title: A composite design for transition from a preliminary to a full-scale study.
abstract: In drug development, a sequence of studies are conducted to evaluate effectiveness (or efficacy) and safety, such as a Phase II study to assess pharmacological activity or safety that is then followed by a definitive Phase III study to assess clinical effectiveness. Rather than conducting separate successive studies, we describe a design in which the patients enrolled in a preliminary (e.g. Phase II) study are continued into a subsequent full-scale (e.g. Phase III) study. This design also applies to a study that uses an internal pilot with a preliminary assessment of efficacy or safety. The combined preliminary to full-scale design potentially reduces the total numbers of patients required and the total duration of the program. The design allows a futility or safety stopping boundary for the preliminary study result that is specified in terms of a lower critical Z-value (Z(L)) and the pursuant type II error probability incurred under a specified alternative hypothesis of a beneficial effect or no toxicity at that stage. This boundary also leads to a deflation of the type I error probability for the final test at the completion of the full-scale study, such that a critical value for the final test (Z(F)) can be determined that provides the desired level of the type I error probability exactly. Thus, it is possible to determine sample sizes at the two stages, and critical values Z(L) and Z(F) that provide specified type I and II error probabilities for the combined study. We describe the design using large-sample normally distributed Z-tests at the two phases, including a test for means, or proportions or survival times, or combinations thereof, such as a test for means at Phase II followed by a test for proportions at Phase III. We compare the properties of this design versus the conduct of two successive studies, and explore the factors that influence the operating characteristics of the design. We also discuss the practical considerations in the implementation of the design.
authors.affiliation: The Biostatistics Center, Department of Epidemiology and Biostatistics, The George Washington University, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852, USA. jml@biostat.bsc.gwu.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: Naji
authors.initials: N
authors.lastname: Younes
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects; D012107:Research Design; D018401:Sample Size
chemical_list: D002097:C-Reactive Protein