Opinion

United States v. Premo Pharmaceutical Laboratories, Inc.

511 F. Supp. 958
1981 U.S. Dist. LEXIS 10660

Court: District Court, D. New Jersey
Filed: Jan 20, 1981
Status: Published
Author: Lacey
On the bench: Lacey
Cited by: 9 cases
Authority: More cited than 60.2%

11-day hearing conducted on 8 products involving the "generic/new drug issue”

How later courts described this case

11-day hearing conducted on 8 products involving the "generic/new drug issue”
courts have power to enjoin present and future violations of section 331 “solely on the basis that such violations have been established”
excellent discussion of factors which may affect bioavailability

Written by the judges who cited it.

The opinion

OPINION

LACEY, District Judge.

INTRODUCTION

The United States sues to enjoin defendants from continuing their alleged violations of the Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. §§ 301-392 (1976 & Supp. I 1977). These violations, as charged in the complaint, are that defend

*960

ants are marketing human drugs in interstate commerce without the requisite approval of the Food and Drug Administration (FDA), and without the testing required to show that the drugs are safe and effective for their intended uses.

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:

No person shall introduce or deliver for introduction into interstate commerce

*961

any new drug, unless an approval of an [NDA] is effective with respect to such drug.

Id.

§ 355(a).

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 second portion of this opinion is intended to advance appellate review in the event the court of appeals decides that the determinative issues are broader than the issue of expert recognition of safety and efficacy. Thus, under my Findings of Fact I have referred to not only the evidence con

*962

sidered under “DISCUSSION,” but also that which was received conditionally and is now determined by me to be irrelevant.

See

p. 961, note 1

supra.

DISCUSSION

The Food and Drug Act of 1906, ch. 8915, 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.

§§ 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.

§ 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.

Weinberger,

412 U.S. 655 , 93 S.Ct. 2498 , 37 L.Ed.2d 244 (1973);

United States v. Articles of Drug (Lannett),

585 F.2d 575 (3d Cir. 1978);

Hoffmann-LaRoche, Inc. v. Weinberger,

425 F.Supp. 890 (D.D.C.1975).

Where a drug product is claimed by its manufacturer to be a copy of a product already approved by FDA on the basis of an NDA, the manufacturer may file with FDA an ANDA which relies upon the safety and effectiveness tests performed with respect to the FDA-approved pioneer product. However, FDA will approve an ANDA only where the “me-too” product is shown to be the therapeutic equivalent of the pioneer and safe and effective in accordance with 21 U.S.C. § 355 (d) (1976).

See Premo Pharmaceutical Laboratories, Inc. v. United States,

629 F.2d 795, at 798 (2d Cir. 1980)

(“Premo

”).

See generally Hoffmann-LaRoche, Inc. v. Weinberger, supra.

No ANDA has been approved for the eight Premo products in suit.

Much of the testimony on this hearing related to bioavailability. Bioavailability is “the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action.” 21 C.F.R. § 320.1 (a) (1980).

See Dorland’s Illustrated Medical Dictionary

200 (25th ed. 1974). If there is no significant difference between the rate and extent of absorption

*963

of two drugs administered at the same molar dose of therapeutic moiety under similar experimental conditions, the drugs are said to be bioequivalent. See 21 C.F.R. § 320 .-1(e) (1980). When two different drug products are to be used interchangeably in the treatment of illness, it can be critical that the products are bioequivalent — -that is, that there be no significant difference in the products’ bioavailability. A drug that is less bioavailable than that for which it is substituted will deliver less of its active ingredient than expected; a drug that is more bioavailable than that which it replaces presents the danger of overdosage.

See

P. Ex. 4, ¶¶ 8-17 (Crout Affidavit); P. Ex. 3, ¶¶ 18-22 (Cortell Affidavit); P. Ex. 6, ¶¶9-11 (Perel Affidavit); P. Ex. 2, ¶39 (Cabana Affidavit).

The Government argues that physicians and patients generally believe or assume that generic versions of “brand-name” products are bioequivalent to the respective pioneer drugs themselves. Because the generic versions are usually significantly less expensive than the pioneer drugs, they are frequently freely substituted for their more expensive counterparts. Thus, the Government contends, it is crucial that the products be, in fact, bioequivalent. Contending that, because so many factors independent of a product’s active ingredient — and even, as indicated below, of its inactive ingredients — can affect a drug product’s bioavailability (and thus its bioequivalence to an FDA-approved medication), the Government concludes that absent preclearance of each of Premo’s products named in the complaint, there can be no assurance of its safety and effectiveness, and it must be considered a “new drug” within the meaning of section 321(p) of the Act.

Premo argues that so long as the active ingredient in its product is the same as the active ingredient in the approved pioneer drug all other questions are irrelevant because the active ingredient, the “drug,” has been recognized as safe and effective by the FDA.

There are many factors that can affect a drug’s bioavailability. Among these are the particle size and crystalline form of the active ingredient; the choice of inactive ingredients (excipients), such as binders and fillers; the facilities and controls used in the manufacture and processing of the drug; and the environmental conditions during manufacture and storage.

*964

The particle size and crystalline form of the active ingredient can be crucial because these factors can affect the drug’s solubility and/or the rate that the drug dissolves in gastrointestinal fluids. This, in turn, can affect the bioavailability of the active ingredient itself.

P. Ex. 1, ¶ 10 (Barr Affidavit); P. Ex. 7, at 4 (Shangraw Affidavit); P. Ex. 2, ¶ 24 (Cabana Affidavit); P. Ex. 4, ¶ 11 (Crout Affidavit).

The choice of inactive ingredients is of great importance, because these ingredients may interact with the product’s active ingredient and thereby significantly increase or decrease the bioavailability of the active ingredient. P. Ex. 1, ¶ 10 (Barr Affidavit); P. Ex. 7, at 6 (Shangraw Affidavit); P. Ex. 2, ¶¶ 14, 25 (Cabana Affidavit); P. Ex. 4, ¶ 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, ¶ 10 (Barr Affidavit); P. Ex. 7, at 9 (Shangraw Affidavit); P. Ex. 2, ¶24 (Cabana Affidavit); P. Ex. 4, ¶ 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.

P. Ex. 7, at 9.

See

P. Ex. 1, ¶ 10 (Barr Affidavit); P. Ex. 2, ¶ 21 (Cabana Affida

*965

vit); P. Ex. 4, ¶ 11 (Crout Affidavit). Dr. Shangraw also noted that the method by which disintegrants are incorporated into the tablet or capsule may significantly affect the effectiveness of the disintegrant. If an incorrect method of disintegration is employed, the drug product may not disintegrate properly, causing an insufficient quantity of the drug to be absorbed and thereby reducing its effectiveness.

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.

Id.

at 8 .

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.

Ill

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.

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 eases 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

*966

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.

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

*967

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)(l)

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.

Id.

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).

*968

The

Lannett

court coupled this

Mykocert

definition with (1) the Supreme Court’s indication in

Hynson

of similarities between generic products and the pioneer drugs they copy and (2) the Government’s concession of identity between Lannett’s products and their approved counterparts, and then concluded that summary judgment on the “new drug” issue should have been denied by the district court. 585 F.2d at 584 .

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 “compartmentalizfed] 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.

*969

Judge Meanor’s analysis is persuasive, particularly for its reading of section 321(p) in conjunction with section 355. In addition, a reading of section 310.3 of FDA’s regulations, upon which the

Lannett

court relied, also proves instructive.

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

*970

court relied, need not be discussed in detail. The

Mykocert

court’s construct for determining “old drug” status, quoted by the court in

Lannett,

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:

[Wjhen 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 question’ed 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.

Id.

On appeal the Court of Appeals for the Second Circuit reversed. It held that

*971

the district court should not have considered the actual safety and effectiveness of Premo’s generic product; this was a question exclusively for FDA resolution and the district court should have limited its inquiry to the narrow question whether there existed general expert recognition of the product’s safety and effectiveness:

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:

[Wjhether the product (including one claimed to be a “me-too” drug) is in fact safe and effective ... is to be determined by the FDA which, as distin

*972

guished from a court, possesses superior expertise, usually of a complex scientific nature, for resolving the issue. The entire statutory scheme envisages that the FDA will perform the difficult task of investigation and scientific evaluation usually required to determine whether a drug product is safe and effective.. . .

... 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.

Id.

at 803.

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^] 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.

*973

Thus, the Second Circuit held Premo’s Insulase to be a “new drug” within the meaning of the Act, reversed the judgment of the district court, and remanded the case with directions to dismiss the complaint.

