Composite Plot for Visualizing Aminotransferase and Bilirubin Changes in Clinical Trials of Subjects with Abnormal Baseline Values

Bereket Tesfaldet (), Tejas Patel, Minjun Chen, Frank Pucino, Lilliam Rosario, Paul Hayashi and Eileen Navarro Almario
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Bereket Tesfaldet: U.S. FDA, Center for Food Safety and Nutrition, Office of Analytics and Outreach
Tejas Patel: U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs
Minjun Chen: U.S. FDA, Office of the Chief Scientist, National Center for Toxicology Research, Division of Bioinformatics and Biostatistics
Frank Pucino: U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs
Lilliam Rosario: U.S. FDA, Center for Drug Evaluation and Research, Office of Translational Sciences, Office of Computational Science
Paul Hayashi: U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs
Eileen Navarro Almario: U.S. FDA, Center for Drug Evaluation and Research, Office of New Drugs

Drug Safety, 2024, vol. 47, issue 7, No 8, 699-710

Abstract: Abstract Introduction On-treatment excursions of liver laboratory test values in clinical trials involving subjects with underlying liver disease are relevant for the efficacy and safety assessment of drug products and biologics. Existing visualization and analysis tools do not efficiently provide an integrated view of these excursions when baseline liver tests are abnormal. Objective The aim of this study was to develop a composite plot that enables visualization of on-treatment changes in liver test results both as multiples of the upper limit of normal defined by each laboratory’s reference population (×ULN) and multiples of the subjects’ baseline (×BLN) values. Methods The composite plot approach combines biochemical evaluation for drug-induced severe hepatotoxicity (eDISH) plots sequentially applied to subjects’ baseline and peak on-treatment liver test results normalized by ULN and integrates them into a four-panel shift plot of peak on-treatment values normalized by BLN. Results The composite plot enabled efficient assessment of improvement in liver test values during treatment compared with pretreatment in subjects treated with the investigational drug (or the natural history of placebo-treated subjects) and identified outlier subjects for potential drug-induced liver injury. Conclusion For studies in subjects with abnormal baseline values, the composite plot has potential application in the assessment of beneficial and concerning on-treatment modifications in liver test values in reference to the individual subject’s baseline and population threshold values.

Date: 2024
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DOI: 10.1007/s40264-024-01425-5

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