title: Drug-induced liver injury and drug development: industry perspective.
abstract: Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.
authors.affiliation: Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Arie
authors.initials: A
authors.lastname: Regev
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D054316:Biomarkers, Pharmacological / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology / Q000517:prevention & control; D002986:Clinical Trials as Topic; D003626:Data Display; D003627:Data Interpretation, Statistical; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004345:Drug Industry; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011358:Product Surveillance, Postmarketing; D018570:Risk Assessment; D028761:Withholding Treatment
chemical_list: D054316:Biomarkers, Pharmacological; D004364:Pharmaceutical Preparations; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin