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3 Ethical, Legal, and Regulatory Considerations This chapter focuses on ethical, legal, and regulatory considerations underlying the committee's approach to responding to the questions posed by the Department of Defense (DoD). It begins with a general discus- sion of those considerations and previous scholarly work concerning them and then addresses considerations regarding the source of specimens. The chapter finishes with an examination of the federal laws and regulations, DoD d irectives and instructions, and Armed Forces Institute of Pathology and Joint Pathology Center (JPC) regulations regarding research on bio specimens and their associated data. THE CHANGING ETHICAL, LEGAL, AND REGULATORY LANDSCAPE OF BIOREPOSITORIES Identifying Changes, Trends, and Gaps The scientific and technologic developments of the last 20 years in genomics and informatics have greatly increased the potential value of bio- repositories for understanding diseases and developing diagnostic, prognos- tic, therapeutic, and preventive modalities. They have also brought about substantial changes in the ethical, legal, and regulatory landscape of tissue repositories. These changes have been propelled by increased informatics capacity and other technologies that allow for larger-scale research; the mounting commercialization of research; public anxieties about possible uses and misuses of genetic information, particularly with ever larger data- sharing networks; expanded conceptions of patients' and research partici- 65
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66 FUTURE USES OF THE DOD JPC BIOREPOSITORY pants' rights; and heightened concerns about legal liability on the part of organizations that hold or study human genetic material and health records (Cambon-Thomsen et al., 2007; Hoeyer, 2008). The changes have also been driven by a series of events that have captured the attention of the public and prompted examination by vari- ous professional and government bodies. Dramatic and troubling cases tend to galvanize public attitudes, thereby altering the social and cultural context of research. Much as the notorious U.S. Public Health Service syphilis study at Tuskegee, the Jewish Chronic Disease Hospital case, the Willowbrook hepatitis study, and other such events in the United States from the 1930s to the 1970s transformed approaches to research involv- ing human subjects (Katz, 1972), recent attention to problematic uses of human biologic m aterials in research have altered the ethical, legal, and regulatory landscape of bio repositories. Some examples are the Havasupai tribe's lawsuit against the Arizona Board of Regents for unapproved sec- ondary uses of tribal members' biologic samples (Harmon, 2010); the legal actions against Texas A&M University's use of bloodspots from newborn screening in genetic research and the Texas Department of Health exchange of such material for money and services, all without parental knowledge or consent (Beleno v. Texas Department of Health Services1; Higgins v. Lakey2); the derivation of the HeLa cell line, a highly important research resource, from tissue clinically removed from a patient without notice to or consent from the patient for research use (Skloot, 2010), and the dispute between a r esearcher and his institution over ownership of a cell repository (Washington University v. Catalona3). Those cases have focused attention and debate on the adequacy of the federal regulations on human- subjects research (principally the C ommon Rule, at 45 CFR Part 46) to address the use of archived biospecimens, especially because--under some circumstances--research use of such specimens is not considered research on human subjects under the regulations. One essential task for the committee has been to identify and assess the crucial changes in this landscape to make it possible to offer recommenda- tions for JPC governance of, policies for, and practices at its repository. This section maps the challenges posed by the changing landscape, identi- fies important normative trends for biobanking, and examines some spe- cific decisions facing the JPC to lay the groundwork for responding to the questions that the committee has been asked to address. The committee's task is complicated by a lack of broad public consensus on the meaning of 1SA-09-CA-188-FB (W.S. Tex., September 17, 2009). 2SA-10-CV-990-XR (W.D. Tex., July 7, 2011). 3437 F. Supp. 2d 985 (E.D. Mo. 2006), aff'd, 490 F.3d 667 (8th Cir 2007), cert. denied, 128 S. Ct. 1122 (2008).
