January 6, 2016 Jerry Menikoff, MD, JD Office for Human Research Protections Department of Health and Human Services 1101 Wootton Parkway, Suite 200 Rockville, MD 20852 Submitted electronically at www.regulations.gov. RE: Docket Number HHS-OPHS-2015-0008, Federal Policy for the Protection of

Human Subjects Notice of Proposed Rulemaking, published in the September 8, 2015 Federal Register (80 FR 53933)

Dear Dr. Menikoff: I write on behalf of PersonalGenomes.org (PG.org),1 and certain of its affiliates, to comment on Question 55 presented in the above NPRM, “whether and how the provision regarding the return of research results in the proposed exemption § __.104(f)(2) should be revised.” PG.org appreciates the tremendous effort that has gone into the NPRM and we appreciate the opportunity to comment on 104(f)(2) as well as a related proposed provision, 111(a)(8). PG.org is a 501(c)(3) nonprofit organization working to generate, aggregate and interpret human biological and trait data on an unprecedented scale. Our mission is to make a wide spectrum of data about humans accessible to increase biological literacy and improve human health. PG.org supports the Personal Genome Project global network. The first Personal Genome Project research study was founded at Harvard Medical School in 2005, and Personal Genome Project sites now exist at leading institutions in four countries. We also produce the annual Genomes, Environments and Traits (GET) Labs and Conference, at which researchers collect a wide range of additional data and biospecimens from Personal Genome Project participants, often analyze that data in combination with participants’ stored genomic and other data, and return individual results to participants. PG.org’s latest project is Open Humans, funded by the Knight Foundation and the Robert Wood Johnson Foundation. Open Humans is a new online portal that aims to break down data silos in human health and research by allowing members to aggregate data from the research in which they participate, thereby connecting individuals willing to share existing research data about themselves with other researchers who are interested in using that data. This, of course, depends on researchers having previously returned individual research results to Open Humans members.

                                                                                                               1 PersonalGenomes.org is in the process of changing its name to Open Humans Foundation.

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PG.org’s efforts are informed by many of the values described in the NPRM, including encouraging greater transparency and collaboration between researchers and research participants. It is in that spirit that we write to express our concerns about proposed exemption § __.104(f)(2)(ii). As you know, §__.104(f)(2)(i) would exempt secondary research using stored biospecimens or identifiable private information, if IRB-approved “broad consent” for unspecified secondary research was previously obtained under §__.104(f)(1). The NPRM contemplates that an investigator, by entering accurate information about her proposed secondary research study into an HHS-created decision tool, could determine herself that it is exempt. Under § __.104(f)(2)(ii), however, if the researcher “anticipates” that “individual research results will be provided to a research subject,” the situation is dramatically different. The research is not exempt; instead, as we read the NPRM, it is subject to full IRB review and researchers must obtain the explicit, fully informed consent from each research participant for each such secondary research project, per §__.116(a)-(b). We appreciate that some individual research results are sensitive, that there are more and less ethically appropriate ways to return such results to participants, and that an IRB (or expert panel or OHRP guidance) can potentially play a useful role in guiding the ethical return of research results. However, we believe that §__.104(f)(2)(ii) unnecessarily sweeps far too broadly, both in the unlimited scope of the individual research results it covers and in the level of IRB review it requires, and provides a strong incentive for researchers to decline to share participants’ own data with them. These results are inimical to the NPRM’s laudable goals of “making the level of review more proportional to the seriousness of the harm or danger to be avoided” (p. 53936) and moving toward a “participant-centered research model that adequately respects participants as partners” (p. 53938). Below, we ask some clarifying questions and also offer several suggestions for revising §__.104(f)(2)(ii) so that it is more consistent with these goals while also protecting participants from receiving carelessly or inaccurately disclosed individual research results. The net result of these suggestions yields the following suggested revision to §__.104(f)(2)(ii):

If the investigator anticipates that clinically relevant individual research results (i.e., those that a reasonable participant would be expected to use in making decisions about his or her health care), not including uninterpreted, raw data, will be provided to a research subject, or if those results are otherwise likely, in light of the available evidence, to cause significant harm to participants, then the research may not be exempted under this provision and the plan to return results must be reviewed by the IRB and informed consent for the research must be obtained to the extent required by §__.116(a) and (b) to ensure that §__111(a)(8) is satisfied.

