FDA bridging analyses confirmed in clinical trial
Authors: Poonam Mishra, Jeffry Florian, Jeffrey Murray
Journal: Hepatology (2014)

We read with great interest the editorial “The FDA, Bridging Data, and Hepatitis C” and appreciate your thoughtful comments about the multidimensional role of the FDA as “regulatory scientists.”1 Although you mentioned some emerging preliminary data from the PROVIDE study suggesting that prior null responders will respond to boceprevir as predicted by the FDA, we would like to note the confirmatory clinical trial data which have become available since the editorial. As noted in our previous article, we were faced with an immense challenge in assessing the effectiveness for boceprevir in prior peginterferon and ribavirin (PR) null responders (defined as <2 log10 decline from baseline in HCV-RNA after 12 weeks of PR treatment), a subgroup that was specifically excluded from boceprevir trials submitted in the initial marketing application.2 To address this, bridging analyses were conducted based on the concept that a patient's virologic response to PR remains relatively unchanged with subsequent treatment courses.2 These analyses predicted a sustained virologic response (SVR) rate of 28-30% in treatment-naïve patients with <0.5 log10 hepatitis C virus (HCV) RNA decline at week 4 (poorly interferon responsive). Based on these analyses, the Food and Drug Administration (FDA) recommended the use of boceprevir in combination with PR for all patients who have failed previous PR therapy.2 However, to ensure that the FDA recommendations were scientifically sound, the data from the PROVIDE study postmarketing provided additional information. Subsequently, data from PROVIDE, a single-arm study of boceprevir in combination with PR in subjects with chronic hepatitis C genotype 1 infection who did not achieve SVR while in the PR control arms of previous Phase 2 and 3 studies of combination therapy with boceprevir, became available.3 Among the subjects who were prior null responders and received the 4-week PR lead-in treatment followed by boceprevir + PR therapy for 44 weeks, 38% (20/52) achieved SVR.3 These results led to labeling revisions to expand the indication to include prior null responders.4 Similar efficacy results (38% SVR) based on intent-to-treat analysis were also noted in a recent publication by Vierling et al.5 It is evident that the results from the clinical trial are similar to the predicted rates based on FDA bridging analyses performed during the review. This confirmation based on clinical data supports the role of bridging analyses in regulatory decision making. In this case, interferon responsiveness in treatment-naïve and prior PR-nonresponders supported that boceprevir would be effective in null responders. The FDA used this approach to facilitate the timely access of the product to patients in need of the treatment while awaiting confirmatory data. Postmarketing studies can be an effective means of confirming observations in subgroups that may have been underrepresented or excluded in the registrational trials while not delaying access to more efficacious treatments to those with an unmet medical need. Poonam Mishra, M.D.1 Jeffry Florian, Ph.D.2 Jeffrey Murray, M.D., MPH1 1Division of Antiviral Products US Food and Drug Administration Silver Spring, MD 2Division of Pharmacometrics US Food and Drug Administration Silver Spring, MD