[Federal Register Volume 72, Number 206 (Thursday, October 25, 2007)]
[Notices]
[Pages 60681-60682]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-21060]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2007D-0396]


Draft Guidance for Industry on Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation; 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availability of a draft guidance for industry entitled ``Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation.'' This guidance is 
intended to assist the pharmaceutical industry and others engaged in 
new drug development in the assessment of the potential of a drug to 
cause severe drug-induced liver injury (DILI). This guidance defines 
severe DILI as injury that is fatal or requires liver transplantation. 
This guidance does not address the postmarketing evaluation of DILI.

DATES:  Although you can comment on any guidance at any time (see 21 
CFR 10.115(g)(5)), to ensure that the agency considers your comment on 
this draft guidance before it begins work on the final version of the 
guidance, submit written or electronic comments on the draft guidance 
by December 24, 2007.

ADDRESSES:  Submit written requests for single copies of the draft 
guidance to the Division of Drug Information (HFD-240), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane,

[[Page 60682]]

Rockville, MD 20857; or the Office of Communication, Training, and 
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and 
Research, 1401 Rockville Pike, Rockville, MD 20852-1448. The draft 
guidance may also be obtained from the Center for Biologics Evaluation 
and Research by mail by calling 1-800-835-4709 or 301-827-1800. 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 Submit written comments on the draft guidance to the 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 or http://www.regulations.gov. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT:
    Tom Moreno, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5143, Silver 
Spring, MD 20993-0002, 301-796-0878; or
    Bruce Schneider, Center for Biologics Evaluation and Research (HFM-
755), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 
20852, 301-827-5102.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for industry 
entitled ``Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation.'' Idiosyncratic hepatotoxicity is an important cause of 
drug withdrawal and has led to considerable FDA attention to the 
subject, beginning with a conference on hepatotoxicity at the National 
Institutes of Health in 1978. The science of detecting and evaluating 
DILI during drug development is evolving, and FDA is working with 
industry, academia, and other government groups toward better 
understanding of the problems and what to do about them.
    Even drugs that prove to be significant hepatotoxins (e.g, 
bromfenac and troglitazone) are unlikely to show cases of severe DILI 
during a drug development program with at most several thousand exposed 
subjects. Therefore, it is critical during drug development to discover 
less severe DILI that may indicate a potential for the drug to cause 
severe DILI. There are a number of signals of liver injury that have 
varying levels of sensitivity and specificity in predicting potential 
for severe DILI. An increased rate of elevated aminotransferase (AT) 
levels compared to control is a highly sensitive indicator of potential 
severe hepatotoxicity, but many drugs that do not cause severe injury 
show AT elevations, so the specificity of this test as a predictor of a 
potential for severe hepatotoxicity is poor. Specificity is increased 
when the signal used is the occurrence of more marked AT elevation (to 
5-, 10-, 20xULN), but the most specific finding to date is an overall 
pattern of AT elevation together with elevated bilirubin (and no 
evidence of bile obstruction) in a small number of subjects.
    This guidance describes the sensitivity and specificity of various 
indicators of hepatotoxic potential, as well as the observations needed 
to evaluate those indicators, including detection, confirmation, and 
monitoring of liver test abnormalities, close evaluation and exclusion 
of other causes, and careful supportive care and followup to normality 
or return to baseline status.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the agency's current thinking on premarketing 
clinical evaluation of drug-induced liver injury. 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 and regulations.

II. The Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). The collections of information in 21 CFR parts 312, 314, and 600 
have been approved under OMB control numbers 0910-0014, 0910-0001, and 
0910-0338, respectively.

III. 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.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/cder/guidance/index.htm, http://www.fda.gov/cber/guidelines.htm, or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: October 19, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-21060 Filed 10-24-07; 8:45 am]
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