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Abstract:
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Adaptive seamless phase 2/3 designs have gained increasing popularity to expedite drug development by combining phase 2 dose selection stage with phase 3 confirmatory stage. In recent oncology drug development, the regulatory requirement in selecting an optimal dose for Phase 3 has moved away from Maximum Tolerated Dose to an overall evaluation of clinical efficacy, safety, and exposure-response analysis. However, at the dose selection stage, it is challenging to collect robust information on long-term clinical efficacy endpoints, which usually serve as the primary or key secondary endpoint in phase 3 trials. Thus, short-term efficacy surrogates/biomarkers may be considered along with other available data to support the dose selection. The authors propose an intermediate/composite endpoint based on the interim data, benefit-risk score, which is comprised of selected clinically meaningful interim efficacy endpoint(s) and safety endpoint(s) that are available at the end of phase 2. The dose arm resulting in the highest benefit-risk score informs the best benefit-risk profile. The performance of the proposed method will be demonstrated through simulation studies.
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