. For projects that are particulary sensitive and/or risky, the increased 

awareness we call for can involve observers, intermediaries, or counselors who are 

available to make sure that the informed consent process functions in the interests of the 

human subjects. It can involve periodic, announced or unannounced, random visits by 

IRE3representatives, both to review pertinent records and to observe the informed consent 

process. It can involve surveys of and/or focus groups with human subjects. As 

illustrated in our report on promising approaches, several IRBs have begun implementing 

these techniques.4’ However it is done, the aim should be to provide IRE& with greater 

assurance that stated intentions involving human subjects are, in fact, being fulfilled. 

3. Enact Federal Requirements that Help Ensure that Investigators 

and IRB Members are Adequately Educated About and Sensitized 

to Human-Subject Protections. 

In the final analysis, the most important continuing protection for human subjects is the 

presence of well-trained and sensitized investigators. Such investigators can also serve to 

minimize the need for regulatory intervention, be it by the Federal government or by IlU3s 

themselves. Accordingly, our recommendation calls for strong Federal action concerning 

education. It is in accord with the President’s May 1997 statement of apology for the 

ethical transgressions of the Tuskegee syphilis study. In that statement, the President 

announced a commitment “to strengthen researchers’ training in bioethics” as a means of 

ensuring that human subjects ’ “rights and dignity will be respected as new drugs, 

treatments, and therapies are tested and used.‘*2 

The NIH is well positioned to assume a leading role here since it funds a significant 

portion of the biomedical and behavioral research in the country. It can help convey to 

researchers that along with the considerable independence that they enjoy in the research 

process there exists a significant responsibility to ensure that human subjects are 

protected in accord with established principles and Federal law. It can assist IRBs and 

their institutions by developing generic educational materials and model curricula. The 

NIH may want to consider working with the FDA, and with groups such as PRIM&R and 

ARENA, to develop these materials. 

15 OEI-Ol-97-00193 IRBS: A Time For Reform 
3 a. Require that Institutions Receiving Funding Under the Public Health Service Act for 

Research Involving Human Subjects Have a Program for Educating its Investigators on 

Human-Subject Protections. 

This is similar to and an extension of a current NIH requirement calling for institutional ’ 

recipients of research training grants to have acceptable plans for instructing trainees in 

the responsible conduct of research.43 It parallels a recommendation offered in 1995 by 

the Commission on Research Integrity44 and is the kind of recommendation that 

NIWOPRR sometimes directs to an institution after it has investigated a lapse in the 

institution’s system of human-subject protections. Such a requirement is currently in 

place for research involving animals. 

The education we call for could be provided through various modalities such as seminars, 

individual instruction, videos, or on-line tutorials. A number of the IRE& we interviewed 

have, of their own accord, developed innovative educational programs along the lines we 

call for. The NIWOPRR could promote these efforts and our recommendation generally 

by calling for an educational assurance as part of its multiple project assurance (MPA) 

with health care institutions. This assurance would more clearly commit the institutions 

to seeing that its investigators have appropriate training in human-subject protections. 

Further, since institutions with MPAs typically apply the IRE3requirements to all research 

conducted by affiliated researchers whether or not they are funded by NIH, such an 

educational assurance could help to reach a larger universe of investigators than just those 

funded under Public Health Service Act programs. 

3 b. Require that Investigators Receiving Funding Under the Public Health Service Act for 

Research Involving Human Subjects Provide a Written Attestation that They Are Familiar 

With and Will Uphold Federal Policies Concerning Human-Subject Protections. 

This recommendation, which again parallels one that the Commission on Research 

Integrity set forth with respect to the “the responsible conduct of research,” asks that the 

investigators acknowledge their awareness of the pertinent policies and procedures. It 

aims to heighten their awareness of their responsibilities as investigators and their interest 

in participating in educational programs addressing human-subject protections. The 

FDA, it is important to note, already requires a similar attestation for investigators 

submitting an investigational new drug application or investigational device exemption to 

the agency!’ Further, some of the institutions we contacted already require that 

investigators sign statements assuring the IRR that they are familiar with and will adhere 

to the human-subject protection requirements. 

Even with such an attestation, we recognize that its effectiveness is likely to depend 

heavily on high-quality educational offerings being readily available to investigators. The 

prior recommendation calling for institutions to provide educational offerings responds to 

this need. The NIWOPRR and FDA could also help meet it by conducting more 

W” educational outreach of their own. This could involve the convening of conferences, as 

they have periodically, as well as preparing and disseminating self-study materials.46 

16 OEI-Ol-97-00193 IRRS: A Time For Reform 
3 c. Require that Each IRB Under the Purview of NIIWOPRR or FDA Have an Orientation 

Program for New IRB Members and a Continuing Education Program for All Members. 

The core content of these education programs should cover not only the basic 

requirements spelled out in Federal law, but also a broader review of ethical principles 

governing human-subject protections and of ways in which IRBs can address those 

principles. For noninstitutional and nonscientific board members, the educational 

programs should also serve as a primer on scientific and research issues, with the intent of 

helping the members gain a better appreciation of key concepts, terms, and context. Here, 

again, a prescription that NIH/OPRR sometimes offers as a corrective action in response 

to an adverse event involving human subjects should be incorporated on the front end as a 

required preventive measure and could be included as part of multiple project assurances. 

4. Help Insulate IRBs from Conflicts that Can Compromise Their 

Mission in Protecting Human Subjects. 

Two long-time analysts of IRBs have described IRB regulations as “a permeable shield, 

with no strong framework to ensure that the subjects’ interests take precedence over 

institutional ones.” They added that in balancing risks and benefits, an IRB “that 

consistently makes the calculus in favor of research will hardly ever be identified.‘d7 

While many Federal and IRB officials are likely to object to this assessment, the minimal 

information they have on the effectiveness of IRBs makes it difficult for them to rebut it. 

Even more troubling, in an environment where IRBs are expected to be responsive to the 

financial pressures facing their parent institutions and/or the sponsors, some IRBs are 

finding it difficult to maintain sufficient focus on their core mission; thus the above 

recommendation. 

Our point is not that IRBs can or should be completely independent entities impervious to 

developments in an increasingly market-based health care system. Rather, it is that they 

and the Federal government must be alert to pressures that might lead some IRBs to 

become overly accommodating to the significant financial pressures that surround them. 

One of the most important roles that NIWOPRR and FDA can play is to help prevent 

such accommodations. 

4 a. Require More Extensive Representation on IRBs of Nonscientific and Noninstitutional 

Members. 

This is a vital matter that responds to a commitment that the President made in his May 

1997 Tuskegee statement.48 Individuals not associated with the institution or with the 

research enterprise can provide a valuable counterbalance to pressures that threaten IRB 

independence. But to do so, it is important not only that they be well-trained, but also 

that there be enough of them on a board so that their-voices are more likely to be heard 

W” and their sense of belonging more likely to be enhanced. The current requirement that 

there be one noninstitutional and one nonscientific member on a board (this requirement 

17 OEI-Ol-97-00193 IRBS: A Time For Reform 
can be satisfied by the selection of a single individual) is clearly inadequate in this regard. 

In its 1978 report the National Commission recommended that at least one third but no 

more than two thirds of IRE3 members be scientists as a way “assure the IRE3’s access to 

[scientific] expertise, yet guard against self-interest influencing or appearing to influence 

IRE3 determination.“’ The case remains strong both for increasing the number of ’ 

noninstitutional and nonscientific members and for requiring that at least one 

noninstitutional member be present at any board meeting where research plans are 

reviewed. It may well be desirable, we would note, to include scientists among the 

noninstitutional members considered for IRBs. 

4 b. Reinforce to IRBs and Their Parent Institutions the Importance of IRBs Maintaining 

Sufficient Independence in Their Mission to Protect Human Subjects. 

We suggest that an IRB with sufficient independence is one that is not under any 

institutional or ownership pressure whatsoever to approve protocols and related 

documents; bases it reviews on the merits of a proposal and the attendant risk/benefit 

ratio, without regard for business concerns; does not report directly to the part of the 

institution responsible for bringing in research funds; is not compensated based on the 

outcome of a review; and has recourse, should it feel subject to any pressure. 

Through “Dear Colleague” and informational letters, NIH/OPRR and FDA could draw 

greater attention to the danger signs that inhibit IRE3sfrom operating with sufficient 

independence and to the kind of preventive measures that they and parent institutions 

might take to ensure a proper focus on their core mission. The FDA, in its compliance 

site visits, could give special attention to the emergence of any of these signs and could 

bring them to the attention of the IRE3 and its parent institution. The NIWOPRR could 

reinforce the issue by including in its multiple project assurances a clause that institutions 

will afford their IRBs sufficient independence in their mission of protecting human 

subjects. Although the immediate, practical effect of such a commitment is uncertain, it 

could serve to generate additional consideration to this important matter. 

4 c. Prohibit IRB equity owners from participating in the IRB review process. 

Such participation, in itself, does not necessarily inhibit the independence of the review 

process, but it creates a situation that can be conducive to ownership influence in that 

process and, certainly, it undermines a perception of impartiality. The OPRR practice of 

prohibiting such participation should be formalized. The FDA should follow suit and 

prohibit ownership participation in IRB reviews for industry-sponsored research on 

products to be submitted to FDA for approval. 

5. Recognize the Seriousness of the Workload Pressures that Many 

IRBs Face and Take Actions that Aim to Moderate Them. 

vu 

18 OEI-Ol-97-00193 IRBS: A Time For Reform 
Federal actions along the lines we have called for in our previous recommendations 

would help reduce IRB workload pressures. IRBs would be freed of a number of 

procedural requirements that are of questionable value and of the torrent of adverse-event 

reports they now receive. Further, if greater educational outreach led to investigators 

becoming better informed about the purpose and particulars of regulations to protect 

human subjects, IRBs quite likely would find that research applications submitted by 

these investigators would require fewer changes (thus saving IRE3s’ time). 

Yet, even with such changes, the adequacy of the resources available to IFU3swould 

remain a significant issue of concern. If the external pressures we have described in this 

report continue (as seems likely) and if IRBs do more continuing reviews and evaluation 

(as we call for), IRBs could still be struggling to maintain a sufficient level of human and 

other resources (such as computer equipment and office space). 

5 a. Require That IRBs Have Access to Sufficient Resources to Enable Them to Carry out 

Their Responsibilities as Intended in Federal Law. 

The resources we refer to are, above all, the human resources represented by staff and 

board members, but also space, computers, and other elements essential to an efficient 

and effective IRE3. We recognize that the term “sufficient” is a general one, not easily 

measured.” Yet, the centrality of the resource issue and the clear shortages that many 

IRBs now face, call for enhanced Federal attention to it. One direction that NIWOPRR 

and FDA could take toward that end could be the development of indicators of minimally 

adequate resource levels, below which IRBs are likely to find themselves in a danger 

zone. For instance, these could involve measures of numbers of staff and board members 

to the number of active protocols, or the number of protocols reviewed per meeting. As a 

starting point, the NIWOPRR and FDA could survey IRBs about their current resource 

levels. 

The NIWOPRR Multiple Project Assurance currently requires institutions to provide 

meeting space and sufficient staff When negotiating an MPA, the NIWOPRR could 

reinforce the importance of resource adequacy by bringing the same scrutiny to it when 

negotiating those assurances as it does when conducting an investigation of an IRB’s 

lapse in protecting human subjects.51 Similarly, the FDA could modify its site visit 

protocol to identify signs of inadequate resource levels to use that information to present 

recommendations, or if serious enough, warning letters to the IRE& involved. 

6. Reengineer the Federal Oversight Process. 

As it now functions, the Federal oversight of IRE& is not equipped to respond effectively 

to the warning signal we present in this report. -l-heFDA conducts just under 200 IRB 

site inspections a year, but its procedural, compliance-focused reviews reveal little about 

IRB effectiveness in protecting human subjects. The NIWOPRR, on the rare occasions 

19 OEI-Ol-97-00193 IRBS: A Time For Reform 
when it visits IRBs, gets closer to assessing IRB performance but its emphasis on upfront 

assurances is of questionable value. Further, while there is some sharing of information 

between the two agencies, they operate in very different domains, rooted in separate 

statutory bases and organizational cultures. 

It is time, we believe, for a fundamental reexamination and reengineering of the HHS 

oversight process, viewed as a whole. The principal aims of this ambitious effort should 

be twofold: (1) to develop more streamlined, coordinated, and probing means of assessing 

IRB performance and (2) to enhance the Federal capacity to identify and respond to 

emerging problems before they result in serious transgressions. 

6 a. Revamp the NIIWOPRR Assurance Process 

We suggest reorienting the assurance process so that it rests essentially on an institutional 

attestation to conform to the IRB requirements set forth in Federal regulations.52 This 

attestation could be provided in a brief statement referencing the pertinent regulations. 

As a result, the scarce NIWOPRR resources that are now devoted to reviewing and 

negotiating assurances could be freed up to conduct periodic performance-based reviews 

along the lines we have been noting and to provide education to help investigators and 

IRB members become knowledgeable about and sensitized to human-subject protections. 

Along this line, we also suggest that NIWOPRR consider providing some incentive for 

smaller IRBs to tie in with larger ones (both hospital-based and independent) that can 

bring more experience to the job. This is important in view of the increased complexity, 

sensitivity, and scale of so much of the research taking place. It is also important because 

it could help concentrate Federal oversight resources more effectively, moving in the 

directions we call for in the prior recommendations. 

6 b. Revamp the FDA On-site Inspection Process. 

This is especially important under current conditions whereby FDA is the only HHS 

agency conducting IRB site visits with any degree of regularity. We recognize that there 

is some value to the compliance checks that are the core of FDA inspections. But we 

suggest that FDA search for ways of revamping its inspections so that they focus less on 

narrow compliance matters and more on performance issues. Such reviews would probe 

deeper and wider and would pay 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. 

We suggest further that FDA and NIWOPRR collaborate on ways in which they could 

focus more directly on “front-line” practices that have particular bearing on human 

subjects. For instance, they might probe 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. They might also examine the marketing approaches being used to *-

20 OEI-Ol-97-00193 IRBS: A Time For Reform 
entice the participation of subjects, paying particular attention to whether too much 

emphasis is given to potential personal benefits and not enough to risks. 

Both FDA and NIWOPRR could enhance a performance focus by finding ways in which 

experienced IRB members and staff could play some on-site role in reviewing IRB 

performance.s3 The Federal agencies could include such a peer review element as part of 

some of its own reviews and/or offer some kind of incentive for IRBs to include it as part 

of a continuous quality improvement effort. In either case, it would represent a way of 

incorporating greater outside expertise into site reviews focusing on performance. 

6 c. Require That All IRBs Register with the Federal Government and on a Regular Basis 

Report Minimal Descriptive Information. 

Uncertainty as to the number of IRBs subject to regulatory oversight by FDA and 

NIH/OPRR is a major hindrance to effective oversight by these agencies. We recognize 

the concerns about Federal intrusions that could add unnecessary burdens to the research 

process. We suggest that a requirement that all IRBs register with the Federal 

government need not be much of an intrusion. It could involve a simple registration 

process in which IRBs regularly update the Federal government on minimal descriptive 

information. This information, for example, could include their location, contact 

information, and the number of protocols and human subjects under their jurisdiction. 

Such a requirement would help NIWOPRR and FDA to target their oversight, to 

communicate more effectively and fully with IRBs, and, in the final analysis, offer 

improved protections to human subjects. 

21 OEI-Ol-97-00193 IRBS: A Time For Reform 
COMMENTS ON THE DRAFT REPORTS 

Within the Department of Health and Human Services (HHS), we received comments on 

our four draft reports from the National Institutes of Health (NIH), the Food and Drug 1 

Administration (FDA), and, jointly, from the Assistant Secretary for Planning and 

Evaluation (ASPE) and the Assistant Secretary for Health (ASH), who is also the 

Surgeon General. We also solicited and received comments from the following external 

organizations: the Applied Research Ethics National Association (ARENA), the 

American Association of Medical Colleges (AAMC), the Consortium of Independent 

Review Boards (CIRB), and Public Citizen’s Health Research Group. We include the 

complete text of the detailed comments in appendix D. Below we summarize the major 

comments and, in italics, offer our responses. 

NIH, FDA, and ASPE/ASH Comments 

The HHS parties responded in generally positive terms. They viewed the reports as 

raising important issues and recommendations warranting serious and widespread 

attention. The NIH urged that the final reports be sent to all 16 Federal agencies adhering 

to the common Federal regulations on human-subject protections; indicated that it will 

take our recommendations to the National Science and Technology Council, which is 

responsible for uniform implementation of the common Federal regulations; and 

suggested that our recommendations will be addressed at the FDA’s March 1999 National 

Forum on Human Subject Protections. The FDA expressed its intention to place some of 

the issues posed in the report on the agenda of the Forum. And ASPE/ASH suggested 

that all the reports be placed on the HHS website. 

Both NIH and FDA also offered comments on our specific recommendations calling for a 

revamping of NIH and FDA practices of overseeing IRBs. The NIH responded that our 

call for reorienting the assurance process so that it rests essentially on an institutional 

attestation to conform to IRB requirements was “well-taken.” It added that the OPRR has 

been seriously considering “a redirection of its intensive assurance effort toward 

performance-based reviews of IRBs.” The FDA, which has a long-established system of 

conducting compliance-oriented inspections of IRBs, responded with some caution to our 

call that the inspections focus less on narrow compliance matters and more on 

performance issues. The FDA indicated that it regarded the current inspection program as 

having “great value,” and that developing performance measures would be “a major 

challenge.” 

