Scientific Publications by FDA Staff

Gastroenterology 2013 Jun;144(7):1450-5.e2

Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies.

Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, Zeng W, Murray J, Birnkrant D

BACKGROUND & AIMS: 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 endpoint. However, there is increasing evidence that most patients who have a 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, and 3 pediatric studies, from 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 endpoint for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.