Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review

This is the authors' abstract. We don't add key points for this paper.

Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016–2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases. Patients with rare genetic diseases most often do not have treatment options, and available options often do not address the root cause of the disease. Gene therapy is the use of genetic material to treat or prevent disease and represents a promising strategy for treating rare genetic diseases. This narrative review explores 12 gene therapies products (approved between 2016 and 2023) to outline key challenges and considerations for programs developing gene therapies. To test treatments, gene therapy programs should carefully select outcomes that are meaningful to patients. They should also use the most appropriate patient groups when first testing their treatments in humans. When planning clinical trials, efforts should be made to identify patients at early disease stages, keep patients in trials, lower the burden of taking part in trials, and explore options to assess patients remotely instead of in clinics. Early discussions with regulatory agencies and patient communities can make it more likely that a gene therapy will be successful. Sometimes it is not feasible to compare a treated group with a placebo group. Treated patients may be compared with similar patients outside the study. It is essential that for any gene therapy on the market, there is reasonable certainty that the treatment will be efficacious before treatment is given because once given, the therapy cannot be taken away and currently removes the possibility of the patient being treated with another gene therapy or getting into other clinical trials.