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Returning Individual Research Results to Participants: Guidance for a New Research Paradigm (2018)

Chapter: 2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations

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Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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2

Principles for the Return of Individual Research Results: Ethical and Societal Considerations

Biomedical research has a high value to society because of its potential to improve population health by generating important knowledge about the physiology and pathology of disease and the safety and efficacy of novel and existing treatments or public health interventions. In addition, such research provides information about clinical practice that can be used to improve the delivery of high-quality health care. Resources for biomedical research, therefore, are precious and require careful and responsible stewardship. The return of individual research results necessarily requires the diversion of some research resources from the primary goal of the research, which is to contribute to generalizable knowledge (Williams et al., 2012). At the same time, it is critical to the biomedical research endeavor to have the voluntary participation of individuals who donate their time, often accept risks to their welfare, and share with investigators their biospecimens, health and health care information, and personal information. When done in a careful and thoughtful way so as to avoid unnecessary risk, providing participants with information about themselves that has been uncovered in the course of the research is one possible means (although certainly not the only one) of demonstrating respect and gratitude for their contributions, and this provision of information may lead to greater trust and engagement in the research enterprise, much to society’s benefit. This chapter examines the ethical and societal considerations surrounding the question of whether the return of individual research results is appropriate or even obligatory as well as issues concerning the potential harms and benefits to individuals, the research enterprise, and society at large. The chapter concludes with a set of guiding principles that the committee developed to inform its thinking on the questions addressed throughout the remaining

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

chapters of this report—specifically, whether, when, and how individual research results should be returned to research participants.

ETHICAL CONSIDERATIONS FOR THE RETURN OF INDIVIDUAL RESULTS IN HUMAN PARTICIPANT RESEARCH1

One of the more difficult ethical research challenges to emerge recently concerns what an investigator’s obligations are—if any—to share information with those who volunteer to participate in his or her research. The recognition is growing that, for many clinical studies, aggregate study results should be shared with the research participants and presented in such a way that the results can be understood by members of the general public. This is consistent with the ethical principles widely used to guide clinical research, which hold that study participants should be treated with respect, acknowledged for the important role they play in advancing science, protected from harm to the extent possible, and receive the maximum possible benefit from their participation (CIOMS, 2016; National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). As discussed below, these same ethical principles are often invoked in discussions about the return of individual research results.

Ethical Principles Relevant to the Return of Individual Research Results

Historically, institutional review boards (IRBs) have actively discouraged the disclosure of research results to individual participants apart from a few exceptional circumstances (Fernandez et al., 2003a; Simon et al., 2012). These circumstances primarily referred to the discovery of an unexpected finding (i.e., secondary finding) that had clear medical significance for the research participant. One example of such a finding would be evidence of a clinically silent central nervous system tumor discovered during a brain imaging test in a study comparing different neuroimaging methods. In this case, it might be argued that the research team has a “duty to warn”2 or a “duty to rescue”3 the participant as he or she is in a position to prevent serious harm at little or no personal cost and the participant might otherwise not discover the condition in time to change its

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1 This section draws on a paper commissioned by the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories: Haavi Morreim, The return of individual-specific research results from research laboratories: Perspectives and ethical underpinnings (see Appendix D).

2 The “duty to warn,” for instance, comes from the age-old principle that, if one person sees that another is unwittingly about to enter a high danger that quite likely he or she would not voluntarily embrace, then the person seeing the danger has an obligation to warn the other. (See Appendix D for a more in-depth discussion.)

3 “Duty to rescue” is based on the premise that, when confronted with a clear and immediate need, an individual who is in a position to help must take action to try to prevent serious harm when the cost or risk to self is minimal” (Beskow and Burke, 2010, p. 1).

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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course. The “duty to warn” and the “duty to rescue” were originally legal concepts, but they have been applied to discussions on the return of individual results, and they are now also seen as referring to an ethical obligation to notify participants when presumably reliable results suggest imminent danger (i.e., death or significant morbidity) (Beskow and Burke, 2010). For those uncommon cases when secondary findings with medical significance arise, expert working groups have developed recommendations for reporting secondary findings and referring participants for follow-up evaluations (Wolf et al., 2008).

More recently, the discussion on the return of individual results has moved beyond incidental or secondary findings to results that are the focus of the research study. Although questions pertaining to the return of individual research results apply to many kinds of studies, it is genomic research in particular that has brought this issue to the forefront over the past couple of decades. Rapid technological advances (e.g., genome sequencing) have enabled the generation of genetic information on an unprecedented scale, and even outside of the context of an investigator’s duty to warn or rescue study participants, many investigators and research participants have argued that participants should have access to such information about themselves. Additionally, the rise of community-based participatory research (CBPR), a gold standard model of community engagement valuing the co-ownership of data, co-learning, and the sharing of knowledge to equalize power, provides a framework that encourages the return of research results (Brody et al., 2007; Morello-Frosch et al., 2009; Wallerstein et al., 2017) (see Box 4-2 in Chapter 4 for additional discussion on CBPR).

Published commentaries on the return of individual research results commonly refer to a number of different ethical principles that the authors suggest support an argument for or against returning individual research results to participants. These principles, which are described in the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979), were established to guide the practice of clinical research, and include

  • respect for persons/autonomy;
  • beneficence/non-maleficence; and
  • justice.

Respect for Persons/Autonomy

The principle of respect for persons calls for the recognition of participants’ autonomy (i.e., their freedom as individuals to determine their own actions). For participants who are capable of self-determination, this means that investigators should respect the participant’s informed choices (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). The requirement for informed consent in clinical research follows from this ethical

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

principle and ensures that participants are not treated as a means to an end and coerced, deceived, or misled into participating in the research.

Shalowitz and Miller (2005) argue that sharing results with interested participants demonstrates respect for these persons in several ways. It respects their integral role in research and the generation of the data. The authors write, “It would be disrespectful to treat research volunteers as conduits for generating scientific data without giving due consideration to their interest in receiving information about themselves derived from their participation in research” (p. 738). Furthermore, it offers participants the opportunity to incorporate the information into personal decision making. However, the fact that a participant may wish to have access to his or her results does not necessarily confer on the investigator an obligation to return them (Clayton and McGuire, 2012; Fabsitz et al., 2010; MRCT Center, 2017b). Respect for persons can still be demonstrated through the consent process by clearly informing participants that individual results will not be returned, thereby enabling them to decide whether to participate in the research. When results will be offered, respect for autonomy implies that the participants should have the choice as to whether they want to receive the results (i.e., participants have a right not to know). In addition, the sharing of general, aggregate study results is a demonstration of respect for the participants.

Beneficence/Non-Maleficence

According to the ethical principle of beneficence, investigators have an obligation to promote and safeguard the well-being of research participants (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). The age-old maxim from medical ethics, “First, do no harm,” can be applied in the research context to mean that investigators should not knowingly cause harm to research participants in order to advance science (non-maleficence). Thus, the health of participants should take precedence over the interests of the research (MRCT Center, 2017b). This is not to say that it is inappropriate to expose individuals to risk, as learning what may cause harm could itself entail risk, but such actions require forethought by investigators, institutions, and research sponsors in the design and planning of the research in order to maximize the possible benefits and minimize possible harms. Judgment must be applied (often by an IRB) to determine when the ratio of potential benefits to potential harms is sufficiently favorable to ethically justify the research.

