The draft FDA guideline on non-inferiority clinical trials: a critical review from European pharmaceutical industry statisticians.

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) engages more than 2000 statisticians through its ten national organizations. Amongst other things, EFSPI is involved in reviewing regulatory guidelines under development, including the draft FDA guideline on non-inferiority clinical trials. This review resulted in several critical comments relating to as follows: (i) the lack of one single standard for proving efficacy of new drugs implied by the guideline; (ii) the problems with the suggested 'fraction of effect to be preserved'; (iii) the formulation of the primary hypothesis in a non-inferiority trial aiming at indirectly demonstrating a new drug is superior to placebo; and (iv) the preference in the guideline for the fixed-margin method over the synthesis method in the analysis. The presumed implications of this guideline, if implemented as is, are (i) increased confusion of how efficacy could be demonstrated when placebo control is not available, (ii) more complicated communication between pharmaceutical industry and FDA because of the apparent disagreements on fundamental statistical matters, and (iii) illogical consequences in the approval process because of which order drugs are approved rather than how they fulfill the regulatory requirements. We believe that the area is not yet ready for such a prescriptive regulatory guidance and that further research and experience are required until the methodology can be finally agreed. A strategy needs to be developed by regulatory agencies together with drug industry and academia for a long term solution for this topic.