Design and Analysis for Drug Abuse Potential Studies: Issues and Strategies for Implementing a Crossover Design
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Ling Chen, PhD Mathematical Statistician, DB VI/Office of Biostatistics/Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration Yi Tsong, PhD Deputy Director, DB VI/Office of Biostatistics/Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration
Key Words Crossover design; Drug abuse potential studies; Mixed carryover effect; Orthogonal Latin squares; Williams design Correspondence Address Ling Chen, Food and Drug Administration, Building 22, Room 5241, 10903 New Hampshire Avenue, Sliver Spring, MD 20993-0002 (e-mail: [email protected]). The views expressed in this article represent the opinions of the authors and do not necessarily represent the views of the US Food and Drug Administration.
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Design and Analysis for Drug Abuse Potential Studies: Issues and Strategies for Implementing a Crossover Design It is important to conduct a drug abuse potential study for a new drug that may have potential to be abused. The acute dose-effect comparisons of the test, positive control, and placebo treatments are often performed on healthy volunteers with histories of drug abuse in drug abuse clinical trials. Because of large between-subject variability in the endpoint measurements based on self-evalu-
INTRODUCTION A drug abuse potential study is required by the Food and Drug Administration (FDA) for those drugs having possible abuse potential. There are five schedules of drugs and substances (C-I to C-V) based on the level of abuse and medical usage. According to the US Controlled Substance Act, (CSA), a drug with a high potential for abuse and no currently acceptable medical use in the United States is listed in Schedule I. Schedule I is the most restrictive schedule of the CSA. The definition for each of the schedules is given in the Appendix. Although abuse liability of a new drug can often be assessed through animal studies, for scheduling a new drug, the sponsor is often requested to conduct a drug abuse potential clinical trial and compare the new drug with a positive control drug and placebo in order to have a more precise assessment of the effect on human beings. The objectives of such a trial are (1) • to provide unique information on the relative abuse potential of new drugs in humans • to predict the likelihood of abuse by recreational drug abusers • to predict the extent of drug diversion and illicit street sales if the new drug becomes available to the drug abuse community
ated responses and the difficulty in recruiting appropriate study subjects; the designs for such studies are typically crossover, with self-control. In this article, design issues and statistical analysis issues are presented. The advantages and disadvantages of currently used study designs are discussed. Some new ideas for improving existing designs are proposed.
The objective of a drug abuse potential study is to answer the following general questions of interest: • Is the study sensitive enough to detect a difference between a drug k