This ethical principle has been invoked as justification both for and against the return of individual research results. Research has the potential to uncover information that could be beneficial to participants in their health management, life planning, or psychological well-being (Ravitsky and Wilfond, 2006). In keeping with the principle of beneficence, some argue that investigators have an ethical obligation to return results that have value to the participants, except where disclosure might compromise the research or a participant’s well-being (for instance,

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

in cases of misattributed paternity). Others maintain that returning results could cause undue distress and may even prompt unwarranted medical intervention, so that, with a few exceptions involving immediate and severe threats to life and health, the risks of return outweigh the potential benefits (Ashida et al., 2010; Bemelmans et al., 2016; Dixon-Woods et al., 2011; Lorimer et al., 2011).

Justice

The principle of justice holds that there should be fairness in the distribution of the benefits and burdens of research (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979). This does not necessarily mean that all participants must be treated equally, as a distribution on the basis of need, effort or contribution, and merit can be justified. However, it is not acceptable to exclude groups and individuals from the opportunity to participate in research or to deny an individual a benefit to which he or she is entitled without a valid reason. Individuals in similar situations should be treated similarly (Darnell et al., 2016). The challenges encountered in engaging certain disenfranchised groups and any concerns related to a lack of resources (e.g., access to follow-up health care) are not justifiable reasons for excluding individuals or groups from research or for denying potential benefits from the return of results.

The challenges in ensuring fairness with regard to the return of individual results have been noted and may argue against the practice or, alternatively, for the establishment of guidelines and infrastructure to enable greater consistency in the return of results. One author observed, for example, that there is a “very real possibility that research participants in studies with larger budgets are more likely to receive results than those in studies with less room for such expenditures” (Meltzer, 2006, p. 29).

Role of the Investigator–Participant Relationship in Obligations to Return Individual Results

Although some ethical arguments for returning results, such as the duty to warn, are largely independent of any relationship between the investigator and the participant, from both a legal (discussed in Chapter 5) and an ethical perspective the nature of this relationship can be a factor in determining whether the disclosure of individual research results is an obligation. The relationship between an investigator and a participant does not necessarily represent the kind of fiduciary relationship that exists between a health care provider and a patient—i.e., the investigator’s primary concern is not the best interests of the participant, but rather the integrity and societal benefit of the research (Burke et al., 2014). Generally, however, a deeper relationship between the investigator and participant gives rise to a greater responsibility to share results that may be of value to the participant.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Several conceptualizations have emerged of the role that the investigator–participant relationship plays in obligations regarding the return of individual research results. Richardson and colleagues note that research participants who volunteer for medical research entrust certain aspects of their health (e.g., confidential medical information, the permission to collect biospecimens) to clinical investigators. As a result of this “partial entrustment,” the authors argue, the investigators assume a moral obligation to provide the participants with ancillary care beyond that required to ensure the safety and validity of the study. The scope of the obligation to provide this ancillary care depends on the specific permissions that needed to be obtained during the consent process, Richardson and colleagues argue, and the strength of the claim is influenced by a number of contextual factors, including the degree of participant vulnerability, the participant’s dependence on the investigators for care, and the depth of the participant–investigator relationship (Richardson, 2008; Richardson and Belsky, 2004; Richardson and Cho, 2012; Richardson et al., 2017). The resulting duties stemming from these moral obligations may include returning any secondary findings or individual research results, depending on the importance of the results to the participant’s health (Beskow and Burke, 2010; Richardson and Cho, 2012).

In contrast to Richardson and colleagues, who base the obligation to return individual results on the specific relationship between the physician investigator and participant, Miller, Mello, and Joffe offer an alternative relationship-based rationale in which the ethical obligations for returning secondary findings stem from the principle of beneficence applied in the context of a professional relationship more generally4—one that does not necessarily have to be a physician–patient relationship (2008b). They assert that research participants entrust private health-related information to investigators who are professionals with enhanced capacities to recognize the significance of secondary findings. The privileged access to information by those with the competence to interpret it gives rise to a moral responsibility to disclose results that are indicative of a risk to the participant’s health (Miller et al., 2008b). The authors note that the same argument could be used to rationalize the return of individual research results, but they emphasize that such results, in contrast to secondary findings, should be anticipated and that their return is supported by the principle of respect for persons in addition to the principle of beneficence.

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4 The authors define a professional as “a person who possesses specialized knowledge, whose work involves the frequent exercise of discretion, and who can claim membership in a learned profession with a regulatory structure and ethical code of conduct. The hallmarks of a professional relationship are that the professional is entrusted by another with access to private information and/or other domains of individual privacy, such as the home or the body. Professional relationships are often, though not always, characterized by a service role, and may, but do not necessarily, involve a fiduciary relationship” (Miller et al., 2008b, p. 274).

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Limitations of Obligations to Return Individual Research Results Arising from Ethical Imperatives

Following a review of a critical analysis of the competing philosophical positions on the issue which are briefly described above and further explored in Appendix D,5 the committee concluded that the return of individual research results is consistent with, but not mandated by, the ethical principles for human research discussed above, except for the rare occasion when presumably reliable results are of significant clinical import and there is a risk of imminent harm to the participant if they are not disclosed. A variety of other mechanisms can be used to recognize the contribution of participants and respect their autonomy. These include

  • setting appropriate expectations in the consent process so that prospective participants can make informed decisions about whether to participate in a study,
  • offering financial compensation for time and effort,
  • returning aggregate study results (which also fosters transparency and trust), and
  • exercising the utmost good stewardship and ensuring the careful management of the participant’s entrustment.

In some cases, aggregate study results will be the most appropriate information to share with participants, and some aggregate results may have individual-level implications. For example, Fernandez et al. (2003b) discuss the hypothetical case “of a childhood cancer survivor who was not informed that the research in which she had participated as a child had revealed an elevated lifetime risk of cancer for survivors such as herself, and who had therefore failed to manage her risk” (Miller et al., 2008c). However, returning aggregate results does not absolve investigators of the responsibility to consider returning individual-specific research results as well. As discussed further in Chapter 4, investigators will need to consider participant needs, preferences, and values. Some participants, such as those engaged in research to identify treatments for rare diseases, may prefer not to receive individual research results if there is a trade-off in terms of diverting resources from the primary research aim and slowing research progress6 and may instead prefer that investigators reciprocate in other ways.

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5 The committee commissioned Haavi Morreim, J.D., Ph.D., to draft a paper on the philosophical perspectives and ethical underpinnings for the return of individual-specific research results from research laboratories (see Appendix D).

6 Testimony of Ellen Wagner of Parent Project Muscular Dystrophy at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

CONCLUSION: Except in cases where reliable research results suggest the participant is in imminent danger, an investigator’s decision not to return results does not necessarily violate the ethical principles for human research, as long as the consent process indicated that results would not be returned. No single ethical principle sufficiently justifies an unrestricted obligation to return individual results to participants, but neither does any ethical principle completely absolve investigators from doing so.

