Supporting undiagnosed participants when clinical genomics studies end

Strapline:

Many large research initiatives have cumulatively enrolled thousands of patients with a range of complex medical issues but no clear genetic etiology. However, it is unclear how researchers, institutions, and funders should manage the data and relationships with those participants who remain undiagnosed when these studies end. In this comment, we outline the current literature relevant to post-study obligations in clinical genomics research and discuss the application of current guidelines to research with undiagnosed participants.

The last 15 years have witnessed the rapid expansion of clinical genomics research focused on applying advances in genomic sequencing to the diagnosis of patients afflicted by rare genetic diseases. These “genomic diagnosis” studies include many large research efforts, such as the Centers for Mendelian Genomics, the Undiagnosed Diseases Network, and multiple sites of the Clinical Sequencing Evidence-Generating Research consortium in the United States.^1–3 International efforts include components of Solve-RD in the European Union, the 100,000 Genomes Pilot on Rare-Disease Diagnosis in the United Kingdom, and sites affiliated with the Undiagnosed Diseases Network International, among others worldwide.^4–6 These studies exist at the boundary between research and clinical care, pursuing the scientific aim of understanding the contribution of genetics to human disease through providing genomic diagnoses for patients.

Measured against the twin goals of advancing research and providing individual diagnoses, these studies have been very successful, identifying diagnoses for approximately 30 percent of enrolled participants and culminating in the publication of hundreds of papers advancing our understanding of the genomic underpinnings of rare diseases.^{e.g., 5,7} However, as a number of these studies near their end, many questions remain unanswered regarding how researchers, institutions, and funders should manage the data and relationships with the thousands of participants who remain undiagnosed. For example, if a variant of unknown significance is recognized as pathogenic next year or five years from now — will participants or their families be notified? If new initiatives are launched (e.g., the GREGoR Consortium, https://gregorconsortium.org/) to evaluate new diagnostic technologies, will participants from other genomic diagnosis studies be eligible to enroll? Will prior participation in genomic diagnosis research limit access to subsequent diagnostic evaluation in the clinical setting, either due to lack of payer coverage or a provider’s perception that their patient’s diagnostic needs had been met through research? Without answers to these and other questions, participants enrolled in genomic diagnosis research are at risk of being marooned by the biomedical research establishment when these studies end, left without a diagnosis and, potentially, with no way to pursue one.

Why Would Post-Study Obligations Apply in Genomic Diagnosis Research?

The ethical guidelines for research in the United States are based in the core principles laid out in The Belmont Report, including respect for persons, beneficence, and justice.⁸ Though the Belmont Report does not explicitly address the question of post-study obligations, its broad principles remain relevant. For example, in adhering to the principle of respect for persons, researchers have the obligation to treat their research participants as whole persons, not simply as a means for achieving research gains. As such, if researchers are working with participants with unmet or ongoing medical needs – and particularly needs that fall within the scope of the original study – the researchers, their institutions and funders together have an obligation to facilitate a pathway to address these needs even when studies end.⁹ Researchers also are obligated to maximize benefits and minimize harms to participants, including ensuring that participation in research — or the ending of participation in this research — does not inadvertently harm participants in the post-study period.¹⁰ Further, the principle of justice asserts that the benefits and burdens of research must be equitably distributed. As such, post-study obligations are particularly critical to protecting those participants who already face challenges to healthcare access, as they may be additionally dependent on research as a source of healthcare, and additionally vulnerable to harms due to study closure.¹¹

