This editorial can be found in the August 2023 issue of the American Journal of Bioethics
In this issue, Morain and Largent raise a pressing issue arising in the context of embedded research—the nature and extent of investigator duties to patient-participants when the line between research and clinical care is blurred. They discuss examples of pragmatic trials that challenge the fundamental assumption that research and clinical care are themselves distinct activities. In directing their readers toward potential solutions, they suggest the need to consider obligations that may be grounded not in the researcher-participant dyad, but in the broader institutional structures supporting research.
We applaud this work and see great value in it—but not only in the context of pragmatic trials. To the contrary, the blurring of lines between research and clinical care is a challenge arising across a range of research contexts. Morain and Largent touch on some of these domains (e.g., learning healthcare systems, the increasing use of big data approaches), as do commentaries from Wilets et al (quality improvement) and Foss (implementation science). Here we add examples from research in rare genetic diseases.
Given the broad reaching nature of the problem Morain and Largent identify, we further argue that expanding to whom duties related to research might extend will first require a clear understanding of the ethical grounding of these duties. We suggest a starting point based in the principles underlying various conceptualizations of ancillary care and the need for a potential expanding of the principles of research ethics to adapt to the evolving landscape of clinical research.
Rare Disease Research Challenges the Distinction between Research and Clinical Care
An estimated 10,000 different rare diseases affect 25–30 million individuals in the United States alone. The majority (70–80%) of rare diseases have a known or suspected genetic etiology. With the rapidly advancing technologies and decreasing costs of genomic sequencing, our ability to identify, diagnose and, increasingly, to intervene upon these diseases with new therapeutic techniques increases daily. These advances have fueled a variety of innovative research paradigms, including studies demonstrating the ability of genomic sequencing technologies to identify new diseases in undiagnosed patients, individualized therapeutics designed, tested and implemented in a single patient-participant, and gene therapies representing an avenue toward cure for many rare diseases. Each of these efforts highlights the blurred boundaries between research and clinical care.
Genomic Diagnosis Research
Over the last decade, advances in genomic sequencing technologies have rapidly expanded our ability to diagnose rare diseases. Much of this success has resulted from large studies focused on applying advances in genomic sequencing to diagnosis of patients with suspected rare diseases, and sequencing technologies are rapidly being integrated into clinical care. However, the nature of genomic sequencing itself, and the potential benefits of reanalysis of sequencing data, creates an iterative loop inextricably linking research and clinical care. Studies suggest that reanalysis of genomic data from undiagnosed patients may result in new diagnoses for between 10 and 20% after just two years, the majority of which will result from discovery of new gene-disease associations in research. As patients receiving sequencing in the context of either research or clinical care may face barriers to re-sequencing, reanalysis may offer the only path toward ending a patient’s diagnostic odyssey. Obligations to reanalyze genomic data have been proposed in the context of both research and clinical care. However, there is currently limited infrastructure in place to facilitate meeting these obligations in a manner that is not unduly burdensome to clinicians or researchers. How do we determine requisite duties for the various parties involved in reanalysis of genomic data for undiagnosed patients in research and clinical care?
Individualized Therapeutics
The landscape of rare disease therapies includes a host of recent innovations, including antisense oligonucleotides (ASOs), a technology designed to act on a pathogenic gene mutation by disrupting or modulating the transcription process. This technology offers a particularly exciting opportunity for patients with so-called “n-of-1” genetic mutations to receive individualized therapies. Since its first use in this manner in eight-year-old Mila Makovec this technology is increasingly used to target ultra-rare disease-causing mutations unique to a single patient. However, this setting also raises substantial questions related to the place of these therapies in the boundary between research and clinical care. Typically, new therapeutics undergo a series of research-based evaluations to determine safety and efficacy prior to approval for clinical use. This process is clearly impracticable in the case of a therapy that will only ever be used by one (or possibly a small handful) of patients with an ultra-rare pathogenic variant. Indeed, the application of these bespoke therapeutics aligns much more easily with a clinical care paradigm while simultaneously being fundamentally experimental. It is unclear when a clinical versus a research paradigm applies when an “n-of-one” therapy is administered to the first—and perhaps only—patient. What ethical principles ought to guide evaluation of these therapies in order to both protect patient safety and allow scientific progress?
