Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
There are approximately 7,000 rare diseases which collectively impact more than 250 million people globally (US FDA, 2019)(Wakap et al., 2020). Approximately 80% of rare diseases are associated with a single gene mutation, and about half of these diseases affect children (Batshaw et al., 2014 ). Many of these rare diseases are life-threatening, and most have no approved disease-modifying therapies, representing substantial unmet medical need among pediatric patient populations. Recognizing this gap, researchers and manufacturers are making strides in the development of new therapies. In particular, there is great opportunity in advancing individualized therapies to treat or provide functional cures for pediatric patients. Given the complexity of these diseases and therapies, collaboration amongst academia, regulatory agencies, and industry is critical to ensure diversity of perspective and innovative approaches to evidence generation, including the use of real-world data (RWD). As planning for the 2025 ISPE Annual meeting begins, we highlight here a recent example of collaboration between ISPE Special Interest Groups (SIGs) that reinforces the importance of sharing perspectives and expertise to inform our panel sessions and discussions, but also therapeutic development and evidence generation more broadly.
At the 2024 ISPE Annual meeting, the Pediatric (Endorser) and Rare Disease SIGs collaborated on a symposium titled “Novel Individualized Therapeutics: Challenges and Opportunities for the Use of Real-World Evidence (RWE) RWE in Rare Disease.” Individualized therapeutics are becoming more prevalent, with the first to use CRISPR approved in 2023. Children account for an outsized number of potential recipients of these therapies, and there are unique regulatory and methodological considerations to using RWE to evaluate these novel medications in rare diseases. As such, the objectives of this symposium were to (1) provide an overview of development of novel individualized therapies, (2) review the regulatory considerations for these products, and (3) identify unique features, opportunities and challenges in studying the safety and effectiveness of these medicines in pediatric populations using real-world data (RWD), in pre- and post- approval phases. With speakers from the regulatory agency, pharmaceutical companies, contract research organizations (CROs), and academia, this session underscored the value of knowledge sharing and collaboration across SIGs. In particular, combining diverse perspectives and experiences from different SIGs can provide insights on effectively harnessing diverse or heterogenous data sources, harmonizing definitions, advancing study methods (e.g., handling missingness), navigating the challenges of small patient populations and scattered geography of where patients are.
In particular, the session emphasized the challenges specific to studying individualized and personalized therapies in RWD. Genetic therapies in humans act to silence, augment, or edit a faulty genomic mutation or introduce a functional or corrected gene through in-vivo or ex-vivo mechanisms. Innovations in next generation genomic sequencing have enabled the development of individualized therapies to address significant unmet medical needs. Whether developed for a single patient or suitable to treat a population of patients, therapies are typically delivered to the patient through inert viral vectors (e.g., adeno-associated virus) or genome editing tools ex-vivo. In studying these novel therapies in the pre-approval setting, the lack of therapeutic alternatives makes randomized controlled trials (RCTs) challenging and necessitate the consideration of other study designs, such as single-arm trials with external control arms. The lack of precedent may also make selection of clinically meaningful endpoints challenging, as outcome measures and biomarkers are often lacking. In the post-approval setting, it may be difficult to track pediatric patients from childhood to adulthood, particularly as they move across/within health care systems. There may also be long gaps in which a patient does not interact with the health care system which creates further hurdles in long-term follow-up (15 years or longer for cell and gene therapies) and assessment of survival. As more individualized cell/gene therapies come to market, there will be new challenges for researchers to navigate, such as selecting appropriate comparator populations, definition of and regulatory justification for unmet need, and potential for selection bias. Finding solutions to these challenges will no doubt require cross-functional and collaborating problem solving.
In studying individualized therapeutics for rare pediatric diseases, digital and decentralized approaches to post-marketing studies may be considered to reduce burden on the patient, caregiver, and site, wherever applicable. There is more interest than ever in bridging the gap between clinical trials and RWE through point-of-care trials in which outcomes may be collected using RWD sources, such as electronic health records (EHRs). The latest guidance from FDA, “Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice Guidance for Industry”, provides considerations and recommendations to support the conduct of RCTs with streamlined protocols and procedures that focus on essential data collection, allowing integration of research into routine clinical practice (US FDA, 2024). The draft guidance is an indicator and an example of the need for innovative evidence generation approaches throughout the drug-product life cycle. However, the applicability and feasibility of these point-of-care trials for individualized therapeutics is often not well characterized, particularly in the global setting. In general, point-of-care trials may have utility in therapeutic areas where large enough numbers of adequately characterized patients could be engaged to determine treatment effects with sufficient statistical power (Duke Margolis Center for Health Policy, 2022).
There is overlap in rare diseases and diseases that effect pediatric patients, but researchers who specialize in rare disease may not necessarily have expertise in navigating the operational and methodological challenges that occur when studying pediatric populations (and vice versa). Sharing challenges and solutions across silos can facilitate innovation and enrich the conversation. Potential topics that could benefit from a collaborative discussion across SIGs and across functional areas of drug development include approaches to evaluating and ensuring data quality, assessing combinability across RWD sources, and development of novel clinical outcome assessments (COAs) and data collection from vulnerable, special, and small populations. Looking forward to 2025, we encourage continued cross-SIG collaboration at the ISPE Annual Meeting, on scientific manuscripts, and through other thought-leadership activities.
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