1. Meaning of “individual research results” for purposes of §__.104(f)(2)(ii) is unclear We find the NPRM’s discussion of §__.104(f)(2)(ii) unclear on the pivotal issue of what constitutes an “individual research result.” The NPRM refers to “‘unexpected’ (i.e., not related to the purpose of the research) genetic findings,” to patient-participants whose “clinical care may

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demand prompt reporting of findings” to them (in which case, the NPRM somewhat optimistically expects that researchers will always have anticipated this possibility and have submitted their protocol to IRB review under 104(f)(2)(ii)), and to genetics studies in which “in a significant percentage of instances investigators will be learning information, not necessarily related to the specific purpose of their studies, that would nonetheless be significant to participants in terms of making decisions about their health care” (p. 53967). This focus on “unexpected” findings fails to consider what is always expected: detailed raw data for every individual—for instance, a variant call file (VCF). Interpretation of data might yield an “unexpected” genetic (or other) finding, but data can be shared without interpretation.2 Similarly, and as discussed further below, the NPRM’s discussion of clinically relevant research results ignores the many kinds of biospecimens research results that are irrelevant to “making decisions about [participants’] health care.” Even when individual research results do not inform a participant’s health care, returning them may constitute a valuable act of respect for participants as partners in research. In some cases, returning results serves as a gesture of gratitude. In other cases, it serves as an incentive to greater participation in research, itself an important goal. And in still other cases, returning results helps rebalance the peculiar information asymmetry that exists between researcher and participant when the researcher learns something about the participant that he or she herself does not know by giving them “equal access”3 to that information. As Madeleine Price Ball notes, in comments submitted to you in her capacity as a private citizen, “Access to our own data balances the disempowerment that occurs when another entity holds information about us.” Participants may perceive a lack equal access, conversely, as disempowering and paternalistic. Equal access to one’s own research results (whether interpreted or not) also enables participants to share that data with other researchers through a platform like Open Humans, thus helping to break down data silos and accelerate scientific progress. We respectfully request clarification regarding what constitutes “individual research results” for purposes of §__.104(f)(2)(ii), and in particular whether it includes raw data and whether it is in some way limited to clinically relevant data. 2. Applicability of §__.111(a)(8) and meaning of “clinically relevant” are unclear NPRM §__.111(a)(8) proposes to add an additional §111 criterion for IRB approval of research: “If the investigator proposes a research plan for returning clinically relevant results to subjects, that the plan is appropriate.” At p. 54016, the NPRM explains:

[This] proposed change relates to the new exemption at §__.104(f)(2) that includes a

                                                                                                               2 Cf. FDA regulation of 23andMe’s return of health-related interpretations, but not raw data files, to users. 3 See Quantified Self Public Health Symposium (April 2014) at pp. 18–20, available at http://quantifiedself.com/symposium/Symposium-2014/QSPublicHealth2014_Report.pdf (describing presentation by Jason Bobe at Robert Wood Johnson-supported symposium).

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criterion at (f)(2)(ii) that the exemptions do not apply if the investigator intends to return individual research results to subjects. Thus, a new provision would be added at §__.111(a)(8) clarifying that IRBs need to review any plan in a research protocol for returning individual research results to subjects and to determine whether it is appropriate.

