Sample Size Reestimation: A Review and Recommendations
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ADAPT I VE DES I GN 475
Sample Size Reestimation: A Review and Recommendations
Christy Chuang-Stein
Pfizer
Keaven Anderson Merck
Paul Gallo
Novartis
Sylva Call1ns
FBCConsulting
Key Words
Adaptivedesign; Blindedand unblindedestimation; Combination test; Groupsequentialdesign
Correspondence Address
ChristyChuang-Stein, GlobalStatistics, PfizerInc.• 2800 Plymouth Road, Ann Arbor, MI48105, USA.
Despite best efforts, some crucial information used to design a confirmatory trial maynot be available, or maybe available but with a high degree of uncertainty, at the design stage. When thishappens, it may be prudent to check the validity of those assumptions using interim data from the study and make midcourse adjustment if necessary. One such adjustment is to modify the sample size. In this article, we focus on sample size reestimation (SSR) for
INTRODUCTION Despite best efforts, some of the crucial information used to design a confirmatory trial is not available, or is available but with a high degree of uncertainty, at the design stage. This could involve the initial estimates of within- or between-patient variation, a control group event rate for a binary outcome, the treatment effect desired to be detected, the recruiting pattern, or patients' compliance, which all have an impact on the ability of the trial to address its primary objective (1). There are many reasons why reliable information about these types of parameters is not available or is barely available. An obvious reason is that the new product has not been studied in the manner intended in the target patient population. This situation is not uncommon with human immunodeficiency virus treatment, for example, when a new product is to be studied in a confirmatory trial as part of a drug cocktail, and the cocktail contains some newly approved antiretroviral medications. Another reason for lack of information could be that changing medical practice might significantly affect an event rate. Thus, estimated rates based on historical data might no longer reflect the current medical environment. A third reason could be a conscious decision by the sponsor to minimize the phase II program, resulting Dmg Informutton.Jourual, Vol. 40. pp. 475-484. 2006.0092-8615/2006
phase III and IV studies. The discussion is relevant to both continuous and binary endpoints even though the basis for SSR might differ for thosetwo cases. We review commonly used approaches to adjust sample size and provide recommendations on how SSR should be implemented to achieve the objectives and maintain the integrity of the trial. The recommendations cover scientific, procedural, and logistic considerations.
in less-than-ideal information at the time the confirmatory trial is being planned. Mehta and Patel (2) discussed a situation in which a sponsor prefers starting out with a small initial commitment of patients but is willing to factor in the possibility that the sample size might need to be increased during the course of the trial. This could be accomplished by taking an interim ass
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