The ASCEND-NHQ trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis-dependent chronic kidney disease

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) Stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the vitality score between baseline and Week 28. Outcome superiority was tested (one-sided alpha level of 0.025) among 614 randomized participants. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A greater proportion of participants receiving daprodustat showed a significant 1 g/dl or more increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a significant 5.4 point Week 28 ADM increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD Stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events

A dynamic perspective on pharmaceutical competition, drug development and cost effectiveness

Limited healthcare budgets result in payers adopting policies at national, regional or local level to achieve allocative efficiency in drug spending. Some of these aim at creating a link between pharmaceutical prices and the value they provide by setting a cost effectiveness (CE) threshold as the maximum acceptable ratio between incremental costs and effects of new drugs. The clinical effectiveness of the comparator used in those CE analyses tends to be greater over time, whilst, due to market competition and loss of exclusivity, their price is expected to be lower. At the same time, research and development (R&D) costs increase with inflation and with efforts to address regulation towards increased safety concerns. As effective patent times decrease, a minimum price constraint raises for the new entrant. These features occur at different rates across disease areas and are expected to result in differently shaped innovation curves. In this scenario, we demonstrate that a general arbitrary threshold may prevent further efficient R&D. Investment may be withdrawn before the optimum innovation point is reached and affordable clinical effectiveness may be lost. We conclude that disease-specific characteristics are an additional consideration in CE decision rules to accommodate the particularities of innovation across disease areas.Pharmaceutical price erosion Cost effectiveness Health technology assessment Pharmaceutical research and development Pharmaceutical innovation

Cost-Effectiveness and Dynamic Efficiency: Does the Solution Lie Within?

The majority of the current systems spread across the world require the value of pharmaceuticals to be demonstrated with an acceptable degree of certainty before a technology is funded. Often involving the notion of cost-effectiveness, one of the key characteristics of such assessments tends to be the consideration of efficiency as a static outcome; with a strong emphasis on current health gains but a disregard for the impact of decision making on the potential health value over time. In this article, we argue that current systems using cost-effectiveness thresholds may provide an incomplete indicator of value. We defend the idea that funding decisions should also be informed by dynamic efficiency considerations and reflect both the current and the future value of achieving a certain level of effectiveness in a specific disease area. We further lay down the foundations for the implementation of such a value assessment framework

Relative changes in cholesterol and triglyceride parameters for dolutegravir versus third agents of interest.

<p>Mean changes (mg/dL [95% Crl] in lipid levels with DTG compared with other third agents are shown for (<b>A</b>) total cholesterol (TC), (<b>B</b>) HDL cholesterol, (<b>C</b>) LDL cholesterol, and (<b>D</b>) triglycerides. In all cases, Crls of mean differences that do not include 0 are considered statistically significant. ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; DTG = dolutegravir; DRV/r = ritonavir-boosted darunavir; EFV = efavirenz; EVG/c = cobicistat-boosted elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LPV/r = lopinavir-boosted ritonavir; NFV = nelfinavir; RAL = raltegravir; RPV = rilpivirine; SQV/r = ritonavir-boosted saquinavir; TC = total cholesterol. *Indicates statistically significant comparison.</p

Estimated probability of virologic suppression and absolute CD4+ cell count change from baseline.

<p>Note: Estimates derived from this meta-analysis may differ from that of any given RCT, due to statistical aggregation of data from several trials.</p><p>Estimated probability of virologic suppression and absolute CD4+ cell count change from baseline.</p

Mean odds ratio (95% CrI) of AEs and discontinuation due to AEs.

<p>*Significant comparisons are in bold with an asterisk.</p><p>Mean odds ratio (95% CrI) of AEs and discontinuation due to AEs.</p

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Chart.

<p>PubMed/MEDLINE, Embase, and Cochrane databases were searched to identify randomized controlled trials evaluating efficacy and/or safety of ATV/r, DRV/r, DTG, EFV, EVG/c, LPV/r, RAL, or RPV in treatment-naive HIV-1–infected patients. Records were screened by independent researchers, who selected study titles and abstracts for full text review. Following several rounds of exclusion based on multiple criteria, 31 trials and publications were selected for subsequent analysis. *Additional records were identified via ClinicalTrials.gov, the Food and Drug Administration (FDA), scientific discussions of the European Medicines Agency (EMA)/European Public Assessment Reports (EPAR), and third-agent package inserts. Each of these were found to be included in initial search records and noted as such. ^†Reasons for exclusion at time of full text review: non-randomized trial; Phase 1/Phase 2 trials; patient population age <13 years; outcomes not of interest; trial duration <12 weeks; and out-of-network comparator. ^‡34 publications were matches to ClinicalTrials.gov registry results (NCTs) to ensure comprehensive extraction of all available data pertaining to outcomes of interest.</p

Comparison of immunologic endpoints with dolutegravir versus third agents of interest.

<p>(<b>A</b>) Odds ratio [95% CrI] for virologic suppression (HIV RNA<50 c/mL) of DTG compared with other third agents. Odds ratio values greater than 1 indicate the comparison favors DTG; CrI intervals that do not contain 1 are considered statistically significant. (<b>B</b>) Mean [95% CrI] CD4+ cell increase with dolutegravir versus third agents of interest. Crls of mean differences that do not contain 0 are considered statistically significant. ATV = atazanavir; ATV/r = ritonavir-boosted atazanavir; Crl = credible interval; DTG = dolutegravir; DRV/r = ritonavir-boosted darunavir; EFV = efavirenz; EVG/c = cobicistat-boosted elvitegravir; FPV/r = ritonavir-boosted fosamprenavir; LPV/r = lopinavir-boosted ritonavir; NFV = nelfinavir; RAL = raltegravir; RPV = rilpivirine; SQV/r = ritonavir-boosted saquinavir. *Indicates statistically significant comparison.</p