Government Affairs Home > Research > Clinical Research > Clinical Research Compliance & Human Subjects Protections

Statement on Institutional Review Boards

Good morning. I am Dr. Robert Levine, Professor of Medicine and Lecturer in Pharmacology at Yale University School of Medicine. I also chair the Institutional Review Board (IRB) at Yale-New Haven Medical Center. I am speaking today on behalf of the Association of American Medical Colleges ¹. The AAMC represents all 125 accredited U.S. medical schools, over 400 teaching hospitals, and 89 scientific and academic societies. Its member institutions conduct the majority of clinical research in this country, and the safety of those who volunteer to participate as research subjects is a significant concern of this organization.

The cornerstone of the current system of protections for human subjects in research is the IRB, and thus the sound functioning of these bodies is of the utmost importance. I have been intensively involved with IRBs on a national level for much of my career over 25 years and, therefore, am intimately familiar with the concerns that led to their establishment. I was, in fact, a special consultant for the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, whose reports included the "Belmont Report," which summarized fundamental ethical principles and articulated the distinctions between research, investigational practices, and standard therapy. The Commission also issued a report on Institutional Review Boards, which contained recommendations that became the mainstream of federal regulations for the protection of human subjects, the so-called "common rule" (-- CFR 46). In addition, the Commission reports on the fetus, prisoners, and children form the basis for current Department of Health and Human Services regulations in these categories.

I also am on the board of Public Responsibility in Research and Medicine (PRIM&R), an organization which for over 20 years has brought the IRB community together to address emerging issues and current problems. In addition, I am currently preparing the third edition of my book, Ethics and Regulation of Clinical Research. Also, since its inception 20 years ago, I have been Editor of IRB: A Review of Human Subjects Research, an important journal for this community. Thus, in my testimony today, I will bring both historical and national perspectives to bear on the issues before the subcommittee.

I will begin by noting that IRBs are not policing bodies, watchdogs, or auditing agents. They were established to weigh the risks the proposed research may pose to the research subjects against the benefits the research may offer to the patient and society. IRBs are thus constituted in a way that enables examination of these ethical considerations in the context of the guiding principles set out by the Belmont Report -- beneficence, justice, and respect for persons. IRBs were established to work collaboratively with investigators, the vast majority of whom are altruistically motivated and intend to do the right thing. IRBs aid investigators in their work by ensuring that subjects are fully informed, and that any risks are reasonable in relation to anticipated benefits.

Part of the impetus for this hearing is a recent draft report of the Department of Health and Human Services (HHS) Inspector General, titled "A System in Jeopardy." This report has created much alarm about the ability of IRBs to fulfill their responsibilities in protecting patients. I would next like to address this very important matter since it has drawn so much public attention. I worry that the title of the report and much of the narrative portrays a system in crisis. It would be easy to infer from this document that there is a systemic threat to patients. Yet, quite to the contrary, the report acknowledges that the study yielded no evidence of harm or abuse to patients. Based on my extensive interactions with IRBs on all levels, I would concur with this last finding, and also agree with the report's assertion that the system is "supported by many conscientious research investigators committed to protecting human subjects and by many dedicated IRB members and staff doing their best...."

The report purports to describe the current state of the IRB system, even though it is based on a literature review, interviews with a limited sampling of IRB representatives, and visits to only six institutions. While certain observations are certainly true anecdotally in single instances or for individual institutions, an impression is given that they apply to all, or even a majority, of IRBs, which may not be the case. I believe that the tone of the report conflicts with its substance, which is misleading and unfortunate.

The report does have some positive aspects that I would like to touch on. Many of the recommendations in the draft report (as opposed to its various observations) are in fact quite reasonable. These were detailed in an AAMC letter of comment that has been attached to my testimony for the record. The report also includes one volume titled "Promising Approaches" which offers constructive examples of how IRBs have been innovative in dealing with an array of issues from education to informed consent to ongoing oversight of protocols. This section of the report is highly useful and offers IRBs the kind of constructive information that should be the emphasis of the report. The report does make some observations that in fact are quite valid. For example, IRBs do indeed face tremendous workloads, and there is no question that they could benefit from greater resources.

