Pediatric Gene Therapy Group Holds Fourth Annual Lecture Series to Discuss Ethical Issues

In late 2023, the working group on Pediatric Gene Therapy and Medical Ethics (PGTME) at the Division of Medical Ethics, NYU Grossman School of Medicine, hosted its fourth annual Lunchtime Lecture Series (LLS). The event featured hour-long multistakeholder panels addressing emerging and ongoing ethical issues in the pediatric gene therapy space. As this area of research continues to grow and new genetic therapies receive regulatory authorization for pediatric use these conversations become even more vital to the safe and ethical development of interventions that aim to improve outcomes for children with serious, often rare, diseases. We hope that all stakeholders can take away something valuable from one or more of these discussions; they are archived here and are briefly summarized below. We encourage you to integrate these ideas, questions, and issues into your work, discuss them with your colleagues, and reach out to PGTME with questions or comments or if you’d like to contribute to and/or keep up with our work.

Day One: The Ethics and Science of Controls in Gene Therapy Studies

Covered in EndPoints News and Pink Sheet.

• Perspectives on risk and benefit: Risk and benefit assessment vary among regulators, patients, and sponsors. Although Code of Federal Regulations (CFR) guidelines contain language about risk, the assessment and treatment of risk differ, especially between different patient communities. Parents and families are often willing to take on more risk than others, and, for many, the risk of inaction––with its known outcomes—may outweigh the risk of trying a gene therapy (GT) with uncertain safety and efficacy. Even within a single patient community, there may be variances in risk tolerance, especially at different stages of the disease. 

• Patient-centric approaches: FDA’s Peter Marks signaled that the agency is interested in allowing more flexibility with regulatory pathways and trial designs in order to bring rare disease therapies to market faster. Panelists encouraged the use of functional endpoints in trials over invasive ones, when possible.

• Education and communication: Patient advocacy groups play a crucial role in providing accurate information. Principal Investigators (PIs) should be involved in education efforts during enrollment and consent, and sponsor representatives should attend patient advocacy group meetings.

Day Two: The Antibody Question: How Does it Impact Trial Enrollment?

• Timing: AAV antibody testing for clinical trial eligibility typically comes late in the trial enrollment process, at which point families of potential trial participants feel they have already made the decision for their child to participate. At that stage, few caregivers expect the patient to become ineligible, so the impact of an antibody test that precludes trial participation can be, emotionally, almost as devastating as the initial diagnosis.

• Setting expectations and following up: Antibody testing is not standardized across the rare disease landscape. Families should be informed that all GTs are different and that the importance of seropositivity depends on how a therapy is administered. Speakers pointed out that no one goes into trial enrollment expecting to be seropositive. How might trialists, advocates, and clinicians better prepare patients and families for this possibility? Further, how can we better support families after they learn that their child is seropositive for an antibody and thus ineligible for a given trial? Families want more information––even if complicated/nuanced––about how to move forward. Can they try a different assay? Should they look for a trial using a different vector? Etc. 

• Education and communication: Patient education is critical and requires a cadre of specialists or experienced advocates who can assist patients and families. Information about antibodies and antibody testing, including plain language summaries of scientific papers, needs to be disease-specific. To help families in their decision-making process, clinicians should be responsive, share information about seroprevalence in a timely way, be honest about the current understanding of antibodies, and be transparent about feasibility of alternative treatment options.

Day Three: Trial on Hold: Balancing Expectations and Understanding of Clinical Investigation

• Parent and caregiver experience: In the rare disease community, holds on trials can have an emotional impact akin to receiving a diagnosis all over again. Being left to manage unfavorable events such as sudden trial terminations without sufficient assistance, can erode trial participants’ (and/or their families’) trust and make them view research with less enthusiasm. Establishing and preserving confidence among target populations is critical to clinical research effectiveness. 

• Aftercare: One panelist put it best: “Building in aftercare needs to be thought about from the very beginning so that it is included, funded, and planned well.” Trialists and Data Safety Monitoring Boards (DSMBs) often assume that local clinical teams will provide ‘aftercare’ and follow-up contact, but that is not always the case. The establishment of post-trial participant aftercare plans––comprising follow-up care, touchpoints, and support services/counselors––is crucial. This is especially important in populations affected by uncommon diseases for which there is little access to continued care. 