Curative Gene Therapies
An additional exciting and equally perplexing therapeutic opportunity in rare disease is that of curative gene therapies. Since the FDA approved the first gene therapy for a rare genetic retinopathy in 2017, four additional gene therapies for rare diseases have been approved, and an estimated 20 new approvals per year are anticipated in the near future. As these therapies target the primary cause of disease—the genetic mutation itself—they offer the exciting possibility of one-time, curative treatment. However, the actual effectiveness and durability of these therapies over the lifespan remains an open question. This uncertainty, paired with the high price tags for these therapies, has led regulators and payers to demand continued collection of real-world evidence for patients who are already receiving these approved therapies in clinical care. How do we integrate rigorous evaluation of the long-term effectiveness and durability of gene therapies administered in what is otherwise routine clinical care?
Addressing Blurred Boundaries Requires Looking Beyond Consent
Though the examples above differ from the pragmatic trials discussed by Morain and Largent in many ways, they also all would potentially benefit from Morain and Largent’s widening of the lens regarding the types of stakeholders who may incur obligations to patient participants receiving these new technologies. However, in addition to (and ideally before) determining to whom duties apply, we must first consider the fundamental ethical grounding of these efforts that are neither solely research or solely clinical care—but both.
As a first step, we suggest that scholarship examining ancillary duties in research—which already explicitly focuses on bridging gaps between research and clinical care—provides a fruitful starting point. Existing work on ancillary duties supports reconsidering the duties of all actors—researchers, institutions, and even funders—based on both clinical and research considerations. Further, this literature introduces additional guiding principles—including a focus on relationships, reciprocity, and recognition of patient-participants’ specific vulnerabilities and dependencies—as flexible tools for grounding a consideration of duties in an evolving research landscape.
In their article, Morain and Largent do consider two ancillary care theories, including Richardson and Belsky’s partial entrustment model and Miller, Mello, and Joffe’s role-based account. But, as Morain and Largent argue, these theories’ focus on consent makes them less than ideal fits for trials that involve waivers of regulatory consent, like many pragmatic clinical trials. Though Richardson’s response in this issue offers one rebuttal to this argument, we agree with Borgerson’s argument in her commentary that there is a broader need for ethical frameworks that are not specific to study design or consent protocol.
Recent work has identified several different ethically significant aspects of the researcher-participant relationship that could potentially provide guidance in this space. For instance, even when consent is (properly) waived, participants remain engaged in a joint project with researchers in which researchers may hold obligations of reciprocity due to participants’ contributions to the research enterprise. Additionally, in cases such as those Morain and Largent highlight in their article, participants remain vulnerable to and dependent on researchers for receiving information about collateral findings that may have implications for participants’ health. Vulnerability and dependence play secondary roles in the two consent-based theories; Morain and Largent’s cases show that their ethical significance remains in place even absent consent.
Reciprocity, vulnerability, and dependence also offer potentially complementary tools when a regulatory consent process is used, such as the cases of rare disease research described above. In each of these cases, patient-participants are engaged in research as a direct result of their pressing medical needs. These circumstances may render them dependent on research to address these needs and particularly vulnerable to therapeutic and/or diagnostic misconception. Given these known challenge to true informed consent, grounding obligations in principles of relationships and reciprocity may provide key tools for ensuring respect for persons beyond regulatory consent. Looking to the multiplicity of ways the researcher-participant relationship can be ethically significant, then, offers hope for navigating the blurred boundary between research and clinical care.
Better understanding the bases for researchers’ responsibilities can also help illuminate why responsibilities extend beyond the researcher-participant dyad; for instance, obligations of reciprocity need not be limited to one-to-one scenarios. Not only might duties extend to organizations, as Largent and Morain argue, but the obligations these duties confer may similarly be ascribed to patient communities more broadly. This paradigm aligns with Tumilty and Smith’s commentary emphasizing the importance of community advisory boards for anchoring ethical questions in patient and family perspectives, as well as Wilets et al’s suggestion that additional efforts toward dissemination of results of pragmatic trials are necessary to ensure respect for patients and communities.
As scholars take up Morain and Largent’s call (which we echo) to reexamine the ethical foundations of researchers’ responsibilities in the increasingly blurred boundary between research and clinical care, they do not need to start fully anew. For research ranging from large pragmatic trials to n-of-1 therapies, promising tools are already at hand.
by Meghan C. Halley and Nate W. Olson