title: Value of preapproval safety data in predicting postapproval hepatic safety and assessing the legitimacy of class warning.
abstract: OBJECTIVE
  The objective of this study was to systematically evaluate whether preapproval safety data for nonhepatotoxic drugs and hepatotoxic drugs can be compared to improve preapproval prediction of postapproval hepatic safety and to assess the legitimacy of applying class warnings.
  
  
  METHODS
  Drugs within a therapeutic class that included at least one drug that had been withdrawn from the market because of liver toxicity or had a warning of potential liver toxicity issued by major regulatory agencies, and at least one drug free from such regulatory action, were identified and divided into two groups: drugs with and drugs without regulatory action. Preapproval clinical data [including the elevation rates of alanine aminotransferse (ALT) and withdrawal due to liver toxicity, the number of patients with combined elevation of ALT and bilirubin, and liver failure] and nonclinical data (including chemical structures, metabolic pathways, and other significant findings in animal studies) were compared between the two groups.
  
  
  RESULTS
  Six drug classes were assessed in this study: thiazolidinediones, cyclooxygenase-2 inhibitors, fluoroquinolones, catechol-O-methyltransferase (COMT) inhibitors, leukotriene receptor inhibitors, and endothelin receptor antagonists. In two classes (COMT inhibitors and endothelin receptor antagonists), drugs with regulatory action had significantly higher rates of ALT elevation of more than threefold and greater numbers of patients with combined elevation of ALT and bilirubin than drugs without regulatory action. Drugs with regulatory action also had chemical structures or metabolic pathways associated with the toxicity. The legitimacy of class warnings was refuted in all six classes of drugs.
  
  
  CONCLUSIONS
  Preapproval safety data may help predict postapproval hepatic safety and can be used to assess the legitimacy of applying class warnings.
authors.forename: Yeong-Liang
authors.initials: YL
authors.lastname: Lin
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Wu
authors.forename: Churn-Shiouh
authors.initials: CS
authors.lastname: Gau
authors.forename: Min-Shung
authors.initials: MS
authors.lastname: Lin
keywords: class; liver toxicity; postapproval; preapproval; prediction
references.citation: J Antimicrob Chemother. 1994 Apr;33(4):685-706
references.pmid: 8056688
references.citation: Adverse Drug React Toxicol Rev. 1999 Nov;18(4):181-233
references.pmid: 10687025
references.citation: Med Clin North Am. 2000 Nov;84(6):1447-69
references.pmid: 11155852
references.citation: J Pharmacol Exp Ther. 2007 Jun;321(3):1170-8
references.pmid: 17374746
references.citation: CMAJ. 2004 May 25;170(11):1668
references.pmid: 15159361
references.citation: Eur J Pharmacol. 1997 Dec 11;340(2-3):287-94
references.pmid: 9537825
references.citation: Can J Physiol Pharmacol. 2010 Jun;88(6):682-91
references.pmid: 20628435
references.citation: World J Gastroenterol. 2010 Dec 7;16(45):5651-61
references.pmid: 21128314
references.citation: Med Clin North Am. 2000 Sep;84(5):1275-311, x
references.pmid: 11026929
references.citation: Chem Res Toxicol. 2005 Sep;18(9):1427-37
references.pmid: 16167835
references.citation: Lancet. 1998 Sep 19;352(9132):958
references.pmid: 9752821
references.citation: Infect Dis Clin North Am. 2000 Jun;14(2):489-513, xi
references.pmid: 10829268
references.citation: J Clin Epidemiol. 1997 Jun;50(6):683-91
references.pmid: 9250266
references.citation: Gastroenterology. 2005 Aug;129(2):512-21
references.pmid: 16083708
references.citation: Clin Liver Dis. 2003 May;7(2):369-79, vi
references.pmid: 12879989
references.citation: Chem Res Toxicol. 2003 Feb;16(2):123-8
references.pmid: 12588182
references.citation: Drug Metab Dispos. 2000 Oct;28(10):1192-7
references.pmid: 10997939
references.citation: Chest. 2002 Jun;121(6):1860-8
references.pmid: 12065350
references.citation: Hepatology. 2005 Aug;42(2):481-9
references.pmid: 16025496
references.citation: J Am Coll Cardiol. 2006 May 16;47(10):2049-56
references.pmid: 16697324
references.citation: Chem Res Toxicol. 2008 Mar;21(3):711-9
references.pmid: 18298092
references.citation: Neurology. 2004 Jan 13;62(1 Suppl 1):S39-46
references.pmid: 14718679
references.citation: J Pharmacol Exp Ther. 2006 Sep;318(3):1068-75
references.pmid: 16720753
references.citation: Nat Genet. 2009 Jul;41(7):816-9
references.pmid: 19483685