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Perspective

Generic Drug Approvals in the US Prior to the Hatch-Waxman Act

By Edward Tabor, MD t is a common misconception that the HatchWaxman Act of 19841 created the generic drug approval process in the US. A recent article claimed there were few generic drugs approved in the US before that act was passed.2 In fact, the US Food and Drug Administration (FDA) approved many generic drugs before 1984, using three separate approval mechanisms: the Abbreviated New Drug Application (ANDA) for drugs originally approved before 1962;3 the "paper NDA," a type of New Drug Application (NDA) for generic copies of drugs approved after 1962;3,4 and the monograph system for generic antibiotics and insulin.5

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FDA to approve ANDAs. FDA began approving ANDAs in 19684 for generic copies of drugs that had originally been approved between 1938 and 1962.3 ANDAs were approved if the generic was bioequivalent to the original product (although bioequivalence studies were not always required) and if the original had been found effective by the DESI program.

"Paper NDAs"

In 1978,3,4 FDA expanded the generic approval program with the paper NDA mechanism, approving generic copies of drugs that had been approved as new drugs after 1962 (i.e., drugs that had not been subject to the DESI review), based upon published studies to support safety and efficacy that the generic applicant submitted in an NDA.4,6 Bioequivalence studies were required in some cases.3 Nineteen original products served as reference drugs for 47 paper NDAs approved by FDA between January 1979 and June 1983.3 Additional paper NDAs were approved by FDA's Division of Anti-Infective Drug Products during the early part of my tenure as director, beginning in August 1983 (recollections of the author).

ANDAs

Before 1962, NDAs had been approved solely on the basis of data demonstrating that the drug was safe, as there were no efficacy requirements. Beginning in 1968, drugs that had been approved between 1938 and 1962 only on the basis of safety were gradually evaluated by FDA's Drug Efficacy Study Implementation (DESI) program for evidence of efficacy by evaluating the drug's marketing history, published clinical studies and the views of outside experts.4 In a sense, the existence of the DESI program enabled

Monographs for Antibiotics and Insulin

Generic copies of antibiotics and insulin were approved under a monograph system from 1945 to 1997.5 The generic copy was required to: · meet originator product specifications as published in an FDA monograph · be shown to be bioequivalent to the originator product · undergo batch release testing by FDA (until batch release testing was fully eliminated in 1982) For antibiotics, the original marketing application was called a "Form 5" and the generic drug application was called a "Form 6."3 Hatch-Waxman Act In 1984, the Hatch-Waxman Act created a formal approval process for generic drugs other than

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antibiotics and insulin. (Approvals of antibiotics and insulin were integrated into the NDA process by the Food and Drug Modernization Act of 1997.5) In practice, the Hatch-Waxman Act primarily affected generic copies of nonantibiotic and noninsulin products originally approved after 1962, since those approved before 1962 and shown to be effective by DESI, as well as all antibiotics and insulin, were already considered to be suitable reference drugs for generic drug applications. In exchange for this extension of the generic drug approval process, the Hatch-Waxman Act provided manufacturers submitting future original NDAs with the opportunity to obtain an extension of their patents and/or a period of market exclusivity at the time of the NDA approval, to compensate for lost patent life during development and regulatory approval of their product. In addition, the Hatch-Waxman Act replaced the paper NDA mechanism with the "505(b) (2) NDA," a mechanism for approving products based upon published or other clinical studies of safety and efficacy that were not conducted by the applicant.

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Anniversary Commemorative Volume of Food and Drug Law, Food and Drug Law Institute, Washington, DC, 1984, p. 242-292 (particularly p. 248-251). Wiesen IL. "FDA antibiotic regulatory scheme: then and now." Berry IR (editor). The Pharmaceutical Regulatory Process. Marcel Dekker (New York). 2005:pp. 241-255 (particularly p. 242-245). Rosen DL. "Generic drug approval process: pre-1984 history concerning generic drugs." Berry IR (editor). The Pharmaceutical Regulatory Process. Marcel Dekker (New York). 2005:pp. 99-106 (particularly p. 105).

Author Edward Tabor, MD is vice president and head of global regulatory strategy for Quintiles in Rockville, MD. He can be reached via email at [email protected]

Summary

While the Hatch-Waxman Act was created to improve the generic drug approval process in the US and expand the number of generic products eligible for approval, FDA had approved many generic drugs prior to the act using the authority it already had at the time.

References 1. The Drug Price Competition and Patent Term Restoration Act of 1984 is commonly known as the Hatch-Waxman Act. 2. Dudzinski DM and Kesselheim AS. "Scientific and legal viability of follow-on protein drugs." New Engl. J. Med. 2008;358:843-849. 3. National Center for Drugs and Biologics. New Drug Evaluation Project Briefing Book. National Technical Information Service, US Department of Commerce, Serial PB 84-103415, September 1983. 4. Kleinfeld, Kaplan and Becker. "Human drug regulation: Comprehensiveness breeds complexity." Seventy-fifth

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