Assessing whether to perform a confirmatory randomized clinical trial.

BACKGROUND

A confirmatory randomized clinical trial is a trial that is aimed at assessing whether a treatment effect observed in a previous randomized trial (or trials) is real and important. There is often considerable disagreement about the need for such confirmatory trials.

PURPOSE

Our aim is to provide a general statistical framework for evaluating whether a confirmatory trial is warranted in a particular situation.

METHODS AND RESULTS

The results of two clinical trials are considered: 1) a Cancer and Leukemia Group B trial comparing induction chemotherapy plus radiotherapy with radiotherapy alone in the treatment of patients with locally advanced non-small-cell lung cancer and 2) a North Central Cancer Treatment Group trial comparing surgery plus adjuvant chemotherapy with surgery alone in the treatment of patients with advanced colon cancer. In our analysis, we argue that differences in the interpretation of results from a randomized trial are based on differences in prior beliefs about the efficacy of the treatment(s) under study. We believe that a major factor in the decision to perform a confirmatory trial is prior skepticism about the clinical worth of the treatment in question. Both the level of prior skepticism and the minimum treatment effect deemed clinically worthwhile require subjective judgment. We develop a Bayesian framework to allow differences in interpretation to be examined systematically and the need for a confirmatory trial to be assessed. Our model allows the addition of prior belief (specified in the form of a prior distribution of treatment effect) to the results of a trial to yield a posterior distribution. The interpretation of trial results is based on the posterior distribution and will vary as the prior distribution (i.e., the prior belief) varies. To aid in the interpretation of trial results, we also advocate the specification of a minimum clinically worthwhile treatment effect at the start of a trial.

CONCLUSIONS AND IMPLICATIONS

Our approach acknowledges that a number of different prior beliefs are possible, giving rise to a range of interpretations of results from a clinical trial. This approach provides a formal and systematic basis for considering both the range of likely opinions and the subsequent decision to be made with regard to the need for a confirmatory trial. We recommend that this approach be considered in the discussion of future confirmatory randomized clinical trials.