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 67 key terms, as well as by the changing--and sometimes conflicting--ethical, legal, and regulatory standards. Characterizing Biorepositories and Their Norms Different terms are used to describe collections of the type held by the JPC, including tissue repository, biorepository, and biobank. Each term has a variety of meanings and somewhat different ethical, legal, and regulatory implications (Cambon-Thomsen et al., 2007; Tutton, 2010; With et al., 2011; Wolf et al., 2012, Appendix). Consider the term tissue repository, which has been used to describe collections of human biologic specimens of the sort that were accumulated over 150 years by what is now the JPC. The term seems accurate enough in suggesting that the JPC is archiving material of potential value. But by placing emphasis on the biologic material, tissue repository fails to signal the presence of associated data in the JPC collec- tions, such as medical records and pathology reports, or of the digital slide collection. The same could be said of the more modern term biorepository, which suggests a place to hold biologic materials and hints at their use for biomedical research.4 However, many biorepositories also include data on the persons whose specimens are in the repositories, which led in the 1990s to coinage of the term biobank, defined as "organized biological sample col- lections with associated personal and clinical data" (Cambon-Thomsen et al., 2007). But the latter term and the related biobanking are still not fully settled with clear and definite boundaries, though the use of the term "bank" rather than "repository" implies a place where not merely deposits but also withdrawals are regularly made. Biobanks have various designs and sizes and include national biobanks set up in a number of countries where people voluntarily place genetic samples and allow the ongoing collection of medi- cal, occupational, and other personal data that are necessary for longitudinal study of potential associations between environmental exposures, genetic variants, and health-related outcomes (Austin et al., 2003). Finally, database and genetic database sometimes also encompass both biologic specimens and associated data; this emphasizes their potential for genomic, epigenomic, proteomic, and related molecular studies (Tutton, 2010). In line with much of the current literature, the present report uses biorepository and repository interchangeably to refer to the organized col- lections of biological samples with associated personal and clinical data now held by the JPC for consultative, educational, and research purposes. Another complexity for the committee's analysis stems from the fact that, 4For instance, the International Society for Biological and Environmental Repositories (ISBER) defines a biorepository as "an entity that receives, stores, processes and/or dissemi- nates specimens as needed" (ISBER, 2008).
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68 FUTURE USES OF THE DOD JPC BIOREPOSITORY unlike a modern biobank created for research purposes, the different col- lections under the JPC's auspices were acquired over a long period in varied ways from military and civilian pathologists primarily in the course of clini- cal care, and they consist of materials that are domestic and international, contemporary and historical. Whatever their label, collections of human biologic specimens with related data, including those held by the JPC, have been used for research and education for well over a century. Some of the collections are held by individual pathologists or academic pathology departments. Others are held by hospitals or other medical-care facilities. The JPC collections are u nusual because they were started in the middle of the 19th century and have accu- mulated millions of specimens. Scale aside, the accumulation of specimens and associated data for consultation, education, and research is a long- established practice. Until fairly recently, these activities continued in the United States with little scrutiny. Only in the recent past have the traditional practices of pathologists and their institutions regarding the use of stored specimens for research and educational purposes and the liberal sharing of such material with medical colleagues come under scrutiny. In 1999, when the National Bioethics Advisory Commission issued a report with recommendations on the ethical use of stored human tissue, it was reflecting a new sensitivity to the ethical, legal, and regulatory issues raised by collecting, storing, and using those specimens and associated data. A substantial literature has since arisen analyzing the ethical and legal issues raised by such collections of human material (Eiseman et al., 2003; Weir and Olick, 2004). Even as pathologists and their institutions have begun to grapple with the implications of performing research on material from source individuals5 who have rights and interests, the rise of prospective, population-based, and research-oriented biobanks has raised questions about the feasibility of meaningful contact with sources when the scale of the biobank is large. Collections, such as the JPC's, with data and specimens obtained from pathologists involved in clinical care, are faced with the practicability of communicating about future research uses of sources' data and specimens when those sources typically have little to no knowledge that their speci- mens are stored and the specimens may have been collected long ago. As the JPC seeks to capitalize on the research potential of its collections and to accumulate new specimens in an era of ever more sophisticated and 5 The term source individual (sometimes abbreviated to source) is used in this report to refer to the individual from whom biospecimens and data were obtained. Unlike the term donor, it does not imply that the person necessarily made a decision about the storage and use of the materials; such an implication would be mistaken in the case of almost all the materials held in the JPC repository.
