The opinion of the court was delivered by: LACEY
Defendant Premo Pharmaceutical Laboratories, Inc. (Premo) is a manufacturer and distributor of prescription drugs. Defendant Seymour N. Blackman, Premo's president, has responsibility for and authority over operation of the corporation. Involved are the following drug products manufactured by Premo: (1) triamterene with hydrochlorothiazide capsules, marketed by Premo under the name Triamthiazide a generic version of Dyazide, manufactured by Smith, Kline and French (used in the treatment of hypertension and edema); (2) allopurinol tablets a generic version of Zyloprim, marketed by Burroughs Wellcome (used in the treatment of the symptoms of gout); (3) chlorthalidone tablets a generic version of the chlorthalidone tablets manufactured by USV Pharmaceuticals under the name Hygroton (used in the treatment of hypertension and edema); (4) betamethasone valerate cream, marketed by Premo under the name Beta Val a generic version of Valisone, produced by Schering Company (used in the treatment of various dermatological conditions); (5) trifluoperazine hydrochloride tablets a generic version of the trifluoperazine tablets marketed by Smith, Kline and French under the name Stelazine (used in the management of manifestations of psychotic disorders); (6) doxylamine succinate and pyridoxine hydrochloride tablets, marketed by Premo under the name Doxine a generic version of Bendectin, manufactured by Merrell-National Laboratories (used to relieve nausea and vomiting during the early months of pregnancy); (7) hydroxyzine pamoate capsules, marketed by Premo under the name Hy Pam a generic version of the antihistamine Vistaril produced by Pfizer Pharmaceuticals (used in the management of emotional distress, anxiety, tension, and psychomotor agitation); and (8) hydroxyzine hydrochloride tablets a generic version of the antihistamine Atarax produced by Pfizer (uses similar to that for Vistaril). As indicated, these products are all generic (or "me-too") versions of FDA-approved "brand name," or "pioneer," medications. It is Premo's version of each of these established products that is in dispute here.
Specifically, the Government charges that the eight drugs just described are "new drugs" within the meaning of 21 U.S.C. § 321(p) (1976), and thus Premo is in violation of section 355(a) of the Act for shipping these products without having first submitted to FDA, and having had approved, a new-drug application (NDA) or an abbreviated new-drug application (ANDA). Section 321(p) provides:
The term "new drug" means
(1) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug is not 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, except that such a drug not so recognized shall not be deemed to be a "new drug" if at any time prior to June 25, 1938 it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or
(2) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions.
21 U.S.C. § 321(p) (1976). Section 355(a) provides:
Defendants concede new drugs must receive an approved NDA from FDA prior to marketing; however, they deny that their products are "new drugs" within the meaning of the Act. Defendants' position is based on the fact that the active ingredients and in some cases the inactive ingredients as well in their generic medications are the same as those in their FDA-approved, pioneer counterparts.
The United States contends that differences in inactive ingredients between two products with the same active ingredients can materially affect the safety and effectiveness of the medication; that the "same" active ingredient from different sources may cause different effects; and that, even if all ingredients are the same, differences in manufacturing practices can cause one manufacturer's product to differ substantially from another in safety and effectiveness.
At the outset of this action, the Government sought a temporary restraining order. That application, based upon a relatively modest submission, was denied, in part because of defendants' agreement to refrain from further shipments of Triamthiazide (triamterene with hydrochlorothiazide), the medication apparently considered by the United States to have the greatest potential for harm. Thereafter, the Government brought on this application for a preliminary injunction.
Given the extent of the disagreement between the parties, the importance of this issue to the public health and safety, and the uncertain state of the law in this circuit, I afforded the parties a broad opportunity to present their evidence and arguments. The resultant record is perhaps the most detailed one developed to date in any case considering the generic/new-drug issue.
Testimony was presented over eleven days on each of the eight products named in the complaint, producing in excess of 2,000 transcript pages. This was supplemented by 2,000 pages of affidavits and depositions, more than 400 pages of pre- and posthearing briefing, and 1,000 pages of other posthearing submissions.
For the reasons hereinafter set forth, the Government's motion for preliminary injunctive relief is granted.
A word about the format of this opinion, and my findings and conclusions of law, is appropriate.
The first portion of this opinion, "DISCUSSION," pp. 962-977 infra, is divided into six parts. Part I provides a brief history of federal regulation of the drug industry. Part II discusses factors that can affect the bioavailability and bioequivalence of drug products, two concepts central to this litigation. Parts III and IV examine the scant but developing law on the generic/new-drug issue and analyze the evidence in light of my determination that the law requires me to resolve only this question in deciding whether a drug product is a "new drug" under the Act: Is the product generally recognized as safe and effective by experts qualified by scientific training and experience to make such a determination? Part V considers certain additional arguments raised by defendants, and Part VI concludes that the Government is entitled to injunctive relief.
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.
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 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.
In addition, a multitude of other factors can affect bioavailability. These include: the method of granulation and compression; granule hardness, size, and size distribution; flow properties of the powder mixture; capsule or tablet coating method; mixing time; compression pressure and compression dwell time; composition and concentration of disintegrants, lubricants, and other excipients, and the drug-to-excipient ratio; and even the order of mixing a drug product's various excipients. P. Ex. 7, at 9-16 (Shangraw Affidavit). Finally, Dr. Shangraw described the choice of lubricants the substances used to reduce adhesion of the drug product, prior to compression, to the punches and dies in the tableting machine as
the single most significant variable that may affect the bioavailability of a drug product. A change in the type or amount of lubricant used, in the method by which a lubricant is incorporated, or in the length of the blending time may significantly affect the bioavailability of a drug product. Because these substances are hydrophobic (water-repellent), use of an excessive amount of a lubricant will have a "raincoat" effect and will reduce the rate and/or extent of dissolution and, consequently, the amount of drug that will be absorbed by the body.
Bioavailability can also be affected by environmental factors. Humidity during manufacture can cause problems ranging from simple discoloration to subpotency. Id. at 17.
See also Findings of Fact 21-51.
While many courts have grappled with the question of what constitutes a "new drug" under the Act, see, e.g., United States v. X-Otag Plus Tablets, 602 F.2d 1387 (10th Cir. 1979); United States v. An Article of Drug ... "Entrol-C Medicated", 513 F.2d 1127 (9th Cir. 1975); USV Pharmaceutical Corp. v. Richardson, 461 F.2d 223 (4th Cir. 1972), aff'd sub nom. USV Pharmaceutical Corp. v. Weinberger, 412 U.S. 655, 93 S. Ct. 2498, 37 L. Ed. 2d 244 (1973); United States v. 41 Cases, More or Less, 420 F.2d 1126 (5th Cir. 1970); Tyler Pharmacal Distributors, Inc. v. HEW, 408 F.2d 95 (7th Cir. 1969); United States v. Articles of Drug (Hormonin), 498 F. Supp. 424 (D.N.J.1980); United States v. Articles of Food and Drug, 444 F. Supp. 266 (E.D.Wis.1978); United States v. Articles of Drug ... "Colchicine," 442 F. Supp. 1236 (S.D.N.Y.1978); United States v. Lanpar Co., 293 F. Supp. 147 (N.D.Tex.1968), only recently has the question been presented in the context of whether drug products that are generic versions of products with approved NDAs are "new drugs" for the purposes of section 321(p). Prior to this action only a limited number of cases have addressed this issue. In addition to the Premo decisions in the court of appeals and district court (475 F. Supp. 52 (S.D.N.Y.1979)), see United States v. Articles of Drug (Lannett), 585 F.2d 575 (3d Cir. 1978) ("Lannett"); United States v. Generix Drug Corp., 498 F. Supp. 288 (S.D.Fla.1980); United States v. Pharmacal, Inc., No. 78-3685 (S.D.Fla. Mar. 2, 1979); Pharmadyne Laboratories, Inc. v. Kennedy, 466 F. Supp. 100 (D.N.J.), aff'd on other grounds, 596 F.2d 568 (3d Cir. 1979) ("Pharmadyne").
These decisions delineate essentially three positions on the generic/new-drug issue: (1) that espoused in dictum by the Court of Appeals for the Third Circuit in Lannett, which, broadly interpreted, suggests that a product is not a "new drug" if "its therapeutically active ingredients are identical with those of a recognized and approved drug both chemically and quantitatively";
(2) that formulated by the district court in Premo and adopted substantially by the district court in Generix which held that in certain circumstances the question of safety and efficacy, as determinative of the new-drug issue, is one for the court; and (3) that set forth by the Court of Appeals for the Second Circuit in the Premo appeal, reversing the district court, which held that the only issue to be decided by a district court presented with a new-drug question is whether, based on use to a material extent or for a material time and on published studies or other publicly available data, an unapproved product is generally recognized by experts as safe and effective.
In Lannett the Government brought an action to condemn certain drug products manufactured by the Lannett Company. Lannett's products were generic versions of established pioneer drugs that had been approved by FDA. FDA had labeled them "new drugs" under the Act and had required Lannett to submit an ANDA to the agency for each of the drugs. Prior to 1975, because the pioneer counterparts to Lannett's products had received FDA approval, FDA had permitted Lannett to market its products pending the outcome of its ANDAs. In 1975, however, the United States District Court for the District of Columbia in Hoffmann-LaRoche, Inc. v. Weinberger, 425 F. Supp. 890 (D.D.C.1975), held that once the FDA denominates a drug product a "new drug," the product may not be marketed without an approved new-drug application; and permitting new drugs to be marketed prior to such approval "contravenes the clear statutory requirement of preclearance mandated by 21 U.S.C. § 355 (1970)." 425 F. Supp. at 894.