To this point this discussion has focused primarily on the ethical obligations arising from a relationship between investigators and participants, or potential participants, who have decision-making capacity. Our analysis suggests that offering to return results can be an important means of fostering transparency, demonstrating respect for the contributions of the participant, and providing benefit to those who volunteer for research. But what about research participants who do not have decision-making capacity or lose that capacity during the research project? This includes younger children, adults and older children who have never had decision-making capacity, and those who lose capacity through disease progression, injury, or death during the conduct of the research. There has been excellent scholarship on these issues in recent years (Anastasova et al., 2013; Beskow and O’Rourke, 2015; Chan et al., 2012; Groisman et al., 2012; Holm et al., 2014; Wolf et al., 2015) and a full exploration of the ethical and legal issues relevant to these participants was not feasible in the time available to the committee. In brief, however, when competent participants express an informed choice regarding results disclosure to family members or others but then lose capacity during the conduct of the study, respect for their autonomy suggests that their preferences should be respected (Wolf et al., 2015). Indeed, for competent participants the optimal approach to this issue is to encourage them to consider at the time of consent how they would want their results to be handled if they are subsequently unable to make a competent choice.

For participants who are not competent at the time of study entry, whether by virtue of minority or cognitive impairment, or who lose competence during the course of the study and have not previously indicated their preferences, we conclude that any ethical responsibility that investigators have to return results to participants is grounded in considerations of beneficence. The return of results may be appropriate when those results have significant health or welfare implications for the participant. Such results generally will be provided to the participant’s legally authorized representative, who in turn will be in a position to decide—if the results suggest risk to other family members—whether to share them with those relatives. When a participant dies without having previously indicated his or her preferences regarding the sharing of results with significant health implications for family members, the analysis is more complex. Investigators cannot be said to have a binding duty of beneficence to people who are not enrolled in the study. However, given the moral value of promoting health whenever possible, it will generally be preferable to share information about serious

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

conditions for which interventions are possible with potentially affected family members. Countervailing considerations in specific cases will include the privacy of the deceased research participant and the burden on the research team. The implications of this ethical foundation relevant to those who lack decision-making capacity will be explored in Chapter 4.

SOCIETAL CONSIDERATIONS FOR THE RETURN OF INDIVIDUAL RESULTS IN HUMAN PARTICIPANT RESEARCH

Although a clear ethical obligation to return individual research results may, as discussed above, be restricted to a small number of cases involving imminent risk to a participant’s well-being, there are other societal considerations that suggest the need for a re-evaluation of the circumstances under which returning individual research results to participants may be appropriate. In addressing its task, the committee considered a broad set of stakeholder perspectives and arguments for and against the return of individual research results, including the potential to maximize benefits and minimize risks to participants, the research enterprise, and society as a whole.

Considerations for Research Participants

Individual research results are commonly not returned to participants despite a growing body of literature demonstrating that many participants are interested in receiving their results (Bollinger et al., 2014; Murphy et al., 2008). Participants are particularly interested in receiving results when the results have direct relevance to their health or that of a loved one or are actionable (Long et al., 2016; Murphy et al., 2008). This theme appears to be increasingly consistent across many studies, although participant preferences for receiving results vary widely (Terry, 2016). Some participants have expressed a desire to receive all of their results, while others have indicated that they volunteered in order to advance the research and do not expect to receive individual results but may like to know the key findings from the study. In some cases, participants may even consider individual-specific results to be a burden (Bollinger et al., 2014).7

Benefits to Participants from Receiving Individual Research Results

Research results may have significant informational value to participants, and in some cases such information might not otherwise be obtained. Participants may benefit from the return of individual research results that inform clinical decision making, life planning, and other actions that may affect health and the quality of life.

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7 Testimony of John Molina of Native Health at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on December 11, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Research results that are clinically actionable—i.e., those that may guide decisions on preventive interventions or treatments or other actions (including surveillance for early detection) that may change the course of a disease or health condition (MRCT Center, 2017a)—have received the greatest attention in arguments for disclosure (Bookman et al., 2006; Fabsitz et al., 2010; National Bioethics Advisory Commission, 1999). However, the committee identified several other important ways that participants may benefit from the return of individual research results. Reproductive planning, for example, may be influenced by results indicating that a participant is a carrier for a recessive or X-linked disorder or that the person may have difficulties carrying a pregnancy to full term, as in the case, for example, of balanced chromosomal translocations (Kavalier, 2005). For participants with certain health conditions (or the caregivers of such individuals), research results may inform other aspects of life planning, such as making insurance (e.g., long-term care) coverage decisions (Caselli et al., 2014; Zick et al., 2005) and anticipating changes in lifestyle (Vernarelli et al., 2010). For example, one parent of a child with a rare degenerative disease spoke to the committee about research results that could predict disease progression, allowing families to plan for the child’s transition to the use of a wheelchair.8 Research results may also inform or help drive individual-level risk reduction efforts, such as taking steps to limit exposure to an environmental contaminant identified in a human biomonitoring study (Ohayon et al., 2017) or changing health behaviors (e.g., exercise, nutrition) to reduce risk factors associated with a disease to which one is found to be at increased risk (Caselli et al., 2014; Chao et al., 2008), though such changes may often not be pursued or sustained (Hollands et al., 2016). In some cases, individual research results may have value to participants even when there is no action to be taken. For example, an individual with a family history of a severe disorder may experience relief in learning that he or she is negative for a susceptibility biomarker (Romero et al., 2005), particularly in cases where no clinical test is yet available. Relief may also result from finally identifying a cause for a heretofore undiagnosed health condition—ending the so-called “diagnostic odyssey”—even if no other resultant clinical action is possible beyond the cessation of diagnostic testing (Beaulieu et al., 2014). Some participants are simply interested in learning more about themselves (Bunnik et al., 2014; SACHRP, 2016).

The benefits of returning individual research results may also extend to others besides the research participant. Some results may have implications for family members, partners, or even whole communities. For example, the genetic results for hereditable conditions, if shared, may lead to cascade testing for family members,9 and individual biomonitoring results may foster activism aimed at

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8 Testimony of Ellen Wagner of Parent Project Muscular Dystrophy at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

9 Testimony of Adam Buchanan of Geisinger Health System at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

driving community-level changes to reduce exposures (Ohayon et al., 2017). In some such cases, however, decisions will need to be made regarding with whom results should be shared. Generally participants have the discretion to decide with whom to share their results, but this valuation of autonomy is not universal (Smith-Morris, 2007). In some tribal communities, for example, the tribe retains ownership over the biospecimens submitted by tribe members (and the results generated from them) rather than the research institution (Chadwick et al., 2014; Mohammed et al., 2012) and may have the corresponding expectation that the results belong to the tribe, not to the individual.10

