A Proposed Modification to Hy's Law and Edish Criteria: Using Aggregated Historical Data of Oncology Clinical Trials/ Generally Healthy Patients' Data

• Activity Number: 547
• Type: Contributed
• Date/Time: Wednesday, August 7, 2013 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Daniel Parks*+ and Xiwu Lin and Kwan Lee
• Companies: GlaxoSmithKline and GSK and GSK
• Keywords: Truncated Robust Outlier Detection ; Hy's Law ; modified eDISH

Abstract

Identifying drug induced liver injury is a critical task in drug development and post-approval real world care. Severe liver injury is identified by the liver chemistry threshold of ALT > 3x upper limit of normal (ULN) and bilirubin > 2xULN, termed "Hy's Law" by the FDA. These thresholds require discontinuation of the causative drug. However since maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. A truncated robust multivariate outlier detection (TRMOD) method uses to develop the decision boundary or threshold for examining liver injury in oncology clinical trials with 31 aggregated oncology clinical trials data. The boundary of TRMOD identified outliers with an ALT limit 5.0xULN and total bilirubin limit 2.7xULN. These higher liver chemistry thresholds examining fold-ULN data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and post-approval settings while helping to avoid premature discontinuation of curative therapy.