[Federal Register Volume 63, Number 120 (Tuesday, June 23, 1998)]
[Notices]
[Pages 34188-34190]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16578]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 77N-0240]


Erythrityl Tetranitrate; Drug Efficacy Study Implementation; 
Revocation of Exemption; Opportunity for a Hearing

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is revoking the 
temporary exemption that has allowed single-entity coronary vasodilator 
drug products containing erythrityl tetranitrate to remain on the 
market beyond the time limits scheduled for implementation of the Drug 
Efficacy Study. FDA is announcing that the products lack substantial 
evidence of effectiveness and is offering an opportunity for a hearing 
on a proposal to withdraw approval of any applicable new drug 
applications (NDA's) or abbreviated new drug applications (ANDA's).

DATES: The revocation of exemption is effective June 23, 1998; requests 
for hearings are due on or before July 23, 1998; data in support of 
hearing requests are due on or before August 24, 1998.

ADDRESSES:  Communications in response to this notice should be 
identified with the reference number DESI 1786 and directed to the 
attention of the appropriate office named below.
    A request for a hearing, supporting data, and other comments are to 
be identified with Docket No. 77N-0240 and submitted to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852.
    A request for an opinion on applicability of this notice to a 
specific product should be directed to the Division of Prescription 
Drug Compliance and Surveillance (HFD-330), Center for Drug Evaluation 
and Research, Food and Drug Administration, 7500 Standish Pl., 
Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:  Mary E. Catchings, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION: 

I. Background

    Under the agency's Drug Efficacy Study Implementation (DESI) 
program, the National Academy of Sciences/National Research Council 
(NAS/NRC) evaluated the effectiveness of certain coronary vasodilators. 
Based on NAS/NRC's recommendations, FDA classified the coronary 
vasodilators as probably and possibly effective for indications 
relating to the management, prophylaxis, or treatment of anginal 
attacks. This classification was announced in the Federal Register of 
February 25, 1972 (37 FR 4001).
    In a notice published in the Federal Register of December 14, 1972 
(37 FR 26623), as amended July 11, 1973 (38 FR 18477), August 26, 1977 
(42 FR 43127), October 21, 1977 (42 FR 56156), and September 15, 1978 
(43 FR 41282), FDA temporarily exempted the single-entity coronary 
vasodilators covered by the DESI program from the time limits 
established for completing the program (Paragraph XIV, Category I 
exemption). FDA granted this exemption to allow manufacturers 
additional time to conduct clinical studies to determine effectiveness 
of the drugs for prevention of anginal attacks. In the August 26, 1977, 
notice, FDA added certain dosage forms of erythrityl tetranitrate (not 
included in the Drug Efficacy Study but regarded as related drugs) to 
the Paragraph XIV, Category I exemption.
    The exemption notices established conditions for marketing the 
single-entity coronary vasodilators pending FDA's conclusions about the 
products. FDA required that each manufacturer conduct bioavailability 
studies on its own product(s) and that at least one manufacturer 
conduct clinical effectiveness studies for each chemical entity to 
which the same effectiveness conclusions would ultimately apply. An

[[Page 34189]]

ANDA was required for marketing of products not the subject of an NDA; 
such products were to be conditionally approved, pending the results of 
ongoing studies. Conditionally approved ANDA's were given the same 
status as the ``deemed approved'' NDA's under review in the DESI 
program, i.e., safe but not proven effective (42 FR 43127 and 43129).
    The following applications for erythrityl tetranitrate received 
conditional approval under the terms of the exemption notices:
    1. ANDA 86-194; Cardilate Chewable Tablets containing 10 milligrams 
(mg) erythrityl tetranitrate per tablet; Glaxo Wellcome (formerly 
Burroughs Wellcome), 3030 Cornwallis Rd., P.O. Box 12700, Research 
Triangle Park, NC 27709-2700.
    2. ANDA 86-203; Cardilate Tablets containing 5, 10, or 15 mg of 
erythrityl tetranitrate per tablet; Glaxo Wellcome.
    In response to the exemption notices, the then Burroughs Wellcome 
Co. submitted efficacy data on its erythrityl tetranitrate products, 
but later requested in separate letters that FDA withdraw approval of 
ANDA's 86-194 and 86-203, stating that the marketing of the products 
had been discontinued. FDA withdrew approval of ANDA 86-194 in the 
Federal Register of February 13, 1996 (61 FR 5562 at 5563). FDA 
considers the requests for withdrawal of the ANDA's to also constitute 
requests for withdrawal of the efficacy data. Accordingly, FDA is now 
proposing to withdraw approval of the applications based on lack of 
substantial evidence of effectiveness.