This explanation could be read as suggesting that §__.111(a)(8) was intended to apply only to research to which §__.104(f)(2) applies, namely, “[r]esearch using biospecimens or identifiable private information that have been stored or maintained for secondary research use” following broad consent.” But as written, §__.111(a)(8) applies whenever “the investigator proposes a research plan for returning clinically relevant results to subjects”; such cases are not limited to secondary research involving biospecimens or identifiable private information. Moreover, §__.111(a)(8) is limited to the return of “clinically relevant” results. “Clinically relevant” is not defined (itself a significant problem), but it is clearly not co-terminous with 104(f)(2) research. Some results of research on stored biospecimens or on identifiable private information will not be clinically relevant by any plausible definition of that phrase, while some non-104(f)(2) research (e.g., some prospective biospecimens research), will be clinically relevant. We request that the relationship between 104(f)(2)(ii) and 111(a)(8) and the meaning of “clinically relevant results” both be clarified. 3. Scope of individual research results requiring IRB review is overbroad As written, although 111(a)(8) would require IRB review of any plans (in any kind of research project) to return only “clinically relevant” individual results, 104(f)(2)(ii) requires full IRB review of any project involving stored biospecimens or identifiable private data that proposes to return any kind of individual research results. This disconnect is itself problematic, in ways already discussed. Here, however, we focus on what we believe is the overly broad scope of results to which 104(f)(2)(ii) applies. In keeping with the NPRM’s commitment to risk-based regulation of human subject research, IRB review of plans to return individual research results should be limited to results whose return to participants poses significant risk. The determination that returning particular research results poses more than minimal risk should rest on a determination that it is likely, based on evidence (not speculation or anecdote) to cause significant harm (not mild, transitory feelings of anxiety, which are part of daily life) to many participants (not to an idiosyncratically sensitive participant, whom it will always be possible for an IRB to imagine). Not all individual results of biospecimens research plausibly meet this risk-based test. For instance, through its GET Labs, PG.org has hosted biospecimens research and the return of individual results to Personal Genome Project participants regarding their ancestry, the composition of their armpit and gut microbes, the nature and extent of their face mites, and how their genome might contribute to the shape, size, and pigmentation of their areolas. An additional study, Flu Near You, collects biospecimens from participants who self-report as ill and test for 8-12 viruses in order to track the prevalence of virus in communities. Researchers return to participants their individual results (whether they tested positive for any virus or not) months

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later, when they are no longer clinically relevant. It is implausible to suppose that returning any of these or similar results poses any significant risk to participants. In particular, such results are very unlikely to implicate the NPRM’s worry about the “[c]hallenges [that] can arise regarding return of individual research results when it is not clear if the findings have clinical validity or utility, or when the knowledge imparted may cause psychological distress or social harm” (p. 53988). In our experience tracking Personal Genome Project participants’ experiences receiving a wide range of results, some of which are both clinically relevant and sensitive, returning results has resulted in exactly zero adverse events. While returning these results is unlikely to pose any significant risks to participants, doing so is likely to confer benefits on both participants and society. The researchers involved in all of these projects, and many others, believe that returning results can be educational for participants and is one way of showing appreciation for participants’ contribution and indeed can help encourage their participation and increase their interest in science and research. Permitting participants to upload their returned results to the Open Humans portal, in turn, allows researchers an unprecedented opportunity to study perhaps the most phenotyped participants in the world. Section __.104(f)(2)(ii) would impose burdens of full IRB review and of individual, study-specific consent on researchers, participants, and IRBs where otherwise no IRB review and no further consent of any kind would be required. Those burdens are unwarranted in the context of such low- and no-risk return of results. Moreover, the difference, from the investigator’s perspective, between 104(f)(2)(i)’s regulatory path and that of 104(f)(2)(ii) constitutes an enormous incentive for researchers to eschew the return of results, even as the NPRM elsewhere touts a move towards a “participant-centered research model that adequately respects participants as partners” (p. 53938). Nor will all investigators find IRB review equally burdensome; 104(f)(2)(ii) is likely to have a disparate impact on junior researchers working under time pressures related to graduation, postdoctoral fellowships, and tenure and on researchers at institutions with understaffed IRBs. This would result in some participants being offered equal access to their results while others are not for reasons that have nothing to do with risks to participants or expected benefits to participants or society, a result that is in some tension with the Belmont Report’s principle of justice.4 To the extent that researchers do find 104(f)(2)(ii)’s regulatory path to be prohibitively burdensome, both society and participants would be deprived of knowledge production and education, without any offsetting benefits in the form of protecting participants.

