by Erin R othw ell, Karen J. M aschke, Jeffrey R. B o t k in , A aron

G o LDENBERC, THOMAS H . MURRAY, AND SUZANNE M . RlVERA

Biobanking Research and Human Subjects Protections: Perspectives of IRB Leaders

lthough biobanks in the United States are these institutions’ IRBs address protections for human a significant resource for genetic and other subjects of biobank-related research may help in the Ahealth-related research in collecting, storing, development of ethically sound policies that permit and and sharing human biospecimens and associated data encourage biospecimen and data sharing within and for systematic access and use (herein referred to as across all institutions where human subjects research is “biobanking”), they raise unique ethical and policy conducted, not only those in the CTSA consortium. challenges on a wide range of issues.1 Conflicting guidance from government agencies, research organi­ Study Methods zations, and professional bodies on issues related to ata for this paper are drawn from a larger multi­ informed consent, privacy and confidentiality, and the Dmethod study of biobanking at a representative return of individual genetic research results to biobank sample of IRBs at CTSA member institutions. As part participants has often left investigators and institutional of this NIH-funded project, we collected both quantita­ review boards (IRBs) unclear about how to develop tive and qualitative data about biobanking policies and biobanking policies in a way that protects biobank practices from the IRBs at these institutions. This paper participants while advancing research. Differences in focuses on the qualitative data from in-depth telephone institutions’ biobanking policies and procedures may interviews with zz IRB leaders (directors and adminis­ impede biobanks’ efforts to share biospecimens and trators) from 17 CTSA-affiliated institutions (five of the associated data with researchers at other institutions, interviews had two respondents). IRB leaders for these which is crucial for the genetic research enterprise. interviews were recruited from institutions selected For this study, we sought to learn about IRBs’ poli­ because of the leaders’ responses to our study’s quanti­ cies and procedures for collecting, storing, and shar­ tative survey of 51 IRBs at CTSA member institutions. ing biospecimens and associated data, how they were This survey asked a number of questions regarding developed, and how they are revised. We also wanted IRB policies related to collecting, storing, and sharing to obtain the perspectives of IRB leaders about their human biospecimens. From these quantitative survey IRBs’ policies and human subjects protection practices. results, we identified 31 IRBs that tended to provide di­ We targeted IRBs at institutions that are members of vergent responses on eight key survey questions (Table the National Institutes of Health’s (NIH’s) Clinical 1, available, along with Table z, on the IRB: Ethics & and Translational Science Awards (CTSA) consortium. Human Research website). “Divergent responses” rep­ There are more than 6o medical research institutions in resent more extreme responses to these eight questions the CTSA consortium, including leading academic med­ (i.e., selecting “always” or “never” on selected policy ical centers, institutions with a diverse population of options). By choosing IRBs with divergent responses, adult and pediatric patients, and institutions with inves­ we sought to identify IRBs that have clear policies tigators that conduct genetic research.2 The goal of the reflecting differences of opinions in the field about the CTSA program is to speed the translation of research most appropriate human subjects protections. Once discoveries into improved health.3 Understanding how the institutions were identified, the same IRB leaders who completed the previous quantitative survey were Rothwell E, Maschke KJ, Botkin JR, et al. Biobanking research and human subjects protections: Perspectives of IRB leaders, IRB: Ethics & Human sent an email inviting them to participate in an in-depth Research 2015;37(2):8-13.

