The FDA, bridging data, and hepatitis C


  • See Articles on Pages 897 and 903.

  • Potential conflicts of interest: Dr. Fried Serves as ad hoc consultant to Genentech/Roche, Vertex, Merck, Gilead, BristolMyers Squibb, Abbott, Janssen. He receives research grants from Genentech/Roche, Vertex, Merck, Janssen, Gilead, BristolMyers Squibb, Rottapharm/Madaus. Dr. Jensen serves as ad hoc consultant to Abbott, Astex, Biotica, Boehringer-Ingelheim, BristolMyers Squibb, Genentech/Roche, Janssen, Gilead, Merck, and Vertex.

The treatment of chronic hepatitis C was transformed more than 1 year ago by the approval of boceprevir and telaprevir. Along with higher rates of sustained virological response, clinicians were confronted with new, and often confusing, treatment guidelines that were recommended to maximize therapeutic response while decreasing exposure to costly and toxic medications.1 Thus, response-guided treatment (RGT) algorithms sought to shorten the duration of therapy among those with the most rapid virological response, optimize efficacy among those with slower response, and discontinue treatment when it was deemed futile. The robust phase III clinical trials of boceprevir and telaprevir, each combined with peginterferon and ribavirin, provided a roadmap for the recommended use of these agents in the treatment-naïve and treatment-experienced populations that paralleled, for the most part, the design and execution of these studies.2-5 However, neither scholars nor soothsayers alike would have accurately predicted the final labeling recommendations that accompanied the approval by the U.S. Food and Drug Administration (FDA).


AIMS, Antiviral Informational Management System; CDER, Center for Drug Evaluation and Research; FDA, U.S. Food and Drug Administration; RGT, response-guided treatment.

The REALIZE trial of telaprevir did not investigate RGT for prior relapsers to peginterferon and ribavirin, although early discontinuation of treatment at week 24 is now recommended for these patients when they achieve an extended rapid virological response.5 Similarly, the RESPOND-2 study specifically excluded prior null responders, yet the product label indicates that these patients may be treated with a 4-week lead-in of peginterferon and ribavirin followed by 44 weeks of triple therapy with boceprevir.4 Finally, in the SPRINT-2 study, slow virological responders received 4 weeks of peginterferon and ribavirin, followed by 24 weeks of triple therapy with boceprevir, and a “tail” of 20 weeks of peginterferon and ribavirin only.4 However, the final treatment algorithm deviated from the phase III study regimen by recommending extending triple therapy with boceprevir to 32 weeks and shortening the peginterferon and ribavirin “tail” to only 12 weeks.6, 7 How were recommendations derived in these three instances when there were no analogous data generated solely from a controlled phase III trial that would fully support these final product insert recommendations (Gasp!)?

The answers can be found in this issue of HEPATOLOGY that contains two important articles authored by scientists at the FDA Center for Drug Evaluation and Research (CDER) that provide key insights into the rationale for these recommendations for boceprevir and telaprevir. The first article describes the justification for RGT in prior relapsers to peginterferon and ribavirin undergoing retreatment with a telaprevir triple therapy regimen.8 The second article informs us about the rationale for the labeling of boceprevir triple therapy for the treatment of prior null responders to peginterferon and ribavirin and also for the recommendations for treatment-naïve patients who exhibit a slow virological response during treatment with the boceprevir regimen.9

The multidimensional role of the FDA as “regulatory scientists” is often overlooked. Clinicians and clinical investigators may inaccurately view the FDA in one dimension only, as a regulatory agency that provides boundaries for pharmaceutical companies about how drugs should be utilized and enforces sanctions when these bounds are exceeded. As described on the CDER website,10 “FDA scientists conduct laboratory, clinical and statistical research to proactively address knowledge gaps created by advances in drug development and healthcare technologies.… Known as regulatory science, this research utilizes cutting-edge analytical tools and techniques to answer questions that apply directly to the evaluation of product safety, efficacy and quality.… Their findings are presented to the scientific community through peer-reviewed manuscripts and at professional meetings.”

FDA scientists developed the Antiviral Informational Management System (AIMS), a powerful relational database within which was deposited standardized data generated during the clinical development of hepatitis C antiviral drugs with the goal of providing extensive quantitative data to improve consistency and better inform study design and dose selection for clinical trials.11 The logic and elegant analyses encompassing CDER regulatory science and AIMS are evident in the current articles that synthesize (or “bridge”) data from multiple datasets provided to them by pharmaceutical sponsors (Merck and Vertex, in this case), made several assumptions, weighed risks and benefits, and then developed modified treatment algorithms that do not completely mirror those regimens studied in phase III trials.6, 7 These analyses have far-ranging implications for patients, clinicians, and for clinical investigators.

In many ways, patients and clinicians can be highly confident that current treatment recommendations, even those that deviate from empiric clinical trial data, optimize therapeutic response. However, can we ever be certain that the FDA analyses are correct in the absence of prospective clinical trial results? Some data are beginning to emerge that the FDA predictions are accurate; recent preliminary results from the PROVIDE study suggest that prior null responders will respond to boceprevir as predicted.12 It is also likely that prior relapsers treated with telaprevir will not be disadvantaged by a shorter duration of treatment in light of their vigorous interferon-responsiveness. It will remain murky, however, whether extending boceprevir triple therapy in slow virological responders is useful until long-term observational studies are positioned to provide confirmation.

These publications also fulfill the mission of CDER and promote transparency of the vast amount of data generated from the drug development programs of sponsors seeking approval for their products. However, one perspective of clinical investigators deserves mention. Clinical investigators play a critical role in the design and execution of clinical trials, in collaboration with industry sponsors. The datasets generated from these studies have been frequently utilized in investigator-initiated secondary analyses that continually advance the management of various diseases. As examples, the extensive mining of these rich datasets that occurred since the approvals of peginterferon alpha-2b (2001) and peginterferon alpha-2a (2002) have improved management strategies and have generated many important collaborative studies. Patients benefited from refinements to care while clinical investigators were recognized for their ongoing contributions in the form of published manuscript. Thus, publication of multiple secondary analyses by the FDA, an agency with federally mandated and unparalleled access to the most comprehensive datasets, could diminish this significant role of clinical investigators.

Indeed, the editors of HEPATOLOGY engaged in a discussion on how to navigate this novel territory during the peer-review of these articles. The quality and significance of the articles was never in question, but should they be classified as original articles or as data-driven editorials? How would clinical investigators be acknowledged? The prominence of these articles in HEPATOLOGY reflects the final editorial recommendations and the high regard for these articles, although subsequent publications should be considered on a case-by-case basis. An online appendix listing all investigators in the relevant studies was inserted at the request of the journal editors.

Future initiatives would benefit from the collaboration between CDER regulatory scientists and the clinical investigators involved in the primary trials who can contribute their clinical expertise to the design and analyses of important secondary clinical questions. Ideally, a mechanism can be developed that would permit the collaboration of qualified clinical investigators and CDER scientists to explore the vast AIMS database, while protecting the sensitive, proprietary nature of certain data elements for the pharmaceutical sponsors. The unprecedented pace of new drug development for hepatitis C will provide many opportunities for collaborations between regulatory scientists and clinical investigators with the mutual overarching goal of improving the outcomes for patients with this disease.