Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Final, July 2009
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Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation Additional copies are available from: Office of Communications, 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 Tel: 301-796-3400; Fax: 301-847-8714; E-mail: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach, and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 Tel: 800-835-4709 or 301-827-1800 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND: DILI ................................................................................................... 2 III. SIGNALS OF DILI AND HY’S LAW............................................................................ 3 IV. CLINICAL EVALUATION OF DILI ............................................................................ 7 A. General Considerations.................................................................................................................7 1. Patients with Liver Abnormalities or Disease .................................................................................7 2. Detection of DILI .............................................................................................................................8 3. Confirmation....................................................................................................................................8 4. Close Observation............................................................................................................................9 5. Decision to Stop Drug Administration.............................................................................................9 6. Evaluating Data for Alternative Causes ........................................................................................10 7. Follow-Up to Resolution................................................................................................................11 8. Rechallenge....................................................................................................................................12 B. Research Opportunities...............................................................................................................12 C. Case Report Forms ......................................................................................................................13 D. Interpretation of Signals of DILI or Acute Liver Failure ........................................................14 1. Frequency and Magnitude of Liver AT Abnormalities ..................................................................14 2. Combined Elevations of Aminotransferases and Bilirubin............................................................14 E. Analysis of Signals of DILI..........................................................................................................15 1. Assessment of Drug Metabolism....................................................................................................15 2. Assessment of Liver-Related Adverse Events in Controlled Trials................................................15 3. Assessment of Liver-Related Adverse Events in the Entire Clinical Trials Database ...................16 4. Assessment of Hy’s Law Cases in the Clinical Trials Database....................................................16 5. Overall Assessment of a Drug’s Potential to Cause DILI .............................................................17 REFERENCES............................................................................................................................ 19 APPENDIX A: ILLUSTRATIVE EXAMPLES OF DILI..................................................... 23 Contains Nonbinding Recommendations Guidance for Industry1 Drug-Induced Liver Injury: Premarketing Clinical Evaluation This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION This guidance is intended to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug2 to cause severe liver injury (i.e., irreversible liver failure that is fatal or requires liver transplantation). In particular, the guidance addresses how laboratory measurements that signal the potential for such drug- induced liver injury (DILI) can be obtained and evaluated during drug development. This evaluation is important because most drugs that cause severe DILI do so infrequently; typical drug development databases with up to a few thousand subjects exposed to a new drug will not show any cases. Databases may, however, show evidence or signals of a drug’s potential for severe DILI if the clinical and laboratory data are properly evaluated for evidence of lesser injury that may not be severe, but may predict the ability to cause more severe injuries. This guidance describes an approach that can be used to distinguish signals of DILI that identify drugs likely to cause severe liver injury from signals that do not suggest such a potential. This guidance does not address issues of preclinical evaluation for signals of DILI, nor the detection and assessment of DILI after drug approval and marketing. FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are 1 This guidance has been prepared by the Division of Gastroenterology Products in the Office of New Drugs, the Office of Medical Policy, and the Office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA). 2 This guidance uses the term drug or product to refer to all products, except whole blood and blood components, regulated by CDER and CBER, including vaccines, and uses the term approval to refer to both drug approval and biologic licensure. 1 Contains Nonbinding Recommendations cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. II. BACKGROUND: DILI DILI has been the most frequent single cause of safety-related drug marketing withdrawals for the past 50 years (e.g., iproniazid), continuing to the present (e.g., ticrynafen, benoxaprofen, bromfenac, troglitazone, nefazodone). Hepatotoxicity discovered after approval for marketing also has limited the use of many drugs, including isoniazid, labetalol, trovafloxacin, tolcapone, and felbamate (Temple 2001). Several drugs have not been approved in the United States because European marketing experience revealed their hepatotoxicity (e.g., ibufenac, perhexiline, alpidem). Finally, some drugs were not approved in the United States because premarketing experience provided evidence of the potential for severe DILI (e.g., dilevalol, tasosartan, ximelagatran). Although most significant hepatotoxins have caused predominantly hepatocellular injury, indicated by leakage of aminotransferase (AT) enzymes from injured liver cells without prominent evidence of hepatobiliary obstruction or intrahepatic cholestasis, the pattern of injury can vary. Many drugs cause cholestasis, but in general this condition is reversible after administration of the offending drug has stopped. Cholestatic injuries are less likely to lead to death or transplant, although there have been exceptions. Drugs cause liver injuries by many different mechanisms. These injuries resemble almost all known liver diseases and there are no pathognomonic findings, even upon liver biopsy, that make diagnosis of DILI certain. Therefore, when possible DILI is suspected, it is essential to gather additional clinical and laboratory information necessary for differential diagnosis of the cause. It is important to observe the time course of the injury, and to seek alternative causes of the liver injury, such as acute viral hepatitis A, B, or C; concomitant use of a hepatotoxic drug or exposure to hepatotoxins; autoimmune or alcoholic