Academic perspectives on the United States Food and Drug Administration's guidance for industry on diabetes mellitus.

The United States Food and Drug Administration (FDA) has issued Guidance for Industry, subtitled Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. From an academic perspective, these regulatory requirements provide undue emphasis on the results of phase 2 trials not designed to test hypotheses about clinical cardiovascular events. Phase 2 trials should be considered hypothesis formulating either alone or in their meta-analyses. Thus, this FDA guidance for industry does not adequately emphasize the importance and necessity of well designed and conducted phase 3 trials of sufficient size, dose, and duration to test the hypothesis formulated from the meta-analysis of the phase 2 trials. We believe that the guiding principle about benefits and risks of drugs should be that rational decisions for individual patients and the health of the general public should be based on a sufficient totality of evidence. When that totality of evidence is incomplete, it is appropriate to remain uncertain. We believe phase 2 trials should be performed mainly for proof of concept and dose ranging. To detect reliably the most plausible small to moderate effects of drugs, the totality of evidence must include large scale randomized phase 3 trials. These individual trials must be of sufficient size, dose, and duration as well as achieve high adherence and follow-up. They must also achieve enough clinical endpoints to distinguish reliably between the null hypothesis of no effect and the most plausible alternative hypotheses of small benefit or harm.