The committee also heard from multiple research participants that the act of sharing of individual research results can, in and of itself, be beneficial for participants. One participant indicated that the lack of reciprocity in clinical research can reinforce negative experiences with the medical enterprise. “When I go into a clinical setting, I lose a great deal of identity, and I almost become anonymous. Because I’ve had so much trauma around hospitals, I feel like I don’t have a voice.” Returning individual research results in a way that makes them meaningful, this participant said, is a way to create a more level playing field and to help participants feel appreciated for their contribution to the research study.11

Potential Risks to Participants from Receiving Individual Research Results

The potential benefits discussed above suggest that there are many reasons to consider expanding the return of individual research results beyond the current practice. However, it is also important to consider the potential risks to participants who choose to receive results. The most commonly cited risks are possible adverse psychosocial effects from receiving results with serious health implications or that have uncertain meaning. Some survey-based data have suggested that the disclosure of such results has the potential to do harm. For example, a study using hypothetical questions to assess the possible risks of harm from presymptomatic testing for Alzheimer’s disease reported that more than 10 percent of respondents agreed with a statement that they would seriously consider suicide if results indicated they were positive for the ε4 allele of apolipoprotein E (APOE-ε4)12 or had a non-genetic biomarker (Caselli et al., 2014). However, there is significant uncertainty regarding the translation of hypothetical scenarios to real-world experiences. Only a limited number of studies have empirically evaluated post-disclosure stress or the onset of a psychological disorder (e.g., anxiety, depression), and to date there is little empirical evidence to support

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10 Testimony of John Molina of Native Health at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on December 11, 2017.

11 Testimony of Stephen Mikita of Aspirin in Reducing Events in the Elderly (ASPREE) study at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on December 11, 2017.

12 The APOE-ε4 genotype is associated with an increased risk of developing Alzheimer’s disease.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

concerns about serious adverse effects (Ashida et al., 2010; Bemelmans et al., 2016; Bradbury et al., 2015; Calzone et al., 2005; Christensen et al., 2011; Green and Farahany, 2014; Green et al., 2004, 2009; Jenkins et al., 2007). The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) studies, for example, evaluated the psychological and behavioral effects of disclosing genetic biomarker results to participants who were first-degree relatives of an Alzheimer’s disease patient (Roberts et al., 2005). Although the disclosure of the APOE-ε4 carrier status was associated with a transient increase in test-related distress, no statistically significant differences in post-disclosure levels of anxiety or depression were observed among three groups of participants: those who were APOE-ε4 carriers, those who were negative for APOE-ε4, and those who were in a non-disclosure group (Green et al., 2009). Similarly, Bradbury and colleagues reported that for a study population of breast cancer patients, the receipt of individual genetic testing research results was not associated with significant increases in anxiety and distress when participants received genetic counseling (Bradbury et al., 2015). In the context of biomonitoring studies, investigators have reported that returning exposure results has resulted in increased concerns and worry among participants but did not generate the harmful levels of worry and panic (Emmett et al., 2009; Ohayon et al., 2017; Ramirez-Andreotta et al., 2016) that some members of the study’s IRB believed could result from the disclosure (Ohayon et al., 2017). Indeed, worry can be a productive force when it stimulates preventive or corrective action (Ohayon et al., 2017).

Still, proceeding with caution is prudent, given that little is known about the effects of participant characteristics, beliefs, and past experiences (e.g., a family history of disease, a history of a psychological disorder) on outcomes following disclosure. Some limited data suggest that receiving test results may affect participant expectations and perceptions about themselves, which in turn can have effects on functioning. In the REVEAL study, APOE-ε4-negative participants who received their results reported higher memory function than APOE-ε4-negative participants who did not receive their results. More concerning was a decrease in subjective and objective measures of memory function in APOE-ε4 carriers who received their results as compared with APOE-ε4 carriers who did not learn their genotype (Lineweaver et al., 2014). Prognostic pessimism—negative feelings about the future course of an individual’s disorder, including feelings of hopelessness and lack of agency—has been associated with beliefs regarding a genetic or biological predisposition to stigmatizing conditions, such as depression or substance abuse disorder (Lebowitz and Appelbaum, 2017; Lebowitz et al., 2013) and is another potential adverse outcome of receiving research results that indicate an increased risk for some health conditions.

Although similar types of concerns have been raised about the psychological effects of disclosing potentially worrying or disturbing test results in both clinical and research contexts (e.g., when such results are not clinically actionable), some investigators and IRBs have apprehension about the return of individual research

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

results because of the uncertainty that is often inherent in a research result and because of a lack of confidence in the validity of the result. When results are inaccurate, misleading, or over-interpreted, harm can result from an inappropriate action (e.g., prophylactic surgery for someone whose results falsely indicated an increased risk of breast cancer) or from inaction (e.g., failure to get proper screenings when the results were negative for a susceptibility factor). The committee did not find many real-world examples of harm to individuals involving inaccurate or misinterpreted research results that had been returned to participants, but a recent case of unwarranted prophylactic surgery involving the misinterpretation of clinical genetic testing results demonstrates the potential risk (Bever, 2017). It should also be noted that so far in the genetics context, research has focused mostly on the return of results from clinically valid, commercially available tests. Thus, it cannot yet be determined whether examples of additional harms may arise from the return of research results that have not been validated for clinical use.

In addition to the potential physical and psychological harms, social consequences may also occur after the return of individual research results to participants (Bookman et al., 2006; Smith-Morris, 2007); these social consequences may include stigmatization, economic impacts, and adverse effects on relationships with others, including family members (e.g., in cases of misattributed paternity) and communities. For example, individuals participating in a personal exposure study expressed concerns about the effects of the results on their property values if the results indicated a contamination problem (Ohayon et al., 2017). Reporting research results to individuals may also risk affecting community norms in Native American communities that practice tribal decision making and community self-determination (Smith-Morris, 2007). Commonly reported concerns of participants include breaches of privacy and exposure to the risk of discrimination associated with individual research results (Ohayon et al., 2017). As discussed further in Chapter 6, some legal protections are in place to prevent discrimination on the basis of genetic test results in employment, educational opportunities, and health insurance, but gaps in protections have been noted.13 For example, federal protections through the Genetic Information Nondiscrimination Act of 2008 do not apply to life, disability, or long-term care insurance (Arias and Karlawish, 2014).

Overall, little is known regarding the actual (versus potential and perceived) risks associated with returning individual research results, but the committee emphasizes that the current state of knowledge reflects a lack of evidence, not conclusive evidence of a lack of effect. Clearly, more research is necessary to better understand the risks associated with results disclosure, including whether certain subsets of individuals are more vulnerable to adverse impacts. What is clear is that many participants want access to their research results and are willing to assume

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13 In the case of environmental exposure research, the lack of legal protections and potential legal liabilities for participants that receive results on household exposure has been raised (Goho, 2016).

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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the risks. Many argue that withholding results on the basis of the potential risks discussed above is overly paternalistic (Bredenoord et al., 2011; Fernandez, 2008; Townsend et al., 2013).

