AMERICAN CYANAMID COMPANY v. Richardson, 71-1388.

• Decision Date: 16 December 1971
• Docket Number: No. 71-1388.,71-1388.
• Citation: 456 F.2d 509
• Parties: AMERICAN CYANAMID COMPANY, Petitioner, v. Elliot L. RICHARDSON, Secretary of Health, Education and Welfare, et al., Respondents.
• Court: U.S. Court of Appeals — First Circuit

456 F.2d 509 (1971)

AMERICAN CYANAMID COMPANY, Petitioner, v. Elliot L. RICHARDSON, Secretary of Health, Education and Welfare, et al., Respondents.

No. 71-1388.

United States Court of Appeals, First Circuit.

Heard December 14, 1971.

Decided December 16, 1971.

James D. St. Clair, with whom Harold Hestnes, Hale & Dorr, Boston, Mass., Robert M. Goolrick, Steptoe & Johnson, Washington, D.C., and Bertram H. Lebeis, Pearl River, N. Y., were on petitioner's memorandum in support of motion for stay pending review.

Howard Epstein, Atty., Dept. of Justice, and Eugene M. Pfeifer, Atty., Dept. of H. E. W., with whom Richard W. McLaren, Asst. Atty. Gen., Gregory Hovendon, Chief Consumer Affairs Section, Peter Barton Hutt, Asst. Gen. Counsel, Alvin L. Cottlieb, Deputy Asst. Gen. Counsel, and Joanne S. Sisk, Atty., Dept. of H. E. W., were on memorandum in opposition to petitioner's motion for a stay pending review.

COFFIN, Circuit Judge.

This motion comes before me as a single judge, in accordance with F.R.A.P 18, requesting a stay pending review of an order of the Commissioner of Food and Drugs (FDA), effective as of December 17, 1971, requiring petitioner, American Cyanamid Company, to cease the manufacture and distribution and to recall outstanding stocks of Achrocidin Compound Tablets and Achrocidin Compound Syrup, fixed-combination prescription drugs consisting principally of an infection-attacking antibiotic (tetra-cycline), an antihistamine (chlorothen citrate in the tablets, pyrilamine maleate in the syrup) and discomfort-relieving analgesics (phenacetin and salicylamide in both compounds). They have been produced and distributed to the medical profession in large quantities for fifteen years by petitioner's Lederle Laboratories Division (Lederle).

Hearing was had and briefs and a voluminous appendix were submitted and studied. My conclusion is that petitioner does not have a reasonable likelihood of ultimately prevailing and that the application for a stay must therefore be denied. Cf. Automatic Radio Mfg. Co. v. Ford Motor Co., 390 F.2d 113 (1st Cir.1968). I concede that denial of a stay may well cause irreparable harm to Lederle. Not only will there be substantial economic loss during and after the period of any stay but perhaps an incalculable loss of good will. Therefore, because of the substantial consequences flowing from my decision in this complicated regulatory field, I shall give lengthier treatment to the facts and issues than is generally appropriate at this stage of proceedings.

Procedural Background

Following the Drug Amendments of 1966, the FDA contracted with the National Academy of Sciences-National Research Council (NAS-NRC) to establish panels for the purpose of reviewing most available drugs. Acting on the reports of the panel which reviewed Achrocidin Tablets and Syrup and found them "ineffective as a fixed combination",¹ the FDA published on September 12, 1969, 34 F.R. 14342, notice of its intention to amend its regulations to bar a number of products, including Achrocidin Tablets and Syrup, which contained antibiotics in combination with antihistamines, analgesics, and/or decongestants. It called on those who might be adversely affected to submit pertinent data which "must . . . consist of adequate and well-controlled studies not previously submitted."

Lederle promptly responded with its objections,² but did not submit a "controlled study" because it felt that to conduct one would be difficult, would involve much time and money, and would show only that the Achrocidin components are as effective in combination as if separately administered—no more and no less. On May 8, 1970, the FDA issued regulations clearly setting forth its requirement that in the absence of adequate and well-controlled clinical investigations, a hearing would not be held. 32 F.R. 7520. The next event of record occurred on September 12, 1970, when the FDA published a finding that the evidence previously submitted by Lederle was not "substantial evidence of effectiveness" and a proposed regulation which would withdraw authorization for fifteen drug combinations including both Achrocidins. Once again, those adversely affected were invited to file objections and request a hearing, showing reasonable grounds therefor, which should include a "well-organized and full-factual analysis of the clinical and other investigational data". 35 F.R. 14392.

Lederle's response, in October, 1970, was to request a hearing on the basis of no more than an elaboration of its objections to the NAS-NRC panel report; to claim lack of notice of issues, prior adjudication, improper delegation, and departure from prior standards; and to argue that each component retained its effectiveness, and that the drug package was convenient and helped avoid patient error. The documentary evidence supporting these arguments was in the form of two general professional journal articles on drug interactions; five similar affidavits from internists endorsing the effectiveness and convenience of Achrocidin; an affidavit from a professor of pharmacology to the effect that controlled clinical investigations of Achrocidin are unnecessary and would be difficult, expensive, and time-consuming; an affidavit from a professor of pharmacy stating that there was some statistical correlation between the number of prescription medications required of a patient and his misuse of them and, a journal article on prescription misuse by the affiant;³ two affidavits by Lederle employees; and a survey of 274 physicians, virtually all of whom—by checking off the appropriate boxes on a Lederle questionnaire—expressed their beliefs that Achrocidin was safe and effective, and should remain available for prescription use.⁴

On February 18, 1971, the FDA published a proposed statement of policy elaborating on its requirement that each ingredient in a combination drug must contribute to its total effect, and saying in part that "the advantage of the combination must obtain for all conditions for which it is labeled, for the various dose schedules recommended, for the duration of dosage suggested, and for most patients for which the produce sic is recommended." 36 F.R. 3126, 3127. While twenty-nine drug manufacturers were among those who responded to this proposed statement, Lederle did not.

As a result of further consideration, the FDA issued a final policy statement on October 15, 1971 to the effect that each component in a fixed-combination drug must make a contribution to the claimed effects and "the dosage of each component (amount, frequency, duration) must be such that the combination is safe and effective for a significant patient population requiring such concurrent therapy . . . ." 36 F.R. 20037, 20038.

Finally, on November 17, 1971, the FDA issued the order attacked in this proceeding, concluding that legal objections which had been lodged against the proposed decertification were insubstantial and that Lederle had failed to present "substantial evidence of effectiveness" for its Achrocidin products which would require a hearing. 36 F.R. 21879. It applied its earlier announced standard of requiring that "each drug in the combination provides an advantage, as combined, for all doses, for the duration suggested, and for a significant patient population." It rejected the individual affidavits and the survey essentially because none of the opinions as to effectiveness was based on an "adequate and well-controlled clinical investigation", saying that such was required "precisely because of the variables involved". 36 F.R. at 21880. It pointed out that the antibiotic component of Achrocidin could only be effective against its intended target, an upper respiratory infection, when present in the blood in high concentrations for a sustained period, while the other components of Achrocidin are directed at relatively transitory symptoms such as headache and runny nose. To continue use of Achrocidin for its antibiotic when the other symptoms have vanished would be to use unnecessary medication....