513 F.2d 1063 | D.C. Cir. | 1975
This is an appeal from a final order
The Commissioner rejected petitioner’s NDA without holding a hearing. He held that because petitioner had submitted no “adequate and well-controlled” studies in support of its NDA, the application was deficient on its face. Therefore there could be no genuine and substantial issue of fact outstanding which required a hearing.
Petitioner contends that it met the threshold evidentiary requirement to entitle it to a hearing on the approvability of its NDA before final action was taken by the Commissioner. It asks this Court to order the Commissioner to hold a hearing on its NDA for Cothyrobal.
The Court grants petitioner’s request. We set aside the final order of the Commissioner and remand this case to the Food and Drug Administration (FDA) for a hearing on the approvability of petitioner’s NDA 16-865.
I.
The Federal Food, Drug, and Cosmetic Act of 1938,
Section 505 of the Act
Section 505(b)
Section 505(d)
The section further defines “substantial evidence” as
*276 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.
A Regulation issued by FDA
Three of the four “recognized” methods of comparison for testing the effectiveness of a new drug consist of comparing the results of patients treated with the new drug with other patients (1) not receiving any treatment, or (2) receiving placebos, or (3) receiving non-drug therapy. The fourth method, used in testing the effectiveness of a new drug for diseases of high and predictable mortality, involves comparing the progress of the disease in patients treated with the new drug with “prior experience historically derived from the adequately documented natural history of the disease or condition . . ..”
The Regulation also states that “uncontrolled studies or partially controlled studies are not acceptable as the sole basis for the approval of claims of effectiveness.”
II.
On May 19, 1969, Edison submitted to FDA an NDA for its drug, Cothyrobal,
By letter dated December 1, 1969, the Commissioner denied the NDA on the ground that the information submitted in its support was inadequate under Section 505(b).
On December 24, 1969, Dr. Murray Israel, the inventor of Cothyrobal, and petitioner Edison Pharmaceutical Company filed an antitrust suit in the United States District Court for the District of Columbia
if . plaintiffs do not then obtain full and fair consideration by the FDA as to the safety and efficacy of their drug Cothyrobal for interstate sale, they may obtain a full hearing in the District Court on all their allegations.19
This Court made it clear that “[t]he essential is that the plaintiffs have a full and fair presentation of all their contentions before an impartial tribunal.”
Thereafter petitioner requested that its NDA for Cothyrobal be reactivated. It submitted no additional information in support of its application. After review by FDA personnel unconnected with the initial review of petitioner’s NDA in 1969,
Edison requested an opportunity to file its NDA over protest. The effect of this was to have the NDA re-examined by still another group of FDA personnel.
On June 28, 1973, the Commissioner published in the Federal Register
In response to this Notice a written appearance and request for a hearing was submitted by Edward “Whitey” Ford, a member of the Board of Directors of the Vascular Research Foundation on behalf of himself and over two
A written appearance and request for a hearing was also submitted by Edison. The request was accompanied by no new data. It consisted of medical and legal arguments as to why data previously submitted met the requirements for approval of NDA 16 — 865.
Upon review the Commissioner decided and stated in his final order of October 26, 1973, that the requests contained no new data which would in any way correct any of the deficiencies which had been noted in the Federal Register.
Accordingly the Commissioner concluded that there was a lack of substantial evidence that Cothyrobal has the effect it purports or is represented to have for its intended use; that the legal arguments were insubstantial; and that petitioner had failed to set forth specific facts showing that there was a genuine and substantial issue of fact in dispute requiring a hearing. This appeal followed.
III.
Petitioner is not challenging the validity of the procedure for approving NDA’s. Nor is it challenging FDA’s summary judgment procedure whereby an NDA may be rejected without a hearing if it does not contain the information required by Section 505(b). Instead petitioner contends that its submission more than meets what it characterizes as the “threshold evidentiary requirement” established by Hynson, Westcott and Dunning v. Richardson, 461 F.2d 215 (4th Cir. 1972), affirmed as modified on another issue
Hynson involved the drug, Lutrexin,
The Fourth Circuit reversed the Commissioner, however, holding that the standard of proof required to secure the right to a hearing is less than that required to prove effectiveness.
