title: US FDA Perspective on Elbasvir/Grazoprevir Treatment for Patients with Chronic Hepatitis C Virus Genotype 1 or 4 Infection.
abstract: Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. sarita.boyd@fda.hhs.gov.
authors.forename: Sarita D
authors.identifier: http://orcid.org/0000-0002-5859-7722
authors.initials: SD
authors.lastname: Boyd
authors.affiliation: Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: LaRee
authors.initials: L
authors.lastname: Tracy
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Takashi E
authors.initials: TE
authors.lastname: Komatsu
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Harrington
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Prabha
authors.initials: P
authors.lastname: Viswanathan
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Murray
authors.affiliation: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Sherwat
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001572:Benzofurans / Q000008:administration & dosage*; D004338:Drug Combinations; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D011810:Quinoxalines / Q000008:administration & dosage*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D004338:Drug Combinations; D007093:Imidazoles; D011810:Quinoxalines; C000611265:elbasvir-grazoprevir drug combination; D012254:Ribavirin