Following Hoffmann-LaRoche, FDA altered its marketing policy and ordered a freeze on the marketing of all "new drugs," including those produced by Lannett, until they were approved by FDA. Lannett continued to market its products, and after ordering Lannett to cease marketing, FDA seized the drugs, and the Government brought the action for condemnation. The district court granted summary judgment in favor of the Government.
On appeal the Court of Appeals for the Third Circuit reversed on the narrow ground that it was "error for the district court to have precluded Lannett from challenging "new drug' status." United States v. Articles of Drug (Lannett), supra, 585 F.2d at 581. In an effort to "lend guidance to prevent another appeal," id. at 582, however, the court proceeded to discuss, in dictum, the question whether generic versions of approved drugs should be considered "new drugs" under the Act.
The court rejected FDA's position that section 321(p) requires general recognition of safety and effectiveness for each specific drug product and, instead, adopted that espoused by Lannett: Drugs that are "the same generically" as a drug already approved as safe and effective by the FDA are not "new drugs"; section 321(p) requires only general recognition of safety and effectiveness, and "bioavailability, bioequivalence, and other quality control tests are irrelevant as to safety and efficacy." Id. In reaching this conclusion, the court examined the "definitions and interpretations" section of FDA's regulations and noting that although they do not purport to be exhaustive the regulations make no specific reference to quality control or "a specific product's capabilities" concluded:
The absence of any regulatory provision setting forth a manufacturer's production techniques as an element making a formulation "new" is powerful evidence that FDA's theory is not based strongly on the statute.
Id. at 583. As a second, related point, the court suggested that, if FDA's position were supported by the Act, section 321(p)(1)
would be superfluous for under the FDA's theory any new manufacture of a generic drug, whether approved or not, would be a "new drug" in the absence of general recognition of the safety and effectiveness of the new manufacture.
Finally, the Lannett court found support for its position in Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 93 S. Ct. 2469, 37 L. Ed. 2d 207 (1973) ("Hynson") and United States v. An Article of Drug ... "Mykocert," 345 F. Supp. 571 (N.D.Ill.1972) ("Mykocert"). In Hynson the Supreme Court held that FDA withdrawal of a pioneer product's NDA is sufficient grounds for the FDA to force withdrawal of every generic version of the pioneer, provided all manufacturers have had an opportunity to be heard. The court of appeals found this supportive of the proposition that " "me-too' drugs carry the same qualities as generic drugs, irrespective of individual manufacturing differences, and therefore should be treated the same for purposes of the Drug Act." 585 F.2d at 584.
Mykocert was a condemnation case in which the plaintiff argued that its drugs should not have been seized, because they were not "new." Although the Mykocert court ultimately rejected plaintiff's claim, it stated:
Claimant's contention that Mykocert is not a new drug can only succeed if it is recognized by experts in the field as safe and effective. There are two possible alternatives that would substantiate claimant's assertions. Either a Mykocert type drug in its exact form, dosage, and application must be recognized by experts (even though the drug may be marketed under a different name) (a generic drug) or each of the component parts of Mykocert must be recognized with the critical caveat that the combination of these parts does not in any way create a new drug under (FDA regulations).
United States v. An Article of Drug ... "Mykocert," supra, 345 F. Supp. at 575, quoted in United States v. Articles of Drug (Lannett), supra, 585 F.2d at 584 (emphasis and brackets added by Lannett court).
As reflected in my findings of fact later set forth, the extensive testimony adduced by the parties in this proceeding has convinced me that adherence to the dictum of the court of appeals in Lannett would pose a substantial danger to public health, given the products here involved. Indeed, with all respect, I find the court's language at odds with the Act, and I share the views expressed by my colleague, Judge Meanor, in Pharmadyne Laboratories, Inc. v. Kennedy, 466 F. Supp. 100 (D.N.J.), aff'd on other grounds, 596 F.2d 568 (3d Cir. 1979), which involved facts matching those here, and which was decided shortly after Lannett. While the Pharmadyne opinion contains several powerful arguments in support of Judge Meanor's determination not to follow Lannett, of particular force is his discussion of the interrelationship between §§ 355 and 321(p) of the Act.
He first construed Lannett to mean that a generic copy of an approved drug product is not a "new drug" for purposes of section 321(p) "if its therapeutically active ingredients are identical to (the) recognized drug both chemically and quantitatively." Id. at 103. Thereafter, however, Judge Meanor did not confine his analysis of the meaning of "new drug" to section 321(p) alone. Stating that the Lannett court had "compartmentaliz(ed) the statute," id., Judge Meanor looked to the new-drug application section of the Act, section 355, "to shed light on the meaning of ("new drug") as defined in § 321," id. Section 355(b) requires that all new-drug applications contain:
... (1) full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use; (2) a full list of the articles used as components of such drug; (3) a full statement of the composition of such drug; (4) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug ....
21 U.S.C. § 355(b) (1976) (emphasis added).
As indicated above, drug products generally contain much in addition to their active ingredients. See discussion of excipients (binders, fillers, disintegrants, etc.), supra, pp. 963-964. Judge Meanor stated that if these components were of concern to Congress for pioneer drugs, as they plainly were, see 21 U.S.C. § 355(b)(2) (1976), then "it is entirely unclear ... why they would not be of similar concern in the manufacture of a "me-too' product." 466 F. Supp. at 104. Similarly, he suggested that if manufacturing methods, facilities, and controls are important considerations with respect to the pioneer, they were intended by Congress to be equally important with respect to the manufacture of that pioneer's generic counterparts. Id. When sections 321 and 355 are read together, the judge concluded, "it should be clear that Congress was concerned with such things as quality control, bioavailability and bioequivalence of the drugs prescribed for and consumed by the public." Id.
As the Lannett court noted, FDA's regulations do not purport to give an exhaustive definition of "newness." The pertinent portion of section 310.3 reads:
(h) The newness of a drug may arise by reason (among other reasons ) of:
(1) The newness for drug use of any substance which composes such drug, in whole or in part, whether it be an active substance or a menstruum, excipient, carrier, coating, or other component.
(2) The newness for drug use of a combination of two or more substances, none of which is a new drug.
(3) The newness for drug use of the proportion of a substance in a combination, even though such combination containing such substance in other proportion is not a new drug.
(4) The newness of use of such drug in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body.
(5) The newness of a dosage, or method or duration of administration or application, or other condition of use prescribed, recommended, or suggested in the labeling of such drug, even though such drug when used in other dosage, or other method or duration of administration or application, or different condition, is not a new drug.
21 C.F.R. § 310.3(h)(1)-(5) (1980) (emphasis added).
Such a qualified listing ("among other reasons") is hardly "powerful evidence" against FDA's position. In fact, I find strong support for the position of the United States in the regulation just quoted.
Section 310.3(h)(1) speaks of the "newness for drug use of any substance which composes such drug" (emphasis added). Excipients, carriers, and coatings are specifically mentioned. And "newness for drug use" contemplates a particular use, see 21 C.F.R. § 310.3(h)(5) (1980). This indicates that different inactive ingredients in a generic version than in its pioneer counterpart will constitute a "new use" if the generic version is used for the same medical indications as the pioneer, regardless of whether these inactive ingredients are generally recognized as safe and effective for other uses. This same argument holds true for the other sections of the regulation which speak of "newness for drug use." For example, § 310.3(h)(2) refers to "the newness for drug use of a combination of two or more substances, none of which is a new drug." Further, with regard to § 310.3(h)(2), that section speaks of a new "combination." This plainly indicates that if the active and inactive ingredients in Premo's products are not identical to those in the products they purport to copy, then Premo's products constitute a new "combination" under § 310.3(h)(2) and are considered "new drugs" under the regulations.
Additional support for the Government's position is contained in § 310.3(h) (3), which concerns "newness for drug use of the proportion of a substance in a combination" even though the same combination in other proportions would not be a "new drug." This is directly applicable to the general/new-drug issue since, even if a manufacturer produces a generic product that has ingredients identical to its pioneer counterpart, if the generic version is more, or less, bioavailable than its pioneer, it is effectively "a new proportion of a substance in combination" and thus considered a new drug under the regulations.
United States v. An Article of Drug ... "Mykocert," supra, on which the Lannett court relied, need not be discussed in detail. The Mykocert court's construct for determining "old drug" status, quoted by the court in Lannett, is dictum only. The court found Mykocert a new drug under the Act, because there was convincing evidence that Mykocert was not generally recognized by experts as safe and effective. In fact, the language the court employed in announcing this determination is telling, and undercuts both the result in Lannett and defendants' position here. Presented with numerous affidavits by Government experts, all denying recognition of Mykocert's safety and effectiveness, the court stated:
(I)t cannot be denied that the affidavits of five of the leading doctors in the field which deny general recognition creates more than a "mere" conflict. It is inconceivable that a drug such as this could be considered generally recognized in the face of such learned non-recognition.
345 F. Supp. at 575 (emphasis added).
Shortly after the Pharmadyne decision, Premo Pharmaceutical Laboratories, Inc. v. United States, 475 F. Supp. 52 (S.D.N.Y.1979), was decided. It establishes something of an intermediate position between Pharmadyne and Lannett.