March-April 2015 IRB: Ethics & Human Research interview. All respondents were emailed a minimum of were considered widely accepted procedures that are two times, and then a research assistant initiated three systematically applied to all studies and are developed follow-up phone calls. Out of the 31 IRBs, 17 agreed and approved by institutional administrators. Guid­ to participate. Reasons for not participating were not ances are sets of best practices that are supported by collected due to the lack of response to emails or tele­ consensus. Most respondents reported that their institu­ phone calls. tion distinguishes between guidance and policy and The interviews took place between January 2013 that they preferred to develop guidance for biobanking. and March 2013. After a respondent(s) gave verbal Reasons for this approach included perceptions about informed consent, an investigator on our project with how rapidly the biobanking landscape changes regard­ experience in qualitative research conducted a semi- ing issues related to consent and subtleties related to structured interview to obtain information about 1) the identifiability of biospecimens and associated data. the given IRB’s biobanking policies, 2) how the IRB’s One respondent noted that biobanking is “a field that biobanking policies were developed and by whom, 3) changes so quickly so we can be more flexible in devel­ the IRB’s process for revising human protection polices oping guidance,” as opposed to having to develop and related to biobanking, and 4) how flexible the IRB change policies. Another respondent pointed out that was about revising biobanking policies. We also asked questions about the history and/or ongoing discussions I r Bs at institutions in the CTSA consortium at the IRB of specific procedures relevant to biobank­ ing such as consent approaches, sharing biospecimens, shared common uncertainties and challenges about and biobank participants’ withdrawing their materials human subjects protections for biobank-related from research. The interview questions were tailored to research. include the responses provided in the previous quantita­ tive survey. Interview questions are listed in Table 2. “somebody’s always coming up with some new twist Each interview lasted an average of 50 minutes, and that the policy might not have considered.” all of the interviews were audiorecorded. The record­ Several respondents noted that their institutions ings were transcribed verbatim, and one member of relied on workgroups as the primary mechanism for the research team verified the transcripts for accuracy. developing guidance for their investigators about Content analysis was used to analyze the data. A biobanking. When asked what sources of information distinguishing feature of content analytic approaches institutions used to develop biobanking guidance and is the use of a consistent set of codes to designate data policies, most respondents said their institution relied segments that contain similar material.4 After the first on guidance from the Office for Human Research three interviews, the transcripts of those interviews Protections (OHRP), the Association for the Accredita­ and the semistructured interview guide were reviewed tion of Human Research Protection Programs (AAH- to develop an initial coding template.5 This template RPP), and their institution’s office of legal counsel. was then used to systematically code the first three Other sources of information included the National transcripts, allowing for the addition of new codes that Cancer Institute’s best practices recommendations for might have been missed with the initial development biorepositories,7 guidance and policies at other research of the codebook.6 All coded data were reviewed and institutions, and feedback from their own investigators verified by a second independent reviewer. No discrep­ who conduct biobanking-related research. Respondents ancies emerged, and the remaining interviews were then reported that guidance-development meetings involved conducted and coded using the same coding template. an iterative process and included IRB members and Additional information about study methods and cod­ administrators, experienced investigators, ethicists, and ing can be obtained on request from the first author. legal counsel. They acknowledged the importance of obtaining input from the community about human sub­ Study Results jects protections in biobanking but noted the difficulty Process for Developing Guidance for Biobank­ of obtaining such input. One respondent admitted that ing. Interviews all started with asking the respondents “maybe we didn’t do a good enough job engaging them to describe their IRB’s process for the development of [the community].” Some respondents said they ob­ policies, guidance, or practices. For this study, policies tained community input by having individuals from the

IRB: Ethics & H uman Research March-A pril 2015 9 community serve on some of their IRB committees. mens are ever really deidentified. Responses along ■ Biobanking versus Other Human Subjects Pro­ these lines included one respondent’s question “Are tection Policies. Most respondents reported that their they truly anonymous?” as well as these remarks from institution’s process for developing guidance about other respondents: “The Nature article recently demon­ biobanking encompassed additional considerations strated how easy it is identify deidentified specimens” that are not typical for other human subjects protec­ and “It’s going to not be feasible to label tissues truly tion policies. For example, the anticipated changes for anonymous in about fifteen or twenty years.” Another biobanking within the federal landscape appeared to issue respondents raised about deidentification was inhibit the development of consistent guidance (“Like the matter of who deidentified the biospecimens. One all of us are waiting, waiting, waiting for changes in respondent said, “Clearly anonymizing makes it not the Common Rule to come out,” one respondent said). human subjects, but there’s some limitations around Other factors considered were the increased need to that: who’s anonymizing?,” and another asked, “Who involve more collaboration among stakeholders and holds the link?” Finally, several respondents stated the community, and limitations on the IRB’s ability to that there was confusion within the research com­ monitor all secondary uses of archived biospecimens. munity about biobanking, deidentification, and what When discussing ways in which guidance about is allowed with secondary uses of biospecimens. For biobanking differed from other types of guidance pro­ example, one respondent pointed out that “[wjithin the vided by IRBs, respondents spoke of the need to trust research community, there’s not quite an understanding investigators. A number of respondents mentioned, for of what biobanking is and what is and is not allowed example, that they did not follow up on investigators to [be done] with samples left over from a previous to assess whether they complied with the details of the study.” And another noted, “There’s always the debate study as outlined in consent forms, such as destroying about what constitutes deidentified specimens.” biospecimens of participants who withdrew from the ■ Consent Forms and Participant Choice Re­ biobank. (“We have to trust—we ask the investiga­ garding Future Research. When respondents were tor, and we have to trust them to do it,” a respondent asked about the consent process, most of them stated said.). Additionally, several respondents mentioned that that the consent approach for biobanking should offer they had to trust researchers to conduct ethical research participants a choice about whether their biospecimen with deidentified biospecimens for which they may not and associated data can be used in the future. When be required to submit information to the IRB. (“What respondents were asked what types of consent options do you do in the case of nonhuman subjects research, should be included regarding how specimens are used biobanking protocol, and even though we don’t have in the future, their responses overall identified two technically a jurisdiction, what’s our role in reviewing general approaches. Some respondents supported a those uses?” one respondent asked.) broad consent that would allow for future, unspeci­ Many of the respondents noted that the issue of fied research. Alternatively, several of the respondents when a biospecimen is not considered human subjects stated that biobank participants should have the option research was a significant factor that influenced the to decide how specifically their specimens or data can process for IRB approval, but there was confusion be used. The primary reason stated for the prefer­ about the point when the use does not qualify as hu­ ence to offer more choices was respect for persons man subjects research and how long this perspective (Respondents said, for example, “Respect for persons would be relevant. For example, some respondents demand[s] that you give people the autonomy at least stated that the decision about whether a biospecimen- to make a myriad set of decisions about what to do related research project was considered human subjects with the sample,” and, “There are certain people that research comes at the time of collection, while other would say, ‘I don’t care if my sample is de-identified. respondents stated that it is made at the time of the I don’t want you using it for reproductive research. biospecimen’s storage, and others stated that it comes Even if my name’s not on it, I don’t support that type at the time when a biospecimen is released for research of research.’”). Respondents who supported a broad from a biobank. Furthermore, many respondents stated consent for future unspecified research provided these that biospecimens may eventually become reidentifi- reasons: the inability to know or predict how speci­ able, which raised concerns about whether biospeci­ mens might be used in the future, the lack of practical

