[Federal Register Volume 74, Number 145 (Thursday, July 30, 2009)]
[Notices]
[Pages 38035-38036]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-18135]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-D-0128] (formerly Docket No. 2007D-0396)


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 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) during the conduct of 
premarketing trials. This guidance defines severe DILI as injury that 
is fatal or requires liver transplantation.

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, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, rm. 2201, Silver Spring, MD 20993-0002; or the Office of 
Communication, Outreach and Development (HFM-40), Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, suite 200N, Rockville, MD 
20852-1448. The 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 
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.regulations.gov. See the 
SUPPLEMENTARY INFORMATION section for electronic access to the guidance 
document.

FOR FURTHER INFORMATION CONTACT:
    Hee Shelia Lianos, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 5329, 
Silver Spring, MD 20993-0002, 301-796-4147; or
    Steve Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852, 310-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation.'' Severe DILI has been an important cause of drug marketing 
withdrawal. This has led FDA to pay particular attention to how the 
risk of severe DILI can be predicted before a drug is approved. 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 how best to do this.
    Even for drugs that prove to be significant hepatotoxins in some 
patients (e.g., bromfenac, troglitazone, and ximelagatran), it is 
unlikely that cases of severe DILI will be identified during a drug 
development program with only a few thousand exposed subjects. 
Therefore, it is critical to discover signals of a drug's potential to 
cause such injury during drug development by detection of lesser 
degrees of liver injury that may be more frequently seen. There are a 
number of such signals that have varying levels of sensitivity and 
specificity in predicting the potential for severe DILI. However, the 
most specific finding to date is a finding of cases of serum 
aminotransferase elevation together with elevated bilirubin 
concentration (and no evidence of biliary obstruction or impaired 
ability to conjugate bilirubin) in some trial subjects (i.e., Hy's Law 
cases).

[[Page 38036]]

    The 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 follow-up to normality 
or return to baseline status. The guidance makes specific 
recommendations about the use of Hy's Law and interpretation of Hy's 
Law cases that are identified during clinical development and suggests 
research opportunities to learn more about what makes certain people 
more susceptible to DILI than are most persons exposed to the drug.
    The guidance was issued in draft form in October 2007 for public 
comments. We received a total of 12 comments submitted to Docket No. 
2007D-0396. FDA organized a public meeting in March 2008 for discussion 
of issues raised by the draft guidance and reopened the public comment 
period from March 6, 2008, to June 30, 2008, with Docket No. FDA-2008-
D-0128 (formerly Docket No. 2007D-0396). One comment was submitted to 
Docket No. FDA-2008-D-0128. The comments are available at http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm071471.htm. 
Presentations, discussion, and materials from the March 2008 public 
meeting also are available at the above Web site.
    FDA considered written and verbal comments submitted to the dockets 
and at the public meeting before finalizing the guidance. The guidance 
reflects clarifying and editorial changes made in response to comments 
and at our own initiative.
    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 the premarketing evaluation of a drug's 
potential for causing severe DILI. 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 601 
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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/cber/guidelines.htm, or 
http://www.regulations.gov.

    Dated: July 22, 2009.
Jeffrey Shuren,
Associate Comissioner for Policy and Planning.
[FR Doc. E9-18135 Filed 7-29-09; 8:45 am]
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