Premo involved an action for a declaratory judgment that plaintiff's Insulase its generic version of the approved pioneer product, Diabinese, used in the treatment of adults with mild to moderate chronic diabetes is not a "new drug" under section 321(p). The active ingredients in Diabinese and Insulase are the same; the inactive ingredients, however, are not. Id. at 53.
The district judge rejected Premo's argument that the word "drug" in the term "new drug" refers only to a drug product's active ingredient. 475 F. Supp. at 54-55. He likewise rejected the arguments proffered by FDA: (1) that any particular drug product is a "new drug" if it is not generally recognized as safe and effective; (2) that a drug product is a new drug if its excipients differ in any way from those in the approved product, even if the active ingredients are the same; and (3) that a drug product is a new drug if there is any difference whatever between the bioavailability curves of the two products. Id. at 55. Thus the court stated:
In interpreting the term "new drug", the Court is mindful that some differences in excipients do affect the safety or effectiveness of a drug product, but that others do not, and that Congress has entrusted the FDA, not the Court, with finally determining the safety and effectiveness of drugs.
Id. Yet, despite the court's assertion of congressional intent, it took extensive evidence and ultimately determined that Insulase is not a "new drug." In doing so, the court applied the following standard:
(W)hen the active ingredient in a questioned drug product is the same as the active ingredient in a drug product already on the market and generally recognized as safe and effective, and when the excipients in the two drug products are different, and when the excipients in the questioned product are generally recognized individually to be safe, the manufacturer of the questioned product is entitled to a declaration that its product is not a "new drug" within the meaning of 21 U.S.C. § 321(p), only if, 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.
Where a dispute exists as to whether a drug product is "generally recognized" by the experts to be safe and effective, the function of the district court is limited to determining that issue, not whether the product (including one claimed to be a "me-too" drug) is in fact safe and effective. The latter issue is to be determined by the FDA ....
Premo Pharmaceutical Laboratories, Inc. v. United States, supra, at 803.
In addition to the "plain language of the statute," id. at 800, the Second Circuit based this conclusion on several grounds. The court found the history of the Act, referred to above, confirmed the "limited scope" of the general recognition exception to the "new drug" standard of § 321(p). Id. at 802. Moreover, the court derived support for its position from the legislative history of the 1961 Amendments to the Act. Citing the report of the Senate Committee on the Judiciary, quoted in the margin,
the court stated: "(T) he legislative history of the 1961 Amendments suggests that Congress intended all new drug products to be subject to FDA premarket clearance procedures." Id. at 802 n.7. "Nothing in the language of the Act or its legislative history," the court added, "suggests that it is the task of the courts to determine in the first instance whether a drug product is safe, effective or "therapeutically equivalent' to an already approved drug." Id. at 803.
Equally important to the court was FDA's scientific expertise:
... The rule that the FDA rather than the courts must first determine the safety and effectiveness of a drug is but an extension of the general principle that the agency is usually better equipped by reason of its expertise to make the determination than the court.
Finally, the Second Circuit rejected the district court's argument that adhering to the "general recognition" requirement of § 321(p) "would require FDA approval for all drug products" and "would frustrate the long-recognized 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 804 (quoting 475 F. Supp. at 55). The court noted that the "general recognition" exemption had permitted many drugs generally recognized as safe prior to the Act's enactment in 1938 and as effective prior to the 1962 Amendments to be marketed without filing NDAs. Id. at 805.
Thus, the court concluded, "the purpose of the Act is to subject all ("me-too") drug products not generally recognized as safe and effective ... to the premarket clearance requirements of the Act." Id. at 805. Because the excipients in the generic and pioneer products differed, however, the Second Circuit explicitly refrained from deciding "whether an identical, precise copy of an FDA-approved drug, which contains the exact same ingredients and excipients in the same proportions may successfully claim general recognition based on FDA-approval of the drug product which has been copied." Id. at 805 n.9.
As to the underlying question of general expert recognition of the generic product at issue, the Second Circuit found dispositive (1) the district court's finding, made prior to the hearing conducted by that court on the Premo product's safety and effectiveness, that "(t)he specific combination of active drug and excipients which constitutes (the generic product) are not at this time generally recognized among experts ... as safe and effective," id. at 801 (quoting district judge's denial of preliminary injunction), and (2) the inability of any of the experts who testified at trial, including Premo's witnesses, to testify that the generic product was generally recognized as safe and effective. Indeed, the studies made by Premo and offered as evidence of its product's safety and efficacy had not been published, id. at 800, and "were not available to the community of experts generally," id. at 804. With regard to this latter point and significant for the present case there is repeated language in the court of appeals' opinion that suggests the absence of published scientific material as to the generic product's safety and effectiveness would have been conclusive as to the general-recognition issue even absent testimony by the Government's experts. See id. at 800, 803, 805.
Moreover, even assuming the existence of such publicly available material, the court specifically found that "a genuine dispute among qualified experts regarding a drug product's safety and effectiveness preclude(s) its qualifying for exclusion as "generally recognized.' " Id. at 803. And on this issue there was a "sharp difference of opinion" among the experts who testified at trial. Id. at 804.
Premo stands not only as a rejection of the approach adopted by the district court in that case, and followed by the court in Generix, but is at odds with the dictum of the Court of Appeals for the Third Circuit in Lannett if that case is read to require only general recognition of the safety and effectiveness of a drug product's active ingredients.
The Lannett court's dictum is, of course, entitled to considerable weight. United States v. Bell, 524 F.2d 202, 205-06 (2d Cir. 1975); Gabbs Exploration Co. v. Udall, 114 U.S. App. D.C. 291, 315 F.2d 37, 39 (1962).11a However, the plain language of the Act and a close examination of the evidence presented in this case lead inexorably to the conclusion that the analysis advanced by the Second Circuit in Premo is correct: A drug product is a "new drug" under the Act unless it is "generally recognized, among experts ... as safe and effective for use under conditions prescribed" and "used to a material extent or for a material time" under noninvestigative conditions. 21 U.S.C. § 321(p) (1976); Premo Pharmaceutical Laboratories, Inc. v. United States, supra, at 801.
Based on the extensive record developed before me, I am convinced that reliance on Lannett's dictum would be misplaced and that, had the court of appeals had before it in Lannett the record developed before me here, it would not have uttered such dictum. I also reject the approach of the district court in Premo.
Applying the Second Circuit's standard to the products at issue here, it is clear that the eight Premo products are "new drugs" for purposes of § 321(p); in fact, I need not even reach the question whether the products have been used to a material extent or for a material time,
because I find that Premo's products are not generally recognized as safe and effective by qualified experts.
Considering first those products that the parties agree have inert ingredients not identical to those of their pioneer counterparts,
the Government presented voluminous testimony from its expert witnesses
that the Premo products are not 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.
As to Premo's Betamethasone valerate (Beta Val) cream, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
As to Premo's chlorthalidone tablets, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 3, P 24 (Cortell Affidavit); P. Ex. 2, PP 41, 45 (Cabana Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
As to Premo's doxylamine succinate with pyridoxine HCL (Doxine) tablets, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 6, P 18 (Perel Affidavit); P. Ex. 2, PP 44, 45 (Cabana Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
As to Premo's Hydroxyzine pamoate (Hy Pam) capsules, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 6, P 18 (Perel Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
As to Premo's hydroxyzine hydrochloride tablets, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 6, P 18 (Perel Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
As to Premo's trifluoperazine hydrochloride tablets, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 6, P 18 (Perel Affidavit); P. Ex. 2, PP 42, 45 (Cabana Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
While I do not believe the Act requires unanimity for a finding of general recognition, it is patent that there is here, at minimum, such "a genuine difference of medical opinion among ... experts" on the question as to preclude a finding of general recognition of safety and effectiveness by experts with respect to the products listed above. See United States v. An Article of Drug Furestrol, 294 F. Supp. 1307, 1311 (N.D.Ga.1968), aff'd on the opinion below, 415 F.2d 390, 392 (5th Cir. 1969); Merritt Corp. v. Folsom, 165 F. Supp. 418, 421 (D.D.C.1958). Moreover, all of the Government experts stated that they themselves do not recognize Premo's products as safe and effective. See P. Ex. 4, P 23 (Court Affidavit); P. Ex. 1, P 23 (Barr Affidavit); P. Ex. 3, P 23 (Cortell Affidavit); P. Ex. 6, P 17 (Perel Affidavit); P. Ex. 2, P P 35, 41-45 (Cabana Affidavit); P. Ex. 7, P 15 (Shangraw Affidavit.)
As the court put it in United States v. An Article of Drug ... "Mykocert," supra, 345 F. Supp. at 575 (emphasis added);
See Premo Pharmaceutical Laboratories v. United States, supra, at 803 ("(A) genuine dispute among qualified experts regarding a drug product's safety and effectiveness preclude(s) its qualifying for exclusion as "generally recognized").
As to the remaining two Premo products, its allopurinol and triamterene with hydrochlorothiazide medications, the Government concedes that at least one is virtually identical to its pioneer counterpart. Government's Response to Defendants' Proposed Finding of Fact No. 99 (sealed). Defendants contend that the final Premo product is also identical to its pioneer, but this is disputed by the Government. Compare Defendants' Proposed Findings of Fact in Opposition to Plaintiff's Motion for Preliminary Injunction No. 138 (sealed) with Government's Responses to Defendants' Proposed Finding of Fact No. 138 (sealed). See also Government's Proposed Findings of Fact and Conclusions of Law 152-56, 204-06 (hereinafter Government's Proposed Findings) and defendants' critiques.
