[Federal Register: April 16, 2004 (Volume 69, Number 74)]
[Notices]               
[Page 20632-20634]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr16ap04-66]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket Nos. 1976N-0151 and 1977N-0203]

 
Isocarboxazid; Drugs for Human Use; Drug Efficacy Study 
Implementation; Revocation of Exemption; Announcement of Marketing 
Conditions; Followup Notice; and Opportunity for 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 isocarboxazid products to remain 
on the market beyond the time limits scheduled for implementation of 
the Drug Efficacy Study. FDA announces the conditions for marketing 
this product for the indication now regarded as effective. 
Isocarboxazid, a monoamine oxidase inhibitor, is used in the treatment 
of depression.

DATES:  The revocation of exemption is effective April 16, 2004. 
Requests for hearing are due by May 17, 2004; information to justify a 
hearing is due by June 15, 2004.

ADDRESSES:  Communications in response to this document are to be 
identified with reference number Drug Efficacy Study Implementation 
(DESI) 11961, and directed to the attention of the appropriate office 
listed in the following paragraphs.
    Original abbreviated new drug applications (ANDAs): Office of 
Generic Drugs (HFD-600), Center for Drug Evaluation and Research, Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855.
    Requests for hearing: (identify with docket numbers found in the 
heading of this document): Division of Dockets Management (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.
    Requests for opinion of the applicability of this document to a 
specific product: Division of New Drugs and Labeling Compliance (HFD-
310), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Mary 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

    The following new drug application (NDA) is the subject of this 
document:
    NDA 11-961; MARPLAN Tablets containing isocarboxazid, 10 milligrams 
(mg); Oxford Pharmaceutical Services, Inc., One U.S. Highway 46 West, 
Totowa, NJ 07512 (formerly held by Roche Laboratories (Roche), Division 
of Hoffman-LaRoche, Inc., Nutley, NJ 07110).
    In a document published in the Federal Register of July 9, 1966 (31 
FR 9426), all holders of NDAs that became effective before October 10, 
1962, on the basis of a showing of safety, were requested to submit to 
FDA reports containing the best data available in support of the 
effectiveness of their products for the claimed indications. Roche, 
then the holder of NDA 11-961, did not submit data on MARPLAN. 
Consequently, MARPLAN was not included in the initial phase of the DESI 
review, that is, the review conducted by the National Academy of 
Sciences-National Research Council. Nevertheless, FDA reviewed 
available information on MARPLAN, including information subsequently 
submitted by Roche, and concluded that substantial evidence of 
effectiveness of the drug was lacking. Accordingly, in the Federal 
Register of October 5, 1976 (41 FR 43938), the agency issued a notice 
of opportunity for hearing (NOOH) on a proposal to withdraw approval of 
NDA 11-961 for MARPLAN Tablets.
    In response to the October 1976 document, Roche submitted evidence 
to document a medical need for MARPLAN and indicated it was making 
arrangements to conduct the necessary studies to determine the 
effectiveness of the drug.
    In a document published in the Federal Register of July 14, 1978 
(43 FR 30351), FDA temporarily exempted isocarboxazid from the time 
limits established for completing the DESI program (paragraph XIV, 
category XX exemption). The exemption allowed the drug to remain on the 
market pending completion and review of additional clinical studies to 
determine its effectiveness. The July 1978 exemption document 
established conditions for marketing isocarboxazid, including a 
requirement that the drug be labeled as probably effective for severe 
reactive or endogenous depression. That document also required ANDAs 
for duplicate products covered by the exemption and established a 
schedule for the submission of protocols, and for the initiation and 
completion of studies. Accordingly, in the same issue of the Federal 
Register (43 FR 30350), FDA published a document rescinding the 1976 
NOOH for MARPLAN.
    In a Federal Register document of August 28, 1979 (44 FR 50409), 
FDA amended the previously published conditions for marketing 
isocarboxazid specified in the July 1978 exemption document (43 FR 
30351). The amended conditions required that isocarboxazid be labeled 
as probably effective for the treatment of depressed patients who are 
refractory to tricyclic antidepressants or electroconvulsive therapy 
and depressed patients in whom tricyclic antidepressants are 
contraindicated. The August 1979 document also extended the time limits 
for submitting protocols and for completing studies on isocarboxazid.
    On the basis of the agency's review of additional data and 
information submitted by the holder of NDA 11-961, the Director of the 
Center for Drug Evaluation and Research (CDER) has determined that 
isocarboxazid (MARPLAN) is effective for the treatment of depression. A 
supplement to NDA 11-961 providing for this indication was approved in 
1998. Isocarboxazid is no longer entitled to the temporary exemption 
announced in 1978. Accordingly, the exemption, as it pertains to 
isocarboxazid, is hereby revoked.
    No other monoamine oxidase inhibitor remains exempt under the 
paragraph XIV, category XX exemption, and category XX is now dissolved.
    Isocarboxazid is regarded as a new drug under section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(p)), and 
an approved application, under section 505 of the act (21 U.S.C. 355), 
is required for marketing an isocarboxazid product.
    In addition to the product specifically named in the previous 
paragraphs, this document applies to any product that is not the 
subject of an approved application and is identical to the product 
named previously. The document may also be applicable, under Sec.  
310.6 (21 CFR 310.6), to a similar or

[[Page 20633]]

related drug product that is not the subject of an approved 
application. It is the responsibility of every drug manufacturer or 
distributor to review this document and 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 document to 
a specific drug product by writing to the Division of New Drugs and 
Labeling Compliance (see ADDRESSES).

II. Conditions for Approval and Marketing

A. Effectiveness Classification

    FDA has reviewed all available evidence and concludes that 
isocarboxazid is effective for the indication in the labeling 
conditions listed in the following sections. The drug product lacks 
substantial evidence of effectiveness for other labeled indications.

