title: Background incidence of liver chemistry abnormalities in a clinical trial population without underlying liver disease.
abstract: BACKGROUND
  The FDA has recently proposed pre-marketing liver chemistry subject stopping criteria. The study was undertaken to determine the background rates of liver chemistry abnormalities in clinical trial populations without underlying liver disease.
  
  
  METHODS
  Data from 28 Phase II-IV trials in diseases with normal risk of underlying liver abnormalities were included. Information on 18,672 subjects, mean age of 44.3 years and 92.3% female was available. Prevalence and incidence of abnormal liver chemistries were calculated.
  
  
  RESULTS
  At baseline, the overall prevalence of alanine aminotransferase (ALT) elevations of 3 x ULN (upper limit of normal) and 5 x ULN was 0.08% and 0.01%, respectively. The prevalence of liver chemistry abnormalities was similar at study entry and exit. Overall, elevated liver chemistry incidence rates per 10,000 person months were 6.5 (95% CI 4.8; 8.5) for ALT 3 x ULN, 2.6 (1.6; 4.0) for ALT 5 x ULN, 0.3 (0.03; 0.9) for ALT 8 x ULN, 0.09 (0.04; 0.2) for alkaline phosphatase (ALP) 2 x ULN, and 0 for combined ALT+bilirubin elevation.
  
  
  CONCLUSIONS
  Elevations of ALT (3 x ULN) and ALP (2 x ULN) are rare in clinical trial populations without underlying liver disease and can be considered a safety signal. No events of ALT 3 x ULN with concomitant bilirubin 1.5 x ULN were noted. These analyses create a liver chemistry evidence base in normal risk clinical trial populations.
authors.affiliation: WW Epidemiology, Neurosciences and International Support, GlaxoSmithKline Research & Development Ltd., New Frontiers Science Park, South Third Avenue, Harlow, Essex CM19 5AW, UK. John.G.Weil@gsk.com
authors.forename: John G
authors.initials: JG
authors.lastname: Weil
authors.forename: Chanchal
authors.initials: C
authors.lastname: Bains
authors.forename: Adam
authors.initials: A
authors.lastname: Linke
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Clark
authors.forename: Heide A
authors.initials: HA
authors.lastname: Stirnadel
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hunt
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D017327:Clinical Trials, Phase IV as Topic; D005260:Female; D006801:Humans; D015994:Incidence; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000453:epidemiology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015995:Prevalence
chemical_list: D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin