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Contributed by Mark Barnes and Melissa Lopes
In 2011, the U.S. Department of Health and Human Services issued an Advanced Notice of Proposed Rulemaking (ANPRM) entitled “Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators.”1 The ANPRM seeks to revise and modernize the federal regulations that govern human subjects research, commonly referred to as the “Common Rule.”2 This represents the first effort in 20 years to alter the regulations that govern the informed consent process and guide the actions of Institutional Review Boards (IRBs). According to two of its authors, the ANPRM is aimed at delineating “options for simultaneously enhancing protections for research subjects and improving the effectiveness of the federal oversight system.”3 However, certain proposals threaten to degrade the IRB’s role as a compass for a well-functioning institutional oversight program (sometimes referred to as a Human Subjects Protection Program (HRPP)). Over the past 20 years, institutions have developed and refined programs in which IRBs serve a core function in the oversight of human subjects research and the protection of human subjects. In examining the ANPRM proposals, two seemingly contradictory themes emerge that call into question the future role of the IRB within an institution’s overall HRPP. Below we highlight select ANPRM proposals that raise particular concerns regarding the future role of the IRB in an institution’s human subjects oversight program.
Shifting Burdens from the IRB to the Investigator
A review of the ANPRM proposals reveals the drafters’ intent to shift much of the burden of human subjects oversight from the IRB to the Investigator. This intent is most evident in the ANPRM proposals to reduce IRB oversight of minimal risk research, to expand the categories of research exempt from IRB review, and to apply “standardized data protections, rather than IRB review” to protect against informational risks.4 These proposals, while purportedly seeking to eliminate burdens and administrative delay, actually, in our view, introduce further burdens on IRBs and/or administrative delay for investigators. Questions include whether removing IRB review from the equation substantially weakens a Human Research Protection Program, where the IRB acts as the locus of oversight; whether the terms and standards proposed in the ANPRM are sufficiently defined to be consistently interpreted by investigators, particularly investigators who do not regularly conduct human subjects research; and whether investigators are sufficiently equipped to make determinations as to what constitutes exempt research or to apply HIPAA standards. A close examination of two specific ANPRM proposals, the elimination of continuing review for expedited studies and the elimination of administrative review for exempt studies, reveals why caution is warranted.
Reducing the IRB's Role in the Oversight of Minimal Risk Research
The ANPRM contemplates eliminating continuing review for all expedited studies and for studies initially reviewed by a convened IRB after the study “reaches the stage where procedures are limited to either (i) analyzing data (even if it is identifiable), or (ii) accessing follow-up clinical data . . ..”5 If an IRB chooses to require continuing review of an expedited study, the ANPRM also proposes to require that IRBs provide explicit justification as to why such review would enhance protection of research subjects. Continuing review plays an important role in investigator management of protocols and human subjects research oversight. Such review captures protocol changes or minor issues that investigators inadvertently may fail to bring to the attention of the IRB or that only become apparent once a study has begun. The elimination of continuing review removes a defined frequency by which the investigator must re-assess the research, and thus places the complete onus on investigators to identify, sua sponte, any changes that increase the level of risk involved and thus necessitate further IRB review. While it may not be necessary for all non-exempt human subjects research to undergo continuing review at least once per year, IRBs should be afforded the flexibility to determine if such review is necessary to ensure adequate human subjects research oversight.
Eliminating the IRB's Role in the Review of Exempt Research
The ANPRM also contemplates eliminating administrative review by IRBs of exempt studies (or “excused studies,” as referenced in the ANPRM), and seeks to expand greatly the categories of research considered to be exempt. The ANPRM’s proposal to eliminate administrative review represents a major shift in responsibility from the IRB, which typically conducts such reviews, to researchers. According to the ANPRM proposal, an investigator would merely be required to file a brief one-page registration with the IRB before commencing what he or she deems to be exempt research. There would be no waiting period or preliminary review by the IRB required prior to the commencement of such research activities. The only review proposed in conjunction with such research is “random retrospective audits of a sample of exempt studies to assess whether the exemptions were being appropriately applied.”6 In our view, these proposals undermine human subjects protections and introduce an additional but unnecessary institutional burden in the general oversight of exempt research. IRBs historically have made exempt determinations, thus developing expertise in understanding each protocol in a greater context and in applying regulations consistently across research projects. Investigators, on the other hand, would make such determinations infrequently and may be motivated to make determinations that their research would be “exempt” or “excused,” leading them to underestimate the risks inherent in their proposed research activities. For such a shift in responsibility to be implemented without adversely affecting human subjects, certain concerns must be addressed. Because this would be a new responsibility for researchers, a waiting period may be indicated between the time at which an investigator determines that his or her research is “exempt” or “excused,” and the time at which the study may commence. Such a “waiting period” would allow the opportunity for an IRB to flag troubling investigator determinations. The proposal to eliminate administrative review of exempt research, and the shifting of responsibility from the IRB to the investigator, raises an additional concern: despite yielding such determinations over to the investigator, the ANPRM is silent on the issue of training and education of researchers. Yet these significant shifts of responsibility should not occur without adequate consideration of and guidance regarding the training necessary for researchers to make such independent determinations. Investigators given this responsibility should be required to have regular, ongoing training in general research ethics issues and investigator responsibilities, as well as specific training on making “excused” determinations. Applying a waiting period and providing guidance on adequate training of investigators might help to ensure that these proposed changes do not significantly lessen the protection of human subjects. The ANPRM also contemplates requiring IRBs to conduct post-hoc audits of studies that were determined to be “exempt” or “excused.” It is unclear from the ANPRM, however, how the one-page registration form that will replace the IRB administrative review process would provide adequate information for an institution to perform such audits of exempt research. The time lag between registration by the researcher and eventual audit by the IRB would necessitate reconstruction of the facts and circumstances by the IRB long after the investigator made the determination, and likely would prove more burdensome on the IRB than the status quo, which typically involves informal consultation and administrative review at the beginning of the process. Further, the ANPRM proposals do not clarify what an IRB should do if, in an audit, it discovers research activities that were inappropriately registered as excused. In short, in trying to reduce regulatory burdens in human subjects research, the ANPRM instead would create additional burdens that may well outweigh any salutary effects.
