- IRB: ETHICS & HUMAN RESEARCH
Evidence-Based Research Ethics and Determinations of “Engagement in Research”
Developing and implementing protections for research participants should be based, when possible, on relevant data that provide evidence of the need for and effectiveness of such protections. This is the rationale for the imperative to conduct empirical research in bioethics.1For example, knowledge of research participants’ experiences, opinions, and perceptions can inform the way research studies and their informed consent processes are designed in order to optimize the protection of human subjects. This kind of research involves studying actual participants in research studies and is itself human subjects research. Yet conducting such research raises the question of how institutional review boards (IRBs) implement federal research regulations and interpret guidance provided by the Office for Human Research Protections (OHRP) in overseeing empirical research on research ethics-related issues. This question is particularly relevant to IRBs, bioethicists, and others who are committed to improving the practice of research ethics oversight.In this article, we focus on how IRBs deal with the issue of what constitutes “engagement in research” in cases where staff members from clinical research studies (which we will call “parent studies,” to distinguish them from the ethics research that focuses on the participants of those studies) take steps to help an ethics study team recruit individuals to enroll in those studies. Our experience indicates that IRBs’ interpretations of the guidance from the OHRP about what constitutes engagement in research could have significant implications for the quality of research on research ethics.
IRB Interpretations of Engagement in Research
The participants in our ethics interview studies are participants in neurosurgical and pharmacological randomized clinical trials, as well as those who declined to enroll in those studies. Our interviews assess individuals’ motivations for participating in clinical trials and their understanding and attitudes regarding various aspects of those trials. Most trial sponsors and principal investigators appreciate the importance of the ethical questions we propose to study and agree to allow us to approach their participants to participate in our interview study. However, recruiting individuals to participate in neurological and pharmacological trials involves considerable time and effort. Thus, given the demands of their own efforts to recruit participants and conduct the parent studies, the sites where these studies are conducted are often wary of potential additional burdens to their recruitment and study activities that an add-on ethics study like ours poses. Thus, recruiting participants from parent studies to participate in our study requires negotiations and sensitivity in working with the parent-study sites. This issue is crucial because effective recruitment for empirical ethics studies is key to gathering generalizable findings. There can be dozens of sites for a clinical trial, and given the potential for significant burdens on sites due to varied and extensive lengths of time needed to coordinate IRB reviews,2there is a need for a regulation-compliant yet efficient method for working with numerous sites to recruit clinical trial participants to enroll in an ethics research study.
Over the years, we have developed regulation-compliant procedures to maximize recruitment without unnecessarily burdening the parent-study sites. Research participants recruited for our ethics studies can directly provide most of the relevant information we need for our studies, so there is little reason to request any participant-specific data from the parent studies. Therefore, there is no need to involve the parent-study sites beyond their providing us with initial access to parent-study participants to recruit for our studies. For such situations, the OHRP has provided clear guidance on how institutions can provide access to actual research participants without creating the need for additional IRB reviews at the parent-study sites. According to the OHRP, an institution isnotengaged in human subjects research when the institution or its employees or agents do the following:
- inform prospective participants about the availability of the research;
- provide prospective participants with information about the research (which may include a copy of the relevant informed consent document and other IRB-approved materials) but do not obtain subjects’ consent for the research or act as representatives of the investigators;
- provide prospective participants with information about contacting investigators for information or enrollment; and/or
- seek or obtain the prospective subjects’ permission for investigators to contact them (an example of this would be when a clinician provides patients with literature about a research study at another institution, including a copy of the informed consent document, and obtains permission from the patient to provide the patient’s name and telephone number to investigators).3
For our studies, staff members at the parent-study sites approach the participants in their study and briefly inform them of our interview study. If any of those participants are interested in speaking with us, the site obtains their permission to forward their contact information to us. This process is documented by the site on a form and forwarded to our research coordinator. No other information (e.g., study data, clinical data, etc.) is shared with our team. Our own institutions’ IRBs accepted the OHRP guidance and agreed that the parent-study sites that provided us with access to their research participants using the above procedures were not “engaged” in our ethics research study. We also subsequently contacted the OHRP directly to confirm that our procedures conformed to the conditions of the guidance on engagement in research. We have found, however, that the parent-study sites are generally not familiar with the OHRP guidance and are wary of unilaterally determining that their involvement in our research (e.g., providing access to their research participants) does not require IRB review. We ask the parent sites to discuss the OHRP guidance and its application to our study with their IRBs and obtain their opinion about whether an IRB review at their sites is necessary. We also provide each parent-study site with a written explanation of our procedures as well as a copy of the OHRP guidance to aid their interactions with their IRB. Since the purpose of contacting the IRBs is to determine whether a formal IRB review is necessary, these interactions with the IRBs are less formal than the usual IRB review. For example, we spoke informally with the staff members of IRB offices at our own institutions to confirm that they agreed with the OHRP guidance on engagement in research.
