Advancing Ethical Discussions in Pediatric Gene Therapy: Takeaways From Multi-Stakeholder Panels

In late 2022, the Working Group on Pediatric Gene Therapy and Medical Ethics (PGTME), housed in the NYU Grossman School of Medicine, hosted its third annual Lunchtime Lecture Series (LLS). Over the course of five days, a diverse group of stakeholders—including regulators, industry members, clinicians, caregivers, patients, and patient advocates—gathered virtually to discuss the rapidly evolving field of gene therapy (GT). 

Children represent a significant number of clinical trial participants for GTs currently in development; three of the FDA-approved GTs are for the treatment of pediatric patients. The inclusion of pediatric populations in GT research, however, raises unique ethical concerns and complicates existing challenges to the clinical development of novel medical products. Children are unable to legally consent to trial participation; thus, their involvement relies on permission from their parents or other surrogate decision-makers.

Long-term uncertainty over the safety and efficacy of GT research merits careful and proactive ethical examination. To this end, PGTME’s 2022 LLS generated five hours of rich public discussion. Here, we briefly describe key takeaways from the five sessions––focusing on the state of the field, unrealistic expectations, GT for sickle cell disease, questions for industry members and regulators, and questions for family members of GT patients––recordings of which are freely available online.

Pediatric Gene Therapy: State of the Field and Future Directions

We kicked off the week with Pediatric Gene Therapy: State of the Field and Future Directions, which focused on recent advances in the GT space, as well as their inherent challenges. Moderated by PGTME co-chair Alison Bateman-House, panelists from industry, clinical research, and the NIH emphasized optimism following the recent wave of GT approvals. “The tide is turning,” said Dr. Louise Rodino-Klapac, head of research and development and chief scientific officer at Sarepta Therapeutics.

The excitement surrounding GT and its possibilities can be overwhelming, however, especially for parents who are new to the rare disease community. While there is a lot of hope for what GT can accomplish, there is also concern that the technology’s promise may cloud parents’ judgment and lead to unrealistic expectations––a topic discussed in greater detail on day two of the lecture series.

While day one’s panelists were optimistic about the future of the field, significant concerns over commercialization, research and development, and funding remain, especially for rare disease patients and patients with rare subtypes of common diseases, and especially diseases that are N-of-1 (or N-of-too small to be commercially viable). For many patients, the GT development pipeline still does not move fast enough. “There are many diseases that could benefit from gene therapy, but the ones that get taken into clinical trials the fastest are often the most common ones,” explained Dr. PJ Brooks of NCATS. 

Further, existing therapies often have competitive recruitment processes that may result in the unequal distribution of clinical trials. On a global scale, low- and middle-income countries (LMICs) continue to struggle to access and deliver GTs, and regional differences in AAV prevalence pose another potential barrier to treatment. 

Panelists emphasized the need for improvements in manufacturing, pricing, and access. Efforts are already underway to develop mechanisms for removing AAV antibodies and implement redosing, patient advocacy groups are helping to drive research for rare diseases, and industry leaders are focusing on making improvements in manufacturing, which should in turn alleviate access issues in LMICs.

Panelists also called for the establishment of a therapeutic platform that would speed up drug development and help lower exorbitant costs. Overall, panelists remain hopeful for the future of the field. While there is certainly more work to be done, getting patients access to GT is always worth celebrating, and there has been considerable progress in the past year.

Unrealistic Expectations and Decision-Making Support

The second panel, Unrealistic Expectations and Decision-Making Support, expanded on the lofty promises of GT. In such a rapidly developing field, it can be challenging to set appropriate expectations.

Balancing hope and uncertainty, especially for diseases with no alternative therapies, is an ongoing challenge further complicated in pediatric populations. GT necessitates long-term and often burdensome follow-up that may extend past when a child reaches the age of legal consent and becomes responsible for their own medical decisions.