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 69 powerful research methods, it must confront the changing ethical, legal, and regulatory standards for biorepositories. A central issue is what sort of recontact or consent, if any, is needed from a source individual for the JPC to permit his or her specimens and data to be used in various ways, includ- ing in research. To address that question, the following section discusses the surrounding ethical and legal landscape and the current challenges posed as the standards evolve. Traditional Ethical Principles and the Need for a Contemporary Approach Three and a half decades have passed since the National Commis- sion for the Protection of Human Subjects of Biomedical and Behavioral Research issued its landmark Belmont Report in response to its mandate from Congress "to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research" (National Research Act, PL 93-348; July 12, 1974). During that time, the three principles that it articulated--respect for persons, beneficence, and justice--have come to provide a foundational means of evaluating the ethics not only of research with human subjects but of patient care. Not surprisingly, those principles carry great weight in the present committee's analysis of the JPC's ethical obligations in managing and using its biorepository. For at least five reasons, however, the committee believes that it must go beyond the original applications of the Belmont principles, especially "respect for persons." In articulating what is meant by respect for persons the National Commission attempted to yoke together "at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protec- tion" (National Commission, 1978). The latter is relevant to the ethics of a biorepository constructed from specimens and related data obtained dur- ing clinical procedures inasmuch as some of the specimens will have come from patients who had diminished capacity to consent, either generally (for example, children and mentally disabled persons) or temporarily (for ex- ample, as a result of injury or disease). Some (perhaps most) of the sources whose material is contained in the JPC repository cannot now be contacted because they are deceased, so whatever their ability to exercise autonomous choice when their material was collected, that ability is now not merely "diminished" but nonexistent as to potential research with the material. The second reason why it is not possible in the JPC context simply to apply the Belmont principle of respecting autonomous choice is that autonomy is usually regarded as requiring--for example, by the Common Rule6--"legally effective informed consent," which involves the disclosure 6The Common Rule is addressed in greater detail later in the chapter.
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70 FUTURE USES OF THE DOD JPC BIOREPOSITORY of a long list of "basic" and "additional" information (45 CFR § 46.116[a] & [b]). As a historical matter, such disclosure and agreement did not ac- company the gathering of the material that now resides in the JPC collec- tions; it seems unlikely that an elaborate form of consent addressing future clinical, educational, and research uses will be obtained regarding the mate- rial routinely referred to the JPC in the future for pathologic examination. That raises the question of whether it is possible, as an ethical matter, to respect the principle of autonomy by a process of informed decision-making that differs from the consent ordinarily expected before people may be enrolled in a clinical trial. A third reason for the apparently limited applicability of "respect for persons" to biorepositories is that specimens separated from the person have traditionally not been regarded as "persons" requiring respect. In the Moore case, the California Supreme Court refused to recognize that John Moore, whose excised tissue had been used in research without his in- formed consent to generate a profitable cell line, had a claim based on con- version of his property (Moore v. Regents of the University of California7). Guidance issued by the Office for Human Research Protections (OHRP), which allows research without consent on de-identified samples that were not originally collected for research, continues this approach by determin- ing that de-identified specimens are not considered "human subjects" at all (OHRP, 2008a). However, recent analyses have appealed to a broader notion of respect for persons to justify attention to the beliefs, values, and preferences of source individuals in the use of their materials in research (Trinidad, 2011). Even in the Moore case, the California Supreme Court indicated that physicians had a fiduciary duty to Moore to disclose the use of his tissue in research. The principle of respect for persons has important implications for the use of persons' specimens in research without entailing that specimens are persons or even the property of persons. A fourth reason to question the simple application of "respect for persons" lies in the difference between research scandals of the sort that propelled the creation of the National Commission (Beecher, 1966; Katz, 1972) and research that involves material from biorepositories. The ethical framework recommended by the National Commission was designed to protect subjects in their dyadic relationship with investigators by impos- ing obligations on the latter and subjecting their decisions to independent review by an institutional review board (IRB) before the start of research. However, biorepository research involves not a relatively small number of subjects who interact directly with an investigator but usually a large number of people who have no direct involvement with investigators in the context of research which may or may not be reviewed by an IRB. 7793 P. 3d 479 (Cal. 1990).
