Case Studies of Expedited Review: AZT and L-Dopa

Kaitin K.I. DiCerbo P.A. Lasagna L. , “The New Drug Approvals of 1987, 1988, and 1989: Trends in Drug Development”, Journal of Clinical Pharmacology, 31(1991): 116–22, at 117.

Id.

See, e.g.: Comptroller General's report to the Subcommittee on Science Research and Technology, United States House of Representatives. “FDA drug approval: A lengthy process that delays the availability of important new drugs”. Washington, D.C., U.S. General Accounting Office, HRD 80–64, May 28, 1980; “Final Report of the National Committee to Review Current Procedures for the Approval of New Drugs For Cancer and AIDS” (The “Lasagna Committee Report”), August 15, 1990.

See, e.g., “Drug development costs may increase by $100 mil. in U.S. due to lengthy approval process, PMA estimates for President's Competitiveness Council”, F-D-C Reports (The Pink Sheet), May 6, 1991: 10–11, at 10.

The FDA first proposed initiatives to speed the development and review of important new drugs in the mid-1970s. The agency's drug classification system and end-of-phase II conference procedure were two such initiatives designed to expedite new drug availability. For a discussion of these initiatives and an analysis of their impact on development and review times, see Kaitin K.I. , “Therapeutic Ratings and End-of-Phase II Conferences: Initiatives to Accelerate the Availability of Important New Drugs”, Journal of Clinical Pharmacology, 31(1991):17–24.

Investigational new drug, antibiotic, and biological drug product regulations; Procedures for drugs intended to treat life-threatening and severely debilitating illnesses. Fed Reg 53:41516–24 (October 21, 1988). Published as an interim rule effective immediately. Codified at 21 C.F.R. 312.80–312.88.

The FDA developed the Subpart E procedures at the request of then Vice President George Bush who, in his capacity as chairman of the Presidential Task Force on Regulatory Relief, asked the FDA in August 1988 to build on the agency's success with AZT to create procedures for expediting the marketing of drugs to treat AIDS and other serious diseases. Between August and October 1988, the FDA received input on the development of the procedures from representatives of other government agencies, AIDS groups, and consumer, health, and academic organizations.

Id., 41519–20. This section calls for greater use of preclinical as well as end-of-phase I and end-of-phase II conferences between the drug sponsor and the FDA to reach agreement on an appropriate and well-planned clinical study design. The intent is to compress the clinical testing phase by answering critical questions about the drug during early phases of clinical development.

Id., 41520. This section provides a bridge between completion of Phase II clinical studies and marketing approval. When early evidence from Phase II results indicate that a drug candidate is promising, the FDA “will actively work with the sponsor to evaluate the appropriateness of a treatment protocol” to permit wider use of the agent outside of the clinical trial setting.

Id., 41520–1. The FDA will take into consideration the severity of the disease and the absence of satisfactory alternative therapy in its evaluation of the drug application. “FDA will consider whether the benefits of the drug outweigh the known or potential risks of the drug and the need to answer remaining questions about risks and benefits of the drug.””

Id., 41521. Expedited development and review will no doubt leave many questions about the drug unanswered at the time marketing approval is granted. This section acknowledges that if NDA approval “is gained on the basis of limited, but sufficient, clinical trials, it will usually be important to conduct postmarketing clinical studies that will extend the knowledge about the drug's safety and efficacy and allow physicians to optimize its use.””

On April 2, 1991, Bristol-Myers Squibb filed an NDA for dideoxyinosine (ddI; brand name Videx), the second antiretroviral drug (after AZT) to be reviewed by the FDA. An advisory committee recommended approval of ddI on July 18, 1991, and the RDA approved the drug on Octobner 14, 1991. See “Bristol-Myers Squibb's Videx (ddI) scheduled for July advisory committee review”, F-D-C Reports (The Pink Sheet), April 22, 1991: T&G 3.

See, e.g.: Wastila L.J. Lasagna L. , “The History of Zidovudine (AZT)”, Journal of Clinical Research and Pharmacoepidemiology, 4(1990):25–37; Barry D.W. Lafon S.W. Pattishall K.H. , “The Development and Use of Azidothymidine in the Treatment of Human Immunodeficiency Virus Infections”, in Nicholson K. , ed., HIV and Other Highly Pathogenic Viruses, Royal Society of Medicine Services International Congress and Symposium Series No. 145, London: Royal Society of Medicine Services Limited, 1988: 19–29; “Burroughs Wellcome Company, The Retrovir Story by B.W. Co. People”, Winston-Salem: Hunter Publishing Co., 1987.

Data on 1987 drugs were obtained from FDA sources as well as from responses to the Center for the Study of Drug Development's (CSDD's) annual survey of the pharmaceutical industry. A new chemical entity (NCE), as defined by the CSDD, is any new molecular compound not previously approved in the United States, excluding biologics, vaccines, diagnostic agents, and new salts, esters, and dosage forms of previously approved compounds. The clinical phase refers to the time from IND filing to NDA submission, the review phase refers to the time from NDA submission to approval by the FDA, and the total phase refers to the time from IND filing to NDA approval.

Burroughs Wellcome, in collaboration with the FDA, developed an extensive phase IV research program including both preclinical and clinical components. The program is described in Perkins J.G. Dalton M. Lyon G.M. , “Utility of Retrovir's Phase IV Research from a Regulatory Perspective”, Drug Information Journal, 24(1990):597–603.

Id. at 602.

There were extensive policy debates in the mid-1970s regarding the objectives, implementation, and value of large postmarketing studies. See, e.g., Finkel M.J. , “Phase IV Testing: FDA Viewpoint and Expectations”, Food Drug and Cosmetic Law Journal, 33(1978):181–90.

“New legal thrust in NDA licensing system disclosed in FDA clearance for Eaton and Roche L-Dopa; continuation of ongoing studies a condition,” F-D-C Reports (The Pink Sheet), June 8, 1970: 6–13, at 7.

Finkel M.J. , “Experiment in Post-Marketing Surveillance of New Drugs”, Rockville, MD: FDA Bureau of Drugs, March 1977.

Mattison N. Richard B.W. , “Postapproval Research Requested by the FDA at the Time of NCE Approval, 1970–1984”, Drug Information Journal, 21(1987):309–29, at 309.

Based on Maxwell R.A. Eckhardt S.B. , “L-Dopa”, in Drug Discovery: A Casebook and Analysis, Clifton, NJ: Humana Press, 1990: 179–91.

Supra note 14, for L-Dopa and 1970 drugs.

Supra note 20.

This finding was corroborated in a recent PAR update covering the years 1985 and 1986. See Richard B.W. Melville A. Lasagna L. , “Postapproval Research as a Condition of Approval: An Update, 1985–1986”, Journal of Clinical Research and Drug Development, 3(1989): 247–57.

Information on postapproval research requirements was obtained from a survey of the pharmaceutical industry as well as from copies, obtained through the Freedom of Information office at the FDA, of all approvable and approval letters for NCEs approved from 1985 through 1989. See also supra note 14.

The longer clinical and review phases for drugs with PAR were due in part to the relatively high percentage of central nervous system, cardio-renal, and anesthetic-analgesic drugs (drugs with typically long development and review times; see supra note 2). Within each therapeutic category, however, there was very little difference in phase lengths between drugs with PAR and those without.