Ubiotica Corporation v. Food and Drug Administration, 19876.

• Decision Date: 05 June 1970
• Docket Number: No. 19876.,19876.
• Citation: 427 F.2d 376
• Parties: UBIOTICA CORPORATION, Petitioner, v. FOOD AND DRUG ADMINISTRATION, Department of Health, Education and Welfare, and Robert W. Finch, Secretary, Department of Health, Education and Welfare, Respondents.
• Court: U.S. Court of Appeals — Sixth Circuit

427 F.2d 376 (1970)

UBIOTICA CORPORATION, Petitioner, v. FOOD AND DRUG ADMINISTRATION, Department of Health, Education and Welfare, and Robert W. Finch, Secretary, Department of Health, Education and Welfare, Respondents.

No. 19876.

United States Court of Appeals, Sixth Circuit.

June 5, 1970.

Leo E. Rattay, Cleveland, Ohio, on brief for petitioner.

Howard S. Epstein, Atty., Dept. of Justice, Washington, D. C., for respondents; Will Wilson, Asst. Atty. Gen., Criminal Division, John L. Murphy, Chief, Administrative Regulations Section, U. S. Dept. of Justice, Washington, D. C., on the brief; William W. Goodrich, Asst. Gen. Counsel, Food, Drugs and Environmental Health Division, Eugene M. Ffeifer, Atty., U. S. Dept. of Health, Education and Welfare, Washington, D. C., of counsel.

Before EDWARDS, McCREE and COMBS, Circuit Judges.

COMBS, Circuit Judge.

This case is here on petition to review an order of the Commissioner of Food and Drugs refusing to approve a new drug application submitted by petitioner Ubiotica Corporation. The application was filed with the Commissioner pursuant to 21 U.S.C. § 355 which prohibits the introduction into interstate commerce of any new drug unless an application therefor has been submitted to and approved by the Commissioner. Petitioner had also filed with the Commissioner a Notice of Claimed Investigational Exemption pursuant to 21 U.S.C. § 355(i) which authorizes the promulgation of regulations for exempting from the new drug requirements drugs intended solely for investigational use by experts.

Petitioner originally filed its new drug application and claim for investigational exemption in June, 1963. The new drug is proposed for treatment of mongolism. It is denominated by the sponsor as "U" Series Drugs and consists of approximately fifty separate ingredients. For a number of years prior to the 1962 amendments to the Food and Drug Act, petitioner had administered the drug to patients under medical supervision.

In November, 1963, the Commissioner notified petitioner that, since certain conditions had not been met, the investigational exemption allowing clinical testing of the drug was terminated. Petitioner unsuccessfully sought to enjoin and vacate this order in Turkel v. Food and Drug Administration, 334 F.2d 844 (6th Cir. 1964). We held there that 21 U.S.C. § 355(h) does not permit review of the withdrawal of an investigational exemption except on appeal from a subsequent order of the Secretary refusing to approve a new drug application. However, prior to our decision in Turkel, petitioner withdrew the new drug application which it had submitted in June, 1963.

Then, in June, 1966, petitioner submitted a second new drug application which was designated as supplemental to the previously withdrawn new drug application. After extended correspondence, petitioner was notified that the Commissioner proposed to issue an order refusing approval of the new drug application. A hearing was held, and subsequently the order was issued which is the subject of this appeal. The record before us consists of numerous exhibits and in excess of 6,000 pages of transcript. On this appeal we are asked to review the Commissioner's action in refusing to approve the new drug application and also in terminating petitioner's investigational exemption. In addition, petitioner alleges that it was denied a fair hearing and that the hearing examiner erroneously refused to require the Food and Drug Administration to make available certain witnesses and to produce various documents.

New Drug Application — The statutory scheme pertaining to the submission and approval or rejection of new drug applications is embodied in 21 U.S.C. § 355. Section 355(b) sets forth the information which is required to be submitted as a part of any new drug application, whereas section 355(d) establishes the permissible grounds for rejection of a new drug application. This latter subsection requires the Secretary to refuse to approve a new drug application if he finds any of the following to exist:

(1) the investigations and reports required to be submitted do not include adequate tests by all methods reasonably applicable to show whether the drug is safe;

(2) the results of such tests show the drug is unsafe or do not show it is safe under the conditions prescribed in the proposed labeling;

(3) the methods used in, and the facilities and controls used for the manufacture and processing of the drug are inadequate to preserve its identity, strength, quality, and purity;

(4) there is insufficient information to determine whether the drug is safe; or

(5) there is a lack of substantial evidence that the drug will have the effect it purports to have.

