Combining evidence from clinical trials in conditional or accelerated approval |
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Authors: | Manja Deforth Charlotte Micheloud Kit C Roes Leonhard Held |
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Institution: | 1. Department of Biostatistics at the Epidemiology, Biostatistics and Prevention Institute (EBPI) and Center for Reproducible Science (CRS), University of Zurich, Zurich, Switzerland;2. Department of Health Evidence, Section Biostatistics, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands |
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Abstract: | Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allows earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean -test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean -test always requires a post-market clinical trial. If the -value from the pre-market clinical trial is , a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean -test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean -test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval. |
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Keywords: | accelerated approval conditional approval harmonic mean chi-squared test interim power sample size calculation two-trials rule |
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