Neither due process nor the Administrative Practice (sic) Act permits an arbitrary denial in any case where it can be fairly said there are “genuine and substantial issues of fact” in dispute.
* * * * * *
Only if it can be fairly said that the clinical tests and medical studies and investigations submitted by the applicant, if credited and accepted (emphasis added), will not support a finding that they provide “substantial evidence” of effectiveness was it proper for the Commissioner to deny the appellant a hearing before entering a final order of withdrawal.32
The Court then noted that “no qualified expert has given an opinion that Lutrexin is ineffective for the uses intended,” and that the Commissioner, in pointing out the deficiencies in the investigations submitted by Hynson, “did not impugn the competency or qualifications of the scientists and medical experts whose investigations were cited by the appellant in support of its claim.”
[ajssuming that all the objections by the Commissioner to these clinical studies, conducted as they were by competent medical authorities, may have some validity (emphasis added), they do not justify a final conclusion, made ex parte, without a hearing, that it “clearly appears” that there is no genuine issue of fact on the effectiveness of Lutrexin, which is the test under the Commissioner’s own regulation for denial of a hearing; at most they merely create a genuine question of fact to be resolved at a hearing upon proper evidence.34
On certiorari, the Supreme Court upheld FDA’s summary judgment procedure for NDA’s.
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. . . . We cannot impute to Congress the design of requiring, nor does due process demand, a hearing when it appears conclusively from the applicant’s “plead*280 ings” that the application cannot succeed.36
The Court then set forth the scope of review of an order denying a hearing:
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.37
But then the Court, without any discussion of the studies submitted by Hynson or the question of how accurately the Commissioner had discussed the studies in his findings, affirmed the Fourth Circuit’s decision that Hynson’s submission was sufficient to warrant a hearing.
IV.
In the case at bar, petitioner submitted five clinical studies in support of its NDA for Cothyrobal. Like the submission in Hynson, these studies were deemed deficient by the Commissioner because none was “adequate and well-controlled” within the meaning of the Act.
Three of these studies the Commissioner characterized as anecdotal, and therefore insufficient by themselves to demonstrate effectiveness. At best they might provide corroboration for well-controlled studies.
There are no well-controlled studies using blind and double-blind cross-over and randomnization techniques or any other kind of control specified in 21 CFR 130.12(a)(5)(ii), so that neither the clinical nor statistical significance of the reported results can be evaluated.40
Petitioner contended in his request for a hearing as it has contended before us that such studies comparing the use of Cothyrobal, levothyroxine, and cyanocobalamin in separate groups of subjects would involve a “risk of death to patients” already taking the thyroid extract, levothyroxine. Thus even though
In his final order the Commissioner dismissed petitioner’s claim that double-blind studies might be dangerous to subjects by saying that “textbook medicine” demonstrates “that the L-thyroxine dosage contained in Co-Thyro-Bal is not ordinarily toxic.”
Petitioner does not deny that the amount of levothyroxine in Cothyrobal could be safely administered to a control group. But it points out that most patients taking injections of Cothyrobal are also taking oral thyroid. Therefore the amount of levothyroxine which a control group would take would equal the sum of levothyroxine in Cothyrobal and the oral thyroid already being taken.
This illustrates the inability of the parties to come to grips with the essential issue in this case. If the petitioner had been given a hearing, it is at least more likely that it could have made its point more clearly. At least it could have been given the attention it deserves.
