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Design Archetypes for Phase 2 Clinical Trials in Central Nervous System Disorders

  • Biostatistics
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Abstract

An overarching framework is proposed to guide the design of phase 2 studies in central nervous system disorders. Archetypes are considered for scenarios where dose response is highly relevant in clinical practice, as in the symptomatic treatment of acute disorders. Archetypes for scenarios where dose response is less relevant, as in disease modification for neurodegenerative disorders, are beyond the scope of this article. Primary design archetypes are determined by axes of development that are defined by optimism for success (probability of efficacy) and signal detection (magnitude of the anticipated effect size). The fast-to-registration primary archetype uses a dose-response study as the first efficacy, that is, proof of concept (PoC), study and is appropriate when the prospects for signal detection and the optimism for efficacy are higher. These conditions may exist when the anticipated effect 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-PoC primary archetype tests one dose arm to establish PoC before assessing dose response and is appropriate when the optimism for efficacy and the prospects for signal detection are lower. These conditions may exist when testing a drug with a novel mechanism and/or the anticipated effect size is smaller. Secondary archetypes are used to mitigate the trade-offs between the quick-kill fast-to-PoC approach and the quick-win fast-to-registration approach, and are key areas where adaptive designs can be beneficial.

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Author information

Authors and Affiliations

  1. Eli Lilly & Co., Lilly Corporate Center, Indiana, 46285, Indianapolis, USA

    Craig H. Mallinckrodt PhD,  William R. Prucka PhD &  Stephen J. Ruberg PhD

  2. MedAvante Research Institute, New Jersey, Hamilton, USA

    Michael J. Detke MD, PhD

  3. Departments of Psychiatry, Indiana University School of Medicine, Indiana, Indianapolis, USA

    Michael J. Detke MD, PhD

  4. Harvard Medical School, Massachusetts, Boston, USA

    Michael J. Detke MD, PhD

  5. McLean Hospital, Massachusetts, Boston, USA

    Michael J. Detke MD, PhD

  6. I-BioStat, Hasselt University, Belgium, Diepenbeek, USA

    Geert Molenberghs PhD

  7. Katholieke Universiteit Leuven, Belgium, Leuven, USA

    Geert Molenberghs PhD

Authors
  1. Craig H. Mallinckrodt PhD
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  2. Michael J. Detke MD, PhD
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  3. William R. Prucka PhD
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  4. Stephen J. Ruberg PhD
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  5. Geert Molenberghs PhD
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Correspondence to Craig H. Mallinckrodt PhD.

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Mallinckrodt, C.H., Detke, M.J., Prucka, W.R. et al. Design Archetypes for Phase 2 Clinical Trials in Central Nervous System Disorders. Ther Innov Regul Sci 44, 421–430 (2010). https://doi.org/10.1177/009286151004400406

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