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Phase III trials are typically undertaken after Phase II studies have identified a potentially safe and effective dose that is considered likely to show an effect on a relevant clinical end point. Typically, regulatory approval in the United States requires two statistically significant, well-controlled clinical trials for the same indication.
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Phase III trials usually enroll several hundred to several thousand subjects at multiple study centers. The major objective in Phase III is to show a statistically significant effect on the relevant efficacy measure to facilitate approval of the drug by regulatory agencies, confirming evidence collected in Phase II that a drug is safe and effective for use in the intended indication and population. Secondary objectives can include evaluating safety and dosing for package labeling; its use in subpopulations, wider populations, and with other medications; and effects on secondary end points (1) (Table 8–1).
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Phase III trials show efficacy by comparing the new therapy to a control, which can be standard therapy, no therapy, or a placebo. The most frequently used trial design is the superiority trial, which aims to show that the new therapy is better than the comparator. When effective treatments for a condition are already available, however, showing superiority against these treatments can be much more difficult than showing it against a placebo. In some cases, such large numbers of patients would be needed to declare superiority that performing such a trial becomes prohibitive. It may be more reasonable to show that the new therapy is equivalent or noninferior to existing standard therapy with regard to efficacy and safety while also showing other characteristics that make it desirable, for example, fewer side effects, shorter half-life, easier to give, or less expensive. The goal of an equivalence trial is to show that the effects of the new therapy differ by no more than a clinically acceptable amount from those of the comparative therapy, whereas the goal of a noninferiority trial is to show that any difference in effectiveness between the new therapy and the control is not worse by a clinically meaningful amount.
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Phase III trials are frequently designed to include specified interim “looks” at the data by an independent committee composed of knowledgeable experts, often referred to as a Data and Safety Monitoring Board (DSMB). This committee assesses the available trial data to determine whether there is sufficient cause for stopping the trial early or modifying trial conduct. Reasons for early stopping include a clear indication that the treatment is superior, a low likelihood of achieving the specified treatment benefit, unacceptable adverse events, and patient accrual that ...