FDA’s Approval of Drugs - A Brief Overview

1930's

FDA’s regulatory premarket oversight was officially extended over human drugs sold in the United States following the passage of the 1938 Food Drug and Cosmetic Act (FDCA) signed into law by President Franklin D. Roosevelt.

Among the many provisions of the 1938 FDCA, was the requirement that all new drugs be required to be shown through FDA’s approval of a premarketing submission that they were "safe" before being legally allowed to be marketed in the U.S.

The results of safety testing would be submitted to FDA in a New Drug Application (NDA) This revision of the earlier 1906 Act also had a provision that any drug which was marketed prior to June 25, 1938, could continue to be marketed without FDA’s approval provided no significant alterations in formulation or labeling had occurred since that time.

That is, such a drug would not be considered a new drug (i.e. grandfather clause.) The law also required that drugs have adequate labeling for safe use. The monitoring of all drug advertising was assigned to the Federal Trade Commission.

1940's

The early 1940s saw three major additions to FDA’s responsibilities in terms of drugs. The Insulin Amendment, passed in 1941, required all batches of insulin to be tested for purity, strength, quality, and identity before marketing. Also starting in 1941, the Agency required prescriber labeling for all new drugs in concert with the adequate directions for use provision of the 1938 Act.

The Penicillin Amendment was passed in 1945, modeled on the Insulin Amendment. The former required batch certification of drugs wholly or partially composed of penicillin. Subsequent amendments extended the certification requirement to other antibiotics. The FDCA and World War II greatly expanded the role of FDA’s overall regulatory oversight.

Wartime demands stimulated the rapid development, availability and marketing of new "wonder drugs", especially antibiotics for treating war casualties. (* Pantopaque was approved for marketing 1944 through support of "safety".) (4)

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1950's

At the start of the 1950's, FDA’s resources were still viewed by Congress and the Agency as seriously deficient for the assigned tasks. FDA’s appropriations and staff in the 1950's, never considered as adequate by Congress, had remained approximately at the same levels as 1938 when Congress passed the FDCA.

The 1951 Durham-Humphrey Amendment to the FDCA further defined U.S. drugs that could not be safely used without medical supervision and restricted the sale of these drugs to receipt of a prescription by a licensed health care provider.

In 1955, FDA undertook a pilot study on adverse drug reaction reporting. In cooperation with the American Society of Hospital Pharmacists, the American Medical Association, and others, the study was focused on reactions that could be reported by hospitals and pharmacists. Adverse reaction reporting was voluntary and reports were usually scarce.

This study blossomed into a more ambitious effort in 1957 to test a large-scale system for voluntary reporting to assist with post-marketing evaluation of new drugs. By 1963 the study had evolved into a voluntary reporting system with almost 20 hospitals participating.

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1960's

In Europe, there was a major safety uproar secondary to the disastrous introduction of the drug thalidomide, a new sleeping pill, and its subsequent association with a production of serious birth defects. However, the United States’s FDA was viewed in a positive light after the cautious actions of FDA’s Medical Office Dr. Frances Kelsey, that had kept the drug from approval for commercial entry onto the U.S. market. Despite lack of FDA approval, more than two million thalidomide tablets had been distributed in the U.S. as "investigational drugs". Investigational drug distribution had been largely unregulated in the US under FDCA.

The FDA’s prudent actions to not approve thalidomide that appeared to have protected US public safety aroused a strong public support for FDA’s role in drug regulation and the need for stronger laws to ensure "drug safety".

In partial response to the issue, FDA’s Commissioner George Larrick established an Advisory Committee on Teratology and Congress was able to obtain the necessary public support to pass the 1962 Kefauver-Harris Drug Amendment to ensure drug "safety and efficacy".

The 1962 Kefauver-Harris Drug Amendments or the Drug Amendments of 1962 to the FDCA continued to require that a "new drug" be required to demonstrate that it was both "safe" but also now that it was "effective" before being allowed commercially onto the U.S. market. As a result of the 1962 Amendment to the FDCA, FDA also retrospectively went back to reassess the "efficacy" of nearly 3,000 prescription drugs that FDA had already allowed to be introduced onto the U.S. market between 1938 and 1962. (*That review included Pantopaque.)

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The FDA responded to this large retrospective review task given to it by Congress by seeking external advice or assistance through a contract with the National Academy of Sciences-National Research Council (NAS-NRC). NAS-NRC membership were required to review previously marketed prescription drugs and made recommendations to FDA regarding safety, efficacy, and labeling(5).