Table 1 summarizes 26 interactions of our parent-study sites and their IRBs regarding the level of IRB review, if any, required for our ethics study. In 14 instances, the IRBs agreed that the parent-study sites were not engaged in research, as defined by the OHRP guidance. But in 12 cases, the IRBs told the parent-study staff members that review by the site’s IRB was needed. However, in 5 of these 12 instances, the IRBs offered an alternative to an IRB review. They said the parent-study staff members could send an “opt-in” letter to their research participants with our study’s contact information, rather than giving us—with the participants’ permission—those participants’ names and contact information. All of these five parent-study sites informed us that they did not have staff resources to bear the burden of shepherding a new application through their IRBs, though they were willing to help our ethics study only if we accepted this opt-in letter process.
In 7 cases, the IRBs at the parent sites required IRB review and did not offer an alternative. Two of these parent-study sites declined to help us recruit their participants to enroll in our study. In both cases, their IRBs required amendments to their parent-study protocols for IRB review, and the sites declined to amend their protocols. In 5 of the 7 cases, the parent-study sites submitted and received IRB approval for our ethics study (one of these was submitted as an amendment to their clinical trial).
Of note, we attempted to recruit individuals who declined to participate in the parent studies. Some of the IRBs raised concerns about this. These IRBs were concerned about the procedure of the parent-study staff members approaching decliners of the parent study and informing them of our ethics study and, if the decliners agreed, passing their contact information along to us. One IRB determined that only an opt-in process was acceptable for decliners. Another IRB allowed the parent site to identify and approach decliners in a prospective fashion only (i.e., as they declined in real time), but not to approach individuals who had already declined. Another IRB prohibited us from recruiting any of the parent-study decliners.
His report raises a seldom-discussed issue in research ethics: when a research ethics study is itself human subjects research, how do IRBs interpret and apply federal research regulations and guidance? Our experience with conducting empirical studies about research ethics raises concerns that current IRB practices could in the long run unnecessarily compromise the quality of research studies that are aimed at improving the human subjects protection system.
Although the majority of the IRBs we dealt with agreed with the OHRP guidance on engagement in research, in 12 of 26 instances, the IRB responses were more restrictive than the guidance recommends. It seems reasonable that the OHRP guidance should, barring special considerations, be followed. There may have been local, administrative reasons for not following the guidance, just as some IRBs decline to exempt any studies as a matter of local policy “to avoid confusion.”4But from an ethical point of view, there are good reasons to doubt that the more restrictive practice is necessary. First, following the OHRP guidance does not mean that there is no IRB oversight of the ethics research study. The ethics study must still be formally reviewed by an IRB (or multiple IRBs if the ethics investigators are from multiple institutions). Second, there is little likelihood of exploitation of or harm to individuals who participate in our studies. All of the participants in our studies were competent adults who would have given specific, documented permission to pass along their names and contact information to us. The risk in being told about our ethics study and having contact information forwarded to us is virtually nil. No breach of confidentiality is involved (since permission is given to pass along the information).
