Navigating Immortal Time Bias: Impacts of Index Date Selection and Analytic Techniques in Rigorous

CERSI Collaborators: Chen Hu, PhD, Mei-Cheng Wang, PhD
FDA Collaborators: Arup Sinha, PhD, Gautam Mehta, MD, Fang Tian, PhD Catherine Lerro, PhD, Shu Wang, PhD, Donna Rivera, PharmD, Kira Leishear, PhD, Pallavi Mishra-Kalyani, PhD 
Project Start Date: 09/20/2024 
Project End Date:

Regulatory Science Challenge:

Randomized clinical trials are the gold standard for evaluating a medical product; however, such designs are not always feasible in oncology and rare diseases. In these rare instances, investigators may consider comparing patients receiving an investigational treatment on a single-arm clinical trial to data from available sources such as electronic health records or prior trials. This can provide additional context for the single-arm trial results. However, choosing the right starting point, or index date, for the study to conduct a comparison is crucial, especially in disease settings with no standard treatment. An incorrect choice can lead to misleading or false results due to bias, affecting the reliability of the findings.

Project Description and Aims/Goals:

The goal of this project is to improve starting point, or index date selection for comparing treatments in externally controlled trials that rely on external data as the control arm instead of a traditional internal control arm in a randomized clinical trial. Through analyzing data from completed phase III trials, and creating simulated patient groups with varying start dates, investigators can evaluate how the choice affects study results. By comparing different methods, investigators aim to discover the most reliable approaches to enhance the reliability of cancer research and inform regulatory science in the evaluation of novel designs for new treatments.

Anticipated Outcomes/Impact:

This work will support the FDA by providing methodological examples that increase understanding of externally controlled trial designs that may potentially inform approaches to regulatory review.  We plan to disseminate scientific knowledge to both FDA and the broader scientific community, through presentation of relevant methodological findings at scientific conferences and publication in peer-reviewed journals.