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,

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 volumi

*974

nous 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, ¶ 23 (Crout Affidavit); P. Ex. 1, ¶ 24 (Barr Affidavit); P. Ex. 7, ¶ 16 (Shangraw Affidavit).

As to Premo’s chlorthalidone tablets,

see

P. Ex. 4, ¶ 23 (Crout Affidavit); P. Ex. 1, ¶ 24 (Barr Affidavit); P. Ex. 3, ¶ 24 (Cortell Affidavit); P. Ex. 2, ¶¶ 41, 45 (Cabana Affidavit); P. Ex. 7, ¶ 16 (Shangraw Affidavit).

As to Premo’s doxylamine succinate with pyridoxine HCL (Doxine) tablets,

see

P. Ex. 4, ¶23 (Crout Affidavit); P. Ex. 1, ¶24 (Barr Affidavit); P. Ex. 6, ¶ 18 (Perel Affidavit); P. Ex. 2, ¶¶ 44, 45 (Cabana Affidavit); P. Ex. 7, ¶ 16 (Shangraw Affidavit).

As to Premo’s Hydroxyzine pamoate (Hy Pam) capsules,

see

P. Ex. 4, ¶ 23 (Crout Affidavit); P. Ex. 1, ¶ 24 (Barr Affidavit); P. Ex. 6, ¶ 18 (Perel Affidavit); P. Ex. 7, ¶ 16 (Shangraw Affidavit).

As to Premo’s hydroxyzine hydrochloride tablets,

see

P. Ex. 4, ¶ 23 (Crout Affidavit); P. Ex. 1, ¶ 24 (Barr Affidavit); P. Ex. 6, ¶ 18 (Perel Affidavit); P. Ex. 7, ¶ 16 (Shangraw Affidavit).

As to Premo’s trifluoperazine hydrochloride tablets,

see

P. Ex. 4, ¶ 23 (Crout Affidavit); P. Ex. 1, ¶ 24 (Barr Affidavit); P. Ex. 6, ¶ 18 (Perel Affidavit); P. Ex. 2, ¶¶ 42, 45 (Cabana Affidavit); P. Ex. 7, ¶ 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, ¶ 23 (Court Affidavit); P. Ex. 1, ¶ 23 (Barr Affidavit); P. Ex. 3, ¶ 23 (Cortell Affidavit); P. Ex. 6, ¶ 17 (Perel Affidavit); P. Ex. 2, ¶ ¶ 35, 41-45 (Cabana Affidavit); P. Ex. 7, ¶ 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);

While we do not express an opinion as to whether a “mere” conflict in expert opin

*975

ion constitutes lack of general recognition, it 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.

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^] 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

Tr. at 473 (Dr. Cabana)). (A)

A. Inactive Ingredients

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), ¶ 10; P. Ex. 2 (Aff. of Dr. Cabana), ¶¶ 23, 25, 30, 32; P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 13-B; P. Ex. 4 (Aff. of Dr. Crout, ¶¶ 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), ¶ 13-B). (A)

B. Active Ingredients

28. The “same” active ingredient from different sources may cause different effects in terms of bioavailability (P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 13-A; P. Ex. 1 (Aff. of Dr. Barr), ¶ 10; P. Ex. 2 (Aff. of Dr. Cabana), ¶¶ 24, 32; P. Ex. 4 (Aff. of Dr. Crout), ¶¶ 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), ¶ 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), ¶ 13-A.2); the association of the active ingredient with different solvents

(id.,

¶ 13-A.3; Tr. at 716 (Dr. Shangraw)); the form of the dissolution properties of the product (P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 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.,

¶ 13-A.5, Tr. at 214 (Dr.

*982

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), ¶ 10; P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 13-C; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 32; P. Ex. 4 (Aff. of Dr.. Crout), ¶¶ 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)

1. Tablets

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), ¶ 13-C.l). (NDBI)

2. Capsules

38. For capsules, manufacturing variables that may affect bioavailability include methods used to reduce bulk for encapsula

*983

tion, granule/powder size and size distribution, disintegrant/dispersents and method of incorporation of disintegrants or dispersents, lubricants and methods of incorporation of lubricants, surfactants and methods of incorporation of surfactants, the compression applied during filling of the capsules, flow properties of the powder mixture, and mixing time (P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 13-C.2). (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) '

*984

48. Magnesium stearate is a lubricant which forms a film on the surfaces of metals and prevents drug powders from sticking to those surfaces in the manufacture of a drug. Because magnesium stearate is “hydrophobic”,

i. e.,

it does not wet with water well, it slows down the dissolution of a drug in water (Tr. at 757 (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)

3. Topical Preparations

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), ¶ 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), ¶ 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), ¶ 14; P. Ex. 1 (Aff. of Dr. Barr), ¶ 18; P. Ex. 3 (Aff. of Dr. Cortell), ¶ 17; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 39-C(l)). (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), ¶ 15; P. Ex. 6 (Aff. of Dr. Perel), ¶ 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), ¶¶ 10, 15-17; P. Ex. 3 (Aff. of Dr. Cortell), ¶¶ 18-19; P. Ex. 6 (Aff. of Dr. Perel), ¶¶ 9-10; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 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), ¶¶ 10-14; P. Ex. 3 (Aff. of Dr. Cortell), ¶¶20, 22; P. Ex. 6 (Aff. of Dr. Perel), ¶¶ 11, 16; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 39).

*985

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), ¶25; P. Ex. 1 (Aff. of Dr. Barr), ¶¶ 25-27; P. Ex. 6 (Aff. of Dr. Perel), ¶ 19; P. Ex. 4 (Aff. of Dr. Crout), ¶ 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), ¶25; P. Ex. 6 (Aff. of Dr. Perel), ¶ 19; P. Ex. 1 (Aff. of Dr. Barr), ¶¶ 25-27; P. Ex. 4 (Aff. of Dr. Crout), ¶ 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)).

Y. 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 á 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)

62.

In vitro

(in beaker) testing may be appropriate for determining the bioavailability only of drugs with no bioavailability problem or where

in vitro

tests have been correlated with the results of

in vivo

testing (Tr. at 478-81 (Dr. Cabana)).

In vitro

tests do not provide a basis for conclusions about

*986

bioavailability unless a correlation has been made between the results of those studies and the results of an

in vivo

study for the drug (Tr. at 898-99 (Dr. Barr);

see also

Tr. at 1615-16 (Dr. Rhodes); P. Ex. 169).

In vitro

tests cannot reliably establish the bioavailability of drug products when those products fall into any of the following three categories: (1) drugs at which dissolution does not appear to be related to bioavailability, for example, where the drug breaks down in the stomach; (2) drugs whose solubility is poor; and (3) drugs for which the minimum dissolution required to achieve good bioavailability is not known (Tr. at 481-83 (Dr. Cabana)). The three main types of bioavailability tests are serum level tests, bioassays, and

in vitro

tests correlated to

in vivo

testing (Tr. at 900-05 (Dr. Barr)). (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 (j. 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)

68. Both Dr. Westlake and Dr. Wagner, relied upon by Dr. Greene, in books they authored set out formulas for power analyses (Tr. at 1915-17 (Dr. Greene); P. Ex. 250). The alternative theory to power anal

*987

ysis, developed by Dr. Westlake, an approach to variance based on confidence intervals, was not used by Dr. Greene in analyzing the Triamthiazide or chlorthalidone bioavailability studies (D. Ex. 83 revised, 84 and 39-A) (Tr. at 1917-18 (Dr. Greene)).

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 sub

*988

mitted NDAs and ANDAs” (P. Ex. 5 (Aff. of Dr. Crout), ¶ 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), ¶¶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), ¶ 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., ¶ 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)).

88. Different methods of manufacturing active ingredients may cause different degradation products (Tr. at 1425 (Dr. Rhodes)). The compendial,

i. e.,

U.S.P.-N.F., assay standards assume that certain processes of drug synthesis have been used, and therefore it is conceivable that the prescribed assay may not pick up other degradation products and other impurities in an

*989

active drag substance synthesized in a different manner (Tr. at 1420-21 (Dr. Rhodes)). (NDBI)

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), ¶ 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), ¶¶ 19-209; P. Ex. 7 (Aff. of Dr. Shangraw), ¶ 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 Drags

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 drag 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 drag formulation and do not normally have expertise in determining what ex-cipients would be used in formulating particular drag 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, Drag and Cosmetic Act (P. Ex. 81-A, page 1; P. Ex. 81-B at 10 (Deposition of J. Blackman)).

