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Doing more harm than good will ultimately force human subject protection system reform.
My personal frustration with institutional review boards reached a boiling point several months ago. A dozen IRBs had each reviewed a general educational brochure prepared by the Center for Information and Study on Clinical Research Participation (CISCRP). The brochure was not specific to any clinical studies and its focus was on explaining the risks and benefits of clinical trial participation. All IRBs had suggested revisions to the educational language. But only one of the 12 IRBs rejected it. The reason for rejecting the brochure: Educational material "...should not include the word hope because the term is coercive."
Kenneth A. Getz
My deep frustration was felt on many levels. The concept of "hope" is central to patients and their families wanting to consider and evaluate clinical trials among their options. Just as risks can be discussed openly and in a language that the lay public understands, general educational information must also openly and honestly acknowledge the potential benefits of participation. Why, you might ask, were IRBs even reviewing a general educational brochure when it falls outside their jurisdiction?1 As an independent non-profit, CISCRP's mission is to provide public education to promote greater, more balanced and informed understanding and awareness of the clinical research process. This is also part of the overall mission of all human subject protection programs. By rejecting CISCRP's educational materials, was this IRB doing a disservice to the very population that it strives to protect?
I'm clearly not alone in my frustration. A large and growing number of government and private-sector clinical research professionals are voicing their concerns and suggesting that our current human subject protection system is ripe for radical reform to change its antiquated, fragmented, bureaucratic, and over-reaching ways. A number of peer-reviewed articles have sounded the alarm including: Salim Yusuf's "Randomized Clinical trials: Slow Death by a Thousand Unnecessary Policies?"2 and Christine Grady's "Do IRBs Protect Human Research Participants?"3 This past year the Institute of Medicine has singled out IRBs as one of the top barriers to achieving efficiencies in clinical research. At a meeting that I attended in October, serious concerns were raised by academic and government leaders that failures of the IRB system are actually hindering the ethical protection of study volunteers.
What's wrong with the system? Or, as some have rephrased the question, what's not wrong with it? Our nation's system of human subject protection programs has evolved into a complex regulatory and legal environment with 19 agencies in addition to the Food and Drug Administration (FDA) sharing oversight for protection of study participants. These agencies include the Social Security Administration and the Department of Homeland Security. After protracted debate, various agencies adopted the Common Rule in 1991 to harmonize human subject protection policies. Many agencies subsequently have added regulations while others have adopted inconsistent guidance on how to interpret the rule. The FDA chose not to even adopt the Common Rule, but did change its IRB and informed consent regulations to more closely correspond to federal policy. Adding to the confusion is the fact that IRBs must follow federal privacy requirements and state laws. Some IRBs must also balance compliance with International Conference on Harmonization (ICH) guidelines for studies outside the United States. This complex and crowded array of organizations have burdened IRBs with substantial inconsistencies in ethics regulations and the challenge of complying with many different and potentially conflicting requirements.
Managing that burden would be enough. But there is the added weight on research sponsors to reconcile and coordinate wide and inconsistent variation in ethical review decisions across multiple IRBs. Current regulations require that each institution and investigative site involved in clinical research receive IRB approval. An ethical review of a single protocol for a multicenter trial requires that many IRBs conduct their own independent reviews. Reviews of the same protocol are not coordinated, they result in contradictory recommendations and outcomes, and they cost the research sponsor and study staff substantial time and resources.
Clinical research professionals in both the public and private sectors widely agree that our current multiple IRB system is wasteful and causes unnecessary delays. In a recent New England Journal of Medicine editorial, OHRP Director Jerry Menikoff, said that duplicative reviews not only provide "relatively few benefits," but the current structure actually might lead to "less-than-optimal protection" of those who volunteer to participate in research.
Menikoff points out that the system results in individual IRBs feeling powerless to change the protocol when risks are identified. If one IRB has serious concerns about the study design, it usually results in that IRB leaving the study—either of its own accord or after being dropped by the sponsor—rather than resulting in a change to the protocol.
A growing number of research sponsors and investigative site staff have expressed frustration and concern about IRBs overseeing more than their jurisdiction dictates. During the past two decades, IRBs have asserted themselves as gatekeepers of all interactions with patients and the public and the protectors of every possible potential or imagined harm that might occur during research. As such, IRBs often impose burdensome, impractical, unnecessary requirements in order to err on the side of extreme caution.
Researchers and institutions complain that IRBs are overly expansive in interpreting regulatory requirements and that they focus on inconsequential details during reviews. Others complain that IRBs have been overwhelmed with obligations that have little to do with protection of research participants, and IRB members tend to focus more on procedures and documentation than on difficult ethical questions and serving patients' and the public's best interests.
As clinical research has become more complex and demanding, the scope of IRB responsibilities has expanded to include compliance with privacy regulations, checking for potential financial conflicts of interest, and reviewing the methodological soundness and scientific merit of a study. Yet as IRBs are asked to take on more responsibilities, they have been criticized for becoming less effective and more susceptible to questionable practices. The now famous sting operation carried out by the General Accounting Office (GAO) in 2008 exposed a national human subject protection system vulnerable to unethical manipulation.
IRB jurisdiction and authority is also virtually never challenged or evaluated. Few sponsors and investigative sites are willing to question an IRB's decisions out of fear that the IRB might scrutinize their proposal more closely or won't approve their research. The IRB's decision is the gospel—taken without question—despite the fact that nowhere in the regulations is an appeal prohibited. There is no data measuring whether IRBs are doing their job in protecting study volunteers from unnecessary risk of harm. The IRB system, which evolved from an institution-based structure with little accountability or data collection, lacks even rudimentary metrics for measuring its own success.
There's no question that frustration among all stakeholders is intensifying and will eventually drive reform. But structural and procedural reforms are likely a long way off given such a complex, crowded, and heavily regulated system.
Many ideas for IRB reform center around streamlining and creating a better, harmonized review process. One approach would be for sponsors to require the use of a central IRB as a condition for sites to participate in a study. Another proposal would change the system to impose more demands on early trials with new interventions while simplifying the oversight of commonly used interventions. Academic and government leaders have recommended collecting more data in order to measure IRB performance.
The FDA and OHRP both support the use of a single, central IRB for multicenter research. Drug sponsors have increasingly contracted with central IRBs to review studies conducted by community-based investigative sites. Most universities and hospitals still opt to use their own internal IRBs when conducting both privately and federally funded research. OHRP is leading an effort to coordinate guidelines across various agencies, and plans to propose the creation of a single new agency to oversee all human subject research in the United States.
As criticism and dissatisfaction grows, our national IRB system has been losing credibility and respect among regulatory agencies, clinical research professionals, patients, and the public. Extreme frustration may drive reform even sooner. After all, we owe it to patients and the public to get this IRB system, or a new one, working right.
Kenneth Getz MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: firstname.lastname@example.org
1. Code of Federal Regulations, Title 21, Part 56, Section 102, 109 (US Government Printing Office, Washington, DC).
2. S. Yusuf, "Randomized Clinical Trials: Slow Death by a Thousand Unnecessary Policies?" Canadian Medical Association Journal, 171 (8) 889-892 (2204).
3. C. Grady, "Do IRBs Protect Human Research Participants?" Journal of the American Medicial Association, 304 (10) 1122-1123 (2010).