on the use of chemical substances added to foods. During the 85th Congress, legislation was agreed upon and the Food Additives Amendment of 1958 was signed into law." Its major provision was the requirement of pre-marketing clearance of chemical additives whose safety is not generally recognized. Substances added to food which qualified scientists generally recognized as safe under the conditions of their intended use, are not "food additives" and are exempt from the pre-marketing clearance requirements. This classification of "generally recognized as safe" (GRAS) may be made either on the basis of data derived from scientific procedure or, in the case of substances in use prior to January 1, 1958, on the basis of experience drawn from common and safe use in food. The Amendment required that the formula and a description of the proposed conditions for use of any substance newly proposed for addition to food must be submitted to and approved by the Food and Drug Administration. Information must be presented showing the identity of the new additive, its chemical composition, how it is manufactured, and the methods to be used to detect and measure its presence in the food supply at the levels of expected use. Data must establish that the proposed testing methods are of sufficient sensitivity to determine compliance with the regulations. There must also be data establishing that the additive will accomplish the intended physical or technical effect in the food, and that the amount proposed is no higher than that reasonably necessary to accomplish this effect. Finally, data must be provided establishing that the additive is safe for its intended use. This requires scientific evidence ordinarily obtained from feeding studies and other tests using the proposed additive at various levels in the diet of two or more species of animals. If the agency approves the application for use of the additive, it can establish the maximum amount of the substance, or tolerances, which would be permitted in foods. Although the Food, Drug, and Cosmetic Act of 1938 already prohibited poisonous or deleterious substances in foods except in certain instances where such substances were allowed in small amounts, the lack of a pre-market clearing requirement had made this provision relatively ineffective. In order to bar the use of a dangerous additive, the FDA had to assume the burden of proof and show the additive was poisonous or deleterious. This process was extremely time-consuming and while it continued, the additive remained on the market. The 1958 Food Additives Amendment applied the principal of pre-market clearance to food additives for the first time. During Congressional consideration of the proposed Food Additives Amendment, two important areas of disagreement arose. The first of the controversies concerned what is now known as the "Delaney anticancer clause." Representative Delaney who had favored strong additive control legislation had sponsored a proviso to forbid approval of additives which were found to be cancer-inducing in man or in animals. The bill reported by the House Committee on Interstate and Foreign Commerce did not contain such a provision, although the Committee had considered the proposal. There was opposition to the clause 21 72 Stat. 1784, 85th Cong., 2d sess.; Sept. 6, 1958. by the Food and Drug Administration, and by a number of scientists who opposed the clause on the grounds that it interfered with the exercise of scientific judgment. Why, they argued, should an additive at safe levels in foods used by man be barred simply because the same substance at higher levels induced cancer in animals? Some also thought it unnecessary to single out one specific disease category within the legislation. In any event, the bill, amended on the House floor, contained the Delaney clause when signed into law: 22 Provided, that no additive shall be deemed to be safe if it is A second problem area in the bill as reported from the House Committee related to the question of how to deal with additives already in use and on the market. Industry spokesmen originally proposed that additives already in use be exempted from the provisions of the bill, while a number of Members objected on the grounds that such an exemption would leave many untested additives still in use. As a result, the bill provided for the following scheme: new additives not in use before January 1, 1958, would be automatically subject to the preclearance requirements set out in the bill; substances generally recognized as safe (GRAS substances) after years of repeated use were to be exempted from the procedures of the bill; additives approved under the old procedures contained in the Food, Drug, and Cosmetic Act or under the meat and poultry inspection laws were also exempted, although they could be removed from the market if later discovered to be hazardous; and additives previously untested and unapproved already on the market as of January 1, 1958, would be subject to the procedure in the bill, except that they were allowed a grace period, ranging from 18 to 30 months. During this time they could apply for or otherwise receive a tolerance