Monitoring liver safety in drug development: the GSK experience.
To promptly identify and evaluate liver safety events, an evidence-based liver safety system was created for global Phase I-III clinical trials. The goals of this system included improving clinical trial subject safety, expanding information on liver safety events, and improving data quality across studies by establishing and communicating: Two different algorithms for liver stopping criteria were developed. The most stringent criteria were selected for healthy volunteers in Phase I studies, where no treatment benefit is anticipated and clinical safety data are limited. With an interest in assessing potential liver "tolerance" or adaptation with accruing safety information, slightly higher liver chemistry thresholds were set for Phase II-III studies. This paper will describe the importance of liver safety in drug development, laboratory tests used to monitor liver safety, the rationale for selected liver chemistry subject stopping criteria, and implementation of this safety system.
Hunt
Christine M
CM
GlaxoSmithKline Research and Development, RTP, Durham, NC 27709, USA. cmh28616@gsk.com
Papay
Julie I
JI
Edwards
Rita I
RI
Theodore
Dickens
D
Alpers
David H
DH
Dollery
Colin
C
Debruin
Tjerk W
TW
Adkison
Kimberly K
KK
Stirnadel
Heide A
HA
Gibbs
Trevor G
TG
D000465:Algorithms; D056486:Chemical and Drug Induced Liver Injury; D002986:Clinical Trials as Topic; D016903:Drug Monitoring / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D023381:Endpoint Determination; D019317:Evidence-Based Medicine; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008111:Liver Function Tests; D028761:Withholding Treatment