Finally, the FDA, as well as some of the subsequent commenters, pointed out that some 

of our recommendations, if enacted, could be “resource intensive” for IRBs and as a 

result could add to the stress on the IRB system. Such impact, it suggested, must be 

carefully considered. 

22 OEI-Ol-97-00193 IRBS: A Time For Reform 
We appreciate the interest in using our reports to stimulate widespread discussion on 

how the IRB system can be reformed to further human-subject protections. We will 

cooperate fully in such efforts. At the same time, we urge immediate attention to the 

spectjic recommendations, such as those concerning information sharing, education, and 

training, which can have important near-term effects in improving protections. We ought 

not allow the needfor discussion to obscure the importance ofpractical actions that can 

be taken immediately to address the vulnerabilities we present in our reports. 

On the matter of revamping NI.OPRR and FDA oversight practices, we strongly urge 

that both agencies give a priority to identtjying spectfic ways of conducting more 

extensive and eflective performance assessments as part of their on-site reviews. We 

recognize that for FDA this will involve a major departure porn a well-established 

compliance approach that does help assure conformance with processes calledfor in 

Federal regulations. But given the scope and signtficance of IRB responsibilities, it is 

imperative, as the Institute of Medicine has indicated, to gain a better understanding of 

how well IRBs are fulfilling their goals to represent the interests of human subjects. Over 

time, this performance assessment could involve developing specific quantitative 

measures that could be helpful in comparing the performance of different IRBs and of 

individual IRBs over time. But the move to performance assessment should not await 

such measures. Many practical steps can be taken in the near-term to help assess or 

veriJL that IRBs are having their intended impact. 

We would be happy to workfurther with FDA and/or NIH to examine specific ways in 

which their on-site reviews might focus more closely and effectively on results. Among 

the key questions that should be addressed in any such effort would be the following: 

How do we know that the informed consent process is carried out in a manner that 

minimizes the possibility of coercion or undue influence? How do we know that the 

process of recruiting and selecting human subjects is being carried out in an equitable 

manner? How do we know tfprotocols that should be submittedfor review are not 

submitted? Or ifapprovedprotocols stray in ways that are not identtjied in paperwork 

submitted to the IRB? These vital questions call for some kind of vertfication by Federal 

parties as well as IRBs themselves. We ought not allow the quest to develop quantitative 

performance measures delay practical steps that can be taken immediately. 

Finally, FDA s point about the resource implications of our recommendations is a very 

important one, warranting further deliberation. We suggest that some of our 

recommendations, such as those that relieve IRBs of some Federal procedural 

requirements and of some of the burden of adverse action reviews, would help free up 

resources. But we recognize that the “trust but verify” thrust we call for is likely to add 

to resource needs as are other forces now being exerted. Most especially, theseforces 

include a potentially sign&ant increase in Federal funding for research on cancer and 

other serious diseases. They also include policy proposals to enhance IRB 

responsibilities to protect individuals participating in genetic tests and to ensure 

conzdentially of information obtained on human subjects. Thejeopardy that we suggest 

exists now could well be exacerbated tfIRBs are not provided with sufficient resources to 

23 OEI-Ol-9740193 IRBS: A Time For Reform 
carry out the vital functions being entrusted to them. This matter, we believe, warrants 

serious attention in both the research and policy communities. 

External Organizations’ Comments 

To varying degrees, the external parties supported many of our findings and 

recommendations. But, overall, they reflected a number of strong concerns. Generally, 

these concerns involved differences of substance and objections to our use of certain 

language. 

Overall, the substantive differences were wide ranging. Public Citizen found many of our 

findings to be alarming and expressed concern that we failed to go far enough with our 

investigations or recommendations. Among other things, it called for more funding of 

IRBs, greater representation on IRBs of disinterested parties (including scientists) from 

outside the institution, and FDA regulation of advertising seeking human subjects for 

clinical trials. On the other hand, the ARENA and AAMC both expressed reservations 

about our call for performance-focused evaluations and for more outside representation 

on IRBs. Both also noted concern that a more active IRB role in conducting continuing 

review could undermine the trust and collegiality that is key to the success of an IRB. 

The AAMC added that our intent to insulate IRBs from conflicts with their parent 

institutions “was improperly framed’ because “nothing could be more in the institutional 

interest than protecting the subjects of research.” 

The concerns about our use of certain terms and language, expressed by ARENA, 

AAMC, and CIRB, were almost as strong as the ones about substance. The ARENA, in 

particular, found our use of the term “IRB oversight” to be misleading because it 

suggested IRB responsibilities greater than those the IRBs are mandated to carry out. 

Further, both ARENA and AAMC raised concerns that some of our wording was 

inappropriately alarmist and more encompassing than our methodology warranted. 

In response to these concerns, we changed some of the terms and language we used in the 

draft reports. Most notably, instead of referring to IRB “oversight, ” we referred to IRB 

responsibilities and authorities to conduct “continuing review. ” We also modtjied some 

statements in ways that we hope more clearly andprecisely express our findings and 

concerns. We made these changes because we seek to focus attention and dialogue on 

the important substantive matters revealed by our inquiry and on the needfor reform Cfor 

which we believe there is widespread support). Our modtjications in no way lessen our 

very real concern that the effectiveness of the IRB system, which has performed a 

valuable protective function for many years, is now in jeopardy. Our wide-ranging data 

gathering involving in-depth discussions and reviews in many different settings provides 

us with a sound basis to present this warning. 

On the substantive matters, we must underscore that tfIRBs are to meet the significant 

challenges facing them in the years ahead, they must become more fully accountable to 

24 OEI-Ol-9740193 IRBS: A Time For Reform 
the public. For the system to be effective, trust in those conducting research must remain 

an important part of the system. But, it must be accompanied by a greater readiness to 

verify that IRBs are accomplishing their consumer protection mission. Such verification 

is allowable under current Federal regulations and, in fact, consistentwith the intent of 

the national commission in the 1970s that laid the groundworkfor those regulations. We 

must also emphasize that in an increasingly commercialized research environment that is 

much different than that which existed when the regulations were first established, 

guarding against conflicts that in subtle ways could compromise the IRBs ’ role in 

protecting human subjects is a matter of increasing urgency. 

25 OEI-Ol-9740193 IRBS: A Time For Reform 
APPENDIX A 

Advertisiw to Recruit Human Subiects 

When Federal human-subject protections were established in the 197Os, a key principle 

was that there should be clear distinctions between research and therapy. Subjects should 

participate in research out of a desire to contribute to generalizable knowledge and they 

should understand that any personal benefits were secondary. Central to their 

participation was an assurance that they understood the risks inherently involved in 

research; their signature on the informed consent document was meant to convey this 

understanding. 

Over the past two decades this distinction has increasingly blurred due to changes in 

subjects’ and the investigators’ perceptions. Many potential subjects have begun to view 

access to research as their best hope for effective therapy and do not want regulators 

inhibiting such access out of a desire to protect them. At the same time, the growth of 

multi-site trials increased the importance of recruiting large numbers of research subjects. 

This, in turn, created increased attention to marketing approaches to attract these potential 

subjects as researchers and their sponsors began to emphasize the personal benefits that 

human subjects could gain from participation in research. An effect of these changes has 

been that the line between research and therapy has become increasingly blurred. As the 

Advisory Committee on Human Radiation Experiments noted: “there is reason to worry 

that participants in research may have unrealistic expectations both about the possibility 

that they will personally benefit from participation and about the discomfort, pain, and 

suffering that sometimes accompany some research.” The committee further stated that 

“it is important that in the informed consent process, it is clearly communicated to the 

potential subject . . .that the primary intent of ‘research’ is to advance medical knowledge 

and not to advance the welfare of particular subjects.“’ 

During the course of our inquiry, we identified and collected many advertisements 

seeking individuals to participate as human research subjects. These advertisements are 

readily accessible to potential subjects, being found in newspapers and on public 

transportation. In a few of these advertisements, even though the study’s experimental 

nature is mentioned, the accompanying language strongly implies that the procedure is 

treatment.* Even when this is not the case, the mention of research is either placed at the 

end of a long list of benefits or is embedded in language so enticing that the inevitable 

’ Advisory Committee on Human Radiation Experiments, Final Report, Washington DC: 

U.S. Government Printing Office, Chapter 18, Section 2 (1995). 

* It is important to note that research advertisements-are not substitutes for the informed 

consent process. Participants must still sign an informed consent document after they contact the 

researchers and agree to participate. 

A-l OEI-Ol-97-00193 IRBS: A Time For Reform 
risks of research are easily overlooked. The advertisements cite an overwhelming array 

of these benefits (see accompanying box and photos at the end of this appendix). In only 

one study did the advertisers 

stress the voluntary nature 

and not personal gain. 

Much more commonly, the 

advertisements supported 

the view that participation in 

research was an opportunity 

for the subject. 

The danger of these 

advertisements is that 

subjects may come to a 

research study with 

misconceptions. For 

example, a person may enter 

into research believing it 

will treat his or her 

depression, panic disorder, 

diabetes, etc. The allure of 

freedom from such an 

ailment is likely to be highly 

motivating. Persons may 

also become attracted to 

research participation by the 

promise of alleviation from 

financial as well as physical 

distress. They may be 

motivated by the promise of 

free treatment, free 

screening, or extra money. 

It is essential, therefore, that 

both the informed consent 

document and the individual 

involved in the recruitment 

of subjects are vigilant in 

making sure the risks 

involved in research are 

Examples of Marketing Efforts Aimed at Recruiting 

Human Subjects 

DO YOU HAVE ASTHMA? 

If you qualifjr for any of our asthma studies, you can: 

- Learn to care for your asthma! 

- Receive free medications! 

- Receive up to $1,730! 

Women: Receive $2710! 

Healthy, non-smoking/drug-free women (20-40) needed 

for USDA research study. Live-in 24 hrs/day for 78 days 

Speed or Cocaine? 

Need help getting clean? 

Free Treatment & Medication. 

Repeat Callers Welcome! ! ! Get Paid $$$ 

Women With PMS 

If you are between the ages of 18 and 40 and suffer from 

PMS (Premenstrual Syndrome), you may qualify to 

participate in a research study using an investigational 

drug for the treatment of PMS. 

If you qualify to participate you will receive: 

Free Medical Exams Free Pap Smears 

Free Labwork Study Medications 

Up to $455 for Time and Travel 

clear. But as we have noted in this report, IRBs devote little attention to how the consent 

process works, focusing all too often solely on the document’s language. 

A-2 OEI-Ol-97-00193 IRBS: A Time For Reform 
The following two photos were taken on a Philadelphia subway car in January 1998. 

Photoscourtesy of the OIG Office of Evaluation and Inspections, Philadelphia Regional Office 

A-3 OEI-OI-97-00193 IRBS: A Time For Reform 
APPENDIX B 

Federal Requirements on IRB Continuing Review 

Institutional review boards’ role in protecting human subjects does not end after the 

completion of an initial review. An IRB is responsible for reviewing, and has the 

authority to monitor, a research protocol from the time of approval onward--until the 

close of the study. The Department of Health and Human Services, through the auspices 

of both OPRR and FDA, has specific requirements concerning how this review should be 

conducted.’ These are specified in the regulations and elaborated on in various agency 

issuances such as OPRR’s “Dear Colleague” letters and FDA’s information sheets. The 

regulations are intended to be used as minimum requirements and IRBs are encouraged to 

impose greater protections as they see fit. 

The continuing review process is multifaceted and involves both an annual review by the 

IRB and the ongoing review of amendments, modifications, and adverse event reports as 

they are received. What follows is a brief description of the elements of this process. 

Continuing Review 

A continuing review must be completed at “intervals appropriate to the degree of risk, but 

not less than once per year.“* This interval has been interpreted as no less than 12 months 

from the date of initial review.3 The review must be completed by a convened board 

unless the protocol qualifies for an expedited review process. The review should include 

an assessment of the protocol and any amendments/modifications. A status report from 

the investigator containing such information as the number of subjects accrued, 

descriptions of any adverse events or withdrawals of subjects, new information pertaining 

to the study and the current informed consent document should also be reviewed! In 

particular, attention should be focused on determining whether the risk-benefit ratio 

remains adequate based on the new information and/or risks that were discovered. 

’ 45 C.F.R., sec. 46 (HHS/OPRR) and 21 C.F.R., sec. 56 (FDA) 

Currently, 16 other Federal departments and agencies abide by these regulations through 

the Common Rule for the protection of human subjects in research, effective August 19, 

1991. 

* Ibid. 

30PRR “Dear Colleague Letter”, 10 January 1995, Continuing Review--Institutional and 

Institutional Review Board Responsibilities. -

41bid, FDA Information Sheets, 1995. 

B-l OEI-Ol-97-00193 IRBS: A Time For Reform 
APPENDIX B 

Modifications and Adverse Event Reports 

Periodically, the IRB may receive amendments/modifications for active protocols. They 

may include a change in address of a sponsor or something more significant such as a ’ 

change in the actual design of a protocol or eligibility requirements. The ongoing review 

of adverse-event reports is another integral and ongoing task for IRBs. An adverse event 

is generally defined by the FDA as a serious experience by a subject that was not 

previously anticipated in nature or severity. “Serious” events include anything fatal, lifethreatening, permanently disabling, or requiring in-patient hospitalization. The 

requirements can be found in 21 C.F.R., section 312 (for drug research) and 21 C.F.R., 

section 8 12 (for device research). They must be reviewed by the IRB or its 

representatives who can then require changes to the protocol. The required changes most 

often result in updating the informed consent document to more accurately explain risks 

to subjects. 

Monitoring 

An IRB has the authority to directly observe (or require a third-party to observe) both the 

consent process or the actual research. 5 IRBs must also follow written procedures for 

determining which studies require verification from a source other than the investigator 

that no changes have occurred and for ensuring that any changes are not initiated without 

IRB review and approval.6 

5 45 C.F.R., sec. 46 (HHWOPRR) 

21 C.F.R., sec. 56 (FDA) 

v- 6 Changes may be initiated before IRB approval if they are necessary to eliminate 

immediate hazards to subjects. See Ibid. 

B-2 OEI-Ol-97-00193 IRBS: A Time For Reform 
APPENDIX C 

Federal Oversight of IRBs 

An estimated 3,000-5,000 IRBs can be found across the country. Two agencies within 

HHS responsible for the oversight of IRBs: OPRR and FDA. Each agency has its own set 

of regulations which have many similarities. However, their processes for oversight are 

markedly different. 

The exact number of IRBs is unknown in part because of each agency’s relationships with 

IRBs. The OPRR becomes aware of IRBs after an assurance is submitted naming the 

IRB as its source of review. Under a single project assurance (see below), the IRB has 

already reviewed the protocol and only NIH funding is needed. The FDA’s contact with 

IRBs comes only at the time of an Investigational New Drug or Investigational Device 

Exemption application. By this time, the IRB has already reviewed and approved the 

protocol and the research is being conducted. Because the exact number is uncertain, the 

FDA acknowledges that it is more difficult to exercise their regulatory oversight. 

Office for Protection from Research Risks (OPRR) 

Assurances 

The OPRR’s oversight of IRBs focuses on an upfront assurance. The assurance is a 

document specifying an institution’s commitment to the human-subject protections 

specified in Federal regulations. It outlines the organization and purview of the IRB in 

addition to its processes for reviewing protocols and other procedural issues. Research 

funded by HHS can only be conducted at a facility holding an assurance with OPRR. 

There are three types of assurances: 

Multiple Project Assurances (MPAs): The MPA allows institutions to conduct any 

number of HHS-funded research projects for an initial period of three years after which it 

can be renewed for 5 year intervals. Regulations require the MPA only for HHS-funded 

efforts, but most of the nearly 450 MPA institutions have extended the protections to all 

research being conducted at their institutions. Though a minority of IRBs hold MPAs, 

these institutions account for nearly 75 percent of NIH-funded research. 

Single Project Assurances (SPAS): For those institutions that do not have the high 

volume of protocols necessary to support the use of an MPA, a single project assurance is 

used. For each project an institution wishes to conduct, it must apply for an SPA. This 

presents extra work for the institution as well as OPRR, who must not only review the 

institutional commitments to the IRB and human-subject protections, but also must 

review the research protocol and informed consent documents for each project assurance. 

Currently, there are approximately 3,000 active SPAS. 

C-l OEI-Ol-97-00193 IRBS: A Time For Reform 
APPENDIX C 

Cooperative Project Assurances (CPAs): The I-II-IS funds approximately 25 

cooperative groups which conduct thousands of clinical trials across the country. An 

institution wishing to conduct any of the groups’ protocols that does not have an MPA can 

apply for a cooperative project assurance. The CPA can then be used for any number of ’ 

cooperative projects. Currently, there are approximately 1,500 CPAs. 

The assurance application process is conducted entirely through document transmittals 

and phone communication. An institution wishing to apply for an assurance can receive a 

template from OPRR. After the institution tailors the template to its specific setting, it is 

submitted to OPRR. There, assurance branch offtcers will review the document.’ Any 

problems or suggestions are worked out through the institutional official(s) and the 

assurance officer before an approval decision is made. 