Expanding Federal Requirements in lieu of Institutional Review
Interestingly, while the ANPRM contains a number of proposals seeking to lessen federal requirements with respect to IRB oversight, an equal or greater number of proposals contemplate expanding federal requirements for human subjects research oversight. Like the proposals seeking to lessen federal requirements, many of these proposals raise human subjects protection concerns and would impact the IRB’s central role in the oversight of human subjects research. The implications for human research oversight become evident through a closer examination of ANPRM proposals to require written consent for the future of use of data and biospecimens and to require the use of a central IRB for multi-site studies.
Requiring General Consent for Future Research Use of Data and Biospecimens
The ANPRM suggests that subjects must be allowed to “opt out” of future research uses of their data and biospecimens. For future use of a subject’s biospecimens, whether collected for research or non-research purposes, whether identified or non-identified, the ANPRM proposes a requirement that there be a general consent for future research uses. Without such a general consent for future research uses, no future use of those biospecimens would be allowed, even if associated data were de-identified; and waivers of informed consent would not be allowed for their future use.7 The proposal further would classify biospecimens as never able to be considered de-identified or anonymized, due to the remote possibility of re-identification by a third party’s obtaining and analyzing other biospecimens from the subject, or correlation of the subject’s biospecimen data with other, existing, databases. Further, the ANPRM proposes to require the use of “opt-outs,” such that a subject would invariably be allowed to “opt out” of future research uses of their data and biospecimens, The clear intent of the ANPRM proposal for the future use of data and biospecimens is to “strengthen and align consent protections . . . while ensuring the pursuit of important research.”8 However, the nature of the general consent for future uses and the proposed rigidity of its application raise concerns as to whether either goal would be achieved. A general consent would not necessarily contribute to the protection of research subjects and may, in fact, afford less protection than the current system of obtaining specific consent at time of donation, setting forth in that consent the presently known range of future uses, and being able to apply to IRBs for waiver of informed consent before undertaking specific future research projects.
Deficiencies Inherent in Requiring Standardized General Consent for Future Research
At the time of initial research consent, no researcher would have a reliable way of predicting the full range of future research uses of data and biospecimens that would be widely acceptable to American society in 25, 50 or 100 years. Informed consent cannot be “informed” unless subjects are given accurate information about the nature of the research and its risks and benefits for them. Since the specific future uses are unknown, their risks and benefits are also unknown. In this context, it is at the least uncertain — and more likely, impossible — for subjects signing such a general consent to know any of the specific information now required for consent. They cannot accurately be apprised of future benefits, or of risks, or even of the research methods that might be employed. Further, a general consent as envisioned by the proposed changes would require so speculative a dialogue at a time when a research subject may be vulnerable and seeking treatment as to make the consent itself inadequate to the task of producing an “enlightened decision” on the part of the research subject. This proposal, while aimed at educating and informing patients, may instead confuse them and make them less likely to consent to research uses of their data and discarded tissues that they would have otherwise allowed. Requiring through regulation a list of “opt-outs” that must be included in such general consent forms would not alleviate the deficiencies associated with a general consent. Again, it would be difficult if not impossible to predict all potential research uses, such that the list of opt-outs would never be all-inclusive. There still may be questions that are raised downstream as to the appropriate use of a biospecimen. Under the current human subjects regulatory structure, the inability of researchers to offer accurate information about future unknown studies, and the inability of subjects to understand them, is accommodated by the waiver of informed consent process. Pursuant to this process, a group of individuals empanelled as an IRB are trusted to consider specific future uses, and to determine whether each research use meets the criteria for waiver. The waiver of consent process allows for IRB involvement and a thoughtful, considered approach to weighing risks, benefits, practicability, options, and the overall welfare of human subjects. The process requires a real-time analysis, based in present facts, of the risks and benefits of proposed research, without requiring researchers invariably to seek out past research subjects and obtain new consent from them. Instead, appropriately, IRBs under the current regulatory regime require re-consent only when practicable and when the risk exceeds a minimal level. Society trusts IRBs to make “go” and “no-go” decisions every day relating to interventional studies in which there can be immediate and substantial risks to subjects; the waiver of informed consent, available only in minimal risk situations, is much less concerning in regard to risk to subjects than most other matters that IRBs routinely decide. The waiver process has, as whole, worked well over the past two or three decades. This mechanism of an IRB’s analyzing waiver applications, which can result either in waiver, or in a direction to researchers to seek new, specific informed consent for new studies, appears to be a more reliable protection for subjects than acquiring from them a general consent of unknown and unknowable breadth. As currently practiced, the waiver of informed consent process is far preferable to the ANPRM proposal, as it is less burdensome and more protective of human subjects, and fully draws upon the value that IRB review brings to these complex issues.
