Building bridges and providing transparency to the hepatitis C virus drug approval process.

hronic hepatitis C is a major Ccause of cirrhosis and hepatocellular carcinoma worldwide and the leading indication for adult liver transplants in the United States and Europe. Although the incidence of chronic hepatitis C is declining in the developed world, the number of deaths owing to complications of the infection is estimated to increase over the next decade. A parallel rise in the cost of managing complications of advanced chronic hepatitis C is projected to increase from a current $6.5 billion to approximately $9.1 billion in 2024 in the United States. Modeling data suggest that implementation of a national screening program linked to effective therapy would have a substantial impact on reducing the burden of disease resulting from chronic hepatitis C. The development of highly effective, safe therapies for chronic hepatitis C holds promise to improve the outcomes of patients with chronic hepatitis C. In December 2013, a potentially game-changing drug, sofosbuvir, a hepatitis C virus NS5B polymerase nucleotide analog inhibitor, was approved by the US Food and Drug Administration (FDA). This drug was afforded breakthrough status (defined as a drug that treats a serious or lifethreatening condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies) by the FDA, which allowed it to receive an expedited review. In seeking approval, the sponsor submitted evidence from 13 phase I, 6 phase II, and 5 phase III trials to support licensing of sofosbuvir in combination with other agents in adults with HCV genotypes 1–6. Notably, only a single-arm, uncontrolled trial was provided as evidence of the drug’s safety and efficacy among untreated patients with HCV genotype 1 in combination with peginterferon alpha and ribavirin. For drug approval, the FDA generally requires 2 studies to show clear evidence of drug effectiveness. In addition, concerns were raised during the review process about the lack of evidence supporting the indication for sofosbuvir with peginterferon and ribavirin in HCV genotype 1 treatment-experienced patients. Ultimately, sofosbuvir was granted approval for both untreated and previously treated populations. In this issue of Gastroenterology, the FDA provides a commentary with a detailed summary of the rationale supporting their recommendation to approve the use of sofosbuvir in combination with peginterferon and ribavirin in a population that previously failed therapy in the absence of clinical data. The FDA cited 3 pieces of evidence that supported the use of sofosbuvir in treatment-experienced patients. First, the FDA reasoned that the high sustained virologic response (SVR) rate (89%) achieved by treatment-naïve HCV genotype 1 subjects enrolled in the NEUTRINO trial suggested that the regimen would be effective in nonresponders because peginterferon and ribavirin are associatedwith a failure rate of approximately 50% in untreated HCV genotype 1 patients. Second, having verified that a combination of pretreatment host and viral factors (interleukin [IL]-28B nonCC genotype, high viral load [>800,000 IU/mL] and presence of F3/F4 fibrosis) derived from analyses of previously published studies could be used to identify untreated patients who would likely fail a peginterferon and ribavirin regimen, it was hypothesized that patients with these baseline characteristics enrolled in NEUTRINO would be representative of the SVR rate of nonresponders to peginterferon and ribavirin. The SVR rate among patients with these pretreatment characteristics (presumed nonresponders) in the NEUTRINO trial was shown to be substantially higher, 71% compared with the observed rate of 5% and 20% in null and partial responders, respectively, retreated with peginterferon and ribavirin. Third, the SVR rates were extrapolated for prior null responders to peginterferon and ribavirin based on an assumption of equivalent odds ratios and relative risk between sofosbuvir plus peginterferon and ribavirin and previous HCV regimens. Taken together, these analyses, which “bridge” data from varying sources, provided evidence that sofosbuvir in combination with peginterferon and ribavirin would have, at a minimum, similar effectiveness as other approved regimens. Although persuasive, this method raises several issues. Should modeling data be used to inform the approval process and how confident can clinicians be of treating patients with a regimen that has not been formally tested in the intended population? With regard to the first question, the FDA’s perspective on this can be summarized briefly: “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 is also encouraged to increase the efficiency by which new drugs and optimal dosing recommendations are made available to patients in need.” There is also a precedent for this with other drugs such as oxcarbazepine and topiramate being approved for the treatment of partial seizures in a pediatric population without a controlled clinical trial and levofloxacin for the treatment of postexposure inhalation anthrax. Indeed, between 2000 and 2008, pharmacometric analyses influenced drug approval and labeling decisions for >60% of submissions to the FDA. For the second question, clinicians can take assurance that response rate predictions generated from bridging analyses with boceprevir and telaprevir in untested populations closely approximated the eventual clinical data. For example, in the boceprevir