However, even assuming an identity of ingredients, qualitatively and quantitatively, between these two Premo products and their pioneers, the Government argues that (1) there is a potentially significant difference between the manufacturing processes
used for one of the Premo products and its pioneer and between the two products' particle size,
Government's Proposed Findings 153-54 (sealed); and (2) with respect to the second Premo product there is no information available as to the particle size and source
of Premo's active ingredient. Government's Proposed Finding 205 (sealed). The significant point here, of course, is not these differences themselves, both real and potential, but that, because of them, the Government witnesses have stated that there is no general expert recognition of the safety and efficacy of these two Premo products. As to allopurinol, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit). As to Premo's Triamthiazide, see P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 24 (Barr Affidavit); P. Ex. 3, P 24 (Cortell Affidavit); P. Ex. 2, PP 35, 45 (Cabana Affidavit); P. Ex. 7, P 16 (Shangraw Affidavit).
Nor do the Government experts themselves recognize Premo's allopurinol and triamterene with hydrochlorothiazide products as safe and effective. See P. Ex. 4, P 23 (Crout Affidavit); P. Ex. 1, P 23 (Barr Affidavit); P. Ex. 3, P 23 (Cortell Affidavit); P. Ex. 2, PP 35, 43 (Cabana Affidavit); P. Ex. 7, P 15 (Shangraw Affidavit).
As indicated, in Premo the Court of Appeals for the Second Circuit explicitly left unresolved the question whether "an identical, precise copy of an FDA-approved drug, which contains the exact same ingredients and excipients in the same proportions may successfully claim general recognition based on FDA-approval of the drug product which has been copied." Premo Pharmaceutical Laboratories v. United States, supra, at 805 n.9. Nevertheless, I find the underlying logic of the Premo decision helpful on the issue. As defendants concede, differences in particle size and source of active ingredients can affect the safety and effectiveness of a drug product. See Defendants' Critique on Government's Proposed Findings of Fact No. 28-30. As defendants also concede, "(differences) in manufacturing techniques can affect the performance of a drug." Defendants' Memorandum on Premo Pharmaceutical Laboratories, Inc. v. United States at 8. See Findings of Fact 31-49. Thus, there is a substantial question as to the safety and efficacy of Premo's products, which is one for FDA unless there is general expert recognition of the safety and effectiveness of the products and they have been used to a material extent or for a material time. Here, again, however, there is no such general recognition; the testimony of the Government witnesses demonstrates, at the least, a "genuine difference of medical opinion among experts" and thereby precludes such a finding.
Defendants raise a number of other arguments in support of their position. Of these, only a few merit even brief attention at this juncture.
Defendants contend that "FDA for over 30 years construed the statute so as to exclude generic versions of established drugs from the new drug definition." Defendants' Initial Post-Hearing Memorandum in Opposition to Plaintiff's Motion for Preliminary Injunction at 10. "Such a contemporaneous construction of a statute by an agency," defendants argue, "is clearly indicative of Congressional intent." Id. at 10-11. This contention is rejected. Regardless of what the agency's position has been in years past and there has indeed been "a great deal of past waffling" on this point, Pharmadyne Laboratories, Inc. v. Kennedy, supra, 466 F. Supp. at 103 it holds to that ground no longer. Indeed, I consider the Senate Report alluded to earlier, see note 11 supra, and the history of the Act itself, see p. 962 supra, as strong evidence that FDA's present interpretation accurately reflects the intent of Congress in enacting the Act.
Defendants also argue that the reading of section 321(p) adopted here renders superfluous the Act's "grandfather clauses, see, e.g., 21 U.S.C. § 321(p)(1) (1976)," thereby violating a venerable tenet of statutory construction. See Jackson v. Kelly, 557 F.2d 735, 740 (10th Cir. 1977); International Telephone & Telegraph Corp. v. American Telephone & Telegraph Co., 444 F. Supp. 1148, 1155 (S.D.N.Y.1978) (every congressional enactment is purposive, and any interpretation that completely emasculates the words in a statute is improper). This argument, too, is without merit. It is answered by the Second Circuit in Premo, rejecting the district court's contention that the "general recognition" standard "would require FDA approval for all drug products." See Premo Pharmaceuticals, Inc. v. United States, supra, at 804.
Finally, defendants suggest the options available to FDA absent preclearance adequately protect the public. They do not. FDA's Good Manufacturing Practice (GMP) regulations, 21 C.F.R. § 210.1 et seq. (1980), are not sufficient to avoid the need for preclearance. The GMP regulations are intended to provide general, industrywide standards for the manufacture of drugs, not monitoring of individual products. P. Ex. 4 P 31 (Crout Affidavit). Nor can FDA inspections provide an effective alternative to the preclearance process. Under the law there may be a time lag of up to six months between initial marketing of a drug and the time the drug is listed with FDA. See 21 U.S.C. § 360(j)(2)(1976). Thus, absent preclearance FDA may not even be aware that a product is on the market until it is too late to protect the public. P. Ex. 4 P 32 (Crout Affidavit).
Moreover, the adulteration provisions of 21 U.S.C. § 351 (1976), which FDA can invoke against imperfectly manufactured drugs, also fall short of ensuring the margin of safety provided by preclearance. Most significant in this regard is the point made by the district court in Pharmadyne. If a specific product is not itself approved but rather marketed as an "old drug" on the basis of FDA-approval of its pioneer and is suddenly found to have disastrous and unanticipated side effects, FDA would have no NDA or ANDA to revoke and would have to resort to the infinitely slower alternative of individual condemnation actions. I share Judge Meanor's doubt "that in such an emergency Congress intended that some drugs could be withdrawn by immediate disapproval of an NDA while their "me-too" counterparts could only be forced from the market by condemnation." Pharmadyne Laboratories, Inc. v. Kennedy, supra, 466 F. Supp. at 106.
For the same reasons, I am not persuaded by arguments that this is a matter best left to Congress. Congress has already acted, in 1938 and again in 1962, and has mandated that a tragedy such as that involving the "Elixir of Sulfanilamide" does not recur.
Premo's eight products are "new drugs" for purposes of 21 U.S.C. § 321(p) (1976). As such, marketing of these products absent premarket clearance by FDA is in clear violation of the Federal Food, Drug, and Cosmetic Act.
There remains only the question of relief. Although defendants have advanced arguments to the contrary, it is clear to me that this court has the power to enjoin present and future violations of the Act, 21 U.S.C. § 332(a) (1976), solely on the basis that such violations have been established. United States v. Diapulse Corp. of America, 457 F.2d 25, 27-28 (2d Cir. 1972); United States v. Nutrition Service, Inc., 347 F.2d 233 (3d Cir. 1965), aff'ing on the basis of the opinion below, 227 F. Supp. 375, 388-89 (W.D.Pa.1964); FTC v. Rhodes Pharmacal Co., 191 F.2d 744, 747 (7th Cir. 1951), rev'd in part on other grounds, 348 U.S. 940, 75 S. Ct. 361, 99 L. Ed. 2d 736 (1955); Shadid v. Fleming, 160 F.2d 752, 753 (10th Cir. 1947); Henderson v. Burd, 133 F.2d 515, 517 (2d Cir. 1943); United States v. Generix Drug Corp., supra, at 293; United States v. Articles of Food & Drug, 441 F. Supp. 772, 775 (E.D.Wisc.1977); United States v. Medwick Laboratories, Inc., 416 F. Supp. 832, 833 (N.D.Ill.1976).
Therefore, subject to an alternative form of order agreed upon by the parties and approved by this court, defendants will be enjoined, as the Government requests, from (1) shipping new drugs in interstate commerce and (2) manufacturing, processing, packing, and labeling any new drugs after shipment of their components in interstate commerce, unless the drugs are approved by FDA or are used in investigations in compliance with applicable regulations.
As to the questions of recall, destruction of in-process and finished stocks, and costs and inspection if recall and destruction are ordered, I desire additional argument and will set this matter down at an early date for such argument.
Following the hearing, at the direction of the court, the parties submitted and exchanged proposed Findings of Fact and Conclusions of Law and thereafter, again at the direction of the court, submitted comments upon each other's proposed findings. Subsequently, each party submitted a reply to these comments. All proposed findings of fact, comments, and replies were annotated to the record, and read by me. Where there was disagreement, my resolution of such disagreement was facilitated by the record references supplied by counsel. In my Findings I have retained those record references to aid appellate review.
In many instances, the parties were in agreement with each other's submissions. In other instances, there was agreement in terms of a proposed finding but disagreement as to its relevancy. The former has been indicated by me with the letter (A); the latter is indicated by (NDBI), standing for "not disputed but irrelevant."
This court is mindful of the fact that findings of fact under Federal Rule of Civil Procedure 52 should be the findings of the court and not the findings of counsel. While I have drawn heavily upon the proposed findings of the parties, and in many instances have adopted the language used, the findings are the court's, not counsel's. For example, as I have indicated above, I have carefully reviewed all of the proposed findings submitted by the United States, read those findings in the light of the critique submitted by the defendants, also giving consideration to the reply of the United States to such critique, and have, in each instance where there is a dispute, carefully reviewed the record references to resolve that dispute.
