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Considerations for Using Positive Controls in Phase 2 Clinical Trials of Central Nervous System Disorders

  • Biostatistics
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Abstract

Active comparators are often included in phase 2 studies as a positive control to assess assay sensitivity, but inclusion of a positive control does not necessarily improve decision making. Examples show that positive controls are more useful in assessing assay sensitivity as the probability the test drug is effective decreases and as power for the contrast of the positive control versus placebo increases. These results suggest that a positive control should be powered at a minimum of 807o, and preferably at 90%. Analogously, a positive control can be used in an estimation framework to assess whether the study performed as expected, thereby indicating whether or not the test drug was assessed under the anticipated conditions. In so doing, the sample would need to be sufficiently large to ensure reliable estimation. The key point again is that results of the positive control must be reliable if they are to be useful, and adding a small sample of patients in a positive control arm can do more harm than good. It is also important to recognize that including a positive control only allows assessment, but not improvement, of assay sensitivity. Actual clinical trial data are used to suggest that two smaller two-arm studies of test drug and placebo instead of one larger study that also includes a positive control may improve assay sensitivity with little to no increase in the total sample size.

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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, New Jersey, Hamilton, USA

    Michael J. Detke MD, PhD

  3. Departments of Psychiatry, Harvard Medical School, Boston, USA

    Michael J. Detke MD, PhD

  4. Massachusett, Belmont, USA

    Michael J. Detke MD, PhD

  5. Indiana University School of Medicine, Indiana, Indianapolis, 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. Considerations for Using Positive Controls in Phase 2 Clinical Trials of Central Nervous System Disorders. Ther Innov Regul Sci 44, 431–441 (2010). https://doi.org/10.1177/009286151004400407

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