[Federal Register Volume 68, Number 249 (Tuesday, December 30, 2003)]
[Notices]
[Pages 75262-75263]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-31917]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003D-0549]


Draft Guidance for Industry: Clozapine Tablets: In Vivo 
Bioequivalence and In Vitro Dissolution Testing, Revision; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for industry entitled ``Clozapine 
Tablets: In Vivo Bioequivalence and In Vitro Dissolution Testing.'' 
This draft guidance provides recommendations for sponsors of 
abbreviated new drug applications (ANDAs) on the design of 
bioequivalence studies for generic clozapine products. This draft 
guidance is being issued because an earlier guidance on this topic 
published in November 1996 needed to be revised to

[[Page 75263]]

reflect current agency recommendations. Because of significant 
potential adverse effects, the agency no longer recommends in vivo 
bioequivalence testing in healthy subjects.

DATES: Submit written or electronic comments on the draft guidance by 
March 1, 2004. General comments on agency guidance documents are 
welcome at any time.

ADDRESSES: Submit written requests for single copies of this draft 
guidance to the Division of Drug Information (HFD-240), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857. Send one self-addressed adhesive label to 
assist that office in processing your requests. Submit written comments 
on the draft guidance to the Division of Dockets Management (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. See the SUPPLEMENTARY INFORMATION section for electronic 
access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Lizzie Sanchez, Center for Drug 
Evaluation and Research (HFD-650), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-5847.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Clozapine Tablets In Vivo Bioequivalence and In Vitro 
Dissolution Testing.'' This draft guidance is intended to provide 
information to sponsors of ANDAs on the design of bioequivalence 
studies for generic clozapine products, and revises the recommendations 
provided in a guidance on the same topic published in November 1996.
    In the earlier version of this draft guidance, the agency 
recommended that doses of clozapine tablets be administered to healthy 
subjects in bioequivalence studies for generic clozapine products. The 
earlier guidance also provided the option of conducting studies in the 
appropriate patient population. Because a high number of healthy 
subjects in bioeqivalence studies for clozapine products have 
experienced serious adverse effects such as hypotension, bradycardia, 
syncope, and asystole during clozapine bioequivalence studies, FDA is 
no longer recommending such studies be done in healthy subjects.
    The draft guidance provides recommendations for two approaches to 
study the product in the appropriate patient population. One approach 
is a study design using patients naive to clozapine. This design uses 
the recommended titration of dosing consistent with the reference 
product labeling. The alternative study design uses the appropriate 
patient population already stable on a dose of clozapine. This 
alternative also appeared in the earlier version of the guidance. The 
agency believes that the previously recommended design using healthy 
subjects was adequate to establish bioequivalence of generic clozapine 
products; however, the safety concerns associated with the use of 
clozapine in healthy subjects are significant, and the agency is no 
longer recommending this practice.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance 
represents the agency's current thinking on studies to demonstrate the 
bioequivalence of clozapine tablets. It does not create or confer any 
rights for or on any person and does not operate to bind FDA or the 
public. An alternative approach may be used if such approach satisfies 
the requirements of the applicable statutes or regulations.

II. Comments

    Interested persons may submit written or electronic comments to the 
Division of Dockets Management (see ADDRESSES). Two copies of mailed 
comments are to be submitted, except that individuals may submit one 
copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. The guidance and received 
comments are available for public examination in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/cder/guidance/index.htm, or through the Division of 
Dockets Management website at http://www.fda.gov/ohrmr/dockets/default.htm.

    Dated: December 17, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-31917 Filed 12-29-03; 8:45 am]
BILLING CODE 4160-01-S