Considerations for the Research Enterprise

Opinions within the research enterprise are mixed on the appropriateness and value of returning individual research results (Meulenkamp et al., 2012). Although few argue that all research results should be returned, a growing number of investigators believe that participants should, at the very least, have access to any of their test results that were generated in the course of research (Burke et al., 2014; Green et al., 2013; Jarvik et al., 2014; Ohayon et al., 2017; PCSBI, 2013; Wolf et al., 2008), and some institutions have developed standardized processes for decision making on when and how such results should be returned.14 Some have argued that the one-way flow of information from research participant to scientist is outdated and paternalistic (Johnson, 2014; Lunshof et al., 2014). In much the same way as prospective participants, report investigators are more likely to support the return of results that have clear implications for the prevention or treatment of a health condition (Meulenkamp et al., 2012). Despite the increased interest from investigators in returning individual results to research participants, countervailing concerns have been raised about the risks to participants, the legal liabilities, and the burdens placed on the research enterprise (Bredenoord et al., 2011; Klitzman et al., 2013; Ohayon et al., 2017).

Research sponsors and funding agencies also appear to have conflicting perspectives. As discussed in Chapter 1, the National Institutes of Health has moved toward policies supporting the return of results in a broader set of circumstances than has traditionally been practiced. It has indicated that “as the biomedical research enterprise increasingly moves to a more participatory model of research, where research participants are treated more as partners than passive subjects, we can expect greater emphasis on returning individual-level results of research to participants” (NIH, 2017). It is not clear that private-sector sponsors are equally persuaded on this issue. In comments submitted to the committee, for example, a Merck representative indicated that although it has no proprietary reason not to make results accessible, it currently does not return results from “research-grade” assays even when they are performed in laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).15 The reasoning provided by Merck is consistent with commonly cited concerns from other research system

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14 Memorial Sloan Kettering Cancer Center, 2017. Comment provided to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, October 20. Available by request through the National Academies’ Public Access Records Office.

15 Comment by Julie Anne Zawiska to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, October 19, 2017. Available by request through the National Academies’ Public Access Records Office.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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stakeholders, which are explored in the section below. On its website, Pfizer indicates that it has allowed clinical trial participants in select studies to access their individual-level results by using the Department of Health and Human Services Blue Button technology, which “enables the secure electronic delivery of medical information gathered in a study directly to trial participants and allows integration into electronic medical records”; the website does not indicate whether results from “research-grade” assays are offered to participants (Pfizer, 2018).

Risks and Burdens for the Research Enterprise from Returning Individual Research Results

To mitigate the risks of returning research results, investigators will need to provide participants with sufficient information and deliver results in ways that enable participants to make informed decisions. From its review of the literature and from input solicited from research system stakeholders, the committee identified several consistent themes regarding the potential risks and burdens to the research enterprise that are associated with the return of research results.

First, the individual-level analysis of research results (e.g., to determine meaning for an individual participant) may differ from the analysis of aggregate results and can be a challenging task for investigators, particularly when the results are generated using novel, cutting-edge technologies and techniques.16 The inherent uncertainty related to research results makes some investigators uncomfortable with the interpretation and return of results, given the risk for misinterpretation by the participant; this is a particular issue when there are no established health guidelines relevant to the result, as is the case in some environmental exposure studies (Hernick et al., 2011). In some cases, interpretation will require medical expertise and even a knowledge of the participant’s medical and family history. Investigators may not always have a relationship with the participant who contributed the biospecimen and, therefore, may not be familiar with that individual’s history; however, as is discussed in Chapter 5, in many cases results can be returned without such individual-level interpretation.

Cost is frequently identified as an argument against returning individual research results because of the potential burdens it could generate for an investigator. These burdens include both financial costs and the potential for lost research productivity caused by the diversion of research team efforts (Bredenoord et al., 2011; Budin-Ljøsne et al., 2016; Christensen et al., 2011; Fernandez et al., 2004; Resnik, 2011).17 The effort involved in re-contacting participants and

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16 Comment by Julie Anne Zawiska to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, October 19, 2017. Available by request through the National Academies’ Public Access Records Office.

17 Comment by Mark E. Sobel to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, August 18, 2017. Available by request through the National Academies’ Public Access Records Office.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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returning results in ways that are responsible and likely to be useful to them can be significant, particularly when disclosure may involve the services of medical professionals (e.g., genetic counselors) or when the results become available after a trial or study has ended. Additional costs may stem from requirements for confirmatory testing or from instituting other processes to ensure the quality of research results returned to participants (Black et al., 2013) (discussed further in Chapter 3). Although the opportunity costs are not well understood, it is clear that meeting the needs of participants and investigators will require substantial investments in infrastructure and training at individual laboratory and institutional levels. The effects of such measures may extend beyond the issue of resources to also include effects on the laboratory culture and training environment. The likely diversion of resources from the conduct of research, particularly at a time when research funding is uncertain, raises concerns that policies requiring investigators to more routinely return individual research results will unduly burden the research enterprise and hinder progress in biomedical research (Black et al., 2013; Bollinger et al., 2014; Resnik, 2011).

Another commonly cited risk is that the routine disclosure of individual research results could conflate or confuse the purposes of research and clinical care (Bredenoord et al., 2011; Clayton and Ross, 2006; Meltzer, 2006). While there is broad agreement that the return of research results should not be a substitute for clinical care and cannot compensate for inadequate health care access, participants sometimes enroll in studies with the intent of accessing testing or care that they cannot otherwise obtain.18 Some argue that the return of individual research results may promote therapeutic misconception, leading participants to mistakenly assume that a research study will yield reliable results with clinical value when, in reality, the clinical implications of research results will only rarely be clear (Clayton and McGuire, 2012). Participants themselves have indicated that the return of clinically relevant genetic results blurs the distinction between research and clinical services, although the significance is not always clear to them (Miller et al., 2008a). Proper consent procedures are important to help mitigate the risks associated with participants’ unrealistic expectations (Appelbaum and Litz, 2008). When participant expectations are not met, it may undermine motivation to volunteer for research studies in the future. The increased connectedness between research and health care delivery should not necessarily be considered a risk, and in some circumstances better integration may be appropriate and beneficial to participants, the research enterprise, and health care (Darnell et al., 2016; Faden et al., 2013; Kullo et al., 2014; Wolf et al., 2018). As one scholar stated, “Research and clinical care are connecting along a translational continuum. Instead of a wall between the two, we now have a permeable membrane. The return

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18 Comment by Leslie Biesecker provided to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, September 7, 2017. Available by request through the National Academies’ Public Access Records Office.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

of results is a debate about how to structure the flow of information through that membrane” (Wolf, 2013, p. 573).

Finally, legal risks also influence investigator and institution decisions about returning individual research results. Perceptions regarding legal risks relate both to regulatory compliance issues (Barnes et al., 2015) and to fears that imposing obligations to return individual research results to participants will open the door to greater legal liability for investigators (Clayton and McGuire, 2012). Legal liability for negligence may arise from results that are returned—e.g., if those results are found to be inaccurate—or from a failure to return results (McGuire et al., 2014). However, investigators have traditionally not been viewed by the courts as having a fiduciary relationship with participants (Meltzer, 2006; Pike et al., 2014), and so far there are no examples where ethics-based recommendations from expert groups have been used to impose legal liability (Wolf, 2012). Approaches to overcoming legal and regulatory barriers are discussed in more detail in Chapter 6, but, generally, the current confusion surrounding the regulatory environment and the paucity of legal precedent are impediments to a more widespread adoption of return-of-results practices.

