[Federal Register: October 25, 2007 (Volume 72, Number 206)]
[Notices]
[Page 60681-60682]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25oc07-85]
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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Draft Guidance for Industry on Drug-Induced Liver Injury: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availability of a draft guidance for industry entitled ``Drug-Induced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this draft guidance before it begins work on the final version of the
guidance, submit written or electronic comments on the draft guidance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ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information (HFD-240), Center for Drug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 The draft
guidance may also be obtained from the Center for Biologics Evaluation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 Submit written comments on the draft guidance to the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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments or http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/guidelines.htm, or http://www.fda.gov/ohrms/dockets/default.htm.
ets/default.htm.
Dated: October 19, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-21060 Filed 10-24-07; 8:45 am]
BILLING CODE 4160-01-S