Evaluation of SARS-CoV-2 RNA Rebound After Nirmatrelvir/Ritonavir Treatment in Randomized, Double-Blind, Placebo-Controlled Trials - United States and International Sites, 2021-2022.

Rebound of SARS-CoV-2 shedding or COVID-19 signs and symptoms has been described after treatment with nirmatrelvir/ritonavir (Paxlovid). The direct association of nirmatrelvir/ritonavir to COVID-19 rebound remains unclear because most reports are based on individual cases or nonrandomized studies. Viral RNA shedding data from two phase 2/3, randomized, double-blind, placebo-controlled clinical trials of nirmatrelvir/ritonavir (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients [EPIC-HR] and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients [EPIC-SR]) were analyzed to investigate the role of nirmatrelvir/ritonavir treatment in COVID-19 rebound. Rates of rebound of SARS-CoV-2 RNA shedding, identified based on an increase in nasopharyngeal viral RNA levels from day 5 (end-of-treatment) to day 10 or day 14, were similar between nirmatrelvir/ritonavir and placebo recipients. Among subjects with a virologic response through day 5, viral RNA rebound occurred in 6.4%-8.4% of nirmatrelvir/ritonavir recipients and 5.9%-6.5% of placebo recipients across EPIC-HR and the 2021/pre-Omicron and 2022/Omicron enrollment periods of EPIC-SR. Viral RNA rebound after nirmatrelvir/ritonavir treatment was not associated with COVID-19-related hospitalization or death. Data from randomized trials demonstrated that SARS-CoV-2 rebound can occur with or without antiviral treatment, supporting the Food and Drug Administration's determination of safety and efficacy of nirmatrelvir/ritonavir in eligible patients at high risk for severe COVID-19.

Considerations and Challenges in the Remdesivir COVID-19 Pediatric Development Program.

The US Food and Drug Administration is committed to the development of effective antiviral regimens for pediatric patients with coronavirus disease 2019 (COVID-19), including infants and neonates. On April 25, 2022, the approved indication of remdesivir (RDV) was expanded to include pediatric patients 28 days and older and weighing at least 3 kg with positive results of direct severe acute respiratory syndrome coronavirus 2 viral testing, who are: Hospitalized, or Not hospitalized and have mild to moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. Given the similar course of COVID-19 in adults and pediatric patients, the approval of RDV for use in pediatric patients is supported by the safety and efficacy data from adequate and well-controlled phase 3 trials in adults and adolescents; and by the safety and pharmacokinetic data from a single-arm, open-label, phase 2/3 pediatric clinical trial of 53 pediatric patients at least 28 days of age and weighing at least 3 kg with confirmed severe acute respiratory syndrome coronavirus 2 infection and mild, moderate, or severe COVID-19. At the time of the April 25, 2022, approval action, the US Food and Drug Administration also revoked the emergency use authorization for RDV that previously covered this pediatric population. This article summarizes key issues and regulatory considerations involved in the RDV COVID-19 pediatric development program, including the evolution of the emergency use authorization issued for RDV as results from registrational studies became available, and discusses lessons learned.

Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration's Evaluation.

The development and approval of brincidofovir for the treatment of smallpox, a disease that was eradicated from the world over 40 years ago, has resulted in the second antiviral approved via the Medical Countermeasure Initiative (MCMi) to combat this disease. Approval of brincidofovir required a unique regulatory approach based on the FDA Animal Rule, and development was supported by many years of research and collaboration among academic investigators, the pharmaceutical industry and multiple government agencies. This article summarizes the FDA regulatory pathway and describes the challenges involved.

Sustained virological response rates with direct-acting antivirals in black subjects with HCV genotype 1 infection: systematic analysis of clinical trials.

