Edison Pharmaceutical Co., Inc. v. Food and Drug Administration, Dept. of Health, Ed., and Welfare

• Decision Date: 21 March 1979
• Docket Number: No. 77-1636,77-1636
• Citation: 600 F.2d 831
• Parties: EDISON PHARMACEUTICAL CO., INC., Petitioner, v. FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, and Joseph A. Califano, Secretary, Department of Health, Education, and Welfare, Respondents.
• Court: U.S. Court of Appeals — District of Columbia Circuit

Page 831

600 F.2d 831

195 U.S.App.D.C. 17

EDISON PHARMACEUTICAL CO., INC., Petitioner, v. FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH EDUCATION, AND WELFARE, and Joseph A. Califano Secretary, Department of Health Education, and Welfare, Respondents.

No. 77-1636.

United States Court of Appeals District of Columbia Circuit.

Argued Nov. 1, 1978.

Decided March 21, 1979.

Howard F. Cerny, New York City, for petitioner.

Margaret A. Cotter, Atty., Dept. of Justice, and Donald O. Beers, Asst. Chief Counsel, Food and Drug Administration, Rockville, Md., with whom Charles R. McConachie and James A. Calderwood, Attys., Dept. of Justice, and Richard M. Cooper, Chief Counsel, and Jeffrey B. Springer, Deputy Chief Counsel, Food and Drug Administration, Washington, D.C., were on the brief, for respondents.

Before J. EDWARD LUMBARD, Senior Circuit Judge for the Second Circuit, ^* and TAMM and LEVENTHAL, Circuit Judges.

Opinion for the court filed by TAMM, Circuit Judge.

TAMM, Circuit Judge:

Petitioner, Edison Pharmaceutical Co., Inc. (Edison) seeks to set aside a final order ¹ of the Commissioner of Food and Drugs (Commissioner) refusing approval of its new drug application (NDA) for the drug Cothyrobal. ² Edison contends that the Commissioner's order is not supported by substantial evidence and that the Food and Drug Administration (FDA) failed to conduct a full and fair evidentiary hearing on all issues relevant to approvability of the NDA, as ordered by this court in Edison Pharmaceutical Co. v. FDA, 168 U.S.App.D.C. 273, 513 F.2d 1063, 1072 (1975). We conclude that Edison's contentions are without merit and accordingly, we affirm the Commissioner's order refusing approval of the NDA.

I BACKGROUND

In the 1950's, Dr. Murray Israel developed Cothyrobal, an injectable drug ³ intended to treat hypercholesterolemia and hypothyroidism. ⁴ Cothyrobal is a combination of the thyroid extract, sodium levothyroxine, and cyanocobalamin (vitamin B 12). Levothyroxine is a cholesterol lowering substance with some toxic side effects. Proponents of Cothyrobal claim that vitamin B 12 inhibits the toxicity of levothyroxine while retaining its medicinal benefits. See Edison Pharmaceutical Co. v. FDA, 168 U.S.App.D.C. 273, 513 F.2d at 1066; 42 Fed.Reg. 28602-03 (1977).

In May 1969, Edison filed the NDA for Cothyrobal that is the subject of this appeal. ⁵ The Commissioner found the information offered in support of the application deficient under section 505(b) of the Federal Food, Drug and Cosmetic Act (Act), 21 U.S.C. § 355(b) (1976), ⁶ and denied the application in December 1969. Dr. Israel and Edison responded by filing an antitrust suit in the United States District Court for the District of Columbia alleging that an FDA consultant, an FDA employee, and manufacturers of a similar drug, Choloxin, ⁷ had conspired to prevent full and fair consideration of Edison's application by the FDA. The district court dismissed the suit, ⁸ but on appeal, this court reinstated the action. ⁹ See Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. 101, 466 F.2d 272, 282 (1972).

After reinstatement of the antitrust suit, Edison requested reactivation of its NDA. Although Edison had an opportunity to supplement the NDA, it offered no additional information. The FDA reviewed Edison's NDA for the second time and again found it deficient. Edison responded by filing its application over protest. See 21 C.F.R. § 314.110(d), (e) (1978). ¹⁰ A third group of FDA personnel examined the NDA and concluded it could not be approved. See Edison Pharmaceutical Co. v. FDA, 168 U.S.App.D.C. 273, 513 F.2d at 1067; 38 Fed.Reg. 17027 (1973).

Edison then requested a hearing. ¹¹ See 21 C.F.R. § 314.200(a)(2) (1978). The Commissioner concluded, Inter alia, that Edison had failed to set forth facts demonstrating the existence of a genuine and substantial issue of fact requiring a hearing on its NDA, See 21 C.F.R. § 314.200(g) (1978), ¹² and denied the request. The basis for the Commissioner's decision was Edison's failure to submit double-blind controlled studies comparing the effects of Cothyrobal and levothyroxine ¹³ which he determined were necessary to prove the efficacy of the drug. Edison appealed that ruling to this court, contending that the studies it had submitted were as scientifically sound as humanly possible. See Edison Pharmaceutical Co. v. FDA, 168 U.S.App.D.C. 273, 513 F.2d at 1070-72. A panel of this court reversed and ordered the Commissioner to hold "a full evidentiary hearing" to determine whether double-blind testing comparing the effects of levothyroxine and Cothyrobal could be conducted safely and to determine "All relevant issues relating to the approvability of (Edison's) application." ¹⁴ Id. at 1071-72 (emphasis in original).

