The US Food and Drug Administration (FDA) on Monday finalized draft guidance on developing direct-acting antiviral (DAA) drugs to treat Hepatitis C after revising the guidance twice.
The guidance addresses nonclinical development, early clinical development and Phase 3 protocol designs, including trial design options, choice of noninferiority margins for active-controlled Phase 3 trials in the evaluation of interferon (IFN)- free regimens, and trial design options and safety evaluations for specific populations, including patients with decompensated cirrhosis, patients either pre- or post-liver transplant and patients with chronic kidney disease and clinical virology considerations.
The 40-page guidance was previously revised in draft form in May 2016 and in October 2013. According to FDA’s Federal Register notice on Monday, changes made between the draft and final versions include:
- The modification of several sections to focus on IFN-free DAA regimens. Additional clarification on trial designs for combinations of investigational DAAs with or without ribavirin.
- Additional clarification on the recommended trial population to include patients with clinical or laboratory evidence of chronic hepatitis C disease, such as the presence of fibrosis by biopsy or noninvasive tests.
- Additional details on DAA drug development in patients with decompensated cirrhosis, including recommendations for a review by an independent adjudication committee for all serious hepatic events, deaths, liver transplantations, and changes in prespecified alanine transaminase, aspartate transaminase, and bilirubin parameters and a recommendation for long-term followup to characterize clinical outcomes such as progression or regression of liver disease, liver-related mortality, occurrence of hepatocellular carcinoma, or liver failure requiring liver transplantation.
- Additional clarification on efficacy endpoints, specifically additional post-treatment followup (e.g., 1 year or longer) may be needed if one or more drugs in the regimen has a long plasma or intracellular half-life or prolonged antiviral activity.