Again, focusing on the positive, I will turn to some of the recommendations of the report that I find sound. I think the IG's proposal to alleviate the perfunctory oversight responsibilities and otherwise to lighten the workloads of IRBs is laudable. For example, in recent years IRBs have been deluged with reports of all "adverse drug experiences" that occur anywhere in the world in connection with studies on investigational new drugs. The vast majority of these reports are often of incidents that are either completely unrelated to the drug or, if related, are already well-known and have already been anticipated in the protocols and consent forms. In the past, IRBs would receive these reports along with some advice from the sponsor regarding the possibility of a causal connection between the drug and the event. Now IRBs almost invariably review formal disclaimers that state that the report itself does not constitute an acknowledgment on the part of the sponsor that there in any causal connection. This system could be made much more efficient. I suggest that the reporting requirement be limited to adverse events that are both serious and not anticipated, meaning that one of the following two criteria is satisfied: 1) the event is unlike anything described in the protocol or consent form, or 2) the event may be like something anticipated in the protocol and consent forms, but is of a much more serious nature than originally anticipated.

Another workload issue involves the vast number of protocols that are reviewed by IRBs but never funded, since federal agencies require IRB review as a condition of their accepting applications for support. Changing the system to require IRB review only after funding decisions have been made would greatly reduce the workload while still ensuring that any research performed with human subjects has had IRB review.

Another activity that is absolutely key is education and training for both investigators and IRB members, something the report emphasizes, and something that the IRBs themselves welcome. Many institutions have made impressive efforts at providing outreach to patient groups, developing mechanisms for educating patients about research protocols, and developing formalized orientation programs for new IRB members. PRIM&R, the group I mentioned earlier, is also conducting these activities at a national level. Through its conferences, some of which have been done in collaboration with the AAMC, IRB administrators and members become educated about the many thorny ethical matters confronting IRBs and engage in workshops to discuss their experiences and solutions to the problems they face. The faculty for these conferences include personnel from the National Institutes of Health's Office for Protection from Research Risks (OPRR), as well as the Food and Drug Administration (FDA) and other federal agencies. PRIM&R will also be sponsoring an "IRB Training Institute" which will take a curriculum for new IRB members and administrators "on the road," if you will, making this kind of training -- which will be led by nationally recognized experts -- accessible to institutions all around the country. The OPRR, too, conducts education and training.

Finally, I would concur that better communication between the FDA and IRBs is highly desirable, and that the role of Data Safety Monitoring Boards must be formalized for multi-site trials, which present particular communication and coordination challenges for IRBs.

There are nonetheless a number of obstacles to implementing some of the recommendations. For example, the report cites the existing federal requirements for the provision of adequate resources by the awardee institution. However, it is difficult if not impossible to develop workable criteria or normative standards for determining the types and levels of resources that would be adequate for the very diverse set of IRBs that are now in existence in highly heterogeneous research institutions. In addition, bureaucratic accretion coupled with institutional cost sharing is making the identification of institutional resources for cost sharing on federal grants increasingly difficult. Institutions do their best to provide IRBs with the materials they need, but could benefit greatly from the development of a specially designated source of federal support for IRB activities, either through a mechanism that would be funded in proportion to NIH-funded human subjects research, or through a more generalized flexible funding mechanism, such as the "Research Innovation Opportunity" program, which the AAMC has proposed as a substitute for the now defunct Biomedical Research Support Grant (BRSG) program.

One significant focus of the report is on ongoing review of protocols. It is important to note that not all protocols entail the same level of risk and complexity, and thus, the need for ongoing review must be assessed according to these criteria. It may conceivably be possible to develop criteria that would stratify protocols according to the level of ongoing review that they would merit, including none. The IG report suggests a "performance" focus for evaluating ongoing review, which may be useful, depending on how the criteria for assessment were defined. The report also notes how some institutions have involved patient advocates as a means of looking after the patient's interests during conduct of the protocol, which can be a workable, though expensive, means of handling some aspects of this issue.

The report also recommends that IRBs have greater representation of non-institutional and non-scientific members. It is important to realize that participating on an IRB is generally a demanding and time-consuming task that people undertake on a voluntary basis. Thus, getting the participation of public members is not easy. Second, once appointed, these individuals often do not become significant contributors to IRB deliberations until they have served for a long enough period of time to develop a relevant ethical and scientific knowledge base. At that point, they generally bring the same concerns and perspectives to the table as their other colleagues on the board. Adding additional non-scientific and non-institutional members is thus likely to put a strain on IRBs while these individuals are recruited and "brought up to speed," which will not be outweighed by the ongoing contributions of such participants. In the end, what benefits the IRB process and patients the most is the quality of outside members and the contributions they make, not simply the number of them on the committee.