Third, in regard to the individuals who declined to participate in the parent clinical trials, the IRBs were even more restrictive than the guidance on engagement in research suggests is necessary. Surveying or interviewing decliners may be particularly important for a more complete picture of what individuals recruited to participate in clinical trials understand about those studies and how they make their decision not to participate. Thus, there should be a countervailing ethical consideration to justify special restrictions on interviewing decliners of research. It is possible that the IRBs of the parent clinical trials reasoned that the decliners of those trials might perceive our study as a further stage of the parent study and thus would feel their autonomy was infringed upon if they were recontacted to participate in another stage of the same study.5The counterargument for this moral intuition would be that it seems unreasonable to assume that simply because a person declines to participate in a particular clinical trial, he or she should not be contacted again to be invited to participate in other studies. Indeed, since decliners of the parent clinical trials had already shown interest in participating in research (although ultimately declining), it is unlikely that they would have wanted to be protected in this way. Which moral intuition regarding the attitudes of decliners is correct is an answerable empirical question. However, if such research is restricted, we will never know the actual attitudes underlying individuals’ decisions about participating in research. And without such data, IRB decision-making about recruiting current research participants to enroll in other studies will continue to rely on assumptions rather than be informed by the perspectives of prospective and actual research participants.
Some may doubt that our experience adequately reflects the practices of IRBs by pointing to some of the limitations of our report. First, we relied on the reports of the research staff members at parent-study sites about their communications with their IRBs. It is possible that those individuals were unfamiliar with the issue of “engagement in research” and did not accurately present the issue to their IRBs. Thus our experience may not reflect “considered judgments” of IRBs about this issue. However, we did provide documentation to the parent-study site staff members to use in their interactions with their IRBs. Moreover, none of the five sites’ IRBs that conducted a review of our research protocol—which would have given them ample opportunities and information to determine that the parent site was not “engaged” in research according to the OHRP guidance—determined later that such a review was unnecessary. Also, those IRBs that offered a choice between an opt-in letter versus an official IRB review obviously understood that an official IRB review was not necessary (given that they were willing to accept an opt-in letter option over a formal review).
Second, the anecdotal nature of our report may limit the generalizability of our findings. This is undoubtedly true. However, the incidence of IRB practices being more restrictive than is suggested by the OHRP guidance was not just one or two cases but 12 out of 26 cases. Also, these were highly experienced IRBs from well-known academic medical research centers and hospitals. Thus, although our report cannot be relied upon to provide precise quantitative estimates, an overall impressionistic conclusion that IRBs may impose conditions more restrictive than what the OHRP says is necessary is warranted.
Empirical research in research ethics is crucial to developing evidence-based policies and practices to protect research subjects. How IRBs oversee such studies has particular salience for ethicists, regulators, and human subjects protection systems. Our experience with the specific issue of interpreting what constitutes “engagement in research” suggests that practices more restrictive than OHRP guidance are not unusual. From an ethical point of view, there does not seem to be a compelling reason to override the OHRP guidance on this issue. And the long-term consequences for the human subjects protection system could be significant, since obstacles to gathering high-quality data on the practices and policies used to oversee human subjects research would effectively cut off an important feedback loop to improve the system.
Renee Wilson, MA,is an associate project manager at the Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY;Karl Kieburtz, MD, MPH,is the Robert J. Joynt Professor in Neurology and the director of the Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY;Robert G. Holloway, MD, MPH,is a professor in the Department of Neurology, University of Rochester, Rochester, NY;Scott Y. H. Kim, MD, PhD,is an associate professor in the Center for Bioethics and Social Sciences in Medicine, University of Michigan, Ann Arbor, MI.
This publication was made possible, in part, by the National Institute for Neurological Disorders and Stroke (R01-NS062770) and the National Center for Research Resources (UL1 RR024160), a component of the National Institutes of Health (NIH) and of the NIH Roadmap for Medical Research. We also thank the two anonymous reviewers who articulated important concerns that forced us to significantly revise and improve the manuscript.
The studies discussed in this manuscript were reviewed by and deemed exempt from federal regulations by the University of Rochester and the University of Michigan institutional review boards.
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3. Department of Health and Human Services.Guidance on Engagement of Institutions in Human Subjects Research. Accessed July 2012. http://www.hhs.gov/ohrp/policy/engage08.html.
4. Prentice ED, Oki GSF, Amdur R, Bankert E. Exempt from IRB review. In: R. Amdur and E. Bankert, ed.,Institutional Review Board: Management and Function. Sudbury, MA: Jones and Bartlett, 2002, pp. 111-113.
5. We thank an anonymous reviewer for this interpretation.