Ethical Issues in Pediatric Gene Therapy: Multistakeholder Approaches

The Working Group on Pediatric Gene Therapy and Medical Ethics (PGTME) hosted its fifth annual Lunchtime Lecture Series (LLS) in December of 2024. As the number of approved gene therapy products increases, so too do questions about their long-term safety, durability, and accessibility. Open dialogue among stakeholder groups is thus vital to the ethical development and use of these interventions in children, both in clinical trials and in the clinic. To this end, PGTME convened diverse groups of gene therapy stakeholders—including patients and advocates, regulators, industry members, clinicians, and ethicists—for six hours of public discussion about emerging and ongoing ethical issues in the pediatric gene therapy space. All five days of the LLS are archived here and briefly summarized below. 

PGTME is a non-profit, academic group with the mission of advancing research, policy, and education regarding ethical issues in the development and use of pediatric genetic interventions. It is housed in the Division of Medical Ethics at the NYY Grossman School of Medicine, and it receives funding from Parent Project Muscular Dystrophy (PPMD). You can learn more about PGTME here. 

Day One — The ABCs of Genetic Medicine: What’s an AAV Anyway?

The week began with a presentation targeted to a beginner audience that explained basic concepts and terminology from the gene therapy field. LLS registrants voted on topics selected for this session, which included viral vectors, delivery routes, dosage, genome editing, exon skipping, ASOs, and more. This presentation and Q&A set the stage for the rest of the week’s more advanced discussions of ethical issues in pediatric gene therapy. 

Day Two — Balancing Risks and Benefits: Gene Therapy Across Diverse Diseases

• Hope and Hype: Families of patients need hope, particularly in the setting of dire chronic and/or progressive conditions. At the same time, physicians must be aware of uncertainties about new therapies and avoid hype. The gene therapy field is still young, and many questions surround it, especially about a candidate or approved therapy’s potentially waning benefit and the need for redosing. For early-onset conditions with severe mutations, for example, early treatment is critical for arresting the progression of the disease, but that may in turn raise concerns about the long-term durability of a novel therapy. In addition to addressing these challenges scientifically, effective and timely sponsor communication is key. Improving transparency while protecting patient privacy also remains a concern in the rare disease space. Sharing information about successes and shortcomings, either too quickly or too slowly, can both be harmful to patient families. 

• Risk Tolerance: Disease severity and the availability of other treatment options affect risk tolerance. Even if there are other therapeutic options to use as a “lifeboat” until a better drug is developed for a condition, the decision whether to try a gene therapy is still difficult. Until the problem of immunogenicity is overcome, patients may not yet want to risk receiving a one-time gene therapy at a dose with unknown long-term durability. Similarly, when other treatments exist, such as for sickle cell disease or hemophilia, the intensity of gene therapy may make it a less appealing option. In the case of pediatric patients, parents may be especially hesitant to make choices for their children that will impact their future autonomy (for example, affecting their range of future treatment options, affecting the child’s fertility, etc.) For those with no alternative treatments, however, the high risks and burdens (including cost, travel, missed work, time away from family, etc.) associated with an effective gene therapy may be worth it. Serious adverse events, including fatalities, are devastating to the entire field and rare disease community. Risk acceptability should be considered from the perspective of the entire care team, including both parents and clinicians.

• Uptake: Patients who feel they currently have a high quality of life may not be interested in undergoing a treatment pathway as demanding as gene therapy. If disease progression and severity worsen, however, they may change their minds. Even for those who want gene therapy, the cost of treatment and of associated hospitalizations, time limits on prior authorizations, family obligations, and financial burdens all impact uptake of approved products. Many patients report being unprepared for these realities of treatment even after being informed about the risks. In the clinic, innovative approaches to informed consent are needed. Funders have a responsibility to recognize and address these barriers, but equity remains a major barrier to uptake throughout the field. 

Day Three — Ethical Questions in Genetic Screening and Testing 

• Policy Barriers: Technological advancement in newborn screening and genetic testing is the first step to alleviating the burden imposed by delayed diagnosis, but policy decisions—at both federal and state levels—often dictate patient access. Though the federal government creates recommendations about which conditions should be included in newborn screening programs, the speed at which states adopt these recommendations, if they adopt them at all, is dependent on state budgets. In the case of diagnostic testing, implementation cannot be realized without effective coverage and reimbursement policies. When policies create barriers to progress, patient advocacy groups and sometimes members of industry play an essential role in sparking change. 

• Emotional Impact: When determining which conditions to include in newborn screening programs, policymakers consider whether a disease can be accurately detected in the general population and if there are existing treatments or care standards. Establishing a precedent for testability may not always be practical, however, as it is difficult to collect data about rare diseases due to small population pools. For example, even though the FDA granted approval for an MPS2 treatment in 2006, it took over fifteen more years for the disease to be added to the federal Recommended Uniform Screening Panel (RUSP) because of insufficient data. These periods of stalemate take a heavy toll on vulnerable families, who may miss out on an early diagnosis and, in turn, early intervention with an approved treatment. Diseases with no available treatments raise further ethical questions, especially whether it is beneficial to mandate screening for unactionable conditions. Opt-in programs for diseases that do not currently have scientifically substantiated standards of care are one potential solution. 

