WEINBERGER, SECRETARY OF HEALTH, EDUCATION, AND WELFARE, ET AL. v. HYNSON, WESTCOTT & DUNNING, INC.
No. 72-394
Supreme Court of the United States
Argued April 17, 1973—Decided June 18, 1973
412 U.S. 609
*Together with No. 72-414, Hynson, Westcott & Dunning, Inc. v. Weinberger, Secretary of Health, Education, and Welfare, et al., also on certiorari to the same court.
Deputy Solicitor General Friedman and Andrew L. Frey argued the cause for petitioners in No. 72-394 and respondents in No. 72-414. With Mr. Frey on the briefs were Solicitor General Griswold, Assistant Attorney Gen-
Edward Brown Williams argued the cause for petitioner in No. 72-414 and respondent in No. 72-394. With him on the briefs was Jan Edward Williams.†
MR. JUSTICE DOUGLAS delivered the opinion of the Court.
These cases, together with Weinberger v. Bentex Pharmaceuticals, Inc., post, p. 645, CIBA Corp. v. Weinberger, post, p. 640, and USV Pharmaceutical Corp. v. Weinberger, post, p. 655, all here on certiorari, raise a series of questions under the 1962 amendments1 to the
The 1962 Act amended § 201 (p)(1) of the 1938 Act to define a “new drug” as a drug not generally recognized among experts as effective as well as safe for its intended use.
Between 1938 and 1962 FDA had permitted 9,457 NDA‘s to become effective. Of these, some 4,000 were still on the market. In addition, there were thousands of drugs which manufacturers had marketed without applying to FDA for clearance. These drugs, known as “me-toos,” are similar to or identical with drugs with effective NDA‘s and are marketed in reliance on the “pioneer” drug application approved by FDA. In some cases, a manufacturer obtained an advisory opinion letter from FDA that its product was generally recognized among experts as safe.
To aid in its task of fulfilling the statutory mandate to review all marketed drugs for their therapeutic efficacy, whether or not previously approved, FDA retained the National Academy of Sciences-National Research Council (NAS-NRC) to create expert panels to review by class the efficacy of each approved drug. Holders of NDA‘s were invited to furnish the panels with
I
Respondent in No. 72-394, Hynson, Westcott & Dunning, Inc., had filed an application under the 1938 Act for a drug called Lutrexin, recommended by Hynson for use in the treatment of premature labor, threatened and habitual abortion, and dysmenorrhea. FDA informed Hynson that Hynson‘s studies submitted with the application were not sufficiently well controlled to justify the claims of effectiveness and urged Hynson not to represent the drug as useful for threatened and habitual abortion. But FDA allowed the application to become effective, since the 1938 Act permitted evaluation of a new drug solely on the grounds of its safety. Before the 1962 amendments Hynson filed an application for a related drug which FDA, again on the basis of the test of safety, allowed to become effective. When the 1962 amendments became effective and NAS-NRC undertook to appraise the efficacy of drugs theretofore approved as safe, Hynson submitted a list of literature references, a copy of an unpublished study, and a representative sample testimonial letter on behalf of Lutrexin. The panel of NAS-NRC
While the District Court litigation was pending, FDA promulgated new regulations establishing minimal standards for “adequate and well-controlled investigations” and limiting the right to a hearing to those applicants who could proffer at least some evidence meeting those standards.8 Although Hynson maintained that it was not subject to the new regulations because its initial request for a hearing predated their issuance, it renewed its request and submitted the material which it claimed constituted “substantial evidence” of Lutrexin‘s effectiveness. The Commissioner denied the request for a hearing and withdrew the NDA for Lutrexin. He ruled that Lutrexin is not exempt from the 1962 amendments and that Hynson had not submitted adequate evidence that Lutrexin is not a new drug or is effective. The Court
Section 505 (e)9 directs FDA to withdraw approval of an NDA if the manufacturer fails to carry the burden of showing there is “substantial evidence”10 respecting the efficacy of the drug. As the Court of Appeals says, “substantial evidence” was substituted for “preponderance” of the evidence. 461 F. 2d, at 220. The Act and the Regulations, in their reduction of that standard to detailed guidelines,11 make FDA‘s so-called administrative summary judgment procedure appropriate.