Additionally, I have reviewed the proposed findings of fact submitted by the defendants, the United States' critique thereof, and the defendants' reply to the government's critique. Again, where I found a dispute between the parties, I used the record references to resolve it.
For a better understanding of these findings, I have adopted the headings and subheadings of the proposed findings of the United States.
1. Defendant Premo Pharmaceutical Laboratories, Inc., ("Premo") is a corporation which trades and does business at 111 Leuning Street, South Hackensack, New Jersey 07606, within the jurisdiction of this Court (Complaint, P 2; Amended Answer, 5th Defense, P 2). (A)
2. Defendant Seymour N. Blackman is president of Premo Pharmaceutical Laboratories and as such, has over-all responsibility for and authority over the operation of the firm, including, but not limited to, the methods, manner, and conditions of manufacture of the firm's products, and whether to submit new-drug applications and whether to ship products for which such applications have not been submitted or approved. He performs his duties at 111 Leuning Street, South Hackensack, New Jersey 07606, within the jurisdiction of this court. (Complaint, P 3; Amended Answer, 5th Defense, P 3). (A)
3. Defendants have been and are now engaged at their plant in 111 Leuning Street, South Hackensack, New Jersey, in manufacturing, processing, packing, labeling, and distributing in interstate commerce various articles of drug. Such drugs include, but are not limited to: allopurinol tablets, betamethasone valerate cream, chlorthalidone tablets, doxylamine succinate with pyridoxine HCl tablets, hydroxyzine pamoate capsules, hydroxyzine hydrochloride tablets, and trifluoperazine tablets. (Complaint, P 4; Amended Answer, 5th Defense, P 4). (A) Premo also manufactures some such products through a related company, Federal Pharmacal, Inc., in St. Croix, the Virgin Islands (P. Ex. 25-A, page 6; P. Ex. 25-B at 69-70 (Deposition of J. Blackman); Tr. at 2111 (Silverang); P. Ex. 72-B at 15-16 (Deposition of N. Martin)).
5. Defendants have manufactured, processed, packed, labeled, and distributed in interstate commerce capsules containing triamterene with hydrochlorothiazide (Complaint, P 4; Amended Answer, 5th Defense, P 4), and will do so again if not enjoined (P. Ex. 85-A, page 2; P. Ex. 85-B at 119 (Deposition of S. Silverang)). (A)
6. Defendants' acts of manufacturing, processing, packing and labeling capsules containing triamterene with hydrochlorothiazide were done while those capsules were held for sale after shipment of one or more of their components in interstate commerce (P. Ex. 64, 11). (A)
7. There is no new drug application, approved by the Food and Drug Administration (FDA) pursuant to 21 U.S.C. § 355(a), on file for any of the drugs listed in PP 3 and 5, supra (Complaint, P 6; Amended Answer, 5th Defense, P 6).
Premo holds IND's (Investigation New Drug exemptions) for allopurinol, 100 and 300 mg, betamethasone valerate, and trifluoperazine, 2 and 5 mg.
Premo sought investigational new-drug exemptions for these products after the complaint in this action was filed. With respect to two of these products (trifluoperazine and betamethasone valerate), Premo has been told by the FDA that it may not begin research until further information has been submitted. Premo has stipulated that it has distributed all of these products commercially (P. Ex. 64), which distribution would violate the Act even if use of the drugs were approved for investigational purposes.
8. Defendants will, in the absence of the entry of injunctive relief, manufacture and distribute the drugs in question.
9. Defendants have, in addition to those drugs set out in PP 3 and 5, also manufactured and shipped other unapproved new drugs (P. Ex. 5 (Second Aff. of Dr. Crout), P 9).
II. Premo's Products Lack Expert General Recognition Under 21 U.S.C. § 321(p)
10. Premo's allopurinol tablet is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 3 (Aff. of Dr. Cortell), P 24; P. Ex. 2 (Aff. of Dr. Cabana), P 43; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
11. Premo's betamethasone valerate cream is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
12. Premo's chlorthalidone tablet is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 3 (Aff. of Dr. Cortell), P 24; P. Ex. 2 (Aff. of Dr. Cabana), PP 41, 45; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
13. Premo's doxylamine succinate with pyridoxine HCl (Doxine) tablet is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 6 (Aff. of Dr. Perel), P 18; P. Ex. 2 (Aff. of Dr. Cabana), PP 44, 45; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
15. Premo's hydroxyzine hydrochlorothiazide tablet is not 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. (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 6 (Aff. of Dr. Perel), P 18; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
16. Premo's trifluoperazine tablet is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 6 (Aff. of Dr. Perel), P 18; P. Ex. 2 (Aff. of Dr. Cabana), PP 42, 45; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
17. Premo's triamterene with hydrochlorothiazide (Triamthiazide) capsule is such that such drug is not 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 (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 24; P. Ex. 3 (Aff. of Dr. Cortell), P 24; P. Ex. 2 (Aff. of Dr. Cabana), PP 35, 45; P. Ex. 7 (Aff. of Dr. Shangraw), P 16).
18. As agreed by Premo's expert, Dr. Rhodes, it is necessary to have more information with respect to a drug product than simply the identity of its active ingredients for that product to be generally recognized as safe and effective (Tr. at 1417). (A)
19. As Dr. Rhodes conceded, the excipients used in Premo's drug products are not known to experts generally (Tr. at 1417-19, 1486 (Dr. Rhodes)). The details of the manufacturing practices used in the manufacture of Premo's drugs are not known generally to experts either (Tr. at 1419 (Dr. Rhodes)). In addition, quality control information with respect to the procedures followed by Premo is not generally known to experts (id.; Tr. at 1486) (Dr. Rhodes)). It is not generally known by scientists what the source of the inactive ingredients is for Premo products (Tr. at 1419-20 (Dr. Rhodes)).
20. Without reliable biological availability, clinical trials and quality control data, and without knowing the excipients of a product, a product cannot be recognized as safe and effective even though the active drug substance is pure (Tr. at 1497-98 (Dr. Rhodes)).
21. In addition to stating their expert testimony that there is a lack of general recognition among experts of the safety and effectiveness of the Premo products named as examples in the complaint, a number of well qualified experts in the evaluation of drug safety and effectiveness have stated that they themselves do not recognize those drugs as safe and effective (P. Ex. 4 (Aff. of Dr. Crout), P 23; P. Ex. 1 (Aff. of Dr. Barr), P 23; P. Ex. 3 (Aff. of Dr. Cortell), P 23; P. Ex. 6 (Aff. of Dr. Perel), P 17; P. Ex. 2 (Aff. of Dr. Cabana), PP 35, 41, 42, 43, 44, 45; P. Ex. 7 (Aff. of Dr. Shangraw), P 15).
These contentions were not withdrawn at trial nor were they weakened or diluted by cross-examination of the affiants.
III. There Is a Clear Potential for Differences in Bioavailability Between Products Purporting To Contain the Same Active Ingredients
23. The sciences of biopharmaceutics and pharmacokinetics, which are concerned with the bioavailability of drug products, are relatively young sciences. They were developed because of the need to evaluate different kinds of dosage forms, particularly as some of the older drugs were coming off patent so that additional companies were beginning to market them and, also, because analytical developments made possible the measurement of small amounts of drugs in the blood, thus permitting bioavailability studies (Tr. at 883 (Dr. Barr)). (A)
24. Bioavailability problems generally occur only when there is more than one product containing a particular active ingredient on the market (Tr. at 885 (Dr. Barr)).
25. Bioequivalence implies that the relative rate and extent of absorption of two drug products are sufficiently equal that one would expect the two drug products to behave, for all practical purposes, the same in a clinical situation (Tr. at 85 (Dr. Barr); see also Tr. at 473 (Dr. Cabana)). (A)
26. Two products, each containing the same active ingredients, can have a different bioavailability because of differences in their inactive ingredients (P. Ex. 1 (Aff. of Dr. Barr), P 10; P. Ex. 2 (Aff. of Dr. Cabana), PP 23, 25, 30, 32; P. Ex. 7 (Aff. of Dr. Shangraw), P 13-B; P. Ex. 4 (Aff. of Dr. Crout, PP 9, 28, 29; Tr. at 472-73 (Dr. Cabana); Tr. at 1288, 1485 (Dr. Rhodes)) and thus can differ in safety and effectiveness (Tr. at 1414-15 (Dr. Rhodes)).
