Masti-Kure Products Co., Inc. v. Califano, MASTI-KURE

• Citation: 190 U.S.App.D.C. 202,587 F.2d 1099
• Decision Date: 16 June 1978
• Docket Number: MASTI-KURE,No. 76-1146,76-1146
• Parties: PRODUCTS COMPANY, INC., Petitioner, v. Joseph A. CALIFANO, Jr., Secretary of U. S. Department of Health, Education and Welfare, Donald Kennedy, Commissioner of Food and Drugs, Food and Drug Administration and C. D. Van Houweling, Director, Bureau of Veterinary Medicine, Food and Drug Administration, Respondents.
• Court: United States Courts of Appeals. United States Court of Appeals (District of Columbia)

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587 F.2d 1099 190 U.S.App.D.C. 202 MASTI-KURE PRODUCTS COMPANY, INC., Petitioner,
v.
Joseph A. CALIFANO, Jr., Secretary of U. S. Department of
Health, Education and Welfare, Donald Kennedy, Commissioner
of Food and Drugs, Food and Drug Administration and C. D.
Van Houweling, Director, Bureau of Veterinary Medicine, Food
and Drug Administration, Respondents. No. 76-1146. United States Court of Appeals,
District of Columbia Circuit. Argued Jan. 11, 1978.
Decided June 16, 1978.

David Chiras, of the Bar of the Supreme Court of Rhode Island, pro hac vice by special leave of Court with William F. Casler, Sr., St. Petersburg Beach, Fla., Carleton L. Weidemeyer, Clearwater, Fla., William J. Bethune and Mark W. Foster, Washington, D. C., were on the brief, for petitioner.

Also John P. Meade, Washington, D. C., entered an appearance for petitioner.

J. Patrick Glynn, Atty., Dept. of Justice, St. Louis, Mo., with whom Charles R. McConachie, Acting Chief, Consumer Affairs Section, Dept. of Justice, Washington, D. C., was on the brief, for respondents.

Before BAZELON, McGOWAN and MacKINNON, Circuit Judges.

Opinion for the Court filed by Circuit Judge BAZELON.

BAZELON, Circuit Judge:

On February 17, 1976, the Deputy Commissioner of Food and Drugs issued an order

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withdrawing approval of new animal drug application (NADA) 65-381 and denying a request for a hearing. 41 Fed.Reg. 7141 (1976). The drug covered by NADA 65-381 is a fixed combination drug containing in each 14-milliliter dosage unit procaine penicillin G (100,000 units) and neomycin sulfate (25 milligrams). The drug is designed for treatment of acute and chronic mastitis in lactating cows. Masti-Kure Products Company, Inc., producer of the drug, petitions this court to set aside the Deputy Commissioner's order. See 21 U.S.C. § 360b(h).

I. BACKGROUND

A. The Statutory and Regulatory Framework

The Federal Food, Drug, and Cosmetic Act (the Act) prohibits the marketing in interstate commerce of any new animal drug ¹ unless an NADA for the drug has been approved. See 21 U.S.C. §§ 360b(a)(1)(A), 351(a)(5), 331(a). The Act states that the Commissioner of the Food and Drug Administration (FDA) may withdraw approval of an NADA if he finds "on the basis of new information before him with respect to such drug, evaluated together with the evidence available to him when the application was approved, that there is a lack of substantial evidence that such drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling thereof . . . ." 21 U.S.C. § 360b(e)(1)(C). The Act defines "substantial evidence" to mean:

evidence consisting of adequate and well-controlled investigations, including field investigation, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.

21 U.S.C. § 360b(d)(3).

FDA has promulgated regulations implementing this statutory scheme. See 21 U.S.C. § 371(a); 21 C.F.R. § 5.1(a)(1) (1977). It has required that for a fixed combination new animal drug such as that covered by NADA 65-381, substantial evidence must be provided both that the drug is effective for its intended use and that "(e)ach ingredient designated as active" contributes to the claimed effects. 21 C.F.R. § 514.1(b)(8)(v) (1977). In addition, FDA has by regulation set out standards for "adequate

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and well-controlled investigations" acceptable as substantial evidence of effectiveness. ²

When the Commissioner determines, on the basis of new information before him, that an approved NADA lacks substantial evidence of effectiveness, FDA regulations require him to notify the holder of the NADA in writing and "afford an opportunity for a hearing on a proposal to withdraw approval of such application." 21 C.F.R. § 514.115(b) (1977). Cf. 21 U.S.C. § 360b(e) (1). FDA has developed summary judgment procedures, however, to be used when the holder of an NADA fails to submit substantial evidence of drug effectiveness sufficient on its face to meet regulatory standards. ³ The Supreme Court has in principle approved such procedures, stating that, "(w)e cannot impute to Congress the design of requiring, nor does due process demand, a hearing when it appears conclusively from the applicant's 'pleadings' that the application cannot succeed." Weinberger

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v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 621, 93 S.Ct. 2469, 2479, 37 L.Ed.2d 207 (1973).