The general contours of “substantial evidence” are defined by § 505 (d) of the Act to include “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, on the basis of which it could fairly and responsibly 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.”
Lower courts have upheld the validity of these regu-
“[A] claim could be rejected if it were found (a) that the investigations were not ‘adequate‘; (b) that they were not ‘well controlled‘; (c) that they had been conducted by experts not qualified to evaluate the effectiveness of the drug for which the application is made; or (d) that the conclusions
drawn by such experts could not fairly and responsibly be derived from their investigations.”
To be sure, the Act requires FDA to give “due notice and opportunity for hearing to the applicant” before it can withdraw its approval of an NDA. § 505 (e),
The propriety of such a procedure was decided in United States v. Storer Broadcasting Co., 351 U. S. 192, 205 (1956), and FPC v. Texaco, 377 U. S. 33, 39 (1964). We said in Texaco:
“[T]he statutory requirement for a hearing under § 7 [of the
Natural Gas Act ] does not preclude the Commission from particularizing statutory standards through the rulemaking process and barring at the threshold those who neither measure up to them nor show reasons why in the public interest the rule should be waived.” Ibid.
The NAS-NRC panels evaluated approximately 16,500 claims made on behalf of the 4,000 drugs marketed pursuant to effective NDA‘s in 1962. Seventy percent of these claims were found not to be supported by substantial evidence of effectiveness, and only 434 drugs were found effective for all their claimed uses. If FDA were required automatically to hold a hearing for each product whose efficacy was questioned by the NAS-NRC study, even though many hearings would be an exercise in futility, we have no doubt that it could not fulfill its statutory mandate to remove from the market all those drugs which do not meet the effectiveness requirements of the Act.
Our conclusion that the summary judgment procedure of FDA is valid does not end the matter, for Hynson argues that its submission to FDA satisfied its threshold burden. In reviewing an order of the Commissioner denying a hearing, a court of appeals must determine whether the Commissioner‘s findings accurately reflect the study in question and if they do, whether the deficiencies he finds conclusively render the study inadequate or uncontrolled in light of the pertinent regulations.19
II
No. 72-414 is a cross-petition by Hynson from the judgment of the Court of Appeals. This cross-petition raises questions concerning the “new drug” provisions of the 1962 amendments. The Court of Appeals suggested that only a district court has authority to determine whether Lutrexin is a “new drug.” The Government contends that the Commissioner has authority to determine new drug status in proceedings to withdraw approval of the product‘s NDA under § 505 (e). Although Hynson agrees, some of the manufacturers, parties to other suits in this group of cases, advance the contrary view.
Prior to 1938 there was no machinery for the premarketing approval of drugs sold in commerce. Under the 1906 Act, 34 Stat. 768, adulterated and misbranded drugs were narrowly defined, and the Act provided only criminal sanctions and seizure by libel for condemnation. As previously noted, the 1938 Act provided for regulatory clearance of drugs prior to marketing and for administrative suspension of any clearance if required in the interests of public safety. To introduce a new drug an application had to be effective with respect to that drug. The application was to become effective within a fixed period unless the agency after notice and opportunity for hearing refused to permit it to become effective, finding that
There was a steady stream of NDA‘s under that Act supported by voluminous data.20 Many new drugs claiming “me-too” status were marketed illegally or were launched with an advisory opinion of FDA that they were recognized as safe. It is estimated that by 1969 there were five identical or similar drugs for every drug with an effective NDA. Enormous administrative problems were created. Each NDA contained about 30 volumes, a stack 10 to 12 feet high; and some contained as many as 400 volumes of data.