To ensure compliance, OPRR has the authority to limit, suspend, or withdraw an 

institution’s assurance or require special reporting. 

Investigations 

Compliance investigations are another component of OPRR’s oversight. The OPRR 

conducts investigations primarily on the basis of subject complaints, after becoming 

aware of incidents that appear to have resulted from protection breakdowns or from 

referrals within the department found as a result of audits.8 The OPRR reports that the 

focus of the investigations has shifted in the past five years from micro-level to systemic 

solutions. There is no set investigational protocol as the corrective actions are prescribed 

according to the violation and the needs of the IRB. Since 1990, there have been 438 

investigations of which 360 are considered complete. However, the great majority of 

investigations occur through paper and phone communication. Only rarely does OPRR 

go on site. Between 1990 and April 1996, OPRR went on site to investigate compliance 

only 18 times. In fact, OPRR conducted only one such visit between April 1997 and May 

1998 because of staffing problems.’ 

7For an SPA, the protocol and informed consent document must be reviewed as well as 

the assurance template. The OPRR reports that it spends much more time on SPAS even though 

more research projects and more subjects are involved under MPAs. 

‘Less frequently, investigations are conducted as a result of suggestions from Congress or 

the media. 

9 “Technical-assistance” site visits are also conducted. These visits are intended to be an 

educational opportunity for IRBs and do not signal noncompliance. Between 1990 and April 

1996, 13 such visits were completed. 

c-2 OEI-Ol-97-00193 IRBS: A Time For Reform 
APPENDIX C 

Food and Drug Administration (FDA) 

Inspections 

The FDA’s oversight of IRBs is one of many activities conducted in the process of 

evaluating the safety and effectiveness of the drugs, biologics, and devices it regulates. 

The goal of the monitoring process is to routinely inspect an IRB once every 5 years!’ 

However, inspections can also be conducted as a part of the product-approval process or 

because of possible noncompliance. There are three centers within FDA that are 

responsible for conducting inspections: Center for Drug Evaluation and Research 

(CDER), Center for Device and Radiologic Health (CDRH), and the Center for Biologics 

Evaluation and Research (CBER). An inspection can be generated by any of the centers, 

but the inspections are carried out by the same group of FDA inspectors in regional 

offices across the country. The following table illustrates FY 1997 data for each of the 

three centers including the number of inspections and the number of official and 

voluntary actions indicated.’ ’ 

The inspection guidelines focus on ensuring compliance through the review of IRB 

records and examination of written procedures. Another component of the inspection is 

the file review of at least three actual research studies approved by the IRB. The files are 

examined to determine such things as a timely continuing review, current consent 

documents were used, adverse-event reports were submitted and reviewed, and whether a 

lo This is difficult to achieve because of workload constraints; IRBs found previously to 

be significantly deficient are re-inspected more often. 

“Actions taken are classified according to the strengthen of the action needed to correct 

the deficiencies noted. “Official action indicated” (OAI) is the most serious and warrants FDA 

action. “Voluntary action indicated” (VAI) signifies that the institution will correct the 

deficiencies and often report their progress to FDA at regular intervals. “No action indicated” 

(NAI) is used for inspections which do not reveal any significant deficiencies. 

c-3 031-01-97-00193 IRBS: A Time For Reform 
APPENDIX C 

quorum was present during the voting procedures. Based on the results of the inspection, 

FDA has the authority to issue a ‘warning letter’ signifying serious deficiencies or enact 

administrative sanctions. 

Research investigators can also be inspected by FDA. Generally speaking, the inspections 

are designed to ensure data integrity and ensure human-subject protections to the extent of 

whether or not the informed consent document was signed and dated in a timely manner. 

c-4 OEI-Ol-97-00193 IRBS: A Time For Reform 
APPENDIX D 

DETAILED COMMENTS ON THE DRAFT REPORTS 

AND OIG RESPONSE TO THE COMMENTS 

In this appendix we present the full comments of all parties that responded to our four 

draft reports and our response to each set of comments. In order, the comments that we 

present in this appendix are from the following parties: 

l The National Institutes of Health, U.S. Department of Health and Human Services 

l The,Food and Drug Administration, U.S. Department of Health and Human Services 

l Assistant Secretary for Planning and Evaluation and the Assistant Secretary for Health/ 

Surgeon General, U.S. Department of Health and Human Services 

l Public Citizen’s Health Research Group 

l Applied Research Ethics National Association 

l American Association of Medical Colleges 

l Consortium of Independent Review Boards 

D-l OEI-Ol-97-00193 IRRS: A Time For Reform 
DEPARTMENT OF HEALTH 8r HUMAN SERVICES 

Ms. June Gibbs Brown 

Inspector General 

U.S. Department of Health and Human Services 

Wilbur J. Cohen Building, Room 5250 

330 Independence Avenue, S.W. 

Washington, DC 20201 

Dear Ms. Brown: 

Public Health Service 

National Institutes of Health 

Bethesda, Maryland 20892 

I am writing in response to your March 26, 1998 memorandum that provides four draft reports 

on Institutional Review Boards (IRBs)’ for review and comment by the National Institutes of 

Health (N&I). 

The requirements for IRB membership, function, operations, review of research, and record 

keeping are,described by the core regulations for Protection of Human Subjects of the 

Department of Health and Human Services (DHHS) at Subpart A of Title 45 Code of Federal 

Regulations Part 46. The regulations at Subpart A are the DHHS manifestation of a common 

rule, the 1991 Federal Policy for the Protection of Human Subjects. In addition to DHHS, the 

1991 Federal Policy is shared by sixteen other agencies.’ Because any proposal to revise 

Subpart A of 45 CFR Part 46 would require consideration and concurrence by these 16 other 

departments and agencies, we ask that you convey the final versions of the four reports to your 

counterpart at each respective department and agency. 

Also to further the broad appreciation of your recommendations, NIH will take your final 

overview and recommendations to the Subcommittee on Human Subjects Research, Committee 

on Science, National Science and Technology Council. The Subcommittee will have great 

interest in your suggestions for any potential changes to the common 1991 Federal Policy for the 

Protection of Human Subjects, as it is responsible for the uniform implementation of those 

common regulations. This committee is chaired and staffed by the Office for Protection from 

Research Risks (OPRR), in the NM. Because of OPRR’s authority in negotiating and approving 

assurances of regulatory compliance for Federal-wide use, policy changes by OPRR of the sort 

‘Institutional Review Boards: Their Role in OverseeingApproved Research(OEI-01-97-00190); 

Institutional Review Boards: Promising Approaches(OEI-01-97-00191); Institutional Review Boards:The 

Emergenceof Independent Boards (OEI-01-97-00192); Institutional Review Boards: A Systemin Jeopardy(OEI01-97-00193). 

‘Agency for International Development; Central Ihtelligence Agency; ConsumerProduct Safety 

Commission; Department of Agriculture; Departmentof Commerce;Departmentof Defense;Departmentof 

Education; Department of Energy; Department of Housing and Urban Development; Departmentof Justice; Social 

Security Administration; Department of Transportation; Departmentof VeteransAffairs; Environmental 

Protection Agency; National Aeronautics and SpaceAdministration; and National ScienceFoundation. 
Page 2 - Ms. June Gibbs Brown 

contemplated in your reports are best not imposed unilaterally. Rather, such policy changes 

need to be shaped by the departments and agencies that will be affected. 

Your report makes many valuable suggestions about the role of increased education for scientists 

and IRB members as well as the need for institutions to manage the process of IRB review with 

an eye to the growing number and complexity of projects for their review. It would appear that 

there could be streamlining in the processes from the Federal side and from the institutional side 

as well. One area that may need further elaboration is the special challenges posed by multi-site 

clinical trials. Many of the steps that you would recommend the IRBs take are already within 

their authority to take; therefore, we expect that your report will prove useful to them as they 

seek to strengthen their processes. 

NIH has already taken some steps to bring improved understanding to one area - informed 

consent. Last year we awarded 13 research grants to scientists who are studying informed 

consent. In regard to the needs for education and training, we have issued two solicitations for 

training initiatives in bioethics. One will provide post-doctoral training for individuals who seek 

a concentrated training experience. The other will support short-term institutional awards to 

make increased training in bioethics available to a larger number of scientists. 

OPRR has increasingly made information that is useful to IRBs available on its website. OPRR 

is committed to vigorous consultation with IRBs and institutional officials. This level of 

consultation, for example, is instrumental in the development of meaningful performance 

measures for IRBs--as called for in your reports. OPRR and the Food and Drug Administration 

(FDA) are scheduled to meet with numerous IRB members and staff in regional conferences in 

seven different U.S. cities. Furthermore, NM will participate in the FDA’s March 1999 

National Forum on Human Subject Protection, at which the recommendations from your reports -__- - as well as other reviews of IRB functioning - will be a focus of discussion. We look forward 

to that meeting as an opportunity to discuss with the IRB community some “best practices” in 

areas of education, orientation, management and assessment of IRBs. Your report recommends 

additional requirements to be placed on IRBs, but we hope to focus on the attainment of the 

improvements rather than increased Federal regulations. 

Your suggestion that the assurance process be reoriented so that it rests essentially on an 

institutional attestation to conform to the IRB requirements set forth in DHHS regulations is 

well-taken. OPRR has been seriously considering a redirection of its intensive assurance effort 

toward performance-based reviews of IRBs. Please know that OPRR will not abandon its 

current preemptive oversight procedures (i.e., negotiation of institutional assurances to comply) 

before putting in place a next-generation, competency-based mechanism for assuring 

compliance. 

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 
Page 3 - Ms. June Gibbs Brown 

protecting human subjects in research. NIH appreciates both the opportunity to comment on 

your evaluation, and your contribution to the ethical conduct of NM-sponsored research. 

We would be willing to meet with your staff and discuss these comments. 

Sincerely, 
APPENDIX D 

OIG RESPONSE TO NIH COMMENTS 

We welcome NIH’s positive response to our reports and its readiness to use them to 

stimulate widespread discussion of our findings and recommendations. Given that 

several Federal departments and agencies share a common Federal policy on IRB 

protections, we agree that it would be particularly important and useful to involve them in 

considerations of our reports. We will send our final reports to each of the departments 

and agencies. 

At the same time, we must note that some of our recommendations have particular 

relevance to NIH and involve matters that we believe warrant near-term action. These 

include our recommendations that Data Safety Monitoring Boards be required for multisite trials that meet specified conditions and that these boards regularly provide to IRBs 

feedback on developments concerning these trials. They also include our 

recommendations concerning education and training of both investigators and IRB board 

members. In these areas, we believe it is important to move quickly to spur developments 

that can provide valuable support to IRBs as they review more and more research 

proposals for NIH funding. 

We recognize and support NIH’s interest in streamlining its review processes and in 

reducing any unnecessary regulatory burden on IRBs and researchers generally. This is in 

accord with encouragement offered in a House of Representatives committee report for 

the 1998 NIH appropriations bill. It is also in accord with our recommendations to 

eliminate or loosen some of the procedural requirements directed to IRBs and to revamp 

the NIH institutional assurance process so that it rests essentially on an institutional 

attestation to conform to the IRB requirements set forth in Federal regulations. 

The NIH adds that it will not “abandon its current preemptive oversight procedures. . . 

before putting in place a next-generation, competency-based mechanism for assuring 

compliance.” We support this commitment and agree that a transition to a different 

system of oversight must be carefully orchestrated. In this redirection, a major challenge 

facing NIH and the IRBs themselves is to devote more continuing inquiry to developing 

mechanisms that will help assure that the intended human-subject protections sought by 

the IRB regulations are, in fact, being achieved. It was striking to us, during our own 

review, how little inquiry of that kind now occurs. The NIH is well-positioned to provide 

leadership and guidance in this important transition. 

Finally, we note that the freed NIH resources that would result from the streamlining 

process would offer an important opportunity for OPRR to become more proactive in 

educating investigators and IRB members to become more knowledgeable about and 

sensitized to human-subject protections. Such outreach could be of great value to IRBs 

and could help in conveying a broader appreciation for the importance of ascertaining just 

how well IRBs are achieving their mission. -

D-5 OEI-Ol-97-00193 IRIS& A Time For Reform 
DEPARTME~ OF HEAtTH & l3umAN SEEVI- Publlo Hwlth Service . 

Food ati Drug Admkrktqtiqn 

Rockvillo Mb’ Z&fi7 

May 11, 1998 

To: InspectorGenerai 

From: Lead Deputy Commissioner 

Subject: Comment6on the March 1998Draft Office of the InspectorGeneralReportson 

Institutional Review Boards 

We appreciatethe opportunity to commenton the March 1998draft report6on Institutional 

Review Board6(IRBs). We believethat thesereportsrepresenta thoughtful and detallcd 

examinationof the IRB systemas well asthe rolesof the Federalandprivate sectorparties 

involved in that system. We will carefully considerthe findings, recommendations,and 

supporting information containedin thesereports, which provide valuableinformation that will 

needto be consideredby FDA in collaborationwith NIH, other federal agencies,andthe 

researchcommunity. 

While we agreewith the reports’ conclusionthat the IRB systemis stressed,we arc pleased 

that the reportsdescribedhow many IN38 havefound successfulandcreativemeasuresto deal 

with this stress. The reportsshould be particularly helpful to that portion of the IRB 

community still struggling with someof the problemsdescribedin the reports. 

We note that 6omeof the recommendationswhich could increasethe protection6provided to 

researchsubject6alSO could be very rcsourc:e‘mtensivefor IRBs, clinical investigators,and 

federal agenciesandcould, if implcment~ asrequirements,increasethe amountof stresson 

the IRE3system. We believethat it is, thc?fore, very Important to considerthe impact of each 

recommendationnot only in termsof its impacton the proteclion of researchsubject6but also 

in terms of burdenon the system. 

In commentingon our complianceactivities asthey relate to IRB inspections,the reports 

recommendshifting to an approachof measuringeffectiveness. We considerthe current FDA 

inspectionprogram to havegreat value, and think that establishmentof effectivenessmeasures 

would bc a major challenge, This is a very complexissue,and WCseethe ricedfor a thorough 

exploration of the possibilities in advanceof any decisions. 

WCrecognizethat thereare significant challengesfacing the IRB system. Your reports 

highlisht and add 6UppOIt to a number of areaswhere we believechangemay be needed(e.g., 

a registration requirementfor IREiswould, amongother things, enhanceour abilities to 

provide educationalmatorialsto all IRE3s).We look forward to receiving the final reportsand 

to working with our federalandprivate sectorcolleaguesin further improving the efftciency 

and effectivenessof the IRE3systom. We anticipateintensediscussionof a number of the 

recommendationsby the researchcommunity at IRB andclinical investigatormeetingsandwe 
.’ . , 

pnge - 2 

intend to place someof theseissueson the agendafor our annualnational conferenceon 

humansubjectprotection to be held March 5,1999. 

I have attacheda number of specific commtn$sthat we hopeyou will considerbefore 

publishing your reports. Again, thank you for providing us the opportunity LOcorrqncnton 

thesedraft reports. 

rnos3n’~L 

Michael A. Friedman, M.D. 

Attachment: Specific comments 
I -

Attachment 

FDA’s Specific Comments on OIG Draft Reports on IRBs 

mlonal .’ . Review Boards; T&i&& in Ov~~~~roved Research 

(pg ii) Heightened Workload Pressures 

Inclusion of numbers to support statements about workload would highlight the 

magnitude of the problem. 

Limited feedback on FDA Actions Against Investigators 

Last line: Insert “routinely” after %om” to read “precluded from routinely” 

(pg iii) FDA Oversight Focuses on Inspections... 

“The FDA conducted just over ZOOsite visits in 1997.” 

FoIlow this statement with the number of IRBs (3,000-5,000). FDA conducts 

’ inspections of lRBs, while OPRR conducts site visits, 

(pg 3) Where Are They Located7 

“An estimated 3,000-5,000 IRRs can be found across the country.” 

It should be noted that the uncertainty in the number of IRBs subject to the 

regulatory oversight by Federal agencies is part of the problem in exercising that 

oversight. 

(pg 4) The Limits of Informed Consent 

“They may not reaiize that the primary mission of the research is 

to advance medical knowledge rather than the welfare of the subjects.” 

This could be misinterpreted to mean that the research is being conducted 

in violation of the Declaration of Helsinki 121CFR 312.120(c)(4)]. , 

It may be clearer to state: “They may not rcaliee they are being 

asked to participate in an experiment rather than being offered an 

approved medical treatment of known safety and efficacy.” This point is 

made in the section immcdiately,following, titled “The Blurring of 

Research and Treutnient”. 8 . 

-l-
(pg 9) Limited Feedback on FDA Actions Taken Against Investigators 

Line beginning “purged”: Change to read “purged of trade secret and confidential 

commercial information, and ...” 