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 71 The nonclinical focus of some types of research on populations, such as studies that use the records and biologic material held in repositories, generates the fifth reason why Belmont cannot be taken as a complete state- ment of the relevant ethical principles for this analysis. Not only is Belmont built on the investigatorsubject dyad but it focuses on protecting subjects as discrete individuals. In recent years, many ethicists have recognized the importance of thinking of research in terms of groups as well as individuals (Goldenberg et al., 2011). That does not mean simply substituting "com- munity" for "individual autonomy" as a main guiding value but rather rec- ognizing that some interests that need protection belong to a group rather than solely to individuals and that a means is needed to allow the welfare of the group to be represented in decisions about whether to go forward with some research. Although issues of that sort were not in the foreground when the Belmont principles were set forth, the desire not to foreclose all research for which obtaining individual informed consent would be difficult or impos- sible was certainly on the minds of the authors of the federal regulations on human-subjects research, now stated in the Common Rule. Influenced in particular by large-scale studies that involved data that were either pub- licly accessible or anonymous or that involved the use of dead bodies or material obtained from them (as was an accepted part of hospital a utopsies and m edical-school education), the rule drafters either excluded from IRB oversight any research that involved such material or data or permitted institutions to waive consent requirements. That kind of research did not expose anyone to a risk of physical harm or of serious harm to other interests (given the nature of the data, such as public records or informa- tion from telephone directories), so the lack of IRB review of it did not seem problematic. Today, however, the extent and types of information that can be generated by analyzing the biologic specimens and data in biorepositories--including genetic and genomic analysis--far exceed what could have been produced when the Belmont Report was written. Thus, just as the literal application of the Belmont Report's autonomy principle could unduly constrain the potential of biorepositories as important com- ponents in the modern system of research, reliance on the exclusions and exemptions of the Common Rule could remove such repositories from ap- propriate oversight. The solution adopted by the committee was to revisit the mission that guided the National Commission and, rather than focus on the particular instantiation of the principles in the Belmont Report, to concentrate on the foundations of the principles that are "generally accepted in our cultural tradition" (National Commission, 1978). In addition, the committee care- fully considered more recent statements of the ethical and legal standards that should govern biorepositories, along with evolving practices. It was
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72 FUTURE USES OF THE DOD JPC BIOREPOSITORY then able both to modify the particular manifestations of the Belmont prin- ciples in current use and to use the principles to develop a framework for biorepository governance, especially if they are understood more broadly and less individualistically than has sometimes been the case (Childress et al., 2006; Weir and Olick, 2004). Later sections of this chapter and the next chapter address the need to specify and balance those and other principles (Beauchamp and Childress, 2009) in the process of developing concrete recommendations for the governance, policies, and practices of the JPC biorepository. Governance refers to organizational structures and processes of decision-making and accountability (Gottweis and Petersen, 2008; Kaye et al., 2012b). In the world of biobanks, governance often includes an organization's policies regarding acquisition, storage, access, and the like, as well as specifying the persons or institutions that set and apply those policies. Some proponents of governance view it as a way to move beyond or provide a substitute for informed consent in light of practical and regula- tory limitations on consent in large-scale contexts (Hoeyer, 2008; Prainsack and Buyx, 2011). Because an obligation to demonstrate respect for persons does not diminish even with good governance, others have proposed using consent to a process, or governance structure, to overcome problems with seeking consent at one point in time for a range of future research uses (Caulfield et al., 2008; Kaye et al., 2012a). Proposals for biobank governance often reflect one or more guiding metaphors, mainly drawn from ownership or from stewardship, custodian ship, and trusteeship (Jeffers, 2001; O'Brien, 2009; Yassin et al., 2010). The latter metaphors recognize the role of the biobank as protector of interests other than its own and stress responsibility for the materials and their uses. It is also important to recognize, where appropriate and pos- sible, responsibility to the individual sources of biological specimens and data--sometimes called participants--even if the research does not qualify as research on human subjects under the Common Rule. Because of the historical nature of the JPC collection, it makes more sense to adopt a gov- ernance framework that captures the fiduciary obligations of the collection holders (such as stewardship over the specimens and data) rather than one that relies on active, engaged partnership with participants. However, there are ways to express the principle of respect for persons and other ethical principles even in these circumstances. Implementing Broader and Richer Conceptions of Respect for Persons and Other Ethical Principles U.S. and European biobank policies tend to differ in important ways regarding the use of biologic specimens and data in research. There is an in-