The FDA’s retrospective efficacy review program was called the "Drug Efficacy Study Implementation Review" or "DESI".

As a result of DESI, in the years following 1962, literally thousands of previously "approved" drugs were removed from the U.S. market by FDA because it was determined that they lacked evidence in the medical literature to support "efficacy".

DESI evaluated 3000 separate drug products and over 16,000 therapeutic claims.

By 1984, FDA had completed final action on 3,443 products; of these, 2,225 were found to be effective; 1,051 were found to not be effective, and 167 the decision was still pending.

FDA also required manufacturers to update their product labeling to reflect the known medical facts regarding drug safety and efficacy determined by DESI and to bring drug labeling into compliance with FDA’s requirements for prescription labeling.

Drug prescription labeling was revised to be more uniform and come into compliance with FDA’s prescription labeling requirements of the FDCA and labeling for other similar products.

To expedite developing drug prescription labeling for similar types of products, FDA turned to the regulated industry itself for models of the "best" designed labeling for each type of product.

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The 1966 Fair Packaging and Labeling Act required all consumer products sold in interstate commerce to be honestly and informatively labeled. FDA became officially responsible for enforcement of labeling provisions for foods, drugs, cosmetics and medical devices.

(*Pantopaque had been approved with "safety" data in 1944, and was included in the FDA’s retrospective drug review (DESI) of the medical literature by NAS-NRC for support of both safety and efficacy.)

FDA required labeling changes that coincided with NAS-NRC medical literature review and labeling of similar products.

In 1963 FDA had required the sponsors of Pantopaque to submit a new NDA for gaining approval of a new strength 15% Iodine Pantopaque, or Pantopaque II. The product for the new NDA would be required to meet the Agency’s new requirements for animal safety testing to assure safety, scientific support of both human safety and efficacy, requirements further developed by FDA since the initial World War II era NDA for Pantopaque I (30% iodine). The new Pantopaque NDA was subsequently left uncompleted and withdrawn by Lafayette Pharmacal in 1969.

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1970's

In Upjohn v. Finch, 1970, the Court of Appeals upheld enforcement of the 1962 Drug Efficacy Amendments by ruling that commercial success alone did not constitute substantial evidence of drug safety and efficacy. FDA’s review actions of drugs for "efficacy" had been curtailed while the Agency waited to learn the final decision of the Courts as to legality of the Agency’s enforcement actions for "efficacy" requirements.

A 1977 Intercenter FDA Task Force established a Bioresearch Monitoring Program for FDA. The need for such a program to monitor clinical trials became evident from a survey of the 6 "conductance of clinical studies" involving FDA-regulated products by FDA’s field inspection operation team between 1972 and 1974. Following a further review of the agency’s inspectional findings, Congress mandated that FDA immediately develop and implement a new agency-wide program for monitoring the conductance of bioresearch and clinical activities.

1980's

In 1982, the Bureau of Biologics and the Bureau of Drugs were merged into a Center for Drugs and Biologics, with Biologics products regulated through the Office of Biologics.

In 1987 the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) officially were divided into two separate and independent FDA review and evaluation Centers.

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1990's

As a result of the U.S. push to obtain cheaper generic drugs and the FDA’s Generic Drug Scandal of the 1990's, (*i.e. manufacturers had supplied FDA with fraudulent data regarding the production of generic drugs), the FDA instituted product-specific, pre-approval inspection of manufacturing sites listed within a sponsor’s marketing applications would extend to generic drug applications.

During pre-marketing approval inspection, FDA was required to review the step-by-step manufacturing process of each product under review. All drug applications were reviewed for their scientific content and for manufacturing procedures as well as validation methods, raw material specifications and container and closure systems used.

By Federal Register, September 10, 1991, FDA’s Notice 56, FR 46191- Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy, the agency announced its final policy that set forth FDA’s approach regarding applicants that sought to subvert the agency’s review and approval process of premarketing applications.

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2000's

CDER 06/19/00 release of the Guidance for Industry- Developing Medical Imaging Drugs and Biological Products. This guidance was prepared by the Division of Medical Imaging and Radiopharmaceutical Drug Products in CDER and the Office of Therapeutics Research and Review in CBER, FDA, with comment from Office of Device Evaluation, Radiological Branch, CDRH. The guidance was to represent the Agency’s current thinking on the development of medical imaging drugs and biologics (i.e.medical imaging agents).

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