Benefits to the Research Enterprise from Returning Individual Research Results

Although commentaries on the return of individual research results often focus on the expected burdens to investigators, there could be benefits to investigators as well. In particular, if the return of results leads to increased trust and public engagement in the research enterprise, it could have multiple positive effects, including possible improvements in the efficiency, generalizability, and participant-centeredness of research.

One growing source of pressure on the research ecosystem to evolve is the set of challenges that many investigators face in the enrollment and retention of participants in research studies. This problem has been well documented for clinical trials and large prospective cohort studies (Comerford et al., 2017; Gul and Ali, 2009; Leighton et al., 2018; Watson and Torgerson, 2006). Enrollment delays and participant dropout can increase the length and cost, as well as reducing the power of a research study, which can jeopardize the implementation and validity of the research (Gul and Ali, 2009; Leighton et al., 2018; Watson and Torgerson, 2006). Despite the general support for the conduct of biomedical research observed in surveys, the majority of Americans have low awareness of and levels of participation in clinical trials and other human research (Ohmann and Deimling, 2004; Woolley and Propst, 2005). One reason for this limited participation is inadequate information sharing by investigators to participants regarding many aspects of study participation. A persistent lack of transparency on the part of investigators, coupled with historical abuses, has raised questions in the public’s mind regarding the trustworthiness of the research enterprise and has dampened interest in participation (Corbie-Smith et al., 1999; Hiratsuka et al., 2012; Northington Gamble, 2006). This issue of lack of

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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trust and transparency was brought up during committee discussions with research participants and community representatives, who suggested that returning research results to participants may stimulate greater transparency and interest in contributing to research.19,20

Some evidence supports the assertion that returning individual research results to participants could improve enrollment and retention. Survey data have shown that receiving results is a strong incentive for participation in research (Christensen et al., 2011; Kaufman et al., 2008, 2016; Murphy et al., 2008), and participants may prefer individual results over aggregate study results (Halverson and Ross, 2012). Increasing trust and enrollment across all participant groups could increase not only the efficiency of research, but also its generalizability. The lack of diversity (e.g., socioeconomic, racial, ethnic, and gender identity/sexual orientation) in many study populations is well documented and limits the applicability of many research findings to the larger heterogeneous population found within the United States and globally (Duma et al., 2017). It is worth noting, however, that questions have been raised regarding the potential for undue inducement for participation (Bledsoe et al., 2012), particularly if investigators overstate the benefits of enrollment in a study (Meltzer, 2006). Investigators and IRBs can help to guard against this possibility by ensuring accuracy in framing the benefits likely to accrue from the return of results. The promise of receiving individual research results may be a larger incentive for those with fewer resources (e.g., insurance) to get medical testing, which raises additional justice-related concerns21 that will need to be considered in the development of policy.

Finally, the return of individual research results may help patient and participant communities to better connect, compare results, and work with investigators to develop and help answer questions that matter to those affected by the conditions under study, thereby improving the participant-centeredness of biomedical research.22 Growing access to data from multiple sources (e.g., mobile technology, patient portals) has empowered patients to take a leadership role in driving precision medicine research (Fliesler, 2015). In the rare disease community, for example, patients and their families are increasingly helping design studies, share data, and leverage social media and digital marketing as recruitment tools (Fliesler, 2015).

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19 Testimony of John Molina of Native Health at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on December 11, 2017.

20 Testimony of Stephen Mikita of Aspirin in Reducing Events in the Elderly (ASPREE) study at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on December 11, 2017.

21 Testimony of Febe Wallace of Cherokee Health Systems at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

22 Testimony of Ellen Wagner of Parent Project Muscular Dystrophy at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Patients, their family members, and advocates have found a way to use new technologies and the Internet and its vast array of social media networks to connect to patients like them, in a way that typical clinical trial recruitment does not. The willingness of people to be engaged with their health information, generate their own research questions, and share their data is providing investigators with immense amounts of information that is contributing to precision medicine initiatives and affecting what participants expect from research and the role they want to play in it.

Considerations for the Health Care Enterprise

Clinicians, clinical laboratory directors, and other members of the health care enterprise are important stakeholders whose perspectives need to be considered in the development of policies related to the return of individual research results. Health care and research systems are increasingly intertwined in the conduct of biomedical research. Clinical trials frequently involve the delivery of clinical care, and some have posited that the return of individual results is transforming other forms of research (e.g., genetic epidemiology studies) into quasi-clinical services.

This hybrid of clinical care and research can face challenges when participant expectations regarding the timely receipt of results delivered with the appropriate sensitivity are not met (Miller et al., 2008a). Research laboratories often are not set up to provide participants with medical information or to ensure follow-up. Therefore, as health care professionals emphasized to the committee, when the research results that will be returned have a potential medical impact, it is important to have stringent protocols for the return process and adequate resources to support qualified health professionals who can translate the results into meaningful information for participants and discuss their questions and concerns (Grove et al., 2014).23 One notable challenge in meeting this need is the short supply of some kinds of medical professionals (e.g., genetic counselors) who have the necessary expertise. Returning results in a scalable way will require paying close attention to the processes for mitigating burdens to the health care system. For example, addressing shortages in genetic counselors could involve removing barriers associated with state licensure restrictions24 and using video-counseling technologies.25 Reimbursement is another issue that will need to be addressed for studies operating at the research–clinical care interface (Wolf et al., 2018).

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23 Comment by Mary E. Freivogel to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, October 20, 2017. Available by request through the National Academies’ Public Access Records Office.

24 Testimony of Jessica Langbaum of Banner Alzheimer’s Institute at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

25 Testimony of Wendy Chung of Columbia University at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

In some cases, clinicians may be the primary investigators (as is often the case in clinical trials) or members of a study team (e.g., clinical geneticists) tasked with communicating with participants about results (Wolf et al., 2018).26 While having clinicians in these roles helps to ensure that health care professionals are available to discuss medically relevant results with participants, the blurring of lines between research and medical care may be confusing for participants, potentially contributing to therapeutic misconception and challenging the traditional understanding of the doctor–patient relationship (Burke et al., 2014); having doctors in a dual role of both clinician and investigator also has the potential to create conflicts of interest (McGuire et al., 2014). In other cases, physicians who are not associated with the study may be asked to discuss and interpret individual research results for their patients. Some research studies have set up processes and infrastructure to deliver research results to the participants’ health care providers. In the Scripps Idiopathic Diseases of Man study, having a physician champion who was willing to work with the research team and return and discuss the genetic results with patients was part of the inclusion criteria for participation (Bloss et al., 2015). However, the committee also heard that clinicians may not want to have the responsibility of explaining results to participants, particularly if they themselves do not have a strong understanding of the test or result.27 To address these kinds of concerns, some research teams offer support to clinicians in the form of informational packets (e.g., with information about the study).28,29

Sometimes physicians with no knowledge of a study may be approached by patients looking for a further explanation of the research results that have been returned to them. This raises concerns regarding the potential burdens on primary care providers and other clinicians, who may feel they have neither the time nor the necessary knowledge to interpret their patients’ research results (Terry, 2012).30

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26 Testimony of Nicholas Newman of the University of California Department of Pediatrics at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on October 24, 2017.

