In the first part of this series, the authors discussed strengths and weaknesses of traditional phase I drug development involving single ascending dose studies followed by multiple ascending dose studies in healthy volunteers. They then discussed how these traditional designs are being challenged by the development of truly novel molecular compounds that are not derived from earlier drugs and how the extent and design of phase I studies will need to be expanded and altered to investigate these novel compounds. In this column, the authors focus in more detail on limitations of traditional phase I studies for investigating truly novel compounds and propose solutions to address these problems. Adaptive trial designs and biomarker endpoints are discussed. (Journal of Psychiatric Practice 2011;17:277–284).
*Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine-Wichita, and KU-Wichita Clinical Trials Unit
†Janssen Pharmceutical Companies of Johnson & Johnson, Titusville, NJ
Dr Preskorn maintains a website at www.preskorn.com where readers can access previous columns and other publications
Material in this column is adapted with permission from the chapter, “Phase I Trials: From Traditional to Newer Approaches”, by Matthew Macaluso, DO, Michael Krams, MD, PhD, and Sheldon H. Preskorn, MD, in Kalali A, ed. Essential CNS Drug Development. Cambridge University Press, in press.
Disclosure statement: Dr Macaluso has conducted clinical trial research as principal investigator funded by Abbott, Envivo, Evotec, Lilly, Naurex, Pfizer/Wyeth, Takeda, and Targacept. Within the last 12 months, Dr Preskorn, as chief science officer of the KU-Wichita Clinical Trials Unit and, in many cases, as principal investigator, has received grants/research support from or has served as a consultant for, on the advisory board, or on the speakers bureau for the following entities: Abbott, Biovail, Boehringer Ingelheim, Bristol-Myers-Squibb, Eisai, Eli Lilly, Evotec, Ipsen, Johnson & Johnson, Link Medicine, Merck, NovaDel Pharma, Naurex, Orexigen, Pfizer, Prexa, Psycho-genetics, Sunovion, Takeda, and Targacept.
*Most drugs produce their beneficial and adverse effects by altering the functional status of a regulatory protein. Target modulation could, for example, involve a drug acting as an agonist, antagonist, or inverse agonist at a specific receptor. Effective target modulation means having the effect at the target (e.g., agonism or antagonism) necessary to produce the desired clinical effect with minimal adverse effects