The Declaration of Helsinki, which provides the most widely-accepted guidance on ethical research internationally, directly addresses the question of post-study obligations, stating that, “sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial.”¹² Though concern for post-study obligations originally emerged in the context of therapeutic clinical trials, these obligations are now recognized as extending beyond post-trial access to experimental treatments.¹⁰ However, the Declaration of Helsinki provides only this limited directive, and more detailed guidance developed by groups such as the Multi-Regional Clinical Trials Center (https://mrctcenter.org/) remain firmly anchored in the language of therapeutic clinical trials, thus requiring adaptation to the context of genomic diagnosis research. For example, in genomic diagnosis research the “intervention” typically includes a range of advanced testing that is tailored to individual participants’ diagnostic needs, as opposed to standardized treatment protocols. Further, the “benefits” of a diagnosis are likely to vary widely and unpredictably depending on individual participant characteristics, including a range of personal benefits to both the participant and his or her family (e.g., through reproductive decision-making) and may accrue many years down the road.¹³ The question of heterogeneity of potential benefits of diagnosis within the undiagnosed community is one that deserves further examination and is beyond the scope of this commentary. However, given that at least one of the explicit goals of these types of studies is to “help individual patients and families,” (https://undiagnosed.hms.harvard.edu/about-us/) any claim that benefits were never actually possible seems counterintuitive at best, and suggestive of a type of therapeutic misconception at worst.¹⁴

Though not explicitly framed in the language of post-study obligations, the existing ethics and policy literature does provide some relevant guidance, including on obligations for returning genomic sequencing results to research participants and for reanalysis and recontact of patients when the interpretation of an individual’s genome changes.^15–17 However, the literature on return of results has tended to focus on return of incidental or secondary findings for study participants (many of whom are otherwise healthy) and typically does not address the post-study period.^{e.g., 18–21} An important and relevant exception is Richardson and Cho’s (2012) examination of the duties of secondary researchers (i.e., those who were not involved in initial participant recruitment or data collection) to return individual research results to participants.²² Using a “partial entrustment” approach – which considers the parameters under which researchers’ obligations to participants might extend beyond the study protocol – they argue that secondary researchers do retain obligations to return results to participants, with a stronger obligation for return of results that relate to serious health conditions and those more likely to impact medical management.²² This perspective suggests that obligations to research participants do not necessarily end with the completion of a single study.

Recent guidelines from the American Society for Human Genetics on reanalysis and recontact of participants in clinical genomics research (as opposed to clinical care)¹⁷ provide some guidance relevant to post-study obligations. The authors state that, “researchers have no responsibility to hunt through or scan genetic and genomic data or literature for changes in variant interpretation or to identify new genetic causes of disease, if such was not part of the original study,” [emphasis added].^17(p585) However, the authors provide no guidance about what to do when “hunting” is indeed central to the design and purpose of the research, as in genomic diagnosis studies. Further, although the authors state that, “any responsibility to recontact research participants is limited to the duration of research funding,” they also suggest that researchers developing new studies, “should plan to complete any recontact for interpretations of variants related to the phenotype under study” without clearly limiting this to the study term.^17(p585) Though these guidelines are related, they do not directly address the broader question of ethical obligations to undiagnosed research participants in the post-study period, or how these obligations might be addressed.

How Might Post-Study Obligations in Genomic Diagnosis Research be Addressed and by Whom?

The rapidly evolving nature of our knowledge of genomics and associated technologies raises unique considerations for post-study obligations in genomic diagnosis research. Studies suggest that reanalysis of genomic data from individuals whose sequencing did not initially lead to a diagnosis may result in new diagnoses for between 10 and 20 percent of these participants after just two years (depending on the participants’ prior diagnostic workup).²³ Further, new diagnostic techniques are frequently emerging that may provide answers to previously unsolved cases.²⁴ Ensuring that participants do not face barriers to future diagnosis will therefore likely include considering available pathways for reanalysis or access to new diagnostic tools and approaches as they become available in the post-study period. Further, as the data collected in the original studies will likely be used by primary and secondary researchers to test these new tools, post-study planning also should include clear mechanisms for communication with patients and families should a diagnosis be identified by a secondary study.

All stakeholders will need to play a role in ensuring that post-study obligations are sufficiently addressed. Researchers may have the most direct relationship with participants and will likely play a key role in communicating post-study options with patients and families. However, obligations do not rest on them alone. Funders will need to play a leading role in requiring, planning for, and financially supporting post-study obligations. Institutions will be essential for providing infrastructure and continuity over time, as has been suggested in pragmatic clinical research more broadly.²⁵ In addition, funders should require investigators to develop a plan for addressing post-study obligations before new genomic diagnosis studies begin, and perhaps even as part of the funding application process.

