Designing the Future of Pediatric Rare Disease Trials for Cell and Gene Therapy

In pediatric rare disease trials, early intervention with cell and gene therapy (CGT) has the potential to fundamentally change the course of a child’s life. These treatments offer new possibilities to address conditions that have previously had a grim prognosis with few or no options. At the same time, the urgency of early intervention, the ethical weight of pediatric-first trials and the operational complexity of these therapies require rigorous planning and precise trial design.

Why Gene Therapy?

Rather than managing symptoms over time, gene therapy aims to correct the underlying genetic defect, often with one intervention. It is particularly beneficial for monogenic conditions with a pediatric onset. With 80% of rare diseases having genetic origins and 70% starting in childhood, treatments have the potential to address a wide range of conditions.¹

Many rare genetic diseases manifest at an early age and progress rapidly.¹ Early CGT intervention has the potential to prevent damage before it occurs and improve long-term outcomes. With gene editing technologies such as CRISPR and base editing, as well as optogenetics now reaching clinical trials, researchers are expanding the reach of what these therapies can treat, from hematological and neurological conditions to inherited vision and hearing disorders.  ^2-4

Navigating Early-Stage Trials in Pediatric Populations

Pediatric rare disease trials introduce an added layer of complexity for research teams. The following elements require careful consideration.

Study Design

The Challenge

When working with ultra-rare pediatric conditions, traditional clinical trial models are often not feasible. Small patient populations, limited epidemiological and natural history data can make protocol design more difficult.⁵ In cases where a control arm is not possible or ethical, sponsors may need to consider alternatives such as historic/contemporary comparators, or even natural history studies.

Potential Solutions

Early engagement with regulators and patient advocacy groups can help shape realistic endpoints, align expectations and ensure the trial is both scientifically valid and ethically sound. These decisions should be made with flexibility in mind, as different age cohorts within the pediatric population may require distinct outcome measures.⁶ Families are also key stakeholders in the pediatric rare disease trial process, and their involvement must begin early.

Trial protocols should also be adaptable to meet the evolving needs of patients, particularly when working with small patient populations or evolving scientific insights. This is especially important in the context of patients treated with CGTs being followed from 5 to 15 years or even for the lifetime of the patient, dependent upon the modality of the CGT.

Enrollment of Vulnerable Subjects

The Challenge

Pediatric CGT trials frequently involve young participants, sometimes even neonates. These patients present unique clinical and ethical challenges. Safety and efficacy monitoring may be more difficult due to limited blood or CSF sampling volumes, and study teams must account for the technical limitations and sensitivities involved in neonatal assessments.⁷

Consent processes can also be complicated when families are in crisis and faced with high-stakes decisions in brief time frames. Additionally, not all families wishing to participate will qualify. One common disqualifying factor is the presence of neutralizing antibodies for adeno-associated viral (AAV) vectors.⁸

Potential Solutions

Easing patient and family burdens includes logistical and emotional considerations. Support strategies should not only be customized at the study level, but at the family level, and should include larger communities that often act as support systems.

Some options include:

• Leveraging hub-and-spoke site models to reduce travel for follow-up care
• Providing education in accessible, age-appropriate formats
• Offering flexible scheduling and reimbursement for out-of-pocket costs
• Supporting cross-border participation and mobile clinical services
• Offering counseling for patients and families
• Building partnerships with patient advocacy organizations to codesign materials and engagement strategies
• Providing alternative paths for patients who screened out by neutralizing antibodies, such as a natural history arm

Investigational Product Considerations

The Challenge

CGT products can involve unfamiliar modalities that require site education and coordination. Many sites have limited experience with cell and gene therapy, or lack specific knowledge around administration routes, safety monitoring or trial-specific procedures. Certain therapies require invasive administration techniques that must be performed at highly specialized centers.

Potential Solutions

Close collaboration with specialized centers and training for staff at sites handling CGT products is essential for the success of these trials. Conducting dry runs can help identify potential risk points in preparation, handling and administration. These exercises allow sponsors and sites to proactively address logistical challenges and ensure that critical steps are in place prior to patient dosing, including registration with Institutional Biosafety Committees (IBCs), development of safety protocols and chain-of-custody procedures. Early and thorough site preparation can reduce delays and support consistent, compliant trial execution across participating centers.

Market Access Strategy

The Challenge

Because many CGT treatments involve a one-time administration and long-term value, they carry high upfront costs.⁹ At the same time, the durability of therapeutic effect and long-term safety profile may not be completely understood at the time of launch.

This process is made more complicated by the fact that healthcare systems are not always set up to deliver gene therapies. For example, diagnostics such as newborn screening are necessary to effectively deliver gene therapy in time if the disease causes permanent damage at an early age. In such cases, developing the therapy itself is only the first barrier.

Potential Solutions

Sponsors should engage early with stakeholders including payors, advocacy groups and regulators to shape evidence strategies and address access challenges. Collaborating with health systems on infrastructure needs, such as newborn screening and long-term follow-up, is critical. Innovative reimbursement models, like outcomes-based agreements, may also be needed to support sustainable access.

Charting the Path Forward

The insights shared in Fortrea’s recent webinar reflect a growing understanding across the industry: Success in pediatric CGT trials depends not only on scientific innovation, but on how well we plan, collaborate and listen.

To explore these topics in more depth, including a powerful firsthand perspective from a patient and caregiver, watch the full webinar. watch the full webinar

References

1. Vaisitti T, Peritore D, Magistroni P, et al. The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy. Orphanet J Rare Dis. 2021;16(1):374. https://doi.org/10.1186/s13023-021-02013-x
2. Rieser N. A sickle cell first: base editing, a new form of gene therapy, leaves patient feeling ‘more than fine.’ Medical Xpress. December 7, 2024. Accessed March 31, 2025. https://medicalxpress.com/news/2024-12-sickle-cell-base-gene-therapy.html
3. Prime Medicine announces FDA clearance of investigational new drug (IND) application for PM359 for the treatment of chronic granulomatous disease (CGD). April 29, 2024. Accessed March 31, 2025. https://investors.primemedicine.com/news-releases/news-release-details/prime-medicine-announces-fda-clearance-investigational-new-drug
4. Sakai D, Tomita H, Maeda A. Optogenetic therapy for visual restoration. International Journal of Molecular Sciences. 2022;23(23):15041. https://doi.org/10.3390/ijms232315041
5. Pizzamiglio C, Vernon HJ, Hanna MG, Pitceathly RDS. Designing clinical trials for rare diseases: unique challenges and opportunities. Nat Rev Methods Primers. 2022;2(1):100. https://doi.org/10.1038/s43586-022-00100-2
6. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population (E11 R1). 2017:1-25. https://database.ich.org/sites/default/files/E11_R1_Addendum.pdf
7. Sivanandan S, Jain K, Plakkal N, et al. Issues, challenges, and the way forward in conducting clinical trials among neonates: investigators’ perspective. Journal of Perinatology. 2019;39:20-30. https://doi.org/10.1038/s41372-019-0469-8
8. Gardin A, Ronzitti G. Current limitations of gene therapy for rare pediatric diseases: lessons learned from clinical experience with AAV vectors. Archives de Pédiatrie. 2023;30(8):8S46-8S52. https://doi.org/10.1016/S0929-693X(23)00227-0
9. Buntz B. With prices topping $4 million, high stakes define cell and gene therapy landscape. Drug Discovery & Development. April 26, 2024. Accessed March 31, 2025. https://www.drugdiscoverytrends.com/how-price-safety-and-efficacy-shape-the-cell-and-gene-therapy-landscape/