B. Conditions for Approval and Marketing

    FDA is prepared to approve ANDAs referencing MARPLAN for products 
containing isocarboxazid for the indication now regarded as effective.
    1. Form of Drug
    The drug product is in tablet form for oral administration. Each 
tablet contains isocarboxazid, 10 mg.
    2. Labeling Conditions
    a. The label bears the statement ``Rx only''.
    b. The drug is labeled to comply with all requirements of the act 
and FDA's regulations, and the labeling bears adequate information for 
safe and effective use of the drug. The indication is as follows:
    Isocarboxazid is indicated for the treatment of depression. 
Because of its potentially serious side effects, isocarboxazid is 
not an antidepressant of first choice in the treatment of newly 
diagnosed depressed patients.
    The efficacy of isocarboxazid in the treatment of depression was 
established in 6-week controlled trials of depressed outpatients. 
These patients had symptoms that corresponded to the Diagnostic and 
Statistical Marwal of Mental Disorders (DSM-IV) category of major 
depressive disorder; however, they often also had signs and symptoms 
of anxiety (anxious mood, panic, and/or phobic symptoms). (See 
Clinical Pharmacology.)
    A major depressive episode (DSM-IV) implies a prominent and 
relatively persistent (nearly every day for at least 2 weeks) 
depressed or dysphoric mood that usually interferes with daily 
functioning, and includes at least five of the following nine 
symptoms: depressed mood, loss of interest in usual activities, 
significant change in weight and/or appetite, insomnia or 
hypersomnia, psychomotor agitation or retardation, increased 
fatigue, feelings of guilt or worthlessness, slowed thinking or 
impaired concentration, and a suicide attempt or suicidal ideation.
    The antidepressant effectiveness of isocarboxazid in 
hospitalized depressed patients, or in endogenomorphically retarded 
and delusionally depressed patients, has not been adequately 
studied.
    The effectiveness of isocarboxazid in long-term use, that is, 
for more than 6 weeks, has not been systematically evaluated in 
controlled trials. Therefore, the physician who elects to use 
isocarboxazid for extended periods should periodically evaluate the 
long-term usefulness of the drug for the individual patient.
    3. Marketing Status
    For unapproved products, approval of an ANDA must be obtained in 
accordance with section 505(j) of the act before marketing such 
products. Marketing prior to approval of an ANDA will subject such 
products, and those persons who caused the products to be marketed, to 
regulatory action.

III. Notice of Opportunity for Hearing

    Notice is given to the holder of the NDA and to all other 
interested persons that the Director of CDER proposes to issue an order 
under section 505(e) of the act withdrawing approval of the NDA and all 
amendments and supplements thereto providing for indications that lack 
substantial evidence of effectiveness (i.e., indications not referred 
to in section II.B.2.b of this document). The basis of the proposed 
action is that new information before the Director of CDER with respect 
to the drug product, evaluated together with the evidence available to 
the Director of CDER when the application was approved, shows there is 
a lack of substantial evidence that the drug product will have all the 
effects it claims or is represented to have under the conditions of use 
prescribed, recommended, or suggested in the labeling for indications 
not referred to in section II.B.2.b of this document. If no hearing is 
requested, then approval of the claims that lack evidence of 
effectiveness will be considered withdrawn, and no further order will 
issue.
    This notice of opportunity for hearing encompasses all issues 
relating to the legal status of the drug product 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 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 (Public Law 
87-781), or for any other reason.
    In accordance with section 505 of the act and the regulations 
issued under that section (21 CFR part 310 and part 314 (21 CFR part 
314)), an applicant and all other persons who manufacture or distribute 
a drug product that is identical, related, or similar to a drug product 
named in this document (Sec.  310.6) and not the subject of an NDA are 
hereby given an opportunity for a hearing to show why approval of those 
portions of the NDA providing for indications that lack substantial 
evidence of effectiveness should not be withdrawn, and an opportunity 
to raise, for administrative determination, all issues relating to the 
legal status of the drug product named above and of all identical, 
related, or similar drug products not the subject of an NDA.
    The applicant or any other person subject to this document under 
Sec.  310.6 who decides to seek a hearing shall file: (1) A written 
notice of appearance and request for hearing (see DATES), and (2) the 
data, information, and analyses relied on to justify a hearing, as 
specified in Sec.  314.200 (see DATES). Any other interested person may 
also submit comments on this proposal to withdraw approval. The 
procedures and requirements governing this notice of opportunity for 
hearing; a notice of appearance and request for hearing; a submission 
of data, information, and analyses to justify a hearing; other 
comments; and a granting or denial of a hearing are contained in Sec.  
314.200 and in 21 CFR part 12.
    The failure of the applicant or any other person subject to this 
notice under Sec.  310.6 to file a timely written notice of appearance 
and request for hearing, as required by Sec.  314.200, constitutes an 
election by the person not to make use of 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. Any such 
drug product labeled for the indications referred to in this notice as 
lacking substantial evidence of effectiveness may not thereafter 
lawfully be marketed, and the FDA will initiate appropriate regulatory 
action to remove such drug product from the market. 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

[[Page 20634]]

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 U.S.C. 1905, the 
submissions may be seen in the Division of Dockets Management between 9 
a.m. and 4 p.m., Monday through Friday.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (secs. 502, 505 (21 U.S.C. 352, 355)) and under the authority 
delegated to the Director, Center for Drug Evaluation and Research (21 
CFR 5.100).

    Dated: April 6, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-8658 Filed 4-15-04; 8:45 am]

BILLING CODE 4160-01-S