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 73 creasing acceptance of broad or general prior consent in European biobanks (Noiville et al., 2011). A person who gives broad or general consent does not surrender the right (within limits) to withdraw biologic materials and data later. Such consent also presupposes that an appropriate ethics commit- tee will review the future research (Elger and Caplan, 2006; T utton, 2010). In the United States, in contrast, requirements for informed consent to research on biologic specimens have generally been closely connected with risks to privacy and confidentiality, considered the major risks posed by research uses of excised tissue and associated data (Elger and Caplan, 2006; Tutton, 2010). If the samples used in research are not identifiable and the risks to the sources are considered to be minor, the samples may be used without informed consent. According to that view, adequate protection of the sources' personal identities through deidentification obviates the need for informed consent to research uses. Proponents of this approach stress that it provides adequate protection for the privacy interests of source indi viduals while costing the organization less. The approach is not unproblematic. First, the definitions of and bound- aries between identifiable and nonidentifiable samples are debatable. Those terms are used in varied and inconsistent ways. Moreover, as a result of scientific and technologic developments, OHRP and others have suggested that in principle all biologic specimens should be viewed as potentially identifiable (HHS, 2011; McGuire and Gibbs, 2006; Schadt et al., 2012). Third, breaches of privacy and confidentiality remain possible, however slightly, and their probabilities are magnified by research networks and wide sharing of data. It is thus important to recognize, but not exaggerate, this risk (Malin et al., 2011). Additional arguments focus on the losses to scientific research and to sources themselves from reliance on deidentification or anonymization. If deidentification is irreversible (that is, a key code for reidentifying indi viduals is not retained or is not accessible), researchers cannot gain access to some information that would be useful in their research and sources cannot receive potentially valuable individual information from the research (Wolf et al., 2012). Regarding the latter, studies indicate that sources attach high value to the disclosure of potentially valuable results and incidental find- ings (Hoeyer, 2008). To be clear, though, it is possible to perform valuable research on deidentified data (Clayton et al., 2010). Obtaining informed consent for biorepository research is not only a possible way to protect sources from harm but serves the purposes of mani- festing respect for persons and allowing sources' values and preferences to shape research. As this report has suggested, biorepositories can and should develop ways to respect persons who are sources of biospecimens as participants in research on archived materials even when informed con- sent to research uses may not be required or may be impossible (Prainsack
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74 FUTURE USES OF THE DOD JPC BIOREPOSITORY and Buyx, 2011). Studies suggest that sources want more control, even though they do not necessarily insist on exercising specific informed con- sent to particular research protocols (Hoeyer, 2008; Wendler and Emanuel, 2002). Of course, caution is required in interpreting surveys and qualitative studies of the perspectives of sources of biospecimens; responses vary for an array of reasons (Hoeyer, 2008). Nevertheless, the preferences for more participation in the research process and for being informed about research results that are particularly relevant to them appear to be widespread and strong views among people who could be the source of biospecimens,8 and new ways are being developed to enable participants to engage in the research process through the use of such tools as interactive information technologies (Kaye et al., 2012a). Several analysts of the changing normative landscape of bio repositories contend that repositories should focus less on informed consent alone and more on becoming institutions that can generate and maintain trust (O'Doherty et al., 2011). One commentator concludes that "it is time to move the debates beyond informed consent and to critically assess what can be done to make biobanks into trustworthy institutions of long-term social durability" (Hoeyer, 2008). Trust is essential for biorepositories (Dabrock et al., 2010; Hansson, 2009; Hawkins and O'Doherty, 2010; Manson and O'Neill, 2007; O'Neill, 2002) because they depend on voluntary participa- tion and without trust cannot succeed. In seeking to generate and maintain trust, it is crucial for biorepositories to develop and display trustworthiness through their governance, policies, and practices (Yarborough et al., 2009). Those points have long been recognized with respect to organ transplanta- tion: the public's trust in the process of organ donation and allocation is crucial to its willingness to donate organs. Studies of industries that have lost public trust and worked to regain it have identified proactive attention to relationships (engagement and communication) and accountability as essential in building trustworthy practices (Yarborough et al., 2009). Other trust conditions often include faithfulness in keeping promises, meeting legitimate explicit or implicit expectations, and truthfulness (Hoeyer, 2008; Prainsack and Buyx, 2011). Transparency also appears on most lists of conditions (O'Doherty et al., 2011). However, some commentators worry that transparency will actually reduce trust (Cambon-Thomsen et al., 2007). When biorepositories' poli- cies and practices are publicly justifiable, transparency can help to generate and maintain trust. Justification should be preceded by engagement with the relevant stakeholders. Exactly what kind of engagement and with whom is both desirable and feasible can be debated and depends upon many factors. 8Hoeyer (2008) has summarized the empirical research, and others have also addressed the topic (Chen et al., 2005; Trinidad et al., 2011; Wendler and Emanuel, 2002).