27. There are a variety of different inactive ingredients that may be present in a drug product, including diluents, binders, disintegrants, and surfactants. In addition, a drug may or may not be prepared with inactive ingredients in a solid solution. Each of these different ingredients and this potential difference in preparation of the active ingredients with inactive ingredients can be the cause of differences between two drug products, each containing the same active ingredients, which have different inactive ingredients (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-B). (A)
28. The "same" active ingredient from different sources may cause different effects in terms of bioavailability (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-A; P. Ex. 1 (Aff. of Dr. Barr), P 10; P. Ex. 2 (Aff. of Dr. Cabana), PP 24, 32; P. Ex. 4 (Aff. of Dr. Crout), PP 9, 28; Tr. at 282-83 (Dr. Crout)). (A)
29. Active drug ingredients from different manufacturers may differ from each other in the following respects: polymorphism, that is, different crystal forms of the same ingredient that are chemically indistinguishable from each other but which may differ significantly with respect to properties such as density, melting point, solubility, the rate at which the active ingredient will go into solution, and stability (P. Ex. 7 (Aff. of Dr. Shangraw), P 13A.1; Tr. at 214 (Dr. Crout); Tr. at 472 (Dr. Cabana)); the state of the active ingredient, that is, for some active ingredients the difference between a possible amorphous or non-structured state and a structured or crystal state (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-A.2); the association of the active ingredient with different solvents (id., P 13-A.3; Tr. at 716 (Dr. Shangraw)); the form of the dissolution properties of the product (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-A.4); particle size and distribution of the active ingredient, which may affect the rate and extent of dissolution of the active ingredient (id., P 13-A.5, Tr. at 214 (Dr. Crout); Tr. at 716 (Dr. Shangraw)). (NDBI)
30. When the particle size of drugs becomes smaller the surface area of the drug is increased, giving a greater opportunity for dissolution of the drug, because dissolution of the drug in the gastric media and intestinal media is a function of surface area (Tr. at 720 (Dr. Shangraw)). For example, grinding granular sugar into powdered sugar would make the sugar dissolve more quickly (Tr. at 712 (Dr. Shangraw)). Breaking particle size down to very minute quantities is termed "micronization" (id.). (NDBI)
C. Manufacturing Variables
31. Even if the characteristics of the active ingredient are the same, and even if the same additives are used, two drug products manufactured by different manufacturers can vary in bioavailability because of differences in the manufacturing practices used (P. Ex. 1 (Aff. of Dr. Barr), P 10; P. Ex. 7 (Aff. of Dr. Shangraw), P 13-C; P. Ex. 2 (Aff. of Dr. Cabana), P 32; P. Ex. 4 (Aff. of Dr. Crout), PP 9, 28, 29; Tr. at 213-14, 282-83 (Dr. Crout); Tr. at 473 (Dr. Cabana); Tr. at 723-24 (Dr. Shangraw); Tr. at 1415 (Dr. Rhodes)). (NDBI)
32. A tablet is made up of a number of ingredients, almost all of which can affect the bioavailability of the drug: the active ingredient, the filler, which is used to provide sufficient volume for the dosage form, disintegrating agents used in tablets to make them break apart, lubricants, used to ease the manufacture of the tablet, and binders (Tr. at 716-17 (Dr. Shangraw)). (NDBI)
33. Fillers can be soluble like lactose, or can be relatively insoluble like calcium sulfate, which is soluble in acid but not as soluble in alkaline or aqueous media. If the filler is not soluble, then it is more difficult for the drug to be released (Tr. at 719-20 (Dr. Shangraw)). Dissolution of a drug product is required for absorption (Tr. at 720 (Dr. Shangraw)). (NDBI)
34. In making a tablet it is very often necessary to "granulate," that is, to glue the small particles of the drug together with a binder to form a substance that will flow in the machine, or die, used to make the tablet and that will compress it (Tr. at 737-38 (Dr. Shangraw)). (NDBI)
35. A lubricant is often used in a tablet to help eject the tablet from the die after it has been made (Tr. at 738 (Dr. Shangraw)). (NDBI)
36. There are three basic manufacturing techniques for tablets: 1) wet granulation, in which a liquid glue is added to the powders to form a moist mass, which is then passed through a screen to break it down again; 2) dry granulation (also known as "slugging") in which the powders are made into a large crude tablet and then ground up into particles that will be larger than the powder so that they will flow in the machines; and, 3) direct compression, in which the drug ingredients are blended together to make the tablet directly without going through a granulation process (Tr. at 738-39; 723-24 (Dr. Shangraw)). In each case, the process is designed to produce a material that will flow in the machinery and that will be coherent when pressure is applied to it (Tr. at 739, 722 (Dr. Shangraw)). (NDBI)
37. Examples of the variables in manufacturing practices for tablets that may affect bioavailability also include method of disintegrant incorporation, choice of binder and granule hardness, granule size and size distribution, flow properties of the powder mixture, coating method, mixing time, presence of surfactant and its method of incorporation, compression pressure and compression dwell time, composition and concentration of disintegrants, lubricants and other excipients, the drug-to-excipient ratio, and the order of mixing drug excipients (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-C.1). (NDBI)
39. The hard shell of a capsule is made up of almost 90% gelatin but may also have small amounts of a plasticizer like propylene glycol or glycerine together with about 10% water and occasionally a little bit of sucrose to form a gelatin film that is fairly hard and brittle (Tr. at 743 (Dr. Shangraw)). (NDBI)
40. The contents of the gelatin capsules include the drug itself and fillers such as those used in tablets, lubricants to improve the flow of the material in the machinery and to keep the machinery from binding during manufacture. In some of the newer automatic machines the capsule contents are first made by forming a plug of powder in a cylinder and then ejecting that plug of powder into the capsule. The process is similar to making a tablet except that the plug in the capsule does not have nearly the density of a tablet (Tr. at 744 (Dr. Shangraw)). (NDBI)
41. Because disintegrating agents do not work in capsules as they do in tablets, it is often necessary to use a wetting agent or some surface active agent instead to help disperse the powder mass in the capsule (Tr. at 759). (NDBI)
42. The two factors that most influence the drug dissolution from a capsule and thus its bioavailability are 1) the properties of the drug, i. e., how soluble it is and how hydrophilic the surfaces of the drug particles are, meaning whether they wet well when they are exposed to water, and 2) the lubricant added to the drug material and how that lubricant is distributed in the powder mass (Tr. at 745; see also Tr. at 725 (Dr. Shangraw)). (NDBI)
43. The lubricant used in a capsule generally will coat the powder, i. e., the drug particles, and particularly with magnesium stearate, given enough blending time, will actually cover every surface of every particle of the drug (Tr. at 745, 769-70 (Dr. Shangraw)). In fact, Dr. Lerk has photographed a particle of sodium chloride which, after eventual dissolution, has left an unfolded sheath of magnesium stearate which had previously enclosed it (P. Ex. 28, page 324, Figure 10).
44. Coating the particles of drug with a lubricant will slow down dissolution of the drug particles (Tr. at 746, 764 (Dr. Shangraw); P. Ex. 30 at 1215). Magnesium stearate's effect on the dissolution of a drug is increased by increased blending time as shown by the work of Dr. Lerk (Tr. at 769-71 (Dr. Shangraw); P. Ex. 28 at 317 and 324, Figure 9). (NDBI)
45. Increasing the time of blending of the drug during its manufacture will more uniformly distribute the lubricant and will therefore slow down the dissolution of the drug (Tr. at 746, 764-65 (Dr. Shangraw); P. Ex. 30 at 1216, Figures 1 and 2). (NDBI)
46. When, in manufacturing a capsule, one increases the concentration of lubricant, the rate of dissolution of drug from that capsule can be dramatically decreased (Tr. at 754, 765 (Dr. Shangraw); P. Ex. 29, page 170, Figure 1, 171; P. Ex. 30 at 1217, Figure 3; cf. Tr. at 1297 (Dr. Rhodes)). A variation in formulation as small as a difference between 2% rather than 1% of magnesium stearate can cause significant differences in bioavailability as Dr. Barr's research has shown, differences great enough to cause a product Dr. Barr studied to be subtherapeutic in some patients (Tr. at 1010-11 (Dr. Barr)). (NDBI)
47. Both the type of filler that is used in a drug and the fluid in which the drug is dissolved can affect dissolution. Thus a filler like dicalcium phosphate, since it is not highly soluble in water but is soluble in acid, when mixed with a drug, will lead to fairly fast dissolution in an acid-like medium such as that found in the stomach and relatively slow dissolution in plain water or in an environment such as that found in the lower GI tract (Tr. at 755-56 (Dr. Shangraw); P. Ex. 29, page 172, Figure 7). (NDBI)
49. How hard one packs the powder mass into a capsule can influence the dissolution of the drug out of that mass (Tr. at 758 (Dr. Shangraw); P. Ex. 29, Figure 10). (NDBI)
50. While FDA waives the requirement for submission of in vivo bioavailability data for topical preparations, variables that may affect bioavailability include the nature of the vehicle, particle size of the drug, solubility of the drug in the vehicle, and the presence or absence of surfactants (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-C.3).
D. Environmental Factors During Manufacture and Storage
51. Environmental factors can also cause differences between two otherwise identical drug products manufactured by different manufacturers (P. Ex. 7 (Aff. of Dr. Shangraw), P 13-D).
The government's point is simply that environmental factors can differ from manufacturing facility to manufacturing facility. A drug manufacturer must identify the manufacturing facility that it will use in any new drug application or abbreviated new drug application it files, see 21 C.F.R. 314.1(c)(2), Form FD-356H(8)(a). A drug manufacturer wishing to change its manufacturing facility for a drug must file a supplemental application, 21 C.F.R. 314.8(a)(4)(iv). The FDA requires bioavailability studies showing bioequivalence of the product manufactured in the new facility to the product manufactured in the approved facility prior to approval of such a supplemental application in appropriate circumstances, 21 C.F.R. 320.21(b)(1). These requirements result in protection of the public from the differences that may occur in different facilities of the same manufacturer when that manufacturer is complying with the new drug application requirement but is not protected from the differences that may be caused by environmental variations between the facilities of the approved manufacturer and those of a manufacturer who markets without approval.
