Cell and gene therapies (CGTs) are revolutionizing treatment for patients, particularly for those with rare and life-threatening diseases. Yet, the path from development to approval is challenging because rare disease clinical trials often involve very small patient populations and pose unique logistical challenges. This week, two FDA guidance documents outline how available innovative trial designs can be employed in the pre-approval phase, followed by robust real-world evidence collection post-approval, to ensure reliability of these treatments.
Traditional randomized controlled trials are often impractical when patient numbers are limited, so the first FDA guidance document highlights alternative clinical trial designs such as single-arm studies, where patients serve as their own controls; externally controlled studies, where the patients in the study are compared to patients in a real-world setting outside the trial; and adaptive and Bayesian trial designs. The guidance also highlights the potential use of natural history protocols to better characterize rare diseases based on historical data and master protocols to evaluate multiple therapies or conditions under one framework.
All these trial designs have been used extensively over the last two decades, so there is significant know-how available in the industry for adequate implementation. These innovative clinical trial designs allow developers to maximize every data point while maintaining rigorous standards of evidence. The guidance also emphasizes broad participant selection to ensure study populations represent the diversity of the rare disease community, including pediatric patients.
The second guidance stresses that approval is not the end of evidence generation for two reasons. First, rare disease products are approved based on limited pre-approval clinical trial data, which need post-market confirmation. Second, because CGTs may have long-lasting or delayed effects, ongoing safety and efficacy monitoring is critical. The FDA recommends several well-established approaches for post-market clinical data collection. Real-world evidence (RWE) using registries, electronic health records, and claims data to monitor outcomes is the most important source of confirming data. Previous Guidance Documents describe the FDA’s expectations for RWE. Collecting standardized, longitudinal data on safety, treatment durability, and patient-reported outcomes for patient registries and coordinated registry networks could provide additional supportive data to the RWE. Long-term follow-up data assessing the durability of the clinical effect closes the loop on the data collected for RWE and registries. The FDA strongly recommends decentralized data collection, leveraging telemedicine, local healthcare providers, and digital health tools to increase participation and retention.
By combining real-world data sources with decentralized collection models, sponsors can build a more complete picture of therapy performance beyond controlled trials. This approach strengthens patient safety and supports regulatory confidence in long-term CGT outcomes.
Taken together, these two FDA guidance documents establish a lifecycle model for cell and gene therapy development. Pre-approval innovative trial designs help overcome the barriers of rare disease clinical trials. Post-approval, real-world evidence collection and long-term monitoring confirm that therapies remain safe, effective, and durable over time. This continuity reflects the FDA’s recognition that CGT development cannot rely on traditional one-time models. For patients with rare diseases, this framework accelerates access to innovative therapies while maintaining accountability across the entire treatment lifecycle.
Cell and gene therapies can potentially transform rare disease treatment, but their development requires both innovation and vigilance. By encouraging adaptive trial designs before approval and real-world monitoring after approval, the FDA recommends a pathway that is flexible yet scientifically rigorous. For sponsors and patients alike, this lifecycle approach ensures that CGTs deliver lasting impact across every stage of their journey.
