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The history of the United States food, drug and cosmetic act and the development of medicine
BIOCHEMICAI
MEDICINE
33,
268-270
(1%)
The History of the United States Food, Drug and Cosmetic Act and the Development of Medicine MICHAEL
R.
HAMRELL’
The Food, Drug and Cosmetic (FD&C) Act of the United States forms the basic framework of the Food and Drug Administration (FDA), the agency that regulates the drug industry in this country. The act deals with the government‘s attempts to protect public health and individual welfare in the development and marketing of essential commodities, in particular drugs. While its basis is administrative law, the act has been influenced greatly by advances in the area of science. As science has evolved this has led to therapeutic advances which ultimately have influenced the law. The first Food and Drug Act in 1906 dealt with adulterated or misbranded food and drugs. This helped for the first time. to set legal and scientific standards for commodities. The 1938 FD&C Act went further to define safety and quality standards following a poisoning incident in 1933. The next change in the FD&C Act was the addition of the Delaney Clause. which attempted to set standards for human risk. A second medical tragedy in the early 1960s led to the 1962 Drug Amendments. These amendments set up guidelines for safety and efficacy testing of new drugs and made the regulatton of drugs the single most important activity of the FDA. Throughout the history of the FD&C Act. scientists of all kinds have been influential in helping to define options and set standards for drugs and testing. Numerous examples of scientistlegislator interaction exist. Recently, the FDA has turned more and more to the use of scientific advisory panels from the academic community to help deal \rith the important scientific-legal issues that they face. As science and medicine continue to change and progress in the coming years. the input of scientific experts will help to shape how new developments are regulated to ensure the best and safest medicine for all. The epitome of the U.S. Food and Drug Act and similar laws in other countt-tes. is that a drug must be safe and effective for use in medicine. The purpose of pharmacological testing is to measure effectiveness. safety, and relative freedom from unwanted side effects in particular. carcinogenicity and teratogenicity. Every ’ Present
address:
FDA,
5600
Fishers
Lane.
Rockville.
Maryland
20857
FOOD,
DRUG,
AND
COSMETIC
ACT
269
drug is studied first in animals and only after it has been found safe and effective in these tests, is it tried in humans. The regulatory aspects of the early food and drug laws in the United States were mostly administrative in nature. In 1938, amendments to the Food & Drug Act established safety as a criterion for new drugs. But even the evaluation of drugs for safety was more bureaucratic than scientific. The 1962 amendments to the act expanded the coverage of the FDA to include an evaluation of the efficacy for all new drugs (1). For the first time, a critical scientific evaluation of the pharmacology and clinical efficacy of a drug was a requirement prior to its approval for human use. In addition, the FDA was mandated to review all pre1962 drugs for efficacy. Major pharmaceutical companies argued that any scientific review of pre-1962 drugs should be performed by an independent scientific authority, not by the agency. Thus in 1966, the FDA contracted with the National Academy of Sciences-National Research Council (NAS-NRC) to conduct such a review. The FDA-working along with the NAS-NRC-undertook a massive program over a lo-year period to evaluate the effectiveness of virtually all drug products marketed prior to 1962. The NAS-NRC review was performed by 30 panels of experts in specific drug categories. They established guidelines delineating the functions of the panels and identifying the sources of evidence for evaluation of effectiveness: (1) available from the scientific literature; (2) available from the FDA, from the manufacturer, or other sources; and (3) the experience and informed judgment of the members of the panels. The NAS-NRC also established six ratings to serve as the basis for evaluating each drug claim ranging from effective, probably effective, possibly effective, ineffective, effective but, and ineffective as a fixed combination. The panels transmitted their first evaluation to the FDA in October 1967 and continued to submit monthly reports until mid-1968. The panels reviewed approximately 4000 different drug formulations. The panels found that about 7% of the drugs were ineffective for ail claims, many effective for all claims, and the majority somewhere in between. As the body with ultimate responsibility for determining drug effectiveness, FDA undertook to review the NAS-NRC findings before releasing the reports. In 1968, the FDA for the first time addressed the issue of the me-too drugs. At a government-industry conference the agency announced that it would apply the applicable panel findings not only to the original drug, but also to all subsequently marketed me-too products. This scientific study by the NAS-NRC and its review and implementation by the FDA become known as the Drug Efficacy Study Implementation review or DES1 review (2). Early in the DESI-review process, it became clear that the complete task of reviewing all current drugs was impossible and certain limitations would need to be applied. The decision was made to concentrate on the prescription drug products, of which there were almost 10,000, and to set aside for the present the nonprescription drugs, which numbered over 300,000. As the DES1 review was proceeding, the FDA concluded that the nonprescription drugs would require a different logistic approach. Instead of considering them on a product-by-product basis, the FDA decided to approach the project on an active ingredient basis. With active ingredients totaling less than a thousand, this alternative was clearly