M arch-A pril 2015 IRB: Ethics & H uman Research 10 mechanisms to enforce limitations on future use or to to particular practices were prompted by individual monitor all the future possibilities, and giving partici­ investigators requesting these changes for a specific pants too many choices limits the potential value of the study. Some respondents indicated that in these cases, resource. One respondent said, “We try to discourage if the request did not conflict with federal regulations, it [tiered consent] because unless you have written a changes were typically approved. Factors that influ­ 4 5-page consent form to describe the implication for enced these exceptions to guidance included the age each of these choices in a way that the average person of the biospecimen (i.e., how long ago a biospecimen can understand, my feeling is you are putting them in a was collected) and where it was collected (a clinical or position where you’re just confusing them.” research setting). Exceptions to existing guidance that The review of consent forms concerning previously respondents mentioned in the interviews included the collected biospecimens was also explored during the absence of an original consent form, the inability to interviews. Many respondents stated that they reviewed contact participants again for a new consent, and when consent forms to ensure protection of human subjects a new study is outside the scope of the original consent and to assess whether the original consent form explic­ form but is minimal risk. One respondent’s comment itly prohibited future uses of the biospecimens in gen­ captured this complexity: eral. If consent forms did not explicitly prohibit future It’s kind of tricky. If a new study is outside the scope uses, then studies typically were approved to use the [of the original consent form], but they’re not getting biospecimens in a new approved research study. One new samples, I’m not exactly sure how all the chairs are respondent said, for example, “The key to not allow­ handling this. I think it depends. I would think that in general, they might let them do it, but it might depend, ing research with anonymous biospecimens is when the too. I mean, we hate to say absolutely no, but we don’t consent form explicitly states that it will not be used want to be so cavalier that we’d say, “Oh, absolutely for any future purposes. If [it] does not address future yes,” either. We don’t know. This is a hard one. They research, then according to the Common Rule, they can could make the argument that it’s impractical to get use them anonymously.” Other responses along these consent, that it’s minimal risk, use all those arguments lines included “As long as the informed consent form for a waiver. But then there’s that ethical component that they said it was this and now it’s that. explains to the best of your ability at the time, the IRB can usually approve secondary use” and “It’s important As exceptions to existing guidance occurred, some to make sure that the subjects were not informed that respondents stated that they were unsure how to retro­ their specimens would never be shared with anybody spectively apply changes specifically to studies that are ever under any circumstance.” Several respondents ongoing and in need of continuing review or to studies noted situations when there are no consent forms for that use clinical samples collected years ago for second­ specimens collected years ago, at a time when future ary purposes. Representative quotations include the use was not a primary concern. “We’re completely following: aware that over the last maybe ten years ago things • What you do is you review things as best you can, changed, but 15 and 20 years ago investigators col­ and then you change your policy at some point or your approach. You have everything coming back in for lected specimens and sometimes got consent, sometimes continuing review, and then what do you do? Do you didn’t, under very different rules,” a respondent stated, retrospectively apply those changes? How strongly do while another said, “The problem is if there is no con­ you apply those? Do you say, this is a deal breaker, we sent to start with.” can’t continue to approve this study for you? Challenges to Current and Retrospective • Are samples that were collected 15 or 20 years ago Changes to Biobanking Guidance. Respondents allowed to be used today if there is no consent form? raised concerns about the difficulty of developing con­ Are samples that were collected years ago from clinical sistent guidance and, consequently, the fact that many procedures allowed to be used for secondary purposes IRB decisions are made on a study-by-study basis. now? Respondents described making changes to a specific guidance or practice as relatively easy (“We take a D i s c u s s i o n study by study approach” one explained, and another nvestigators conducting genetic research need access said, “This would be vetted right now [on] an individ­ Ito biospecimens and associated data and may need ual basis to make decisions.”). In other words, changes to request those materials from biobanks at institutions

