Hostname: page-component-78c5997874-8bhkd Total loading time: 0 Render date: 2024-11-06T12:09:24.579Z Has data issue: false hasContentIssue false
  • English
  • Français

Case Studies of Expedited Review: AZT and L-Dopa

Published online by Cambridge University Press:  29 April 2021

Kenneth I. Kaitin
Get access Rights & Permissions [Opens in a new window]

Extract

The HIV epidemic has led to a reassessment of attitudes regarding public access to new therapeutic agents for the treatment of life-threatening and severely debilitating diseases. People with AIDS and their advocates have relentlessly attacked the process by which new drugs are developed and approved for marketing in this country, a process characterized as overly conservative, risk-averse, and paternalistic. In response to growing pressure to accelerate access to important new therapeutic agents, the Food and Drug Administration (FDA) has issued several bold initiatives designed to facilitate the development of experimental drugs used in the treatment of serious or immediately life-threatening diseases.

The clinical testing and regulatory review of new therapeutic agents in the United States are lengthy processes. A recent analysis of new chemical entities (NCE) approved by the FDA in 1987,1988, and 1989 has revealed that, on average, the clinical development phase for new drugs exceeds five years (63 months).

Type
Article
Information
Law, Medicine and Healthcare , Volume 19 , Issue 3-4 , Fall Winter 1991 , pp. 242 - 246
Copyright
Copyright © American Society of Law, Medicine and Ethics 1991

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

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.Google Scholar
Id.Google Scholar
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.Google Scholar
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.Google Scholar
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. et al, “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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.””Google Scholar
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.”Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar
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.CrossRefGoogle Scholar
Id. at 602.Google Scholar
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.Google Scholar
“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.Google Scholar
Finkel, M.J. et al, “Experiment in Post-Marketing Surveillance of New Drugs”, Rockville, MD: FDA Bureau of Drugs, March 1977.Google Scholar
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.Google Scholar
Based on Maxwell, R.A. Eckhardt, S.B., “L-Dopa”, in Drug Discovery: A Casebook and Analysis, Clifton, NJ: Humana Press, 1990: 179–91.Google Scholar
Supra note 14, for L-Dopa and 1970 drugs.Google Scholar
Supra note 20.Google Scholar
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.Google Scholar
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.Google Scholar
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.Google Scholar