In enacting section 355, Congress clearly placed on the applicant the burden of establishing that the drug proposed to be distributed in interstate commerce is both safe and effective for the intended use. See Turkel v. Food and Drug Administration, 334 F.2d 844, 845. Here, the hearing examiner properly phrased the issues in terms of the statutory grounds for rejection set forth in section 355(d), and the Government came forward with proof as to why petitioner had not satisfied the burden of proof required of a new drug applicant under section 355. The Commissioner adopted the findings of the hearing examiner and concluded that the new drug application should not be approved in that it was deficient in each of the five respects enumerated above under section 355(d). The question here is whether those findings are supported by substantial evidence. 21 U.S.C. § 355(h). We conclude that they are and that the Commissioner properly refused to approve the new drug application. In light of the voluminous and complex nature of this record, we will only briefly summarize the salient features of the testimony adduced from the Commissioner's witnesses, all of whom are eminently well qualified in their particular realm of expertise.

Dr. Thomas Bumbalo conducted a "double blind" study on a group of children having mongolism, the results of which were published in the American Medical Association Journal. Dr. Bumbalo testified that the double blind study is the accepted procedure in evaluating any new drug. Under this technique, one-half of the group studied was given the "U" Series Drugs continually for a one year period while the other half (the control group) was given a placebo. The clinical investigators did not know which group was receiving the drug. Dr. Henry Turkel, developer of the new drug, was informed of the Bumbalo study and prescribed the dosage to be given and its duration. Numerous laboratory studies were performed both at the beginning and end of the study, including physical examinations and measurements, urinalysis, x-rays, and chromosome, psychometric and other tests. Dr. Bumbalo and his team concluded that, although no untoward effect or reaction was noted, there was neither physical nor mental progression during the one year period the "U" Series Drugs were administered. Although aware of the Bumbalo study, petitioner did not submit the results of that study with its new drug application.

Dr. John Nestor, a specialist in pediatric cardiology and treatment of mongoloids, evaluated the new drug application in terms of the case histories of patients who had received the "U" Series Drugs contained therein. Dr. Nestor testified that, in his opinion, the new drug application did not include full reports of adequate tests by all methods reasonably applicable to show safety and efficacy; that the clinical reports did not contain adequate detailed information as to each case treated including the age, sex, conditions treated, dosage, frequency of administration, duration, and results; and that there was insufficient clinical data to establish safety or effectiveness.

Specifically, Dr. Nestor testified that the new drug application did not contain an accepted protocol.¹ Dr. Nestor particularly emphasized that in many instances the conclusions drawn in the reports submitted were not substantiated by objective data. For example, there was no evidence of the performance of such laboratory tests as chromosome studies to determine if a patient in fact was a mongoloid; x-rays, electrocardiograms, fluoroscope studies, psychometric tests, and other studies were frequently omitted from the reports. Dr. Nestor also pointed to the fact that in other cases treatment with the "U" Series Drugs was discontinued without explanation. Moreover, the reports contained in the new drug application often failed to report any medication given prior to or in conjunction with the "U" Series Drugs. Lastly, in certain cases, no reason was given why the doses administered did not conform to the doses suggested in the proposed labeling.

Dr. Frances Kelsey, a pharmacologist, evaluated the animal studies submitted as a part of the new drug application. Based upon this evaluation, Dr. Kelsey testified that the information was too meager to permit any definite conclusion as to the safety or toxicity of the "U" Series Drugs in the rats and dogs tested; that at most the study only provided a rough screening or preliminary idea of toxicity, indicating the need for additional studies. In particular, Dr. Kelsey noted the absence of microscopic slides and detailed pathology reports; the small number of animals tested; the absence of certain laboratory work and the fragmentary nature of other laboratory studies; and the...