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Optimal designs for phase II/III drug development programs including methods for discounting of phase II results

  • Erdmann, Stella1
  • Kirchner, Marietta1
  • Götte, Heiko2
  • Kieser, Meinhard1
  • 1 University of Heidelberg, Im Neuenheimer Feld 130.3, Heidelberg, D-69120, Germany , Heidelberg (Germany)
  • 2 Merck Healthcare KGaA, Frankfurter Str. 250, Darmstadt, D-64293, Germany , Darmstadt (Germany)
Published Article
BMC Medical Research Methodology
Springer (Biomed Central Ltd.)
Publication Date
Oct 09, 2020
DOI: 10.1186/s12874-020-01093-w
Springer Nature


BackgroundGo/no-go decisions after phase II and sample size chosen for phase III are usually based on phase II results (e.g., the treatment effect estimate of phase II). Due to the decision rule (only promising phase II results lead to phase III), treatment effect estimates from phase II that initiate a phase III trial commonly overestimate the true treatment effect. Underpowered phase III trials are the consequence. Optimistic findings may then not be reproduced, leading to the failure of potentially expensive drug development programs. For some disease areas these failure rates are described to be quite high: 62.5%.MethodsWe integrate the ideas of multiplicative and additive adjustment of treatment effect estimates after go decisions in a utility-based framework for optimizing drug development programs. The design of a phase II/III program, i.e., the “right amount of adjustment”, the allocation of the resources to phase II and III in terms of sample size, and the rule applied to decide whether to stop or to proceed with phase III influences its success considerably. Given specific drug development program characteristics (e.g., fixed and variable per patient costs for phase II and III, probable gain in case of market launch), optimal designs with respect to the maximal expected utility can be identified by the proposed Bayesian-frequentist approach. The method will be illustrated by application to practical examples characteristic for oncological studies.ResultsIn general, our results show that the program set-ups with adjusted treatment effect estimate used for phase III planning are superior to the “naïve” program set-ups with respect to the maximal expected utility. Therefore, we recommend considering an adjusted phase II treatment effect estimate for the phase III sample size calculation. However, there is no one-fits-all design.ConclusionIndividual drug development planning for a specific program is necessary to find the optimal design. The optimal choice of the design parameters for a specific drug development program at hand can be found by our user friendly R Shiny application and package (both assessable open-source via [1]).

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