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).

Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?

OBJECTIVES: Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue. DESIGN/METHODS: DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV-RIF interaction were also explored. RESULTS: In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype. CONCLUSION: Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF.

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.

Are literature references sufficient for dose recommendations? An FDA case study of efavirenz and rifampin.

One of the numerous regulatory functions of the Food and Drug Administration (FDA) is the evaluation of drug-drug interactions and the determination of appropriate dose adjustments, if necessary, to ensure the safe and effective use of medications. The FDA considers several data sources when determining the significance of drug-drug interactions. The majority of dose adjustment recommendations are based on specific drug-drug interactions studies. The FDA reviews individual patient pharmacokinetic and safety data from drug interaction studies, determines appropriate dose adjustments, and provides recommendations to update the respective product labeling. Sometimes literature references are submitted to the FDA to support dosing recommendations. Determining an appropriate dose adjustment recommendation based on literature reports is a challenge for the FDA due to the lack of individual patient pharmacokinetic or safety data from these studies. Recently, the FDA encountered a challenging regulatory situation when evaluating literature reports to determine the appropriate dose of efavirenz and rifampin. Although numerous studies were found in the literature about this combination, a dosing recommendation cannot be concluded from the reported data. This article reviews the process the FDA used to evaluate literature to support potential dose adjustments for efavirenz when coadministered with rifampin and the challenges encountered during the process.

Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration's Adverse Event Reporting System.

The risk of nephrolithiasis associated with atazanavir is not well characterized. The US Food and Drug Administration's Adverse Event Reporting System was searched for reports of nephrolithiasis in HIV-infected patients taking an atazanavir-based regimen. Thirty cases were identified. Many patients required hospitalization for management, including lithotripsy, ureteral stent insertion, or endoscopic stone removal. Some cases of nephrolithiasis resulted in atazanavir discontinuation. Healthcare professionals and patients should be informed that nephrolithiasis is a possible adverse event with atazanavir.

How Often Are Drugs Made Available Under the Food and Drug Administration's Expanded Access Process Approved?

In this review of individual patient expanded-access requests to the Center for Drug Evaluation and Research for the period Fiscal Year 2010 to Fiscal Year 2014, we evaluated the number of applications received and the number allowed to proceed. We also evaluated whether drugs and certain biologics obtained under expanded access went on to be approved by the Food and Drug Administration. Finally, we considered concerns that adverse events occurring during expanded access might place sponsors at risk for legal liability. Overall, 98% of individual patient expanded-access requests were allowed to proceed. During the study period, among drugs without a previous approval for any indication or dosage form, 24% of unique drugs (ie, multiple applications for access to the same drug were considered to relate to 1 unique drug), and 20% of expanded-access applications received marketing approval by 1 year after initial submission; 43% and 33%, respectively, were approved by 5 years after initial submission. A search of 3 legal databases and a database of news articles did not appear to identify any product liability cases arising from the use of a product in expanded access. Our analyses seek to give physicians and patients a realistic perspective on the likelihood of a drug's approval as well as certain information regarding the product liability risks for commercial sponsors when providing expanded access to investigational drugs. The US Food and Drug Administration (FDA)'s expanded-access program maintains a careful balance between authorizing patient access to potentially beneficial drugs and protecting them from drugs that may have unknown risks. At the same time, the agency wishes to maintain the integrity of the clinical trials process, ultimately the best way to get safe and effective drugs to patients.

Acute renal failure and nephrotic range proteinuria due to amyloidosis in an HIV-infected patient.

Amyloidosis is an uncommon cause of renal disease in HIV-positive patients. Diagnosis is challenging, treatment options are limited, and prognosis remains poor. We discuss an HIV-positive patient with acute renal failure and nephrotic range proteinuria. The differential diagnosis included nephropathy due to trimethoprim/sulfamethoxazole, tenofovir, HIV, hepatitis C, heroin, or multifactorial causes. Serum and urine study findings were inconclusive. Rapid clinical deterioration ensued and a renal biopsy was performed. Pathologic examination revealed eosinophilic, amorphous material in the glomerular tufts that stained red-orange with Congo red stain. Immunohistochemical analysis confirmed amyloid A (AA) amyloidosis. AA amyloidosis occurs as a complication of chronic infection or chronic inflammatory disease. It has been reported in intravenous or subcutaneous drug abusers, some of whom were HIV-positive. This case underscores the importance of tissue diagnosis to determine the cause of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, viral load, and degree of proteinuria, may not predict the pathological diagnosis in HIV-positive patients.

Immune reconstitution inflammatory syndrome presenting as sinusitis with inflammatory pseudotumor in an HIV-infected patient: a case report and review of the literature.

Immune reconstitution inflammatory syndrome (IRIS) encompasses a variety of conditions that occur among HIV-infected patients in a temporal relationship with increases in CD4 cell count as a result of highly active antiretroviral therapy (HAART). Most conditions associated with IRIS are infectious. Malignancies, such as Kaposi's sarcoma, have also been reported. We report a case of sinusitis with presumptive inflammatory pseudotumor as a manifestation of IRIS that occurred 20 weeks after the initiation of HAART.

Successful treatment with atazanavir and lopinavir/ritonavir combination therapy in protease inhibitor-susceptible and protease inhibitor-resistant HIV-infected patients.

The combination of atazanavir (ATV) plus lopinavir/ritonavir (LPV/r) has been used in practice. However, clinical data supporting its use are limited. The objective of this study was to evaluate the efficacy and tolerability of regimens with ATV + LPV/r in protease inhibitor (PI)-susceptible and PI-resistant patients. A retrospective review of 2703 charts was performed to identify all patients who received ATV + LPV/r. From June 2003 to January 2005, 33 patients received ATV + LPV/r with nucleoside reverse transcriptase inhibitors (NRTIs) for 3 months or more. Virologic success (HIV-RNA < 400 copies per milliliter) was achieved in 30 patients (91%) in a median of 10 weeks (range, 2-68). Nineteen of the 23 patients (83%) who had ultrasensitive viral load (VL) assays were nondetectable. Among patients with 6 or more protease resistance (PR) mutations (PI-resistant), 11 of 14 (79%) achieved virologic success. Eleven of those received phenotypic testing (10 Virtual Phenotype, VircoLab, Baltimore, MD). Despite predicted phenotypic resistance to ATV (6 patients) and LPV/r (7 patients), virologic success was achieved in 4 of 6 (67%) and 4 of 7 (57%), respectively. The 3 PI-resistant patients who were virologic failures had extensive prior LPV/r use, 8-11 PR mutations, and predicted phenotypic resistance to LPV/r, but 2 of 3 had CD4 increases with ATV + LPV/r. Overall, 28 patients (85%) continue to tolerate ATV + LPV/r for a median of 32 weeks follow-up (range, 12-76). Combination ATV + LPV/r with NRTIs appears safe, tolerable, and efficacious in PI-resistant patients (>/=6 PR mutations) and predicted phenotypic resistance to ATV and LPV/r. Further studies of ATV + LPV/r in HIV-treatment are warranted.

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.