B. Proceedings Before FDA

On August 30, 1974, FDA published in the Federal Register a notice proposing to withdraw approval of NADA 65-381. ⁴ 39 Fed.Reg. 31678 (1974). The notice stated there were insufficient data to demonstrate that the ingredients of NADA 65-381 were effective in accordance with the requirements for fixed combination drugs as set forth in 21 C.F.R. § 514.1(b)(8)(v) (1977). ⁵ Masti-Kure thereupon requested a hearing and submitted data purporting to demonstrate the efficacy of the drug covered by NADA 65-381. Joint Appendix (J.A.) at 160. On March 5, 1975, FDA served upon Masti-Kure a proposed order analyzing Masti-Kure's submission and concluding that summary judgment should be instituted since the data submitted failed on its face to meet regulatory standards. J.A. at 684. Masti-Kure was given sixty days "to respond with sufficient data, information, and analyses to demonstrate that there is a genuine and substantial issue of fact which justifies a hearing." Id. Masti-Kure responded on May 9 with a revised evidentiary submission. FDA concluded, however, that the deficiencies in the data were unremedied, and, on February 17, 1976, issued its final order withdrawing approval of NADA 65-381 and denying Masti-Kure's request for a hearing. 41 Fed.Reg. 7141 (1976).

II. THE APPROPRIATENESS OF SUMMARY JUDGMENT

The drug covered by NADA 65-381 is a combination antibiotic containing penicillin and neomycin. It is designed to treat mastitis in lactating cows. Masti-Kure's rationale for combining penicillin and neomycin in a single drug is that bovine mastitis is an infectious disease that results from pathogenic microorganisms, principally Streptococcus agalactiae (strep) and Staphylococcus aureus (staph). Although penicillin is usually effective in eliminating the infection caused by strep, it is sometimes ineffective against staph, which is known to produce an enzyme capable of destroying penicillin. Neomycin, it is postulated, is usually effective against staph, although not against strep. In actual field use, infecting organisms are not identified and the susceptibility patterns not determined before commencing treatment of mastitis. Use of penicillin or neomycin alone, therefore, will produce treatment failures in cows infected with organisms resistant to the drug used. Combining the drugs will result in fewer failures, because an infection resistant to one may respond to the other.

To substantiate that the drug covered by NADA 65-381 is thus effective under the combination drug policy, 21 C.F.R. § 514.1(b)(8)(v) (1977), Masti-Kure must demonstrate the validity of two assumptions. First, it must show that the combination of penicillin and neomycin is more effective in treating staph infections than is penicillin alone. Second, and more critical, it must show that in a population of cows with bacteriologically uncharacterized mastitis infections which is the intended patient population under Masti-Kure's rationale there exists a statistically significant proportion of infections that are resistant to

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one of NADA 65-381's two ingredients but susceptible to the other (or that the combination for any reason cures more infections than does either of its components alone). See 41 Fed.Reg. at 7142.

Masti-Kure must demonstrate the validity of these two assumptions through "evidence consisting of adequate and well-controlled investigations, Including field investigation . . . ." 21 U.S.C. § 360b(d)(3) (emphasis added). Masti-Kure submitted to FDA two field investigations, one conducted in 1973, and one in 1974. Applying its regulatory criteria of adequate and well-controlled investigations, Supra note 2, FDA found numerous deficiencies in both studies. Should we find each study to be conclusively deficient with respect to even a single regulatory standard, we must sustain FDA's February 17, 1976 order. ⁶

Our inquiry is controlled by Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 93 S.Ct. 2469, 37 L.Ed.2d 207 (1973). In that case the Supreme Court examined FDA regulations specifying standards for the "well-controlled investigations" required by the Act to demonstrate the efficacy of new drugs designed for human use, and concluded that they provided "drug manufacturers . . . full and precise notice of the evidence they must present to sustain their NDA's . . . ." ⁷ Id. at 622, 93 S.Ct. at 2479. ⁸ Given such specific regulations, FDA was not required to "provide a formal hearing where it is apparent at the threshold that the applicant has not tendered Any evidence which On its face meets the statutory standards as particularized by the regulations." Id. at 620, 93 S.Ct. at 2478. This reasoning, of course, only applies "to those regulations that are precise." Id. at 621 n. 17, 93 S.Ct. at 2479. The Court offered as an example of a "precise"

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regulation 21 C.F.R. § 314.111(a)(5)(ii)(a)(5) (1977), which provides that the plan or protocol for a study must include a "summary of the methods of analysis and an evaluation of data derived from the study, including any appropriate statistical methods." Compare 21 C.F.R. § 514.111(a)(5)(iv) (1977), Supra note 2. The Court stated that "(a)...