When does a single positive adequate and well-controlled study of a new drug meet the statutory requirement to demonstrate substantial evidence of effectiveness? The answer to this question, particularly with respect to new molecular entities, has been of considerable debate since 1962 when the requirement that new drugs prove their benefit to patients became law. A 1997 revision to the statute provided one pathway to a single-study approval (a single adequate and well-controlled study plus confirmatory evidence), while a 1998 guidance issued by FDA provided additional pathways, one of which is the one that is most frequently cited by FDA (a single statistically very persuasive study). This paper explains these 2 distinct pathways and provides illustrative examples of how FDA uses each of these 2 pathways. Regulators, industry, patients, and investors should each find this exegesis of these 2 independent, yet equally viable and valuable, pathways to an FDA approval both illuminating and invaluable.
Keywords: FDAMA 115; confirmatory evidence; effectiveness; evidence guidance; substantial evidence.