title: Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies.
abstract: OBJECTIVE
  Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development.
  
  
  METHODS
  We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals.
  
  
  RESULTS
  The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection.
  
  
  CONCLUSIONS
  SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA.
authors.forename: Jianmeng
authors.initials: J
authors.lastname: Chen
authors.forename: Jeffry
authors.initials: J
authors.lastname: Florian
authors.forename: Wendy
authors.initials: W
authors.lastname: Carter
authors.forename: Russell D
authors.initials: RD
authors.lastname: Fleischer
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Hammerstrom
authors.forename: Pravin R
authors.initials: PR
authors.lastname: Jadhav
authors.forename: Wen
authors.initials: W
authors.lastname: Zeng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Murray
authors.forename: Debra
authors.initials: D
authors.lastname: Birnkrant
mesh_terms: D000293:Adolescent; D000328:Adult; D000418:Albumins / Q000008:administration & dosage / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D017277:Drug Approval; D023381:Endpoint Determination / Q000379:methods*; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000418:Albumins; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C531108:albinterferon alfa-2b; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a