Generally, drugs in clinical development have a slim chance of approval.
Between 2006 and 2015, less than 10 percent of drugs in clinical development received marketing authorization, according to Frontiers in Pharmacology. But even when drugs advance, there's always the risk that they'll lose approval in the post-marketing phase. When that happens, it's often due to hepatotoxicity.
Researchers say this highlights the shortcomings of existing disease modeling in preclinical studies, where preclinical animal models, such as rats, often don't accurately predict human liver risk or liability.
"The correlation between animal tests and human clinical outcomes is 50 to 60 percent," said Feng Li, Ph.D., a development associate at Corning Life Sciences. "It's maybe slightly better than flipping a coin, which is not great for predicting liver liability for any new drug candidate. It's a very well-acknowledged problem by pharmaceutical companies and regulatory agencies."
Drug-induced liver injury remains a leading cause of drug attrition, post-marketing withdrawal and warning label and has led to tragic consequences. Consider Fialuridine: The Hepatitis B drug passed preclinical animal studies in the early 1990s and showed no evidence of drug-induced liver injury — until it reached human trials, Li says.
In one trial, as chronicled by a review in the National Academies Press, seven patients in a National Institutes of Health trial developed severe liver toxicity. Five died, and two more survived only after liver transplants.
Fialuridine isn't the only drug to be withdrawn. Troglitazone and TAK-875, both investigational treatments for Type 2 diabetes, similarly failed in human trials.*