title: Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials.
abstract: There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: H M James
authors.initials: HM
authors.lastname: Hung
authors.affiliation: b Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: Peiling
authors.initials: P
authors.lastname: Yang
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Jin
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: John
authors.initials: J
authors.lastname: Lawrence
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: George
authors.initials: G
authors.lastname: Kordzakhia
authors.affiliation: a Division of Biometrics I, Office of Biostatistics , Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: Massie
mesh_terms: D002317:Cardiovascular Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D002491:Central Nervous System Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D002986:Clinical Trials as Topic; D006801:Humans; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D002317:Cardiovascular Agents; D002491:Central Nervous System Agents
keywords: Adaptive design; adaptive selection; adaptive statistical information; branching decision rule; multiplicity; type I error