The Commissioner did not consider the toxicity of this combined amount of levothyroxine in his final order. Instead he attempted to circumvent the issue by saying that
it should be stressed . . . that whether such toxicity exists or not and whether a study of the L-thyroxine alone would be dangerous or not is in part irrelevant, since the Commissioner finds that not even an adequate and well-controlled study comparing CoThyro-Bal itself with a placebo has been performed.44
From this statement, repeated four times in FDA’s brief
Thus it appears to us that the factual question of whether the double-blind tests comparing levothyroxine and Cothyrobal are too dangerous to perform is still “relevant.” Indeed, we deem this a sufficiently material fact in dispute to require an evidentiary hearing on Edison’s NDA before the Commissioner may issue a final order. The Commissioner cannot have it both ways. Either the double-blind tests comparing Cothyrobal with a placebo would be sufficient so that the question of whether levothyroxine
Therefore, for the aforementioned reasons, we hold that the threshold question whether it is “humanly possible” to acquire evidence which meets the statutory standards (as interpreted by FDA regulations) requires a full evidentiary hearing.
We also find it appropriate to require the Commissioner to hold a full evidentiary hearing on all relevant issues relating to the approvability of petitioner’s application, whichever way he decides the threshold issue. In so doing we are not establishing a new requirement for a full hearing whenever only a threshold issue is in dispute. We are mindful of the fact, noticed by the Supreme Court in Hynson;
We make an exception here only because of the facts of this case. Petitioner first filed NDA 16 — 865 over six years ago. In the interim its application has been denied on three separate occasions without an opportunity for hearing despite direction to the contrary from this Court.
We are re-enforced in our decision by the fact that between May 8, 1970, when FDA’s summary judgment regulations went into effect, and April 4, 1973, when the government submitted its reply brief in Hynson, the Commissioner had not granted a single request for a hearing on an NDA.
. Co-Thyro-Bal; Final Order on Objections and Request for a Hearing regarding Refusal to Approve New Drug Application, dated October 26, 1973 and published in the Federal Register on November 1, 1973 (38 Fed.Reg. 30121) (hereinafter referred to as “Final Order.”).
. 52 Stat. 1040, 21 U.S.C. § 301 et seq.
. The Drug Amendments of 1962, P.L. 87-781, added the requirement that new drugs be shown to be not only safe, as under the Act, but also effective for their intended use.
. Authority to promulgate regulations for the efficient enforcement of the Act is vested in the Secretary of Health, Education and Welfare in Section 701(a) of the Act, 21 U.S.C. § 371(a).
. “New Drug” is defined in Section 201(p) of the Act, 21 U.S.C. § 321(p). It is not contested that Cothyrobal is a “new drug” within the meaning of that section.
. 21 U.S.C. § 355.
. 21 C.F.R. § 130.
. 21 U.S.C. § 355(b).
. 21 U.S.C. § 355(d).
. There are other grounds as well which are described below.
. 21 C.F.R. § 130.12(a)(5)(ii)(a).
. 21 C.F.R. § 130.12(a)(5)(ii)(c). The Regulation adds, however, that “[s]uch 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 . ..”
. Or “Co-Thryo-Bal”.
. 21 U.S.C. § 355(b), summarized supra, at 4.
. Murray Israel, M.D., et al. v. Baxter Laboratories, Inc., et al., Civ.A.No. 3626-69.
. Under the doctrine enunciated in Eastern Railroad Presidents’ Conference v. Noerr Motor Freight, Inc., 365 U.S. 127, 81 S.Ct. 523, 5 L.Ed.2d 464 (1961) and United Mine Workers of America v. Pennington, 381 U.S. 657, 85 S.Ct. 1585, 14 L.Ed.2d 626 (1965).
. Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. 101, 466 F.2d 272 (1972).
. Under the “sham” exception to the Noerr-Pennington doctrine noted in California Motor Transport Co. v. Trucking Unlimited, 404 U.S. 508, 92 S.Ct. 609, 30 L.Ed.2d 642 (1971).
. Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. at 111, 466 F.2d at 282.
. Id. in footnote 19. Nonetheless on March 22, 1974, the District Court granted summary judgment in favor of Marion Finkel, the FDA employee, on grounds of official immunity, and in favor of Baxter and Travenol Laboratories “since any injury suffered by plaintiffs in this case was contributed to by their own failure to submit required information to the Food and Drug Administration and not by any alleged acts of the defendants . . .That case is now on appeal before this Court.