standard and could remain on the market during this period of time. Congress passed legislation in 1961 23 and 1964 24 which extended the grace period through December 31, 1965. XIV. ORANGE COLORING In 1959, Congress passed legislation to allow a new coal-tar dye, FD&C Red No. 2, to be used to color oranges until September 6, 1961.25 The legislation was necessary because the dye was found toxic at certain levels and therefore its use was prohibited under the Food, Drug, and Cosmetic Act of 1938. Similar legislation had been passed in 1956 to permit the use of FD&C Red No. 32, a slightly more toxic coloring. In both instances, the FDA held that it did not have the authority to establish tolerance levels for coal-tar dyes even at levels which presented no danger to health. On December 15, 1958, the Supreme Court upheld the FDA's interpretation that the 1938 Act outlawed the use of any coal-tar dye in any 22 Congressman Delaney, a member of the House Rules Committee, convinced the Administration of the wisdom of accepting his amendment. 23 75 Stat. 42. 87th Cong., 1st sess.; Apr. 7, 1961. amount.26 The Court ruled that Red 32 could not be used after March 1, 1959. The decision had a wide impact; it affected the use of all coal-tar dyes not only in foods but in drugs and cosmetics. As a result of the ruling, the food, drug and cosmetic industry called for a revision of the Act to allow tolerances to be set for safe use of colors. The FDA was in favor of such a change and had sent a letter proposing such to the House Committee on Interstate and Foreign Commerce on June 27, 1958 and again on February 19, 1959. However, although legislation regarding the use of all color additives would not be passed until 1960, this emergency legislation was passed in 1959 to allow the orange growers to continue use of FD&C Red No. 2. XV. INSECTICIDE AMENDMENTS OF 1959 The Pesticide Chemical Amendments of 1954 established controls on residues of pesticides left on fresh fruits and vegetables. Subsequent to its enactment, new forms of chemical insecticides were developed for use in agriculture which were not covered by the existing provisions. These new insecticides were nematocides, defoliants, dessicants, and plant regulators. In 1959, Congress passed legislation which brought these chemicals under the 1954 Pesticide Chemical Amendments.27 XVI. COLOR ADDITIVE AMENDMENTS OF 1960 In 1960, Congress revised the provisions of the 1938 Food, Drug, and Cosmetic Act regarding the use of color additives. One of the major provisions of the Amendment was the requirement that the conditions for safe use of a color additive be established by regulation. The new law placed on the manufacturer the burden of proof that a color additive was safe for the intended use whereas before it had been up to the Government to prove an additive was unsafe. The regulations regarding use of an additive could set forth tolerance limitations which specified the maximum amount of the additive permitted to remain on or in the product. In addition, the Amendment also required all color additives to be batch-certified unless exempted by the Secretary of HEW. These color additives already on the market were allowed up to two-and-a-half years to obtain FDA approval. Premarket testing and batch certification had previously been required only for coal-tar dyes. A change was also made in the existing requirement that a coal-tar dye could be used only if found to be harmless in any amount. The new legislation allowed the use of any coal-tar dye or any other color additive if it could be established that the substance was safe for the intended use, a change in the Food, Drug, and Cosmetic Act which was supported by both spokesmen from industry and HEW. The cosmetic industry had a particular interest in the provision as the FDA had recently removed 14 dyes used for coloring lipstick from the list of approved coal-tar dyes even though many of the dyes were considered safe as they were being used. The controversial Delaney Clause which prohibited use of any food additives known to produce cancer in man or animals was applied to 28 Flemming v. Florida Citrus Exchange, 358 U.S. 153, cert. denied, 358 U.S. 948. 27 73 Stat. 286, 86th Cong., 1st sess.; Aug. 7, 1959. color additives. Many industry spokesmen who opposed the Delaney Clause in 1958 also opposed its inclusion in the Color Additives Amendments. However, the Secretary of HEW testified strongly supporting application of the Delaney Clause to color additives.28 The preponderance of scientific evidence clearly dictates our position: our advocacy of the anticancer proviso in the proposed color additives amendment is based on the simple fact that no one knows how to set a safe tolerance for substances in human foods when those substances are known to cause cancer when added to the diet of animals. XVII. THE DRUG AMENDMENTS OF 1962 (THE KEFAUVER-HARRIS The Drug Amendments of 1962 were, like the 1938 Act, enacted into law following a serious drug incident, the "thalidomide disaster".29 Use of thalidomide, a sedative, by pregnant women can cause a severe deformity of the child called phocomelia. Although the drug was never approved by the FDA for commercial marketing, it was distributed to doctors for experimental purposes. A 1962 survey by the FDA showed the drug was given to 3,879 women of child-bearing age, nine of whom gave birth to a malformed child. Legislation to achieve many of the objectives of the 1962 Amendments, like the 1938 legislation, was pending before the Congress when the thalidomide incident occurred. Unlike the 1938 Act, however, the Drug Amendments of 1962 did not represent an entire revision of current law or the drafting of a completely new proposal. Instead, the legislation extended, expanded, and strengthened the regulatory authority of the Food and Drug Administration, particularly as to prescription drugs. The Food and Drug Administration had taken the position that the 1938 law was defective in the following ways: 30 1. The producer of a new drug did not have to establish that his product would be effective, as well as safe, for its intended uses. 2. FDA had to work against deadlines of 60 and 180 days to prevent the automatic approval of new drug products. 3. There were no provisions requiring regular record keeping and reporting of clinical and other experience with new drugs. 4. The FDA could not remove a new drug from the market unless it could prove that it was an unsafe product; it was not enough just to show that new developments had drawn the question of the drug's safety into issue. 5. There were inadequate controls over the distribution and use of investigational drugs, as the thalidomide episode showed. 6. Prescription drug advertising was virtually unregulated. 7. Trade names for products were being used without proper reference to generic or established names, resulting in confusion for the medical profession. 28 House of Representatives. Committee on Interstate and Foreign Commerce, Subcommittee on Public Health and Environment. Report on Color Additive Amendments of 1958, 86th Cong., 2d sess.: June 7, 1960. 20 76 Stat. 780, 87th Cong., 2d sess. ; Oct. 10, 1962. 30 Hearings before a Subcommittee of the House Committee on Government Operations on Drug Safety; statement by George P. Larrick, Commissioner, Food and Drug Administration; Mar. 24, 1964. 56-782 O 75 - 22 8. The quality of "old" drugs was not assured, as it was with “new drugs". 9. Only five classes of antibiotic drugs were subject to routine batchtesting and certification. 10. Factory inspection authority was severely restrictive. The changes brought about by the 1962 Amendments included the following: 1. The Food and Drug Administration was authorized to establish for drugs, by regulation, current good manufacturing practices. Drugs which are not manufactured under conforming methods or in conforming facilities are considered adulterated. 2. The factory inspection authority was widely expanded to all matters bearing on violations of the Act. Included within the reach of this authority are data concerning the qualifications of technical and professional personnel employed by the manufacturer. Each establishment must be inspected at least once every two years. 3. Every manufacturer had to register annually with the Department of Health, Education, and Welfare. This provision aids in identifying and inspecting all places where drugs are manufactured, and aids in certain enforcement areas. Drugs coming from non-registered plants are deemed misbranded. 4. The Amendments provided that a new drug cannot be marketed until the FDA approves it as having met the statutory requirements for safety and efficacy. The 1938 law permitted automatic clearance of drugs through lapse of time without FDA action. Approval was now conditioned upon the showing of "substantial evidence" of efficacy, and the burden for proof rested with the manufacturer. 5. Labeling now took on a material bearing on the matter of new drug approval-it must not be false or misleading in an particular. This prohibition relates to the claimed effects of such drugs, as well as to other aspects of labeling. 6. The Secretary of HEW, on finding an imminent hazard to the public health, could immediately suspend a new drug approval, with the manufacturer afforded an expedited hearing, 7. Withdrawal from the market of a previously approved drug could be made for any one of the following reasons: (a) if its labeling is found to be false or misleading in any particular and it is not corrected within a reasonable time after notice from FDA; (b) if, after reevaluation in the light of new evidence, its safety cannot be established or its claimed efficacy is not supported by substantial evidence; (c) if, after reevaluation in the light of new evidence, it is found that manufacturing facilities, methods, or controls employed in manufacturing or packaging do not conform with standards of good manufacturing practices and are not changed after a reasonable period of time; and (d) if the manufacturer fails to establish a system of maintaining adequate records, fails to make required reports, or refuses to give the FDA access to such records. 8. With respect to drugs already on the market, the manufacturer was now required to report promptly to the FDA information con |