title: Reconsidering some aspects of the two-trials paradigm.
abstract: A common standard for the demonstration of efficacy in a clinical submission is a statistically significant outcome in at least two pivotal trials ("two-trials convention"). When the data structures in different trials are sufficiently similar to allow pooling of the data across trials for a combined analysis, we argue here that such an analysis is a more logical and efficient basis for a judgment regarding efficacy. Criteria for combined analyses may be established, which ensure the same false positive rate protection as the two-trials convention. A combined analysis will generally have much more power than the corresponding application of the two-trials approach that has the same false positive rate protection. In addition, we describe the behavior of modified versions of pure combined analysis, which incorporate a formal standard for reproducibility of trial results by limiting the larger of the individual trial p-values. These modifications are shown to maintain the desirable behavior of the pure combined analysis, namely, higher power compared to the two-trials convention.
authors.affiliation: Novartis Pharmaceuticals, East Hanover, NJ 07869, USA.
authors.forename: J
authors.initials: J
authors.lastname: Maca
authors.forename: P
authors.initials: P
authors.lastname: Gallo
authors.forename: M
authors.initials: M
authors.lastname: Branson
authors.forename: W
authors.initials: W
authors.lastname: Maurer
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data*; D006801:Humans; D008962:Models, Theoretical