Document Headings

                    Document headings vary by document type but may contain                    the following:                  
                -                       the agency or agencies that issued and signed a document                    
                -                       the number of the CFR title and the number of each part                      the document amends, proposes to amend, or is directly                      related to                    
                -                       the agency docket number / agency internal file number                    
                -                       the RIN which identifies each regulatory action listed in                      the Unified Agenda of Federal Regulatory and Deregulatory                      Actions                    

                    See the                                          Document Drafting Handbook                                        for more details.                  

###### Department of Health and Human Services

###### Food and Drug Administration

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

# AGENCY:

Food and Drug Administration, HHS.

# ACTION:

Notice.

# 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).                          ( print 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]

BILLING CODE 4160-01-S