Next sentence: Change “inspectors” to “inspections” 

Last line: Insert “with IRBs and sponsors” after “ information” 

. Review Baards..Promisinn 

(pg 8) Promising Approaches 

The meaning of the last sentence of the first paragraph could be improved if 

“howcvcr, as” were changed to “because each” 

(pg 15) Federal Reference Points 

The last sentence should clearly state that “FDA information sheets” is a set of 

* documcnta. The proper citation for these sheets is “FDA Information Sheets for 

IRBs and Clinical Investigators” 

Jostitutis& Review 

(pg ii) Independent IRBs Offer Advantages That Institutional IRBs Find Hard to Match 

Third paragraph may be strengthened by a description of what is meant by “single 

souw of review.” While it is true that the IRB would be the only review board 

for all sites it la also true that the board would have to review the protocol for each 

Individual site that wants to conduct the study, For each submission the lRB 

would want to discuss the needs of the individual community (ethnic groups in the 

community, research subjects available in each community, cnsul’c that the 

protocol can be conducted in each community, etc.) before approving the protocol 

for that community. 

(pg iii) Conclusion 

Last sentence in the second paragraph. Change “At the same, . . . ” to “At the 

same time, * a.” 

-2-
(Pg 4) While There am Relatively Few of Them, Their Number has been Growing 

Although the report recognizes the growth of independent IRBs, the report does 

not provide a reason for their tormation. We suggest that the mason for more 

independent IRBs stems from’s change in FDA’s lcgulutions in 1981. lqrior to 

1981, FDA required IRB review of studies involving institutionalid subjects or 

studies conducted in an institution accepting responsibility for the study (e.g., what 

would now be considered an institution with a multiple project assurance of 

compliance with HHS). In 1981, FDA expanded the scope of its IRB. tegulations 

to include a requircmcnt for IRB review of studies conducted outside of an 

institution (e.g., by private practitioners). In making this change, FDA explained 

its rationale: human subje+s, whether institutionalized or not, aw entitled to the 

protections that these rcgu!atidns offer, The agency rccogniztd th$ in,somc 

instances such physicians may not be affiliated with an institution or have direct 

accessto an IRB. In the preamble to the regulations, the agency dc+c@bedthree 

options available to these physicians: request review of a sludy from an existing 

IRB, request rcvicw from an IRB crtaicd under the auspices of a local or State 

government, institution, society, foundation, or organization, or use an IRB 

created by the sponsor. Inflcpcndent IRBs WCIXcreated to fill this void and fulfill 

the 1981 r~uircment for LRQ+vI~w of all studies involving FDA regulated ’ p1@lcts. , 

. . In.Ftltutlonal Review Born . 

(pg 13) Recommendation 2.a 

The report should note that there is one regulation which requires the 

establishment of an indepcndcrit dath monitoring committee. The FDA regulation 

that provides for an cxcepiion from the informed consent requhtments in certain 

cmergtncy research (21 CFR 50.24) quires that a study conducted under the 

exception have establishe! an iindependentdata safety monitoring bovardto review 

data during the study in order to exercise oversight of the study. 

-3-
APPENDIX D 

OIG RESPONSE TO FDA COMMENTS 

We appreciate FDA’s commitment to carefully consider the findings, recommendations, 

and supporting information presented in our reports and to place some of the issues we 

raise on the agenda of the annual national conference on human-subject protections to be 

held in March 1999. Such deliberations can be of great importance in fostering the 

follow-through that we hope will occur as a result of our inquiry. 

As we suggested in our response to NIH, however, we believe it is important to link this 

longer term deliberation with some near-term actions that can begin to address 

vulnerabilities we point out in our report. With respect to FDA, we particularly urge 

near-term action in ensuring that it routinely provide IRBs with feedback on any actions it 

takes against investigators under the jurisdiction of IRBs. If IRBs are to carry out their 

protective role adequately, it is essential, we believe, for them to be fully informed on 

such matters. Further, we urge FDA to begin examining how it can incorporate a more 

results-oriented focus into its on-site inspection process. 

In making this recommendation to FDA, we do not intend to discredit the complianceoriented inspection process that it has established. We recognize the contributions that 

process has made and that it helps to ensure that IRB processes conform to the letter of 

the law. Yet, we strongly suggest that the increasingly results-oriented approach that has 

come to characterize health care quality assurance/improvement efforts also has 

applicability for both IRBs and Federal bodies overseeing their performance. It is 

especially important that FDA take initiative in refocusing Federal oversight because, at 

least at the present time, it has more on-site IRB presence than any other HHS entity. 

To focus more on how well IRBs are actually protecting human subjects, it would be 

helpful to develop specific measures of IRB performance. This, we recognize, is a 

complex undertaking that should involve other Federal agencies and the IRB community. 

But progress in developing more performance-based reviews should not be dependent on 

just such measures. There is much that FDA can and should do in the near-term to help it 

assess more fully how well IRBs are protecting human subjects. 

We would be happy to work with FDA to identify ways in which they might focus their 

oversight more closely and effectively on results. Among the key questions that could 

guide this process are the following: How do we know that the informed consent process 

is carried out in a manner that minimizes the possibility of coercion or undue influence? 

How do we know that the process of recruiting and selecting human subjects is being 

carried out in an equitable manner ? How do we know if protocols that should be 

subjected to review are not being submitted for review? How do we know if protocols 

stray from the directions set forth in the paperwork reviewed by an IRB? The FDA can 

begin to obtain better answers to such questions through selected reviews at actual 

research sites, through interviews with human subjects themselves, through different lines 

of inquiry with IRB staff and board members, and through other methods. 

D- 11 OEI-Ol-97-00193 IRBS: A Time For Reform 
DEPARTMENT OF HEALTH & HUMAN SERVICES DffkOOfthOSeast#y 

W8rhiwton. 0.6. 20201 

TO: Juiie Gibbs Brown 

InspectorGeneral‘. . 

FROM: Assistant Stcrctary for Planning and Evaluation 

Assistant Secretaryfor Health and SurgeonGeneral 

SUBJECT: Coinmcnts on the Four Draft Reports on Institutional Review Boards 

Thank you very much for the opportunity to review andprovide comments on the four draft OIG 

reports on institutional review boards (IRBs). We appreciatethe amount of workand effort that 

your staff has devoted to preparing thesereports. It showsnot only in their understanding of the 

organization and functions ofinstitutional review boardsbut also in the nature of the 

recommendationsthat have beenproposed. 

Your principal Ending that the IRB system is experiencingsignificant vulnerabilities is an issue 

that we do take seriously.’ Inasmuch asthis system is responsiblefor protecting human subjects 

involved in researchfunded or conductedby the F&ml Government,we rely on it to safeguard 

the rights and interestsof all thosewho participate assubjectsof suchresearch We appreciate 

your recognition of the hundredsof diligent and conscientiousIRB members, s-and principal 

investigators who are strongly committed to the protection of human subjectsand who labor 

towards this cnd’in lessthan ideal circumstances. 

Your observationsregarding the current stresseson the systemarewelltake&; and it is certain 

that, absentstrengthening and corrective measures,suchpressureswillincrease as a result of a 

likely growth in the number and complexity of clinical trials, including trials to evaluateand 

validate genetic tests and trials of xenotranplantation them& 

We also recognize that institutions at which IRBs resideare our partnersin this system to protect 

human subjects. Thus we have a responsibility to shamwith them the findings that your office 

hasmade and to engagethem further in strengtheningthe IRB system. To this end, we hope you 

will make the final reports available on the DHHS.website. 

David Satcher,M.D., Ph.D. 
APPENDIX D 

OIG RESPONSE TO ASPE/ASH COMMENTS 

The ASPE and ASH stress the role of 1RB.s as safeguards and agree that they face 

vulnerabilities that must be taken seriously. We applaud their further comment that 

without “strengthening and corrective measures” the pressures on IRE&sare likely to 

intensify. Our recommendations are offered to mitigate those pressures and shore up 

IRBs for the vital roles they will continue to play. 

We particularly welcome the interest of ASPE and ASH in these issues because their 

broad, department-wide focus on the functioning of IRBs can be enormously important in 

moving forward with the kind of reforms we urge. As we note in this overview report, 

the primary HHS agencies responsible for oversight of Irks, NIH and FDA, have very 

different jurisdictions, mandates, and operating approaches. If they are to respond 

effectively to the warning we present, they will have to collaborate. It would appear that 

ASPE and ASH could play an important role in ensuring that such collaboration goes 

beyond surface-level efforts to substantive interactions that address the seriousness of the 

current situation. 

D- 13 OEI-Ol-97-00193 IRBS: A Time For Reform 
Comments by Sidney M. Wolfe, MD and Peter Lurie, MD, MPH 

Public Citizen’s Health Research Group 

Concerning the HHS Inspector General Reports on Institutional Review Boards 

(GEI-OI-97-0019-f-93) 

Since these reports find that “the System,” referring to Institutional Review 

Boards (IRBs), is “in jeopardy,” it is clear to us that the health and safety of thousands 

of human experimental subjects are also in jeopardy since the protection of people in 

these experiments is the most important function of the IRB system. Although these 

reports conclude that there are not “widespread abuses of human research subjects,” 

the increasingly large number of violations found by FDA investigators in IRB-approved 

informed consent documents, the dangerous lack of on-site inspections for HHSfunded researcti by NIH’s Office of Protection from Research Risks (OPRR), the rise of 

for-profit IRBs-much of whose work is to monitor research done by for-profit clinical 

trials companies-and many other problems documented in these reports belie the 

conclusion of “no widespread abuse.” This conclusion seems particularly inappropriate 

as no systematic search for abuses was conducted nor were known abuses examined. 

The most alarmina findinas of the Inspector General’s Reports are: 

1. Unsafe workload of IRBs: According to the Inspector General’s Report, “at the sites 

we visited, the [IRB] meetings typically lasted about 2 1Xhours and included an average 

of 18 initial [research proposal] reviews, 9 expedited reviews, 43 protocol amendments, 

and 21 adverse event reports.” The report cites other studies finding that the average 

academic medical center IRB was reviewing 297 proposals a year. It is clear that 

adequate time is not being devoted to this difficult task. Worse, there is “minimal” 

attention spent by the IRBs on monitoring the research after it has begun to see if the 

study’s conduct is consistent with the approved protocols. 

2. Massive number of informed consent violations: According to the report, the FDA 

annually does site visits to only about 200 of the 1,500 to 1,700 IRBs involved in 

overseeing research which includes FDA-regulated products. These investigations are 

mainly not done for cause and therefore it can be assumed that the sites inspected in a 

given year are representative of the larger universe of IRBs. In FY1997, there were a 

total of 74 informed consent deficiencies found at the 210 IRBs visited. Since 210 is 

210/l ,500 or only 14% of all of the IRBs, it is reasonable to project that in 1997 there 

were a total of 528 informed consent deficiencies (74/14%). Of the inspection findings 

deemed by FDA to be “most serious”, there were 8 in FY 97 among the 210 IRBs 

inspected which projects to a total of 56 for the whole country in that one year alone. 

3. Misleading advertisements to recruit patients to join experiments: 60 

newspaper or public transportation advertisements were examined to estimate the 

extent to which the line between treatment and research was being blurred. People are 

1 
lured into experiments by emphasizing treatment instead of research: “the mention of 

research is either placed at the end of a long list of benefits or is embedded in language 

so enticing that the inevitable risks of research are easily overlooked....The danger of 

these advertisements is that subjects may come to a research study with 

misconceptions.... They may be motivated by the promise of free treatment, free 

screening or extra money.” One ad illustrating this stated: “Do you have asthma? If you 

qualify for any of our asthma studies, you can: learn to care for your asthma, receive 

free medication, receive up to $1,730!” 

4. New conflict of interest problems with “Independent” (For-profit) IRBs: Because 

a progressively larger fraction of research undertaken in order to get drugs and medical 

devices approved is done by for-profit drug and device testing companies which are not 

part of university medical centers, there has been a proliferation of “independent” IRBs 

to service them. Although they are “independent” of an academic research institution, 

as for-profit entities they are quite dependent on pleasing their customers (the for-profit 

research companies) and their owners. The Inspector General study found that “some 

IRB officials are concerned that an independent, for-profit IRB might compromise its 

revievu-process to advance the financial well-being of the firm. Such concerns are 

heightened’td-the extent that corporate-equity owners or employees serve on the IRB 

review boards and are sustained to some extent by the fact that reviewers are paid for 

their services.” An additional problem involves the fact that most of these are 

nationwide and therefore do not have local representation and input from the localities 

where the trials are being conducted. 

5. Inadequate oversight of IRBs by FDA or OPRR: As mentioned above, only 210 

out of 1,500 to 1,700 IRBS which review studies involving FDA-regulated products are 

inspected by the FDA in a given year: Thus, it may be five or more years between 

inspections, during which hundreds or more studies will have been approved by the IRB 

with no on-site oversight. OPRR does even fewer on-site inspections of IRB monitoring 

functions, mainly employing phone and paper investigations. “Only rarely does OPRR 

go on-site. Between 1990 and April 1996, OPRR conducted only 18 compliance 

visits...[there were] no on-site visits between April 1997 and February 1998 because of 

staffing problems.” Thus, with thousands of NIH-funded human experiments being 

monitored by IRBs, there is dangerously little oversight by the OPRR which is, in 

another example of conflict of interest, part of NIH. 

6. Little evaluation of real effectiveness of IRBs: According to the Inspector 

General’s Report, “officials [of IRBs] reported that during the past year they seldom 

visited the research site. Although many would like to, none oversees the informed 

consent process or solicits feedback from subjects.” One IRB member said “he reviews 

the continuing review summaries during the board meeting to see if a patient has died. 

If no patient has died, then he generally will not raise questions.” 

2 
Reco 

Inadequacies of lnsoector General lnvestiaations 

There is an enormous amount of important information and recommendations in 

these reports but there are two areas of investigation which would have been useful to 

include: 

1. Failure to interview subjects of human experiments: Since IRBs themselves do 

not find out if informed consent was really obtained (see #6 above), relying on a review 

of the document content instead of finding out if patients actually understand the nature 

of the experiment in which they agreed to participate, it would have been useful to 

interview a representative sample of patients in trials, particularly those who had 

finished trials. 

2. Failure to assess differences between boards based on review of a 

standardized protocol or to collect data on differences between IRBs in rejection 

rates or rates of requiring serious modifications in protocols: In the United 

Kingdom, studies have shown that ethical review committees, the equivalent of IRBs, 

differ greatly inthe way they approach and criticize a standardized protocol. Rather 

than collecting such systematic-data, the Inspector General reports depend primarily on 

site visits and qualitative information. Such data would be very instructive in better 

training and education of IRB members. Data examining the extent to which the rate of 

rejection or serious modification of studies reviewed by IRBs differed from one IRB to 

the next might focus on conflicts of interest or other problems with the training and 

education of IRB members. It would also set standards by which IRBs could be 

objectively compared. 

?tlonsde enda ’ e by the Insp ector Genera I 

1. Funding for more adequate review by IRBs: This should be done as an automatic 

predetermined portion of academic overhead for clinical trials. In other words, since 

academic centers are getting funded to do the trials, a sufficient portion of this overhead 

should go to assuring that a much more rigorous review of the research, initially and 

while the trial is underway, is done. 

2. Change in composition of IRBs including much more attention to conflicts of 

interest, especially at for-profit IRBs: Despite recommendations dating back 25 

years that scientists from outside the institution and non-health professional lay persons 

should be included in IRBs,’ this need, especially the outside scientist element, is not 

being adequately addressed. Given the strong institutional bias to say yes to the 

I Barber B, Lally JA, Makarushka JL, Sullivan D. Research on Human 

Subjects. Russell Sage Foundation, New York. 1973. 

3 
possible flow of money, it is particularly important to temper the institutional enthusiasm 

with these more disinterested parties. 

The idea of a for-profit IRB is appalling. It is one thing for a loyal academic to say 

yes to a research proposal which will benefit his or her institution but another for the 

IRB member, possibly an executive or a major stockholder in the IRB, to personally 

gain from approving research proposals. The policy for HHS-funded research reviews 

by for-profit IRBs is to exclude IRB equity owners from participating in the review 

process, but there is no such policy for industry-sponsored studies which are to be 

submitted to the FDA. If it is not possible to abolish for-profit IRBs, at least this extreme 

conflict of interest for the approval of studies of drugs, devices and other FDAregulated products should be ended. This conflict of interest also facilitates the 

phenomenon of IRB-shopping, in which sponsors take a protocol rejected at one IRB 

(perhaps a University IRB as in a recent case mentioned in congressional testimony 2, 

and take it instead to a for-profit IRB which has every incentive to approve the protocol 

lest it gain a reputation as “too strict” and therefore lose business. 

3. Refjulatjon-by the FDA of advertising done by clinical trials units: As discussed 

under finding #3 above, patients can easily be lured into participating in human 

experiments by the misleading advertising discussed in the Inspector General’s Report. 

The FDA should expand its’ regulation of IRBs to include the recruiting materials such 

as advertisements and these materials should also be part of the materials received by 

the IRBs. Combined with misleading information in the informed consent forms, the 

result may be for patients to participate in an experiment without adequate informed 

consent. 

4. Requirements for a central registry of all trials and that the results of all trials 

be made public within one year of completion. In a recent article entitled, Are 

Research Ethics Committees Behaving Unethically? Some Suggestions for Improving 

Performance and Accountabilify, British researchers concluded that the committees 

were behaving unethically “by endorsing new research which is unnecessary and by 

acquiescing in biased underreporting of research which they have approved.” 3 They 

concluded that-research ethics committees should: 

2 Wilfond B. Testimony before the House Subcommittee on Human 

Resources, Committee on Government Reform and Oversight, U.S. House of 

Representatives, May 8, 1997. 