(NDBI)

*990

IX. Premo’s Actions Demonstrate That if There is No Premarketing Clearance Requirement for Generic Copies of Approved Drugs, Generic Manufacturers Will Place Drugs on the Market Without Proper Testing and Without Even Consulting Their Expert Consultants

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 and the amount of starch in the product on November 8,1979 (P. Ex. 83-A, page 1; P. Ex. 83-B at 61-63 (Deposition of S. Kahan); D. Ex. 306-1). (NDBI)

97. Premo began marketing betamethasone valerate cream in May of 1979, (P. Ex. 64). The record reveals no testing of that product that had been completed at that time. Nor is there any evidence in the record that Premo had analyzed the innovator product to determine whether its product contained the same active ingredients as the innovator. (NDBI)

98. Premo began to market its hydroxyzine hydrochloride tablets in April 1978 (P. Ex. 64). There is no evidence in the record that there was any testing of this product before marketing or that Premo sought to analyze the innovator product to match its ingredients. (NDBI)

99. Premo began to market its hydroxyzine pamoate capsules in May of 1978 (P. Ex. 64). There is no evidence in the record that Premo performed any bioavailability or other testing on this product before marketing, and no evidence that it analyzed the innovator product to determine its ingredients to copy them prior to marketing its product. (NDBI)

100. Premo began to market its product containing doxylamine succinate and pyridoxine hydrochloride in September of 1978 (P. Ex. 64). Premo presented no evidence that it had performed any bioavailability or other testing of this product prior to marketing, or that it had analyzed the innovator product in an attempt to match its active ingredients. (NDBI)'

101. Premo began to market its trifluoperazine hydrochloride tablets in November of 1979 (P. Ex. 64). Premo has presented no evidence that it performed bioavailability or other testing of these tablets prior to marketing or that it analyzed the innovator product in an attempt to match its ingredients prior to the marketing date. (NDBI)

102. Premo began to market its Triamthiazide (triamterene plus hydrochlorothiazide) capsules on November 14, 1979. (NDBI)

103. Premo had not received any bioavailability or blood level data with respect to the Triamthiazide product prior to marketing (Tr. at 2238 (S. Blackman)). (NDBI)

104. Premo had no information before it started marketing Triamthiazide that its product was bioequivalent to the innovator Dyazide (P. Ex. 25-A, page 4; P. Ex. 25-B at 54 (Deposition of J. Blackman)). (NDBI)

105. When Premo began to market its Triamthiazide product it had no clinical data with respect to the edema indications for that product (P. Ex. 26-A, page 7; P. Ex. 26-B at 203 (Deposition of J. Black-man); Tr. at 2238 (S. Blackman)). (NDBI)

*991

106. Mr. Seymour Blackman states he was present at a phone conversation in which an oral final report of a clinical study concerning a Triamthiazide product was received by Walter Epler from Norman Robillard prior to the decision to market Premo’s Triamthiazide product (Tr. at 2237 (S. Blackman)); Walter Epler, however, denied having received an oral report concerning the values or conclusions to be drawn from the clinical study concerning Premo’s Triamthiazide product before receipt of the final report dated November 26, 1979 (P. Ex. 27-A, page 3; P. Ex. 27-B at 25). (NDBI)

107. While John Blackman states that Premo relies upon its experts, Premo required Dr. Rhodes’ advice to do a bioavailability study of Triamthiazide (Tr. at 1430-31 (Dr. Rhodes)). As to Dr. Tessler, upon whom Premo also said it relied, and who John Blackman thought was monitoring the clinical study of Triamthiazide, he was, as Blackman knew, in federal court as a party during the period from September and October up until November of 1979 (P. Ex. 25-A, page 4; P. Ex. 25-B at 48-49, 50 (Deposition of J. Blackman)).

108. John Blackman has admitted that Premo received the final report of the clinical study of Premo’s Triamthiazide product on November 26, twelve days after marketing was begun (P. Ex. at 25-A, page 3; P. Ex. 25-B at 47). (NDBI)

109. Premo had received an interim report of the clinical study of Triamthiazide from Dr. Tessler prior to marketing the product (P. Ex. 25-A, pages 3-4; P. Ex. 25-B and 47-48 (Deposition of J. Black-man)). (NDBI)

110. The interim report, dated August 21, 1979, received by Premo prior to its marketing of its Triamthiazide product, states that Premo’s Triamthiazide “is equally,

if not more,

effective than Dyazide in the control of uncomplicated essential hypertension” (emphasis added) (P. Ex. 26-C-6A, page 3). (NDBI)

111. Premo does not know the manufacturing techniques used by Smith, Kline and French in its production of Dyazide and Premo is not 100% positive about the actual ingredients used in the manufacture of Dyazide (P. Ex. 26-A, page 6; P. Ex. 26-B at 186-87). (NDBI)

B. Marketing Without Consulting Experts

112. Mr. John Blackman states that Dr. Rhodes consults with his department on a regular basis (P. Ex. 25-A, page 2; P. Ex. 25-B at 17;

cf.

Tr. at 1427 (Dr. Rhodes)). (NDBI)

113. Neither Dr. Rhodes nor Dr. Greene was consulted on whether Premo should market its Triamthiazide product and neither knew that it was being marketed until one of their graduate students brought each a sample capsule which had been obtained on the open market (Tr. at 1326, 1442 (Dr. Rhodes); Tr. at 1928-29 (Dr. Greene)). (NDBI)

114. Dr. Rhodes was not consulted with respect to the marketing of Premo’s trifluoperazine hydrochloride product and did not learn that it was being marketed until he saw that it was named as one of the drugs in this case (Tr. at 1443 (Dr. Rhodes)). Dr. Greene did not even know at the time of his testimony that Premo was selling trifluoperazine (Tr. at 1931-32 (Dr. Greene)). (A)

115. Dr. Rhodes was not consulted prior to Premo marketing its chlorthalidone products and did not learn of that marketing until this case began (Tr. at 1444 (Dr. Rhodes)). Dr. Greene was not consulted on the marketing of chlorthalidone and learned about it when a pharmacy student brought a tablet to him (Tr. at 1929-30 (Dr. Greene)). (NDBI)

116. Dr. Rhodes was not consulted with respect to the marketing of Premo’s allopurinol product and did not know that it was being marketed prior to the start of this case (Tr. at 1445 (Dr. Rhodes)). Dr. Greene was not aware even at the time of the law suit that Premo was marketing allopurinol (Tr. at 1932 (Dr. Greene)). (NDBI)

117. Dr. Rhodes did not become aware that Premo was marketing betamethasone valerate cream until August or September

*992

of 1979 and at that time did not know whether or not Premo had submitted a new drug application for the product (Tr. at 1445-46 (Dr. Rhodes)). Dr. Greene was not consulted on whether this product should be marketed (Tr. at 1933 (Dr. Greene)). (NDBI)

118. Prior to this case Dr. Rhodes was not aware that Premo was marketing its doxylamine succinate with pyridoxine hydrochloride combination (Tr. at 1446 (Dr. Rhodes)). Dr. Greene was not consulted on the marketing of this drug (Tr. at 1933 (Dr. Greene)). (NDBI)

119. Prior to this case, Dr. Rhodes was not aware that Premo was marketing either its hydroxyzine hydrochloride or hydroxyzine pamoate products (Tr. at 1447 (Dr. Rhodes)). Dr. Greene did not know at the time of trial whether hydroxyzine hydrochloride or hydroxyzine pamoate were being marketed by Premo (Tr. at 1932 (Dr. Greene)). (NDBI)

X. Dr. Rhodes’ Suggestion That Bioequivalent Generic Products Can Be Made by Analysis of Approved Products in an Attempt To Copy Their Ingredients, a Suggestion Not Followed by Premo in Most Instances in any Case, Is Not Supported by Evidence in the Record

120. If a drug company starts out to make a generic version of a product and uses different generic components and different methods of preparing the drug product, that approach is likely to produce a product that may show significant biological availability differences between the generic product and the innovator product (Tr. at 1041^42 (Dr. Rhodes)). (A)

121. An alternative approach, acceptable in Dr. Rhodes’ view, to formulating a drug product includes making an attempt, through use of an independent testing laboratory, to determine the constituents of a drug product (Tr. at 1494, 1042 (Dr. Rhodes)). Yet, there was no evidence that Premo followed this procedure for any of its products other than Triamthiazide prior to marketing or for any product other than allopurinol after marketing (see Proposed Findings 98-104, supra). (NDBI)

122. Fittelson Laboratories, which tested Premo products by contract with United States Testing Co. (P. Ex. 83-A, page 2; P.Ex. 83-B at 101 (Deposition of S. Kahan)), is seldom asked to break down a tablet or capsule into the excipients and lubricants and other materials which may be present (P. Ex. 83-A, page 1; P. Ex. 83-B at 10-11 (Deposition of S. Kahan)). That laboratory, while equipped to do so, would be reluctant to do a complete analysis of a tablet without an idea of the individual components of the tablet (P. Ex. 83-A, page 1; P. Ex. 83-B at 11-12 (Deposition of S. Kahan);

see also

Tr. at 1497 (Dr. Rhodes)).