• Data: What happens to data when a trial goes on hold? Families often feel personal ownership over their loved ones’ data, but they also hope it will benefit others in the disease community. Yet, data is also seen as valuable property by researchers, institutions, and sponsors, among others.

• Education and communication: Messaging about trial holds can be delayed because investigators need IRB approval. Thus, such sensitive information might be delivered by someone outside of a child’s care team or by other enrolled families, as many rare disease communities are in close contact. Speakers were encouraged by the idea of including patient advocates on DSMBs to help mitigate some of these concerns.

Day Four: What Are We Talking About When We Talk About Risk?

• Responsible data sharing in development: Companies developing gene therapies should embrace responsible data sharing practices, including for safety and technical data, which can benefit the entire field by expediting and enhancing the safety and accessibility of gene therapy development.

• Unique challenges of dose escalation: Dose escalation in early-phase trials presents unique challenges specific to GT. Timing becomes crucial in conditions where every moment counts, further complicating trial design and execution.

• Limited spots in rare disease trials: Rare disease trials often have a limited number of spots available, increasing the pressure on participants and their families to enroll. Because of vector immunity, single-dose GTs mean gambling on exclusion from future, potentially more effective, treatments.

• Perspectives from FDA and healthcare providers (HCPs): When dealing with serious disease, there is risk to inaction, as well as to action; thus, the risks of trial participation must be weighed against known negative outcomes of failing to participate. 

Day Five: Fetal Gene Therapy

• Case study: A case study presented at this session centered on a family who had already had a child diagnosed with a rare disease and was treated unsuccessfully postnatally with the standard of care treatment. This led the team to pursue a single-patient Investigational New Drug application rather than a formal clinical trial for a fetal administration of a standard of care treatment when the family conceived a second affected fetus. The team considered the benefits, risks, and ethical considerations in deciding whether to proceed with a formal clinical trial for other such fetuses. The team also considered the father’s input, ensuring that both parents’ autonomy and well-being were respected. Consent should be approached the way it is with other reproductive decisions, respecting the autonomy and well-being of the pregnant person.

• Key considerations: What strategies should be employed to address the ethical complexity of having two patients—the mother and the fetus—prompting the development of a protocol and application for a single patient IND from the FDA? What measures can be implemented to monitor the safety of both mother and fetus during treatment, and what protocols should be considered for continued monitoring post-delivery to address any lingering safety concerns?

• Ethical challenges: In the case study, the drug, though FDA approved, was administered in a research setting, necessitating collaboration with the pharmaceutical company along with the institution’s IRB. Additionally, the involvement of two patients, along with the safeguards outlined in 45 Code of Federal Regulations 46 subpart B for pregnant women and fetuses, must be considered. Despite historical tensions between maternal and fetal interests, it’s crucial to weigh the risks and benefits for both, taking into account the family’s past experiences and their current concerns. This prompts the question: Can having a dedicated advocate for the mother adequately address these multifaceted issues? Considering the complexities involved, it’s important to acknowledge that, in the face of unknown efficacy, families may feel that any shot at early intervention may be preferable to none.

• Dosing: The GT used in this case was approved for postnatal use, but determining the appropriate dose for pregnant carriers and non-carriers of a genetic mutation is challenging. What dose is safe for an adult who is a carrier for the disease but does not have it? How will this dose be distributed to the fetus? Monitoring posed an additional challenge in this case, as the decision was made to forgo fetal cord blood sampling due to additional risks. Rather, drug levels in the mother were checked every two weeks, and at birth samples of cord blood, amniotic fluid, and maternal blood were collected for further analysis.

Ayden Eilmus is the project associate for the Division of Medical Ethics at NYU Grossman School of Medicine.

Nevaeh Everett is the undergraduate intern for the working group on Pediatric Gene Therapy and Medical Ethics. She is a junior studying Public Health and Sociology with a Minor in Africana Studies at Muhlenberg College in Allentown, PA.

Cara Hunt is the program coordinator for the working group on Pediatric Gene Therapy and Medical Ethics, a research associate in the division of medical ethics at NYU Langone’s Department of Population Health, and an associate member of ASGCT.