Debra Birnkrant

The Emergency Use Authorization of Peramivir for Treatment of 2009 H1N1 Influenza

On October 23 the FDA issued an Emergency Use Authorization for peramivir for the treatment of suspected or confirmed cases of 2009 H1N1 influenza. Drs. Debra Birnkrant and Edward Cox discuss the limited data on safety and efficacy and the criteria for emergency use of peramivir.

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.

Emergency Use Authorization for Intravenous Peramivir: Evaluation of Safety in the Treatment of Hospitalized Patients Infected with 2009 H1N1 Influenza A Virus

BACKGROUND On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information.

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

Response-guided telaprevir therapy in prior relapsers? The role of bridging data from treatment-naïve and experienced subjects.

The purpose of this report is to illustrate the US Food and Drug Administrations rationale for approving response‐guided therapy (RGT) for telaprevir (TVR) in combination with pegylated interferon‐α and ribavirin (P/R) for the treatment of adults with genotype 1 chronic hepatitis C who were prior relapsers. RGT was prospectively evaluated in two registration trials of treatment‐naïve subjects. In these studies, RGT allowed subjects who achieved undetectable hepatitis C virus RNA from weeks 4 and 12, known as extended rapid virologic response (eRVR), to stop all treatments at 24 weeks. A patient without eRVR received an additional 36 weeks of P/R after 12 weeks of a TVR triple regimen (total of 48 weeks). However, RGT in prior P/R relapsers was not prospectively evaluated. Empirical cross‐trial data indicated high sustained virologic response rates (>90%) in prior relapsers achieving eRVR, irrespective of P/R duration (24 or 48 weeks). Further analyses demonstrated that interferon responsiveness does not change in P/R‐experienced subjects with a second round of P/R. The comparability in interferon responsiveness across treatment courses allowed us to bridge data between treatment‐naïve and P/R‐experienced subjects to support the approval of RGT in prior relapse subjects. (HEPATOLOGY 2013)

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.

Clinical experience with intravenous zanamivir under an Emergency IND program in the United States (2011-2014).

BACKGROUND Since the emergence of 2009 H1N1 virus, intravenous (IV) zanamivir has been authorized as an investigational treatment for patients with serious and life-threatening influenza through an Emergency Investigational New Drug application (EIND). This review encompasses the FDAs EIND database from May 2011 to June 2014. METHODS This is a retrospective descriptive review of patient clinical data in the FDAs IV zanamivir EIND database from May 2011 to June 2014. RESULTS Of 364 IV zanamivir EIND requests, most (83%) patients were aged 18-64 years, 8 (2%) were pregnant, and 29 (8%) were children. 234 (64%) patients had ≥1 comorbidity reported. The majority (87%) were receiving oseltamivir when IV zanamivir was requested, and 33% had suspected (n=120; no improvement or worsening on oseltamivir) H275Y oseltamivir resistance. Influenza A was reported for 300 patients: confirmed 2009 H1N1 (n=163), suspected 2009 H1N1 (n=8), confirmed H3N2 (n=4) and not subtyped (n=125). Influenza B was reported for 25 patients. Many patients (87%) required invasive mechanical ventilation, 23 (6%) received high frequency oscillatory ventilation, and 74 (20%) received extracorporeal membrane oxygenation (ECMO). 289 (79%) patients had ≥1 complication such as renal failure (n=124; 77/124 required dialysis), bacteraemia (n=18), shock (n=95) or pneumonia (n=159). Of 134 (37%) patients with available outcome data, 83 died and 51 survived. CONCLUSIONS IV zanamivir EIND authorizations were for treatment of critically ill adult patients with 2009 H1N1, including a substantial number with suspected oseltamivir resistance. Data from prospective, randomized controlled trials are needed and are ongoing to assess the safety and efficacy of IV zanamivir for treatment of hospitalized patients with severe influenza.

Use of Viral Load as a Surrogate Marker in Clinical Studies of Cytomegalovirus in Solid Organ Transplantation: A Systematic Review and Meta-analysis

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

CDC and FDA response to risk of confusion in dosing Tamiflu oral suspension.

To the Editor: On September 23, Parker et al.1 described a case in which Tamiflu (oseltamivir) for oral suspension was dispensed with pharmacy instructions to administer the drug in volume units (t...