Appeal from a judgment of the District Court for the Southern District of New York entered by Judge Milton Pollack after a non-jury trial declaring that "Insulase," a drug product manufactured by Premo Pharmaceutical Laboratories, Inc., for use in the treatment of diabetes, is not a "new drug" within the meaning of § 201(p) of the Food, Drug and Cosmetic Act, 21 U.S.C. § 321(p), and that it may be marketed without first obtaining approval of a new drug application filed with the Food and Drug Administration pursuant to 21 U.S.C. § 355. Reversed and remanded with directions to dismiss the complaint.
Before Mansfield and Newman, Circuit Judges.*fn*
In this action by Premo Pharmaceutical Laboratories Inc. (Premo), a manufacturer of drugs, for a declaratory judgment and injunctive relief, 28 U.S.C. §§ 2201, 1331(a), the Government, the Secretary of Health, Education and Welfare and the Commissioner of Food and Drugs appeal from a decision and judgment of the District Court for the Southern District of New York entered on August 2, 1979, by Judge Milton Pollack and reported at 475 F. Supp. 52, declaring (1) that "Insulase," a drug product manufactured by plaintiff-appellee, Premo, for use in the treatment of diabetes, is not a "new drug" within the meaning of § 201(p) of the Food, Drug and Cosmetic Act, 21 U.S.C. § 321(p),*fn1 (2) that any regulatory action by the Government on the basis that Insulase is a "new drug" is unlawful, and holding that Premo may market Insulase without obtaining approval of its new drug application from the Food and Drug Administration (FDA), filed pursuant to 21 U.S.C. § 355(a).*fn2 We reverse and remand with directions to dismiss the complaint.
The active ingredient in Premo's Insulase is chlorpropamide (CPA), which is also the active ingredient in "Diabinese," an FDA-approved drug product which has been made and marketed by Pfizer Laboratories, Inc. for many years. However, the inactive ingredients in the two drugs, known as excipients, differ. Excipients are typically added to an active ingredient to form a tablet, capsule coating, coloring or flavor. As the district court found, although an inactive ingredient may by itself be safe, it may, when combined with an active drug ingredient, affect a drug's safety and effectiveness.
Under § 505 of the Act, 21 U.S.C. § 355, no person may market a new drug unless he files with the FDA a new drug application (NDA) demonstrating that the drug is both safe and effective for the use for which it is intended and obtains FDA approval. Normally the applicant furnishes controlled chemical tests and investigations showing that the product is safe and effective, 21 U.S.C. § 355(d). But where the drug product is claimed to be a copy of one already approved by the FDA on the basis of such submissions sometimes called a "me-too" drug the applicant may file with the FDA an "abbreviated new drug application" (ANDA), which relies upon the safety and effectiveness tests conducted with respect to the FDA-approved drug (sometimes called the "pioneer drug"). The FDA will only approve an ANDA, however, where the "me-too" drug product is shown to be the therapeutic equivalent of the pioneer and safe and effective in accordance with 21 U.S.C. § 355(d). See generally, Hoffmann-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C.1975).
In the present case Premo in 1978 first filed with the FDA an ANDA for Insulase, submitting among other things a comparative bioavailability study*fn3 with respect to the Insulase and Pfizer's Diabinese. The FDA found the data insufficient to establish therapeutic bioequivalence*fn4 and requested further evidence demonstrating the performance of Insulase under conditions similar to actual use. Premo chose not to comply and began marketing Insulase without FDA approval, which led the FDA in December, 1978, to file seizure actions against Insulase in five United States district courts pursuant to 21 U.S.C. § 334*fn5 on the ground that Insulase was a new drug being marketed without prior FDA approval.
In the meantime, in November, 1978, Premo had commenced the present action seeking to enjoin the FDA from instituting any regulatory action against it under 21 U.S.C. § 334 and in January, 1979 it amended its complaint to seek a declaratory judgment to the effect that Insulase was not a "new drug" within the meaning of 21 U.S.C. § 321(p). It also sought an injunction restraining the defendants from instituting any seizure action under the Act. The court denied preliminary injunction on the ground that there were unresolved questions as to the safety and effectiveness of Insulase and held a trial to determine whether Insulase was a "new drug."