Unintended Effects of Requiring a Central IRB for Multi-site Studies
To streamline IRB review of multi-site studies, the ANPRM contemplates requiring a single IRB of record for domestic multi-site studies. Such a proposal may lead to efficiencies if implemented properly, but several questions and concerns, however, counsel against the immediate adoption of a regulatory mandate for a central IRB. How would the lead IRB be selected to avoid forum-shopping by investigators? Depending upon how the lead IRB is chosen, there is a concern that there may be a race to the bottom in terms of IRB oversight. What regulatory responsibilities, if any, would continue to be held by institutions and IRBs that had effectively ceded review to a central IRB? The responsibilities and attendant liabilities of these “ceding review” institutions and IRBs would need to be carefully considered and detailed in any OHRP proposal to require a single IRB of record for domestic multi-site studies. Can such a mandate be implemented without dismantling or disrupting well-developed Human Research Protection Programs (HRPPs) at local sites of a multi-site study? IRBs often act as the spoke of the wheel or the air traffic controller for an institution’s HRPP. Would the immediate adoption of such a mandate degrade the research review process by eliminating from it meaningful site-specific, local considerations and concerns? Further, the central IRB proposal is both over- and under-inclusive, in that it regards all domestic sites as being sufficiently alike that a central IRB is appropriate, and regards all international sites as sufficiently dissimilar that a central IRB should not be similarly required. Neither scenario can be cast in such absolute terms. A central IRB, for example, may be more appropriate for a study sited in New York and Amsterdam, than for a study sited in New York and rural Alabama or Alaska. A full examination of these complex issues and the possible unintended effects of such a regulatory mandate would seem indicated before adopting such a departure from current, established practice. At this time, a mandate of central IRB review for multi-site studies, without exceedingly careful implementation, would predictably result in: (1) regulatory uncertainty and implementation gridlock, (2) likely failure of much central IRB review adequately to consider and accommodate critical local requirements and concerns, and (3) an aggregate reduction in protection of human subjects. A more measured and careful process of encouraging central IRB use, accompanied in a step-wise way by OHRP issuance of guidance on critical issues attending central IRB review, would result in less disruption of the research enterprise, and eventually, improvements in a central IRB process that is anchored in deep collective experience. Efforts to revise the federal human subjects protection regulations must consider each proposed change’s effect on a well-functioning institutional oversight program for human subjects research. While overburdening an IRB threatens the effective functioning of an HRPP, wholly eliminating the IRB from areas of the research oversight enterprise also threatens the effective functioning of an HRPP and the protection of research subjects. What is needed is a more measured approach that provides IRBs the flexibility to streamline oversight, makes use of the IRB’s considerable expertise in research oversight, and recognizes the IRB’s central role in an institution’s program for ensuring human subjects protections.
Mark Barnes serves as Senior Associate Provost for Research and University Research Compliance Officer at Harvard University, and as the institutional official for human subjects research for Harvard's Cambridge campus. He has faculty appointments at Harvard Law School and Yale Medical School. Prior to coming to Harvard, he was executive vice president and chief administrative officer at St Jude Children's Research Hospital, and was for many years a partner at Ropes & Gray. He has held senior appointed roles in the New York City and State Departments of Health. Melissa J. Lopes serves as the Associate Director for Research Policy and Implementation and the administrator of the Embryonic Stem Cell Research Oversight Committee at Harvard University. Prior to coming to Harvard, she was Deputy General Counsel for the Massachusetts Department of Public Health, focusing on the regulation of stem cell research, pharmaceutical marketing and clinical labs. She also previously practiced as a healthcare attorney with Choate, Hall and Stewart and served as a Kellogg healthcare advocacy fellow. Some of the text of this article may previously have appeared in the ANPRM comments of Harvard University and of the HHS Secretary’s Advisory Committee on Human Research Protections; such portions as appear in this article were personally authored by Mr. Barnes, assisted in various portions by Ms. Lopes.
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