Additionally, families must weigh the benefits of pursuing an available therapy now versus waiting for a potentially more effective therapy in the future. While many feel that the biggest risk to their child’s health is doing nothing, it is important that they be given all of the information and support necessary to make a truly informed decision about pursuing GT.

For those who do participate in clinical trials, building trust is critical. GT is a major commitment with implications that extend beyond the realm of medicine, including financial strain, travel costs, and taking time off work. Especially for those who have faced discrimination in the healthcare system, this is a lot to ask.

John Masembe of the Fred Hutchinson Cancer Center shared his experiences working with predominantly Black African patients with sickle cell disease (SCD), where systemic barriers and historical traumas contribute to hesitancy to participate in GT research. “It’s a huge commitment in terms of time, finances, et cetera for folks who have faced systemic discrimination in the healthcare system,” Masembe said. 

Panelists emphasized the need for cultural competency training for clinicians and better education for patients and families in order to begin breaking down these barriers. Well-designed clinical trials offer ongoing follow-up and open pathways of communication between participants, study coordinators, and clinicians. 

Mental and spiritual support are also critical, as is demonstrated by the many patients and families who find community in rare disease support groups. Loneliness is a prevalent issue in many patient populations, and undergoing a clinical trial can be further isolating. While contact with fellow trial participants can be beneficial, panelists cautioned against families sharing trial results and personal experiences with each other too quickly because it may pose a risk to research integrity.

Currently, there are no validated measures for evaluating the burden of GT on families. As we look forward, developing an objective way to measure these challenges will allow us to better address them. 

Gene Therapy for Sickle Cell Disease 

During the third panel, Gene Therapy for Sickle Cell Disease, a patient advocate, a pediatric hematologist, a psychologist, and a bone marrow transplant physician discussed the need for transparency in SCD research and treatment. The U.S. SCD patient population is predominantly Black and Latinx, and the historic and current discriminations faced by these populations in the healthcare system erodes the trust that is critical for GT, as was pointed out on day two.

Being transparent and having open conversations with patients about the systemic barriers they face are necessary parts of healing relationships and improving outcomes, emphasized Dr. Lori E. Crosby of Cincinnati Children’s Hospital Medical Center. Mistrust contributes to suspicion and the spread of misinformation, and panelists called for better education and clearer communication about treatment expectations and participation burden, in line with the points raised in the first half of the week.

GT is extremely costly and challenging to access, and financial strain continues after treatment. “Even when a gene therapy works, they don’t talk about the after,” said Sheila Citron, the mother of two SCD patients, one of whom received a GT. Although GT is controversially referred to as a “cure,” panelists pointed out that these treatments cannot reverse disease progression and their long-term efficacy remains unknown. Even if GT is successful, many patients continue to need expensive medical care.

With the price tag of most GTs in the millions, SCD patients have a lot to consider when weighing treatment options. In contrast to the overwhelming optimism expressed on day one, this session highlighted the unsustainable and inequitable nature of the current GT model and suggested big-picture, systemic areas for improvement.

Ask an Industry Member and Regulator

Day four’s event, Ask an Industry Member and Regulator, dove deeper into the GT development process. Representatives from Pfizer, Encoded, and the FDA answered questions about research areas of interest, commercialization, trial design, and regulation. When selecting therapeutic areas to pursue, industry members said they look at level of unmet need, level of scientific understanding, and commercial opportunity.

For rare and ultra-rare diseases, this often means additional incentives (such as the Orphan Drug Act) and funding sources (such as the Bespoke Gene Therapy Consortium and n-Lorem Foundation) are necessary. Patient advocacy groups play a vital role in driving rare disease innovation. In addition to providing funding and educational resources, community-led efforts to gather detailed natural history studies are critical for the development of viable trials and clinical endpoints in the rare disease space.

The better we understand a disease, the less risky drug development becomes, and patients and advocates have the power to make serious contributions to these efforts. This is especially important in pediatric populations, where trial design differs significantly from adult GT and other small molecule research. Diversity in children’s development further complicates already heterogenous rare diseases, and in the absence of validated assessments it is hard to design streamlined trials without focusing on a narrow age range.

