Design Archetypes for Phase 2 Clinical Trials in Central Nervous System Disorders
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Craig H. Mallinckrodt, PhD Eli Lilly 6. Co., Lilly Corporate Center, Indianapolis, Indiana Michael 1. Detke, MD, PhD MedAvante Research Institute. Hamilton, New Jersey; Departments of Psychiatry. Indiana University School of Medicine. Indianapolis. Indiana; Haward Medical School, Boston. Massachusetts; McLean Hospital. Belmont, Massachusetts William R. Prrcka, PhD Eli Lilly 6. Co., Lilly Corporate Center, Indianapolis. Indiana Stephen 1. Rrberg, PhD Eli Lilly 6. Co.. Lilly Corporate Center, Indianapolis, Indiana Geert Malenberghs, PhD I-BioStat, Hasselt University, Diepenbeek, Belgium; Katholieke Universiteii Leuven, Leuven, Belgium
Key Words Clinical trial; Phase 2: Clinical trial design Correspondence Address Dr. Craig H . Mallinckrodt. Lily Corporate Center, Indianapolis, IN 4 6285 (email: [email protected]).
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Design Archetypes for Phase 2 Clinical Trials in Central Nervous System Disorders An overarchingframeworkis proposed to guide the design of phase 2 studies in central nervous system disorders.Archetypesare consideredfor scenarioswhere dose response is highb rdevant in clinical practice, as in the symptomatic treatment of acute disorders. Archetypes for scenarios where dose response is less rdevant, as in disease modificationfor neurodqenerative disorders, are beyond the scope of this artide. Primary design archetypesare determined by axes of development that are definedby optimism for success @robabilityof eficacy) and signal detection (magnitude of the anticipated fled size). The fast-to-registration primary archetype uses a dose-response study as the first eficacy, that is, proof of concept (PoC), study and is appropriatewhen the prospectsfor
INTRODUCTION The focus of this article is on optimizing the design of phase 2 studies of treatments for psychiatric disorders. Phase 2 studies play an important role in drug development because the design of such studies must be optimized in conjunction with optimizing phase 3 and 4 studies, and the phase 2 plan implies that certain goals must be reached in phase 1 to support the subsequent studies. In addition, given that phase 2 is the middle of the three phases required for marketing approval, it is a focal point for achieving objectives sequentially, in parallel, or seamlessly via adaptive approaches. The usefulness of various phase 2 designs has been extensively examined for some diseases, such as cancer (1,2). In psychiatric disorders, there have been elaborate examinations of trial design features, such as blinded lead-in periods (3-6). placebo response and its impact on drug-placebo discrimination (7- 11), assessment scales and sensitivity of scales and subscales (6,12-18), and relationships between other design features, analytic methods, and outcome (6,19-23). as well as general design
signal detection and the optimism for eficacy are higher. These conditions may exist when the anticipated fled size is large and when either testing a drug with a proven mechanism of action or when a favorable biomarker result was obtained in phase 1. The fast-to-Po
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