Paragraphs 123 through 128 are contained in the sealed portion of these findings.

XI. Premo’s Products Differ from the Products for Which They May Be Substituted and Those Differences May Be Important

A. Premo’s Triamthiazide Product Differs Significantly in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Innovator Product for Which It May Be Substituted

1. If Premo’s Triamthiazide Differs in Bioavailability from the Innovator Product, That Fact Could Cause Serious Harm to Patients

129. The use of a Triamthiazide product that is more bioavailable than Dyazide could lead to a significant danger of hyperkalemia which can cause the heart muscle to beat irregularly and stop,

thus leading to death

(P. Ex. 3 (Aff. of Dr. Cortell), ¶ 19; P. Ex. 4 (Aff. of Dr. Crout), ¶¶ 15-17; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 39.c). Use of Triamthiazide product that is significantly more bioavailable than Dyazide could also lead to the formation of kidney stones (renal calculi) (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 39.d).

130. If the Premo Triamthiazide product were less bioavailable than the Dyazide

*993

product that fact would also lead to risk to patients because patients treated with the Triamthiazide would find that drug ineffective in controlling the conditions for which it was prescribed, a therapeutic failure that can lead to, among other things, dysfunction of cardiac rhythm

and sudden death

(P. Ex. 3 (Aff. of Dr. Cortell), ¶ 20; P. Ex. 4 (Aff. of Dr. Crout), ¶¶ 12 and 14; P. Ex. 2 (Aff. of Dr. Cabana), ¶ 39.e).

131. Patients taking drugs such as triamterene plus hydrochlorothiazide are often on other drug products as well (Tr. at 1575 (Dr. Rhodes)), and often have other diseased states which are being treated by these other drugs

(id.),

such as instances in which drugs such as Digitalis would be used

(id.).

This fact can increase the medical significance of any bioavailability problem with Triamthiazide (Tr. at 618-19 (Dr. Cabana)).

132. Many patients taking a combination product containing triamterene with hydrochlorothiazide have a condition known as diabetes mellitus, adult onset (Tr. at 1575 (Dr. Rhodes)) and with respect to such patients an increasingly potent triamterene with hydrochlorothiazide would present distinct possibility of complications

(id.).

(NDBI)

133. The toxic effects associated with combinations of triamterene plus hydrochlorothiazide represent a relatively steep dosage response, that is, an increase in effective dosage of the drug brings a marked increase in the toxic effects for the drug (Tr. at 934-36 (Dr. Barr)).

134. In one study involving elderly patients, twenty-two patients treated with triamterene plus hydrochlorothiazide moved from a normal serum potassium range into the range defined by Dr. Rhodes as hyperkalemic (Tr. at 1585 (Dr. Rhodes); D. Ex. 140, page 170, table 5).

135. Hypokalemia is dose responsive to hydrochlorothiazide, that is, an increase in the amount of hydrochlorothiazide is likely to bring an increase in the potassium excretion of the patient (Tr. at 1622-24 (Dr. Rhodes)). (NDBI)

2. There Are Bioavailability Problems with Products That Contain, as Does Triamthiazide, Triamterene Plus Hydrochlorothiazide

136. Dr. Rhodes advised Premo it was necessary to perform a bioavailability study for the drug product containing triamterene and hydrochlorothiazide even though they might have the clinical study underway and he told them it was perfectly feasible to assay the drug in body fluids (Tr. at 1430-31 (Dr. Rhodes)). (NDBI)

137. FDA’s files contain data which identify significant differences in both the dissolution and bioavailability of products containing triamterene plus hydrochlorothiazide (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 36).

138. Differences in bioavailability of triamterene plus hydrochlorothiazide products may come from changes in manufacturing processes, such as simply changing from a laboratory batch to a full production batch or from changing the order in which the components of the drug are mixed

(id.,

¶ 37.b).

139. A bioavailability study in the files of the FDA has shown a difference in peak plasma levels of four to five times between a formulation containing triamterene plus hydrochlorothiazide and the currently marketed product, Dyazide

(id.,

¶ 37.c). (NDBI)

140. A protocol submitted by Premo to the FDA for its product Triamthiazide states that preliminary study, which Premo now argues was of an experimental formula, suggests a seven to eight fold difference in bioavailability of the Premo formulation compared to the marketed product, Dyazide

(id.,

¶ 38.c). This is not, however, entitled to substantial weight, since it represents data generated from only one subject taking the Premo formulation in comparison with an entirely different subject taking the Dyazide formulation.

141. Innovator products may not be well absorbed so that products that imitate the innovator’s may be absorbed a great deal more than the innovator’s. Thus, for example, if only 10% of the innovator product is absorbed in the blood the imitator may be

*994

absorbed as much as 10 times as much as the innovator (Tr. at 977-78 (Dr. Barr)). The innovator product copied by Triamthiazide is probably absorbed only 10 to 20% itself. (Tr. at 977).

142. Dr. Rhodes, in a February 14, 1980, evaluation of a preliminary bioavailability study of Premo’s triamterene with hydrochlorothiazide products saw bioavailability problems with the drug, stating that the data in that study “does not indicate bioequivalence, rather it suggests that the Premo products are yielding a significantly higher proportion of triamterene. I suspect that this finding indicates some major problem in the Smith Kline product.” (P. Ex. 244, page 2; Tr. at 1652 (Dr. Rhodes)). Dr. Rhodes, at trial, attempted, not entirely successfully, to explain away this evaluation.

143. The two active ingredients of drugs containing triamterene and hydrochlorothiazide present bioavailability problems. See ¶¶ 144-147,

infra.

144. Triamterene is a drug with a known bioavailability problem (Tr. at 1597 (Dr. Rhodes)), as Dr. Rhodes advised Premo on September 21,1979

(id.).

Triamterene is extremely insoluble in water, a fact that suggests a possible bioavailability problem

(id.;

Tr. at 484 (Dr. Cabana); Tr. at 1895, 1900 (Dr. Greene)). Triamterene is subject to considerable metabolism and is subject to a first pass effect that may alter the absorption of the drug into the human system (Tr. at 1598 (Dr. Rhodes); Tr. at 1897 (Dr. Greene)). (NDBI)

145. There has been documentation of up to a 300% difference in bioavailability of triamterene by two different firms in submissions to the FDA (Tr. at 484, 590 (Dr. Cabana)).

146. There is documentation in the published literature and in studies submitted to the FDA that the drug hydrochlorothiazide has a bioavailability problem (Tr. at 484, 589-91, 616 (Dr. Cabana)).

147. Hydrochlorothiazide is a product with limited solubility (Tr. at 484 (Dr. Cabana)). (NDBI)

3. The Formulation of Premo’s Triamthiazide, When Compared to the Formulation of the Innovator Dyazide, Suggests That Triamthiazide Will Differ from Dyazide in Bioavailability

Paragraphs 148 through 151 are contained in the sealed portion of these findings.

152. There are, based upon their formulations, predictable differences in bioavailability between the Premo Triamthiazide drug and the innovator product it imitates (Tr. at 833 (Dr. Shangraw)).

B. Premo’s Trifluoperazine Product Differs Significantly in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Innovator Product for Which It May Be Substituted

1. If There Is a Difference Between the Bioavailability of Premo’s Trifluoperazine and the Innovator Product, That Fact Can Cause Serious Harm to Patients

153. Drug products containing trifluoperazine hydrochloride (“trifluoperazine”) are given in small amounts (Tr. at 335 (Dr. Perel)). Trifluoperazine is an extremely potent drug, which is used in both children and adults

(id.).