Suggestions for risk-based regulation of return of individual research results We appreciate that codifying criteria for distinguishing low-risk from high-risk return of results is difficult, as is the more general task of codifying which categories of research are sufficiently low-risk as to merit exemption, exclusion, and expedited review. However, this difficulty is

                                                                                                               4 Cf. NPRM at p. 53967 (“[I]t is likely that many IRBs do not have any particular unique expertise in making these determinations about returning results, which again could lead to inappropriate variability in disclosure from study to study, and would seem to be in conflict with the ethical goal of justice.).

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inherent and inescapable in the risk-based approach to regulation to which the NPRM is (commendably) committed. Below, we suggest three different options for limiting the scope of individual results to which 104(f)(2)(ii) applies. All, in our view, would be significantly preferable to §__.104(f)(2)(ii), as currently drafted. In all three cases, we imagine that our proposed criterion for triggering §__.104(f)(2)(ii) could be incorporated into the decision tool, so that researchers themselves could determine whether their secondary research is exempt under §__.104(f)(2)(i) or not. A. One possibility—perhaps the cleanest, given 111(a)(8)—would be for §__.104(f)(2)(ii) to mirror the NPRM’s proposed new criterion for IRB approval of research, § __.111(a)(8), which, as discussed above, requires IRBs to determine that any plan for “returning clinically relevant results to subjects” is appropriate (emphasis added). That is, §__.104(f)(2)(ii) might provide:

If the investigator anticipates that clinically relevant individual research results will be provided to a research subject . . . .

Section 104(f)(2) research involving the return of results that are not “clinically relevant” would therefore be exempt under §__.104(f)(2)(i). However, we think it would be important for either final rule to define, or OHRP to issue guidance regarding, the meaning of “clinically relevant.” We do not favor borrowing from NPRM §__.102(b)’s definition of “clinical trial” and defining as “clinically relevant” any result that relates to “biomedical or behavioral health,” as this is entirely too broad and captures many results whose return would pose little or no risk to participants. B. A variation on this first option, then, would be to further specify the meaning of “clinically relevant” by limiting the scope of §__.104(f)(2)(ii) to individual research results “that are expected to be used to guide clinical care” or, in the NPRM’s own words, “that would . . . be significant to participants in terms of making decisions about their health care.” To help keep IRBs from being distracted by thoughts of what some imagined participant might hypothetically do, an even better qualifier might be something like “those results that a reasonable participant would be expected to use in making decisions about his or her health care.” Any of these alternative wordings would help clarify that something like Flu Near You results, which are received well after an illness has ended, do not trigger §__.104(f)(2)(ii). C. It may be that “clinically relevant” and its cognates are in the end too crude a proxy for risk, being both underinclusive and overinclusive. For instance, non-paternity results do not have direct clinical relevance, but they are certainly sensitive. Conversely, it is not obvious that returning results to participants about their gut microbiome, which may have “clinical relevance” for overweight or obesity, is especially risky. One way of addressing this concern would be to limit the scope of 104(f)(2)(ii) to “clinically relevant” results or to some specified version of the same, as just discussed, but to include an additional prong under which IRB review might be triggered, such that 104(f)(2)(ii) would apply to clinically relevant results or “results that are otherwise likely, in light of the available evidence, to cause significant harm to participants.”

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D. A different solution would be to limit §__.104(f)(2)(ii) to results that meet criteria that are published (and regularly updated) in the Federal Register (similar to the list of categories of research eligible for expedited review under Common Rule § 46.110). That list could be created either by HHS or by an expert federal panel similar to the one that the NPRM contemplates (but used for a somewhat different purpose5). Returning results that fall outside of this list would not be subject to §__.104(f)(2)(ii) and the research would be exempt under §__.104(f)(2)(i). There are advantages to having HHS or a standing expert panel identify the criteria for determining which individual research results may and may not be returned without IRB review, compared to codifying such criteria in the Common Rule itself. Relying on an expert panel whose determinations evolve would allow flexibility as the research community learns more both about the range of biospecimens research results that investigators may wish to return and participants wish to receive and the outcomes for participants who receive such results. (On the latter point, we strongly urge OHRP to track, or encourage others to track, participant outcomes of receiving a wide range of individual research results so that policy regarding return of results is evidence-based.)