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 75 The materials in the JPC repository were collected largely from military personnel and their families, with some additional materials from difficult civilian cases submitted for consultation. The JPC may be able to engage military personnel and their families in ways that can inform its governance. Such engagement may increase the likelihood that its policies and practices will be consistent with the values of that community, address group con- cerns, and reduce the risk of harm to the group and its members (McCarty et al., 2008; Newman et al., 2011). Practices vary widely, depending on the needs of the repository and the community it is serving, from com- munity representatives on data-access committees participating in every data-release decision to community advisory boards (CABs) that consult on policy and general directions for the repository rather than on day-to-day decisions (O'Doherty et al., 2011). Those contemporary approaches to biobank governance also draw on the other traditional principles that guide research ethics: beneficence and justice. The principle of beneficence has generally been specified through two complementary general rules: to do no harm and to maximize possible benefits and minimize possible harms (National Commission, 1978). Those rules have obvious application to biorepositories in that the realization of their potential benefits for scientific and technologic progress is more likely if their governance is responsive and adaptive. Specifically, the principle of beneficence requires minimizing harms, costs, and other burdens on research participants and balancing any that remain against the potential benefits of the research. Governance mechanisms, such as data-access com- mittees and CABs, and traditional oversight mechanisms, such as IRBs, can go a long way toward assessing whether a proposed use of specimens in the collection will minimize harm and maximize benefits. Input from the speci- men sources can, for example, help ensure that the evaluation of benefit expresses the perspectives of the source population as much as possible, rather than merely reflecting scientific perspectives. Figure 3-1 provides an example of a governance mechanism that uses a scientific review committee, a committee on data and material access, a CAB, and an IRB. The third principle articulated in Belmont (along with respect for per- sons and beneficence)--justice or fairness in the distribution of the benefits and burdens of research--likewise has several implications for biorepository governance. An obvious one concerns fair access to biologic specimens and data for research, education, and consultation, especially in the case of rare and unique materials. This is an important issue for the JPC's governance. The taxpayer funding of the repository appears to support the broadest possible access subject to appropriate priorities and limits. Reasonable pri- ority setting could, for example, include meeting the needs of the military and of military personnel and veterans first; defensible limits could include protection of national security. Ensuring the sustainability of the collections
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98 FUTURE USES OF THE DOD JPC BIOREPOSITORY whether obtaining consent to the research use of human biological mate- rials in a research or clinical setting, and whether the consent is new or renewed, efforts should be made to be as explicit as possible about the uses to which the material might be put and whether it is possible that the research might be conducted in such a way that the individual could be identified. . . . The current debate about the appropriate use of millions of stored specimens endures because of the uncertain nature of past consents. Investigators and others who collected and stored human biological mate- rials now have the opportunity to correct past inadequacies by obtaining more specific and clearly understood informed consent. It also specifically addressed research use of pre-existing samples--those obtained before the implementation of its recommendations--urging (p. 64) that general releases for research given in conjunction with a clinical or surgi cal procedure must not be presumed to cover all types of research over an indefinite period of time. Investigators and IRBs should review exist- ing consent documents to determine whether the subjects anticipated and agreed to participate in the type of research proposed. If the existing docu ments are inadequate and consent cannot be waived, the investigator must obtain informed consent from the subjects for the current research or in appropriate circumstances have the identifiers stripped so that samples are unlinked. [emphasis added] The NBAC noted that research on identified samples is human-subjects research and ordinarily requires consent and that "seeking this consent demonstrates respect for the person's right to choose whether to cooperate with the scientific enterprise, and it permits individuals to protect them- selves against unwanted or risky invasions of privacy" (p. 66). The NBAC's reasoning suggests that unless consent to research use is waived under ap- plicable regulations, ethical research use of tissue, materials, and data that carry