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  • IRB: ETHICS & HUMAN RESEARCH

Determining Minimal Risk for Comparative Effectiveness Research

Decisions about whether or not a study involves minimal risk structure critical procedural and substantive determinations by institutional review boards (IRBs). In particular, minimal risk is a necessary—though not a sufficient—condition for deciding whether a study may qualify for expedited review and whether a waiver of the requirement for informed consent might be permissible. In addition, the determination that a study involves minimal risk has important implications for how investigators should describe it to prospective research participants in consent documents and during the consent process.

Judgments about minimal risk are particularly challenging in the setting of comparative effectiveness clinical trials, in which the procedures that participants undergo and the risks they face commonly mirror those inherent in ordinary medical care. Depending on how one counts the risks of the ordinary medical care that comparative effectiveness trials incorporate, these trials may be seen as either high- or low-risk endeavors. The recent controversy over the study called the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT)—which randomized extremely premature infants to receive oxygen therapy titrated to achieve blood oxygen saturations at either the low or the high end of the range considered to be standard of care outside the trial—highlights contemporary uncertainties about risk assessment in comparative effectiveness trials.1 The ongoing reevaluation of oversight models for research conducted within learning health care systems, with questions raised about whether regulations governing protection of human subjects in research unjustifiably burden lower-risk learning activities,2 further demonstrates the need for clarity regarding risk assessment in comparative effectiveness trials.

The importance of minimal-risk determinations is heightened in cluster-randomized trials, a methodological mainstay of comparative effectiveness research. Such trials, which involve randomization at the group rather than the individual level, pose special challenges for research oversight.3 Because interventions may be environmental in nature or may be delivered across an entire unit, institution, or community, it may not be possible to seek informed consent from participants in these studies. In a review of articles describing the results of cluster-randomized trials, Giraudeau and colleagues found that when the intervention was delivered at the cluster level, participant consent—often encompassing collection of study data but not delivery of the intervention itself—was obtained in 67% of trials.4 As an example, the recent study, Randomized Evaluation of Decolonization vs. Universal Clearance to Eliminate MRSA (REDUCE MRSA)—which compared three approaches to decontamination of patients in intensive care units in order to prevent hospital-acquired methicillin-resistant Staphylococcus aureus infections—necessitated a waiver of the requirement for written informed consent.5 When a waiver of consent is needed for methodological or logistical reasons, the research cannot proceed unless the relevant IRB first determines that the trial involves minimal risk.

According to federal regulations governing research with humans (the Common Rule), minimal risk means that “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” (for brevity, we will call this the “daily life standard”).6 The critical phrase “anticipated in the research” appears to direct IRBs to consider all the risks of the study interventions in deciding whether or not a trial involves minimal risk. On this reading, few comparative effectiveness trials of drugs, devices, and other biomedical interventions will qualify as minimal risk. We contend, however, that this reading is mistaken.

Consider the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. The trial compared the effectiveness of several antipsychotic medications that are widely used and approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia.7 Common, serious toxicities of these medications include movement disorders (extrapyramidal signs and tardive dyskinesia), weight gain, and altered glucose and lipid metabolism. The trial included neither a placebo arm nor additional research procedures beyond those required for standard care. How should IRBs reviewing this trial evaluate its risks? Under one approach, an IRB might seek to assess the absolute risks of the study interventions. Using this approach, the IRB would examine the toxicity profile of each drug and then judge whether the identified risks exceeded the daily life standard specified in the Common Rule. It would undoubtedly determine that the trial involves greater than minimal risk.

Alternatively, an IRB might seek to assess the incremental risks of the study interventions, as compared with the risks of the treatments that study participants would likely receive as patients in the clinical setting.8 Under this approach, the IRB would then judge whether the incremental risks, if any, exceeded the daily life standard. Because all regimens used within the trial would themselves be standard, the incremental approach might reasonably yield the conclusion that, despite the substantial risks of the individual antipsychotic medications, trial participation would nevertheless involve minimal risk. This conclusion entails neither that the trial should undergo expedited review nor that it would qualify for a waiver of the requirement for informed consent. However, it does suggest that investigators presenting the trial to prospective research participants might accurately describe study participation, in both consent forms and discussions, as involving no more than minimal risk.

Two lines of regulatory evidence support the incremental approach to determining minimal risk. First, the Common Rule states, “In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research).”9 Following this logic, risks of standard therapies that subjects would receive outside the research are the proper baseline against which the risks of the trial intervention should be evaluated. If the IRB determines that the incremental risks of trial participation, over and above receipt of usual therapy outside the trial, do not exceed the daily life standard, then it can justifiably conclude that the trial involves only minimal risk.

Second, consider the process the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (DHHS) outlines for determining which studies are eligible for expedited rather than full-board IRB review. A study must satisfy two conditions to be approved under expedited procedures: it must be judged to involve no more than minimal risk, and all study procedures must fit within one or more of the categories on a list published by OHRP/DHHS.10 The purpose of the list is to enumerate classes of research that are presumptively minimal risk. Category 1 includes “research on drugs for which an investigational new drug application . . . is not required,” which typically holds true when the drug’s use in the trial is consistent with its FDA-approved indication. That the use of drugs (or devices) in accordance with their labeled indications is included on the list of procedures eligible for expedited review suggests that OHRP/DHHS views such studies as presumptively minimal risk. This presumption can be understood only if one adopts the incremental approach.