27 Testimony of Wendy Chung of Columbia University at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

28 Testimony of Adam Buchanan of Geisinger Health System at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

29 Testimony of Joanne Murabito of Framingham Heart Study at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

30 Testimony of Febe Wallace of Cherokee Health Systems at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Failure of those clinicians to meet patients’ expectations for an explanation could erode confidence and trust in health care providers.31

Another contentious issue in the return of individual research results relates to the type of laboratory in which testing is conducted. Research laboratories are not held to the same quality assurance and quality control requirements as clinical laboratories, which means that there is a greater risk of pre-analytic, analytic, and reporting errors (e.g., specimen mix-up) when testing is done in research laboratories. Thus, it was stressed to the committee that any test results that could be used to inform patient care decisions should be generated in CLIA-certified laboratories.32,33,34 Otherwise, a loophole could be created that would enable the generation of results for clinical decision making in non-CLIA-certified research laboratories without medical oversight.35

Another issue relates to the potential for research results to be incorporated into electronic health records (EHRs). The Electronic Medical Records and Genomics (eMERGE) Network, for example, makes it possible for investigators to use EHRs to return clinically relevant genomic research results (e.g., genetic variant and pharmacogenomics results) for use by participants and their health care providers (Kullo et al., 2014). However, some fear that providers who are not aware of the limitations of research results in the EHR may misinterpret the significance of the result for patient care decisions,36 compromising patient safety and also exposing the provider to liability.

Considerations for Society

The benefits and risks to participants, the research enterprise, and the health care system from the return of individual research results can in many cases be seen as benefits and risks to society. However, some implications of the issues

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31 Testimony of Febe Wallace of Cherokee Health Systems at the public meeting of the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories on September 6, 2017.

32 Comment provided by the College of American Pathologists to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, September 7, 2017. Available by request through the National Academies’ Public Access Records Office.

33 Comment by Douglas A. Beigel to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, September 27, 2017. Available by request through the National Academies’ Public Access Records Office.

34 Comment by Mark E. Sobel to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, August 18, 2017. Available by request through the National Academies’ Public Access Records Office.

35 Comment provided by the College of American Pathologists to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, September 7, 2017. Available by request through the National Academies’ Public Access Records Office.

36 Comment provided by the College of American Pathologists to the Committee on the Return of Individual-Specific Research Results Generated in Research Laboratories, Washington, DC, September 7, 2017. Available by request through the National Academies’ Public Access Records Office.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

discussed above warrant an explicit mention in the society-level context. In particular, increased public engagement and trust in research has many potential societal benefits, including improved health and science literacy, increased activism related to human and environmental health, greater public advocacy for biomedical research, the acceleration of biomedical discoveries, and an increased likelihood that scientific advances will be translated into policy (Ohayon et al., 2017; Terry, 2012). Informing the public about research can affect policy decision making, particularly for public health funding as occurs in the Canadian system (Jbilou et al., 2013). All of these could have positive effects on public health. If, however, the return of individual results is not done in a thorough, responsible, and equitable manner, there are also risks to public health and society, including creating greater health and health care disparities because of more limited mechanisms to engage certain communities. For example, in the absence of efforts to address barriers to increasing diversity in research participant populations, communities that have been traditionally underrepresented in research studies may not have equal access to the benefits from the return of research results, inadvertently perpetuating existing disparities (Yu et al., 2014). Moreover, if sufficient efforts are not undertaken and checks put in place to ensure that the results returned to participants are valid (discussed further in Chapter 3), there is a potential for the spread of misinformation, public disengagement, and further loss of trust in the research and medical enterprises.

RECOMMENDATION AND GUIDING PRINCIPLES FOR THE RETURN OF INDIVIDUAL RESEARCH RESULTS

The committee carefully considered the competing ethical justifications for the responsibilities of investigators to return, or not to return, individual research results as well as the perspectives of different stakeholders and the many societal considerations. Although no clear philosophical justification exists for an unrestricted obligation to return individual results to participants, strong justifications can be offered for returning some results in many circumstances beyond traditional and current practices. However, caution is warranted, given the potential adverse effects on participants and the research enterprise. The effects of returning individual research results will need to be continuously evaluated to build a stronger empirical evidence base.

CONCLUSION: Considering the full spectrum of ethical and societal considerations for the return of individual research results, it is clear that there are certain circumstances when there are compelling reasons to return individual results to participants and others in which it is appropriate to limit and constrain the return of results. In determining whether to return results for any given study, the various ethical principles must be balanced, and the specific context of the situation must be carefully considered.

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

Investigators, with oversight from their IRBs and institutions, will ultimately be responsible for making decisions on a case-by-case basis regarding whether and how to return individual research results, as the decisions require careful consideration of many factors, which are described below. However, as discussed in Chapter 4, research sponsors and funding agencies also have an important role in reviewing return-of-results plans in funding applications in order to support reasonable consistency across research studies and institutions. Although these oversight mechanisms are not foolproof at preventing harm, and increased responsibilities need to be accompanied by a corresponding increase in resources and training if they are to be effective (Icenogle, 2003), the committee believes that at this time institutional review is the most practical and reasonable approach to support decision making regarding the return of individual research results. Chapter 4 presents the committee’s framework that can support investigators and IRBs in their decision making. The committee recognizes that it will be challenging for IRBs to foster the return of results and to assess the risks and benefits of this practice in the near future before experience and an evidence base has fully developed. In the meantime, we encourage IRB professionals to approach the issue reflectively, regularly engage stakeholders, attend to accumulating data and institutional experiences, and share experiences, data, and protocols with colleagues through professional meetings and publications. Current practices and research into the return of results taking place in National Institutes of Health (NIH)-funded research like the All of Us Research Program, the Clinical Sequencing Evidence-Generating Research consortium, and the eMERGE Network can be used to develop initial guidance for IRBs. NIH could also assist IRBs by convening a workshop or working group with other research funders to examine current practices regarding the return of results from biospecimens and explore lessons learned from biomonitoring programs and other domains such as radiology, imaging, and social and behavioral health research. As the evidence base expands, there may be a further role for government agencies to develop guidance to support investigators and their IRBs in their decision-making process.

Decisions about whether and how to return individual results will be influenced by many factors that require careful consideration. These include the potential value of the information to the participant; the nature of the relationship, if any, between the participant and the investigator; the analytic and clinical validity of the research result; and the potential risks, challenges, costs, and burdens of returning results as well as the resources available to do so effectively and

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

appropriately. The benefits to participants and the research enterprise have to be weighed against risks, including potential harms to individuals, the diversion of resources and investigator efforts away from conducting research, liabilities, risks of privacy breach, and discrimination. These factors, along with a framework for a decision-making process and recommendations to provide guidance and support for investigators, IRBs, and their institutions as they navigate this process are discussed in more detail in Chapters 3 and 4. As the committee explored these factors and developed its recommendations, its deliberations were guided by the following six principles:

Principle 1: Participants bring essential and valuable information to the research enterprise without which research cannot be conducted. Because research results have value to many participants, as a matter of reciprocity, respect, transparency, and trust the return of results should be routinely considered in the design of research protocols involving human participants.