• Clinical Questions in Care & Accessibility: Novel technology like newborn genomic sequencing can alleviate the diagnostic odyssey, but varying availability and inequitable access threaten its potential therapeutic benefit. In areas of the country without access to academic medical centers, genetic diseases may go undetected for years. Even in areas that have sufficient resources for making genetic diagnoses, many general physicians, though skilled in other facets of medicine, are unable to translate genomic findings into precision care. To revitalize and maintain trust within the healthcare system, policies must be enacted to both improve availability and standardize access to diagnostic testing and translate test results into personalized care.  

• Financial Burden & Relief: Local access to newborn screening and diagnostic testing reduces the need for out-of-state visits and other burdensome tests to receive a diagnosis, which can alleviate financial strain on families. In addition to benefiting patients, such screening also saves the healthcare system a significant amount of money. Unfortunately, implementation nonetheless remains a struggle. Most states’ Medicaid programs must be nearly cost neutral in a single-year period, but the cost savings associated with newborn screening programs can only be demonstrated over the course of longer time periods.  

Day Four — What’s Up with Long-Term Follow-Up? Ethical, Regulatory, and Operational Challenges

(co-sponsored by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard)

• Decision-Making: When developing novel gene therapies with uncertain safety profiles, delayed and/or rare adverse events may not be detected in initial clinical trials due to small sample sizes and short follow-up periods. Conducting longer-term studies, known as long-term follow-up studies, helps companies and regulators identify late-onset adverse events such as immune reactions, insertion mutagenesis, and even cancer, to better assess the benefit and risk profile of a gene therapy products. Data collected in long-term follow-up studies is valuable for patients, caregivers, clinicians, regulators, companies and payers. Most importantly, it can inform future clinical decision-making. 

• Patient-Centric Approaches: While data from long-term follow-up studies is valuable, researchers must listen to patients and their families to ensure that five-, ten-, or fifteen-year studies do not inflict undue burdens such as travel costs, work absences, and childcare expenses. Many patients are willing to take on the strain of gene therapy trial participation when studies are investigational. However, after treatment with an investigational or approved gene therapy, patients may wish to visit the doctor less frequently and focus on living their lives. For this reason, when designing follow-up studies, sponsors, sites, and patients must be willing to compromise on frequency of appointments, consider the possibility of telehealth visits or decentralized testing, and eliminate invasive procedures whenever possible.  

• Types of Data & Data Entry: To further minimize the strain of long-term follow-up, observational studies, questionnaires, and check-ups should be consolidated. Otherwise, the study begins to resemble a fifteen-year clinical trial with extensive monitoring. Standardization in long-term follow-up protocols may promote the sustainability of a study, while also allowing for comparison across products. Data sharing through collaborative databases and patient registries are important innovative approaches to long-term follow up. However, these databases and registries are expensive and labor intensive, especially for small, disease-centered non-profit organizations. More support and infrastructure are needed. 

Day Five — Data Sharing in the Gene Therapy Space

• Success in Synergy: Limited patient populations and fragmented research efforts necessitate collaboration across various rare diseases, which often have similar symptoms, mechanisms, and progressions. Data sharing supports the design of predictive models, natural history studies, and clinical trial endpoints, especially when potential therapeutics share similar pharmacological properties such as stability and biodistribution. Throughout this session, panelists exchanged several data sharing success stories: a gene therapy for Duchenne muscular dystrophy developed from Becker muscular dystrophy patient data, twenty-seven gene therapies developed from the N-of-1 initiative for individualized care in ultra-rare diseases, and multiple gene therapies manufactured using data from terminated Pfizer trials.  

• Intellectual Property Considerations: Taking a different approach to intellectual property (IP) is the key to unlocking growth in the data sharing space. For diseases with large populations, traditional competition allows for more safe and effective therapies to be developed. However, in the currently underserved rare disease space, a more open model is required. In this setting, collaboration allows scientists and pharmaceutical companies to learn from a variety of rare diseases with similar characteristics, as opposed to being limited by a single indication.  

• Ethical Data Collection: Though privacy concerns may be a potential obstacle to data sharing, patients with rare diseases are often willing to share their data with scientists who wish to advance research. In the rare disease context, unique clinical experiences are valuable when consolidated and more powerful than imperfect animal models, which can lead scientists astray and ultimately restrict access and increase costs. When harnessing clinical data, however, scientists must not take advantage of small patient populations for profit. Many pharmaceutical companies envision manufacturing a “million-dollar molecule” that could place themselves on the map and revolutionize their commercial futures. However, in the case rare diseases, this attitude threatens the future of data sharing, as it makes companies more likely to silo potentially life-saving treatment options. 

Samantha Rose is a student volunteer for the Working Group on Pediatric Gene Therapy & Medical Ethics. She is a senior in high school and will be attending Duke University in the fall on a pre-medicine track.

Ayden Eilmus is the Program Coordinator of the Working Group on Pediatric Gene Therapy & Medical Ethics at NYU Grossman School of Medicine.