to assist sponsors in designing and conducting trials that will meet FDA standards. In many cases, a sponsor will seek assistance from FDA on the preparation of an IND application. Sponsors are required to keep the FDA informed of changes in trial strategy.

If the sponsor concludes that the results of its clinical trials will support FDA approval of a drug, then the sponsor files a New Drug Application (NDA), which FDA must review and approve before a drug can legally be marketed. For generic drugs, the requirement is for approval of an Abbreviated New Drug Application (ANDA). Sponsors may file supplemental applications for approval of new indications for a drug, new formulations, and other purposes.

To secure FDA approval to market a drug, sponsors must provide substantial evidence of the drug’s safety and effectiveness for its intended use. As described in statute (21 USC 355(d)), substantial evidence

means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.

For many years, FDA interpreted the plural term “investigations” in the statute as requiring at least two phase III clinical studies to support new drug approval, with some rare case-by-case exceptions (e.g., drugs for a life-threatening or severely debilitating disease when one large, well-designed, multicenter study showed robust results) (53 Fed. Reg. 41516, 41521). In the FDA Modernization Act of 1997 (P.L. 105-115), Congress added a sentence clarifying that data from one adequate and well-controlled study, together with confirmatory evidence obtained before or after that study, can constitute “substantial evidence” of effectiveness for any new drug.

FDA regulations specify further details about characteristics of adequate and well-controlled studies (21 CFR 314.126; see also CDER-CBER, 1998). Summarized, they state that studies and study reports should

  • provide a clear statement of purpose;

  • permit a valid comparison of the experimental group with a control group;

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