. This was necessary because Dr. Israel and Edison had alleged in their antitrust suit that an FDA employee and an FDA consultant who evaluated Cothyrobal’s NDA were involved in a conspiracy against Cothyrobal and this Court had said that “FDA should be encouraged to make [a determination about Cothyrobal’s NDA] by personnel and standards which are unimpeachable.” Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. at 112, 466 F.2d at 283.
. 21 C.F.R. § 130.5(d).
. 38 Fed.Reg. 17027, hereinafter referred to as “Notice.”
. 21 C.F.R. § 130.14 specifies the contents of notice of hearing.
. Notice at 10729, citing 21 C.F.R. § 130.14(b).
. 21 C.F.R. § 130.14(b) states that “[w]hen 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 which precludes the refusal to approve the application . . ., e. g., no adequate and well-controlled clinical investigations to support the claims of effectiveness have been identified, the Commissioner will enter an order on this data, making findings and conclusions on such data .
. The issue was who has authority to determine whether Lutrexin was a “new drug” under the 1962 amendments. The Fourth Circuit had suggested that only a District Court could make this decision. 461 F.2d at 219. The Supreme Court held that FDA has that authority, subject to judicial review when administrative remedies have been exhausted. 412 U.S. at 623-634, 93 S.Ct. 2469.
. Petitioner also contends that the Commissioner should have modified or set aside his final order when Edison submitted additional data to FDA (which FDA found inapplicable to NDA 16-865 because the ingredients of the drug were different), and that this Court’s ruling in Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. 101, 466 F.2d 272 (1972) required the Commissioner to provide a hearing on its NDA for Cothyrobal. There is no need for the Court to reach either of these questions because we have found that petitioner’s NDA meets the threshold evidentiary requirement established in Hynson. Therefore petitioner will finally receive that “full and fair consideration” of its NDA envisioned by this Court.
. Lutrexin is a drug recommended for use in the treatment of premature labor, threatened and habitual abortion, and dysmenorrhea.
. Drugs such as Lutrexin approved prior to the 1962 amendments were given two years to develop substantial evidence of effectiveness. This evidence was then examined by expert panels of the National Academy of Sciences-National Research Council, which reported their findings to FDA. If they reported that a drug lacked “substantial evidence of effectiveness,” that drug’s previously approved NDA could be withdrawn by FDA. Drug Amendments of 1962, § 107(c)(2) and (c)(3)(B), 76 Stat. 788, note following 21 U.S.C. § 321.
. Hynson had submitted three studies which it claimed to be adequate and well-controlled in support of its NDA for Lutrexin. It had also submitted eight case studies of the use of Lutrexin which it conceded were not adequate and well-controlled but which could provide corroboration for well-controlled studies and also yield raw data which might be of use in evaluating efficacy. See footnote 12, supra. The dispute in Hynson thus centered on the
The Commissioner found several major deficiencies in these studies. Some patients had received concurrent medication, but the studies did not indicate what other drugs had been used and in what amounts; a study plan had not been used for the selection of subjects for the study that had purported to insure comparability; two studies failed to include a summary or explanation of the statistical methodology, and the other study’s statistical design and statistical evaluation were inadequate.
. Id.
. 412 U.S. 609, 93 S.Ct. 2469. Justices Brennan and Stewart took no part in the decision of the cases. Justice Powell filed an opinion joining in the Court’s opinion on the issue of who has authority to determine whether Lutrexin was a “new drug” under the 1962 amendments (see footnote 27, supra) and concurring in the result of the Court’s opinion on the issue of whether Lutrexin should be given a hearing. He declined to agree “with any implications or conclusions in the Court’s opinion to the effect that the regulations — as, construed and applied by the Commissioner in this case — are either compatible with the statutory scheme or constitutional under the Due Process Clause. . . 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.’ ” 412 U.S. at 638, 93 S.Ct. at 2487.