The FDA held the required hearings in December 1975 and January 1976. The administrative law judge (ALJ) concluded that limited double-blind testing could be performed safely. He further found that the studies submitted with the NDA failed to demonstrate the safety and efficacy of Cothyrobal, as required by section 505(d) of the Act, 21 U.S.C. § 355(d) (1976), ¹⁵ and that Edison had failed in a variety of ways to comply with statutes and regulations governing NDA approval. Accordingly, the ALJ refused approval of the NDA. See Joint Appendix (J.A.) at 8a-14a.

That decision was affirmed by the Commissioner on May 27, 1977. In a thorough opinion, See 42 Fed.Reg. 28602-23, the Commissioner reviewed the ALJ's decision and Edison's exceptions. The Commissioner concluded: (1) that double-blind control group testing comparing the effects of Cothyrobal and levothyroxine could safely and ethically be performed on non-cardiac patients after preliminary testing, that such double-blind testing could not safely be performed on cardiac patients, and that it would be unsafe and unethical to administer Cothyrobal to cardiac patients before testing with non-cardiac patients was complete; (2) that even if double-blind controlled testing could not be performed, Edison's NDA, as submitted, did not sufficiently prove the safety and efficacy of Cothyrobal, and failed to comply with various statutory and regulatory provisions; and (3) that the administrative hearing was complete and fair. Id. at 28607, 28622-23.

In this court, Edison contends (1) that the Commissioner's refusal of its NDA is not supported by substantial evidence, See 21 U.S.C. § 355(h) (1976); and (2) that the FDA failed to provide the full evidentiary hearing mandated in Edison Pharmaceutical Co. v. FDA, 168 U.S.App.D.C. 273, 513 F.2d 1063.

II SUBSTANTIAL EVIDENCE

Before a new drug intended for human use ¹⁶ can be marketed in interstate commerce, it must be "clinically tested" ¹⁷ to establish it is both safe and effective. The Act requires an applicant to include reports of these tests in the NDA. 21 U.S.C. § 355(a), (b). NDAs must also contain certain technical information, See 21 U.S.C. § 355(b) (1976), and must be filed in accord with procedural specifications, See 21 C.F.R. § 314.1 (1978). The Commissioner concluded that Edison's NDA failed to demonstrate either the safety or efficacy of Cothyrobal. He further found that Edison had not complied with labeling specifications and rules requiring submission of samples and certain manufacturing information.

A. Efficacy of Cothyrobal

Under section 505(d)(5) of the Act, 21 U.S.C. § 355(d)(5), an NDA must be denied if there is a lack of "substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use" contained in the proposed labeling. Substantial evidence is "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved." 21 U.S.C. § 355(d). Uncontrolled studies or partially controlled studies alone are insufficient proof of a drug's efficacy. 21 C.F.R. § 314.111(a)(5)(ii)(C ) (1978). "Isolated case reports, random experience, and reports lacking details which permit scientific evaluation will not be considered." Id. An "adequate and well-controlled investigation," as defined in 21 C.F.R. § 314.111(a)(5)(ii)(A )(4 ) (1978), ¹⁸ is, Inter alia, one which "(p)rovides a comparison of the results of treatment or diagnosis with a control in such a fashion as to permit quantitative evaluation."

Clinically controlled testing usually involves administration of treatment to two groups of comparable subjects afflicted with the same condition. The first group receives the test drug; the second group, the control group, receives either an inactive preparation known as a placebo or a known drug to which the test drug is being compared. ¹⁹ The results of the two groups are then analyzed. Since human reaction to disease treatment may be influenced by a patient's expectations, and since observation of symptoms, particularly subjective symptoms, may be influenced by an observer's expectations, controlled investigations are usually conducted so neither subject nor observer knows which patient is receiving the test drug and which patient is part of the control group. This technique is called double-blinding. Double-blinding techniques ²⁰ are generally required to assure the formation of a scientifically valid judgment as to the therapeutic efficacy of a particular treatment. See J.A. at 7a. In certain circumstances, however, such as those involving diseases with high and predictable mortality rates, or signs and symptoms of predictable duration or severity, the regulations permit the use of historical controls. 21 C.F.R. § 314.111(a)(5)(ii)(A )(4 )(Iv ) (1978). In an historically controlled study, the effects of the medication on a test population are compared with adequately documented accounts of the natural history of the disease instead of with control groups.

A double-blind controlled clinical investigation of...