ArticleIndividualized interventions for rare genetic conditions and the research-treatment spectrum: Stakeholder perspectives
Introduction
Advances in methods to manipulate genes and gene expression are leading to the development of an array of targeted therapies for individual patients with rare genetic diseases. These “individualized interventions,” sometimes referred to as “individualized therapeutics,” closely resemble innovative clinical care in which treatment is tailored for an individual’s therapeutic benefit. This approach also resembles research in which the administration of a novel intervention is carried out systematically in the hopes of producing knowledge that can benefit a broader patient population. An example is milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient’s rare genetic variant and diagnosis of Batten disease, which was funded through crowdsourcing of $3 million by a single patient’s family.1,2 In addition to the cost of development, the expense incurred for administering the drug requires diverse financial models to make drugs such as this possible for 1 patient.3,4 Milasen is only one of several emerging individualized interventions, including atipeksen, which targets a specific ataxia telangiectasia variant, and jacifusen for a specific amyotrophic lateral sclerosis causing variant in the FUS gene.5 The lack of evidence on effectiveness and the significant cost raise questions about who should review and fund this sort of experimental approach.
Viewpoints in the literature vary and reflect little consensus over whether individualized interventions should be categorized as research or clinical care.6, 7, 8 Similar questions are raised in the literature on single patient trials, often called N-of-1 trials, which typically compare alternative treatments, involve innovation to customize care, and implement multiple interventions in hopes of finding the best therapeutic option for the single patient.4,9
Individualized therapy trials deviate from the norms for systematic investigation because they involve one or very few patients and evaluate experimental treatments that are often unapproved medical products and/or are administered outside of randomized clinical trials. Some argue that interventions can be deemed research if the intention is to create generalizable knowledge and/or if studies share attributes of traditional clinical trials such as systematic data collection or measurement of end points;7 however, they acknowledge that these practices will vary because of the unique context of these applications.10,11 Chapman12 highlights similar concerns regarding therapeutic outcomes for phase 1 trials, because the prospect of direct benefit is small and uncertain. Noting the views of “benefit enthusiasts” for whom these trials are motivated by “therapeutic intent” and scientific purpose, she raises ethical concerns about having individuals bear the brunt of risks while allowing society to gain the potential benefit derived from research knowledge. Justifications based on possible benefit for phase 1 trials identified by Chapman12 resemble those frequently offered for individualized interventions.
The significant cost of individualized interventions raises additional questions about the sources of funding and how cost should be distributed depending on the phase of administration. Furthermore, these costs of administering the intervention as well as potential unintended consequences raise the question of how payers will approach complications that arise and/or how this affects the initiation of treatment.9,13,14 There is a common understanding that commercial and governmental sponsors may be disincentivized because of the extremely small number of people who can expect to benefit from the specific intervention along with the usual financial risks of bringing a therapy or group of similar therapies to market.8 Others have proposed alternative funding models for novel interventions targeted at very small numbers of patients, including individualized genetically based therapies, which involve third parties such as government groups, manufacturers, academic groups, advocacy organizations, and/or multistakeholder partnerships.15, 16, 17, 18
As part of a larger study of ethical issues related to individualized interventions for ultrarare genetic conditions, we conducted an empirical investigation of stakeholder perspectives and considered the implications of designating these interventions as research or clinical care. To investigate these perspectives, we conducted an exploratory qualitative study with key stakeholder groups. In this article, we present a subset of those findings focused on how these stakeholders understand the relationship between research and clinical care.
Section snippets
Materials and Methods
In this exploratory, qualitative research, we took a purposive sampling approach to recruit participants.19,20 We were interested in investigating stakeholder perspectives, which did not rely only on a hypothetical case study, and specifically recruited individuals who had experience with individualized interventions. This study investigated the perspectives of 3 stakeholder groups: parents of affected children, clinical geneticists, and institutional review board (IRB) members. Individuals
Results
Our analysis showed that study participants expressed uncertainty over categorizing the interventions as research or clinical care and did not categorize individualized interventions clearly. Despite recognizing their highly experimental nature, most respondents expected generalizable knowledge to result from the development and application of each individualized intervention and held a capacious view of benefit as extending to unknown future patients. Participants also acknowledged the
Discussion
We present results of a qualitative investigation of multiple stakeholder perspectives on individualized interventions for ultrarare genetic conditions, with a focus on how they understand the research and clinical care aspects of the interventions. Supplementary material presents exemplar quotes that reflect stakeholder perspectives. Our data suggest the limitations of a binary framing of research vs clinical care to reflect and address the unique characteristics of emerging approaches to
Data Availability
Because the data are qualitative and context specific, it is not possible to completely remove all identifiers. Data are not available for public use as guided by the institutional review board. Qualitative data are available for individual researchers upon request.
Conflict of Interest
W.K.C. is on the Board of Directors of Prime Medicine. All other authors declare no conflicts of interest.
Acknowledgments
We thank the individuals in this study, who generously shared their time and insights.
Funding
This work was supported by the National Institutes of Health (3RM1HG007257-08S1).
Author Information
Conceptualization: S.S.-J.L., J.J., P.S.A.; Data Curation: S.S.-J.L., M.C., P.S.A.; Formal Analysis: S.S.-J.L., M.C., P.S.A.; Funding Acquisition: P.S.A.; Investigation: S.S.-J.L., M.C., P.S.A.; Methodology: S.S.-J.L., W.K.C., P.S.A.; Writing-original draft: S.S.-J.L., M.C.; Writing-review and editing: S.S.-J.L., M.C., W.K.C.,
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