Jeffrey Murray

Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies

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 end point. However, there is increasing evidence that most patients who have an 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, 3 pediatric studies, and 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 end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.

Meta-Analysis of Gender Differences in Efficacy Outcomes for HIV-Positive Subjects in Randomized Controlled Clinical Trials of Antiretroviral Therapy (2000–2008)

Women are often underrepresented in randomized clinical trials (RCT) of HIV-1 drugs. As a result, determining whether women have different virologic outcomes compared to men is not always possible because the gender-related analyses usually lack statistical power. To address this important public health concern, the Food and Drug Administrations (FDA) Division of Antiviral Products (DAVP) created a database including 20,328 HIV-positive subjects from 40 RCTs in 18 New Drug Applications (NDAs) submitted to the FDA between 2000 and 2008. These RCTs were conducted for at least 48 weeks in duration and were used to support approval of new molecular entity, new formulation, or major label change. To delineate potential gender differences in antiretroviral treatment (ART), we evaluated the percentage of subjects with HIV RNA less than 50 copies per milliliter at 48 weeks. Analyses of the database represent the most systematic review of gender-related ART efficacy data to date. Overall, the meta-analyses did not demonstrate statistically or clinically significant gender differences in virologic outcome at week 48. However, the corresponding subgroup analyses appear to show several statistically significant gender differences favoring males.

Statistical issues for HIV surrogate endpoints: point/counterpoint

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

Development of novel agents for the treatment of chronic hepatitis C infection: Summary of the FDA Antiviral Products Advisory Committee recommendations

Hepatitis C virus (HCV) infection has emerged as a major contributor to morbidity and mortality in the United States and abroad. In the United States, liver disease is the 12th leading cause of death among all age groups, and increases to the fifth leading cause of mortality among those in the 35to 54-year-old age group.1 HCV alone or with alcohol abuse accounts for approximately two-thirds of identified liver disease in surveillance cohorts.2 HCV is a small positive-strand RNA virus in the Flaviviridae family. Its RNA genome is nearly 10,000 nucleotides long and codes for capsid and envelope proteins, as well as functional nonstructural proteins involved with its replication strategy. Potential drug targets include the internal ribosomal entry site, the serine protease, a helicase, and an RNA-dependent RNA polymerase. Other targets include agents that might interfere with cellular binding, entry, uncoating, formation of replication complexes, assembly and maturation, or viral release.3 The HCV virus is thought to replicate primarily in hepatocytes within the liver, though up to 4% of replication may occur in extrahepatic sites including lymphocytes.4 Extremely high levels of replication on the order of 1010-1012 virions/day lead to frequent mutations and genomic drift.5,6 Codominant genomic forms within an individual patient are referred to as quasispecies. Genotypes represent significant shifts in the master sequence of the virus, which developed in unique geographic areas. Both forms of mutation are highly relevant to new drug development, because binding site targeting may be genotype specific and emergence of site polymorphisms may lead to viral escape.7 Chronic HCV infection leads to development of liver fibrosis in many but not all patients. Variable rates of fibrotic progression are described, and may be influenced by gender, age, and comorbidities including HIV coinfection, alcohol use, and presence of fatty liver (steatosis).8 Advanced fibrosis or cirrhosis leads to physiologic changes associated with development of hepatic decompensation manifested by ascites, encephalopathy, variceal bleeding, and coagulopathy. Predictive modeling suggests that without effective treatment interventions, the U.S. population will experience significant increases in HCV-associated liver morbidity, mortality, and health care costs.9,10 Current treatment of HCV is based upon administration of pegylated interferon (PEG-IFN) with ribavirin.11-13 Genotype-specific durations of therapy lead to treatment cycles of 24 to 48 weeks of continuous drug administration. The primary treatment outcome is sustained viral response (SVR), which is defined as HCV viral undetectability using a sensitive polymerase chain reaction–based assay 24 weeks following completion of therapy. This response is thought to be highly durable, and may result in improvement in liver fibrosis over time. There is also evidence from retrospective data that SVR reduces the risk of developing hepatocellular carcinoma and overall liver-related mortality.14 Response rates in highly selected subjects are 40%-45% for genotype 1 HCV and greater than 70% for genotypes 2 and 3. However, PEG-IFN and ribavirin are associated with a poorly tolerated adverse event profile, which limits treatment in many patients.15 Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; MELD, model for end-stage liver disease; PEG-IFN, pegylated interferon; SOC, standard of care; SVR, sustained viral response. From the 1University of Cincinnati College of Medicine, Cincinnati, OH; and the 2Division of Antiviral Products, US Food and Drug Administration, Silver Spring, MD. Received May 9, 2007; accepted August 14, 2007 The opinions expressed in this article are those of the authors and do not necessarily reflect those of the US Food and Drug Administration. As such, no official support for or endorsement of this article by the US FDA is intended or should be inferred. Address reprint requests to: Kenneth E. Sherman, M.D., Ph.D., Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595. E-mail: kenneth.sherman@uc.edu; fax: 513-558-1744. Copyright