It is clear to us that FDA has power to determine whether particular drugs require an approved NDA in order to be sold to the public. FDA is indeed the administrative agency selected by Congress to administer the Act, and it cannot administer the Act intelligently and rationally unless it has authority to determine what drugs are “new drugs” under § 201 (p) and whether they are exempt from the efficacy requirements of the 1962 amendments by the grandfather clause of § 107 (c) (4).
Regulatory agencies have by the requirements of particular statutes usually proceeded on a case-by-case basis, giving each person subject to regulation separate hear-
FDA maintains that a withdrawal of any NDA approval covers all “me-too” drugs. For the reasons stated, that procedure is a permissible one where every manufacturer of a challenged drug has an opportunity to be heard. FDA under
It is argued, however, that the only lawful purpose of an FDA hearing is to allow it a method for determining which lawsuits it will file in the future. Yet that is only another version of the tactics of delay and procras-
Its determination that a product is a “new drug” or a “me-too” drug is, of course, reviewable. But its jurisdiction to determine whether it has jurisdiction is as essential to its effective operation as is a court‘s like power. Cf. United States v. Shipp, 203 U. S. 563, 573 (1906). The heart of the new procedures designed by Congress is the grant of primary jurisdiction to FDA, the expert agency it created. FDA does not have the final say, for review may be had, not in a district court (except in a limited group of cases we will discuss), but in a court of appeals. FDA does not have unbridled discretion to do what it pleases. Its procedures must satisfy the rudiments of fair play. Judicial relief is available only after administrative remedies have been exhausted.
It is argued that though FDA is empowered to decide the threshold question whether the drug is a “new drug,” that power is only an incident to its power to approve or withdraw approval of NDA‘s. Some manufacturers, however, have no NDA‘s in effect and are not seeking approval of any drugs. Nevertheless, FDA may make a declaratory order that a drug is a “new drug.” While that order is not reviewable in the court of appeals under § 505 (h), it is reviewable by the district court under the
The thrust of
As noted, the 1962 amendments for the first time gave FDA power to scrutinize and evaluate drugs for effectiveness as well as safety. The Act requires the Commissioner to disapprove any application when there is a lack of “substantial evidence” that the applicant‘s drug is effective.
Moreover, the interpretation of
It is well established that our task in interpreting separate provisions of a single Act is to give the Act “the most harmonious, comprehensive meaning possible” in
Finally, we cannot agree with Hynson that Lutrexin is exempt from the provisions of the Act by virtue of
Moreover, Hynson‘s argument, as the Court of Appeals recognized, would render clause (C) superfluous. Under Hynson‘s reasoning, any drug that could satisfy clause (B)—i. e., any drug that had become generally recognized as safe—automatically would satisfy clause (C). This construction, therefore, offends the well-settled rule of statutory construction that all parts of a statute, if at all possible, are to be given effect. See, e. g., Jarecki v. G. D. Searle & Co., 367 U. S. 303, 307; Ginsberg & Sons v. Popkin, 285 U. S. 204, 208. The
Except for the modification with respect to Lutrexin‘s “new drug” status, the judgment of the Court of Appeals is
Affirmed.
MR. JUSTICE BRENNAN took no part in the consideration or decision of these cases. MR. JUSTICE STEWART took no part in the decision of these cases.
APPENDIX TO OPINION OF THE COURT
(ii) The following principles have been developed over a period of years and are recognized by the scientific community as the essentials of adequate and well-controlled clinical investigations. They provide the basis for the determination whether there is “substantial evidence” to support the claims of effectiveness for “new drugs” and antibiotic drugs.
(1) A clear statement of the objectives of the study,
(2) A method of selection of the subjects that—
(i) Provides adequate assurance that they are suitable for the purposes of the study, diagnostic criteria of the condition to be treated or diagnosed, confirmatory laboratory tests where appropriate, and, in the case of prophylactic agents, evidence of susceptibility and exposure to the condition against which prophylaxis is desired.
(ii) Assigns the subjects to test groups in such a way as to minimize bias.