                                                                                                               5 Because “it is likely that many IRBs do not have any particular unique expertise in making these determinations about returning results,” the NPRM contemplates the creation of an expert panel to “make determinations about which unexpected findings should be disclosed to human subjects in research, and what information should be given to subjects about themselves” (p. 53967, emphasis added). In that case, 104(f)(2) research would be exempt even if it involves the return of individual results, “so long as disclosures were made consistent with the rules announced by the federal panel.” It is unclear whether the second clause, “what information should be given to subjects about themselves,” refers to what expected results should be returned to participants or to what information should be disclosed to them regarding particular kinds of results (i.e., how results should be returned). As for the first clause, it would seem to have the NPRM contemplating a role for a federal panel in determining whether, not how, unexpected findings should be disclosed. Yet in its discussion of the primary alternative to such a panel, the NPRM explicitly limits §__.111(a)(8) to IRB review of the appropriateness of any plan the researcher may happen to propose and not to a determination of “whether there should be a plan for returning individual research results” (p. 53988). If, in that brief paragraph at p. 53967, the NPRM is indeed proposing an expert panel to decide whether there should be a plan for returning results (either unexpected and/or expected)—a task that is in fact different from, and so not a substitute for, the IRB’s proposed task under 111(a)(8)—we suggest that the NPRM has provided insufficient notice to the public that HHS intends to regulate the threshold question of “whether” results “should” be returned. As a result, HHS should take no further action on that matter at this time. Should HHS nevertheless proceed to contemplate such a role for a panel, however, we acknowledge that, relative to individual IRBs, many of whom lack relevant expertise, either a standing expert panel or OHRP guidance (perhaps developed in consultation with such a panel) could helpfully summarize the current (but quickly evolving) empirical literature about the effects of different methods of returning results to participants, the extent to which a finding that seems valid today is likely to remain so in the near future, and so on. We note, however, that one advantage of individual IRBs is that, using expert guidance, they could ensure an appropriate plan for returning results that is study- and participant cohort-specific. For instance, in the case of the Harvard Personal Genome Project (a pioneer in returning individual research results), the Harvard IRB initially approved enrolment and return of results to participants who held the equivalent of a Masters degree in genetics, and later, after tracking outcomes, expanded the inclusion criteria to any participants who pass a comprehension test. Other relatively sophisticated populations have been shown to comprehend complex, sensitive results quite well. See, e.g., JE Osterren et al. “How well do customers of direct-to-consumer personal genomic testing services comprehend genetic test results? Findings from the impact of Personal Genomics Study.” Public Health Genomics June 16, 2015, DOI: 10.1159/000431250. IRBs could also attend to other local factors such as researcher resources. We would find it extremely problematic from the perspective of beneficence, respect for persons, and justice if a federal panel produced universally-applicable rules that failed to recognize and accommodate heterogeneity among participants, researchers, and results.