Boceprevir dosing for late responders and null responders: The role of bridging data between treatment‐naïve and ‐experienced subjects

O n May 13th, 2011 the U.S. Food and Drug Administration (FDA) approved boceprevir (BOC) for use in combination with peginterferon alpha and ribavirin (P/R) for the treatment of genotype 1 chronic hepatitis C virus (HCV) in adults who are either P/R treatment-naı̈ve or -experienced. BOC is an HCV NS3/4A protease inhibitor and represents a new class of small molecules that directly targets HCV replication. The pivotal Phase III trials supporting BOC approval were SPRINT-II, which included treatment-naı̈ve subjects, and RESPOND-II, which included subjects who were prior P/R relapsers (HCV RNA-negative at end of treatment with P/R but rebound of HCV RNA off treatment) or partial responders ( 2 log10 decline in HCV RNA and HCV RNA detected at week 12 but never achieving HCV RNA undetected). Two key questions that the FDA needed to consider for BOC labeling recommendations included: (1) Is there evidence of effectiveness for prior P/R null responders (defined as <2 log10 decline from baseline in HCV-RNA after 12 weeks of P/R treatment), a subgroup that was specifically excluded from RESPONDII? (2) What is an appropriate dosing regimen for a subset of treatment-naı̈ve subjects who are late responders (as defined below)? To address these questions, analyses were performed by bridging knowledge from the sponsor’s two registrational trials, which ultimately supported certain dosing recommendations that were not prospectively evaluated during Phase 3 registrational trials. These bridging analyses are based on the concept that a patient’s virologic response to P/R remains relatively unchanged with subsequent treatment courses. 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. 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. This report summarizes the rationale to support the BOC dosing recommendations in prior P/R-null responders and treatment-naı̈ve BOC late responders.

Interferon Responsiveness Does Not Change in Treatment-Experienced Hepatitis C Subjects: Implications for Drug Development and Clinical Decisions

BACKGROUND The purpose of this research was to compare interferon (IFN) responsiveness in treatment-naive and pegylated interferon α-ribavirin (P/R)-experienced subjects and to understand the implications of comparability in IFN responsiveness across treatment courses on drug development and clinical decision making. METHODS Data from 3750 subjects treated with P/R in 8 trials were reviewed. The change in hepatitis C virus (HCV) RNA at week 4 in response to P/R was compared according to end-of-study (EOS) status (responder, relapser, partial and null responder) for treatment-naive subjects and the previous P/R response status (known as prior relapsers, prior partial responders, and prior null responders at the baseline) for P/R-experienced subjects. RESULTS In subjects receiving a first course of P/R treatment (treatment-naive subjects), HCV RNA change after 4 weeks of P/R was correlated with EOS status on a P/R regimen. Importantly, for the first time, we have quantitatively demonstrated that IFN responsiveness in P/R-experienced subjects administered a second course of P/R treatment was similar to the IFN responsiveness in the treatment-naive subjects with corresponding EOS status. CONCLUSIONS We contend that P/R-experienced subjects are represented within treatment-naive subjects. There are 2 important implications of this finding: (1) from a drug development perspective, a successful direct antiviral plus P/R therapy (IFN-based triple therapy) trial in P/R-experienced subjects may serve as supportive evidence in treatment-naive subjects; and (2) from a clinical decision perspective, previous P/R exposure should not alter new treatment decisions involving IFN-based triple therapy, as the IFN responsiveness to a second course of IFN is comparable.

FDA bridging analyses confirmed in clinical trial

1. Jung SW, Park NH, Shin JW, Park BR, Kim CJ, Lee JE, et al. Prognostic impact of telomere maintenance gene polymorphisms in hepatocellular carcinoma patients with chronic hepatitis B. HEPATOLOGY 2014;59: 1912-1920. 2. Bell PA, Chaturvedi S, Gelfand CA, Huang CY, Kochersberger N, Kopla R, Modica F, et al. SNPstreamVR UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques 2002;32(Suppl):S70-S77.

NIAID Workshop, Memphis, Tennessee, 25-26 March 1997: Statistical issues for HIV surrogate endpoints: Point/counterpoint

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.

NIAID Workshop, Memphis, Tennessee, 25-26 March 1997

This paper summarizes the proceedings of an NIAID-sponsored workshop on statistical issues for HIV surrogate endpoints. The workshop brought together statisticians and clinicians in an attempt to shed light on some unresolved issues in the use of HIV laboratory markers (such as HIV RNA and CD4+ cell counts) in the design and analysis of clinical studies and in patient management. Utilizing a debate format, the workshop explored a series of specific questions dealing with the relationship between markers and clinical endpoints, and the choice of endpoints and methods of analysis in clinical studies. This paper provides the position statements from the two debaters on each issue. Consensus conclusions, based on the presentations and discussion, are outlined. While not providing final answers, we hope that these discussions have helped clarify a number of issues, and will stimulate further consideration of some of the highlighted problems. These issues will be critical in the proper assessment and use of future therapies for HIV disease.