Estimands for long-term follow-up trials in gene therapy products

Gene and genetically modified cell therapies offer incredible potential but may come with certain risks and unknowns of delayed adverse events due to unique characteristics of these products. Major regulatory agencies all require long-term follow-up (LTFU) trials, which can be as long as 15 years, to monitor potential delayed adverse events and the durability of effectiveness. Various innovative approaches have been proposed to reduce the operational burden of gene and genetically modified cell therapy LTFU trials. In this article, the authors aim to apply the ICH E9(R1) estimand framework in the context of such LTFU trials, which can be beneficial during the protocol development stage. A hypothetical LTFU study is used to illustrate the estimand considerations discussed in the current manuscript. Proper estimand specifications for a LTFU study of a gene or genetically modified cell therapy can help add clarity to the study design, data collection, and statistical analysis plan, and help ensure the study is robust, transparent, and capable of addressing the important research questions posed by these advanced therapies.