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With respect to the composition of any such panel, we think that it would be important to include members beyond the clinical genomics community, including social scientists, as clinical genomics does not begin to exhaust the category of biospecimens research potentially subject to §__.104(f)(2)(ii), as currently written. We also recommend that the panel include some members who themselves have been through the process of receiving a range of individual research results, and some patient advocates. The comments submitted to you by Steven Keating in his capacity as a private citizen struggling to obtain equal access to the data he has donated to scientific research in the wake of a cancer diagnosis are indicative of the kinds of important perspectives that are omitted when decision-makers are insufficiently diverse. 4. Scope of IRB review required under 104(f)(2)(ii) is overbroad The NPRM remarks that “[i]f this alternative proposal [for an expert panel] were adopted, then it would not be necessary to have full IRB review of these protocols.” Actually, full IRB review of protocols that contemplate the return of results is not necessary under any circumstance, not even as regards “risky” results (however determined). In all cases, IRB review of plans to return individual research results should be limited to a review of the plan to return results. Absent a researcher’s anticipation that she will return results, under §__.104(f)(2)(i), the secondary research would be exempt and subject to no additional IRB review (beyond the limited IRB review involved in ensuring adequate broad consent for storing the biospecimens or identifiable private information under §104(f)(1)(i) in the first place). Because the only difference between a secondary research protocol in which the researcher anticipates returning results and the identical protocol in which she does not is the plan to return results, any IRB review logically should be limited to review of that plan. A researcher’s laudable willingness to offer to return individual research results to participants should not operate as an open invitation to the IRB to second-guess “the importance of the knowledge that may reasonably be expected to result from” the secondary research or otherwise to relitigate the risk-benefit compromise the NPRM has already struck in permitting secondary research to be conducted on biospecimens and identifiable private information with broad consent, to question whether subject selection is equitable, or to evaluate the underlying secondary research proposal under any of the other elements of §__.111(a)(1)–(7). Instead, to whatever extent the final rule requires IRB review under §__.104(f)(2), that review should be explicitly limited to § __.111(a)(8), ensuring that, “[i]f the investigator proposes a research plan for returning clinically relevant results to subjects, that the plan is appropriate.” (We have retained the limiting clause, “clinically relevant,” that appears in NPRM § __.111(a)(8). Obviously, the wording there should match whatever criteria is used to separate low-risk from higher-risk return of results at §__.104(f)(2), discussed in section 2 of these comments.) The NPRM itself explains that protocols that contemplate returning individual research results “would undergo full IRB review primarily for the purpose of determining what information participants should be provided regarding such . . . findings.” We think that the word “primarily” is unnecessary, and in any case is unexplained and unjustified in the NPRM. There is already

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precedent in the NPRM, at §__.104(f)(1), for requiring a form of “limited IRB review.” And requiring only limited review would reduce the disparity in burdens between the 104(f)(2)(i) and 104(f)(2)(ii) regulatory pathways that we discussed in section 3 of these comments. 5. Scope of informed consent required under 104(f)(2)(ii) is overbroad Similarly, we can perceive no justification, simply because the researcher wishes to offer participants the opportunity to receive their results, for converting a protocol that, under §__.104(f)(2)(i), would require no further consent to one in which researchers are required to obtain fully informed consent under §__.116(a) and (b) from each participant, not only to receive results, but also to the use of their stored biospecimens or identifiable private data in this particular research study (something to which they have already given broad consent). Participants should of course be permitted to choose whether or not to receive individual results (except, perhaps, in relatively rare circumstances in which warning a participant of a research result is expected to prevent death or serious injury to them—something that is beyond the scope of these comments and, we believe, the NPRM). And in making that decision, participants should be provided with sound information about the risks and potential benefits of receiving such results. But we presume that this is precisely the purpose of § __.111(a)(8)’s requirement that the IRB determine that the plan for returning results is “appropriate.” Any requirement of additional disclosure and consent about the study is unwarranted and would only serve to burden researchers, IRBs, and participants (who would be asked to read and comprehend the informed consent for an entire protocol despite having already given broad consent for research). Conversely, requiring participants to consent only to receiving individual results would reduce the disparity in burdens between the 104(f)(2)(i) and 104(f)(2)(ii) regulatory pathways that we discussed in section 3 of these comments. 6. What constitutes “appropriate” plans for returning results is unclear If the final rule requires IRBs to review the “appropriateness” of plans to return individual research results under §__111(a)(8), we strongly urge OHRP to issue guidance regarding when a plan is “appropriate” (and, as applicable, regarding when results are “clinically relevant”), or otherwise facilitate appropriate IRB review of the “appropriateness” of plans to return results. As Misha Angrist notes in comments submitted to you in his capacity as a private citizen, not only does the NPRM create a strong disincentive to return results; even those researchers who might nevertheless assume the regulatory burden of returning results are likely, according to the NPRM itself, to face review by an IRB that “do[es] not have any particular unique expertise in making these determinations about returning results” (p. 53967). Under these circumstances, any mandate that IRBs review plans to return individual results that is unaccompanied by a commitment to facilitate appropriate IRB review is likely to result in wide variation among IRBs and in IRB decisions based on speculation rather than data. We are concerned that IRBs that are explicitly required for the first time, upon pain of violating federal regulations, to ensure that the return of results is “appropriate,” and who do so in a guidance vacuum, are likely to be highly risk-averse relative to existing data about the outcomes of receiving various kinds of results.

