[Federal Register Volume 64, Number 54 (Monday, March 22, 1999)]
[Notices]
[Pages 13802-13804]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-6808]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 77N-0240; DESI 1786]


Certain Single-Entity Coronary Vasodilators Containing Isosorbide 
Dinitrate; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
withdraw approval of 25 abbreviated new drug applications (ANDA's) for 
certain single-entity coronary vasodilator drug products containing 
isosorbide dinitrate. FDA is offering the holders of the applications 
an opportunity for a hearing on the proposal. The basis for the 
proposal is that the sponsors of these products have failed to submit 
acceptable data on bioavailability and bioequivalence.

DATES: Requests for a hearing are due by April 21, 1999; data and 
information in support of hearing requests are due by May 21, 1999.

ADDRESSES: A request for 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 20857.
     Comments in response to this notice, identified with the reference 
number DESI 1786 and a request for 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

     In a notice (DESI 1786) published in the Federal Register of 
February 25, 1972 (37 FR 4001), FDA announced its evaluation of reports 
received from the National Academy of Sciences/National Research 
Council, Drug Efficacy Study Group on certain coronary vasodilator 
drugs. FDA classified isosorbide dinitrate drug products as: Probably 
effective for the treatment and prevention of anginal attacks when 
administered sublingually, and possibly effective for their labeled 
indications relating to the management, prophylaxis, or treatment of 
anginal attacks when administered orally.
     In notices published in the Federal Register of December 14, 1972 
(37 FR 26623), 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 certain single-entity coronary 
vasodilators, including isosorbide dinitrate, from the time limits 
established for the Drug Efficacy Study Implementation (DESI) program. 
The notices established conditions for marketing these products and 
identical, similar, or related products Sec. 310.6 (21 CFR 310.6) 
whether or not they had been marketed and whether or not they were 
subjects of approved new drug applications (NDA's). FDA required 
manufacturers and distributors to have ANDA's (conditionally approved, 
pending the results of ongoing studies) to market a product not the 
subject of NDA's. If at least one drug sponsor was conducting clinical 
studies on a chemical entity, FDA permitted the marketing of all firms' 
products containing the same chemical entity in a similar dosage form, 
provided each product met the other conditions. Not all sponsors, 
therefore, were required to conduct clinical studies. Because 
bioavailability is specific for an individual product, however, FDA 
required each firm to conduct a bioavailability study on its own 
product.
     In a notice published in the Federal Register of August 3, 1984 
(49 FR 31151), after completing its review of the clinical studies 
submitted for single-entity isosorbide dinitrate, FDA announced its 
conclusions that these drugs are effective. The notice set forth the 
marketing and labeling conditions for the products. Additionally, FDA 
required the submission of supplements providing acceptable in vitro 
dissolution tests and in vivo bioavailability/bioequivalence studies. 
The August 3, 1984, notice stated that supplements not fully approved 
within 1 year would be subject to proceedings to withdraw the previous 
approval and to remove the products from the market. This deadline was 
extended to June 26, 1987, in a notice published in the Federal 
Register of December 26, 1985 (50 FR 52856).
     The sponsors of the drug products listed in section II of this 
document are not in compliance with the notices of August 3, 1984, and 
December 26, 1985, in that they either have not submitted any 
bioavailability/bioequivalence data or have not submitted additional 
data on incomplete or inadequate studies. Accordingly, this notice 
reclassifies the products listed in section II of this document as 
lacking substantial evidence of effectiveness, proposes to withdraw 
approval of the applications, and offers an opportunity for a hearing 
on the proposal.

 II. ANDA'S Subject to This Notice

     1. ANDA 85-783; Isordil Chewable Tablets containing 10 milligrams 
(mg) of isosorbide dinitrate per tablet; Wyeth-Ayerst Laboratories 
(formerly held by Ives Laboratories, Inc.), P.O. Box 8299, 
Philadelphia, PA 19101.
     2. ANDA 86-045; Isosorbide Dinitrate Tablets containing 5 mg of 
the drug per tablet; Bolar Pharmaceutical Co., Inc., 130 Lincoln St., 
Copiague, NY 11726.
     3. ANDA 86-186; Isosorbide Dinitrate (controlled release, colored) 
Capsules containing 40 mg of the drug per capsule; Eon Labs 
Manufacturing, Inc. (formerly held by The Vitarine Co., Inc.), 227-15 
North Conduit Ave., Laurelton, NY 11413.
     4. ANDA 86-191; Isosorbide Dinitrate (sublingual) Tablets 
containing 5 mg of the drug per tablet; Bolar.
     5. ANDA 86-224; Isosorbide Dinitrate (controlled release) Tablets 
containing 40 mg of the drug per tablet; Geneva Pharmaceuticals, 
Inc.(formerly held by Cord Laboratories, Inc.), 2555 West Midway Blvd., 
P.O. Box 446, Broomfield, CO 80038-0446.
     6. ANDA 86-362; Isosorbide Dinitrate (sublingual) Tablets 
containing 2.5 mg of the drug per tablet; Bolar.
     7. ANDA 86-388; Sorbitrate (chewable) Tablets containing 10 mg of 
isosorbide dinitrate per tablet; Zeneca Pharmaceuticals, 1800 Concord 
Pike, Wilmington, DE 19897.
     8. ANDA 86-788; Isosorbide Dinitrate (controlled release, green) 
Tablets containing 40 mg of the drug per tablet; Forest Laboratories, 
Inc., 919 Third Ave., New York, NY 10022.