identifiers requires either informed consent for the contemplated work or deidentification. A substantial literature over the last decade argues for recognizing a biorepository duty of responsible custodianship, a concept introduced earlier in this chapter. The National Cancer Institute, for example, in its 2011 Best Practices for Biospecimen Resources (updating its 2007 Best Practices) stresses that "responsible custodianship requires careful planning and transparent policies to ensure the long-term physical quality of the bio- specimens, the privacy of human research participants, the confidentiality of associated data, and the appropriate use of biospecimens and data" (NCI, 2011, p. 31). The best practices formulated by the International Society for Biological and Environmental Repositories (ISBER, 2008) maintain that
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 99 biobanks need to provide responsible "custodianship" of the tissues and data that they collect, maintain, and share. Biobanks--private and public-- commonly have a variety of committees and governance structures to ad- dress operational and ethical issues, including access to data and samples by secondary researchers (Eiseman et al., 2003; ISBER, 2008; NCI, 2011). Core issues addressed in discussions of biobank ethics include consent and withdrawal of consent, as well as protection of privacy and confidentiality. Several well-recognized challenges regarding informed consent to re- search involve archival biospecimens. Even when recontact and consent or reconsent are possible because the individual sources are still alive, request- ing consent for already archived materials can be prohibitively expensive; further, the act of contacting a source for consent can itself be regarded as an invasion of the privacy or, at the least an unwelcome intrusion, especially for persons who were unaware that their or their family's tissue was used for research (Bathe and McGuire, 2009). When comprehensive collections of material have been assembled--such as specimens from all patients with a particular diagnosis or a common exposure--having to obtain consent for research use may introduce a selection bias if some of those contacted decline to consent. The use of archival tissues requires a balance between the possibility of suboptimal consent and the use of valuable resources. Figure 3-2 illustrates Bathe and McGuire's suggested framework for using archived tissue samples derived from clinical care. Bathe and McGuire suggest reconsent if research presents greater than minimal risk; even if the research presents only minimal risk, they call for reconsent if it is practicable. Only if research presents minimal risk and reconsent is impracticable do they indicate that research should be allowed with a waiver of consent. They go on (Bathe and McGuire, 2009, pp. 714715) to identify a set of guiding principles for making such deci- sions, including the following: · The primary objective of the ethics committee is to balance benefits of research against risks of harm. · Privacy risks need to be assessed; but if risks are minimal and re- consent is impracticable, informed consent may be waived. · Risks are minimal if samples or data are in databases restricted to "bona fide researchers," data-access requests are reviewed for merit and ethics standards, the proposed research is consistent with any existing consent, and the research is not "stigmatizing or sensitive." · Impracticability of recontact should be judged by such factors as availability of contact information, probability of the subject's be- ing alive, harm in recontact, and time or expense of recontact. · If privacy risks are greater than minimal, reconsent should be required.
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100 FUTURE USES OF THE DOD JPC BIOREPOSITORY Request for Access to and Use of Archival Tissues and/or Clinical Data for Research Does the proposed study have a reasonable likelihood of generating bene cial and scienti cally valid data? Reconsider Study Yes No Design Prior to Approval Is there existing informed consent for the proposed study? No Yes Conduct Research; No Need to Is the proposed research minimal risk (data Re-Consent shared in restricted database, ethical review, con dentiality, research not potentially stigmatizing or sensitive)? Yes No Re-Consent Is it impracticable to re-consent participants (consider Required access to contact information, likelihood of nding participants, probability of harm, expense, and time)? Yes No May Access Tissue and Future Access to Information or Institutional Data with a Tissue Will Require Re-Review Waiver of Consent by Oversight Committee FIGURE 3-2A framework for accessing archival tissues and clinical data for research. Reprinted by permission from Macmillan Publishers Ltd: Genetics in Medicine (Bathe and McGuire, 2009). Copyright 2009. Figure 3-2 · Preventive consent should be considered if risks to privacy and stigmatization cannot be accurately predicted. · "Data derived from unconsented patients should never be shared in a publicly accessible database. It may be permissible to share data in a database with controlled access. However, any future access to information or tissue from such a database mandates review by an ethics or data access committee."