OBJECTIVES: Under representation of black subjects in trials of hepatitis C virus (HCV) direct-acting antivirals (DAAs) complicates assessment of differential outcomes for black individuals vs non-black individuals. HCV trials submitted to the Food and Drug Administration (2013-2017) to support approval or to expand an indication of 12-week interferon-free DAA regimens with or without ribavirin to treat HCV genotype 1 (GT1) infection were pooled to explore efficacy comparisons by ethnicity. METHODS: Twenty-six trials were pooled and included 2869 individuals with HCV GT1 alone and 742 individuals with both HCV GT1 and HIV. RESULTS: Of the 2869 HCV GT1-mono-infected subjects, 408 (14.2%) were black. Sustained virological response assessed 12 weeks following cessation of treatment (SVR12) was 92%-100% in black individuals and 87.5%-100.0% in non-black individuals. In pooled analyses, SVR12 was numerically similar between black and non-black subjects (97.1% vs 97.3%). Baseline characteristics did not affect SVR12 for the two groups. Of the 742 subjects with both HCV GT1 and HIV, 243 (32.7%) were black: SVR12 was 89.5%-100% in black individuals and 94.4%-100% in non-black individuals. In pooled analyses for HCV GT1/HIV co-infection, black individuals had a 4% (95% confidence interval -7.7% to 0.3%) lower SVR12 than non-black individuals (93.4% vs 97.0%). This difference was driven by ION-4 in which study SVR12 was approximately 10% lower for black than for non-black individuals (89.5% vs 99.1%). Baseline characteristics did not affect SVR12 for the two groups. CONCLUSION: No notable SVR12 differences were seen in between black and non-black individuals with HCV GT1 alone. Although a numerical difference was observed between black and non-black individuals with both HCV GT1 and HIV, this finding was driven by results from a single trial and may be due to reasons other than ethnicity: 19 subgroup analyses showed baseline characteristics did not affect SVR12 for black and non-black individuals with both HCV GT1 and HIV.

Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox.

The development and ultimate approval of tecovirimat for the antiviral treatment of smallpox, a disease that has been eradicated from the world for nearly 40 years, required a unique regulatory approach based on the US Food and Drug Administration's Animal Rule. We summarise the regulatory pathway and describe the challenges involved.

Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration's evaluation.

On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) fixed-dose combination (FDC), an interferon-free, complete regimen for adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing a nonstructural protein 5A (NS5A) inhibitor; and • genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Approval was based on an acceptable safety profile and high sustained virological response rates 12 weeks after the end of treatment (SVR12) in two phase 3 clinical trials in subjects previously treated with a direct-acting antiviral (DAA) regimen. In POLARIS-1, 96% of SOF/VEL/VOX-treated subjects achieved SVR12. In POLARIS-4, 98% of SOF/VEL/VOX-treated subjects achieved SVR12. A key and challenging question in evaluating the data was determining the contribution of VOX to SOF/VEL and how this differed depending on the genotype and patient population. In this article, we provide our perspective on the issues considered in making these determinations, especially regarding the POLARIS-4 data in subjects who have previously been treated with a chronic HCV regimen containing sofosbuvir without an NS5A inhibitor. Conclusion: We seek to provide context as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6) while the indication for NS5A inhibitor- naïve patients was limited to HCV genotypes 1a and 3 only. (Hepatology 2018;67:482-491).

Direct-acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: Scientific and regulatory approaches to clinical trial designs.

Therapeutic options for treatment of chronic hepatitis C have improved substantially since the approval of direct-acting antiviral agents (DAAs). Several interferon (IFN)-free or IFN- and ribavirin (RBV)-free treatment regimens with shorter durations and improved efficacy and safety profiles are now available. The U.S. Food and Drug Administration (FDA) used several scientific approaches and regulatory mechanisms, such as (1) use of a "validated" surrogate (sustained virological response) for a primary endpoint, (2) shortening the time point for measuring the surrogate by 12 weeks, (3) use of historical controls when clinically appropriate, and (4) use of modeling when scientifically sound to extend treatment indications to subpopulations not fully evaluated in clinical trials, which had an impact on DAA development and subsequent approvals. This article intends to provide increased transparency about the FDA's scientific approaches and regulatory processes that supported drug development and marketing approval of DAAs for treatment of hepatitis C, a serious, life-threatening infection.

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 FDA's EIND database from May 2011 to June 2014. METHODS: This is a retrospective descriptive review of patient clinical data in the FDA's 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.

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.

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 Administration's 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.

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 Administration's (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.

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.