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We note, first, an ambiguity in 111(a)(8)’s requirement that IRBs determine “that the plan [to return results] is appropriate.” This might call on IRBs to determine whether or not researchers will be permitted to offer results to participants under any circumstances, or it may call on IRBs to ensure that the way in which the researcher proposes to return results is appropriate, or both. In theory, returning some research results might be so risky that there is no “appropriate” way to return them. Yet the available data do not appear to bear out this worry even in the context of APoE genotyping.6 Where participants are competent adults, review should almost always focus on how, not whether, results may be offered. With respect to results that could reasonably be expected to cause significant harm if misunderstood, the “how” might, if necessary, involve making return of results contingent on participants passing a comprehension test, similar to the one that the Personal Genome Project pioneered in returning an analysis of whole genome sequence results to participants. If a willing researcher wishes to return results to a willing participant who demonstrates his or her ability to comprehend the nature of those results (their risks, uncertainty, and so on), we can perceive little justification for IRB veto. We echo our remarks from section 3 that, in keeping with the NPRM’s commitment to risk-based regulation of human subject research, IRB review of plans to return individual research results, including often cost-prohibitive IRB-imposed requirements such as the availability of 24-hour, in-person counseling, should focus on research results that are likely, based on evidence (not speculation or anecdote) to cause significant harm (not mild, transitory feelings of anxiety, which are part of daily life) to many participants (not to an idiosyncratically sensitive participant, whom only the least imaginative IRB member will be unable to conjure). More likely, the possibility of harm arises not from the bare act of returning results but from a combination of a sensitive result and misinterpretation or poor communication of that result (e.g., carrier status marked by significant false negative or positive rates that could unduly influence reproductive decisions). There are clearly better and worse ways of communicating probabilistic and other complex information to laypersons, and IRBs in theory have an important role to play in that respect. 7. Interaction of HIPAA and §__.104(f)(2)(ii) is unclear The NPRM states:

It is understood that the prospective IRB review provision set forth here does not override existing law, such as the HIPAA Privacy Rule or the Federal Privacy Act, which give individuals the right to access certain information about themselves in specified circumstances.

We request that OHRP clarify how the proposed rule and these others laws would interact. For instance, we assume that if a participant requests her research data from a HIPAA lab as part of her “designated record set,” this request by a participant would not trigger IRB review and informed consent under §__.104(f)(2)(ii), since the lab, and not the researcher, would be                                                                                                                6 See, e.g., RC Green et al. “Disclosure of APOE genotype for risk of Alzheimer’s Disease.” NEJM 2009; 361(3): 245–54.

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“returning” individual results. Similarly, we assume that if a researcher alerted participants to their HIPAA rights or enabled them to avail themselves of those rights (say, by creating a standard), that these, too, would not trigger §__.104(f)(2)(ii). However, we would appreciate clarification on these points. Respectfully submitted,

Michelle N. Meyer, PhD, JD Board of Directors, PersonalGenomes.org On behalf of George Church, PhD Founder and Chair, PersonalGenomes.org Principal Investigator, Harvard Personal Genome Project Jason Bobe, MS Executive Director, PersonalGenomes.org Co-Founder, Open Humans Misha Angrist, PhD, MFA Board of Directors, PersonalGenomes.org Madeleine Price Ball, PhD Director of Research, PersonalGenomes.org and Harvard Personal Genome Project Co-Founder, Open Humans John H. Cammack, MBA (Columbia Graduate School of Business) Board of Directors, PersonalGenomes.org Michael F. Chou, PhD Director of Human Subjects Research, Harvard Personal Genome Project Esther Dyson, BA in Economics (Harvard) Board of Directors, PersonalGenomes.org Juan Enriquez, MBA Board of Directors, PersonalGenomes.org Steven Keating, PhD Candidate (MIT) Board of Directors, PersonalGenomes.org Jeantine E. Lunshof, PhD Ethics Consultant to the Harvard Personal Genome Project

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Ryan Phelan, BA (University of California at Berkeley) Board of Directors, PersonalGenomes.org Alexander Wait Zaranek, PhD Director of Informatics, Harvard Personal Genome Project