3 Savulescu J, Chalmers I, Blunt J. Are research ethics committees 

behaving unethically? Some suggestions for improving performance and accountability. 

British Med J 1996; 313: 1390-3. 

4 
a/ Require systematic reviews of existing research before approving research; 

b/ Require that a summary of relevant systematic reviews be made available to 

potential participants; 

c/ Require registration of clinical trials at inception as a condition of approval [national 

registry]; 

d/ Require a commitment by investigators to make the results publicly accessible as a 

condition of approval; and 

e/ Audit the reporting of results of research previously approved by them. (IRB 

monitoring of publication is critical to avoid publication bias or .debacles such as Knoll 

Pharmaceutical’s suppression of the levothyroxine equivalency study.‘) 

5. Analysis of close votes at lRBs to see if and why those protocols got approved. 

6. Retrospective analyses of IRB meetings which approved trials now considered 

unethical. c I .I 

7. Remove: OPRR from NIH because of conflict of interest: As long as OPRR is part 

of the institutional block diagram and under the control of the NIH, over whose research 

it is supposed to exert independent control, it is highly unlikely that it will be able to fulfill 

its important mission. It should be .moved outside of the NIH but still within HHS. 

8. Implementing as mandatory for lRBs some of the strategies discussed in 

lnstifutional Review Boards: Promising Approaches (0E1101097-00190) : With the 

growing number of research applications, it seems reasonable at the present time to 

put a limit on the number of applications a given IRB can review per year. iRBs should 

also be required to provide some educational outreach to faculty and students, at a 

minimum including a lecture series on ethics, including lectures on recent controversies 

and new directions in ethics. We were particularly impressed with the 

computer-assisted monitoring of research activity at the University of California, San 

Diego which detemrined that fully 10% of recent publications by faculty members had 

not received IRB approval; this monitoring function, which is rapid and inexpensive, 

should also be made mandatory. Periodic informed consent audits by third parties, as 

conducted at the University of Texas Health Sciences Center, should also be required, 

as should the presence of a bioethicist on the IRB. 

: 

4 Rennie 0. Thyroid storm. JAMA 1997; 277:1238-43. 

5 
APPENDIX D 

OIG RESPONSE TO PUBLIC CITIZEN COMMENTS 

Public Citizen incorrectly states that we concluded that there are no widespread abuses of 

human subjects. Our concluding assessment on this point was that “we do not claim 

there are widespread abuses” of such subjects. We made that point to place our main 

finding about the jeopardy that exists in context and to try to avoid overly alarmist 

reactions to it. As Public Citizen correctly indicates, in this study we did not conduct a 

systematic search for abuses, nor did we investigate known abuses. Rather, our focus was 

on the big picture. We sought to bring greater clarity and understanding to the overall 

system of protections that exist in a varied and rapidly changing environment. 

Concerned about the seriousness of our findings, Public Citizen regrets that we did not go 

further with our review. In particular, it suggests that it would have been useful to have 

interviewed human subjects themselves and to have used a standardized protocol as a way 

to assess differences among IRE&. We agree that both of these techniques could have 

value. However, we were unable to incorporate them as part of our review. We amended 

our report to indicate that such techniques should be considered as part of the regular 

performance-focused evaluations of IRE3sthat we recommend. 

Public Citizen also offers a number of recommendations beyond those that we presented 

in the report. They are thoughtful recommendations that warrant careful consideration by 

the policy and research communities. In two cases, our own consideration of them led us 

to make some changes in the text. In our recommendation calling for more 

noninstitutional members on IRE&., we clarified that such members could well include 

scientists from outside the institution. In our findings and recommendations concerning 

conflict of interest, we clarified that while equity owners are precluded from participating 

in the review process for studies under NIH purview, they are not precluded from doing 

so for those just under FDA’s jurisdiction. We added a recommendation specifying that 

such participation should be disallowed in all cases involving NIH or FDA jurisdiction. 

At the very least, the involvement of equity owners of IRE& in reviewing research 

protocols undermines the public credibility of what should be an independent review. 

Public Citizen’s comments about the importance of proper funding parallel those of FDA 

and other parties. They are well-taken. We reinforce this concern in the introduction to 

our recommendations when we note that “sufficient financial provisions” must be made 

to buttress IRE3and Federal efforts to protect human subjects.” 

Finally, we also take note of Public Citizen’s call for FDA regulation of advertising done 

by clinical trials units. While we are not ready at this point to make such a 

recommendation, we do have considerable concern, as we indicate in the reports, that 

such advertising is currently being used in ways that give potential subjects an unbalanced 

perspective of the risks and benefits of participating in research and that both IRE3 

continuing review processes and Federal oversight processes fail to give sufficient 

attention to this matter. 

D- 19 OEI-01-97-00193 IRBS: A Time For Reform 
--- -- 

May 12, 1998 

June Gibbs Brown, Inspector General 

Department of Health & Human Services 

Office of the Inspector General/Office of Evaluations and Inspections 

Room 5458 Kohen Bldg. 

Washington, D.C. 20201 

Dear Dr. Brown: 

Than& you for giving the Applied Research Ethics National Association (ARENA) the 

opportunity to:comment on the four draft inspection reports (OEI-Ol -97-00190,OO 19 1,00192, 

00 193) on the Institutional Review Board (IRB) system. ARENA is a subsidiary of the Public 

Responsibility in Medicine and Research (PRIM&R), which is a nonprofit organization 

dedicated to promoting the ethical conduct of research. ARENA is a professional association 

with over 800 members who are administrators or members of Institutional Review Boards and 

Institutional Animal Care and Use Committees throughout the United States. ARENA’s 

membership is in part dedicated to the protection of human research subjects and compliance 

with federal regulations governing IRB operations and informed consent. 

ARENA applauds your efforts to address the complex research culture in which IRBs currently 

function. The inspection report entitled “Institutional Review Boards: Promising Approaches” 

provides excellent examples of innovative IRB strategies for enhancing effectiveness and 

efficiency in protecting human subjects. This report illustrates that many IRBs have developed 

creative and effective approaches to managing the challenges presented by the changing research 

environment. 

We support the recommendations delineated in the summary report (OEI-0 l-97-001 93) but have 

general concerns about the four reports’ findings. The general concerns and our specific 

comments on the recommendations are discussed below. 

GENEIWL CONCERNS 

Use of the phrase “FRB oversight” is not appropriate and is misleading to readers who do 

not have IRB expertise. This phrase has been confused with the mandated charge of IRBs to 

conduct continuing review, review of unanticipated problems, and review of proposed changes in 

approved research. IRBs are not man&ted to conduct data monitoring or daily quality assurance 

132 BOYLSTON STREET 

BOSTON. MASSACHUSmS 021 f6 

61742ZJ-4112 phone: 617423-l 165 fax - - -. mn., _ .-.“,, 
of research procedures carried out under approved protocols, as the phrase “oversight” clearly 

implies. The responsibility for oversight and safety monitoring rests with federal regulatory 

agencies, sponsors, and Data Safety Monitoring Boards. The phrase should not be used in the 

headings, subtitles, or the narrative of the four reports because it does not accurately refer to the 

IRB mandate for continuing review. 

The uglobal” language used in the title, the introductory text and the subtitles found in the 

OEI-Ol-97-00193 and OEI-01-97-00190 is very problematic. The general public, 

congressional leaders, and anyone who does not read the report in detail may be left with a 

blanket condemnation of the IRB system. Based on our assessment of the methodology used in 

conducting the OIG inspection, global generalizations which appear alarmist need to be avoided. 

The OIG sample was small and the study used qualitative interviews, not quantitative measures 

to determine I&B effectiveness. Although the reports acknowledge the limitations in the 

methodology and appropriately point to strengths in the system, these limitations are lost amid 

global statements like “rarely does, ” “the little review that does occur.. .,” and “few IRBs seem 

to be able.. .” 

For example, in OEI-0 l-97-00 193 the OIG refers to a prior study that focused on investigational 

medical deviees in which significant deviations from IRB approved procedures were identified. 

The report goes on to state “in this study, which was more broadly based, we found little basis 

for easing those concerns; in fact, they have been intensified.” A representative from one of the 

six academic health science centers site-visited, who also reviewed these draft reports, was 

troubled by this sweeping statement. That person pointed out that during the three day OIG sitevisit the OIG did not review any specific protocol. It is therefore difficult to understand why the 

OIG would conclude that deviations from a specific IRB can be applied to a more broad based 

look at IRBs and ascertain there is a widespread problem. 

Another general concern is that it is unclear in the report on continuing review and the 

summary report whether the findings and recommendations apply only to selected 

segments of the IRB community or whether they apply to the entire community of IRBs 

including independent boards. As currently written, it appears that OEI-0 l-97-00 190 findings 

and recommendations only apply to institutional IRBs. There is no mention in the methodology 

section of the continuing review report that 11 independent IRBs were also interviewed. There is 

no discussion of the continuing review topic included in the report on independent boards. Also, 

in the methodology section of the summary report, there is no mention of interviews with 

independent board representatives. However; some of the findings appear to include 

independent boards; others do not. 

SUMMARY REPORT RECOMMENDATIONS 

As indicated above, in general ARENA supports the recommendations in the summary report. 

However, we do have some specific concerns, which are included in the following discussion. 
Recommendation 1: Recast Federal IRB Requirements so That They Grant IRBs Greater 

Flexibility and Hold Them More Accountable for Results 

ARENA agrees that IRB effectiveness would be greatly improved if the federal policies that 

focus upon “paper trail” aspects of IRB operations or perfunctory review processes were 

eliminated or recast. For example, in two of the reports it is stated that ongoing review of 

adverse event reports is an integral and ongoing task for IRBs. An argument can be made that 

monitoring for adverse events is actually a Food and Drug Administration (FDA) and sponsor 

function that has over time been delegated to the IRB through FDA policy and procedures rather 

than regulatory mandate. The Department of Health and Human Services (DHHS) and FDA 

IRB regulations do not specifically address adverse event monitoring responsibilities. ARENA 

acknowledges that IRBs have a role in reviewing adverse events, but the scope of that role is 

subject to debate. In accord with regulatory requirements, all adverse event reports are sent to 

the FDA. FDA, with trained scientific reviewers, is in the position to evaluate the reports and 

determine if risks for a test article have changed. The FDA could transmit this information to 

sponsors and IRBs if the recommendation to register IRBs is adopted. 

In principle, ARENA supports the recommendations that IRBs undergo performance-focused 

evaluations. However, based upon past experience with the federal regulatory process, we are 

concerned that developing an evaluation system of this type could lead to increased bureaucratic 

workload, which would further drain limited IRB staff resources. 

Developing an effective “performance-focused” evaluation program would be an exceedingly 

difftcult task, which would require identification of appropriate performance-based criteria and 

considerable infusion of resources in both the development and implementation phases. 

Performance-based criteria should be developed by those heavily experienced in IRB processes. 

The criteria should be standardized and universal in its applicability. IRB review is a peer 

review process. Ethical decision-making does not lend itself to traditional procedures for 

assessing effectiveness. In part, that is the reason why the current inspection system tends to 

focus upon the “quantitative” measures (presence of a quorum, continuing review conducted 

within 365 days and so forth) rather than qualitative ones. 

The report also recommends that the evaluations be made available to the public. We question 

how valuable that information would be to the lay public. The performance-based system should 

first be developed before the decision is made on whether the evaluations provide enough 

valuable information to warrant dissemination to the general public. 

Recommendation 2: Strengthen Continuing Protections for Human Subjects Participating 

in Research 

ARENA agrees that the role of Data Safety Monitoring Boards should be expanded and that 

providing IRBs with feedback on the developments in multi-site trials would strengthen human 

subjects’ protections. Also, ARENA concurs that IRBs should be provided with feedback about 

FDA actions against investigators. Many IRBs have compensated for the lack of feedback from 
auditing organizations by requiring the results of any inspection be reported to the IRB as part of 

the continuing review application. 

In addition, ARENA members have expressed serious concerns about the potential in the current 

system for sponsors to seek out IRE3s which do not raise substantive issues or request numerous 

modifications in the informed consent document. We support any recommendations which 

would discourage “IRB shopping” for ease of approval. We support the recommendation that 

sponsors and investigators notify independent boards of prior reviews of research plans. 

Implementing this recommendation may not be appropriate for institutional IRBs which review 

multi-site trials that have previously been reviewed by numerous other IRBs at other sites. 

There are some safeguards currently in the system that deter “IRE3 shopping.” The FDA form 

FD1572 requires an investigator to report any change of IRB. Most independent Irks ask about 

submission to other IRBs when they fust receive a protocol for review. Many of the multi-site 

studies seen by independent IRBs are also reviewed by one or more institutionally-based boards. 

Also, it is commonplace for institutions to require investigators to use their internal IRBs. An 

investigator in an institution generally has no choice about which IRB to use. He or she must use 

the ERR covered by the Office for Protection from Research Risks (OPRR) Assurance for that 

institution. ..i 

In principle, we support the recommendation that IRBs should have increased awareness of onsite practices. However, ARENA has two concerns. First, our experience in the field suggests 

that the most effective IRBs are ones that have a collegial relationship with investigators. 

Violation of the long established “ethic of trust” would undermine IRB effectiveness. We agrzc 

with OIG assessment that one of the most significant challenges facing IRBs is how to achieve 

increased awareness of on-site practices without unde mining the “ethic of trust.” Our other 

concern is a practical one. The approaches for increasing awareness of on-site practices 

suggested in the report (e.g., random audits, observing the consent process) would require 

considerable staff and IRB resources to implement. This concern is addressed in more detail in 

the comments on Recommendation 5. 

Recommendation 3: Enact Federal Requirements That Help Ensure That Investigators and 

IRB Members are Adequately Educated About and Sensitized to Human-Subject 

Protections 

philosophically, ARENA supports the recommendation for mandatory training of investigators 

and board members. However, institutions and IRE3sdo not have adequate resources to comply 

with mandated requirements for training programs. These efforts should be a shared 

responsibility and should not fall solely upon the IRB or the institution. The responsibility of 

conducting ethical and sound scientific research is a shared responsibility of the investigators. 

Training on the ethical conduct of research should become part of the medical or graduate school 

curriculum. Investigators should also be responsible for providing training to their entire 

research team. 

4 
Responsibility for providing training should also be shared with federal agencies. Both FDA and 

OPRR should be provided the resources to expand their training initiatives. Also, a number of 

national organizations such as ARENA and PRIM&R offer training and are in the process of 

developing new programs which focus on both investigators and board members. DHHS 

funding programs should be developed to support initiatives of this type. Also, expenses for 

providing ethical conduct of research training should be an allowable cost for all DHHS funding 

mechanisms. Efforts to cap indirect costs only serve to further drain dwindling institutional 

resources. 

ARENA does not support the recommendation that investigators provide written attestation of 

their familiarity with and commitment to human subject protections. This procedure would not 

serve as an effective training tool. Our experience suggests that investigators submitting grant 

proposals have a number of demands upon their time. Signing the attestation statement will 

become just another bureaucratic hoop that investigators go through in submitting the grant 

application. 

Recommendation 4: Help Insulate IRBs from Conflicts that can Compromise Their 

Mission in Protecting Human Subjects 

Although ARENA would agree that IRBs should be insulated from conflicts, we are 

uncomfortable with this recommendation because it implies that the IRB mission is currently 

compromised. In fact, our experiences have not supported that conclusion. We acknowledge 

that at institutional IRBs there is increased pressure from both investigators and the 

administration to “do more faster.” However, the focus has generally been on “improving 

efftciency” not upon diminishing protections for human subjects. Most institutions are 

committed to protecting human research subjects as are the IRB members and staff. ARENA 

also found this recommendation confusing because it did not include any reference to 

independent board confkts. Not addressing this issue in the recommendations implies that 

conflicts are only problematic for institutional based IRBs; this conclusion conflicts with the 

observations regarding potential financial conflict of interest included in the OEI-0 l-97-00 192 

report. 

Although ARENA agrees that nonscientific and noninstitutional members serve an important 

role in reviewing protocols, we do not support the recommendation that additional federal 

requirements for increased representation be enacted. We do not agree with the OIG conclusion 

that the current requirements are inadequate. Regulations and federal policy require that the 

membership include a nonscientist and a noninstitutional representative. Meeting these 

requirements by appointing a single individual is not a standard IRB practice. In addition, the 

requirements specify that a nonscientific member must be present to conduct a full review. The 

decision to “add” additional members should be left to the discretion of the IRB. From a 

practical standpoint, obtaining a quorum for “full review” is difficult and increasing the total 

number of members will only serve to exacerbate this problem. Based upon our experiences, we 

do not agree with the OIG statement that few “outside members” are on boards. Our experience 

suggests that this is simply not the case. IRBs always include at least one such member and 

many IRBs include additional noninstitutional members. Also, the statement “Few IRBs seem to 

5 
seek or be able, on a consistent basis, to recruit and maintain lay members.. .” may be true for 

some IRBs but in our experience is not true for the majority of IRBs. 

