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 amendments
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. 21 U. S. C. § 321 (p) (1). A new drug, as now defined, still may not be marketed unless an NDA is in effect. FDA is now directed to refuse approval of an NDA and to withdraw any prior approval if "substantial evidence"
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
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.
Section 505 (e)
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." 21 U. S. C. § 355 (d). Acting pursuant
Lower courts have upheld the validity of these regulations,
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), 21 U. S. C. § 355 (e). FDA, however, by regulation, requires any applicant who desires a hearing to submit reasons "why the application . . . should not be withdrawn, together with a well-organized and full-factual analysis of the clinical and other investigational data he is prepared to prove in support of his opposition to the notice of opportunity for a hearing. . . . When it clearly appears from the data in the application and from the reasons and factual analysis in the request for the hearing that there is no genuine and substantial issue of fact . . . . e. g., no adequate and well-controlled clinical investigations to support the claims of effectiveness," the Commissioner may deny a hearing and enter an order withdrawing the application based solely on these data. 21 CFR § 130.14 (b). What the agency has said, then, is that it will not 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.
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.
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.
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 hearings.
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 § 554 of the Administrative Procedure Act may issue a declaratory order governing all drugs covered by a particular NDA. 5 U. S. C. § 554 (e). That section prescribes the procedures an agency must follow "in every case of adjudication required by statute to be determined on the record after opportunity for an agency hearing." § 554 (a). The industry maintains that § 554 (e) is of no avail to FDA because in a withdrawal proceeding a common issue is whether a drug is a "new drug." That issue, it is argued, can be resolved only in a court proceeding where there is an adjudication
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 procrastination
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. 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 by the court of appeals under § 505 (h), it is reviewable by the district court under the Administrative Procedure Act. 5 U. S. C. §§ 701-704; Citizens to Preserve Overton Park v. Volpe, 401 U.S. 402, 410; Abbott Laboratories v. Gardner, supra, at 139-148. By analogy an agency order declaring a commodity not exempt from regulation is normally a declaratory order that is reviewable, as we held in Frozen Food Express v. United States, 351 U.S. 40.
The thrust of § 201 (p) is both qualitative and quantitative. The Act, however, nowhere defines what constitutes "general recognition" among experts. Hynson contends that the "lack of substantial evidence" is applicable only to proof of the actual effectiveness of drugs that fall within the definition of a new drug and not to the initial determination under § 201 (p) whether a drug is "generally recognized" as effective. It would rely solely on the testimony of physicians and the extant literature, evidence that has been characterized as "anecdotal." We agree with FDA, however, that the statutory scheme and overriding purpose of the 1962 amendments compel the conclusion that the hurdle of "general recognition" of effectiveness requires at least "substantial evidence" of effectiveness for approval of an NDA. In the absence of any evidence of adequate and well-controlled investigation supporting the efficacy of Lutrexin, a fortiori
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. § 505 (d), 21 U. S. C. § 355 (d). Similarly, he may withdraw approval for any drug if he subsequently determines that there is a lack of such evidence. § 505 (e), 21 U. S. C. § 355 (e). Evidence may be accepted only if it consists 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 . . . ." § 505 (d), 21 U. S. C. § 355 (d). The legislative history of the Act indicates that the test was to be rigorous one. The "substantial evidence" requirements reflects the conclusion of Congress, based upon hearings,
Moreover, the interpretation of § 201 (p) urged by Hynson is not consistent with the statutory scheme as it operates on a purely prospective basis. Under subsection (2), a drug cannot transcend "new drug" status until it has been used "to a material extent or for a material time." Yet, a drug cannot be marketed lawfully before an NDA has been approved by the Commissioner on the basis of "substantial evidence." As the Solicitor General argues, "the Act is designed so that drugs on the market, unless exempt, will have mustered the requisite scientifically reliable evidence of effectiveness long before they are in a position to drop out of active regulation by ceasing to be a `new drug.' "
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 § 107 (c) (4) of the 1962 amendments. That section provides that no drug will be treated as a "new drug" if, on the day preceding the adoption of the amendments, the drug "(A) was commercially used or sold in the United States, (B) was not a new drug as defined by section 201 (p) of the basic Act as then in force, and (C) was not covered by an effective application under section 505 of that Act . . . ." The applicability of this section turns solely on whether Lutrexin was "covered" by an effective NDA immediately prior to the adoption of the 1962 amendments. Hynson argues that when Lutrexin became generally recognized as safe and was no longer a "new drug," its NDA ceased to be effective.
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 wellsettled 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
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
Title 21 CFR § 130.12 (a) (5) provides:
(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 particular
(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 from 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 investigation," 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." 21 U. S. C. § 355 (e). There is also a genuine issue of procedural due process where, as in this case, the Commissioner construes his regulations to deny a hearing as to the efficacy of a drug established and used by the medical profession for two decades, and where its effectiveness
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.
"The Secretary shall, after due notice and opportunity for hearing to the applicant, withdraw approval of an application with respect to any drug under this section if the Secretary finds . . . (3) 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 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 thereof . . . ."
"The term `new drug' means—
"(1) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof, except that such a drug not so recognized shall not be deemed to be a `new drug' if at any time prior to the enactment of this chapter it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use; or
"(2) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such that such drug, as a result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, otherwise than in such investigations, been used to a material extent or for a material time under such conditions."
"In the case of any drug which, on the day immediately preceding the enactment date, (A) was commercially used or sold in the United States, (B) was not a new drug as defined by section 201 (p) of the basic Act as then in force, and (C) was not covered by an effective application under section 505 of that Act, the amendments to section 201 (p) made by this Act shall not apply to such drug when intended solely for use under conditions prescribed, recommended, or suggested in labeling with respect to such drug on that day."
"An application filed pursuant to section 505 (b) of the basic Act which was `effective' within the meaning of that Act on the day immediately preceding the enactment date shall be deemed, as of the enactment date, to be an application `approved' by the Secretary within the meaning of the basic Act as amended by this Act."
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 § 107 (c) (2). Consequently, there was no approval that could be withdrawn in administrative proceedings pursuant to § 505 (e).
This argument shares a common thread with the argument under § 107 (c) (4)—that the NDA for Lutrexin had ceased to be effective. The argument is no more persuasive under § 107 (c) (2) than § 107 (c) (4). In addition, the construction offered by Hynson would upset the carefully drawn transitionary provisions of §§ 107 (c) (2) and (c) (3). Since the Commissioner now must affirmatively approve or disapprove all NDA's, § 107 (c) (2) was enacted to remove the administrative burden of approving each and every NDA then effective. It also protected the marketing authority of all manufacturers that had effective NDA's. Without this provision, no manufacturer whose drug had become generally recognized as safe could have continued to market the drug if it was not also generally recognized as effective.