U.S. v. Undetermined Quantities of Various Articles of Drug ... Equidantin Nitrofurantoin Suspension

• Citation: 675 F.2d 994
• Decision Date: 15 April 1982
• Docket Number: No. 81-1793,81-1793
• Parties: UNITED STATES of America, Appellee, v. UNDETERMINED QUANTITIES OF VARIOUS ARTICLES OF DRUG ... EQUIDANTIN NITROFURANTOIN SUSPENSION .... Appeal of PERFORMANCE PRODUCTS, INC.
• Court: United States Courts of Appeals. United States Court of Appeals (8th Circuit)

Page 994

675 F.2d 994

UNITED STATES of America, Appellee, v. UNDETERMINED QUANTITIES OF VARIOUS ARTICLES OF DRUG ...

EQUIDANTIN NITROFURANTOIN SUSPENSION ....

Appeal of PERFORMANCE PRODUCTS, INC.

No. 81-1793.

United States Court of Appeals,

Eighth Circuit.

Submitted Feb. 9, 1982.

Decided April 15, 1982.

John F. Lemker, Jr., Burditt & Calkins, Chicago, Ill., Joseph F. Devereux, Jr., Gunn, Lane & Devereux, P.C., St. Louis, Mo., for Performance Products, Inc., claimant-appellant.

William F. Baxter, Asst. Atty. Gen., John J. Powers, III, Frederic Freilicher, Attys., Dept. of Justice, Washington, D.C., for appellee.

Before LAY, Chief Judge, McMILLIAN, Circuit Judge, and OVERTON, ^* District Judge.

McMILLIAN, Circuit Judge.

Performance Products, Inc. (Performance) appeals from a final judgment entered in the District Court ¹ for the Eastern District of Missouri condemning as adulterated and seizing certain quantities of an animal drug called Equidantin and other materials used in its manufacture. For reversal Performance argues that Equidantin is not a "new animal drug" within the meaning of 21 U.S.C. § 321(w), and thus not subject to premarketing clearance by the Food and Drug Administration (FDA) under 21 U.S.C. § 360b(b), because (1) Equidantin is generally recognized as safe and effective and (2) Equidantin is a generic drug or copy of Dantafur, a drug that has been approved by the FDA. For the reasons discussed below, we affirm the judgment of the district court.

Performance is the manufacturer of Equidantin. Equidantin has been on the market since 1970 and is intended for use in the treatment of equine tracheopharyngitis ("race track cough") and equine urinary tract bacterial infections. The active ingredient in Equidantin is nitrofurantoin, which is also the active ingredient in Dantafur, an FDA-approved drug manufactured and marketed by Norwich-Eaton Pharmaceuticals. Equidantin and Dantafur contain the same amount of nitrofurantoin per dosage unit. However, the inactive ingredients in the two drugs are different. Dantafur contains alcohol among other inactive ingredients. According to the government's evidence, Equidantin contains the following inactive ingredients: xantham gum (a suspending agent), magnesium aluminum silicate (a suspending agent), potassium sorbate (a preservative), propylene glycol, citric acid (a buffer), anethole (a flavoring agent), sodium saccharin (a flavoring agent), vanillin, and deionized water.

Equidantin is a generic drug or copy (a "me-too" version) of Dantafur, the FDA-approved "brand name" or pioneer drug. A generic drug contains the same active ingredient or "incipient" as an FDA-approved pioneer drug but may contain different inactive ingredients or "excipients." The manufacturing techniques used by each manufacturer may also differ. It is not disputed that differences in the manufacturing process and variations in the inactive ingredients may affect a drug's "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) (1981).

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 drug 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.

United States v. Premo Pharmaceutical Laboratories, Inc., 511 F.Supp. 958, 962-63 (D.N.J.1981) (Premo II ) (footnote omitted) (excellent discussion of factors which may affect bioavailability); see United States v. Generix Drug Corp., 654 F.2d 1114 (5th Cir. 1981) (Generix), cert. granted, --- U.S. ----, 102 S.Ct. 1610, 71 L.Ed.2d --- (1982); Premo Pharmaceutical Laboratories, Inc. v. United States, 629 F.2d 795 (2d Cir. 1980) (Premo I); United States v. Articles of Drug (Lannett Co.), 585 F.2d 575 (3d Cir. 1978) (Lannett); see also Pharmadyne Laboratories, Inc. v. Kennedy, 466 F.Supp. 100, 103 (D.N.J.) (Pharmadyne), aff'd on other grounds, 596 F.2d 568 (3d Cir. 1979).