Efforts to develop clinically relevant biomarkers often look for large treatments effects in the hopes of proving long-term benefit and, in turn, commercial viability. Patients, however, are interested in even modest results. Under the current model, balancing patient concerns and company interests remains a challenge. For this reason, panelists underscored the importance of companies and regulatory bodies soliciting feedback from and actively engaging with patients and patient advocates directly and early-on in the drug development process. 

Ask a Family Member

During the final day’s event, Ask a Family Member, we heard from siblings, parents, patients, and advocates about the multifaceted experience of participating in a GT trial. Though GT can be a life-changing treatment, the sacrifices that must be made in order to participate in a trial can rival the challenges of living with the disease itself. As pediatric palliative care social worker Danielle Jonas noted, receiving a diagnosis is difficult and deciding about pursuing a therapy can be even harder. “Resources can be a huge barrier…there is no single answer on whether or not to participate, every family is different,” she explained.

Building trust and promoting transparency about disease progression and treatment opportunities was a major theme throughout the entire lecture series. Day five was no different, and panelists emphasized the importance of extending this imperative to the entire family.  

They also shared their stories and personal experiences of the challenges to pursuing GT. Maria Jose Contreras’ family lived in a different country and didn’t speak English at the time of her sons’ diagnoses with Duchenne Muscular Dystrophy. Their financial and educational advantages allowed them to move to the US to receive treatment, but relocating was a challenge further exacerbated by the recency of their diagnoses and their unfamiliarity with the rare disease community.

Gabriel McFadyen spoke about the little things that many families with a rare disease diagnosis have to consider when relocating to receive treatment, such as what will happen to their pets or how they will overcome a language barrier.

Isaac McFadyen, a patient with MPS VI, spoke about trial enrollment and AAV antibody testing. Even after being accepted to a GT trial, young participants and their households must continue be diligent about the possibility of developing AAV antibodies. In Maria’s case, this meant splitting up their family to avoid one son passing antibodies to another. 

The coronavirus pandemic proved to be an additional barrier. In recent years, COVID-19 protocols allowed only one family member in hospital rooms at a time. Extended stays in lockdown after relocating for treatment were further isolating, and GT left patients immunocompromised during a period of high infectious disease risk.

Despite obstacles, some families–such as Matthew Vo’s–found support in those who were going through the same thing. Many families in GT trials crave these connections with other participants but are discouraged from contacting each other due to HIPPA and research integrity concerns. Being unable to communicate with other families can be isolating and emotionally taxing, and some panelists felt they had received insufficient emotional support from trial teams. Many families turn instead to patient advocacy groups such as PPMD (Parent Project Muscular Dystrophy) as a source of connection and community. 

Conclusion

This year’s Lunchtime Lecture Series focused on big-picture ethical dilemmas in the GT landscape, as well as the highly personal experiences of individuals within it. Panelists from a wide variety of stakeholder groups shared their opinions on pricing, safety, equity, and future directions of the field, in addition to their own intimate and often emotional stories about pursuing GT. 

Captioned recordings of all the sessions of the series can be found on the PGTME YouTube channel. PGTME invites you to attend our 4th annual LLS this fall for more discussions like these. Until then, we will continue our mission of advancing research, policy, and education regarding ethical issues surrounding pediatric GT trials.

To follow PGTME’s work, please contact Ayden Eilmus (ayden.eilmus@nyulangone.org), who will add you to the mailing list. We hope to see you this fall!

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

Anya Hamil is the undergraduate intern for the Working Group on Pediatric Gene Therapy and Medical Ethics. She is a junior studying Biological Science at Rutgers University-New Brunswick. 

Cara Hunt is the project manager for the Working Group on Pediatric Gene Therapy and Medical Ethics and a research associate in the Division of Medical Ethics at NYU Langone’s Department of Population Health.