(A)

154. Trifluoperazine products have a narrow therapeutic range,

i. e.,

the dosage in the blood at which one observes adverse effects is very close to the dosage in the blood at which the chief therapeutic response is observed (Tr. at 336 (Dr. Perel); P. Ex. 69-A, page 1; P.’ Ex. 69-B at 78 (Deposition of Dr. Seife)). (A)

155. Trifluoperazine causes several types of serious side effects: pseudo-parkinsonism side effects,

e., trembling or shaking, painful muscular spasms, etc., an effect occurring at low blood levels of the drug (Tr. at 337 (Dr. Perel)); tardive dyskinesia, which takes place after chronic administration of trifluoperazine and involves involuntary movements affecting the mouth and trunk and extremities and which can cause permanent irreversible impairment in 10-

*995

20% of those persons exhibiting those side effects (P. Ex. 6 (Aff. of Dr. Perel), ¶ 10; Tr. at 338-40 (Dr. Perel);

see also

P. Ex. 69-A, page 1; P. Ex. 69-B at 78 (Deposition of Dr. Seife)); and cardiovascular side effects, including a significant amount of hypertension (Tr. at 339 (Dr. Perel)). (A)

156. If a clinician used a generic trifluoperazine product that was more bioavailable than Stelazine, the approved product containing trifluoperazine, that would increase the possibility of tardive dyskinesia. This is true because the effects of the product which was more bioavailable than expected would be masked since the clinician would prescribe a higher dosage to cover the first signs of involuntary movements associated with tardive dyskinesia (Tr. at 340 — 43 (Dr. Perel)). This effect is more likely to occur with institutionalized patients who would not be observed as closely by physicians as would those that are not institutionalized (Tr. at 347-48 (Dr. Perel)). (A)

157. If a clinician prescribes a generic drug purportedly containing the same active ingredient as Stelazine but less bioavailable than Stelazine, that drug would not have the expected therapeutic effect. The fact that the drug was not working would not be discovered for from 8 to 14 weeks, during which time the patient would be institutionalized. (Tr. at 344 (Dr. Perel)). (A)

158. If a patient is stabilized on Stelazine, and a drug is substituted for Stelazine that is less bioavailable, the patient would relapse but the relapse would likely be considered disease-related rather than drug-related (Tr. at 344-45 (Dr. Perel)). (A)

159. If lower bioavailability of a generic product leads a clinician to conclude that trifluoperazine is ineffective in a patient, that patient may simply not be helped by any medication, may be unable to function in the community, and may thus be institutionalized (Tr. at 345-47 (Dr. Perel)). (A)

160. The committee on Bioavailability and Bioequivalence of Psychotropic Drugs of The American College of Neuropsychopharmacology has recommended against use of multi-source psychotropic drug products such as trifluoperazine interchangeably unless bioequivalence has been shown (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 42.g). (A)

161. Bioequivalence problems with trifluoperazine would present a medically significant problem that might go unrecognized in the context of treatment of patients with this drug (Tr. at 620-21 (Dr. Cabana)). (A)

2. Trifluoperazine Is a Drug with Potential Bioavailability Problems

162. Trifluoperazine hydrochloride (“trifluoperazine”) is a member of the phenothiazine drug class for which there are documented bioavailability problems (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 42.c; Tr. at 489, 613-14 (Dr. Cabana)). (A) -

163. Trifluoperazine is a drug whose rate and extent of absorption,

i. e.,

bioavailability, is extremely critical because the drug is rapidly metabolized (changed) by the liver. Thus, if the rate of absorption is slow, the first pass metabolism by the liver can obliterate the pharmacological effects of the drug because inadequate amounts of the drug will be available to act at the site of action. (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 42.d; Tr. at 489, 614 (Dr. Cabana)). Alternatively, if the imitator drug has too fast absorption, it may send much more drug to the site of action because the liver would break down less of the drug during the first pass than it would of a less quickly absorbed drug (Tr. at 818-19 (Dr. Shangraw)). (A)

3. Comparison of the Formula of Premo’s Trifluoperazine and That of the Innovator Product Suggests That the Two Products Will Differ in Bioavailability

164. The ingredients in Premo’s trifluoperazine products differ as to inactive ingredients from those of the innovator products (P. Ex. 12; P. Ex. 15). (A)

Paragraphs 165 through 167 are contained in the sealed portion of these findings.

4. Although Bioavailability Testing of Trifluoperazine Is Possible, Premo Has Done None

168. There are, based on their formulations, predictable differences in bioavaila

*996

bility between the Premo trifluoperazine product and the innovator it imitates (Tr. at 833 (Dr. Shangraw)). (A)

169. There are three known means of assaying trifluoperazine in the blood (Tr. at 348-56 (Dr. Perel); Tr. at 545 (Dr. Cabana)) —radioimmunoassay techniques (Tr. at 350, 352 (Dr. Perel)); Tr. at 545 (Dr. Cabana)); radio receptor technique (Tr. at 352-353 (Dr. Perel); Tr. at 545 (Dr. Cabana)); and GCMS (Gas Chromotography-Mass Spectrometry) (Tr. at 354-55 (Dr. Perel); Tr. at 545-46 (Dr. Cabana)).

170. The method development study using measures of pupillometry to attempt to quantitate amounts of trifluoperazine did not measure any Premo product and is not a bioavailability study that would show Premo’s product to be bioequivalent to the approved product (Tr. at 368-69 (Dr. Perel)). (NDBI)

Premo has presented no evidence that any other bioavailability test of its trifluoperazine product was performed.

C. Premo’s Chlorthalidone Product Differs Significantly in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Innovator Product for Which It May Be Substituted

1. If Premo’s Chlorthalidone Product Differs in Bioavailability from the Innovator Product, That Fact Could Cause Serious Harm to Patients

171. If Premo’s chlorthalidone is more bioavailable than the marketed product it can produce unwanted toxic effects, including hypokalemia which, particularly when this drug is used concurrently with other drugs, can lead to serious cardiac toxicity and possibly sudden death (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 41.e).

172. If Premo’s chlorthalidone product is significantly less bioavailable than the approved product, Premo’s drug would be inadequate to control high blood pressure in edema for which it is prescribed, leading to therapeutic failure which can cause risk to a patient. (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 41.e; P. Ex. 3 (Aff. of Dr. Cortell), ¶22; P. Ex. 4 (Aff. of Dr. Crout), ¶¶ 13-14).

173. The medical significance of bioavailability problems with chlorthalidone will be enhanced in patients treated for heart disease and cardiac conditions who might be treated concurrently with other drugs (Tr. at 618-19 (Dr. Cabana)).

174. A switch from 50 mg of chlorthalidone to 75 or 100 mg of chlorthalidone would alter serum potassium levels, an effect particularly dangerous in patients on digitalis (Tr. at 603 (Dr. Cabana); Tr. at 985 (Dr. Barr)). (NDBI)

175. A bioavailability difference of less than two-fold, 100% increase, or 100% decrease, would be definitely significant in chlorthalidone in terms of the effect on potassium (Tr. at 618 (Dr. Cabana)).

176. The dose response curve for the toxicity of chlorthalidone is steep, that is, increases in the effective dosage of chlorthalidone result in increased uric acid levels and increased potassium excretion at a relatively high rate (Tr. at 934-35 (Dr. Barr); P. Ex. 63). The article by Tweedale

et a1.

shows clear dose response curves that are steep for serum potassium, which would correlate with potassium excretion (Tr. at 986-87).

177. The incidence of hypokalemia, hyperuricemia, and increased serum chloride, all potentially toxic effects, increases at a small rate as dosages of chlorthalidone increase (Tr. at 1629 (Dr. Rhodes)). There is no plateau curve in the dose response to these products

(id.).

178. The dosage of chlorthalidone that would be toxic would depend upon the individual involved (Tr. at 574 (Dr. Cabana)). (NDBI)

179. According to data submitted to FDA, an increase in dosage from 50 mg chlorthalidone to 75 mg chlorthalidone has been shown to be toxic in some patients (Tr. at 574-75 (Dr. Cabana)). Dosages above 50 mg of chlorthalidone cause a change in potassium in a very large percentage of subjects. That change may be dangerous if the patient is taking digoxin. Two million

*997

patients in the United States do take digoxin, and many of those patients are also taking chlorthalidone (Tr. at 575 (Dr. Cabana)).

180. Dr. Rhodes is aware of no clear statement in the literature that there is no medically significant bioavailability problem with chlorthalidone (Tr. at 1220-21 (Dr. Rhodes)). (A)

181. An explanation for why there has been no documented therapeutic failure due to the bioavailability of chlorthalidone is that there has been no product other than the approved product on the market until very recently (Tr. at 605 (Dr. Cabana)).

