A pre-marketing ALT signal predicts post-marketing liver safety

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ≥ 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ≥ 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ≥ 3× ULN in treated versus placebo) was examined. An ALT signal of ≥ 1.2% was significantly associated with a post-marketing liver safety signal (p ≤ 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ≥ 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety.