under "DISCUSSION," but also that which was received conditionally and is now determined by me to be irrelevant. See p. 961, note 1 supra.
The Food and Drug Act of 1906, ch. 3915, 34 Stat. 768, was the first legislation of national scope directed at the regulation of drug products. The Act set standards of purity for drugs sold in the United States and required accurate labeling of the drugs' contents. Id. §§ 1, 2, 7. The Act also made unlawful the marketing of adulterated or misbranded drugs and provided for removal of such drugs from the market through libel actions. Id. § 2. There were, however, no provisions regulating false claims of efficacy until the Food and Drug Act of 1906 was amended in 1912 to declare misbranded drugs that were not effective for use under the conditions for which they were recommended.
The greatest defect in the Act, however, was its failure to provide any mechanism for premarketing agency clearance. It was impossible to prevent an unsafe or ineffective drug from reaching the market. In 1938 the "wonder drug" "Elixir of Sulfanilamide," a solution based on diethylene glycol and (significantly for the present case) a presumed harmless, inert solvent ingredient, went on the market. Apparently, no tests for toxicity were performed prior to marketing; and almost one hundred people died before the drug could be withdrawn.
This Sulfanilamide tragedy led to the Federal Food, Drug, and Cosmetic Act of 1938, 21 U.S.C. §§ 301-392 (1976 & Supp. I 1977) (amended 1962), with provisions for premarketing review of new drugs. This review, however, was directed solely to assuring drug-product safety. It was not until the Act was amended in 1962 that the definition of "new drug" was enlarged to include drugs not generally recognized as safe and effective.
The 1962 amendments changed the data-reporting requirements of the "new drug" procedure to require submission of data showing efficacy and, in place of automatic approval of NDAs not disapproved, the procedure under the 1938 Act, the 1962 amendments required positive agency approval to make an NDA effective. See Note, Drug Efficacy and the 1962 Drug Amendments, 60 Geo.L.J. 185 (1971). For further discussion of the history of drug regulation by the federal government, see Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 93 S. Ct. 2469, 37 L. Ed. 2d 207 (1973); USV Pharmaceutical Corp. v. Weinberger, 412 U.S. 655, 93 S. Ct. 2498, 37 L. Ed. 2d 244 (1973); United States v. Articles of Drug (Lannett), 585 F.2d 575 (3d Cir. 1978); Hoffmann-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C.1975).
Where a drug product is claimed by its manufacturer to be a copy of a product already approved by FDA on the basis of an NDA, the manufacturer may file with FDA an ANDA which relies upon the safety and effectiveness tests performed with respect to the FDA-approved pioneer product. However, FDA will approve an ANDA only where the "me-too" product is shown to be the therapeutic equivalent of the pioneer and safe and effective in accordance with 21 U.S.C. § 355(d) (1976). See Premo Pharmaceutical Laboratories, Inc. v. United States, 629 F.2d 795, at 798 (2d Cir. 1980) ("Premo "). See generally Hoffmann-LaRoche, Inc. v. Weinberger, supra. No ANDA has been approved for the eight Premo products in suit.
Much of the testimony on this hearing related to bioavailability. Bioavailability is "the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action." 21 C.F.R. § 320.1(a) (1980). See Dorland's Illustrated Medical Dictionary 200 (25th ed. 1974). If there is no significant difference between the rate and extent of absorption of two drugs administered at the same molar dose of therapeutic moiety under similar experimental conditions, the drugs are said to be bioequivalent. See 21 C.F.R. § 320.1(e) (1980). When two different drug products are to be used interchangeably in the treatment of illness, it can be critical that the products are bioequivalent that is, that there be no significant difference in the products' bioavailability. A drug that is less bioavailable than that for which it is substituted will deliver less of its active ingredient than expected; a drug that is more bioavailable than that which it replaces presents the danger of overdosage.
See P. Ex. 4, PP 8-17 (Crout Affidavit); P. Ex. 3, PP 18-22 (Cortell Affidavit); P. Ex. 6, PP 9-11 (Perel Affidavit); P. Ex. 2, P 39 (Cabana Affidavit).
The Government argues that physicians and patients generally believe or assume that generic versions of "brand-name" products are bioequivalent to the respective pioneer drugs themselves. Because the generic versions are usually significantly less expensive than the pioneer drugs, they are frequently freely substituted for their more expensive counterparts. Thus, the Government contends, it is crucial that the products be, in fact, bioequivalent. Contending that, because so many factors independent of a product's active ingredient and even, as indicated below, of its inactive ingredients can affect a drug product's bioavailability (and thus its bioequivalence to an FDA-approved medication), the Government concludes that absent preclearance of each of Premo's products named in the complaint, there can be no assurance of its safety and effectiveness, and it must be considered a "new drug" within the meaning of section 321(p) of the Act.
Premo argues that so long as the active ingredient in its product is the same as the active ingredient in the approved pioneer drug all other questions are irrelevant because the active ingredient, the "drug," has been recognized as safe and effective by the FDA.
There are many factors that can affect a drug's bioavailability. Among these are the particle size and crystalline form of the active ingredient; the choice of inactive ingredients (excipients), such as binders and fillers; the facilities and controls used in the manufacture and processing of the drug; and the environmental conditions during manufacture and storage.
The particle size and crystalline form of the active ingredient can be crucial because these factors can affect the drug's solubility and/or the rate that the drug dissolves in gastrointestinal fluids. This, in turn, can affect the bioavailability of the active ingredient itself.
P. Ex. 1, P 10 (Barr Affidavit); P. Ex. 7, at 4 (Shangraw Affidavit); P. Ex. 2, P 24 (Cabana Affidavit); P. Ex. 4, P 11 (Crout Affidavit).
The choice of inactive ingredients is of great importance, because these ingredients may interact with the product's active ingredient and thereby significantly increase or decrease the bioavailability of the active ingredient. P. Ex. 1, P 10 (Barr Affidavit); P. Ex. 7, at 6 (Shangraw Affidavit); P. Ex. 2, PP 14, 25 (Cabana Affidavit); P. Ex. 4, P 11 (Crout Affidavit). Diluents, used to provide tablet bulk, can affect bioavailability in numerous ways, such as by interfering with the drug's absorption. P. Ex. 7, at 7 (Shangraw Affidavit). Binders, used to provide tablet cohesion, may retard the rate and extent of dissolution when used inappropriately. Id. And disintegrants and surfactants, added to tablets or capsules to cause them to break up after ingestion, can also affect the drug's dissolution and thus its bioavailability. Id. at 7-8.
Even if the characteristics of a product's active ingredient are kept constant, and precisely the same excipients are used, the pharmacological properties of a "me-too" drug product may still differ substantially from those of the pioneer drug because of the manufacturing process itself. P. Ex. 1, P 10 (Barr Affidavit); P. Ex. 7, at 9 (Shangraw Affidavit); P. Ex. 2, P 24 (Cabana Affidavit); P. Ex. 4, P 11 (Crout Affidavit). In fact, as set forth in an affidavit submitted on behalf of the Government, Dr. Ralph Shangraw, Chairman of the Department of Pharmaceutics at the University of Maryland School of Pharmacy, states:
(E)ven if different manufacturers of the same tablet-form drug product start with the same active ingredient (manufactured under the same conditions by the same firm), use exactly the same inactive ingredients from the same sources, and manufacture the product under exactly the same conditions, using exactly the same equipment, it still may be possible that the finished dosage form (tablet) will not perform in an identical manner in the same patient.