There are a variety of ways in which post-study obligations could be addressed, though the specific approaches may vary by study, or even by an individual participant’s characteristics or preferences. As noted above, there is wide heterogeneity in the undiagnosed community in terms of the severity and urgency of their medical issues, their socioeconomic vulnerability and current access to care, and their values and priorities in terms of managing their health.¹³ All of these may have ethical implications when determining approaches to post-study management. Further, different approaches to post-study obligations have important tradeoffs in terms of the resources required, the researchers’ intellectual stake in the study, and the need for cross-stakeholder collaboration. Planning for post-study obligations also must be balanced against considerations of costs, including the extent to which meeting these obligations may hinder current or future research. However, ethical obligations do not disappear simply because meeting such obligations is difficult. Addressing post-study obligations in this population will therefore require consideration of multiple different approaches.

One option for addressing post-study obligations could involve explicitly transitioning oversight of ongoing diagnostic evaluation to a clinical setting. This option may require fewer research resources in the post-study period and may even be preferred by participants who elect to prioritize symptom management over efforts toward genomic diagnosis. However, this approach may not serve the needs of many participants, including those whose complex cases are unlikely to be solved by clinically available testing, those whose lack of a genomic diagnosis is perceived as complicating treatment decision-making, and those who face socioeconomic barriers to accessing clinical care. Indeed, the emphasis on recruitment of historically underserved individuals into clinical genomics research in recent years has resulted in large numbers of research participants who enroll in research specifically because they face insurance or financial barriers to genetic and genomic testing that is already clinically available.^2,26 Strategies for addressing post-study obligations for these participants will likely need to look different than for those whose insurance or socioeconomic status provides them with resources for navigating both clinical care and research.

A second option for addressing post-study obligations could involve transitioning undiagnosed patients to other new or ongoing studies. Indeed, this type of an approach can be seen in collaborative research efforts in Canada (http://care4rare.ca/). However, this option hinges on the availability of such studies, their accessibility to patients and families, and coordination across institutions and funders. Further, it may be viewed as less preferable by researchers who have invested in the original data collection and participant evaluation and are expected to produce the scientific products of these investments by their funders and institutions.

Given these varying tradeoffs, funders may wish to support the development of systematic, long-term strategies for addressing post-study obligations. For example, the International Rare Diseases Research Consortium has proposed the development of an “unsolved rare disease cohort” consisting of patients who remain unsolved after clinical exome sequencing.²⁷ Development of such a cohort could streamline post-trial efforts across studies. In addition to providing participants with continued access to further diagnostic testing, such a cohort could offer a powerful tool for evaluation of emerging diagnostic technologies, providing a mechanism for aligning ethical obligations to patients with opportunities for scientific advancement. Until a long-term solution is in place, however, there is an urgent need to develop plans for addressing post-study obligations to participants currently enrolled in genomic diagnosis studies nearing their sunset.

Close engagement with current research participants and their families will also be essential to addressing key questions related to consent, privacy and data sharing in the post-study period.²⁸ Some current participants may not wish to be part of ongoing genomic diagnosis research. New approaches, such as “dynamic consent,” could provide a valuable tool for addressing such issues by allowing participants to opt-in or out of various post-study opportunities.²⁹ Approaches involving data sharing will require patient and family engagement in order to strike the right balance between protecting privacy and maximizing the potential for diagnosis. Resources such as My46, a web-based tool for participants to dynamically set and modify their preferences for participation, could help to facilitate greater transparency and control for research participants.³⁰ This engagement needs to begin immediately, as it is arguably already long overdue.

In summary, the current approach to genomic diagnosis research risks creating a revolving door of undiagnosed research participants who enter seeking a diagnosis, only to come out disoriented, without a clear path forward in the post-study period. Failure to address post-study obligations for this rapidly growing group risks harm to individuals as well as decreased trust in scientific research long term. Collaboration between funders, institutions and researchers will be crucial to fulfilling ethical obligations to these patients and families, whose research participation has made so many advances in the science of genomics possible.