Determining that many paradigmatic comparative effectiveness trials satisfy the minimal-risk standard can decrease markedly the regulatory burdens that these trials face and can promote accurate disclosures about risk, without substantively compromising the protections afforded to research participants. In making this determination, IRBs should assess the incremental risks of the interventions in the study, as compared with the risks of standard treatments that participants would experience if they did not join the trial. IRBs should then consider whether those incremental risks exceed the daily life standard specified in the Common Rule. This approach to determining minimal risk is consistent with the letter and spirit of human subjects regulations while protecting subjects against exposure to excess research-related risk.

Steven Joffe, MD, MPH, is Emanuel and Robert Hart Associate Professor of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Alan Wertheimer, PhD, is professor emeritus of Political Science, University of Vermont, Burlington, VT.

Acknowledgments

Dr. Joffe’s work on this project was supported by a grant from the Greenwall Foundation through the Greenwall Faculty Scholars Program. The Greenwall Foundation had no role in the development of the arguments presented here; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors wish to thank Scott Halpern, MD, PhD, for helpful comments on an earlier draft of this manuscript.

Disclosure

Dr. Joffe was a paid member of a Data Monitoring Committee for Genzyme/Sanofi until November 2012. He is currently an expert witness for counsel representing Johns Hopkins University in Partlow v. Johns Hopkins University. Dr. Wertheimer has no conflicts of interest to declare.

References

1. Drazen JM, Solomon CG, Greene MF. Informed consent and SUPPORT. NEJM 2013;368:1929-1931; Hudson KL, Guttmacher AE, Collins FS. In support of SUPPORT—a view from the NIH. NEJM 2013;368:2349-2351; Network Support Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, Finer NN, et al. Target ranges of oxygen saturation in extremely preterm infants. NEJM 2010;362:1959-1969; Wilfond BS, Magnus D, Antommaria AH, et al. The OHRP and SUPPORT. NEJM 2013;368(25):e36; and Macklin R, Shepherd L, Dreger A, et al. The OHRP and SUPPORT—another view. NEJM 2013;369(2):e3.

2. Faden RR, Kass NE, Goodman SN, et al. An ethics framework for a learning healthcare system: A departure from traditional research ethics and clinical ethics. Hastings Center Report 2013;43(1):S16-S27; Kass NE, Faden RR, Goodman SN, et al. The research-treatment distinction: A problematic approach for determining which activities should have ethical oversight. Hastings Center Report 2013;43(1):S4-S15; Kass NE, Faden RR, Tunis S. Addressing low-risk comparative effectiveness research in proposed changes to US federal regulations governing research. JAMA 2012;307:1589-1590; Largent EA, Joffe S, Miller FG. Can research and care be ethically integrated? Hastings Center Report 2011;41(4):37-46.

3. See Weijer C, Grimshaw JM, Eccles MP, et al. The Ottawa statement on the ethical design and conduct of cluster randomized trials. PLoS Medicine 2012;9(11):e1001346; Mazor KM, Sabin JE, Goff SL, et al. Cluster randomized trials to study the comparative effectiveness of therapeutics: Stakeholders’ concerns and recommendations. Pharmacoepidemiology and Drug Safety 2009;18(7):554-561; McRae AD, Weijer C, Bink A, et al. When is informed consent required in cluster randomized trials in health research? Trials 2011;12:202; Eldridge SM, Ashby D, Feder GS. Informed patient consent to participation in cluster randomized trials: An empirical exploration of trials in primary care. Clinical Trials 2005;2(2):91-98; Sim J, Dawson A. Informed consent and cluster-randomized trials. American Journal of Public Health 2012;102(3):480-485; Chaudhry SH, Brehaut JC, Grimshaw JM, et al. Challenges in the research ethics review of cluster randomized trials: International survey of investigators. Clinical Trials 2013;10(2):257-268.

4. Giraudeau B, Caille A, Le Gouge A, et al. Participant informed consent in cluster randomized trials. PLoS ONE 2012;7(7):e40436.

5. Huang SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU infection. NEJM 2013;368:2255-2265.

6. U.S. Department of Health and Human Services. Protection of Human Subjects. 45 CFR 46.

7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. NEJM 2005;353:1209-1223.

8. Wendler D, Miller FG. Assessing research risks systematically: The net risks test. Journal of Medical Ethics 2007;33(8):481-486; Rid A, Wendler D. A framework for risk-benefit evaluations in biomedical research. Kennedy Institute of Ethics Journal 2011;21(2):141-179; Morris MC, Nelson RM. Randomized, controlled trials as minimal risk: An ethical analysis. Critical Care Medicine 2007;35(3):940-944.

9. See ref. 6, U.S. Department of Health and Human Services 45 CFR 46.111(a)(2).

10. Office for Human Research Protections. Categories of research that may be reviewed by the Institutional Review Board (IRB) through an expedited review procedure. Federal Register 1998;63(216):60364-60367. http://www.hhs.gov/ohrp/policy/expedited98.html.

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