Recommendation 5: Recognize the Seriousness of the Workload Pressures that Many IR,Bs 

Face and Take Actions that Aim to Moderate Them 

ARENA applauds OIG’s recommendation to require that IRBs have access to adequate resources 

but does not think that “requiring” is sufficient. One of ARENA’s overriding concerns about the 

recommendations is that they have the potential to establish a number of Ymfunded” mandates. 

Recommendations 1,2, and 3 will require considerable additional resources to implement. The 

fmdings of the assessment as outlined in the continuing review and the summary reports clearly 

indicate that IRBs are currently lacking in adequate resources; yet, the implementation of the 

recommendations will only serve to increase costs and the need for additional staff and 

resources. Many institutions are committed to providing adequate resources but in fact do not 

have sufficient funds to do so. At the federal level, the problem is exacerbated by increased 

agency requirements for cost sharing and continual efforts to reduce indirect cost rates. DHHS 

needs to develop support mechanisms to assist in funding the new initiatives. The OIG should 

include acknowledgment that it is likely the proposed recommendations will not be effective 

unless additional resources are available. 

Recommendation 6: Re-engineer the Federal Oversight Process 

ARENA agrees with the recommendations to revamp the National Institute of Health/Office for 

Protection Corn Research Risks (NIWOPRR) assurance mechanism and refocus the FDA on-site 

inspection process on performance based criteria. As pointed out in our comments on 

Recommendation 1, we support performance-based evaluations but are concerned about the 

difficulties in developing a system of that type. Efforts must be made to ensure that in reengineering the Federal oversight process that the “old” bureaucratic hoops are not simply 

replaced with “new” bureaucratic hoops with only marginal relationship to quality and 

effectiveness of reviews. ARENA feels that it is important to periodically evaluate the IRB 

review system. It is equally important that this system be assessed fairly and appropriately. 

ARENA also wants to stress the importance of FDA and NII-IYOPRR continuing to coordinate 

federal policy development. If FDA and OPRR policies are as uniform as possible, given the 

legislative mandate for each agency, the bureaucratic burden on IRBs would be greatly reduced. 

Also, we strongly support the recommendation that experienced IRB members and staff should 

play an on-site role in reviewing IRB performance and the suggestion that Federal agencies 

include a peer review element or offer IRBs some type of incentive as part of a continuous 

quality improvement effort. We also support the recommendation that all IRBs be registered 

with the Federal Government, provided the mechanism is streamlined. Based upon our 

experiences in the field, ARENA is concerned that even though the registration process is 

proposed to be “simple” the procedures could, in fact, become “complicated,” adding to the 

already unmanageable IRB administrative workload. 

6 
In conclusion, ARENA acknowledgesthe effort OIG made in reviewing IRB regulations and 

procedures. It is a difficult task to write reports that encompassthe activities of IRBs from such 

a wide variety of facilities and institutions involved in the conduct of human subject research. 

ARENA also appreciatesthe inclusion of innovative proceduresselectIRBs have developed to 

copewith the ever burgeoning task of IRB review. It provides a balancefor what will be 

perceived as a negative report on IRB processes. Many IRBs do conduct substantivereviews 

and simply do not get the recognition deservedfor the ethical diligence. 

The recommendations made by OIG, for the most part, are onesthat could be implemented by 

many IRBs to improve the quality of their reviews. It is true that with additional resourcesmany 

IREiscould become more sophisticatedin their review processes.It is not clear Eromthe report, 

however, from where theseresourceswill originate. It is a long leap from “requiring” such 

resourcesto actually receiving them. 

ARENA thanks you for the opportunity to comment on the reports. If any additional information 

is required, pleasedo not hesitateto contact us. 

Sinc~ely,~, :,! 

William Freeman,M.D. 

ARENA President 

Drafting Committee: 

Gary Chadwick 

Norma Epiey 

SharonFriend 

Karen Hansen 

Ada Sue Selwitz, M.A. 

Chair, Public Policy Committee 

Erica Heath Gwenn Oki 

Moira Keene JoanRachli.n 

SusanKometsky Beth Ribbeck 

Helen McGough Pat Scannell 

7 
APPENDIX D 

OIG RESPONSE TO ARENA COMMENTS 

In our review, we gained great respect for the work and commitment of IRB 

administrators and members, often under very trying circumstances. We listened, 

sometimes at considerable length, to them articulate concerns about the developments 

that threaten the effectiveness of their boards. Sometimes we were able to supplement 

these conversations with a review of records and reports concerning their operations. In 

its response to our draft report, ARENA, whose members are IRB administrators and 

members, did not tend to reflect the same message we heard so consistently from the 

individual administrators and members during our year-long inquiry. 

As the ARENA response itself suggests, perhaps to some degree this disconnect is 

attributable to some of the language we used in our draft reports. In an effort to improve 

communication and focus attention on the necessary reforms, for which we believe there 

is considerable support, we have changed some of the language we used. Thus, we have 

changed the title of this overview report from “A System in Jeopardy,” to “A Time for 

Reform.” We have made other such changes and elaborations to indicate, even to the 

casual reader, that our reports are not intended as a “blanket condemnation” of the work 

of IRE3.s.At the same time, we must stress that we still find that the effectiveness of the 

system is, indeed, in jeopardy. As an independent overseer, it is vital that we present such 

a warning when we find it applicable, and do so in a manner that is clearly 

communicated. Thus, within the report, the jeopardy warning remains as our central 

finding. 

Another key linguistic change we made was in the use of the term “oversight.” Given 

ARENA’s concerns, we reserved that term for the monitoring of IRBs done by the 

Federal agencies (NIH and FDA). With respect to IRE& themselves, we now refer to their 

role in conducting “continuing review” of approved research rather than oversight. This 

is consistent with the language used in the Federal regulations concerning IRE&. We 

must note, however, that those regulations clearly give IRE3sthe authority “to observe or 

have a third party observe the consent process and the research”--something that, in fact, 

they rarely do. Further, an OPRR “Dear Colleague” letter to IRE3scalls for continuing 

review to be “substantive and meaningful”-- a characterization that many IRE! officials say 

does not describe current practice. This limited attention to continuing review is 

unfortunate, because while to varying degrees other parties conduct continuing review of 

approved research, they, unlike IRE&, do not have a central mission of protecting human 

subjects. 

Our focus on continuing review emerged because a prior OIG inspection concerning 

investigational medical devices found, in four case studies, considerable evidence of 

inadequate continuing review, and because of the findings of various other studies cited 

in the report. We state in this report that our inquiry has led us to become even more 

concerned about the inadequacy of continuing review. The ARENA questions the basis 

for that conclusion, citing the observation of a representative of one of the academic 

D - 27 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX D 

health centers we visited. That person wondered how we could reach such a conclusion 

when during the 3 days we spent at that center we did not review any specific protocol. 

Our response is that, as we note in the report, we did not seek in this inquiry to conduct 

any audits of particular protocols or investigations of specific cases. It was our broader 

systemic analysis that led us to recognize the limits of the continuing review that Irks do 

conduct. It was the substantial accumulating evidence associated with that awareness that 

led to the intensification of our concerns about the adequacy of continuing review. 

In regard to ARENA’s comments on our recommendations, we must stress what we 

perceive to be the importance of IRESsbecoming more fully accountable to the public. It 

is toward this end that we strongly urge ARENA to recognize the overriding importance 

of performance-focused evaluation, not just in terms of the complex task of developing 

performance measures, but even more so in terms of concrete actions that IRELscan and 

should take to assess and verify the actual results of their efforts in protecting human 

subjects. (Our response to FDA elaborated on some of the questions that could be raised 

in this regard.) It is toward the same end of shoring up public accountability that we urge 

greater representation of outside interests on IRE&. As 1-s become more involved in 

conducting reviews involving genetics research, which raises vital issues involving the 

use and confidentiality of information, such broader representation will become even 

more important. The public credibility of the entire IRI3 review process could depend 

heavily on such representation. We know that many IRB officials agree with this 

assessment and that they have been frustrated by their lack of success in recruiting and 

maintaining a sufficient core of nonaffiliated members who provide an effective 

counterbalance to institutional interests. 

With respect to our recommendation calling for investigators to provide a written 

attestation of their familiarity with and commitment to human-subject protections, we 

regret that ARENA viewed it as an unjustifiable demand on investigators’ time. This 

recommendation parallels one carefully considered and presented by the Commission on 

Research Integrity. We submit that the signing of the attestation by investigators would 

take minimal time, but would represent an important formal commitment to take 

seriously their responsibilities in upholding human-subject protections as called for in 

Federal regulations. Many IRB officials themselves suggested that they had a difficult 

time getting investigators to devote sufficient attention to those regulations. 

On the matter of insulating IRESsfrom conflicts, we agree with the comment that our draft 

report made it appear that the possibility of conflicts were greater for institutionally based 

Irks than for independent ones. Accordingly, we have revised the text to more fully and 

clearly express our concern about how conflicts can compromise the mission of all types 

of IRBs. We also agree with the concerns raised about the adequacy of resources, as we 

have commented on in response to the FDA comments. 

Finally, in response to ARENA’s concern about the type of IRBs to which our findings 

and recommendations apply, we note that they are presented as applicable to the IRIS 

D - 28 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX D 

community as a whole. Obviously, some will be more relevant to some types of IRBs 

than others. Occasionally we point that out when we have reason to believe that to be the 

case. Overall, we have given more attention to IRBs in academic health centers, where, 

as we point out, a significant portion of research continues to be conducted. So our 

findings have particular applicability to them. But in the course of our inquiry we have 

interacted with representatives of IRBs in many other settings, including hospitals of 

various sizes, public agencies, and independent, free-standing bodies. We would not 

exclude them from the main thrust of our findings. 

D - 29 OEI-01-97-00193 IRBS: A Time For Reform 
24x) N STFtEFL N%! WASHINGTON, IX 20057-1127 

PHONE 202-828-0400 FAX 202-828-1125 

May 4, 1998 

JuneGibbs Brown ’ 

Inspector General 

Department of Health and Human Services 

Fifth Floor 

330 IndependenceAvenue, N.W. 

Washington,D.C. 20201 

Dear Ms. Brown: 

Jordan J. Cohen, M.D., President 

On behalf of the Association of American Medical Colleges(AAMC), I would like to thank you 

for sharingwith us your March 1998 draft report on institutional review boards. The AAMC’s 

membership- all 125 accreditedU.S. medical schools,over 400 teachinghospitals,and 89 

scientific and academicsocieties-- conductsthe majority of clinical researchin this country, and 

ensuringthe safety of those who volunteer to participate as subjectsis a significant concernof this 

Association. The keystone of the current systemof protections is the institutional review board 

(IRB), and thus the sound functioning of thesebodies is of the utmost importance. 

The study your office conductedwas reported in four volumes,but they include many recurrent 

themesand observations. Thus, for the sakeof simplicity and brevity, this letter will focus on the 

most salient issuesand recommendations,rather than comment on eachreport separately. First, a 

few very general observationsare in order. 

Taken together, the reports do not adequatelyacknowledgethe proper role of IRBs in assuring 

the protection of human subjectsin research. IRBs were establishedas a consequenceof the 

report of the National Commission for the Protectionof Human Subjectsof Biomedical and 

Behavioral Research(Belmont Report), which identified the basicprinciples of beneficence, 

justice, and respectfor personsthat havebecomethe cornerstonesof ethical clinical research. 

Guided by theseprinciples, the role of the IRB is to weigh the risks posedby the researchagainst 

the benefits that the researchmay offer to the patient and society. IRBs arethus constituted in a 

way that enablesexamination of theseethical considerations. They were establishedto work 

collaboratively with investigators,the vast majority of whom arealtruistically motivated and 

intend to do the right thing. IRBs aid investigators in their work by ensuringthat subjectsare 

fully informed, and that any risks are reasonablein relation to anticipatedbenefits. 

In contrast to theseobjectives,the report seemsto presumeinsteada policing or auditing role 

that, in fact, is inconsistentwith the mission articulated for IRBs in the Belmont Report. For 
June Gibbs Brown 

May 4, 1998 

Page 2 . 

example, the summary report observes,“the IRB processis rooted in trust,” and assertsthat this 

characteristic is in conflict with the oversight role of theseboards. This observationseemsto 

serve as a premise for much of the report and reflects a fundamental tisunderstandiig about how 

IRBs were intended to function. It is the trust that existsbetween the IRB and investigator that 

permits this systemto work effectively becauseit encouragesopenness,responsiveness,and 

collaboration. 

Nonetheless,asthe report amply notes, IRBs indeed face tremendousstressesat this time. They 

unquestionably bear enormous workloads and could undeniably benefit from additional resources. 

The AAMC is sympatheticto many of the observationscited in the report along theselines, but 

finds that the title of the report and some of the introductory text are disproportionately alarming.’ 

The systemis neither in crisis, nor on the verge of collapse,as somemight infer. As your cover 

letter-appropriately states,the system is “supported by many conscientiousresearchinvestigators 

committed to protecting human subjectsand by many dedicatedIRB membersand staffdoing 

their best...” This fact is beautifully illustrated by the volume of your report on Promising 

Approaches, which provides in a very constructive and positive way useful examplesof how 

particular JRBs havebeen especially innovative in overcoming obstaclesand in enhancingtheir 

effectiveness.As a consequenceof this dedication and resourcefulness,the systemhasworked 

remarkably well in the face of many challenges. 

The report is also prone to generalizations and very sweepingconclusions,eventhough it is based 

on a literature review, interviews with alimited sampling of IRB representatives,andvisits to only 

six institutions. While certain observations are certainly true anecdotally, an impressionis given 

that they apply to all, or even a majority, of IRBs, which may not be the case. Statementsin the 

report concerning continuing review are a particularly salient exampleof this type of writing. 

On the topic of resources,the report notes the extent to which IRBs needto have adequate 

material SUppOtt to enable them to carry out their responsibiities. The AAMC concurswith this 

statement,but notes that the greatest challengeis finding the necessaryfunds to develop and to 

make available such resourcesas office space,computers, and administrative support. Institutions 

face both increasing cost sharing on federally supportedresearch(through the cap on . 

reimbursementof administrative costs, for example) coupled with an accretion of compliance and 

other regulatory requirements, and thus funds for thesesorts of resourcesare increasingly scarce. 

One solution may be to develop a specially-designatedsource of federal support for IPB 

activities, either through a mechanismthat would be funded in proportion to NlIMmded human 

subjectsresearch,or through a more general&d flexible fimdiig mechanism,such asthe 

“ResearchInnovation Oppot-&mit$‘. program, which the AAMC hasproposed as a substitute for 

the now defunct BRSG program. 
June Gibbs Brown 

May 4, 1998 

Page 3 

While many of the recommendationsin the report are reasonable,some are problematic or in need 

of refinement. Detailed commentsare provided below: 

Recommendation 1: Recast Federal IRR Requirements so that They Grant JR.& Greater 

Flexibility and Hold Them More Accountable for Results - The Association agreesthat IRBs 

spendtoo much of their attention on perfunctory review responsibilities, and that lesseningsome 

of theserequirementswould be a usefbl step, particularly review of protocols that ultimately 

neverget funded. Performance-focusedevaluationscan be desirablefor certain activities, but may 

be problematic for IRBs. The key will be to discernthe appropriate performance-basedcriteria to 

usefor evaluation of IRB performance, which is very qualitative in nature. The report 

recommendsmaking IRB evaluationsavailableto the public, but it is not clear what types of 

information,would be provided and how lay people could assessit meaningfully. Until this is 

better defined, the AAMC would discourageroutine public disseminationof suchreports. 

Recommendation 2: Strengthen Continuing Protections for Human Subjects Participating 

in Research - Multi-site trials do indeed pose specialchallengesfor oversight, and it would be 

reasonableto require that Data Safety Monitoring Boards play a significant role in assessing, 

summarizing,and determiningwhen and how to follow up on adverse-eventreports. The AAMC 

also agreesthat IRBs shouldbe informed about the progressof multi-site trials as a whole, even 

though an individual board’s review may be limited to the,work being conducted at a particular 

institution. Indeed, IRBs needto be aware of adverseeventsoccurring elsewhere,suchthat the 

risks of the protocol canbe reassessedfor the local study population. More systematic 

communication from the FDA to IRBs about actionstaken againstinvestigatorsis also a laudable 

objective, asunderscoredin the report. 

Finally, while appreciatingthe intent of recommendation2e -- increasedIRB awarenessof on-site 

researchpractices- it should not be conducted in a mannerthat threatensthe collaborative 

relationship betweenthe IRB and investigator. As statedearlier, IRBs are not watchdogs, and 

neither havethe resourcesnor mission to be expectedto conduct surprise visits on investigators. 

Recommendation 3: Enact Federal Requirements that Help Ensure that Investigators and 

DU3 Members are Adequately Educated About and Sensitized to Human-Subject 

Protections - This is perhapsone of the most important recommendationsin this report. 

Problems,when they occur, are most often attributable to inadequatetraining and sensitizationon 

the part of investigators. Individual institutions, aswell as national organizations, suchasPublic 

Responsibility in Medicine and Research(PRIM&R), are developing educational programs, some 

targeted at investigatorsand others focused on IRB members. NE&supported mechanisms 
JuneGibbs Brown 

May 4, 1998 

Page4 

should be developedto support thesekinds of outreachand clinical researchtraining activities 

that require significant resourcesto function effectively. 

