[Federal Register: December 30, 2003 (Volume 68, Number 249)]
[Notices]
[Page 75262-75263]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr30de03-83]
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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Draft Guidance for Industry: Clozapine Tablets: In Vivo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availability of a draft guidance for industry entitled ``Clozapine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This draft guidance provides recommendations for sponsors of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 This draft
guidance is being issued because an earlier guidance on this topic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DATES: Submit written or electronic comments on the draft guidance by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ADDRESSES: Submit written requests for single copies of this draft
guidance to the Division of Drug Information (HFD-240), Center for Drug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on the draft guidance to the Division of Dockets Management (HFA-305),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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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access to the draft guidance document.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FDA is announcing the availability of a draft guidance for industry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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm, or through the Division of Dockets Management website at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrmr/dockets/
/dockets/
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