Exploring Indicators of Hepatotoxicity-Related Post-Marketing Regulatory Actions: A Retrospective Analysis of Drug Approval Data

Abstract

<b><i>Background:</i></b> Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. <b><i>Objective:</i></b> To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Methods:</i></b> Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. <b><i>Predictors (Covariates):</i></b> We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Outcome (Dependent Variable):</i></b> Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. <b><i>Statistical Analysis:</i></b> Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. <b><i>Results:</i></b> A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. <b><i>Conclusion:</i></b> Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.