182. A hundred milligram chlorthalidone dose is not justified in view of the toxic side effects which have been documented (Tr. at 1633 (Dr. Rhodes); see

also

P. Ex. 4, Ex. 6). (NDBI)

2. Chlorthalidone Is a Drug with Known Bioavailability Problems

183. Chlorthalidone has known bioavailability problems (Tr. at 1629-30 (Dr. Rhodes)).

184. Drug products containing chlorthalidone present a bioavailability problem because chlorthalidone has a solubility problem (Tr. at 485, 602 (Dr. Cabana); P. Ex. 4 (Aff. of Dr. Crout), Attachment 6). (A)

185. There is no U.S.P. dissolution standard appropriate to assure the bioavailability of chlorthalidone (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 41.a; Tr. at 566-68; D. Ex. 82). (NDBI)

3. Comparison of the Formulations of Premo’s Chlorthalidone Product and That of the Innovator Product Suggests Potential Differences in Bioavailability Between the Premo Product and the Innovator Product

186. The ingredients in Premo’s chlorthalidone products differ, in some respects, from those in the innovator products (P. Ex. 12; P. Ex. 13). (NDBI)

Paragraphs 187 through 188 are contained in the sealed portion of these findings.

189. The differences between the USV chlorthalidone product and the Premo chlorthalidone product could significantly affect bioavailability (Tr. at 813 (Dr. Shangraw)), that is, in view of the differences one could not with any reasonable degree of certainty predict bioequivalence for the drug (Tr. at 814).

D. Premo’s Allopurinol Product May Differ Significantly in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Innovator Product for Which It May Be Substituted

1. A Difference in Bioavailability Between Premo’s Allopurinol Product and the Innovator Product Could Have Serious Health Consequences

190. Certain cancer chemotherapy causes a rush of uric acid into the kidneys after treatment, which has a potential for crystallizing in the kidneys and significantly impairing renal function (Tr. at 1633-34 (Dr. Rhodes)). (A)

191. If an allopurinol product is less bioavailable than expected, there could be a build up of uric acid in the kidneys and resultant urinary failure, particularly in patients treated with allopurinol in connection with chemotherapy (Tr. at 1635 (Dr. Rhodes)); Tr. at 47-48, 45 (Dr. Crout)).

192. Some literature suggests that allopurinol may be useful in removing some of the cancer chemotherapy drugs which are themselves potentially carcinogenic (Tr. at 1634-35 (Dr. Rhodes)). (A)

2. Allopurinol Presents' ,a Bioavailability Problem

193. Allopurinol presents a bioavailability problem. (Tr. at 605 (Dr. Cabana);

see also

Tr. at 843 (Dr. Shangraw)).

194. Dr. Rhodes suggested that a bioavailability study be performed with respect to allopurinol (Tr. at 1637 (Dr. Rhodes)). (A)

195. Dr. Rhodes was asked to design in a general way a bioavailability study for Premo’s allopurinol product (Tr. at 1432-35; cf. 1602 (Dr. Rhodes)). (A)

196. There is no appropriate dissolution standard for allopurinol to assure the bioa

*998

vailability of allopurinol tablets without an

in vivo

bioavailability test (P. Ex. 2 (Aff. of Dr. Cabana), ¶ 43.a). (NDBI)

3. Comparison of the Formulation of Premo’s Allopurinol with That of the Innovator Product Provides no Basis for Concluding That Those Products Would Not Differ in Bioavailability

197. Plaintiff has shown it is not determinable whether the ingredients in Premo’s allopurinol products differ in any respects from those in the innovator products (P. Ex. 12; P. Ex. 14; Tr. at 816-17 (Dr. Shangraw)).

Paragraph 198 is contained in the sealed portion of these findings.

199. Without knowing the intrinsic dissolution of the allopurinol drug substance, or its wettability, it is not predictable that the Premo product will be equivalent to the innovator product it imitates (Tr. at 836, 837 (Dr. Shangraw)). Wettability is the ability of water or gastric fluid to come into contact with a molecule of the drug on the surface of the solid particles; if the surface will not wet, then the particle will not dissolve (Tr. at 839-40).

200. Dr. Rhodes’ conclusion that Premo’s allopurinol product is therapeutically equivalent to the innovator product is based in part on data produced by United States Testing Co. that the products contain the same inert components present in the same or very similar concentrations, (Tr. at 1406 (Dr. Rhodes)), a conclusion not supported by the actual United States Testing Results (see sealed findings 127-28, supra).

E. Premo’s Doxine (Doxylamine Succinate Plus Pyridoxine Hydrochloride) Product Differs in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Product It Copies

1. A Lack of Bioequivalence Between the Premo Product and the Innovator Could Have Significant Health Effects

201. This drug combination is used in pregnant women to combat nausea and vomiting (“morning sickness”). (A)

An effective overdosage because of bioavailability differences would result in adverse reactions such as dizziness, headache, and drowsiness while underdosage would result in therapeutic failure (P. Ex. 6 (Aff. of Dr. Perel), ¶ 15). (NDBI)

202. The question whether the product doxylamine succinate with pyridoxine hydrochloride is a drug having high or low therapeutic ratio is the subject of some debate (Tr. at 1360-61 (Dr. Rhodes)). (NDBI)

203. The fact that the active ingredients of a combination drug are separately safe and effective — as the active ingredients of this combination are alleged by Premo to be — would not indicate that the combination of those ingredients will be safe and effective. The drugs may interfere with each other or there may not be a proper medical rationale for the combination that would justify the increased risk from the two products (Tr. at 696-97 (Dr. Cabana)).

2. This Product. Has Potential Bioavailability Problems

204. Premo’s product containing doxylamine succinate with pryidoxine hydrochloride imitates an innovator product which is a controlled release dosage form, designed to delay the release of the drug substance over 8 to 10 hours. Controlled release dosage forms prevent severe bioavailability problems (Tr. at 577-78 (Dr. Cabana); P. Ex. 2 (Aff. of Dr. Cabana) ¶ 44.e). (NDBI)

3. Differences Between the Premo Formulation and That of the Innovator Raise ■ Questions Concerning the Bioequivalence of These Two Products

205. The ingredients in Premo’s doxylamine succinate plus pyridoxine hydrochloride product differ, in some respects, from those in the innovator product (P. Ex. 12; P. Ex. 17). (NDBI) .

Paragraphs 206 through 207 are contained in the sealed portion of these findings.

208. Even if the active ingredients in this drug in a simple formulation would not

*999

provide significant problems, a formulation involving a slow release rate, such as the one found here, raises questions in terms of equivalence (Tr. at 829 (Dr. Shangraw)).

4. It Can Not Be Concluded That Premo’s Doxine Product Is Equivalent to the Innovator Product

209. Because there has been no comparison of

in vivo

and

in vitro

data for Premo’s doxylamine succinate with pyridoxine hydrochloride product, no firm conclusion concerning the bioequivalence of Premo’s product to the innovator product can be made (Tr. at 1384 (Dr. Rhodes)).

F. Premo’s Hydroxyzine Pamoate Product Differs in Composition from the Innovator Product and Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Product It Copies

1. A Lack of Bioequivalence Between Premo’s Hydroxyzine Pamoate Product and the Innovator Could Have Significant Health Effects

210. Hydroxyzine pamoate is used in the management of anxiety, tension, and psychomotor agitation, during episodes of emotional stress and occasionally for the control of nausea. It is commonly used as an adjunct to psychotherapy. (A)

The failure of this drug to work because its bioavailability is too low, or because unexpected adverse reactions result from too high bioavailability, can result in setting back the effects of therapy that would, in some cases, otherwise allow afflicted patients to lead a reasonably normal life (P. Ex. 6 (Aff. of Dr. Perel), ¶¶ 12, 16).

211. A significant overdosage of this active ingredient because of bioavailability problems could cause drowsiness, tremors and, rarely, convulsive episodes (P. Ex. 6 (Aff. of Dr. Perel), ¶ 13). (NDBI)

212. An unintentional underdosage of hydroxyzine because of bioavailability problems would result in a therapeutic failure of the drug in the patients in question. Patients treated with the drug would thus be subject to anxiety, in some cases severe anxiety, which might interfere with the progress of their psychotherapy (P. Ex. 6 (Aff. of Dr. Perel), ¶ 14). (NDBI)

2. This Drug' Presents a Bioavailability Problem

213. Hydroxyzine pamoate is an extremely insoluble salt and poses a good potential for a bioavailability problem (Tr. at 606 (Dr. Cabana); Tr. at 827 (Dr. Shangraw)). (NDBI)

214. In addition, because the hydroxyzine pamoate is labeled as equivalent to the hydroxyzine hydrochloride, it is necessary to show that the product is bioequivalent to hydroxyzine hydrochloride (Tr. at 606-07 (Dr. Cabana)).

