Index date selection for external comparators in assessment of cancer therapies

CERSI Collaborators: Triangle CERSI: Michele Jonsson Funk, PhD, FISPE; Jennifer Lund, MSPH, PhD, FISPE; Til Stürmer, MD, MPH, PhD, FISPE; Mollie Wood, PhD, MPH; William Wood, MD, MPH; Michael Hudgens, PhD

FDA Collaborators: Pallavi Mishra-Kalyani, PhD; Gautam Mehta, MD; Arup Sinha, PhD

Project Start Date: September 23, 2024

Regulatory Science Framework:
Modernize development and evaluation of FDA-regulated products, Methods to Assess Real-World Data to serve as Real-World Evidence

Regulatory Science Challenge:
Comparator groups in clinical trials allow researchers and regulators to compare the effects of a new treatment to an available standard of care therapy, natural history, or placebo. To contextualize findings from single-arm trials where all participants receive the investigational treatment, researchers are increasingly using various data sources to construct an external control group to serve as a comparator. One important challenge with this approach is figuring out the appropriate point in time to start tracking outcomes for the group that does not receive the investigational treatment (e.g. in the standard of care or control arm). This decision is very influential because it determines who is eligible to be in the comparator group, what information we use to compare the two groups at the start, which outcomes will be measured, how long it takes for events to occur, and whether there are any time-related biases in the study. Depending on the point in time (also referred to as index date) we select, the results for the group receiving the investigational treatment might vary compared to the external group because of methods issues, regardless of the actual effect of the treatment. Using appropriate approaches to externally controlled trial design improves the interpretability and reliability of findings and can provide a basis for better understanding treatment benefits.

Project Description and Goals:
Our main goal for this project is to generate evidence that enhances the design, analysis, and understanding of single-arm trials that use external comparators, often referred to as externally controlled trials. Through assessment of different ways of selecting the starting timepoint (index date) for studies of cancer treatment drugs using an external comparator group, we can evaluate how these choices affect the results. First, we will compare these strategies across several scenarios using simulations where we control the actual treatment effect. This will help us see how different strategies for choosing the index date affect the results when there are several possible starting timepoints. Next, using clinical trial case examples, we will use real-world data and historical clinical trial data as external comparators to evaluate how different starting timepoints affect the interpretation of outcomes.

Anticipated Outcomes/Impact:
This project will provide important information on how different methods for choosing the starting timepoint (or index date) can affect the results in externally controlled trials. Results from our case examples can inform regulatory knowledge about the best methods for selecting index dates and how to test the validity of findings from these types of studies. This work is intended to: 1) enhance regulatory science understanding of externally controlled trial assessment to inform review, 2) disseminate scientific knowledge through a final report on project findings, presentations to FDA staff and at scientific meetings, and publication in peer-reviewed journals, and 3) enhance awareness through Collaborative Summits in which interested parties (scientists, advocacy groups, sponsors) share insights and challenges on the design decision of selecting appropriate index dates for externally controlled study designs.