Researchers have ethical duties to research participants that derive from several primary sources. Federal regulations governing human subjects research (both the Common Rule used by a large number of federal agencies49
and variants at other agencies such as the FDA50
) set substantive requirements for ethical research and a procedural system for applying them through local IRBs. However, a large literature on research ethics interprets those rules and bases further researcher obligations on additional statements of research ethics (e.g
., by professional societies and international bodies)51
as well as analysis of the research participant’s vulnerability and the researcher’s special obligations toward participants.52
Our analysis of key ethics sources concludes that researchers have an obligation to address the possibility of discovering IFs not only in their protocol and communications with the IRB, but also in their consent forms and communications with those being recruited to the study and research participants. Researchers have a further obligation to establish a pathway for handling suspected IFs and to communicate that to the IRB and research participants. In many, but not all circumstances, researchers have an obligation to offer to report IFs to research participants. In the case of minor or incompetent participants, this duty obligates the researcher to offer IFs to the participant’s guardian or representative. In research on archived data not fully anonymized, IFs of high importance should prompt researchers to consider an effort to contact research participants; that effort may best be undertaken by the original researcher who had contact with the research participant rather than the secondary researcher who had none. We elaborate below.
It is important to recognize at the outset of our analysis that IFs raise the question of when the researchers
should initiate evaluation and disclosure of information uncovered in research. There is a distinct debate on returning research information at the request of research participants
. Federal privacy rules under HIPAA are relevant to the latter question,53
as is NIH and NHGRI policy.54
However, the rules on participant-initiated disclosure do not resolve the question of how researchers should define, evaluate, and handle IFs.
While federal regulations on human subjects research do not address IFs explicitly, a number of provisions apply. With studies increasingly documenting the prevalence of IFs, IFs are both a predictable risk and benefit of research. This dual character makes a number of protections germane.
First, federal regulations require that consent forms and the consent process address both risks and benefits of the research. Consent forms must describe “any reasonably foreseeable risks” and “any benefits.”55
For a research participant recruited as a normal control, discovery of an IF suggesting pathology may trigger anxiety, burdens, and the costs of further evaluation to verify or rule out a clinical problem. Even research participants with known pathology risk discovery of an unrelated IF, triggering the same. These risks are present whether or not discovery of the IF leads to a clinically useful diagnosis.
If an IF is identified and thought to merit a clinical evaluation, it may turn out to be a false-positive, once the suspected pathology is ruled out, or it may yield ambiguous results at work-up, with pathology neither verified nor ruled out. In both of these cases, identification of the IF yields burden with no clear benefit. Identification of such IFs is a predictable risk of research. However, some IFs will lead to diagnoses of clinical importance. Identifying an operable brain tumor in a college student serving as a normal control in an fMRI study of cognition, for example, may prove life-saving. For such a research participant, taking part in the study imposes both the risk of discovering an IF and potential benefit of discovering serious pathology in time to intervene.
These risks and potential benefits are intrinsic to research modalities that have the potential to yield information beyond the variables directly under study. Imaging research is a classic example, with fMRI neuroimaging research visualizing cranial anatomy and CT colonography research imaging extracolonic anatomy throughout the torso. But genetic family research similarly reveals genetic relatedness or nonrelatedness, even when that is not the object of the study and is unacknowledged within the family. Both genetic and genomic research may also reveal genetic or chromosomal variants of concern beyond the specific genes, chromosomes, or genomic relationships under study.