Recommendation 4: Help Insulate IRBs from Conflicts that Can Compromise Their 

Mission in Protecting Human Subjects - This recommendationis improperly tied and 

problematic in practice. The observationsmadeat the outset of this recommendation imply that 

IEU3sregularly havethe institutional interest in heart at the expenseof those of researchsubjects. 

This setsup a false logic whereby the subjects’ interestsare presumedto be in conflict with those 

of the institution, and that the IRB somehow must choosebetweenthe two. The fact of the. 

matter is that nothing could be more in the institutional interestthan protecting the subjectsof 

research. Apart from the firm commitment that all medical schoolshaveto the ethical principles 

underlying the Belmont Report, violations of those principles put institutions at extremerisk. 

Thus, the predominant pressurethat IRBs feel fi-om their parent institutions is to be rigorous in 

their review. -

At the very least, any amplification of the current requirementfor representationof non-scientific 

and non-institutional membersshould be at the discretionof the IRB. First, participation on an 

IRB is done voluntarily and demandssign&ant amount of time. Finding membersof the public 

who are willing to give of themselvesto this degreecanbe exceedinglydifiicult. Second,once 

appointed, theseindividuals often do not becomesignificant contributors to IRB deliberations 

until they have servedfor a long enough period of time to developa relevant ethical and scientific 

knowledge base. At that point, they generally bring the sameconcernsand perspectivesto the 

table astheir other colleagueson the board. Adding additional non-scientific and non-institutional 

membersis thus likely to put a strain on IRBs while theseindividuals are recruited and“brought 

up to speed” that will not be outweighed by the ongoing contributions of suchparticipants. In the 

end, what benefits the IRB processand patientsthe most is the quality of outside membersand 

the contributions they make, not simply the numberof them on the committee. 

Recommendation 5: Recognize the Seribusness of’the Workload Pressures that Many IRBs 

Face and Take Actions that Aim to Moderate Them - The needthat JRBs havefor ample 

resourcescannot be overstated,yet merely to require adequateresourcesis insufficient. As stated 

earlier, bureaucratic accretion coupled with institutional cost sharingis making the provision of 

resourcesincreasingly d*ZEicultat a time when IRBs faceunprecedentedburdens. Institutions do 

their best to provide IRBs with the materials they need,but a specialNJH support mechanismas 

previously describedshould be developed. In addition, the provision of adequateresources 

should be a priority, but is not implementable asaformaZ requirement. It would be diicult if not 

impossible to develop workable criteria for determiningthe types and levels of resourcesthat 

would be adequatefor the very diverse set of IRBs that are now in existence. Their workloads 

and local circumstancesarevery different, as are consequentlytheir resourceneeds. 
JuneGibbs Brown 

May 4, 1998 

Page5 

Recommendation 6: Reengineer the Federal Oversight Process - The report repeatedlycites 

the inadequaciesof IRB oversight of ongoing protocols. It is important to note that the needfor 

oversight varieswidely, dependingon the complexity and risks posedby eachprotocol. Thus, 

any performance-basedassessmentsshould take this into account. With this in mind, the AAMC 

particularly supportsthe proposalsto emphasizeinstitutional assurancesof confommncewith 

federal IRB requirements,and education to help investigatorsandIRB membersbecomeas 

attuned as possibleto human subjectsconcerns. Similarly, the shift in emphasisproposedfor 

FDA review - from narrow compliance checksto more performance-basedcriteria - may be 

workable, but should take into account the caveatexpressedearlier about-theneedto develop 

soundperformancebasedcriteria first. We particularly applaudthe proposed involvement of 

experiencedIRB membersin reviewing II& performanceasa form of “peer review.” The 

registration of all IRBs with the government seemsreasonable,aswell. 

Special Issues: Advertising to Recruit Human Subjects - All advertising for the purposesof 

patient recruitment is consideredpart of the researchprotocol, andthus must be reviewed and 

approvedby an IRB. IRE3sthus examinethe text of theseadvertisementswith an eyeon ensuring 

that they are not overly coercive with regard to financial inducements,nor misleadingwith regard 

to the statedbenefits of participation in research. Nonetheless,patient recruitment canbe a 

challenge,sincevolunteers must give of their time and often must be inconveniencedto 

participate in a protocol. Thus somemodest level of compensationis generally reasonable. 

The specific advertisementsprovided in the report are highly anecdotaland do not enhancethe 

reader’sunderstandingof the predominant way in which suchadvertisingoccurs. Nor doesthis 

approachrecognizethe extent to which subjectsbecomeinformed of clinical researchthrough 

their physicians,voluntary health societies,or patient advocacygroups, which havehistorically 

actedquite responsiblyand often with the benefit of IRB input, either directly or indirectly. 

In conclusion, it is important to emphasizethat, overall, this is a systemthat hasworked 

remarkably well, and one that is not on the verge of collapse. Thus the alarmist tone in some 

sectionsof the report, particularly the overview, shouldbe lessenedto make the level of concern 

expressedmore proportional to the magnitude of the problemsidentified in the report. We also 

strongly suggestthat the title of the report be changedto be lesssensationaland more 

constructive in tone. In addition, the traditional and proper role of IRBs in ensuringthe 

application of the Belmont Report principles to humansubjectsresearchmust be emphasized,and 

text implying an auditing or policing role should be eliminated. 

On the other hand, the AAMC findsthe OIG’s report to raisemanyvalid and important 

observations. The most salient include those that relateto the extent to which IRBs face 
JuneGibbs Brown 

May4, 1998 

Page6 

tremendousworkloads and could benefit Corn additional resources. The report also provides 

much useful and constructive information on how specific institutions havebeeninnovative in 

enhancingIRB effectiveness. This material, found largely in the volume on Promising 

Approaches, should be amplified andbecomea central focus of the report. 

The AAMC thanks you once again for this opportunity to comment and invites you to cantact the 

Association again if we can be of service. 
APPENDIX D 

OIG RESPONSE TO AAMC COMMENTS 

We concur with AAMC that the IRBs are the keystones of the current system of 

protections and that “the sound functioning of these bodies is of the utmost significance.” 

That is why we have given so much attention to just how they are functioning and how 

they might be improved. Obviously, we disagree with AAMC on a number of the 

particulars. 

One of the most important of these particulars has to do with how we interpret the role of 

IRBs in carrying out their protective responsibilities. The AAMC stresses that from the 

beginning the essence of that role has been one based on trust, whereby IRBs work 

collaboratively with investigators to help them ensure that the necessary human-subject 

protections are in place. It points to the Belmont Report, produced in 1979 by the 

National Commission for the Protection of Human Subjects of Biomedical and 

Behavioral Research, as establishing the basis for this collegial role. It suggests that we 

misunderstand this backdrop and assume “a policing or auditing role” for IRBs. 

As we note in our reports, we recognize the fundamental importance of trust between 

IRBs and the research community. At the same time, we underscore that trust in itself is 

insufficient. This is particularly true today as IRBs face many possible conflicts in an 

increasingly commercialized research environment. But even in the 1970s the National 

Commission noted above had more than trust and collegiality in mind when delineating 

the role of IRBs. The Belmont Report cited by AAMC is an important report setting forth 

ethical principles of research. But prior to it, the National Commission produced many 

other reports. One, as we elaborate on in Footnote 28 of our report on continuing review, 

focused specifically on IRBs. In that report, the Commission elaborated on the 

verification efforts that IRBs might undertake. These included interviews with human 

subjects, requirements that investigators give subjects a form through which they may 

report their research experiences to IRBs, and even, in certain cases, requirements that a 

neutral party be present to help a potential subject to consider the pros and cons of 

participating in a research effort. 

We emphasize this matter here at the outset of our response because it is fundamental to 

the kind of reforms we (and many others) regard as necessary. If our calls for greater 

accountability through more results-focused assessments, broader representation on IRBs, 

and other measures, are routinely dismissed as violating the essential principles of IREs, 

then little progress is likely. Thus, further discussion of this important matter in the 

research and policy communities would be highly desirable. Our intent is to maintain the 

foundation of trust, but to complement it with various types of verification that are 

essential for a review body having a vital role in protecting human beings. 

The changes we have made in some of the language we use, as we noted in our response 

to ARENA, may help address some of the concerns AAMC expresses about our 

generalizations and conclusions. We do not conclude that the IRB system is necessarily 

D - 36 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX D 

“on the verge of collapse,” but we certainly do have reason to conclude that its 

effectiveness is in jeopardy. We have tried in these final reports to use language even 

more carefully to express our serious concern without conveying a greater degree of 

imminent danger than we have basis to suggest. 

The AAMC, as other commenters, addressed the matter of resources and how they might 

best be tapped to support the IRBs’ important role. It suggested that some specially 

designated source of Federal support might be developed. As we have noted in other 

responses in this appendix and in the introduction to our recommendations, we recognize 

that this is an important issue warranting further examination, especially as IRB 

responsibilities expand. 

The AAMC supports our recommendation that IRBs be granted greater flexibility in 

carrying out their responsibilities, but is wary of performance-focused evaluations, 

especially if made available to the public. As we have noted in response to FDA and 

ARENA, there are many practical ways of incorporating a greater focus on results, both in 

the IRBs’ own continuing review efforts and in outside assessments of IRBs. And we 

would add that these could be carried out and presented in ways that lay people would 

find quite possible to understand. Further, we stress that a greater accountability for 

results must be integrally associated with efforts to grant IRBs greater flexibility. 

In regard to our recommendation urging that NIH and FDA help insulate IIU3s from 

conflicts that can compromise their protective mission, AAMC indicates that “nothing 

could be more in the institutional interest than protecting the subjects of research.” We 

agree with the principle expressed in that comment. But in settings where clinical 

research represents as much as a quarter or more of the operating income of IRBs’ parent 

institutions, where IRBs are urged to expedite their review processes and make other 

adaptations to accommodate sponsors, where IRBs serve under the auspices of 

organizational units primarily responsible for bringing in research dollars, we submit that 

it is reasonable to be concerned about the kind of conflicts we point out. Many IRB 

officials themselves have emphasized this point to us, quite strongly. 

Finally, on the matter of advertising to recruit human subjects, AAMC indicates that our 

warning is “highly anecdotal” and that we exaggerate the danger associated with these 

advertisements. Our response is that with little difficulty we accumulated 60 

advertisements that were highly imbalanced in presenting risks (rarely mentioned) and 

benefits and that we could easily have collected many times that number. 

Notwithstanding the fact that many subjects are recruited through quite responsible means 

and that all must sign an informed consent form, we suggest that the advertisements do 

represent a danger that warrants careful attention. Just a mere glance at the inducements 

offered in many of these advertisements makes that quite obvious. 

D - 37 OEI-01-97-00193 IRBS: A Time For Reform 
CONSORKWMOF INDEPENDENTREVIEWBOARDS 

May.4, 1998 

June Gibbs Brown 

Inspector General .. 

Oflke of Inspector General 

Department of Health and h&n Se&c 

330 Independence Avenue, S.W. 

Washington, DC. 2020 1 

Rt: Draft Reports Conttrnlng Institutional Rtvitw Boards 

Dear Ms. Brown: 

On behalf of the Consortium of Independent Review Boards (“CIRB”), we congratulate 

the Department of Health and Iiuman Services’ (“I-NY) Office of Inspector General (“OIG”) on 

its four comprehensive reports on a difficult issue. In addition, CIRB thanks you for the 

opportunity to meet with you and comment on the 010 reports concerning the effectiveness of 

current Institutional Review Board (“IIZB”) regulations, policies, and practices. Provided below 

are our comments concerning the following documents: (1) Inrtifutional Revtew Boar& A 

System in Jeopardy (Drafl); and (2) Institutional Review Boards: The Emergence of Independent 

Boards (Drafi). The CIIU3 membership hopes that these comments will be helpful to 010 as it 

finalizes the draft documents. 

1. INSTITUTIONAL REVIEW BOARDS: A SYSTEM IN JEOPARDY 

(DRAFT) .. . 

As the document fnsritlitfonal Review Boar& A System in Jeopardy (Drafi) clearly 

reflects, the environment within which IRBs currently operate is very different from that which 

existed when the Federal IRB regulations were first implemented. Thus, CIRB agrees with the 

OIG’s recommendation to recast these regulations so that the focus wiil be on IRE performance 

rather than merely IRB compliance. OIG’s suggestions to mod@ or eliminate certain 

perfunctory Federal requirements that may not be necessaryto proteot human subjects, and to 

establish new Federal regulations or guidances that require, and set standards for, IRB 

Performance-Focused Evaluations wilI greatIy assistin implementing this recommendation. The 

OIG report correctly observes that many IRBs operate under significant timeand resource 

constraints. While a large proportion of the Federal regulations certainly support human subject 

protection, when IRBs must spend precious time complying with redundant or unnecessary 

Consortium of Independent Review Boards Phone: (513) 7614100 

10 Knollcrest Drive, Suite 200 Fax: (513) 761-1460 

Cincinnati, OH 45237 
MS. June Gibbs Brow 

May 4, 1998 

Page 2 

Federal regulations, inadequate time and resources are I& for ongoing activities. Elimination of 

such regulations would allow IRBs to focus their limited resourceson strategies that would allow 

more effective initial review of rescarch activities by providing time to carefully consider the 

research and the protocol. 

In addition, CIFU3strongly endorses rho recommendation that NIH/OPRR and FDA 

convene symposia with IRBs to discuss performance measuresand self-evaluation measures that 

will encourage IRE3accountability to its stated purpose: the protection of human subjects. We 

believe that such symposia would~result in fruitful dialogue between the agencies, the Irks, and 

other interested parties or users of IRBs, such as investigators and sponsors, and would allow the 

agencies to develop effective oversight policies. 

We also strongiy support the 010’s recommendations concerning “information sharing.” 

While the majority of sponsors and investigators have demonstratedintegrity during the IRE3 

review process, we believe it is important that these parties be obligated to inform a reviewing 

IRE3about any prior reviews. Further, so that an 1RB can function effectively, it should be 

provided copies of a11FDA and OPRR regulatory inspectional reports and correspondence with 

investigators concerning clinical studies which the IRB has approved and for which it continues 

to provide oversight. Finally, becauseclinical investigations are already subject to government, 

contract research organization, and sponsor auditing and tnonitoring, we believe that extending 

the required “information-sharing” between the parties could bc extremely helpful in providing 

“oversight” without adding the burdens of additional site visits to an already overworked clinical 

investigator. 

We do have one concern, and that is the definition of the following terms: “continuing 

review,” ”monitoring, ” “oversight, ” “visits,” and “inspections.” Chrly, these terms can have 

different meanings to different people and it is not completely clear how these terms are being 

defined in this report. 

2. INSTITUTIONAL REVIEW BOARDS: THE EMERGENCE OF 

INDEPENDENT BOARDS (DRAFT) 

While we agree with much of what is reported in the document entitled Institutional 

Review Boar&: The Emergence of Independent Boa& (Drafi), we are concerned about the 

report’s emphasis on the independent IRB’s ability to consider local concerns and attitudes as it 

reviews research protocols. We note at the outset that the ready availability of information 

sharing tools, such as the Internet, has made it more feasible for independent IRBs to become 

knowledgeable about local attitudes and interests. Moreover, as the OIG’s draft report, 

Institutional Review Boards: A e.rfem in Jeopardy, aptly reflects, the environment in which 

IRBs operate has,changed significantly over the past twenty years in that, among other things, 

there has been a steady rise in national and multi-site studies. An advantage of an independent 

board reviewing a multi-center or national trial is that it can develop a benor understanding of the 

safety profile of the product because it receives a broad spectrum of serious adverse event reports 
Ms. June Gibbs Brown 

May 4, 1998 

Page 3 

from multiple sites. Such information may not be made available to single site boards. Thus, 

while it is important to maintain a review system that addresseslocal attitudes and concerns, in a 

national or multi-center study environment, the local community is best protected where IRBs 

have the ability to work with a number of sites. 

Moreover, as the report notes, in the last twenty yeara there has been an incredible 

increase in the number of protocols requiring IRB review, while at the same time, the research 

community and pharmaceutical industry are demanding that protocols be reviewed more quickly 

and efficiently. As a result, the need to address local attitude must be assessedin light of the 

national nends that have developed since the early 1970s. We believe that this is a multi-faceted 

issue which is ripe for discussion in a symposium setting. . .. 

Again, we txtend,qur congratulations on the report and thank you for the opportunity to 

comment on these draft documents. We hope that the OIG will feel tie to contact CIRB if we 

can be of any assistance. 

AMBfamb 

cc: ChesapeakeResearchReview, Inc. 

Essex IRB _. 

Ethical Review Committee 

Independent Review Consulting 

Quintilw, Inc. 

New England IREl 

Sincerely, 

John Isidor, J.D. 

Chairman 

Research Consultants Review Committee 

Schuhnan Associates IRB, Inc. 

WestemIRB 1.’ 
APPENDIX D 

OIG RESPONSE TO CIRB COMMENTS 

We appreciate CIRB’s generally positive comments about the reports. With respect to its 

concerns about the definition of certain terms, we have, as noted in prior comments, 

sought to be more precise in our use of the terms “continuing review” and “oversight.” 

