Leveraging external control for accelerating development: A case study from cell gene therapy in Duchenne muscular dystrophy.

Abstract

Cell and gene therapies (CGTs) hold transformative potential for rare genetic diseases by offering durable or even curative outcomes. However, the development of CGTs for conditions such as Duchenne muscular dystrophy (DMD) is particularly challenging due to small patient populations, high treatment cost, and ethical concerns surrounding the use of placebo control. These constraints make traditional randomized clinical trials challenging to conduct, necessitating alternative strategies like external control groups to support clinical development. However, the use of external controls requires careful data and methodological considerations to ensure valid and unbiased comparisons. Key elements include rigorous data selection, precise estimand definition, and statistical adjustments to address potential confounding and selection bias. Regulatory agencies emphasize the importance of rigorous methodologies to ensure credibility of treatment effect findings derived from external controls. To illustrate these principles, we present a case study of a single-arm DMD trial incorporating an external control. By evaluating data sources, assessing exchangeability, applying statistical adjustments, and conducting sensitivity analyses, the case study illustrates the potential for using external control in studies designed to rigorously explore the benefits of CGTs in rare genetic conditions.