(iii) Assures comparability in test and control groups of pertinent variables, such as age, sex, severity, or duration of disease, and use of drugs other than the test drug.
(3) Explains the methods of observation and recording of results, including the variables measured, quantitation, assessment of any subject‘s response, and steps taken to minimize bias on the part of the subject and observer.
(4) Provides a comparison of the results of treatment or diagnosis with a control in such a fashion as to permit quantitative evaluation. The precise nature of the control must be stated and an explanation given of the methods used to minimize bias on the part of the observers and the analysts of the data. Level and methods of “blinding,” if used, are to be documented. Generally, four types of comparison are recognized:
(i) No treatment: Where objective measurements of effectiveness are available and placebo effect is negligible, comparison of the objective results in comparable groups of treated and untreated patients.
(ii) Placebo control: Comparison of the results of use of the new drug entity with an inactive preparation designed to resemble the test drug as far as possible.
(iv) Historical control: In certain circumstances, such as those involving diseases with high and predictable mortality (acute leukemia of childhood), with signs and symptoms of predictable duration or severity (fever in certain infections), or in case of prophylaxis, where morbidity is predictable, the results of use of a new drug entity may be compared quantitatively with prior experience historically derived from the adequately documented natural history of the disease or condition in comparable patients or populations with no treatment or with a regimen (therapeutic, diagnostic, prophylactic) the effectiveness of which is established.
(5) A summary of the methods of analysis and an evaluation of data derived from the study, including any appropriate statistical methods.
Provided, however, That any of the above criteria may be waived in whole or in part, either prior to the investigation or in the evaluation of a completed study, by the Director of the Bureau of Drugs with respect to a specific clinical investigation; a petition for such a waiver may be filed by any person who would be adversely affected by the application of the criteria to a particular clinical investigation; the petition should show that some or all of the criteria are not reasonably applicable to the investigation and that alternative procedures can be, or have been, followed, the results of which will or have yielded data that can and should be accepted as substantial evidence of the drug‘s effectiveness. A petition for a waiver shall set forth clearly and concisely the specific provision or provisions in the criteria from which waiver is sought, why the criteria are not reasonably applicable to the par-
(b) For such an investigation to be considered adequate for approval of a new drug, it is required that the test drug be standardized as to identity, strength, quality, purity, and dosage form to give significance to the results of the investigation.
(c) Uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness. Such studies, carefully conducted and documented, may provide corroborative support of well-controlled studies regarding efficacy and may yield valuable data regarding safety of the test drug. Such studies will be considered on their merits in the light of the principles listed here, with the exception of the requirement for the comparison of the treated subjects with controls. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered.
MR. JUSTICE POWELL, concurring in part, and concurring in the result in part.
I concur in Part II of the Court‘s opinion, which disposes of the issues raised by Hynson, Westcott & Dunning, Inc., in its cross-petition (No. 72-414). As to Part I, which addresses issues raised in the petition filed by the Commissioner of FDA (No. 72-394), I concur only in the result and state briefly the limited sense in which I accept the Court‘s conclusion.
Insofar as the Court today sustains the holding below that Hynson‘s submission to FDA raised “a genuine and
Were we required to reach these issues, there might well be serious doubt whether the Commissioner‘s rigorous threshold specifications as to proof of “adequate and well-controlled investigations,” coupled with his restrictive summary judgment regulation, go beyond the statutory requirements and in effect frustrate the congressional mandate for a prewithdrawal “opportunity for hearing.”
These important and complex questions should await decision in future cases in which the issues are briefed fully and are necessary to the Court‘s decision.
Notes
Hynson also argues that Lutrexin is exempt by operation of
“An application filed pursuant to
Hynson contends that Lutrexin, generally recognized as safe prior to 1962, was not a “new drug” under applicable standards before the 1962 amendments. Thus, the argument goes, its NDA had ceased to be effective and could not be deemed “approved” under
This argument shares a common thread with the argument under