Updating the ethical guidance for gene and cell therapy research participation
Authors: Stephanie Solomon Cargill, Andrea Eidsvik, Marilyn Lamm
Journal: Molecular Therapy (2021)

Since the US Food and Drug Administration (FDA) approved the first gene therapy in 2017, five additional modalities of gene and cell therapy (GCT) have been approved1US Food and Drug Administration. Approved Cellular and Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.Google Scholar and 3,032 clinial trials worldwide employ GCT technologies targeting a broad array of diseases and conditions (https://asgct.careboxhealth.com). Many of these studies target diseases or conditions that have currently approved clinical treatments and are also being offered to patients before they have tried and failed these alternative treatment options, thus potentially conflicting with existing ethical standards. We argue here that the current trend toward enrolling patients into early-phase GCT trials as a front-line approach is not unethical, but nevertheless problematic, unless it is approached with caution and consistency. Guidance is needed to assist researchers, sponsors, and review bodies in determining whether to offer GCT trial participation as a front-line option to patients and the key information to disclose to them if or when they do. Historically, enrollment of participants in early-phase GCT trials proceeded with extreme caution.2Chapman A. Addressing the ethical challenges of first in-human trials.J. Clin. Res. Bioeth. 2011; 2: 1-8Crossref Google Scholar, 3Anderson W.F. Human gene therapy: scientific and ethical considerations.J. Med. Philos. 1985; 10: 275-291Crossref PubMed Google Scholar, 4Riva L. Petrini C. A few ethical issues in translational research for gene and cell therapy.J. Transl. Med. 2019; 17: 395Crossref PubMed Scopus (13) Google Scholar Conditions for ethical enrollment required that participants have a very serious unmet medical need and only when patients have no other options (i.e., the "only line" approach) or when patients are treatment-refractory (i.e., the "last line" approach). Moreover, it has been considered unethical to offer participation to treatment-naive patients or patients who are on other treatments but who might desire to enroll in GCT trials instead (i.e., a front-line approach). The absence of "viable and reasonable" alternatives is a part of nearly all historic and current ethical criteria for early-phase GCT clinical trial participation. While this threshold is clear for diseases with no treatment options, it becomes more complex when applied to diseases or disorders that do have clinical alternatives. In these cases, the ethical standard is frequently assumed to require attempting and failing any clinically approved treatment options available. While equating any approved standard of care with a viable and reasonable alternative is understandable both for ease of application and intuitive appeal, this equation is problematic for several reasons. First, this interpretation is not in line with existing guidance on the issue, including from the National Academies of Science,5National Academies of SciencesEngineering. Human Genome Editing: Science, Ethics, and Governance. National Academies Press, 2017Google Scholar the FDA,6US Food and Drug Administration. Accelerated Approval. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval.Google Scholar and bioethicists,7Walters L. Palmer J. The Ethics of Human Gene Therapy. Oxford University Press, New York, NY1997Google Scholar,8Kimmelman J. Stable ethics: enrolling non-treatment-refractory volunteers in novel gene transfer trials.Mol. Ther. 2007; 15: 1904-1906Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar who emphasize that the standard is meant to be based on judgments about alternatives in particular circumstances, not applied to any alternatives. While standard of care treatments are inherently more predictable than experimental ones because of a history of evidence and clinical usage, they should not thereby be assumed to be less risky or more beneficial than clinical trial alternatives. Many approved interventions, especially in the treatment of rare diseases, cancer, and chronic diseases, are suboptimal in many ways and carry with them significant risks as well as limited benefits. Patient lifestyle, stage of disease progression, and disease manifestation, as well as socioeconomic and psychological circumstances, also impact the success rate and acceptability of various existing treatments. Further, in the decades since the tragic deaths of Jesse Gelsinger and Jolee Mohr, the landscape of GCT has changed significantly. More is known about GCT and it "is increasingly becoming an important tool in the medical armamentarium for medical treatment."9Capone F. Nappi F. Galli M. Gene therapy clinical trials: Past, present, future.in: Vertes A. Dowden N. Smith D. Qureshi N. Second Generation Cell and Gene-Based Therapies. First Edition. Academic Press, Cambridge, MA2020: 285-301Crossref Google Scholar While GCT technology is still relatively new and evolving, it is a mistake to consider all GCT clinical trials as characterized by the global uncertainties of decades ago. Vector designs and packaging systems have evolved to minimize risks of insertional mutagenesis, immune responses, cytotoxicity, and recombination with wild-type viruses, leading to improved safety. This increase in knowledge provides a good reason to revisit the standard ethical approach as it undermines the assumption of global uncertainty about the risks and benefits of GCT clinical trials in comparison to existing treatments. In 1997, bioethicist Leroy Walters consequently proposed that, as the field of gene therapy matured, the requirement that there be no effective alternative therapy may need to be relaxed.7Walters L. Palmer J. The Ethics of Human Gene Therapy. Oxford University Press, New York, NY1997Google Scholar While there are good reasons to challenge the standard approach, we must be wary of abandoning