title: Validation of multivariate outlier detection analyses used to identify potential drug-induced liver injury in clinical trial populations.
abstract: BACKGROUND
  Potential severe liver injury is identified in clinical trials by ALT >3 × upper limits of normal (ULN) and total bilirubin >2 × ULN, and termed 'Hy's Law' by the US FDA. However, there is limited evidence or validation of these thresholds in clinical trial populations. Using liver chemistry data from clinical trials, decision boundaries were built empirically with truncated robust multivariate outlier detection (TRMOD), in a statistically robust manner, and then compared with these fixed thresholds. Additionally, as the analysis of liver chemistry change from baseline has been recently suggested for the identification of liver signals, fold-baseline data was also assessed.
  
  
  OBJECTIVE
  The aim of the study was to examine and validate the performance of fixed and empirically derived thresholds for severe liver injury in generally healthy clinical trial populations (i.e. populations without underlying renal, haematological or liver disease).
  
  
  METHODS
  Using phase II-IV clinical trial data, ALT and total bilirubin data were analysed using outlier detection methods to compare with empirically derived and fixed thresholds of the FDA's Hy's Law limits, which were then assessed graphically with the FDA's evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) assessing fold-ULN, as well as a modified eDISH (mDISH) to assess fold-baseline liver chemistries. Data from 28 phase II-IV clinical trials conducted by GlaxoSmithKline were aggregated and analysed by the TRMOD algorithm to create decision boundaries. The data consisted of 18 672 predominantly female subjects with a mean age of 44 years and without known liver disease.
  
  
  RESULTS
  Among generally healthy clinical trial subjects, the empirically-derived TRMOD boundaries were approximately equivalent to 'Hy's Law'. TRMOD boundaries for identifying outliers were an ALT limit of 3.4 × ULN and a bilirubin limit of 2.1 × ULN, compared with the FDA's 'Hy's Law' of 3 × ULN and bilirubin 2 × ULN. Inter-laboratory data variations were observed across the 28 studies, and were diminished by use of baseline-corrected data. By applying TRMOD to baseline-corrected data, these boundaries became ALT limit of 3.8 × baseline and bilirubin limit of 4.8 × baseline. Cumulative incidence plots of liver signals identified over time were examined. TRMOD analyses identified normative boundaries and outliers that provide comparative data to detect liver signals in similar trial populations.
  
  
  CONCLUSIONS
  TRMOD liver chemistry analyses of clinical trial data in generally healthy subjects have confirmed the FDA's Hy's Law threshold as a robust means of detecting liver safety outliers. TRMOD evaluation of liver chemistry data, by both fold-ULN and fold-baseline, provides complementary analyses and valuable normative data for comparison in similar patient populations. No liver signal is present when new clinical trial data from similar patient populations lies within these normative boundaries. Use of baseline-corrected data diminishes inter-laboratory variation and may be more sensitive to possible drug effects. We suggest examining liver chemistries using graphical depictions of both ULN-corrected data (eDISH) and baseline-corrected data (mDISH), as complementary methods.
authors.affiliation: Medical Analytics, GlaxoSmithKline, Collegeville, PA 19426, USA. xiwu.2.lin@gsk.com
authors.forename: Xiwu
authors.initials: X
authors.lastname: Lin
authors.forename: Daniel
authors.initials: D
authors.lastname: Parks
authors.forename: Jeffery
authors.initials: J
authors.lastname: Painter
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hunt
authors.forename: Heide A
authors.initials: HA
authors.lastname: Stirnadel-Farrant
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Alan
authors.initials: A
authors.lastname: Menius
authors.forename: Kwan
authors.initials: K
authors.lastname: Lee
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D017327:Clinical Trials, Phase IV as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D015999:Multivariate Analysis
chemical_list: D000410:Alanine Transaminase; D001663:Bilirubin