II. Revocation of Exemption

    According to FDA's records, no person other than Glaxo Wellcome has 
submitted data or expressed an intention to perform clinical studies on 
single-entity erythrityl tetranitrate, and it is now reclassified to 
lacking substantial evidence of effectiveness. The temporary exemption, 
as it pertains to the drug, is revoked.
    No other single-entity coronary vasodilators remain exempt under 
the Paragraph XIV, Category I exemption, and Category I is now 
dissolved.

III. Notice of Opportunity for a Hearing

    On the basis of all the data and information available to her, the 
Director of the Center for Drug Evaluation and Research is unaware of 
any adequate and well-controlled clinical investigation, conducted by 
experts who are qualified by scientific training and experience, 
meeting the requirements of section 505 of the Federal Food, Drug, and 
Cosmetic Act (the act)(21 U.S.C. 355) and 21 CFR 314.126, that 
demonstrates effectiveness of single-entity erythrityl tetranitrate.
    Notice is given to the holder of any NDA or ANDA for single-entity 
erythrityl tetranitrate, to manufacturers or distributors of the drug, 
and to all other interested persons, that the Director of the Center 
for Drug Evaluation and Research proposes to issue an order under 
section 505(e) of the act withdrawing approval of any NDA or ANDA and 
all amendments and supplements thereto providing for single-entity 
erythrityl tetranitrate and its indication relating to the management, 
prophylaxis, or treatment of anginal attacks. The Director of the 
Center for Drug Evaluation and Research finds that new information 
before her with respect to the drug, evaluated together with the 
evidence available to her when applications were approved under the 
exempting notices, shows 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.
    This notice applies to any person who manufactures or distributes a 
drug product containing single-entity erythrityl tetranitrate that is 
not the subject of an approved NDA and that is identical, related, or 
similar as defined in Sec. 310.6 (21 CFR 310.6). It is the 
responsibility of every drug manufacturer or distributor to review this 
notice to determine whether it covers any drug product that the person 
manufactures or distributes. Any person may request an opinion of the 
applicability of this notice to a specific drug product by writing to 
the Division of Prescription Drug Compliance and Surveillance (address 
above).
    This notice of opportunity for a hearing encompasses all issues 
relating to the legal status of the drug products subject to it 
(including identical, related, or similar drug products as defined in 
Sec. 310.6), e.g., any contention that any such product is not a new 
drug because it is generally recognized as safe and effective within 
the meaning of section 201(p) of the act (21 U.S.C. 321(p)) or because 
it is exempt from part or all of the new drug provisions of the act 
under the exemption for products marketed before June 25, 1938, in 
section 201(p) of the act, or under section 107(c) of the Drug 
Amendments of 1962 (Pub. L. 87-781), or for any other reason.
    In accordance with section 505 of the act and the regulations 
issued under it (21 CFR parts 310 and 314), an applicant and all other 
persons subject to this notice are hereby given a opportunity for a 
hearing to show why approval of any applicable NDA's or ANDA's should 
not be withdrawn.
    An applicant or any other person subject to this notice who decides 
to seek a hearing shall file: (1) On or before July 23, 1998, a written 
notice of appearance and request for a hearing, and (2) on or before 
August 24, 1998, the data, information, and analyses relied on to 
demonstrate that there is a genuine issue of material fact to justify a 
hearing, as specified in Sec. 314.200. Any other interested person may 
also submit comments on this notice. The procedures and requirements 
governing this notice of opportunity for a hearing, a notice of 
appearance and request for a hearing, information and analyses to 
justify a hearing, other comments, and a grant or denial of a hearing 
are contained in Secs. 314.150 and 314.200, and in 21 CFR part 12.
    The failure of an applicant or any other person subject to this 
notice to file a timely written notice of appearance and request for a 
hearing, as required by Sec. 314.200, constitutes an election by that 
person not to use the opportunity for a hearing concerning the action 
proposed and a waiver of any contentions concerning the legal status of 
that person's drug product(s). Any new drug product marketed without an 
approved NDA is subject to regulatory action at any time.
    A request for a hearing may not rest upon mere allegations or 
denials, but must present specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If it 
conclusively appears from the face of the data, information, and 
factual analyses in the request for a hearing that there is no genuine 
and substantial issue of fact which precludes the withdrawal of 
approval of the application, or when a request for a hearing is not 
made in the required format or with the required analyses, the 
Commissioner of Food and Drugs will enter summary judgment against the 
person(s) who requests the hearing, making findings and conclusions, 
and denying a hearing.
    All submissions pursuant to this notice of opportunity for a 
hearing are to be filed in four copies. Except for data and information 
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 
1905, the submissions may be seen in the Dockets Management Branch 
(address above) between 9 a.m. and 4 p.m., Monday through Friday.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the 
Director of the

[[Page 34190]]

Center for Drug Evaluation and Research (21 CFR 5.70 and 5.82).

    Dated: May 28, 1998.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 98-16578 Filed 6-22-98; 8:45 am]
BILLING CODE 4160-01-F