Direct‐acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: Scientific and regulatory approaches to clinical trial designs

Abstract

Therapeutic options for treatment of chronic hepatitis C have improved substantially since the approval of direct-acting antiviral agents (DAAs). Several interferon (IFN)-free or IFNand ribavirin (RBV)-free treatment regimens with shorter durations and improved efficacy and safety profiles are now available. The U.S. Food and Drug Administration (FDA) used several scientific approaches and regulatory mechanisms, such as (1) use of a "validated" surrogate (sustained virological response) for a primary endpoint, (2) shortening the time point for measuring the surrogate by 12 weeks, (3) use of historical controls when clinically appropriate, and (4) use of modeling when scientifically sound to extend treatment indications to subpopulations not fully evaluated in clinical trials, which had an impact on DAA development and subsequent approvals. This article intends to provide increased transparency about the FDA's scientific approaches and regulatory processes that supported drug development and marketing approval of DAAs for treatment of hepatitis C, a serious, life-threatening infection. (HEPATOLOGY 2015;62:1298-1303

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1‐infected patients without cirrhosis: OPTIMIST‐1, a phase 3, randomized study

“…In OPTIMIST‐1, SVR12 rates were compared against a composite historical control calculated based on the highest SVR12 rates obtained with approved DAA‐based regimens available at the time of study design (all with pegIFN/RBV). This approach is well established and in accordance with Food and Drug Administration guidance …”

Simeprevir in combination with sofosbuvir in treatment‐naïve and ‐experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open‐label, single‐arm study (PLUTO)

“…In addition, the patient population was predominantly Caucasian and therefore the results need to be confirmed in the HCV genotype 4‐infected populations in many countries. The open‐label nature of the study and the lack of a comparator arm could formally be viewed as potential limitations; however, the US Food and Drug Administration draft guidance, and guidance from the European Medicines Agency, include historical‐controlled trials as one of the accepted Phase 3 study designs …”

CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C

“…Hepatitis C virus (HCV) infection carries a risk of progression to liver cirrhosis or hepatocellular carcinoma (HCC), which is a poor prognostic factor for patients with chronic hepatitis C (CHC) . Recently, direct‐acting antiviral agents (DAAs) have become standard treatments for HCV, and DAA therapy produces a sustained virological response (SVR) in 90% to 95% of patients . Although DAA therapy has improved the SVR rate, investigation of immunoregulatory mechanisms in patients with CHC is required to develop new therapies that can achieve complete eradication of HCV.…”