The emergence of the participant-centric model for research is changing the paradigm from a system that traditionally focused on minimizing the risks of harms to participants to a system that more fully recognizes the rights and interests of the research participants. Accordingly, there is an emerging obligation to consider the personal values of the people who contribute to the research. Research participants are not disembodied providers of biomedical materials—they should be treated as active collaborators on the research (Kohane et al., 2007; Partridge and Winer, 2002). One means of expressing gratitude and respect is to recognize participants’ generosity with appropriate reciprocity (Illes et al., 2006), i.e., by communicating results that may be of value to participants.

Principle 2: Research has significant societal value. The potential value of returning individual research results must be carefully considered along with the trade-offs for research participants, investigators, research institutions, and society.

The purpose of biomedical research is to expand generalizable knowledge in order to advance our understanding of pathophysiology and medicine, with the ultimate goal of improving health outcomes for patients and the public. The return of results presents trade-offs for research stakeholders and requires careful consideration of the potential value, benefits, costs, and harms. The appropriate return of individual research results will entail additional resources, capabilities, and processes by and for the research enterprise. The possibility that these associated costs will lead to less investment in new research and a slowdown in biomedical advances is a potential harm to all research stakeholders—investigators, research institutions, participants, and the public. Similarly, each stakeholder has the potential to benefit from returning research results in terms of increased

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

participant enrollment and retention in research studies and greater public trust in the research enterprise. Determining the best approach to implementing this practice to balance the potential trade-offs will be context dependent. The return of individual research results (other than life-threatening and emergent results) should only be considered at a time, and by a method, that does not compromise the overall study results. Chapter 4 addresses the factors that go into decision making regarding the return of individual research results on a study-specific basis.

Principle 3: When individual research results are offered, participants have the right to decide whether to receive or to share their results.

By offering research results to participants, investigators are respecting participant needs and preferences in the research process; however, participants retain their choice about whether to receive results. As a matter of respect for participant autonomy, investigators may offer the results of their study to its participants; however, what a participant ultimately decides to receive will be contingent on his or her perspective at the time of offer, even if the participant had previously consented to receiving research results. Additionally, investigators should elicit participants’ preferences (and invite participants to designate a representative regarding decisions) for sharing their results with relatives, including health care providers, upon their deaths (Wolf et al., 2015). While surveys have shown that “a majority of participants expected to learn their own genetic research results, would feel obligated to share their results with blood relatives while alive, and would want genetic research results to be shared with relatives after their death” (Breitkopf et al., 2015, p. 10), investigators should not assume this to be the case for all studies or for all participants uniformly. Therefore, decisions to share or not should be handled on a case-by-case basis, and investigators should respect participants’ decisions.

Principle 4: When individual research results are returned, the process of communication is important to promote understanding of the meaning, potential uses, and limitations of the information.

Addressing the degree of analytic and clinical validity and being clear about uncertainty in the accuracy or significance of a research result is critical to helping the participant understand the result. Generally speaking, research results are not intended to be used in clinical decision making, although this depends on the specific result and how it was generated, so drawing clinical implications from research results should be done with great caution. Communicating results effectively will require attention to communication skills and strategies and will need to take into account the full context of the result, including the characteristics of the research, the test, the quality of the systems used in the research laboratory,

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

and the participant. Communication is always a function of the ability of the individual doing the communicating and of the resources at hand. Relevant resources can include trained health communicators working in partnership with investigators or investigators with communication aides such as health information technologies, typed descriptions, or other tools or training.

Principle 5: The value of research results to investigators, participants, and society depends on the validity and reliability of the result. High standards of laboratory quality, from the acquisition of specimens to the communication of results, enhance the validity and reliability of the results generated in research laboratories.

Participants can be misled or harmed by false or inaccurate test results which are more likely to arise when the quality of the testing is not optimal. The validity of research results depends on the quality management system used for testing in the laboratory, which includes sample collection, processing, storage, test method validation, equipment maintenance, personnel training and competency, and other quality standards or criteria that ensure the accuracy of the test result for an individual. To contribute to the generation of valid and reproducible research results, research laboratories that use human biospecimens should use appropriate quality standards, and tests should be performed under a quality management system with external verification of compliance.

Principle 6: The conduct of high-quality, generalizable, and equitable research involves the inclusion of diverse populations and requires investigators to return individual research results in a manner that accommodates the full spectrum of community needs and preferences, regardless of participant social or economic status. The potential value of results, which is best assessed with input from the participant, community, or trusted proxy, should be considered.

Research is enhanced by the broad participation of people of different backgrounds, including those who have been traditionally underserved or have limited resources. Working to recruit a diverse pool of research participants may lead to results that are more generalizable and that can engender trust within disenfranchised communities. Consistent with the principle of justice, investigators must strive for equity in participation, access to research, and value for the participant. Investigators cannot fail to include certain groups in research simply because they are perceived as more difficult to engage or because of other social characteristics, such as insurance status (relevant because many clinical research studies bill research participants or their insurers for standard-of-care services not related to the study) (OHSU, 2018).

It follows then that the return of individual results should not contribute to health disparities and inequities in health care or health research. Research

Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
×

participants should have the same access to research results regardless of their socioeconomic status or their ability to access follow-up care when results indicate medical attention may be needed. The inclusion of diverse populations will affect the manner in which the return of results is performed, and in formulating the return-of-results plans, investigators should take into consideration the full spectrum of community needs. Great care should be taken to address the preferences and needs of disenfranchised populations, including those for whom English is a second language, individuals without health insurance, racial and ethnic minorities, and those with fewer socioeconomic resources. Investigators will require community or participant input in advance of a study’s launch and during the return process in order to appropriately consider the preferences and needs of these populations.

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Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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Suggested Citation:"2 Principles for the Return of Individual Research Results: Ethical and Societal Considerations." National Academies of Sciences, Engineering, and Medicine. 2018. Returning Individual Research Results to Participants: Guidance for a New Research Paradigm. Washington, DC: The National Academies Press. doi: 10.17226/25094.
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When is it appropriate to return individual research results to participants? The immense interest in this question has been fostered by the growing movement toward greater transparency and participant engagement in the research enterprise. Yet, the risks of returning individual research results—such as results with unknown validity—and the associated burdens on the research enterprise are competing considerations.

Returning Individual Research Results to Participants reviews the current evidence on the benefits, harms, and costs of returning individual research results, while also considering the ethical, social, operational, and regulatory aspects of the practice. This report includes 12 recommendations directed to various stakeholders—investigators, sponsors, research institutions, institutional review boards (IRBs), regulators, and participants—and are designed to help (1) support decision making regarding the return of results on a study-by-study basis, (2) promote high-quality individual research results, (3) foster participant understanding of individual research results, and (4) revise and harmonize current regulations.

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