IV. Continued Marketing by Premo of Products Not Shown to be Bioequivalent to the Products They Copy Potentially Endangers the Public
52. In the normal course of business Premo's products can be expected to be substituted by pharmacists for the approved drug products that have the same active ingredients (P. Ex. 4 (Aff. of Dr. Crout), P 14; P. Ex. 1 (Aff. of Dr. Barr), P 18; P. Ex. 3 (Aff. of Dr. Cortell), P 17; P. Ex. 2 (Aff. of Dr. Cabana), P 39-C(1)). (A)
53. Physicians initially prescribing some of the approved drug products which Premo copies may be expected to carefully adjust the dosage for each patient (P. Ex. 4 (Aff. of Dr. Crout), P 15; P. Ex. 6 (Aff. of Dr. Perel), P 18). They may do so by monitoring a pharmacological response, for example, by checking uric acid levels for allopurinol (see, e.g., Tr. at 393 (Dr. Bloom)) and potassium levels for triamterene plus hydrochlorothiazide (see, e.g., Tr. at 98 (Dr. Crout); cf. Tr. at 430 (Dr. Bloom)).
54. If the Premo product is more bioavailable than the drug for which it is substituted, the resulting effective overdosage of the drug may, with respect to some products, present a risk for the patient (P. Ex. 4 (Aff. of Dr. Crout), PP 10, 15-17; P. Ex. 3 (Aff. of Dr. Cortell), PP 18-19; P. Ex. 6 (Aff. of Dr. Perel), PP 9-10; P. Ex. 2 (Aff. of Dr. Cabana), P 39-C, D).
55. If a difference in bioavailability between Premo's drug and the approved product containing the same ingredients results in an effective underdosage of the active ingredient of the drug product in patients, that result could lead to therapeutic failures that, for some products in some patients, could constitute a risk for patients (P. Ex. 4 (Aff. of Dr. Crout), PP 10-14; P. Ex. 3 (Aff. of Dr. Cortell), PP 20, 22; P. Ex. 6 (Aff. of Dr. Perel), PP 11, 16; P. Ex. 2 (Aff. of Dr. Cabana), P 39).
56. Unless a physician is alerted to look for a drug-related therapeutic failure from low bioavailability or adverse reactions from high bioavailability, he may mistakenly attribute the problem he sees to the disease state being treated (P. Ex. 3 (Aff. of Dr. Cortell), P 25; P. Ex. 1 (Aff. of Dr. Barr), PP 25-27; P. Ex. 6 (Aff. of Dr. Perel), P 19; P. Ex. 4 (Aff. of Dr. Crout), P 30; Tr. at 899, 905-07 (Dr. Barr)). For this reason, the relatively short amount of time each of the Premo products has been marketed (see P. Ex. 64) makes it impossible to draw a valid conclusion about the safety and effectiveness of those drugs (P. Ex. 3 (Aff. of Dr. Cortell), P 25; P. Ex. 6 (Aff. of Dr. Perel), P 19; P. Ex. 1 (Aff. of Dr. Barr), PP 25-27; P. Ex. 4 (Aff. of Dr. Crout), P 30).
57. It is possible for a drug to exhibit both a shallow dose-response curve and a steep dose-response curve at the same time: Although with some drugs an increase in dosage will not result in increased therapeutic effect (yielding a shallow curve), the same increase in dosage may result in an increased toxic effect (yielding a steep curve) (Tr. at 928-33 (Dr. Barr); P. Ex. 63). In other words, there could be an increase in toxic or adverse effects in response to an increase in effective dosage without any change in therapeutic response (Tr. at 933 (Dr. Barr)).
58. Even where differences in bioavailability of products assumed to be equivalent do not result in clear risks to the patients, these differences can cause undesirable confusion in the drug marketplace (Tr. at 29 (Dr. Crout)).
V. The Need for In Vivo Bioavailability Testing, and the Standards by Which Such Tests Are Judged, Are Well Recognized by Scientists
A. Bioavailability Tests Can Substitute for More Extensive Clinical Testing
59. Prior to marketing of an innovator drug, the marketer must first show safety through animal studies, then progress to very limited controlled clinical studies to show efficacy, then more detailed clinical studies to show that the product will be safe and effective in controlled clinical settings in large numbers of people (Tr. at 887-88 (Dr. Barr)). (A)
60. When a second manufacturer seeks to market a copy of a drug product that has gone through the required clinical testing, it is "satisfactory from a scientific point of view" for that company to demonstrate that its drug product delivers that drug entity to the systemic circulation or the blood stream at exactly the same rate and the same amount as the product of the innovator, that is, by performing a well-conducted bioavailability study (Tr. at 891 (Dr. Barr)).
B. Bioavailability Testing, To Be an Acceptable Substitute for Clinical Tests, Must Meet Accepted Standards
61. There are three methods for determining bioavailability in vivo (in the human body): (1) determination of blood levels or urine levels of the drug or its metabolite following administration, the preferable method; (2) failing that, a valid pharmacological method may be acceptable; or (3) a clinical trial comparing clinical activity which is sensitive to the drug (Tr. at 476-78 (Dr. Cabana)). The three forms of testing are listed in descending order of accuracy, sensitivity, and reproducibility: the second method is acceptable only when the first is not possible and the third is acceptable only when the first and second are impossible to perform (21 C.F.R. 320.24(c)). (A)
63. The usual method of determining whether products are bioequivalent is a blood level study, which is used to determine the relative rate and extent of absorption of the drug in the blood stream (Tr. at 898 (Dr. Barr)). In some cases one can use other body fluids, such as excretion of the drug into the urine, to assess the relative amount of the drug which has been absorbed (id.). The three usual parameters compared in a bioavailability blood level test are the area under the blood level curve (AUC), maximum concentration of the drug in the blood (C. Max.), and the time to reach the maximum concentration of the drug in the blood (T. Max.) (Tr. at 894-95 (Dr. Barr)).
64. The assay used in a bioavailability test is critical. It must be specific. It must measure only the drug and not drug metabolites, that is, those substances that the body forms after you give the drugs where the body transforms it into other materials which may be active or inactive. It must be reproducible "from one study to the next." It must be precise in its ability to measure exact amounts of the drug product (Tr. at 908 (Dr. Barr)).
65. Evaluation of a bioavailability study involves a testing of more than one hypothesis. First, one determines whether the test shows that with a 95% degree of confidence (i. e., 95 times out of 100) the two products have not been shown to differ from each other (Tr. at 910-11 (Dr. Barr)).
Second, the "power" of the test is determined, that is, it is determined whether the test itself has enough precision so as to be able to detect the real differences between the drugs if differences exist, e.g., whether the test could detect a real difference of 20% between the bioavailabilities of the two drugs 80% of the time. In other words, if 100 studies of the design of that study were done, 80% of the time those studies would say that there was no difference greater than 20% between the two drugs (Tr. at 912 (Dr. Barr)). (NDBI)
C. A Bioavailability Test Must Have the Sensitivity, or "Power," To Detect a Difference if There Is One
66. The concept of "power" of a test used to determine bioequivalence is of tremendous significance in biopharmaceutics and pharmacokinetics (Tr. at 909 (Dr. Barr)). If one seeks, by performing a test, to determine whether two products differ from each other, a failure of that test to determine a difference may mean simply that the test is too insensitive to detect that difference rather than that there is no difference. For example, two aspirin tablets, one weighing 50% more than the other, put on a truck balance, would not be shown to weigh different amounts, simply because the instrument used is relatively insensitive to determine that difference. (Tr. at 909-10 (Dr. Barr)).
67. Mr. Robillard of Clinical Concepts would have done a power analysis on a final report of the tests to determine triamterene blood levels and hydrochlorothiazide blood levels in a bioavailability study of Premo's Triamthiazide product had that study been completed. (P. Ex. 84-A, page 2; P. Ex. 84-B at 328 (Deposition of N. Robillard). (NDBI)
69. While Dr. Greene testified that he found only three articles in the Journal of Pharmaceutical Sciences between 1970 and 1980 that involved bioavailability tests with power analysis, he could recall few articles concerning bioavailability tests published in that journal, which limits publication to "state of the art developments" (Tr. at 1891 (Dr. Greene)). (NDBI)
70. A power analysis is absolutely necessary for a complete bioavailability test, since otherwise a test involving a great deal of variability among subjects or with an insensitive assay could be used to show that there was no detected difference between two drug products (Tr. at 913 (Dr. Barr)). A bioavailability test without some way to evaluate the overall sensitivity of the test is meaningless (Tr. at 914).
VI. The Need for Premarket Clearance of Generic Copies Is Recognized by Those Knowledgeable in the Field
71. It is necessary to be concerned about the quality of drug products very much more than other consumer products because if drug products fail in quality the results can be extremely serious, disastrous in some cases (Tr. at 1413 (Dr. Rhodes)). A definition for quality for drug products includes release of the active ingredient for a full biological effect (Tr. at 1414 (Dr. Rhodes)). (NDBI)
72. It is reasonable to require that a new drug product be demonstrated to be safe and effective (Tr. at 1416-17). (NDBI)
73. If there were no preclearance system in the form of approved new drug applications or abbreviated new drug applications, drug companies could develop products containing the same active ingredients as products already marketed, use safe and suitable active and inactive ingredients, follow good manufacturing practices and comply with all compendium standards in existence and yet produce a product with significantly different bioavailability from the product already on the market (Tr. at 1487-93 (Dr. Rhodes)). If there were no such preclearance mechanism it would be possible that such a biological availability difference would not be known until the product was actually physically in the market place (Tr. at 1493-94 (Dr. Rhodes)). (A)
74. The chance of companies manufacturing products having differences in bioavailability is too great simply to allow those products onto the market without someone reviewing them first, even if the same active or same amount of active drug ingredient is present (Tr. at 831 (Dr. Shangraw)).
