B Amzal

An Indirect Comparison of Everolimus Versus Axitinib in US Patients With Advanced Renal Cell Carcinoma in Whom Prior Sunitinib Therapy Failed

PURPOSE The purpose of this study was to perform a weight-adjusted indirect comparison to approximate the relative efficacy of everolimus versus axitinib among patients with second-line metastatic renal cell carcinoma in whom sunitinib therapy previously failed. METHODS Individual patient data from the RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) Phase III clinical trial provided information for patients taking everolimus. Summary baseline clinical and demographic characteristics and progression-free survival (PFS) outcomes were available for patients taking axitinib who were included in the AXIS (axitinib versus sorafenib) Phase III clinical trial. A Bayesian latent class mixture model differentiating responders and nonresponders and with imbedded Weibull regression on PFS was used to identify sex, Memorial Sloan-Kettering Cancer Center risk score, and time receiving prior sunitinib therapy as prognostic factors for PFS based on posterior probability >95%. Patients taking everolimus were weighted up or down based on their combination of prognostic variables. Weights were calculated by dividing the proportion of patients observed in AXIS for a given characteristic by the proportion observed in RECORD-1 and taking the product of the values derived for all three weighting variables considered. Weighted PFS distributions were derived with bootstrapped 95% CIs and compared with those reported for the AXIS trial. FINDINGS After weighting, distributions of the 3 key baseline characteristics were more closely aligned between the 2 studies; however, some differences remained. A slightly lower rate of poor-risk patients was evident in RECORD-1 (30%) versus AXIS (36%), and a 9% lower proportion of males was observed in the everolimus group compared with the axitinib group. Distributions of time receiving prior sunitinib therapy were almost equivalent between the treatment arms. A median PFS of 4.7 months (95% CI, 3.5-10.6 months) was observed for patients in the weighted everolimus group compared with 4.8 months (95% CI, 4.5-6.4 months) in the AXIS trial. IMPLICATIONS Similar median PFS point estimates and overlapping CIs suggest that everolimus and axitinib have similar efficacy. Although these results do not negate the need for direct comparison, this study may be used to inform clinical and reimbursement decisions until such evidence is available.

Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib and best supportive care: A network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma

Background Relative effect of therapies indicated for the treatment of advanced renal cell carcinoma (aRCC) after failure of first line treatment is currently not known. The objective of the present study is to evaluate progression-free survival (PFS) and overall survival (OS) of cabozantinib compared to everolimus, nivolumab, axitinib, sorafenib, and best supportive care (BSC) in aRCC patients who progressed after previous VEGFR tyrosine-kinase inhibitor (TKI) treatment. Methodology & findings Systematic literature search identified 5 studies for inclusion in this analysis. The assessment of the proportional hazard (PH) assumption between the survival curves for different treatment arms in the identified studies showed that survival curves in two of the studies did not fulfil the PH assumption, making comparisons of constant hazard ratios (HRs) inappropriate. Consequently, a parametric survival network meta-analysis model was implemented with five families of functions being jointly fitted in a Bayesian framework to PFS, then OS, data on all treatments. The comparison relied on data digitized from the Kaplan-Meier curves of published studies, except for cabozantinib and its comparator everolimus where patient level data were available. This analysis applied a Bayesian fixed-effects network meta-analysis model to compare PFS and OS of cabozantinib versus its comparators. The log-normal fixed-effects model displayed the best fit of data for both PFS and OS, and showed that patients on cabozantinib had a higher probability of longer PFS and OS than patients exposed to comparators. The survival advantage of cabozantinib increased over time for OS. For PFS the survival advantage reached its maximum at the end of the first year’s treatment and then decreased over time to zero. Conclusion With all five families of distributions, cabozantinib was superior to all its comparators with a higher probability of longer PFS and OS during the analyzed 3 years, except with the Gompertz model, where nivolumab was preferred after 24 months.

