Escandon is the founder and principal of DGBI Clinical Research and Ethics Consulting, a consultancy for the biotechnology industry. Caplan is Mitty professor of medical ethics at the NYU Grossman School of Medicine. They are both members of the Pediatric Gene Therapy & Medical Ethics Working Group in the department of medical ethics at the NYU Grossman School of Medicine.
On Nov. 18, a female pediatric patient participating in a clinical trial suffered a systemic hyperinflammatory syndrome and died about two weeks after receiving a gene therapy. Her death comes as both a setback for GT and a warning about managing future research. It is time to put the sharing of information among research teams ahead of the current prioritization of secrecy for commercial purposes.
The young girl's death came barely two years after a comparable syndrome resulted in the death of a 27-year-old man with Duchenne muscular dystrophy. He had received a similar viral vector via a different route of administration, carrying a different genetic cargo. Two other deaths due to acute reactions and organ toxicity in early commercial use of the same viral vector occurred in 2022. In 2020 and 2021, a clinical trial of a GT using yet a different viral vector and carrying a different genetic cargo resulted in the deaths of four boys soon after administration.
These tragic deaths highlight something important: The industry needs to examine whether safety and prevention of catastrophic adverse events in early-stage and early commercial experience with GTs can be done better -- and, if so, how. But that will be virtually impossible without major changes.
Currently, safety monitoring in early trials includes sponsors, investigators, regulators, ethics committees, and data safety monitoring committees. All are tasked with ensuring that emerging serious adverse events are identified and quickly reported in each individual trial. This arrangement is generally adequate to ensure that such events are identified and reported reasonably quickly within a particular trial. However, if a safety event occurs in a specific trial, the sponsor's report, and the regulator's evaluation of it, determines whether it meets the threshold of requiring action by many or all GT stakeholders.
Unfortunately, companies rarely if ever willingly share emerging safety data with others developing similar GTs. Secrecy and intellectual property protections established in the competitive pharmaceutical space prohibit the FDA and other regulators from disclosing details of relevant adverse events and any identifiable predisposing characteristics among those in the GT space unless they meet a very high bar. The insistence on secrecy leaves only the regulator in the position to execute meaningful analyses conducted across many companies' trials. These secrecy requirements put an untenable burden on the FDA and other regulators, as a search of clinicaltrials.gov identifies approximately 1,400 currently active early GT trials.
If companies were more willing and regulators better able to share information, some of the false assurances that GT sponsors currently draw from use of different vector serotypes, transgenes, doses, routes of administration, immunosuppression methods, pre-existing antibody titers, and the like would be reduced. A mechanism for sponsors, investigators, institutional review boards (IRBs), and data safety monitoring committee (DSMC) members to know better how the precautions in their protocols stacked up against those of other GT programs would also likely lower the risk of catastrophic events. Further, if informed more completely and rapidly of serious events, this may inspire more frequent within-trial analyses, resulting in voluntary actions that provide greater protections. If gene therapies are to flourish, the industry must embrace and give regulators permission for rapid and wide sharing of more complete information about emerging adverse events.
Currently, regulators' only available action is placing a clinical hold on all similar trials. Clinical holds most often come with incomplete context and out of an abundance of caution. While that caution is laudable, the months (even years) it can take to be released from overly broad holds are not themselves harmless -- particularly for patients with rapidly progressive, irreversible conditions with narrow time windows for interventions to be administered. If GT sponsors and regulators could openly cooperate, regulators and companies could likely take necessary risk-reducing actions more rapidly.
Sponsors, investigators, and regulators all want participants to benefit and experience as little harm as possible. Therefore, a logical first step might be a standardized reporting mechanism or framework from regulators that notifies all relevant stakeholders urgently when an event meeting a certain threshold of interest occurs.
Such a notification would be more information than is available now. It would also reduce guesswork and allow each company to forward such information to their DSMCs to review and voluntarily consider whether a pause to dosing in their trial is warranted.
Of course, doing this while protecting commercial interests is not simple and requires debate. The FDA is required to protect each company's secrecy, and investors are entitled to know material information about their investments in companies developing GTs. Unfortunately, all sponsors are not equal in their capacity to weather and address significant safety concerns should they emerge. Furthermore, companies fear how Wall Street will interpret any safety data that seems even remotely negative. While a company with a diverse portfolio is better suited to survive a catastrophic trial event, a single GT-product company is not, and for rare genetic diseases, single-product companies are over-represented.
Given this segmentation, we believe one solution is for sponsors to voluntarily allow the FDA to more openly disclose to key stakeholders' relevant details of safety events that are currently behind hundreds of individual curtains of secrecy. Doing so trades a portion of individual secrecy for the opportunity to engage the large collection of excellent scientific minds currently contributing but siloed within their respective companies or agencies. This level of transparency would allow companies, IRBs, and DSMCs to reduce current guesswork, limiting false senses of security often based on assumptions. A greater collective knowledge stands a better chance to advance GTs as a therapeutic modality than the data segmentation that we see today.
Properly explaining adverse events across the GT development landscape in understandable, nontechnical terms for lay audiences is a must. That means appropriately emphasizing the knowns -- current experience, relevance of comorbidities, and prior adverse signals in animals -- as well as the unknowns. Regulators, sponsors, clinicians, investors, the media, and participants all need to know how to interpret various adverse events -- and none can do so or have full context without greater transparency and voluntary cooperation from all parties.
Any such improvements in information sharing and transparency move GT development in the direction of establishing the highest level of protection for all the courageous and altruistic participants willing to be involved in early GT clinical trials.