Eight key topics that may benefit from review, clarification, research, and discussion between industry, academia, and regulators as the FDA works to address DILI risk assessment are highlighted.
Abstract
Drug induced liver injury (DILI) continues to be a significant challenge in drug development. Just one or two cases of severe hepatotoxicity in a clinical trial can be enough to raise drug approvability concerns. Though great strides were made in DILI risk assessment and mitigation in clinical trials during the early 2000s, drugs continue to fail in development due to DILI, while severe cases still occur in late phase clinical trials and post-market. Also, changes in drug development will challenge the US Food and Drug Administration's (FDA) current paradigms for DILI risk assessment. Such changes include the rise in biologic agents which may cause hepatotoxicity distinctly different from small molecule drugs, the increasing reliance on smaller underpowered clinical trials for rare diseases, and the growing interest in drugs for acute and chronic liver diseases. We highlight eight key topics that may benefit from review, clarification, research, and discussion between industry, academia, and regulators as the FDA works to address these issues.
INTRODUCTION
Drug-Induced Liver Injury (DILI) is a leading cause of drug attrition, postmarketing withdrawals, and acute liver failure. It presents a major barrier to the safe development of new therapeutics, particularly due to its unpredictable pathogenesis and the lack of reliable preclinical models. Current diagnos...
Ashok Thulluru, Vrushabh Patil, C. Jangme et al.· Mini-Reviews in Medical Chem...· 0 citations
Hepatotoxicity is the most frequent reason for post-marketing withdrawal of medicines, yet in clinical practice drug-induced liver injury (DILI) remains a diagnosis of exclusion with no confirmatory biomarker. In the Prospective European DILI Registry, antibacterials (40%) and antineoplastic/immunomodulating agents (27...
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Ghulam Hassam U. Din Tarrar, Syed Shafaat Hussain, M. Sarfraz et al.· Prague Medical Report· 0 citations
The expansion of self-medication, broad over-the-counter drug availability, seasonal surges in symptomatic medication use, and polypharmacy have made drug-induced liver injury and systemic adverse drug reactions a problem of both clinical medicine and medicinal chemistry. The aim of this re-view is to propose a digital...
V. Kutsenko, I. Ushal, E. Papina et al.· Problems of Biological Medic...· 0 citations
Teratogenicity and hyperuricemia are considered as the major adverse effects of favipiravir, but less is known about other possible side effects which includes drug-induced liver damage and renal injury. In the current research, assessment of favipiravir-induced liver injury was performed by evaluating liver enzymes am...
Ahmed Hamza Al-shammari, Mohammed Abd Ali Shahadha· Journal of population therap...· 5 citations· ⚡1
The recent conditional US Food and Drug Administration (FDA) approval of two therapies, resmetirom (Rezdiffra) and semaglutide (Wegovy), marks the first time clinicians have pharmacological therapy for metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2-F3) without cirrhosis, a disease...
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