IRB: Ethics & H uman Research M arch-A pril 2015 other than their own. Ensuring that investigators can debates surrounding the ability under certain circum­ obtain the biospecimens and data they need requires stances to deidentify biospecimens—that is, to link a practical, ethically sound approaches within and across specific biospecimen to identifiable information about institutions to the complex issues of informed con­ the person from whom it was obtained—complicate sent, storing and sharing of biospecimens and associ­ the development of guidance and policies for human ated data, and protecting the interests and welfare of subjects protections for biobank-related research. The research participants. Our study was designed to learn concern about “reidentification” is reflected in the about policies for biobanking at IRBs and about IRB Department of Health and Human Services proposal leaders’ perspectives regarding those policies. While to change the Common Rule10 so that archived bio­ we intentionally selected institutions with divergent specimens are defined as inherently reidentifiable, thus responses to key items on a previous quantitative requiring consent from the individuals from whom survey, we found that the IRBs at these institutions they were obtained before they can be used for research shared common uncertainties and challenges about hu­ even when all personal identifiers are removed before man subjects protections for biobank-related research. the biospecimens are placed into storage. Additionally, In general, we found that IRBs preferred to develop state health departments are struggling with questions guidance that was applied on a flexible, case-by-case about how to create policies that would facilitate the basis rather than develop rigid policies. And we found use of residual dried bloodspots from newborn screen­ that there were more similarities than differences across ing blood samples obtained without parental consent IRBs regarding their approach to human subjects pro­ while at the same time protecting the rights of parents tections for biobank-related research. and newborns who may wish that their child’s biospeci­ The findings of our study highlight several key mens not be used in research without their consent. 11 challenges to developing consistent approaches for Finally, the findings reported here raise concerns about the collection, storage, and use of biospecimens for the impact of variation across IRBs regarding human research. For example, some IRBs strongly encourage subjects protections for biobank-related research. If their investigators to use a tiered consent approach that IRBs make case-by-case decisions about consent ap­ gives biospecimen contributors a number of choices for proaches and what constitutes human subjects research how their biospecimens can be used in future research, in the biobanking context, their decision-making could while other IRBs strongly favor broad consent for inhibit intra- and interinstitutional sharing of biospeci­ future, unspecified research. That IRBs have diver­ mens and associated data. gent views about the consent approach for obtaining It is important to note that there are several limita­ biospecimens for research reflects the ongoing debate tions to this study. There was a low response rate by about broad consent versus tiered consent.8 Nonethe­ IRB leaders to agree to be interviewed, and this re­ less, more participants in our sample supported broad sponse bias may influence the results. For example, the consent to increase the utility of biospecimens collected results may suggest more similarities across institutions and to minimize the logistical challenges of tracking the than actually are present, and, if all of the individuals use of biospecimens obtained under a tiered consent that were approached had agreed to participate, more approach. However, it is important to note that the differences might have emerged. Furthermore, IRB main reason that some respondents said their IRB leaders who were interviewed were employed within supported a tiered consent approach was to uphold a particular group of IRBs (those in the CTSA consor­ the ethical principle of respect for persons by giving tium), and this may not be representative of IRBs in biospecimen contributors autonomy over deciding how general. their biospecimens can be used. Some commentators In summary, biobanks raise a unique set of issues for have pointed out that the autonomy argument can also researchers and IRBs that can complicate the applica­ be used to support a broad consent approach in that tion of human subjects protections. These may include broad consent honors the individual’s right to elect unclear and changing perspectives on the identifiabil- future unspecified uses rather than denying him or her ity of stored specimens, a potential lack of control or that option.9 Our findings also reveal an uncertainty knowledge about the consent process for biospecimen about the important issue of what kinds of biospeci­ contributors, and, often, little to no connections to men use constitute human subjects research. Current those individuals. Our data highlight that IRBs are