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ETHICAL, LEGAL, AND REGULATORY CONSIDERATIONS 101 · Security procedures "should be commensurate with the sensitivity of the information recorded." Helgesson and colleagues (2007) suggest a similar framework that seeks to balance individual risks against the value of research. To weigh the risks and benefits, the authors suggest use of an ethics review board. If no previous consent or refusal exists and the study "is not particularly sensitive . . . genetic analyses of identifiable samples should be permitted without [new] consent" provided that there is strict coding, secrecy laws apply, and "vital research interests are at stake" (p. 975). If the JPC continues to collect biospecimens and associated data, it will need to determine what kind of consent is appropriate for the research use of the newly acquired materials and the extent (if any) to which it can sug- gest or even prescribe language regarding consent to use materials submit- ted to it in subsequent research. A schematic presentation of the arguments for and against different types of consent is presented in Table 3-3.
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TABLE 3-3 Ethical Considerations Regarding Different Source Consent Options to Provide Access to Data and 102 Specimens for Research Purposes No Consent from Source Notification to Source and Opt-In by Source Opt-In by Source Option (Exemptions or Waivers) Opt-Out (Broad Consent) (Reconsent) Arguments for · IRB responsible for · Respects persons by · Respect for autonomous · Emerging technology is ensuring acceptable informing them about choice: person assesses permitting dynamic consent, (minimal) risk vs. benefits sample use riskbenefit tradeoff which permits diverse gained · Meaningful choice · Issues at stake for participant preferences and · Respects negative right is possible without individuals other than facilitates recontact of privacy through overburdening source or risk of reidentification · HIPAA requires purpose- requiring minimal risk of institution with consent (anonymization is not the specific information for reidentification processes only concern) consent · Other governance · Accountability · Positive right to privacy: · Enhanced control may mechanisms (oversight, obligations are enacted ability to control who encourage diverse data-use review) can through transparency sees my data or specimens participation from provide protections for regarding intentions · Repository managers are historically mistreated sources · Permits diverse custodians of samples but populations · Recontact uses resources participant preferences not "owners" (individuals · Positive right to privacy: otherwise needed for · Provides lower bar (than retain control) ability to control who sees research opting in) for remaining my data or specimens · Research is advancing in the collection · Repository managers are the "common good" and, · Increased health and custodians of samples but as an act of altruism or science literacy through not "owners" (individuals solidarity, individuals transparency retain control) should release control of their specimens or data
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Arguments · Removes sources' right · Can be resource-intensive · Resource-intensive · Resource-intensive against to know or control what · Existing oversight and · Broad or blanket consent · Exceedingly difficult to is happening to their protections should be does not achieve the keep track of participants samples sufficient goal of informed choice to update current contact · Genetic material is · Supererogatory (exceeds (therefore, requiring information inherently unique (even if current regulatory broad opt-in does · Risks sample bias due to not "readily" identifiable) requirements) not meet autonomy nonresponders · Misses an important · Can be difficult to obligations while creating · Can be difficult to ensure public education identify all data and undue burdens) that notification has been opportunity specimens for removal · Can be difficult to ensure read and understood correctly consent has been read or, · Can be difficult to ensure given the broad nature of that notification has been consent, understood read and understood · Can be disruptive to the research collection Special · Current standard of · Preventive approach to · Historically traumatized · As technology improves our considerations practice in most settings liability risk populations may need ability to manage individual · Useful for routine · Public websites and additional choice options preferences, these dynamic projects and minimal risk materials can serve to build trust consent options should or high-public-benefit multiple purposes (such · Proposed changes to the become more useful projects (such as public- as marketing, outreach) Common Rule require · Maintaining current health concerns) consent for specimen use contact information is a (even deidentified) responsibility of the source, as well as the repository manager References Shickle, 2006 Brothers and Clayton, 2009 Emanuel and Menikoff, Kaye et al., 2012a Pulley et al., 2010 2011 Ludman et al., 2010 Lunshof et al., 2008 Saha and Hurlbut, 2012 Trinidad et al., 2010, 2011 103
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