This document is intended to provide guidance to applicants planning to file new drug applications (NDAs), biologics license applications (BLAs), or applications for supplemental indications on the evidence to be provided to demonstrate effectiveness. This guidance complements and expands on the 1998 guidance entitled Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (the 1998 guidance).

The 1998 guidance was issued in response to the Food and Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105–115), which stated that the substantial evidence requirement for effectiveness, which had generally been interpreted as calling for two adequate and well-controlled trials, could also be met by a single trial plus confirmatory evidence. The 1998 guidance, therefore, provided many examples of the types of evidence that could be considered confirmatory evidence, with a specific focus on adequate and well-controlled trials of the test agent in related populations or indications, as well as a number of illustrations of a single adequate and well-controlled trial supported by convincing evidence of the drug’s mechanism of action in treating a disease or condition.

FDAMA thus introduced a specific new area of flexibility in the evidence needed to support effectiveness, but there are many other characteristics of the evidence supporting effectiveness that can vary (notably, trial designs, trial endpoints, statistical methodology), and evidence that varies in such ways potentially can provide substantial evidence of effectiveness but because of these characteristics may provide greater or lesser certainty. These characteristics also deserve consideration and were not discussed in the 1998 guidance. FDA’s consideration of these various designs, endpoints, and analyses which can differ in the strength of evidence they provide, reflects the Agency’s longstanding flexibility when considering the types of data and evidence that can meet the substantial evidence requirement.

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