Outcome Monitoring and Intermediate End Points for Gene Therapy

Gene therapy, a technique that seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use, has evolved significantly. The design of gene therapy clinical trials, and in particular outcome monitoring and end point design, is of paramount clinical, scientific, and regulatory relevance, with practical, ethical, and financial implications for health care systems and society at large. Gene therapies are potentially irreversible, which demands that principal effects of the drug on the disease pathophysiology as well as clinical meaningfulness of the therapy, via end point specification, is well defined and measured reliably. Considering that gene therapy trials typically target rare disease and/or are resource-intensive, the sample sizes are limited, which creates a unique set of challenges. This further demands careful selection in the choice of the appropriate and feasible end points, best determined through multidisciplinary discussions that take into consideration the most appropriate statistical approach for the data analysis. In this review, we discuss the framework necessary for rational and robust outcome monitoring for gene therapy trials, and we review the currently used end points for gene therapy trials.