The government's basic position in the present case, and in the above cited cases, all of which involve generic drugs, is that because many factors, particularly the manufacturing process and choice of inactive ingredients, may affect a generic drug's bioavailability and thus its bioequivalence to its pioneer drug, the generic drug is a "new drug" (or "new animal drug") and thus subject to premarketing clearance by the FDA, even though the pioneer drug has already been approved by the FDA. Not surprisingly, the manufacturers of generic drugs oppose the FDA's position. Basically the position of the manufacturers is that because the generic drug contains the same active ingredient as the FDA-approved pioneer drug, the generic drug is not a "new drug" (or "new animal drug") and thus not subject to FDA premarketing clearance. The manufacturers argue that bioavailability and bioequivalence are not relevant to the question of "new drug" (or "new animal drug") status. Two circuit courts have addressed this issue; the Second Circuit has essentially agreed with the government's position, see Premo I, 629 F.2d 795; the Fifth Circuit has essentially agreed with the manufacturers' position, see Generix, 654 F.2d 1114.

The present action began in July 1979 when the government filed a complaint in district court seeking condemnation and seizure of undetermined quantities of Equidantin and materials used in its manufacture. The government argued that Equidantin was an adulterated drug within the meaning of 21 U.S.C. § 351(a)(5) ² and as such subject to seizure under 21 U.S.C. § 334(a)(1). ³ The government's characterization of Equidantin as an adulterated drug depended upon Equidantin's status as a "new animal drug" within the meaning of 21 U.S.C. § 321(w). ⁴ Because a new animal drug cannot be marketed without an FDA-approved "new animal drug application" or an abbreviated new animal drug application, 21 U.S.C. § 360b(b), ⁵ and it was not disputed that there was no FDA-approved new animal drug application on file for Equidantin, the government argued that Equidantin was "unsafe" under 21 U.S.C. § 360b(a)(1) (A) ⁶ and therefore "adulterated" under 21 U.S.C. § 351(a)(5). The district court issued the warrant and the United States Marshal seized approximately 86 quarts of Equidantin, approximately 410 gallons of in-process drug product, 3.4 kilograms of bulk nitrofurantoin powder, and labels and accompanying materials.

Performance intervened in the condemnation action and filed a claim to the seized items. Performance did not dispute that FDA approval is the prerequisite to marketing a new animal drug, but argued that Equidantin is not a new animal drug within the meaning of 21 U.S.C. § 321(w) because it is generally recognized as safe and effective and because it is a generic or copy of Dantafur, the FDA-approved pioneer drug.

Following a bench trial in which both sides presented expert testimony, the district court found that Equidantin was a new animal drug within the meaning of 21 U.S.C. § 321(w) because it was not generally recognized among qualified experts as safe and effective. United States v. Undetermined Quantities of Various Articles of Drug (Equidantin Nitrofurantoin Suspension), No. 79-0913-C(C) (E.D.Mo. May 29, 1981) (slip op. at 5-6). The district court also found that FDA approval of Dantafur did not constitute general recognition among qualified experts that either Dantafur or Equidantin was safe and effective within the meaning of 21 U.S.C. § 321(w) and, further, that even if Dantafur was generally recognized among qualified experts as safe and effective, Equidantin would not be exempt from FDA premarketing clearance as a new animal drug because the two drugs' inactive ingredients and manufacturing processes differed. Id. at 5. The district court then ordered the seized items destroyed, but later stayed that order pending appeal.

The issue in this case is thus whether Equidantin is a "new animal drug" within the meaning of 21 U.S.C. § 321(w). The scope of FDA regulation depends upon the statutory definitions. A brief outline of the history of FDA regulation will provide a background and perspective to our discussion. 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); see generally Note, Drug Efficacy and the 1962 Drug Amendments, 60 Geo.L.J. 185 (1971). It should also be noted that the analysis followed in the cases is the same for human and animal drugs. United States v. Naremco, Inc., 553 F.2d 1138, 1142 n.5 (8th Cir. 1977), citing United States v. Articles of Food and Drug (Coli-Trol 80 Medicated), 372 F.Supp. 915, 921 (N.D.Ga.1974), aff'd, 518 F.2d 743 (5th Cir. 1975).

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...