587 F.2d 1099

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.

*1100David Chiras, of the Bar of the Supreme Court of Rhode Island, pro hac vice by special leave of Court with William F. easier, 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. McCo-nachie, 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 or*1101der 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 neo-mycin 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 drug1 unless an NADA for the drug has been approved. See 21 U.S.C. §§ 360b(a)(l)(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)(l)(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.-l(b)(8)(v) (1977). In addition, FDA has by regulation set out standards for “adequate *1102and 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)(l). 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.” Weinber- *1103 ger 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 evidentia-ry submission. FDA concluded, however, that the deficiencies in the data were un-remedied, 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.-l(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 *1104one 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 “pre*1105cise” regulation 21 C.F.R. § 314.-lll(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] mere reading of the study submitted will indicate whether the study is totally deficient in this regard.” 412 U.S. at 621 n. 17, 93 S.Ct. at 2479.9 Although we have elsewhere noted that the FDA regulations defining “well-controlled investigations” cannot be categorically classified as precise or imprecise, Cooper Laboratories, Inc. v. FDA, 163 U.S.App.D.C. 212, 220, 501 F.2d 772, 780 (1974), we conclude in this case that, since Masti-Kure’s field investigations violate manifestly clear regulations, FDA must be sustained in its order of summary judgment.

In its 1973 study Masti-Kure infected cows with mastitis caused by both strep and staph. Approximately 20% of the infected cows were randomly selected to serve as no-treatment controls. The remaining cows were treated by the drug covered by NADA 65-381. FDA’s criticism of this study was that it logically proved only that treatment by the drug covered by NADA 65-381 was more effective than doing nothing, and thus that it failed utterly to demonstrate whether the combination drug was more effective than either penicillin or neomycin alone, as required by 21 C.F.R. § 514.1(b)(8)(v) (1977). According to regulatory standards, the latter conclusion can be demonstrated only by comparing the effect of the drug covered by NADA 65-381 on a test population against the effect on control populations of neomycin and penicillin. See 21 C.F.R. § 514.111(a)(5)(vi), supra note 2. The regulatory requirement that a “well-controlled investigation” include a control group is precise, and since Masti-Kure completely failed to comply with it, we sustain FDA’s finding that the 1973 study is conclusively “inadequate or uncontrolled in light of the pertinent regulations.” Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 622, 93 S.Ct. 2469, 2479, 37 L.Ed.2d 207 (1973).

In its 1974 field investigation, Masti-Kure combined the results of experiments on three separate herds: the Harvey herd, the Cleveland herd, and the Reeves herd. Parts of the udders (quarters) of the cows in these three herds were infected with staph and strep.10 All quarters treated in the Harvey and Cleveland herds were treated with penicillin, 100,000 units.11 In the Reeves herd tests were conducted using both the drug *1106covered by NADA 65-381 and penicillin, 100,000 units. Those quarters in the Reeves herd which were infected with strep and which were treated with penicillin demonstrated a cure rate of 28/30.12 Those infected with strep and treated with the experimental drug demonstrated a 35/36 cure rate. The cure rates for quarters in the Reeves herd infected with staph, however, were 3/5 for penicillin and 1/2 for the drug covered by NADA 65-381.13

FDA regulations require that an adequate and well-controlled investigation include a “method of selection of the animals to be studied and those to serve as controls” which “provides for . . . Assignment of the animals and control groups to test under conditions which exclude or minimize bias.” 21 C.F.R. § 514.111(a)(5)(ii)(b), supra note 2. In addition FDA regulations require such an investigation to include “[a] description of the steps taken to document comparability of variables such as species, age, sex, duration, and severity of disease, management practices, and use of drugs other than those being studied.” 21 C.F.R. § 514.111(a)(5)(iv), supra note 2. These requirements are particularly important with respect to Masti-Kure’s 1974 field investigation, since the drug covered by NADA 65-381 was used only on the Reeves herd and not randomly applied to the cows studied. The test group was thus drawn exclusively from the Reeves herd, whereas the control group (insofar as effectiveness under the combination drug policy was to be demonstrated) consisted of cows drawn from all three herds. FDA notes that herds of cows are likely to differ according to important variables, such as management practices, sanitation, and general health. See 41 Fed. Reg. at 7146. The 1974 field investigation, however, fails to provide any “description of the steps taken to document comparability” of test and control groups. No explanation at all was offered for the odd distribution of test animals. We conclude that the investigation’s complete violation of the letter and spirit of FDA regulations renders it conclusively inadequate.14 See Weinberger v. Hynson, Wescott & Dunning, 412 U.S. 609, 621 n. 17, 93 S.Ct. 2469, 37 L.Ed.2d 207 (1973).

Masti-Kure also attempts to combine the data of the 1973 and 1974 field studies so as to produce yet a third set of results. This procedure is unacceptable, however, because, among many other reasons, Masti-Kure has failed to provide a “description of the steps taken to document comparability of variables” among the test and control groups thus constituted. The issue is not, as Masti-Kure phrases it, whether “multiple data studies in different years” is forbidden by FDA regulations, reply brief for petitioner at 22, but whether, if such multiple data studies are attempted, an adequate description of the steps taken to assure comparability is also included. Since Masti-Kure did not include such a description, we agree with FDA that pooling of the data is impermissible.

*1107Masti-Kure submitted a third study in support of its claim for the effectiveness of the drug covered by NADA 65-381. See note 6 supra. Both in its proposed order of March 5, 1975, and in its final order of February 17, 1976, FDA characterized this third study as a clinical rather than a field investigation. Although this court is unaware of the criteria distinguishing field from clinical investigations, Masti-Kure did not contest FDA’s characterization of Masti-Kure’s third study in its May 9th submission to the agency, nor does Masti-Kure now dispute FDA’s characterization in its briefs before this court. Therefore, since Masti-Kure failed to submit, as required by statute, any adequate and well-controlled field investigations, we conclude that FDA’s order withdrawing approval from NADA 65-381 and denying a hearing must be affirmed.15

So Ordered.

Masti-Kure Products Co. v. Califano
587 F.2d 1099

Case Details

Name
Masti-Kure Products Co. v. Califano
Decision Date
Jun 16, 1978
Citations

587 F.2d 1099

Jurisdiction
United States

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