4 This is unlike treatment with directly targeting antivirals, such as those for HCV or HIV, where treatment failure is often associated with drug resistance that can affect responsiveness to subsequent courses of treatment. Other examples where bridging analyses have impacted regulatory decision making include oxcarbazepine, topiramate, clevidipine,

and levofloxacin, to name a few.5-8 Bridging knowledge to provide clinical evidence of effectiveness and to support dosing recommendations not only is acceptable from a regulatory perspective, but when scientifically supported and warranted it is also encouraged to increase the efficiency by which new drugs and optimal dosing recommendations are made available to patients in need.9 This report summarizes the rationale to support the BOC dosing recommendations in prior P/R-null responders and treatment-naïve BOC late responders.10 BOC, boceprevir; FDA, U.S. Food selleck inhibitor and Drug Administration; HCV, hepatitis C virus; P/R, peginterferon alpha and ribavirin; RGT, response-guided therapy; SVR, sustained virologic response. The SPRINT-II and RESPOND-II

trial designs are illustrated find more in Fig. 1. The primary endpoint for both SPRINT-II and RESPOND-II was the proportion of subjects with SVR (sustained virologic response), defined as HCV RNA undetected at 24 weeks after the last dose of the study drug. Both trials had three treatment arms: (1) P/R for 48 weeks (Arm 1, P/R); (2) a response-guided therapy (RGT) arm with P/R lead-in for 4 weeks, followed by P/R with BOC for 24 weeks in SPRINT-II and 32 weeks in RESPOND-II (Arm 2, BOC-RGT); Racecadotril and (3) P/R lead-in for 4 weeks, followed by BOC with P/R for 44 weeks (BOC44) (Arm 3, BOC44). In SPRINT-II subjects randomized to the RGT arm who had HCV RNA undetected at weeks 8 through week 24 stopped all treatment

at week 28 and were classified as BOC treatment-naïve early responders. The remaining subjects in the RGT arm, who had HCV RNA detected at treatment week 8 or any subsequent week, but who had HCV RNA undetected at week 24, stopped BOC at week 28 but received P/R through week 48. These subjects are referred to as BOC treatment-naïve late responders. In the RGT arm of RESPOND-II treatment-experienced early responders (subjects with HCV RNA undetected at weeks 8 through 12) stopped all treatment at week 36, whereas treatment-experienced late responders (HCV RNA detected at week 8 but HCV RNA undetected at week 12) stopped BOC at week 36 but continued P/R through week 48. Although prior P/R null responders were excluded from RESPOND-II, the sponsor proposed that data from treatment-naïve subjects could be used to estimate the treatment effect in prior null responders because included among treatment-naïve subjects are a subset of subjects who are intrinsically poor responders to interferon.