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Comparison of adaptive seamless Phase 2/3 designs for dose selection in clinical trials with multiple endpoints
1AbbVie Inc., North Chicago, IL, USA.
Abstract:
Adaptive seamless Phase 2/3 designs provide possible pathways to expedite drug development by combining dose selection and confirmatory evaluation on the selected dose with the control group in the same trial. Various methods have been developed to demonstrate the potential advantages compared to conventional development plan with separate Phase 2 and 3 trials. More practical and complicated situations occur when we want to achieve the goal of combining dose selection and confirmatory evaluation in clinical trials with multiple endpoints. Examples of multiple endpoints include multiple efficacy endpoints needed in the final stage for regulatory submissions. In this article, a few inferential adaptive seamless Phase 2/3 designs have been proposed which can combine dose selection and confirmatory stage in clinical trials evaluating multiple endpoints, including adaptive graph-based multiple testing procedure, adaptive seamless design with graph-based combination test, and seamless design with rank-based Dunnett-adjusted test. Simulations are conducted to confirm the control of the familywise type I error rate with an illustrated example design and assess the power. These designs can preserve the familywise type I error rate, and adaptive graph-based multiple testing procedure is more powerful than the others.
Insights
Adaptive seamless Phase 2/3 clinical trial designs expedite drug development by combining dose selection and confirmation. Novel methods, including graph-based procedures, efficiently evaluate multiple endpoints while controlling statistical error rates.
Area of Science:
- Biostatistics
- Clinical Trial Design
- Pharmaceutical Development
Background:
- Conventional drug development involves separate Phase 2 and Phase 3 trials.
- Adaptive seamless designs offer a streamlined approach by integrating dose selection and confirmatory phases.
- Evaluating multiple endpoints in seamless trials presents unique statistical challenges.
Purpose of the Study:
- To propose and evaluate inferential adaptive seamless Phase 2/3 designs for clinical trials with multiple endpoints.
- To assess the statistical performance, including Type I error control and power, of these novel designs.
- To compare the efficiency of different adaptive strategies for multi-endpoint trials.
Main Methods:
- Development of adaptive graph-based multiple testing procedures.
- Implementation of adaptive seamless designs incorporating graph-based combination tests.
- Utilizing rank-based Dunnett-adjusted tests within a seamless design framework.
- Conducting simulation studies to evaluate familywise error rate and statistical power.
Main Results:
- Proposed designs effectively preserve the familywise type I error rate.
- The adaptive graph-based multiple testing procedure demonstrated superior statistical power compared to other evaluated methods.
- Simulations confirmed the validity and performance of the illustrated example design.
Conclusions:
- Adaptive seamless Phase 2/3 designs are viable for expediting drug development with multiple endpoints.
- The adaptive graph-based multiple testing procedure offers a powerful and statistically sound approach for such trials.
- These methods provide practical solutions for complex clinical trial scenarios requiring efficient evaluation of multiple efficacy measures.
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