it completely. If we uncritically enroll participants in novel GCT trials as a front-line approach, we risk overromanticizing the anticipated (but as yet unproven) benefits and underplaying their risks and uncertainties. Without close consideration of the available standard alternatives in each case, optimism among researchers and patients about GCT is likely to overshadow the standard care even in cases when the approved alternatives may be the more beneficial treatment options for patients. The potential and expectation for GCT has driven and pressured researchers to advance the field for new clinical treatments as quickly as possible. We agree with critics who urge that optimism should be balanced with caution.7Walters L. Palmer J. The Ethics of Human Gene Therapy. Oxford University Press, New York, NY1997Google Scholar Thus, an evaluation will need to be made that takes into consideration the specific factors of a GCT study to determine whether front-line enrollment is ethical. For this more nuanced judgement, a framework of considerations is needed to guide enrollment decisions, ensuring that the choices made are consistent and justified. We suggest four considerations that must be applied by researchers and review bodies to determine when enrollment in GCT trials can ethically be offered as a front-line approach to participants. While first-in-human phase I GCT studies that only have previous evidence of safety and efficacy from animal models should remain on the precautionary end of the spectrum, often early phase trials are assessing well-studied components with only slight modifications that classify them as experimental. While any novelty introduced into a clinical trial design has the possibility to alter its safety or efficacy profile, studies that use well-studied investigational products should require a lower threshold for comparison to existing treatments as those that involve more novel components. Further, dose escalation studies, where it is likely that participants may receive a subclinical dose, should be considered more cautiously than dose expansion trials where the range between the minimum effective dose and the maximum tolerated dose has been established and some efficacy can be expected for all participants. The safety and efficacy of existing clinical alternatives should be compared with the safety/efficacy profile produced from consideration number one. This should include considerations of the side effects, toxicities, clinical effectiveness, length of effectiveness, etc. of the standard alternatives. Comparisons with interventions approved through alternative mechanisms (such as accelerated approvals by the FDA6US Food and Drug Administration. Accelerated Approval. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval.Google Scholar) should acknowledge that the safety and efficacy thresholds required for approval may have been lower than in standard approval mechanisms. Many GCT trials have therapeutic windows for eligibility. Patients with degenerative diseases can only participate in these trials prior to a certain point of disease progression or a certain age.10Govoni A. Gagliardi D. Comi G.P. Corti S. Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy.Mol. Neurobiol. 2018; 55: 6307-6318Crossref PubMed Scopus (28) Google Scholar When there are clinical alternatives, an important consideration is whether these alternatives can be delayed, paused, or continued and with what drawbacks, in light of the potential benefits, of participating in a trial within its therapeutic window. The risk-benefit comparison between GCT trials and the clinically approved alternatives involves not only information regarding safety and efficacy, but also subjective or context-based considerations of interest to patients. Echoing Kimmelman,8Kimmelman J. Stable ethics: enrolling non-treatment-refractory volunteers in novel gene transfer trials.Mol. Ther. 2007; 15: 1904-1906Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar we suggest involving patient and disease advocacy organizations to provide input about the contextual risks and burdens of clinical alternatives.8Kimmelman J. Stable ethics: enrolling non-treatment-refractory volunteers in novel gene transfer trials.Mol. Ther. 2007; 15: 1904-1906Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar It is crucial for researchers and isponsors to be aware of these concerns and refer to them explicitly in their justification for offering front-line GCT, especially when consideration number two may indicate that standard of care is preferable. We recognize that these stakeholders may embrace the romanticization of GCT that could lead to studies that pose an unacceptable risk to participants. On the other hand, with well-supported guidance from disease groups and stakeholders, both the permission to enroll in these studies as well as strategies to explain the alternatives transparently (see below) can prove these enrollment decisions are ethically justified based on the autonomy of the participants. Ultimately the ethical balance for GCT enrollment is struck in two ways. First, the historical ethical standard of excluding front-line participants should remain only as a default, with the burden of justification placed on enrolling front-line participants. If the four considerations above demonstrate that the clinical alternatives are not clearly superior to the GCT approach under study, then early-phase GCT trials can be justified as a front-line option. Second, when GCT research is being offered as a front-line approach, the ethical onus shifts from the enrollment to the consent process. To ethically enroll patients into early GCT studies who have other clinical alternatives, these alternatives must be laid out clearly, honestly, and specifically in the consent process. This responsibility lies with both those who design and deliver the consent process, as well as those who review it. In this way, caution is preserved while acknowledging the evolving state of the field of GCT.