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UNITED STATES v. ARTICLES OF DRUG

November 20, 1985

UNITED STATES OF AMERICA, PLAINTIFF,
v.
ARTICLES OF DRUG . . . PROMISE TOOTHPASTE FOR SENSITIVE TEETH . . . ACTIVE INGREDIENTS: POTASSIUM NITRATE, SODIUM MONOFLUOROPHOSPHATE . . . SENSODYNE-F TOOTHPASTE FOR SENSITIVE TEETH . . . ACTIVE INGREDIENTS: POTASSIUM NITRATE, SODIUM MONOFLUOROPHOSPHATE . . . AND BLOCK DRUG COMPANY, INC., AND LEONARD N. BLOCK AND JAMES A. BLOCK, DEFENDANTS.



The opinion of the court was delivered by: Getzendanner, District Judge:

MEMORANDUM OPINION AND ORDER

In this drug enforcement action, the United States seeks seizure and condemnation of certain over-the-counter ("OTC") drug products, Promise toothpaste with Fluoride and Sensodyne-F toothpaste. The government alleges that these products are "new drugs" within the meaning of 21 U.S.C. § 321(p)(1), and were introduced into interstate commerce without an approved New Drug Application ("NDA"), as required by 21 U.S.C. § 355(a). The government also seeks injunctive relief against the manufacturer Block Drug Company, Inc. ("Block"), and two of its officers, Leonard N. Block and James A. Block, to restrain further marketing of these products. Block has filed a claim in the in rem proceeding.

On July 30, 1984, this court denied the defendants' motion to dismiss and ruled that the Compliance Policy Guide ("CPG") of the Food and Drug Administration ("FDA") did not bar the present action pending completion of further administration review; the court also ruled that a remand of proceedings to the FDA would be inappropriate. United States v. Articles of Drug . . . Promise Toothpaste for Sensitive Teeth, 594 F. Supp. 211 (N.D.Ill. 1984). The opinion denying that motion contains an extensive overview of new drug regulations and the FDA's review of OTC dentifrices, which will not be repeated here. The matter is currently before the court on the government's motion for summary judgment, or alternatively, for a preliminary injunction. For the reasons set forth herein, the motion for summary judgment is granted.

Statement of the Case

The sole issue presented by the motion for summary judgment is whether, as a matter of law, Promise with Fluoride and Sensodyne-F are "new drugs" within the meaning of § 321(p)(1). Under the Food Drug and Cosmetic Act, a drug product must be classified as a new drug unless its manufacturer can show that it is "generally recognized among experts" to be "safe and effective" for its recommended uses. 21 U.S.C. § 321(p)(1). It is established by regulation that the "newness of a drug may arise by reason . . . of" combining two or more drugs. 21 C.F.R. § 310.3(h). See also 21 C.F.R. § 330.10(a)(4)(iv). Thus, even though the component parts of a new drug may be generally recognized as safe and effective, the combination itself may not be. See United States v. Articles of Food and Drug . . . Coli-Trol 80, 518 F.2d 743, 746 (5th Cir. 1975); United States v. An Article of Drug . . . Entrol-C Medicated, 513 F.2d 1127, 1129 (9th Cir. 1975); United States v. An Article of Drug . . . Neo-Terramycin, 540 F. Supp. 363, 376 (N.D.Tex. 1982), aff'd 725 F.2d 976 (5th Cir. 1984); United States v. X-Otag Plus Tablets, 441 F. Supp. 105, 111 (D.Colo. 1977), aff'd in part, remanded in part, 602 F.2d 1387 (10th Cir. 1979); United States v. An Article of Drug . . . Mykocert, 345 F. Supp. 571, 575 (N.D.Ill. 1972). The rationale for this rigorous treatment of combination drugs is that a single component of a drug may react with other components, thereby reducing the total effect of the drug or producing unexpected side effects. Coli-Trol 80, 518 F.2d at 746; X-Otag Plus Tablets, 441 F. Supp. at 111.

