A pre-marketing ALT signal predicts post-marketing liver safety Cynthia A. Moylan a,b,⇑ , Ayako Suzuki a , Julie I. Papay c , Nancy A. Yuen c , Michael Ames d , Christine M. Hunt c a Division of Gastroenterology and Hepatology, Duke University, Durham, NC 27710, USA b Department of Medicine, Durham Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27710, USA c GlaxoSmithKline, Global Clinical Safety and Pharmacovigilance, 5 Moore Drive, Research Triangle Park, NC 27709, USA d GlaxoSmithKline, Clinical Statistics, 5 Moore Drive, Research Triangle Park, NC 27709, USA article info Article history: Received 29 March 2012 Available online 2 June 2012 Keywords: Drug induced liver injury Alanine aminotransferase Food and Drug Administration New drug application Adverse Event Reporting System Hepatotoxicity abstract Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an ‘‘ALT signal’’. We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hep- atotoxicity. Incidence of ALT elevations (ALT P 3 times upper limits normal [Â ULN]) for drug and pla- cebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 P 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT P 3Â ULN in treated versus placebo) was examined. An ALT signal of P 1.2% was significantly associated with a post-marketing liver safety signal (p 6 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT P 3Â ULN in treated versus placebo groups provides an easily calculated method for pre- dicting post-marketing liver safety. Published by Elsevier Inc. 1. Introduction Drug-induced liver injury is the leading cause of death from acute liver failure in the United States (Ostapowicz et al., 2002). Drug-induced liver injury is also a common adverse drug reaction causing drug withdrawal and failure of new drug approvals by the United States Food and Drug Administration (FDA) (FDA Clinical White Paper; FDA Drug Safety Guidance for Industry). It is there- fore critical to identify sensitive measures that signal the potential for drug-induced liver injury during drug development. Severe hepatocellular drug-induced liver injury which leads to liver failure, death, or need for liver transplantation is typically accompanied by elevations of both transaminases and bilirubin (Bjornsson and Olsson, 2005). This observation was initially de- scribed by Hy Zimmerman and the FDA now uses ‘‘Hy’s Law’’ in the evaluation of investigational drugs with potential hepatotoxic- ity during drug development (Bjornsson, 2010). Hy’s Law is consid- ered to predict serious safety concerns in the post-marketing phase and its validity has been confirmed in several studies. The large Spanish and Swedish Drug-induced Liver Injury Registry datasets reveal that events accompanied by alanine aminotransferase (ALT) P 3 times the upper limit of normal (x ULN) and concomi- tant jaundice were associated with a 9–12% mortality (Andrade et al., 2005; Bjornsson and Olsson, 2005). More recently, similar findings have been reported in the United States (Chalasani et al., 2008). Identification of these rare, severe cases pre-marketing can often be difficult however as very large numbers of treated pa- tients are needed to thoroughly assess risk. Therefore, most clinical trials lack sufficient statistical power to use severe liver injury events for detection of hepatotoxicity (FDA Drug Safety Guidance for Industry; Weil et al., 2008). 0273-2300/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.yrtph.2012.05.016 Abbreviations: DILI, drug induced liver injury; FDA, Food and Drug Administra- tion; AERS, Adverse Event Reporting System; ALT, alanine aminotransferase; ULN, upper limit of normal; NDA, new drug application; EMA, European Medicines Agency; PDR, Physician’s Desk Reference; DPA, disproportionality analysis; Med- DRA, Medical Dictionary for Regulatory Activities; MGPS, Multi-Item Gamma Poisson Shrinker; EBGM, Empiric Bayes Geometric Mean; EB05, Empiric Bayes lower 95% confidence interval limit; EB95, Empiric Bayes upper 95% confidence interval limit; IQR, interquartile range. ⇑ Corresponding author at: Division of Gastroenterology and Hepatology, Duke University Medical Center (DUMC 3256), 595 LaSalle Street, Synderman Building, Room 2035, Durham, NC 27710, USA. Fax: +1 919 684 4183. E-mail address: cynthia.moylan@dm.duke.edu (C.A. Moylan). Regulatory Toxicology and Pharmacology 63 (2012) 433–439 Contents lists available at SciVerse ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph