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A randomized group sequential enrichment design for immunotherapy and targeted therapy
1Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, United States of America.
Abstract:
In targeted therapy or immunotherapy, it is common that only a subpopulation of patients are sensitive to and thus may benefit from the therapy. In practice, based on pre-clinical data, it is often assumed that the sensitive subpopulation is known. Subsequent clinical trial data, however, often show that this assumptions is false. We propose a randomized, group sequential enrichment (GSE) design to evaluate an experimental treatment against a control. The GSE design starts by enrolling patients under broad eligibility criteria and then alters the entry criteria to restrict enrollment to treatment-sensitive patients based on accumulating data of short-term and long-term survival endpoints. The short-term endpoint is used to facilitate enrichment when a limited number of survival events are observed, while the final determination of treatment efficacy and sensitive subpopulation is based on the survival. The group sequential approach is adopted to implement the adaptive enrichment strategy. The proposed design simultaneously achieves two primary goals of precision medicine: to determine whether the experimental drug is superior to the control and to identify the target population that is sensitive to the treatment. A simulation study shows that the proposed design well controls the type I error rate and yields substantially higher power than the conventional group sequential design and existing two-stage enrichment design.
Insights
This study introduces a group sequential enrichment (GSE) design for clinical trials to identify patient subpopulations sensitive to targeted therapies. The GSE design enhances precision medicine by confirming treatment efficacy and pinpointing the responsive patient group.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Pharmacology
Background:
- Many patients benefit from targeted therapy or immunotherapy, but only a specific subpopulation is sensitive.
- Pre-clinical data often incorrectly identifies the sensitive subpopulation, leading to challenges in clinical trials.
- Existing methods struggle to accurately identify responsive patient groups in real-time during trials.
Purpose of the Study:
- To propose a novel randomized, group sequential enrichment (GSE) design for clinical trials.
- To simultaneously determine experimental treatment efficacy and identify the sensitive patient subpopulation.
- To improve upon conventional and existing two-stage enrichment designs.
Main Methods:
- The GSE design enrolls patients broadly initially, then adapts eligibility criteria using short-term and long-term survival endpoints.
- It employs a group sequential approach for adaptive enrichment based on accumulating trial data.
- Short-term endpoints facilitate enrichment with limited survival events, while survival data confirms efficacy.
Main Results:
- Simulation studies demonstrate that the GSE design effectively controls the type I error rate.
- The proposed design shows substantially higher statistical power compared to conventional group sequential designs.
- It outperforms existing two-stage enrichment designs in identifying sensitive subpopulations.
Conclusions:
- The GSE design is a robust adaptive strategy for precision medicine in clinical trials.
- It successfully balances the goals of confirming treatment efficacy and identifying the target patient population.
- This approach offers a more powerful and accurate method for evaluating experimental treatments in sensitive subpopulations.