The Food Drug and Cosmetic Act nowhere defines the term "generally recognized among experts . . . [as] safe and effective." Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 629, 93 S.Ct. 2469, 2483, 37 L.Ed.2d 207 (1973); United States v. Articles of Drug . . . 5,906 Boxes, 745 F.2d 105, 119 n. 22 (1st Cir. 1984), cert. denied, sub nom. Alcon Laboratories, Inc. v. United States, ___ U.S. ___, 105 S.Ct. 1358, 84 L.Ed.2d 379 (1985). At a minimum, however, courts have construed "general recognition" to require a consensus of expert opinion based on the same "substantial evidence" of effectiveness based on "adequate and well-controlled investigations" which would be required for approval of a new drug application under 21 U.S.C. § 355(d). See, e.g., Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653, 93 S.Ct. 2488, 2494, 37 L.Ed.2d 235 (1973) (reach of scientific inquiry for effectiveness under § 355(d) and § 321(p) is "precisely the same"); Hynson, 412 U.S. at 628-32, 93 S.Ct. at 2482-84 (procedural requirements applicable for approval of new drugs must be applied to the definitional requirements for "new drugs"); 5,906 Boxes, 745 F.2d at 116-19 (same); United States v. An Article of Drug . . . 4,680 Pails, 725 F.2d 976, 985-87 (5th Cir. 1984) (general recognition requires a showing of both expert consensus in fact and substantial evidence (i.e., adequate and well controlled investigations) to support that consensus); United States v. Western Serum Co., 666 F.2d 335, 338 (9th Cir. 1982) (consensus of informed opinion must be "founded on well-controlled clinical tests").

Many courts have gone further and held that, in order for a drug to be "generally recognized" as effective, the data relied on for that opinion must not only constitute "substantial evidence" within the meaning of § 355(d) but must also be published and available generally to experts in drug evaluation. See, e.g., United States v. Undetermined Quantities . . . Equidantin, 675 F.2d 994, 1001 (8th Cir. 1982), cert. denied sub nom. Performance Products, Inc. v. United States, 460 U.S. 1051, 103 S.Ct. 1497, 75 L.Ed.2d 929 (1983); United States v. 41 Cases . . . Naremco, 420 F.2d 1126, 1130 (5th Cir. 1970); United States v. Articles of Drug . . . Hormonin, 498 F. Supp. 424, 432 (D.N.J. 1980), aff'd, 672 F.2d 904 (3d Cir. 1981); United States v. Articles of Drug . . . Colchicine, 442 F. Supp. 1236, 1243 (S.D.N.Y. 1978). As the Supreme Court said in Bentex Pharmaceuticals, "[w]hether a particular drug is a `new drug' depends in part on the expert knowledge and experience of scientists based on controlled clinical experimentation and backed by substantial support in scientific literataure." 412 U.S. at 652, 93 S.Ct. at 2493. See Premo Pharmaceutical Laboratories, Inc. v. United States, 629 F.2d 795, 803 (2d Cir. 1980) ("[n]ormally the general expert consensus is supported not only by clinical experience but by publication in the scientific literature"); 21 C.F.R. § 330.10(4)(ii) ("[g]eneral recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data"). The reason behind the publication requirement is inherent in the statutory concept of a "new" drug. As explained in Premo Pharmaceutical, "only those pre-existing drug products found through careful study by scientific experts to have been generally recognized on the basis of usage and documentation to be safe and effective [are] entitled to the exemption. . . ." 629 F.2d at 802-03. Unawareness of the drug by experts generally precludes its qualifying as a pre-existing drug. Id.

Finally, any drug which has become generally recognized as safe and effective due to clinical investigations, but which has not otherwise "been used to a material extent or for a material time" under the conditions prescribed, recommended, or suggested in the labeling of the drug must be considered a "new drug" requiring approval of an NDA before being marketed. 21 U.S.C. § 321(p)(2). See Hynson, 412 U.S. at 631, 93 S.Ct. at 2484 (Act is designed to exempt only those drugs on the market which "have mustered the requisite scientifically reliable evidence of effectiveness long before they are in a position to drop out of active regulation by ceasing to be a `new drug.'") The government in this case has not argued that Promise with Fluoride and Sensodyne-F fail to meet this particular requirement, and the court will not address the issue further.