270
MICHAEL
R. HAMRELL
preferable and more realistic. The FDA conceived the “OTC Drug review.“” which has just been completed after almost I2 years of work. The OTC review was organized and operated by the FDA itself. A series of 17 advisory panelscomposed of about 250 outside nongovernment experts-were established with each panel responsible for a particular therapeutic or pharmacologic class of drugs. The panels, which were staffed by the FDA, reviewed 20.000 volumes of data, held 508 meetings over 1047 days, and participated in numerous other conferences, exchanges, and deliberations (21. This OTC review has transformed the nonprescription drug market into one that has been established as safe and effective for the first time. This will allow the practitioner and the public to make educated decisions in the proper selection and use of such products in the future. The public fear of a single toxicologic parameter-carcinogenesis-has placed a heavy burden on toxicology for which science, at this point in time, is not prepared to provide definitive answers. Those involved in new drug development must be aware of both the science and politics of toxicology, as these forces impact on planning for future studies. They must attempt to provide understanding of the basic concepts involved. rather than conduct experiments and tests blindly following a fixed regulatory demand. Scientific knowledge is continually expanding. and new knowledge requires new evaluation of how to best apply the new concepts to the problems of safety evaluation (31. SUMMARY The future role of pharmacologists in the evaluation of drugs will increase as scientific knowledge and our understanding of drugs and disease processes increase. In addition, political issues and public fears will place further demands on the scientific community to try to influence the drug regulatory process. The FDA continually issues directives which guide all phases of drug development. from the identification of a chemical as being of potential interest on therapy. through all animal tests and clinical phases (41. REFERENCES 1. “Food Drug & Cosmetic Act.” United States Code, Title ?I & Amendmentr. 2. “Food & Drug Law. Cases and Materials” (R. A. Merrill and P. B. Hutt. Eds.!. pp. 37b.394 439-455. Foundation Press. New York. 1980. 3. “Drug Development” IC. E. Hamner. Ed.). pp. 66-67. 79-80. CRC Press. Boca Katon. 1;1;1.. 1982. 4. “Decision Making in Drug Research” (F. Gross. Ed.). pp. j--5. Raven Press. New York, 1983.
MEDICINE
33,
268-270
(1%)
The History of the United States Food, Drug and Cosmetic Act and the Development of Medicine MICHAEL
R.
HAMRELL’
The Food, Drug and Cosmetic (FD&C) Act of the United States forms the basic framework of the Food and Drug Administration (FDA), the agency that regulates the drug industry in this country. The act deals with the government‘s attempts to protect public health and individual welfare in the development and marketing of essential commodities, in particular drugs. While its basis is administrative law, the act has been influenced greatly by advances in the area of science. As science has evolved this has led to therapeutic advances which ultimately have influenced the law. The first Food and Drug Act in 1906 dealt with adulterated or misbranded food and drugs. This helped for the first time. to set legal and scientific standards for commodities. The 1938 FD&C Act went further to define safety and quality standards following a poisoning incident in 1933. The next change in the FD&C Act was the addition of the Delaney Clause. which attempted to set standards for human risk. A second medical tragedy in the early 1960s led to the 1962 Drug Amendments. These amendments set up guidelines for safety and efficacy testing of new drugs and made the regulatton of drugs the single most important activity of the FDA. Throughout the history of the FD&C Act. scientists of all kinds have been influential in helping to define options and set standards for drugs and testing. Numerous examples of scientistlegislator interaction exist. Recently, the FDA has turned more and more to the use of scientific advisory panels from the academic community to help deal \rith the important scientific-legal issues that they face. As science and medicine continue to change and progress in the coming years. the input of scientific experts will help to shape how new developments are regulated to ensure the best and safest medicine for all. The epitome of the U.S. Food and Drug Act and similar laws in other countt-tes. is that a drug must be safe and effective for use in medicine. The purpose of pharmacological testing is to measure effectiveness. safety, and relative freedom from unwanted side effects in particular. carcinogenicity and teratogenicity. Every ’ Present
address:
FDA,
5600
Fishers
Lane.
Rockville.