Pragmatic Multicriteria Decision Analysis (MCDA) Combined With Advanced Pharmacoepidemiology for Benefit-Risk Assessments of Medicines Adapted to the Real-Life Constraints of Regulators Development and Case Study

Background: Multicriteria decision analysis (MCDA) represents a promising method for benefit-risk assessment. Our goal was to develop features of pragmatic MCDA (EVIDEM [Evidence and Value: Impact on DEcisionMaking]) addressing real-life regulatory decision-making needs, incorporate advanced pharmacoepidemiology, and test the resulting benefit-risk framework using a case study. Methods: The Intervention Outcomes domain of EVIDEM was transformed into a generic benefit-risk framework including clinical efficacy, patient-reported outcomes, and adverse event (AE) criteria. The concept of relative benefit-risk balance (RBRB) was developed for comparability across products and therapeutic areas and over time. Evidence matrix was designed to include most relevant data from trials, observational studies, and models, including Bayesian and longitudinal modeling. The framework was tested with a panel of stakeholders using efalizumab for psoriasis as retrospective case study. Uncertainty was explored. Results: The MCDA benefit-risk tree was adapted with psoriasis-specific subcriteria. Panelists assigned similar weights to benefits (0.48; SD, 0.20-0.70) and risks (0.52; SD, 0.10-0.60), with large variations reflecting diverse perspectives. Panelist scores reflected higher efficacy versus placebo, lower efficacy versus active comparators, and serious and fatal AEs identified postlicensing. Efalizumab’s RBRB was positive at licensing in 2004 (0.29, scale –1 to +1) and ranged from –0.41 (vs active comparators) to 0.01 (vs placebo) in 2009, when its market authorization was withdrawn. Retesting indicated good reproducibility. Panelists acknowledged good face validity and the importance of criteria beyond benefit-risk in real-life assessments. Conclusions: The approach allows quantification and visualization of benefit-risk over time and across comparators. Combination of pragmatic MCDA designed to integrate criteria beyond benefit-risk and advanced statistics supports application of MCDA to further accountable benefit-risk assessments for real-life decision making.

Age Related Consultation Rates of Clinically-Diagnosed Influenza And Acute Respiratory Illnesses Observed Through A Network of Gp Practices Across England.

Fifty one percent severely dehydrated with Systolic BP ranged 0.0–160.0mmHg, median 90.0mmHg. Diastolic BP ranged 0.0-110.0 mmHg, median 60.0mmHg. Total fluids given ranged 0.0–13.9 L, median 5.2 L. Only 1.4% had fluid output monitored. Lacking health insurance (POR= 2.52, CI0.48-13.25), being referred (POR= 0.05, CI0.010.21), male (POR= 0.82, CI0.32-2.16), single (POR= 0.80, CI0.26-2.46) were associated with late hospital presentation COnClusIOns: Instituting routine cholera death audits in Ghana is crucial to reducing case fatality as late presentation, inadequacy of assessment, rehydration, monitoring and lack of Health Insurance were main prevalent factors among deaths in the outbreak.

A retrospective observational analysis of post-pandemic influenza-related outcomes in the United Kingdom, 2010–2014

ABSTRACT This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010–2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group. Upper respiratory tract infection diagnoses were most frequently recorded (mean seasonal practice level incidence; 3,762 consultations per 100,000 [SD = 1,989]), and influenza-related diagnoses were least frequently recorded across all seasons, except one. Incidence rates for the under 18 population were higher than those for the general population, in particular for upper respiratory tract infection (range of 8,024–9,950 versus 3,228–4,120, respectively) and otitis media diagnoses (2,668–3,652 versus 782–1,057, respectively). For influenza-related diagnoses, the 65+ age group, the 0 to <2 and 2 to <4 groups had a higher risk (risk ratio = 1.33, 1.12 and 1.16, respectively) than other age groups. This study provides valuable insight into the incidence of influenza- and respiratory-related diagnoses in the primary care setting in England, and suggests a higher burden of disease in young children and the elderly. The study also indicates that some influenza illness is likely to be reported under respiratory-related diagnoses, given the low incidence of influenza-related diagnoses in the study.

Second-line cabozantinib versus nivolumab in advanced renal cell carcinoma: Systematic review and indirect treatment comparison

BACKGROUND Nivolumab and cabozantinib, two new treatment options for previously-treated advanced/metastatic renal cell carcinoma (aRCC), have recently been approved. METHODS Two independent reviewers performed study selection, data extraction, and risk of bias assessment. Indirect treatment comparisons were carried out by directly assessing HR differences and statistical modeling of Kaplan-Meier curves from these two trials. RESULTS Publications identified showed that no head-to-head comparisons had been carried out. Two indirect treatment comparisons used agreed that there was no significant difference in OS between cabozantinib and nivolumab and that cabozantinib significantly improved PFS compared to nivolumab. CONCLUSIONS The field of aRCC treatments is evolving rapidly, creating opportunities for individualized treatments and challenges for clinicians to keep up with the evidence. In lieu of availability of direct comparisons of all options, advanced modeling results presented herein can help to inform and improve personalized treatments.