75. At the present time, the Food and Drug Administration is the only "reasonable body" capable of reviewing drug products for bioequivalence (Tr. at 871 (Dr. Shangraw)).
76. An incident in this proceeding demonstrated the necessity of a review by FDA experts, not employed by the sponsoring drug company, of testing done to support that company's drugs. Dr. Rhodes, one of defendant's experts, prior to listening to Dr. Cabana's "penetrating analysis" of the Premo chlorthalidone study, was unaware of problems with that study and made conclusions that "had to be re-examined" after the review by the FDA and by Dr. Cabana pointed out problems with the study (Tr. at 1693-94 (Dr. Rhodes)). Dr. Rhodes agreed that when he stated in his sworn affidavit that "Premo has commissioned a well-designed and executed bioavailability study in which their product was compared with the bioavailability of the innovator's product," he was wrong (Tr. at 1694 (Dr. Rhodes)).
77. If FDA must, as part of enforcement actions, review, for court evaluation, studies concerning drug products designed to show those products' actual safety and effectiveness each time FDA seeks to remove a new drug product from the market pending premarket review, "the FDA will very soon be unable to perform with any degree of fairness to other manufacturers its assigned task of reviewing legally submitted NDAs and ANDAs" (P. Ex. 5 (Aff. of Dr. Crout), P 14, page 7).
78. The Food and Drug Administration has developed a compliance policy with respect to enforcement of the "new drug" provisions as they relate to prescription drugs that constitutes a rational determination of how to use limited enforcement resources to effectuate compliance with the law (Tr. at 67, 70-79, 80 (Dr. Crout); P. Ex. 4 (Aff. of Dr. Crout), PP 4-8). The Food and Drug Administration's compliance policy has been made widely available to the drug industry (Tr. at 81-82 (Dr. Crout)), and can not be said to constitute arbitrary decisionmaking by the agency. (A)
VII. Compliance with Compendial Guidelines Is No Substitute for Premarket Clearance
79. The United States Pharmacopeia ("U.S.P.") does not assume responsibility for insuring bioequivalence of different drug products for a particular drug and compliance with U.S.P. monographs does not assure bioequivalence (Tr. at 936-37 (Dr. Barr); Tr. at 726 (Dr. Shangraw)). Tetracycline capsules, all of which met U.S.P. standards, have been shown to produce significant differences in bioavailability (Tr. at 1011 (Dr. Barr)). (NDBI)
80. The U.S.P. and the National Formulary ("N.F.") both lack the internal and external resources required to develop a rational and modern standard. The reliance on such limited resources is anachronistic and inadequate for the scientific activities necessary to ensure pharmaceutical equivalence of drug products (Tr. at 1520 (Dr. Rhodes)). (NDBI)
81. Many active ingredients and excipients are not included in the U.S.P. even today (Tr. at 1520 (Dr. Rhodes)). There is, in any case, no monograph in an official compendium for a drug product containing the combination of triamterene and hydrochlorothiazide (P. Ex. 2 (Aff. of Dr. Cabana), P 35.a), nor is there anywhere else a publicly available monograph for this drug to establish a standard for identity, quality, strength, and purity for drug products containing these ingredients (id., P 35.b). (A)
82. Even where excipients are included in a U.S.P. monograph, specific tests and standards applicable to their use as components in drug products such as tablets or capsules are not always available (Tr. at 1520-21 (Dr. Rhodes)). (A)
83. At least with respect to some drugs in the U.S.P. the monographs do not address the problem of interaction between active ingredients and excipients (Tr. at 1521 (Dr. Rhodes)). (A)
84. Most U.S.P. monographs do not have specifications for granulation or precomposition mixtures (Tr. at 1521 (Dr. Rhodes)), even though with respect to some drugs the particle size of the active ingredient is quite important (Tr. at 1522). (A)
85. Only a small number (10-12) of the drugs in the new combination National Formulary and United States Pharmacopeia have in vitro or dissolution monographs that are correlated with in vivo results (Tr. at 728 (Dr. Shangraw)). In the absence of a correlation between in vitro dissolution studies and in vivo bioavailability studies there can be no assurance that a dissolution test will demonstrate bioequivalence of one drug to another (Tr. at 727-28, 729-30 (Dr. Shangraw)). (A)
86. U.S.P. disintegration tests are so imprecise as to have a 40% chance of allowing defective tablets to pass the test (Tr. at 1523-25 (Dr. Rhodes)). Some dissolution testing in the U.S.P. is so imprecise as to allow a 60% error to go undetected (Tr. at 1524-27 (Dr. Rhodes)).
87. If there are polymorphic differences in the active ingredient of a drug, that type of difference would not be detectable by methods included in the U.S.P. monographs (Tr. at 571-72 (Dr. Cabana)).
89. A U.S.P. monograph would not be changed until there was clear and convincing evidence of the inadequacies of the assay in that monograph, although if a serious problem came to light in a monograph this could be changed (Tr. at 1423-23 (Dr. Rhodes)).
90. Even though digoxin in tablet form can vary greatly with respect to bioavailability (Tr. at 1511 (Dr. Rhodes)), and people began to realize that fact about 15 years ago (id.), there was a monograph in the U.S.P. in 1970, compliance with which did not insure that the drug product containing digoxin did not have significant bioavailability problems (Tr. at 1512-13; P. Ex. 212). (NDBI)
91. Dr. William Barr, one of the six trustees who serve as a policymaking group of the U.S.P. (Tr. at 878-79 (Dr. Barr)), and Dr. Shangraw, a member of the executive committee of the U.S.P. and chairman of the Formulations Committee of the Committee of Revision of the U.S.P. (P. Ex. 7 (Aff. of Dr. Shangraw), P 7; Tr. at 713 (Dr. Shangraw)), believe FDA premarketing clearance of generic copies of approved drugs is essential (see P. Ex. 1 (Aff. of Dr. Barr), PP 19-209; P. Ex. 7 (Aff. of Dr. Shangraw), P 17; Tr. at 831 (Dr. Shangraw)). (NDBI)
VIII. Compliance with Good Manufacturing Practice Regulations Does Not Adequately Assure the Safety and Effectiveness of Generic Copies of Approved Drugs
92. Compliance with good manufacturing practices ("GMPs") would not assure the safety and effectiveness of generic copies of innovator products for the following reasons:
A. GMPs do not specify which excipients should be used in any particular drug product (Tr. at 1527-28 (Dr. Rhodes)).
B. GMPs do not specify particular manufacturing processes (Tr. at 1528).
C. GMPs do not specify the source of the active ingredient of the drug product (id.).
D. GMPs do not specify the particle size with respect to manufacturing processes (id.).
E. GMPs do not guarantee that any particular product will be stable (Tr. at 1529). (NDBI)
93. GMP inspections by FDA inspectors would not be a substitute for premarket clearance because FDA inspectors are not experts in pharmacokinetics or biopharmaceutics (Tr. at 1530 (Dr. Rhodes)), only a sampling of drug products are selected for inspection during a GMP inspection (Tr. at 1531), most FDA inspectors are not specialists in drug formulation and do not normally have expertise in determining what excipients would be used in formulating particular drug products (id.), and most FDA inspectors have no particular expertise as to techniques used in manufacturing (id.; see also Tr. at 1532). Also, it is possible for a drug manufacturer to be manufacturing and distributing a drug product for up to six months before the FDA is even aware that the manufacturer is selling the product (Tr. at 1532 (Dr. Rhodes)), and GMP inspections can be as infrequent as once every other year (id., see also Tr. at 319-20 (Dr. Crout)). (NDBI)
94. When Mr. John Blackman stated that there were at least 85 visits by Food and Drug Administration inspectors as part of good manufacturing practice inspections at the Premo plant during a certain recent period of time, he was including inspections other than GMP inspections, i. e., inspections to learn of possible violations of the new-drug provisions of the Federal Food, Drug and Cosmetic Act (P. Ex. 81-A, page 1; P. Ex. 81-B at 10 (Deposition of J. Blackman)).
A. Marketing Without Testing
95. Premo began marketing chlorthalidone tablets in June 1979 (P. Ex. 64). It has presented no evidence of any testing of this product that was completed at that time. The flawed bioavailability test of chlorthalidone was not analyzed and reported to Premo until December of 1979 (D. Ex. 39; P. Ex. 84-A, page 1; P. Ex. 84-B at 150 (Deposition of N. Robillard)). No evidence has been presented that Premo even sought to analyze the innovator product to determine its ingredients so that it could be copied. (NDBI)
96. Premo began to market allopurinol tablets in October 1979 (P. Ex. 64), despite the fact that no in vivo bioavailability testing of this product had been completed at that time. No evidence has been submitted of an analysis of the innovator product to determine whether Premo's product was equivalent to it in ingredients that predated the marketing of Premo's allopurinol. Fittelson Laboratories, with which United States Testing Company contracts to analyze drug products, submitted a report on the innovator allopurinol product that dealt only with analysis to determine the amount of lactose ...