Stratification Studies

In pivotal studies, large numbers of patients are studied so that their diverse clinical characteristics can imitate better the ordinary patient population than in earlier, more selective, trials. When a variety of concomitant factors (e.g. other diagnoses, wider degree of disease severity, concomitant medications, etc.) are suspected, and may interact with drug tolerability or efficacy, then patients may be stratified into randomization groups according to the presence or absence of such factors. For example, patients with Crohn's disease might be stratified according to whether or not they also have cutaneous manifestations, and each stratum then randomized to active or placebo for a total of four treatment groups, although only two test treatments. Separate statistical analyses for the strata can then be planned, and the study size adjusted accordingly. The efficacy of the new drug may be found to be restricted to one or more particular patient subset(s). Regulatory authorities will often approve indications with caveats based on such subsets. For example, in the USA, one indication for aprotonin is '. . . to reduce perioperative blood loss ...in selected cases of primary coronary artery bypass graft surgery where the risk of bleeding is especially high, e.g. impaired hemo-stasis, presence of aspirin, or coagulopathy of other origin'. The risk of stratification studies is that conservative regulatory authorities will want to see statistical significance in all patient subsets before allowing a short, broad indication in labeling.

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