Pursuant to the above cases, the government can prove lack of "general recognition" by proving an absence of material fact as to any of the following three issues: (1) general recognition in fact among the nation's experts that the seized drugs are safe and effective for their intended use; (2) the existence of adequate and well-controlled studies which constitute the "substantial evidence" of safety and effectiveness § 355(d) requires for approval of an NDA; and (3) generally available scientific literature substantiating an expert consensus of safety and effectiveness. The government has not alleged that the seized drugs are unsafe in any way, and the parties accordingly have confined their discussion to the question of "general recognition." The actual effectiveness of the drug is not in issue. Undetermined Quantities . . . Equidantin, 675 F.2d at 1001; Premo Pharmaceutical Laboratories, 629 F.2d at 803-04; Tyler Pharmacal Distributors, Inc. v. H.E.W., 408 F.2d 95, 99 (7th Cir. 1969). With these overall standards in mind (to be elaborated further), the court now addresses the evidence presented by the parties.

Facts

The following facts are undisputed. On January 1, 1983, defendant and claimant Block Drug Company began to market the products Promise with Fluoride and Sensodyne-F. (Def. Response to Pltf's First Set of Interrogatories Nos. 19 and 20). Each of these products contains a combination of .76% sodium monofluorophosphate (commonly known as "MFP") to prevent cavities, and 5% potassium nitrate to desensitize dentin in people with hypersensitive teeth. The toothpaste thus serves to maintain anti-cavity fluoride protection for people who suffer from dentinal hypersensitivity and who require special toothpastes for that reason.

In 1980, sodium mfp was classified by the FDA's Advisory Review Panel on OTC Dentifrices and Dental Care Drug Products to be generally recognized as safe and effective for preventing cavities. 45 Fed.Reg. 20682-90. Given the numerous clinical trials for fluoride compounds, the panel and the American Dental Association (ADA) both recommended that satisfaction of certain laboratory testing profiles could replace further clinical investigations in determining whether a particular toothpaste containing an approved fluoride combination is safe and effective for preventing cavities. Id. at 20677-78. The panel also recommended, however, that products combining an anticaries agent such as sodium mfp with another agent be considered new drugs and be required to submit NDAS. Id. at 20674, 20690.

In May 1982, the panel issued a proposed monograph for oral discomfort products. 47 Fed.Reg. 22712 (1982). The panel concluded that potassium nitrate, the other active ingredient in defendant's toothpaste, was safe at specified dosages, but concluded that there was insufficient data to establish its effectiveness as a tooth desensitizer. Id. at 22754-55. The Panel recommended that certain combinations containing potassium nitrate be permitted; none of these combinations included mfp or any other anticaries agent. Id. at 22719-23. The panel also concluded that sodium monofluorophosphate was safe for use as a desensitizing agent, but that the data were insufficient to establish its effectiveness for the purpose. Id. at 22752-53.

The proposed monograph did not consider any data which had become available after 1978, and the panel invited the submission of comments and new data. 47 Fed.Reg. 22759. In response, both Block and Richardson-Vicks, Inc., manufacturer of Denquel, a toothpaste containing potassium nitrate, submitted post-1978 data on potassium nitrate, including at least six studies concerning the effectiveness of potassium nitrate, as well as copies of several studies published in scientific or medical journals. The ADA and the Proprietary Association, a health organization, also submitted comments on potassium nitrate; both organizations recommended it for its effectiveness as a tooth desensitizer. (Def.Ex. 8 at 2; Ex. 9 at 9-10). While there appears to be significant scholarly dispute on this point, see Mandel Dep. Exs. 8 & 9, at least one of the government's experts, admitted his position to be a minority view. (Ash Dep. at 14). For purposes of the present motion, the court will therefore ...


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