.412 U.S. at 620-621, 93 S.Ct. at 2479. The Court added in a footnote that “[t]his applies, of course, only to those regulations that are precise. For example, the plan or protocol for a study must include ‘[a] summary of the methods of analysis and an evaluation of data derived from the study including any appropriate statistical methods.’ 21 CFR § 130.-12(a)(5)(ii)(a)(5). A mere reading of the study submitted will indicate whether the study is totally deficient in this regard. Some of the regulations, however, are not precise, as they call for the exercise of discretion or subjective judgment in determining whether a study is adequate and well controlled. For example, § 130.12(a)(5)(ii)(a)(2)(i) requires that the plan or protocol for the study include a method of selection of the subjects that provide ‘adequate assurance that they are suitable for the purposes of the study.’ The qualitative standards ‘adequate’ and ‘suitable’ do not lend themselves to clear-cut definition, and it may not be possible to tell from the face of a study whether the standards have been met. Thus, it might not be proper to deny a hearing on the ground that the study did not comply with this regulation.”
. 412 U.S. at 622, 93 S.Ct. at 2479.
. The Court noted, however, that “[tjhere is a contrariety of opinion within the Court concerning the adequacy of Hynson’s submission.” But a majority were of the view that the submission was sufficient to warrant a hearing. 412 U.S. at 623, 93 S.Ct. 2469, at 2480.
. See footnote 12, supra.
. 38 Fed.Reg. 17029 (June 28, 1973).
. In Pharmaceutical Manufacturers’ Association v. Richardson, the United States District Court for the District of Delaware used this phrase to define “substantial evidence” and “adequate and well-controlled clinical investigations.” 318 F.Supp. at 309 (1970).
FDA has made much of the fact that petitioner never requested 'a waiver under 21 C.F.R. § 130.12(a)(5)(ii)(a)(5), alleging this danger. But in light of the history of this case it is unlikely that a request for waiver would have been granted.
. Final Order, 38 Fed.Reg. at 30123 (November 1, 1973).
. Reply Brief of Petitioner at 24.
. Final Order, 38 Fed.Reg. at 30123 (November 1, 1973).
. “[The Brusch] ‘study’ merely measures a series of subjective complaints, without placebo control.” At 16. “Neither untreated nor placebo control populations, though necessary for a number of reasons, were used” in the Israel study. At 16. “While the study mentions the administration of a placebo, Russek does not even make clear to whom it was administered.” At 17-18. “Edison has not even performed an adequate and well-controlled study comparing Cothyrobal itself with a placebo.” At 21-22.
. The Supreme Court’s test in Weinberger v. Hynson, Westcott & Dunning, 412 U.S. at 620, 93 S.Ct. 2469 at 2478.
. In an amount equal to that used in Cothyrobal plus the oral thyroid the patient is receiving.
. Weinberger v. Hynson, Westcott & Dunning, 412 U.S. at 621, 93 S.Ct. 2469.
. Israel v. Baxter Laboratories, Inc., 151 U.S.App.D.C. at 111, 466 F.2d at 282.
. Reply Brief of Petitioner (US) at 31, Weinberger v. Hynson, Westcott & Dunning, 412 U.S. 609, 93 S.Ct. 2469, 37 L.Ed.2d 207 (1973).
. Weinberger v. Hynson, Westcott & Dunning, id., was decided on June 18, 1973. Petitioner had filed its NDA over protest on March 16, 1973. On June 20, two days after Hynson came down, the Commissioner proposed to give notice to Edison that he was again refusing to approve NDA 16-865. This Notice of Opportunity for Hearing was published in the Federal Register on June 28, 1973 (38 Fed.Reg. 17027). Petitioner submitted its request for a hearing, citing Hynson, on July 28, 1973. In his final order of October 26, 1973, the Commissioner stated that “Hynson is of no help to applicant since applicant has not tendered any evidence which on its face meets the statutory requirements.” (38 Fed.Reg. 30126 (November 1, 1973)). We do not agree. It is premature to determine that evidence of “adequate and well-controlled investigations” has not been submitted, and therefore the NDA. is fatally defective, before it has been determined whether such investigations are “humanly possible.”
.At oral argument on petitioner’s appeal, November 27, 1974, we asked counsel for the government how many requests for hearings had been granted since Hynson, but counsel did not know of any.