The risks and benefits of discovering IFs in research require explicit discussion in the consent process.56
Without that, research participants may not appreciate the risk of discovering an IF, being offered information they did not expect, and triggering an evaluation. They may also have unrealistic expectations on the benefit side. Here, two errors are likely. Participants may underestimate benefit by failing to appreciate that the burden of discovering an IF will in some cases be offset by ultimate clinical benefit. But more likely (given relative inattention to research IFs until recently) is that participants may overestimate benefit by expecting that any anatomy imaged or genetics/genomics being studied is thereby being screened for clinical problems. This is a new form of the well-documented therapeutic misconception, research participants’ mistaken assumption that research interventions will benefit them clinically.57
In the IFs context, the misconception is not that the research intervention (e.g
., a drug under study) will yield clinical benefit, but that the research process itself (e.g
., the imaging or genetic analysis) will yield such benefit. Research participants may assume that researchers will identify and report any clinical problems in anatomy imaged or genetic regions analyzed; researchers’ silence on the topic of clinical problems may be misinterpreted by research participants as a clean bill of health. Research participants may not appreciate that the MRI sequences and scans used to image their brain in a study were not optimized for clinical diagnosis, because the purpose was research. Participants in a genetic or genomic study similarly may not understand what genetic or chromosomal domains were not analyzed as part of the research and that the analytic tests used were not validated for clinical use.
Thus, it is essential to address the risks and benefits associated with IFs in the consent process. This is reinforced by regulatory provisions that IRBs may require consent forms to include a “statement that significant new findings developed during the course of research which may relate to the subject’s willingness to continue participation will be provided to the subject.”58
An IF suggesting a brain tumor or an aneurysm requiring immediate work-up may well affect a participant’s willingness to continue in neuroimaging research. In genetic or genomic research, discovery of an IF suggesting a serious genetic problem not under study may derail a participant’s willingness to continue in the research. In genetic family research, an IF revealing undisclosed adoption or other nonrelatedness may affect the participant’s willingness to continue in the study; indeed, that individual’s genetic makeup may no longer be relevant to the research.
So far, we have simply suggested that researchers should address with participants the risks and benefits associated with IFs. However, researchers need to do more, to address both with participants and with the IRB how IFs will be handled as part of the research protocol. Indeed, the pathway established for handling IFs will determine the character and magnitude of the risks and benefits involved. For example, a non-M.D. neuroimaging research team with no process for consulting a radiologist or neuroradiologist may both miss IFs of concern and misconstrue normal images as suggesting an IF. Further, with no process set up for fast consultation, they may not be able to provide the benefit of timely identification of an IF meriting immediate work-up.
Researchers have an obligation to set up a process for recognizing IFs, verifying whether there is indeed a suspicious finding of concern, and offering the finding to the research participant (or the guardian or representative of a minor or incompetent participant) for clinical evaluation and follow-up. The regulations require not only that risks to participants be communicated as part of the consent process, but that risks be minimized.59
This suggests that researchers should minimize several risks relating to IFs: the risk of failing to recognize an IF that may require clinical follow-up, the risk of identifying an IF but ignoring it or failing to offer information to the research participant, and the risk of communicating an IF to a participant causing anxiety and follow-up when more careful scrutiny shows no IF or the finding turns out to be benign. All of this suggests an obligation to set up a process for identifying, assessing, and communicating IFs.
That obligation is further supported by the regulatory requirement that risks be “reasonable in relation to anticipated benefits, if any, to subjects.”60
The risk of IFs is intrinsic to research generating any information beyond the variables directly under study. That risk must be offset by the benefits that can flow from timely identification, assessment, and communication of IFs, allowing clinical evaluation and intervention. We recommend below specific steps for managing IFs.
Recognizing researcher obligations to offer participants information on IFs of likely health or reproductive importance is consistent with an emerging view that researchers bear some clinical obligations toward research participants. Research ethics has traditionally drawn a sharp distinction between the responsibilities of health professionals rendering clinical care and the responsibilities of researchers. Clinicians’ duty of care has not been imposed on researchers. However, Richardson and Belsky have challenged this paradigm, arguing that research participants’ vulnerability and researchers’ discretion mean that researchers might owe participants a limited duty to provide ”ancillary care,” including evaluating research brain scans and then following up appropriately on life-threatening findings.61
They argue that researchers are neither personal physicians with a full-blown duty of care, nor “mere scientists” with no obligation of care, but instead occupy an intermediate category. Research participants entrust aspects of their welfare to researchers, and within that scope of entrustment, may be entitled to identification, evaluation, and communication of clinically important IFs.62
Note that this view would impose full duties of care on a personal physician acting as researcher toward the patient/participant, and lesser duties of care on the researcher who is not personal physician. Even the non-M.D. researcher would have duties by virtue
We strike a middle ground. We show respect for research participants’ objective welfare as well as their subjective interests by including IFs of likely health or reproductive importance to the participant. At the same time, we focus on participants’ health and reproductive interests, not all conceivable interests.
