[Federal Register Volume 70, Number 117 (Monday, June 20, 2005)]
[Notices]
[Pages 35447-35448]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-12039]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003D-0549]


Guidance for Industry on Clozapine Tablets: In Vivo 
Bioequivalence and In Vitro Dissolution Testing; 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 guidance for industry entitled ``Clozapine Tablets: 
In Vivo Bioequivalence and In Vitro Dissolution Testing.'' The guidance 
was originally published in November 1996. However, because of 
potentially significant adverse effects seen in healthy subjects who 
had not previously used clozapine, FDA proposed a revision to the 
guidance in a draft published in December 2003. FDA did not receive 
comments on the draft guidance during the comment period. This final 
version of the 2003 draft guidance includes a change in the recommended 
patient population as well as other minor changes that are based on 
current information available to FDA.

DATES: Submit written or electronic comments on agency guidances at any 
time.

ADDRESSES: Submit written requests for single copies of this 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 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 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 guidance for industry 
entitled ``Clozapine Tablets: In Vivo Bioequivalence and In Vitro 
Dissolution Testing.'' This guidance is being issued because of 
necessary changes to recommendations provided in a previous guidance on 
the same topic that published in November 1996. In the Federal Register 
of December 30, 2003 (68 FR 75262), FDA published a document that 
proposed revisions to the 1996 guidance and that provided information 
to the pharmaceutical industry regarding the design of bioequivalence 
studies for generic clozapine products.
    In the 1996 guidance, FDA recommended that doses of one-half of a 
25 milligram clozapine tablet be administered to healthy subjects in 
bioequivalence studies for generic clozapine products. The guidance 
also provided an option for conducting studies in the appropriate 
patient population. However, in the 2003 draft guidance, FDA proposed 
that such studies not be conducted in healthy subjects because a high 
number of healthy subjects experienced serious adverse effects such as 
hypotension, bradycardia, syncope, and asystole during clozapine 
bioequivalence studies. FDA did not receive comments on the 2003 draft 
guidance during the comment period.
    This final version of the 2003 draft guidance has been further 
revised to provide recommendations describing the use of an appropriate 
patient population that is already stable on a dose of clozapine. The 
use of healthy subjects who had not previously used clozapine is no 
longer recommended in this final version of the guidance, which will 
ensure the safety of subjects in bioequivalence studies on clozapine.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
agency's current thinking on clozapine tablets: in vivo and in vitro 
dissolution testing. It does not create or confer any rights for

[[Page 35448]]

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 and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen 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 
either http://www.fda.gov/cder/guidance/index.htm or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: June 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-12039 Filed 6-17-05; 8:45 am]
BILLING CODE 4160-01-S