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few hundred subjects who have the disorder the drug is intended to treat. These studies are usually double-blind and placebo-controlled to minimize investigator and subject bias. Phase III of the investigation consists of well-controlled trials to gather evidence on both effectiveness and safety of the drug and information needed for labeling. These are large trials of several hundred to several thousand subjects.

The data collected in all of the clinical studies enable FDA to approve or disapprove a drug based on a risk-benefit analysis. Once a drug is approved and marketed, additional safety information continues to be collected through mandatory submission of adverse event information from the manufacturer to FDA via MedWatch and other reporting mechanisms. FDA may also require the manufacturer to conduct postmarketing studies.


The process above describes the steps required for a new drug approval (NDA). In the years after proof of effectiveness was added to the NDA requirements, FDA wrestled with how to deal with the thousands of OTC drugs that were on the market though not covered by approved NDAs. Rather than make case-by-case challenges to such products, FDA decided to review them by therapeutic class with the assistance of expert advisory committees. The process that FDA established to accomplish this mission is known as the OTC Drug Review.

In 1972 FDA, with the help of 17 advisory panels, began its review of the more than 700 active ingredients with almost 1,500 uses in marketed OTC drug products. The aim of the review was to prepare monographs establishing the conditions under which OTC drugs would be considered generally recognized as safe and effective, and not misbranded, and thus exempt from the NDA process.

The OTC Drug Review consists of several phases. In the first phase, now complete, the advisory panels made recommendations regarding the categorization of products. Category I was for those drugs that the panel deemed to be generally recognized as safe and effective, and not misbranded if they satisfied specified conditions, including, among others, active ingredients and labeling indications. Category II was for products with active ingredients, labeling claims, or other conditions that resulted in them not being generally recognized as safe or effective or resulted in them being misbranded. Category III was for products with active ingredients, labeling claims, or other conditions for which the data were insufficient and for which further testing was thus required.

In the second phase of the review, FDA published the panels’ recommendations as Advanced Notices of Proposed Rulemaking (ANPRs). These ANPRs included proposed monographs establishing the conditions under

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