of the research participant’s trust, vulnerability, and dependency. The Ph.D. researcher performing fMRI research may alone have information suggesting that the participant’s brain may harbor a life-threatening aneurysm in need of work-up. Thus, that researcher may have a duty to share the scan with a neuroradiologist who can verify the presence of a suspicious finding of likely health importance, and then a duty to offer this information to the research participant for follow-up.
This view that researchers have some duties toward research participants including identifying, verifying, and communicating IFs of health or reproductive significance can be based on researcher duties to respect the autonomy and interests of research participants.63
Shalowitz and Miller, discussing research participants’ interest in being told individual research results of clinical importance, state that participants have a “presumptive entitlement to information about themselves.”64
In addition to respect for persons, Illes et al. cite reciprocity as a principle supporting an obligation to disclose IFs of potential health importance to research participants.65
Beauchamp and Childress discuss “a reciprocity-based justification for obligations of beneficence.”66
In the research context, reciprocity captures the notion that research participants are contributing to the research enterprise and are entitled to receive in return information about IFs of likely health or reproductive significance.
Recognizing a researcher duty to handle IFs responsibly and disclose them to research participants is also consistent with recent trends in the law. The Grimes
case in Maryland held that researchers in that state had special obligations to research participants, citing international codes such as the Nuremberg Code and Helsinki Declaration as well as legal cases.67
Though the case has been controversial, the court concluded that a “special relationship” grows out of researchers’ knowledge of the risks that participants face and research participants’ vulnerability68
— this relationship grounds researchers’ duties toward research participants. In addition, researchers’ promises to participants in research consent forms can ground researcher duties toward participants.69
Research participants have brought a number of other lawsuits against researchers and their institutions claiming that a duty owed by the researcher was breached.70
The Office for Human Research Protections (OHRP) and other federal regulators and funders have long recognized that researchers have duties toward subjects; violation of those duties can provoke federal investigation and sanctions.71
The ethical and legal trend toward recognizing researchers’ duties toward participants is apparent.
Including among researcher duties an obligation to offer to disclose to participants IFs that have likely health or reproductive importance is consistent not only with legal recognition of researchers’ special obligations toward participants, but also with legal doctrine imposing a duty to warn of foreseeable harm.72
This doctrine is more familiar in the context of patient care, not research. However, it is based on recognizing that the physician may have unique access to information of health importance, the physician has obligations to prevent harm, and the patient is dependent upon the physician. All three of these propositions apply to researchers in their relationship to research participants (laying to one side, for now, the complex case of secondary researchers using archived data that their team did not collect). Certainly the researcher will have access to less information than the physician providing patient care, a more limited set of obligations that are grounded in averting harm in the research process, and usually a participant less dependent than is a patient relying on a physician for health care. This suggests that researcher obligations will be more limited, but that researchers do shoulder obligations that include the proper handling of unexpected information of potential health or reproductive importance, including disclosure to participants when potential harm may be averted.
