title: Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran.
abstract: Ximelagatran was denied marketing approval in the USA and was withdrawn from those markets in which it had been approved, because of concerns over potential liver toxicity. A retrospective analysis of phase 2 data relating to liver toxicity is performed using the methods of extreme value modelling. The analysis reveals that the phase 2 data were predictive of the phase 3 results and, had the methods been available at the time, such analysis would have provided valuable information relating to the decision to proceed with further development of the compound.
authors.affiliation: Data Clarity Consulting Limited, Bridgewater House, Caspian Road, Atlantic Street, Altrincham, U.K.
authors.forename: Harry
authors.initials: H
authors.lastname: Southworth
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D000925:Anticoagulants / Q000009:adverse effects*; D001384:Azetidines / Q000009:adverse effects*; D001596:Benzylamines / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D017322:Clinical Trials, Phase II as Topic / Q000592:standards*; D006801:Humans; D015233:Models, Statistical; D011237:Predictive Value of Tests; D012189:Retrospective Studies
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C426686:ximelagatran; D000410:Alanine Transaminase
keywords: drug safety; extreme value modelling; generalized Pareto distribution; liver toxicity