215. Dr. Rhodes is aware of no literature that says there is no documented bioequivalence problem with hydroxyzine pamoate (Tr. at 1220-21 (Dr. Rhodes)). (NDBI)

3. Differences Between the Premo Formulation and That of the Innovator Raise Questions Concerning the Bioequivalence of These Two Products

216. The ingredients in the Premo hydroxyzine pamoate product differ, in some respects, from those in the innovator product (P. Ex. 12; P. Ex. 32-A, B & C).

Paragraphs 217 through 218 are contained in the sealed portion of these findings.

G. Premo’s Hydroxyzine Hydrochloride Product Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Product It Copies

1. A Lack of Bioequivalence Between Premo’s Hydroxyzine Hydrochloride Product and the Innovator Could Have Significant Health Effects

219. Hydroxyzine hydrochloride is used in the management of anxiety, tension, and psychomotor agitation, during episodes of emotional stress and occasionally for the control of nausea. It is commonly used as an adjunct to psychotherapy. (A)

*1000

2. Differences Between the Premo Formulation and That of the Innovator Raise Questions Concerning the Bioequivalence of These Two Products

220. The ingredients in the Premo hydroxyzine hydrochloride product differ, in some respects, from those in the innovator product (P. Ex. 12; P. Ex. 16).

Paragraph 221 is contained in the sealed portion of these findings.

222. In light of the differences in manufacture between the Premo and innovator hydroxyzine hydrochloride products, additional data would be necessary in order to show the bioavailability of the drug (Tr. at 824 (Dr. Shangraw)).

H. Premo’s Betamethasone Valerate Product Has Not Been Shown To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Product It Copies

I. If This Product Is Not as Effective as Expected Because It Is Not Bioequivalent to the Approved Product That Fact Can Have Serious Consequences

223. If Premo’s betamethasone valerate cream is not effective, resort to a more potent oral drug would be a real possibility (Tr. at 1260 (Dr. Kanof)). (NDBI)

2. This Drug Has Potential Bioequivalence Problems

224. Betamethasone valerate cream is a drug with a potential bioequivalence problem. There is relatively little absorption of drugs from ointments through the skin and there is some evidence indicating significant effects of the formulation on the absorption of the drug at the site of application. A highly lipid ointment applied against an aqueous membrane may cause the drug to stay in the ointment rather than getting into the site of drug action on or through the skin (Tr. at 610 (Dr. Cabana)).

225. Dr. Rhodes agreed that a clinical study of betamethasone valerate should be done (Tr. at 1436). (A)

3. Comparison of the Formulations of the Premo Product and That of the Innovator Raise Questions Concerning the Bioequivalence of Those Products

226. The ingredients in Premo’s betamethasone valerate cream differ, in some respects, from those of the innovator product (P. Ex. 12; P. Ex. 18).

Paragraph 227 is contained in the sealed portion of these findings.

228. Lack of knowledge concerning the particle size of the active ingredient of the betamethasone valerate products and the degree of occlusiveness of the products make it impossible to determine that Premo’s product is equivalent to the innovator product (Tr. at 830-31).

XII. There Is No Dispute That a Significant Number of Drugs Have Bioequivalence Problems and That the FDA’s Standards for Concluding That Bioequivalence Testing Is Needed Are Reasonable

229. Dr. Rhodes’ estimate of the number of prescription drugs with bioequivalence problems was limited only to “less than say 25%” (Tr. at 1264). (A)

230. Dr. Rhodes disputes that it is possible to determine therapeutic equivalence in all products by

in vitro

tests (Tr. at 1615 (Dr. Rhodes)), and there are many occasions when it is essential to conduct a biological availability study (Tr. at 1616). (A)

XIII. What Testing Premo Has Performed of Its Products Fails To Show Those Products Equivalent to the Innovators for Which They May Be Substituting

A. Premo’s Clinical Study (D. Ex. 53) of Its Triamthiazide Study Does Not Show That Product To Be Bioequivalent or Equivalent in Safety and Effectiveness to the Innovator Product

231. The clinical trial submitted by Premo as comparing Premo’s Triamthiazide with Dyazide in fifty subjects has the following flaws—

a. The trial does not evaluate the therapeutic effectiveness of the triamterene com

*1001

ponent of the Premo combination with respect to its intended use

(see

P. Ex. 80-A, page 1; P. Ex. 80-B at 115 (Deposition of F. Ballantyne)) in preventing the development of low blood potassium or treating low blood potassium if it occurs, in that there was no measurement of serum potassium in the study (Tr. at 119-20 (Dr. Crout); Tr. at 155 (Dr. Cortell);

see also

Tr. at 1331 (Dr. Rhodes)).

b. The electrocardiograms said to have been done at two points in this trial would not be capable of measuring serum potassium at levels that would, if they were higher or lower than normal, be significant (Tr. at 127-29 (Dr. Crout); Tr. at 155-56, 172-73 (Dr. Cortell)). The acid-base status of a patient would affect the ability of electrocardiograms to reveal serum potassium levels (Tr. at 173 (Dr. Cortell)). In fact, by the time potassium level effects appeared on electrocardiograms, there would be real safety problems for the subjects of the test (Tr. at 128 (Dr. Crout); Tr. at 169-71 (Dr. Cortell)).

c. The test was not double-blind, that is the investigator was not blinded and because the investigator knew which patients were getting which drugs at which times there was a potential for subtle observer bias (Tr. at 121 (Dr. Crout)). The test was not even single-blind (P. Ex. 80-A, page 4; P. Ex. 80-B at 198 (Deposition of F. Ballantyne)).

d. A sequencing effect would occur, that is any effect going on simultaneously with the trial could influence the results from one drug more than the results from another. For example, a flu epidemic or a seasonal hot spell that occurred during a part of the trial in which the results of one drug was being measured might result in an incorrect evaluation of the effects of the drugs (Tr. at 121, 123 (Dr. Crout)).

e. The trial is not very sensitive or discriminating in that it does not use a placebo group and it is not possible to know whether the patients used as subjects had their blood pressure under control (Tr. at 123 (Dr. Crout)).

f. The investigators violated their own entrance criteria by using fourteen subjects whose blood pressure varied more than 20 mm systolic over 10 mm diastolic,

e., patients whose blood pressure was not sufficiently controlled to satisfy the entrance requirements of the test (Tr. at 124 (Dr. Crout)).

g. The report of the test does not say whether the subjects were using drugs which varied in their dosage during the trial, which variance would be a fatal flaw in the trial (Tr. at 124-25 (Dr. Crout)).

h. The trial was inadequate even to determine whether the Premo product was equivalent to the approved product in its effect as an antihypertensive drug because the report does not reveal the variability of blood pressure in each patient, the circumstances under which the blood pressures reported were measured, or a determination that the blood pressures of the subjects had been adequately controlled on the first medication before the subjects were switched to the second medication (Tr. at 154 (Dr. Cortell)).

i. To the extent that this study shows anything, it shows a difference in the effectiveness of the Premo product as opposed to the approved product in controlling hypertension, with the Premo product appearing to be more effective in decreasing blood pressure (Tr. at 156 (Dr. Cortell);

see also

D. Ex. 53, page 6). This increase in potency of the Premo product, if real, could lead to hypotension (decreased blood pressure (Tr. at 159)), a condition that would be a cause for concern to the treating physician in patients who might be switched from the approved product to this product (Tr. at 156-59 (Dr. Cortell)).

232. The methods used in the clinical trial performed by Dr. Ballantyne do not meet the rigorous standards that would be needed for a full clinical trial of a new drug substance (Tr. at 1318-19 (Dr. Rhodes)).

233. Dr. Ballantyne, who performed the study on Premo’s Triamthiazide product, admits that that study did not establish the influence of that product, or of the reference product, Dyazide, on serum potassium

*1002

levels (P. Ex. 80-A, page 4; P. Ex. 80-B at 199 (Deposition of Dr. Ballantyne)).

234. Even Premo’s own witnesses finally declined to support the position that the failure of EKG’s taken in this study to show increases in potassium with patients treated with Triamthiazide showed that Premo’s product did not significantly increase potassium levels.

235. Hyperkalemia,

i. e.,

by Dr. Bloom’s definition serum potassium of greater than 5.5 milligrams per deciliter (Tr. at 434), would probably not result in any changes on electrocardiograms (Tr. at 433 (Dr. Bloom)). (A)

236. An EKG “might” show changes in potassium level in blood serum if the figure was 7 milliequivalents of potassium per liter of blood (Ballantyne deposition at 170). A patient with a figure of 6 milliequivalents of potassium per liter of blood is in a serious state

(id.).

Patients have died with a potassium figure of less than 6 (Ballantyne deposition at 171). A potassium reading of 6 requires serious medical attention and would cause Dr. Ballantyne to be quite alarmed if he saw that figure in his patients in a routine physical examination

(id.).

A patient with a figure of a 6 milliequivalents of potassium per liter of blood would probably be in the hospital already (Dr. Ballantyne deposition at 172). Thus, before an EKG would show changes in potassium levels, the patient should already be in the hospital (id). (NDBI)

237. Dr. Rhodes is unqualified to disagree with the statements referred to,

supra,

made by Dr. Ballantyne in his deposition (Tr. at 1662 (Dr. Rhodes)). (NDBI)

238. There may be no electrocardiographic changes with slight elevations in serum potassium concentration and, at best, an imperfect correlation with moderate or large elevations — electrocardiographic changes usually appear only when the serum potassium exceeds 6.5 to 7.4 milliequivalents per liter (P. Ex. 230, page 1656), a fact that Dr. Rhodes does not question (Tr. at 1663-64 (Dr. Rhodes)). (NDBI)

239. Another source relied upon by Dr. Rhodes (D. Ex. 141, page 397) states that until recently there have been no reports of electrocardiographic changes occurring in patients who develop hyperkalemia from triamterene or the combination of triamterene and hydrochlorothiazide (Tr. at 1665 (Dr. Rhodes)). (A)

240. Premo’s witnesses Dr. Rhodes and Dr. Tessler would say only that the Premo clinical study of Triamthiazide performed by Dr. Ballantyne showed therapeutic equivalence in reducing blood pressure (Tr. at 1320 (Dr. Rhodes); Tessler Deposition at 107).

241. Premo’s Dr. Tessler agrees that an electrolyte measurement in the clinical study performed for Premo on its Triamthiazide product would have been useful in the context of showing that there was no material change from switching from the innovator product to Triamthiazide (P. Ex. 86-A, page 2; P. Ex. 86-B at 158-59 (Deposition of Dr. Tessler)).

242. Because the reference standard on the EKG charts used in this study was, in some instances, cut off, any physician other than Dr. Ballantyne could not verify whether those charts were consistent with hyperkalemia and thus would simply have to take his word for it (P. Ex. 80-A, page 4; P. Ex. 80-B at 178-79 (Deposition of Dr. Ballantyne)).

243. The failure to measure potassium levels in the blood, the most important parameter in determining whether use of Premo’s Triamthiazide as a substitute for Dyazide is safe, was the result of a conscious decision to perform this study where potassium levels could not be measured:

a. If it were easy to obtain a measurement of serum potassium with respect to the 50 patients in the clinical tests of Premo’s Triamthiazide drug, that would be the prudent thing to do (P. Ex. 80-A, page 2; P. Ex. 80-B at 135).

b. Dr. Ballantyne and his technicians are accomplished in spinning down blood into serum for transport to the United States for analysis (P. Ex. 80-B at 116).

*1003

After being spun down the serum is frozen and then transported to the United States (P. Ex. 80-A, page 1; P. Ex. 80-B at 116-117). When serum is sent to the United States in a frozen state it is possible to test for electrolytes, such as potassium levels (Ballantyne deposition at 117). The test is a simple one (P. Ex. 80-A, page 1; P. Ex. 80-B at 117).

c. Blood serum that was, according to the protocol, to be transported to the United States for analysis was not transported because Biometric Testing, Inc. did not provide an individual to carry it from the Virgin Islands to the United States (P. Ex. 80-A, page

P. Ex. 80-B at 118-20).

d. Dr. Ballantyne was aware that the laboratory that would analyze serum samples from his test, Rockland Medilabs, had the ability to perform electrolyte testing on those serum samples at the time that he was involved in consulting on the design and carrying out of a clinical test on Premo’s Triamthiazide drug (P. Ex. 80-A, page 2; P. Ex. 80-B at 127).

e. Electrolyte analysis of blood taken in St. Vincent’s at a laboratory in the United States is possible if the blood has been spun down into serum. However, an impediment to such analysis is the danger that some of the blood would hemolyze during transport between clinics in the countryside, which do not have a centrifuge to spin down blood into serum, and the Kingston General Hospital on St. Vincent’s, which does have a centrifuge (P. Ex. 80-A, page 2; P. Ex. 80-B at 136).

f. The only real piece of equipment you need to spin down blood into serum is a centrifuge, which is not a very expensive piece of medical equipment (P. Ex. 80-A, page 2; P. Ex. 80-B at 135). There is only one centrifuge on St. Vincent’s Island (id.). Biometrics could have provided centrifuges to Dr. Ballantyne for use in outlying clinics if it chose to do so (Tessler deposition at 162-63).

g. If Dr. Ballantyne had had centrifuges in his clinics in the countryside he could have spun the blood down and preserved the serum until it could be frozen and shipped to the United States (P. Ex. 80-A, page 2; P. Ex. 80-B at 128). If he had brought the patients into the hospital in Kingston he could also have done so (P. Ex. 80-A, page 2; P. Ex. 80-B at 128-29).

h. About half of the patients in the study were drawn from the Kingston General Hospital and, with respect to those patients, the blood could have been spun down into serum without any danger of hemolyzing and thus could have been analyzed for electrolytes (P. Ex. 80-A, page 2; P. Ex. 80-B at 133-34). This was not, however, done

(id).

i. Dr. Tessler knew that a study done in the Virgin Islands that was not centralized in Kingston would not have facilities to do the testing for potassium levels in the blood (P. Ex. 80-A, page 3; P. Ex. 80-B at 151-53; P. Ex. 86-A, page 2; P. Ex. 86-B at 159-60, 161-62 (Deposition of Dr. Tessler)). Yet, Dr. Tessler did not discuss with Dr. Ballantyne centralizing this test in Kingston nor did he discuss the electrolytes problem at all (P. Ex. 80-A, page 3; P. Ex. 80-B at 153-54 (Deposition of Dr. Ballantyne)).

244. Dr. Tessler does not know that the Triamthiazide used in the clinical study of Triamthiazide performed by Biometric Testing, Inc., was from a production batch of Triamthiazide (P. Ex. 86-A, page 1; P. Ex. 86-B at 143 (Deposition of Dr. Tessler)) and the record contains no proof that it was.

245. There is no clinical study showing the effectiveness of Premo’s triamterene with hydrochlorothiazide product in edemous patients (Tr. at 1666 (Dr. Rhodes)).

B. The “Potassium Sparing” Study (P. Ex. 22-A) of Premo’s Triamthiazide Does Not Demonstrate That Premo’s Product Does Not Cause Greater Potassium Loss than the Innovator Product

246. The study submitted by Premo that purports to evaluate the short term effect of Premo’s combination product containing triamterene and hydrochlorothiazide on serum potassium and on urinary excretion of potassium (P. Ex. 22-A) is insufficient to

*1004

demonstrate that the triamterene component of Premo’s Triamthiazide would fulfill its function of preventing potassium build up (Tr. at 131 (Dr. Crout)). This study (P. Ex. 22-A) has the following flaws:

a. This study does not address the question of the effects of chronic administration of Premo’s Triamthiazide on potassium build up in the body, which is the question of importance in evaluating the effectiveness of the triamterene component of Triamthiazide (Tr. at 131, 177 (Dr. Crout); Tr. at 160-61 (Dr. Cortell)).

b. The urinary excretion of potassium was reported only in milliequivalents per liter of urine, a measurement that does not tell how much actual potassium was excreted in the urine because the volume of urine is not reported (Tr. at 139-41, 177-79 (Dr. Crout)).

c. The results reported are, at least in some instances, internally inconsistent. For example, in Figure One of P. Ex. 22-A, the serum potassium levels are falling while there is no increase in urinary potassium, a finding that is internally inconsistent and makes no sense (Tr. at 141-42 (Dr. Crout)).

d. One of the thirteen patients in the study was dropped from the study without any explanation of the criteria for selecting the patient that was dropped (Tr. at 142 — 44 (Dr. Crout); P. Ex. 84-A; P. Ex. 84-B at 175,

This text is long and has been trimmed here. Open the source document for the complete record.

This is a copy of a public record, reproduced as it was published. It is not legal advice, and it may not be the version a court would rely on. Check the official source before you cite it.