I might add that there is a false impression that only individuals who have no connection with the institution can provide an "outsider" perspective. Medical students can be extremely effective members of IRBs. Because they understand the language and the risks, there is little that escapes their attention.

The challenge of getting people to serve on IRBs also is quite germane to faculty. It used to be easy to recruit the "best and the brightest" faculty when they felt that they were doing something important and that it was appreciated. But now it is not. There are several factors that undermine faculty motivation and a sense of satisfaction for serving on an IRB, ranging from the increased workload and the amount of time and energy that must be expended to address and document in detail even relatively minor issues to the negative publicity surrounding IRBs.

It must be re-emphasized that this is a voluntary system. It requires a significant amount of time that is uncompensated from people who tend to be very busy with clinical and academic responsibilities. There is a widely held misconception that we could increase the motivation of academics to serve on IRBs by formally recognizing the contributions they make in terms of time and commitment. Certainly, they should get compensated in salary and release time. But this alone will not accomplish the desired ends. People choose academic careers because they want to do research and they want to teach. The true coins of the academic realm lie in recognition by peers of their academic accomplishments. Academics routinely accept lower salaries to find "protected" time to do their research. In a certain vitally important sense nothing can compensate them for the time and energy devoted to committee work. They should at least have a sense that they are doing something important and that they are appreciated for doing it.

One aspect of the report that merits correction is the perception given that IRBs are conflicted in conducting their duties. This observation implies that IRBs regularly have the institutional interest at heart at the expense of those of research subjects. This sets up a false logic whereby the subjects' interests are presumed to be in conflict with those of the institution, and the IRB somehow must choose between the two. The fact of the matter is that nothing could be more in the institutional interest than protecting the subjects of research. Apart from the firm commitment that all medical schools have to the ethical principles underlying the Belmont Report, violations of those principles put institutions at extreme risk. Thus, the predominant pressure that IRBs feel from their parent institutions is to be rigorous in their review.

With those observations made, I will be happy to take any questions.

Robert J. Levine is Professor of Medicine and Lecturer in Pharmacology at Yale University School of Medicine and Chairperson of the Institutional Review Board at Yale-New Haven Medical Center. He is a fellow of the Hastings Center, the American College of Physicians and the American Association for the Advancement of Science; a member of the American Society for Clinical Investigation and American Society for Pharmacology and Experimental Therapeutics; Past-President of the American Society of Law, Medicine & Ethics; and Past-Chairman of the Connecticut Humanities Council. Dr. Levine, former editor of Clinical Research, is the current editor of IRB: A Review of Human Subjects Research, and has served as consultant to several federal and international agencies involved in the development of policy for the protection of human subjects.* He is the author of numerous publications and is currently preparing the third edition of his book, Ethics and Regulation of Clinical Research.

* Recent activities include:

• Member of the AIDS Program Advisory Committee, National Institutes of Health, and Chairman of its Subcommittee, the National Human Subject Protections Review Panel.

• Member of the Ethics Subcommittee of the Director's Advisory Committee, Centers for Disease Control and Prevention.

• Joint United Nations Programme on HIV/AIDS (UNAIDS), Project on ethics in HIV vaccine trials, chairperson of the project to develop a "Guidance Document" for trials of preventive HIV vaccines.

• World Association of Medical Editors: Chairperson: Ethics Committee.

1 - For fiscal years 1995-97, the AAMC received $1,956,359 in Federal Funding from the Agency for Health Care Policy and Research ($809,314), National Institutes of Health ($641,063) and the Health Resources and Services Administration ($505,982). Dr. Levine has received the following grant and contract support from the federal government during the past 3 years: Since August 1997, through a grant to Yale University to support its Center for Interdisciplinary Research in AIDS, he receives $3,125 each month as part of his University salary. For service on various committees and for various consultations with various federal agencies -- including, but not limited to NIH, CDC, FDA, DOE, DOD, NASA -- he has received an average of $1,500 per year.