Special issue: cell and gene causal inference in the design and analysis of gene therapy clinical trials

The introduction of gene therapies to treat and potentially cure various diseases has led to new considerations in the design, analysis and conduct of clinical trials involving these treatments. In this article, we consider the use of causal inference techniques to improve our understanding of aspects of these trials, focusing primarily on single-arm studies. While the ICH E9 R1 guidance provide a strong connection to causal inference ideas, we show how other aspects of gene therapy trials are amenable to causal thinking. We provide a review of the potential outcomes model and its assumptions. Next, we summarize the ICH E9 R1 guidelines on estimands. We then describe the implications of various aspects of causal inference for gene therapy clinical trials. Finally, we discuss how current and future clinical trials involving gene therapy in cystic fibrosis can benefit from causal inferential thinking.