Maryland
20857
FOOD,
DRUG,
AND
COSMETIC
ACT
269
drug is studied first in animals and only after it has been found safe and effective in these tests, is it tried in humans. The regulatory aspects of the early food and drug laws in the United States were mostly administrative in nature. In 1938, amendments to the Food & Drug Act established safety as a criterion for new drugs. But even the evaluation of drugs for safety was more bureaucratic than scientific. The 1962 amendments to the act expanded the coverage of the FDA to include an evaluation of the efficacy for all new drugs (1). For the first time, a critical scientific evaluation of the pharmacology and clinical efficacy of a drug was a requirement prior to its approval for human use. In addition, the FDA was mandated to review all pre1962 drugs for efficacy. Major pharmaceutical companies argued that any scientific review of pre-1962 drugs should be performed by an independent scientific authority, not by the agency. Thus in 1966, the FDA contracted with the National Academy of Sciences-National Research Council (NAS-NRC) to conduct such a review. The FDA-working along with the NAS-NRC-undertook a massive program over a lo-year period to evaluate the effectiveness of virtually all drug products marketed prior to 1962. The NAS-NRC review was performed by 30 panels of experts in specific drug categories. They established guidelines delineating the functions of the panels and identifying the sources of evidence for evaluation of effectiveness: (1) available from the scientific literature; (2) available from the FDA, from the manufacturer, or other sources; and (3) the experience and informed judgment of the members of the panels. The NAS-NRC also established six ratings to serve as the basis for evaluating each drug claim ranging from effective, probably effective, possibly effective, ineffective, effective but, and ineffective as a fixed combination. The panels transmitted their first evaluation to the FDA in October 1967 and continued to submit monthly reports until mid-1968. The panels reviewed approximately 4000 different drug formulations. The panels found that about 7% of the drugs were ineffective for ail claims, many effective for all claims, and the majority somewhere in between. As the body with ultimate responsibility for determining drug effectiveness, FDA undertook to review the NAS-NRC findings before releasing the reports. In 1968, the FDA for the first time addressed the issue of the me-too drugs. At a government-industry conference the agency announced that it would apply the applicable panel findings not only to the original drug, but also to all subsequently marketed me-too products. This scientific study by the NAS-NRC and its review and implementation by the FDA become known as the Drug Efficacy Study Implementation review or DES1 review (2). Early in the DESI-review process, it became clear that the complete task of reviewing all current drugs was impossible and certain limitations would need to be applied. The decision was made to concentrate on the prescription drug products, of which there were almost 10,000, and to set aside for the present the nonprescription drugs, which numbered over 300,000. As the DES1 review was proceeding, the FDA concluded that the nonprescription drugs would require a different logistic approach. Instead of considering them on a product-by-product basis, the FDA decided to approach the project on an active ingredient basis. With active ingredients totaling less than a thousand, this alternative was clearly
270
MICHAEL
R. HAMRELL
preferable and more realistic. The FDA conceived the “OTC Drug review.“” which has just been completed after almost I2 years of work. The OTC review was organized and operated by the FDA itself. A series of 17 advisory panelscomposed of about 250 outside nongovernment experts-were established with each panel responsible for a particular therapeutic or pharmacologic class of drugs. The panels, which were staffed by the FDA, reviewed 20.000 volumes of data, held 508 meetings over 1047 days, and participated in numerous other conferences, exchanges, and deliberations (21. This OTC review has transformed the nonprescription drug market into one that has been established as safe and effective for the first time. This will allow the practitioner and the public to make educated decisions in the proper selection and use of such products in the future. The public fear of a single toxicologic parameter-carcinogenesis-has placed a heavy burden on toxicology for which science, at this point in time, is not prepared to provide definitive answers. Those involved in new drug development must be aware of both the science and politics of toxicology, as these forces impact on planning for future studies. They must attempt to provide understanding of the basic concepts involved. rather than conduct experiments and tests blindly following a fixed regulatory demand. Scientific knowledge is continually expanding. and new knowledge requires new evaluation of how to best apply the new concepts to the problems of safety evaluation (31. SUMMARY The future role of pharmacologists in the evaluation of drugs will increase as scientific knowledge and our understanding of drugs and disease processes increase. In addition, political issues and public fears will place further demands on the scientific community to try to influence the drug regulatory process. The FDA continually issues directives which guide all phases of drug development. from the identification of a chemical as being of potential interest on therapy. through all animal tests and clinical phases (41. REFERENCES 1. “Food Drug & Cosmetic Act.” United States Code, Title ?I & Amendmentr. 2. “Food & Drug Law. Cases and Materials” (R. A. Merrill and P. B. Hutt. Eds.!. pp. 37b.394 439-455. Foundation Press. New York. 1980. 3. “Drug Development” IC. E. Hamner. Ed.). pp. 66-67. 79-80. CRC Press. Boca Katon. 1;1;1.. 1982. 4. “Decision Making in Drug Research” (F. Gross. Ed.). pp. j--5. Raven Press. New York, 1983.