We use the term “monitoring” infrequently and mainly in context of the work of bodies 

other than IRE&s. We use the term “inspections” mainly in context of FDA’s regular onsite inspections of IRE3and the term “visits” to refer to visits to the IRE3 site, whatever the 

basis for the visit. 

The CIRE3 also expresses concern about our “emphasis” on independent IRIS “ability to 

consider local concerns and attitudes as it reviews research protocols.” It elaborates on 

how these IRE& are able to take into account local issues and how in the case of multi-site 

trials the independent IRE& are able to tap into a broad spectrum of information from 

multiple sites. 

We recognize the latter as one of the perceived advantages of independent IRE3sand 

indicated that in our report on independent IRBs. At the same time, we felt compelled to 

note the lack of a local presence as one of the perceived disadvantages of independent 

IRE3.s. We did not emphasize the point. We simply cited it as one of the factors that 

many in the IRB community express concern about when assessing the role and 

contributions of independent IRE3s. We reiterate here that our report on the independent 

1-s is not an evaluation of their performance but rather a description of their growing 

role and of the major advantages and disadvantages attributed to them. 

D-41 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

Endnotes 

1. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and 

Behavioral Research, Implementing Human Research Regulations: Second Biennial Report in 

the Adequacy and Untformity of Federal Rules and Policies, and of their Implementation, for the 

Protection of Human Subjects, (Washington, DC: U.S. Government Printing Office, 1983). 

2. For a fuller explanations of these concerns see Nancy E. Kass and Jeremy Sugarman, “Are 

Research Subjects Adequately Protected? A Review and Discussion of Studies Conducted by the 

Advisory Committee on Human Radiation Experiments,” Kennedy Institute of Ethics Journal, 

Vol. 6, (1996), No. 3, pp. 27 l-82, and the Advisory Committee on Human Radiation 

Experiments, Final Report, (Washington DC: U.S. Government Printing Office, 1995). 

3. U.S. General Accounting Office, Scienttfic Research: Continued Vigilance Critical to 

Protecting Human Subjects, GAOHEHS-96-72, March 1996. 

4. Department of Health and Human Services, Office of Inspector General, Investigational 

Devices: Four Case Studies (OEI-05-94-OOl OO), April 1995. 

5. According to the President’s Budget for Fiscal Year 1999, the NIH, which is the flagship of 

the President’s Research Fund for America, would be increased by nearly half over five years. 

For more discussion, see Robert Pear, “Medical Research To Get More Money From 

Government,” New York Times, Saturday, 3 January 1998, pp. Al and A8. 

The Task Force on Genetic Testing calls for placing greater emphasis on the role of the IRB in 

evaluating genetic research protocols. (Eds. Neil A. Holtzrnan, and Michael S. Watson, 

Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task 

Force on Genetic Testing, NIH-DOE Working Group on Ethical, Legal, and Social Implications 

of the Human Genome Research, September 1997.) In addition, a recent Senate bill would rely 

on the IRB to determine measures of confidentiality, such as whether subject identifiers should 

be retained (S. 192 1, 105’h Congress, sponsored by Senators Jeffords and Dodd). 

6. The body is the National Bioethics Advisory Commission. It was established by Presidential 

executive order on October 3, 1995. Its charter, issued in July 1996 by the Assistant to the 

President for Science and Technology, calls for it to focus its attention on: “A. Protection of the 

rights and welfare of human research subjects; and B. Issues in the management and use of 

genetics information including but not limited to human gene patenting.” For some background 

on the Commission and its emergence, see Alexander Morgan Capron, “An Egg takes Flight: 

The Once and Future Life of the National Bioethics Advisory Commission,” Kennedy Institute of 

Ethics Journal, Vol. 7, (March 1997) No. 1, pp. 63-80. 

7. We use the term “academic health centers” in accord with the following definition offered by 

Blumenthal, et al: “One of 125 institutions in the United States that consist of at least a medical 

school and an owned or closely affiliated clinical facility in which faculty instruct physicians-inE-l OEI-Ol-97-00193 IRRS: A Time For Reform 
APPENDIX E 

training. These centers classically conduct teaching, patient care and, in many cases, research.” 

(David Blumenthal, Eric G. Campbell, Joel S. Weissman, “The Social Missions of Academic 

Health Centers,” New England Journal of Medicine, Vol. 337,20 November 1997, No. 2 1, pp. 

1550-53.) 

8. These IRBs are overseeing research at institutions receiving over 1.4 billion dollars of Public 

Health Service (PHS) awards. As of March 1998, these institutions received over 27 percent of 

the PHS dollars awarded extramurally for human-subject research. 

9. These six institutions alone account for over half a billion dollars of Public Health Service 

(PHS) awards. As of March 1998, these institutions received over 11 percent of the total PHS 

dollars awarded extramurally for human-subject research. 

10. Charles Mar-wick, “Institutional Review Boards Under Stress: Will they Explode or 

Change?” Journal of the American Medical Association, Vol. 276, (27 November, 1996), No. 20, 

pp. 1623-1626. 

11. Charles MacKay, NIH Office of Policy for Extramural Research Administration, Letter to 

Reports Clearance Officer, PHS, Request for Office of Management and Budget (OMB) Review 

and Approval for the study “Evaluation of NIH Implementation of Section 491 of the Public 

Health Service Act, Mandating a Program of Protection for Research Subjects”, Concept 

Clearance 9025-0404, March 10, 1995. See also Harold Edgar and David J. Rothman, “The IRB 

and Beyond: Future Challenges to the Ethics of Human Experimentation,” The Milbank 

Quarterly, Vol. 73 (1995) No.4, pp. 489-506. 

12. This according to the comments of Dr. Jim Childress, meeting transcript of the National 

Bioethics Advisory Commission, 9 January 1997, (Eberlin Reporting Service: Silver Spring, 

MD), p. 20. 

While this phenomenon was true for drug studies, the situation was’reversed for medical device 

studies. The intraocular lenses studies involved thousands of subjects. Most of the studies were 

conducted at small community hospitals. 

13. Comments of Dr. Jim Childress, meeting transcript of the National Bioethics Advisory 

Commission, 9 January 1997, (Eberlin Reporting Service: Silver Spring, MD), p. 21. 

14. Between 1974 and 1975, IRBs reviewed an average of 43 proposals per annum. (Institutional 

Review Boards: Report and Recommendation of the National Commission for the Protection of 

Human Subjects of Biomedical and Behavioral Research, 43 Federal Register, 10 November 

1978, p. 56186.) 

15. Barbara Mishkin, “Ethics, Law and Public Policy”, Professional Ethics Report (a publication 

of the American Association for the Advancement of Science), Vol. 7, (Spring 1994), No. 2, 

pp. 4-6. 

E-2 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

16. U.S. General Accounting Office, Scientljic Research: Continued Vigilance Critical to 

Protecting Human Subjects, GAOIHEHS-96-72, March 1996, p. 17. 

17. The FDA reports, however, that it is in the process of revising its policies on disclosure of 

such information. 

18. We do not claim that this practice is widespread, but IRB representatives we spoke with did 

identify situations where such information was not conveyed. These representatives emphasized 

a certain vulnerability they felt about not being sufficiently informed about any prior IRB 

reviews. Some of the independent IRB officials we spoke with were particularly concerned 

about this practice. 

The FDA cites 2 1 C.F.R., sec. 8 12.150(b) when this situation occurs: “A sponsor shall upon 

request by a reviewing IRB or FDA, provide accurate complete, and current information about 

any aspect of the investigation.” We believe, however, that the rules regarding notification 

should be made more explicit. 

19. The FDA and OPRR also offer frequent interpretations in more informal ways: over the 

telephone, by electronic mail, fax, or in person. Many IRB officials we spoke with stressed that 

these clarifications were helpful to them. 

20. Charles Marwick, “Institutional Review Boards Under Stress: Will They Explode or 

Change?” Journal of the American Medical Association, Vol. 276, (27 November 1996), No. 20, 

pp. 1623-1626. 

2 1. Contract Research Organizations manage clinical trials for drug and device manufacturers. 

22. For more information about the independent, for-profit IRBs, see our companion report 

Department of Health and Human Services, Office of Inspector General, Institutional Review 

Boards: The Emergence of Independent Boards (OEI-0 l-97-00 192) June 1998. 

23. Gregory J. Hayes, Steven C. Hayes, and Thane Dykstra, “A Survey of University 

Institutional Review Boards: Characteristics, Policies, and Procedures”, IRB, Vol. 17, (May-June 

1995), No. 3, pp. 1-6. 

24. The National Service Research Award Act of 1974 established the assurance as the primary 

mechanism by which the Department was to oversee research involving human subjects. 

(National Service Research Award Act of 1974, Public L. No. 93-348, sec. 474, 88 Stat. 342.) 

25. We use NIH and FDA as the two focal points because they are parallel constituent agencies 

of HHS. We add OPRR to the NIH side because in the IRB community, OPRR, a component of 

NIH, is typically viewed as the focal point for IRB oversight. 

26. Department of Health and Human Services, Office of Inspector General, Institutional Review 

Boards: Promising Approaches (OEI-01-97-0019 1) June 1998. 

E-3 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

27. HCFA Press Office, “New Results-Oriented Medicare Rules Proposed For Hospitals,” 

December 19, 1997. Available on the world wide web at www.dhhs.gov. 

28. The suggested revisions to the IRB expedited review list move in the direction we call for 

here. (Federal Register, Vol. 62, No. 217, 10 November 10 1997, p. 60604.) 

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

U.S. Government Printing Office, 1995), Chapter 18, Recommendation 13( 1). 

30. Ruth Ellen Bulger, Elizabeth Meyer Bobby, and Harvey V. Fineberg, Editors, Society’s 

Choices: Social and Ethical Decision Making in Biomedicine, (National Academy Press: 

Washington, DC, 1995) p. 182. 

3 1. In reviewing our reports, the group Public Citizen suggested that the following types of 

evaluations would provide useful information about IRBs. While these suggestions were not 

directed per se to NIWOPRR or FDA, we felt that they might help to stimulate discussion. The 

suggestions include: (1) assessing the differences between IRBs based on a review of a 

standardized protocol; (2) collecting data on differences between IRBs in rejection rates or rates 

of requiring serious modifications in protocols; (3) analyses of close votes at IRBs to see if and 

why those protocols got approved; and (4) retrospective analyses of IRB meetings which 

approved trials now considered unethical. 

32. These concerned serious matters such as the implantation of a device in three times the 

number of human subjects specified in the IRB-approved research protocol, the initiation of a 

research effort without changes that the IRB called for in the informed consent document, and the 

continuation of a research project for six weeks beyond when the IRE3had suspended it 

Department of Health and Human Services, Office of Inspector General, Investigational Devices: 

Four Case Studies (OEI-05-94-00 loo), April 1995. 

33. Comments of Dr. Jim Childress, meeting transcript of the National Bioethics Advisory 

Commission, January 9, 1997, (Eberlin Reporting Service: Silver Spring, MD), p. 20. 

34. At some large research institutions, multi-site trials now account for about one-half of all 

active research protocols. 

35. There is one regulation which requires the establishment of an independent data monitoring 

committee. The FDA regulation that provides for an exception from the informed consent 

requirements in certain emergency research (21 C.F.R., sec. 50.24) requires that a study 

conducted under the exception have established an independent data safety monitoring board to 

review data during the study in order to exercise oversight of the study. 

36. One large academic health center we visited reported that it has requested and regularly 

receives feedback from DSMBs. But this is contrary to the experience of other IRBs we had 

contact with. 

E-4 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

37. A cooperative group is a formal, free-standing government-sponsored entity responsible for 

conducting multi-site trials. There are, for example, 11 such groups associated with the National 

Cancer Institute (NCI). According to Federal requirements, NC1 cooperative groups are required 

to monitor their research sites once every 36 months. 

38. Periodically, when the cooperative group believes that its monitoring has identified 

information that may be pertinent to the IRB, it will inform OPRR, which, in turn, will inform 

the IRB. In addition, the IRBs sometimes will obtain information from the on-site principal 

investigators. 

39. The FDA cites 21 C.F.R., sec. 812.50(b) when this situation occurs: “A sponsor shall upon 

request by a reviewing IRB or FDA, provide accurate complete, and current information about 

any aspect of the investigation.” We believe, however, that the rules regarding notification 

should be made more explicit. 

40. The National commission that developed the current system of human protections in the 

197Os, envisioned a more proactive role for IRBs. In its report, it noted that IRBs may interview 

human subjects about their research experience or require that investigators provide subjects with 

a form through which they may report to the IRB their research experiences. It cautioned about 

observing the consent process, but noted that “certain research will warrant observation to assure 

the protection of subjects and in such cases IRBs have an obligation to take suitable measures.” 

It further noted that the documentation of informed consent should not be confused with the 

substance of informed consent and that in certain cases the IRB may well require that a neutral 

party be present to assist a potential human subject considering participation in a research effort. 

(Institutional Review Boards: Report and Recommendations of the National Commission for the 

Protection of Human Subjects of Biomedical and Behavioral Research, 43 Federal Register, 10 

November 1978, p. 56174.) 

The IRB regulations, which were adopted in 198 1, provide IRBs with the authority to “observe or 

have a third party observe the consent process and the research. (45 C.F.R., sec. 46.109(e) and 

21 C.F.R., sec. 56.109(e)) 

41. Some cancer centers and clinical research centers are particularly active in auditing 

investigators and assuring that protocols are being conducted as approved. Many IRBs do 

attempt from time to time to visit research sites to obtain first-hand knowledge about research 

practices. But, certainly, the workload pressures and other barriers we noted in our report on 

continuing review significantly limit the frequency and effectiveness of such efforts. 

42. Remarks by the President in Apology for the Study Done in Tuskegee, White House Press 

Release, May 16, 1997. 

43. See Alicia K. Dustira, “The Federal Role in Influencing Research Ethics Education and 

Standards in Science,” Professional Ethics, Vo1.5, Nos. 1 & 2, pp. 143-4; and Office of Research 

Integrity, “NIH Strengthens Responsible Conduct of Research Requirement in Training Grant 

Applications,” Office of Research Integrity Newsletter, Vol.1, No.2, April 1993, pp.1 and 8. 

E-5 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

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

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

45. In the “Statement of Investigator” (FDA Form 1572), the investigator is asked to make a 

number of attestations (or as the form states, “commitments”). These include the following: 

1. “I agree to inform any patients or any persons used as controls, that the drugs are being 

used for investigational purposes and I will ensure that the requirements relating to obtaining 

informed consent in 21 C.F.R., sec. 50 and institutional review board (IRB) review and approval 

in 21 C.F.R., sec. 56 are met.” 

2. “I will ensure that an IRB that complies with the requirements of 21 C.F.R., sec. 56 

will be responsible for the initial and continuing review and approval of the clinical 

investigation. I also agree to promptly report to the IRB all changes in the research activity and 

all unanticipated problems involving risks to human subjects or others. Additionally, I will not 

make any changes in the research without IRB approval, except where necessary to eliminate 

apparent immediate hazards to human subjects.” 

46. For example, the NIH has developed a computer-based tutorial about human-subject 

protections. It is available to the public and can be downloaded from the NIH web site. 

47. Harold Edgar and David J. Rothman, “The Institutional Review Board and Beyond: Future 

Challenges to the Ethics of Human Experimentation,” The Milbank Quarterly, Vol. 73, 1995, 

No. 4, pp. 489-506. 

48. In that statement, the President said: “We commit to increase our community involvement so 

that we may begin restoring lost trust. The study at Tuskegee served to sow distrust of our 

medial institutions, especially where research is involved.” (Remarks by the President in 

Apology for the Study Done in Tuskegee, White House Press Release, May 16, 1997.) 

49. Institutional Review Boards: Report and Recommendation of the National Commission for 

the Protection of Human Subjects of Biomedical and Behavioral Research, 43 Fed. Reg., 10 

November 1978, p. 56178. 

50. At present the HHS regulations for IRBs address this issue by calling for research 

institutions engaged in federally funded research to assure that “provisions are made for meeting 

space and sufficient staff to support the IRB’s review and record keeping duties.” 

(45 C.F.R., sec. 46.103(2)) 

5 1. In such cases, OPRR has been quite explicit in informing an IRB of its lack of adequate staff 

support and in calling for an increased commitment of staff and other resources. It has also 

called for the parent institutions to give greater recognition to IRB members for the critical 

services they provide. 

52. Such a reorientation would be in accord with the directive set forth in the House 

Appropriations Committee report on the 1998 Balanced Budget Act to lessen the regulatory 

burden associated with extramural scientific research. 

E-6 OEI-01-97-00193 IRBS: A Time For Reform 
APPENDIX E 

53. This parallels a recommendation called for by a Presidential advisory commission 15 years 

ago: “A broad educational and monitoring program covering the protection of human subjects 

and designed to reach investigators, IRB members, research administrators should be conducted. 

Among the various activities included in the program should be site visits of research institutions 

.using experienced IRB members and staff as site visitors.” (President’s Commission for the 

Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Implementing 

Human Research Regulations: Second Biennial Report in the Adequacy and Uniformity of 

Federal Rules and Policies, and of their Implementation, for the Protection of Human Subjects, 

Washington, DC: U.S. Government Printing Office, 1983, pp. 135-137.) 

E-7 OEI-01-97-00193 IRBS: A Time For Reform