Specifying how researchers should handle IFs to meet these obligations is challenging. It is instructive to compare the literature on offering individual research results to participants (as opposed to offering aggregate research results to a study population, as in a newsletter73
). The literature on returning research results has evolved over time.74
(See .) In 1999, NBAC argued that disclosure of individual research results should be the exception, not the rule.75
Disclosure should occur only when findings are valid and confirmed, have significant health implications, and the health problem can be treated. In 2001 a CDC-sponsored group focusing on population-based genetic research echoed NBAC recommendations: “When the risks identified in the study are both valid and associated with a proven intervention for risk reduction, disclosure may be appropriate.”76
In 2004 an NHLBI Working Group considering return of genetic research results conditioned return on a significant risk of disease (specific relative risk >2.0), the disease having important health implications (fatal or substantial morbidity or significant reproductive implications), and the availability of therapeutic or preventive interventions.77
Debate continues on these issues. (As noted above, there is separate policy addressing research participants’ requests for research data — policy from DHHS under HIPAA78
and from NIH and NHGRI.79
Comparison of Recommendations on Returning Individual Research Results
While it is tempting to see IFs as merely a species of research results, there are key differences. As noted above, research results are on variables under study, the research aims to understand these data, and thus the researcher is likely to have whatever expertise exists to interpret those data. In contrast, because IFs are not on variables under study and may be beyond the researcher’s interpretive expertise, interpreting them may well require clinical experts beyond the research team. Second, the literature on whether to return individual research results commonly discourages returning results that lack clinical validity and clinical utility80
; much of the debate focuses on results whose uncertain meaning and importance is the reason for the research. However, because IFs are not on variables under study, the key question will more often be whether the suspected anomaly (e.g
., an unexpected tumor) is really there; if so, its health importance may be clear.
That said, aspects of the debate over offering research results are relevant. First, insistence on checking analytic validity and trying to establish clinical validity before offering research results suggests the importance of taking several steps when the research team identifies an IF of potential importance: (1) recheck the scan or data to confirm analytic validity (Is it this participant’s scan or analysis? Was the scan or analysis run properly? Should we run another sample?), (2) collaborate with an expert consultant (if the research team does not have adequate expertise) to confirm that there indeed is a suspicious finding and one of likely health or reproductive importance (analytic and clinical validity), and collaboratively determine whether the IF should be disclosed based on factors including its seriousness and likely importance to the research participant. (See Tables and .) For example, a Ph.D. principal investigator on an fMRI study may well want a neuroradiologist to review the research scan and confirm the presence of a suspicious finding of likely health importance before the researchers offers this information to the research participant, triggering anxiety and follow-up. In the case of a genetic IF, step 2 may involve sending the sample to a CLIA-approved lab. Note, however, that for some conditions, testing in a CLIA-approved lab will not be available. This raises a problem: the NHLBI Working Group suggested that an IF could still be disclosed as long as it was labeled a research finding rather than a clinical finding and this was explained, but there is concern that this may not comport with CLIA’s restrictions.81
More work may need to be done to resolve this problem. As in the case of research results, a third step should involve evaluating the seriousness and likely utility of the IF to determine whether the IF should be disclosed, though we define “utility” to include informational importance to the research participant even if no treatment is available.82
We elaborate below.
Recommended Pathway for Handling IFs in Research
Recommended Classification of Incidental Findings
Second, the literature on returning research results cautions that such results should be offered to research participants, not foisted upon them.83
This is consistent with the literature on genetic testing in particular, which recognizes a right not to know results. This caution is probably appropriate for IFs as well, though researchers may understandably be hesitant to accept a research participant’s waiver of information about an IF likely to be life-threatening or grave and ameliorable, unless the participant appreciates that the information being waived may be of high health importance.
Third, the literature on offering research results states that results should have important implications for health in order to justify causing anxiety and follow-up in research participants and burdening researchers with the duty to offer these results. NHLBI’s Working Group urged that health importance includes significant reproductive implications; genetic or genomic data may lead participants to take steps to avoid serious as well as fatal genetic conditions for offspring.84
The requirement of health importance, including reproductive importance, would apply to IFs. However, determining what kind of findings would have such importance is not easy.85
Stanford’s Working Group on Reporting Results of Genetic Research distinguishes 3 categories of findings. Category I findings have “analytic validity, high clinical validity and utility and...a high probability and magnitude of harm resulting from not offering the information (i.e., life threatening, serious consequences...), and...effective preventive measures exist, or it is easy to avoid exacerbating risk factors.”86
Category II findings “do not rise to the level of Category I and do not fall into Category III.” Category III findings fail to “meet baseline analytic...or clinical validity standards.” The Working Group argues that Category I findings should be offered to participants, Category II findings may be offered, and Category III findings should not be provided even if requested by the participant. Other authors have similarly focused on analytic and clinical validity plus clinical utility or value to distinguish the kind of results that should be offered to research participants,87
though some commentators have argued for greater information sharing.88
This category framework cannot be imported wholesale to IFs. It was developed focusing on research results in genetic and genomic studies. There, the primary concern is giving research participants the results of genetic or genomic tests before the tests are validated and the phenotypic implications are understood, when most genetic and genomic results will not have immediate health implications. However, some IFs (especially from imaging studies) will indeed have immediate health implications. They will require clinical work-up and verification, at which point clinicians will often be able to use established clinical tests of clear validity. Unlike research results, whose ambiguity may be the very reason they are under study, a number of IFs may be entirely susceptible to clinical validation and management. The IF issues focus more on what duties researchers have to identify, evaluate, and communicate these findings of potential clinical importance.