M arch-A rril 2015 IRB: Ethics & H uman Research 12 struggling with the issues surrounding biobanking and Reserve University; Thomas H. Murray, PhD, is president emeritus with proposed changes from federal regulators about of The Hastings Center and is Chen Su Lan Centennial Chair at the National University of Singapore; and Suzanne M. Rivera is assistant human subjects protections. There may be a need for professor of bioethics and vice president for research at Case Western more detailed guidance on study-specific issues such as Reserve University. when an original consent form is unavailable, use of R eferences samples outside the scope of the original consent form 1. McGraw SA, Wood-Nutter CA, Solomon MZ, Maschke K, in a minimal risk study, or developing consistent terms Benson JT, Irwin DE. Clarity and appeal of a mulitmedia informed to describe genetic data. It may be beneficial to seek consent tool for biobanking. IRB: Ethics and Human Research examples of studies with unique and difficult circum­ 2012;34:9-19. 2. Kon AA. The Clinical and Translational Science Award (CTSA) stances from IRBs to provide more specific and practi­ Consortium and the translational research model. American Journal cal guidance. o f Bioethics 2008;8:58-60. 3. Zerhouni EA. Translational research: Moving discovery to practice. Clinical Pharmacology and Therapeutics 2007;81:126-128. Tables 4. Elo S, Kyngas H. The qualitative content analysis process. The two tables for this article are available on the IRB: Journal of Advanced Nursing 2008;62:107-115. Ethics & Human Research website. 5. Rothwell E, Anderson R, Goldenberg A, et al. Assessing public attitudes on the retention and use of residual newborn screening blood samples: A focus group study. Social Science & Medicine D isclosure 2012;74:1305-1309; Rothwell E, Anderson R, Swoboda KJ, Stark L, Botkin J. Public attitudes regarding a pilot study of newborn Gregory E. Kaebnick, the editor of the Hastings Center screening for spinal muscular atrophy. American Journal o f Medical Report, managed the review process for this manuscript Genetics 2012;i 6i A:679-686. in place of Karen Maschke, the editor of IRB: Ethics & 6. See ref. 4, Elo and Kyngas 2008. Human Research. 7. National Cancer Institute. NCI Best Practices for Biospecimen Resources, http://biospecimens.cancer.gov/practices/2011 bp.asp 8. Hansson M, Dilner J, Bartram C, Carlson J, Helgesson G. Acknowledgments Should donors be allowed to give broad consent to future biobank re­ This work was made possible by grant NG005691 search? Lancet Oncology 2006;7:266-269; Hofmann B. Broadening from the National Human Genome Research Institute, consent and diluting ethics? Journal of Medical Ethics zoo9;yy.izy 129; Steinsbekk S, Myskja B, Solberg B. Broad consent versus dy­ part of the National Institutes of Health. The authors namic consent in biobank research: Is passive participation an ethical would like to express their gratitude to Dr. Leona Cuttler, problem? European Journal o f Human Genetics 2013;21:897-902. who provided the leadership for this work but unfortu­ 9. See ref. 11, Hansson et al. 2006. nately passed away before its completion; they offer their 10. The Department of Health and Human Services and the Food condolences to her family. and Drug Administration. Human subjects research protections: En­ hancing protections for research subjects and reducing burden, delay, ■ Erin Rothwell, PhD, is associate professor of research at the and ambiguity for investigators. Action: Advance notice of proposed University of Utah; Karen J. Maschke, PhD, is editor of IRB: Ethics rulemaking. Federal Register 20ii;76(i43):445i2-4453i. http:// & Human Research and research scholar at The Hastings Center; Jef­ www.hhs.gov/0hrp/humansubjects/anprm2011page.html. frey R. Botkin, MD, is professor of pediatrics and medical ethics and 11. Botkin J, Goldenberg A, Rothwell E, Anderson R, Lewis M. associate vice president for research at the University of Utah; Aaron Policy guidance for the retention and research use of residual new­ Goldenberg, PhD, is assistant professor of bioethics at Case Western born screening bloodspots. Pediatrics 2013;131:120-7.

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