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     9. ANDA 86-790; Isosorbide Dinitrate (controlled release, yellow) 
Tablets containing 40 mg of the drug per tablet; Forest.
     10. ANDA 87-314; Isosorbide Dinitrate (chewable) Tablets 
containing 10 mg of the drug per tablet; D. M. Graham Laboratories, 
Inc., 58 Pearl St., P.O. Box P, Hobart, NY 13788.
     11. ANDA 87-414; Isosorbide Dinitrate (controlled release scarlet/
clear) Capsules containing 40 mg of the drug per capsule; Eon Labs.
     12. ANDA 87-461; Isosorbide Dinitrate (controlled release orange/
clear) Capsules containing 40 mg of the drug per capsule; Eon Labs.
     13. ANDA 87-477; Isosorbide Dinitrate (sublingual) Tablets 
containing 2.5 mg of the drug per tablet; Ascot Hospital 
Pharmaceuticals, Inc., 8055 North Ridgeway Ave., Skokie, IL 60076.
     14. ANDA 87-482; Isosorbide Dinitrate (controlled release) Tablets 
containing 40 mg of the drug per tablet; Ascot.
     15. ANDA 87-507; Isosorbide Dinitrate (controlled release white/
amethyst) Capsules containing 40 mg of the drug per capsule; Eon Labs.
     16. ANDA 87-558; Isosorbide Dinitrate (controlled release) Tablets 
containing 40 mg of the drug per tablet; Par Pharmaceutical, Inc., One 
Ram Ridge Rd., Spring Valley, NY 10977.
     17. ANDA 87-680; Isosorbide Dinitrate (controlled release white/
clear) Capsules containing 40 mg of the drug; Eon Labs.
     18. ANDA 87-694; Isosorbide Dinitrate (sublingual) Tablets 
containing 5 mg of the drug per tablet; Vangard Labs, Inc., P.O. Box 
1268, Glasgow, KY 42142-1268.
     19. ANDA 87-700; Isosorbide Dinitrate (sublingual) Tablets 
containing 2.5 mg of the drug per tablet; Vangard.
     20. ANDA 88-074; Sorbitrate Tablets containing 20 mg of isosorbide 
dinitrate per tablet; Zeneca.
     21. ANDA 88-428; Isosorbide Dinitrate (controlled release) Tablets 
containing 20 mg of the drug per tablet; Forest.
     22. ANDA 88-589; Isosorbide Dinitrate Tablets containing 5 mg of 
the drug per tablet; Barr Laboratories, Inc., Two Quaker Rd., P. O. Box 
2900, Pomona, NY 10970-0519.
     23. ANDA 88-590; Isosorbide Dinitrate Tablets containing 5 mg of 
the drug per tablet; Barr.
     24. ANDA 88-591; Isosorbide Dinitrate Tablets containing 20 mg of 
the drug per tablet; Barr.
     25. ANDA 88-592; Isosorbide Dinitrate (sublingual) Tablets 
containing 2.5 mg of the drug per tablet; Barr.

 III. Notice of Opportunity for a Hearing

     On the basis of all available data and information, 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), 21 CFR 314.126, and 21 CFR part 
320 that demonstrates effectiveness (i.e., bioavailability/
bioequivalence) of the drugs that are in compliance with the conditions 
established for continued marketing.
     Therefore, notice is given to the holders of the ANDA's listed 
previously and to a ll 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 the 
applications and all amendments and supplements thereto on the ground 
that new information before her with respect to the drug products, 
evaluated together with the evidence available to her when the 
applications were approved, shows there is a lack of substantial 
evidence that the drug products will have the effect they purport or 
are represented to have under the conditions of use prescribed, 
recommended, or suggested in the labeling.
     In addition to the holders of the applications specifically named 
in section II of the document, this notice of opportunity for hearing 
applies to all persons who manufacture or distribute a drug product, 
not the subject of an approved application, that is identical, related, 
or similar to a drug product named previously, as defined in 
Sec. 310.6. It is the responsibility of every drug manufacturer or 
distributor to review this notice of opportunity for hearing to 
determine whether it covers any drug product that they manufacture or 
distribute. Such persons may request an opinion on the applicability of 
this notice to a specific drug product by writing to the Division of 
Prescription Drug Compliance and Surveillance (address given above).
     This notice of opportunity for 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, 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 an opportunity for 
hearing to show why approval of the applications 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 April 21, 1999, 
a written notice of appearance and request for hearing, and (2) on or 
before May 21, 1999, 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. 314.151 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 
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 new drug application 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 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 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 under 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

[[Page 13804]]

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

    Dated: March 3, 1999.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 99-6808 Filed 3-19-99; 8:45 am]
BILLING CODE 4160-01-F