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Draft Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation; Availability

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Food and Drug Administration, HHS.




The Food and Drug Administration (FDA) is announcing the availability of a draft guidance for industry entitled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation.”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.


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on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the agency considers your comment on this draft guidance before it begins work on the final version of the guidance, submit written or electronic comments on the draft guidance by December 24, 2007.


Submit written requests for single copies of the draft guidance to the Division of Drug Information (HFD-240), Center for Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers Lane, Start Printed Page 60682Rockville, 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 The draft guidance may also be obtained from the Center for Biologics Evaluation and Research by mail by calling 1-800-835-4709 or 301-827-1800.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 Submit written comments on the draft guidance to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.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electronic comments to​dockets/​ecomments or See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance document.

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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.

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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​cder/​guidance/​index.htm,​cber/​guidelines.htm, or​ohrms/​dockets/​default.htm.

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Dated: October 19, 2007.

Jeffrey Shuren,

Assistant Commissioner for Policy.

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[FR Doc. E7-21060 Filed 10-24-07; 8:45 am]