At trial Premo contended that the term "drug" as used in "new drug" refers only to the active ingredient in the product, as distinguished from excipients. Judge Pollack properly rejected this argument, pointing out that "drug" as defined in § 201(g)(1)(B) of the Act, 21 U.S.C. § 321(g)(1)(B)*fn6 encompasses drug products as well as active ingredients, 475 F. Supp. at 54, and that "differences in excipients may impair the safety or effectiveness of a drug product even though its active ingredient is generally recognized as safe and effective." Id. at 55. See in accord Pharmadyne Laboratories, Inc. v. Kennedy, 466 F. Supp. 100, 104 (D.N.J.), affd., 596 F.2d 568, 571 n.6 (3d Cir. 1979). The Government contended, relying on the language of 21 U.S.C. § 321(p), that any drug product constitutes a "new drug" unless it is shown that the drug is "generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use . . . ." This reliance on the plain language of the statute was rejected by the district court on the ground that it would require FDA approval of all drug products, frustrating the "purpose of the Act to allow the marketing of safe and effective "me-too' drug products without costly and time-consuming FDA approval." Id. at 55. The district court ruled that where the active ingredient in a questioned product is the same as that in a product already approved by the FDA as safe and effective, but the excipients differ, the questioned product is not a "new drug" if the excipients are "generally recognized individually to be safe" and "the evidence has shown no reasonable possibility that differences between the excipients in the recognized and questioned products will make the questioned product less safe or effective than the recognized product." Id. at 55.
The district court's approach to the "new drug" issue resulted in its undertaking the task of resolving complex scientific issues as to whether Insulase had the same bioavailability as Diabinese and thus was a safe and effective therapeutic equivalent, rather than confining itself to determining whether, based on material usage over a substantial period of time, and published scientific studies or other publicly available data, scientific experts "generally recognized" Insulase to be safe and effective and therefore not a "new drug." The trial was reduced largely to a battle of scientific experts centered around private, unpublished tests made by Premo to determine the bioavailability of Insulase as compared with Diabinese. Premo's experts were of the opinion, based on these studies, that subject to some qualifications the two drugs were therapeutically equivalent and therefore interchangeable. The Government experts criticized severely the analytical methods employed by Premo's researchers in making the studies, the use by Premo of a computer to predict steady blood levels of Insulase rather than of a multiple dosage test, and the failure to use a "titration" procedure to determine the amount of drug in a patient's blood. They also differed in their interpretation of the results of the studies. Since the studies had not been published and most (if not all) of the witnesses had learned of Insulase only in preparation for trial, none of the experts, including Premo's witnesses, could testify that Insulase was generally recognized as safe and effective or as the therapeutic equivalent of Diabinese.
Judge Pollack, using his own definition of a "new drug," found that Premo's bioavailability study "was conducted in accordance with accepted and reliable scientific methods," 475 F. Supp. at 56, that it was "of no clinical significance that Diabinese delivers more CPA (chlorpropamide) than Insulase after the first tablet is taken," that the "differences in the steady state blood levels achieved by the two products are not significant," and "that Insulase is not less safe and effective than Diabinese." Based on these scientific findings he concluded that the two drugs were therapeutic equivalents and that Insulase was therefore not a "new drug." The district court did not withdraw or change its earlier finding made in denying a preliminary injunction to the effect that
"(T)he specific combination of active drug and excipients which constitutes Insulase are not at this time generally recognized among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs as safe and effective for use under the conditions prescribed, recommended or suggested in the labeling thereof." (A. 301).
Accordingly the district court entered a judgment declaring that Premo's Insulase "is not a new drug within the meaning of the Federal Food, Drug and Cosmetic Act" and that "Regulatory action by the defendants against Premo and/or Premo's chlorpropamide's (sic) tablets on the basis that said product is a new drug is unlawful." From this judgment defendants appeal.
At the outset we must consider whether the district court had subject matter jurisdiction over this lawsuit, in view of the pendency of seizure actions instituted against Insulase by the Government in five other districts and the pendency of Premo's ANDA before the FDA for approval of Insulase as safe and effective. Had the district court issued an order enjoining the multiple seizure cases, we might well dismiss the present action in accordance with the well settled principle that federal courts lack jurisdiction to enjoin seizure actions instituted by the FDA under 21 U.S.C. § 334. Ewing v. Mytinger & Casselberry, Inc., 339 U.S. 594, 601, 70 S. Ct. 870, 873, 94 L. Ed. 1088 (1950). See also Abbott Laboratories v. Gardner 387 U.S. 136, 146-48, 87 S. Ct. 1507, 1514-15, 18 L. Ed. 2d 681 (1967); Pharmadyne Laboratories, Inc. v. Kennedy, 596 F.2d 568 (3d Cir. 1979). Here, however, the district court denied injunctive relief and instead merely issued a declaratory judgment. Declaratory judgment actions on "new drug" issues have been entertained by the courts in the past, see A. M. P. v. Gardner, 389 F.2d 825 (2d Cir.), cert. denied, 393 U.S. 825, 89 S. Ct. 86, 21 L. Ed. 2d 95 (1968), and the applicability of Ewing to declaratory judgments as opposed to injunctive relief is unsettled. The ...