title: Sample size planning for phase II trials based on success probabilities for phase III.
abstract: In recent years, high failure rates in phase III trials were observed. One of the main reasons is overoptimistic assumptions for the planning of phase III resulting from limited phase II information and/or unawareness of realistic success probabilities. We present an approach for planning a phase II trial in a time-to-event setting that considers the whole phase II/III clinical development programme. We derive stopping boundaries after phase II that minimise the number of events under side conditions for the conditional probabilities of correct go/no-go decision after phase II as well as the conditional success probabilities for phase III. In addition, we give general recommendations for the choice of phase II sample size. Our simulations show that unconditional probabilities of go/no-go decision as well as the unconditional success probabilities for phase III are influenced by the number of events observed in phase II. However, choosing more than 150 events in phase II seems not necessary as the impact on these probabilities then becomes quite small. We recommend considering aspects like the number of compounds in phase II and the resources available when determining the sample size. The lower the number of compounds and the lower the resources are for phase III, the higher the investment for phase II should be.
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Götte
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Schüler
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Kirchner
authors.affiliation: Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Meinhard
authors.initials: M
authors.lastname: Kieser
mesh_terms: D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D006801:Humans; D011336:Probability; D012107:Research Design; D018401:Sample Size
keywords: drug development programme; phase II trials; probability of success; sample size; time-to-event analysis