should be conducted in abstinent former users. In contrast, with both passive immunization and sustained-release formulations, initial safety can be tested with a single dose in healthy non-users or abstinent former users (Kosten and Kranzler, this volume).

Phase II testing seeks to determine the optimum dosage of a medication and may also include comparison of the effects of new medications with those of a placebo treatment. Potential indications for use become important with phase II testing. FDA requirements may be different for depot medications than they would be for other kinds of new drugs. Because, in most cases, efficacy of the oral medication will already be established for sustained-release formulations, placebo-controlled testing may not be required as part of phase III (or phase II) testing (Kirchmayer, Davoli, and Verster, 2002). However, the efficacy of depot formulations will need to be tested against placebos.

Phase III testing is designed to establish safety and efficacy with large-scale, placebo-controlled studies. The specific outcomes of the studies and their designs may differ on the basis of the indications that are being considered. These indications will also affect the population from which subjects are recruited. For instance, if relapse prevention is the outcome of interest, former drug users who are currently abstinent would be the population of interest. The committee believes that a diverse group of patients who need relapse prevention ought to be examined during the phase III testing process, before moving to protection protocols or special populations, such as pregnant women.

Phase IV testing is used to monitor the use of a medication once it has been approved and is available for clinical practice. Populations that were not originally studied might be assessed, and relatively rare side effects might be detected. This standard stage-wise strategy for completing clinical trials is very unlikely to provide any information about the use of these interventions for a variety of important clinical applications. In particular, the committee believes that significant ethical issues in phase IV testing will arise with immunotherapies and sustained-release formulations.


The surveillance that is an intrinsic part of the postmarketing experience will be critical, particularly for monitoring off-label uses in which premature applications may place certain populations at unacceptable risk. There is likely to be pressure to use these therapies in populations for which insufficient safety or efficacy data are available from the clinical trials, such as adolescents, pregnant women, polydrug abusers, criminal justice populations, or even military personnel. In these untested populations, as well as in those initially included in the clinical trials to support

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