Nonetheless, researchers properly note an IF of potential health or reproductive importance and then kick off the evaluation process (leading to decisions about the likely importance of the IF) when the suspected finding may affect the research participant’s health in the foreseeable future or affect the participant’s reproductive decisions. Emphasizing “health” importance means that we are addressing findings that a research participant would be likely to find important for their health care or health planning, not all findings that may change diet, lifestyle, or individual behavior. We are not suggesting that researchers become clinicians, but rather that when research unexpectedly yields information of likely importance to the participant’s health or reproductive decision-making, the researcher may have an obligation or discretionary option to communicate that information, depending on the seriousness of the finding.
In so defining those IFs that researchers may have a duty or option to disclose to research participants, we reject two extremes. At one extreme, researchers would disclose only IFs of established analytic and clinical validity, clear clinical utility, and grave health importance. This would anchor the category on what a clinician would deem highly significant to avert harm, ignoring the broader category of what a research participant might find important health or reproductive information. At the other extreme, researchers would have a duty to disclose any IF of analytic validity, so that the research participant could decide if the information was useful and important.89
This would anchor the category on what a research participant might find important for any reason. Under this definition, researchers would have a very broad duty to communicate findings, so broad that it would become difficult to distinguish some forms of research from therapeutic intervention.90
We strike a middle ground. We show respect for research participants’ objective welfare as well as their subjective interests by including IFs of likely health or reproductive importance to the participant. At the same time, we focus on participants’ health and reproductive interests, not all conceivable interests. Further, we envision that the researcher and expert consultant (e.g.
, a neuroradiologist reviewing a brain scan for a suspected IF) will make a determination of what a reasonable research participant would likely find relevant to their health or reproductive decisions. This determination can be individuated and guided by asking the research participant at the time of consent to participate in the research what categories of information they would like to receive.91
We thus recognize what Richardson and Belsky call researchers’ “ancillary-care responsibilities” (discussed more below), without turning researchers into clinicians.92
We also try to identify a reasonable and practical limit to researchers’ duties to identify, evaluate, and disclose IFs.
This approach is consistent with recommendations on offering research findings that recognize the importance of a finding’s validity and health or reproductive utility, but we define “utility” to include information that a research participant is likely to find important, even if clinicians cannot use that information to alter the participant’s clinical course. We thus recognize a spectrum of utility to the participant, ranging from life-saving to ameliorative to useful in heightening surveil-lance to useful in thinking and planning about health. This rejects an approach to utility grounded solely in what a clinician would find useful. We broaden “utility” to ask also what a research participant would find useful, recognizing not only treatment utility but also health or reproductive information utility. Working to harmonize recommendations of research findings and IFs is important because in some research contexts, such as discovery research using genomic microarrays, the line between research findings and IFs will be hard to discern. Our approach advances thinking in both realms by reconceiving what is properly meant by “utility,” recognizing that researchers may need to collaborate with expert colleagues to evaluate the validity and broad utility of research or incidental findings, and by recognizing some key differences between research findings and IFs, particularly the clear need to plan for prompt evaluation of IFs, possible disclosure to research participants, and clinical referral. We consider below how this chain of events should best occur to properly handle IFs, what duties devolve on researchers, and what actions are permissible even if not required.