A state-of-the-art multi-criteria model for drug benefit-risk analysis

Drug benefit-risk analysis is based on firm clinical evidence related to various safety and efficacy outcomes, such as tolerability, treatment response, and adverse events. In this paper, we propose a new approach for constructing a supporting multi-criteria model that fully takes into account this evidence. Our approach is based on the Stochastic Multicriteria Acceptability Analysis (SMAA) methodology, which allows us to compute the typical value judgments that support a decision, to quantify uncertainty, and to compute a comprehensive benefit-risk profile. As an example, we constructed a multi-criteria model for the therapeutic group of second-generation antidepressants. We analyzed Fluoxetine, Paroxetine, Sertraline, and Venlafaxine according to relative efficacy and absolute rates of several common adverse drug reactions using meta-analytical data from the literature. Our model showed that there are clear trade-offs among the four drugs. Based on our experiences from this study, SMAA appears to be a suitable approach for quantifying trade-offs and decision uncertainty in drug benefit-risk analysis.

Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality

BACKGROUND: Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). METHODS AND RESULTS: We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. CONCLUSIONS: Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD

Structured frameworks to increase the transparency of the assessment of benefits and risks of medicines: current status and possible future directions

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

Perpetrating Cyber Dating Abuse: A Brief Report on the Role of Aggression, Romantic Jealousy and Gender

There is increasing evidence that the use of elec-tronic communication technology (ECT) is being integrated into romantic relationships, which can be used as a medium to control a romantic partner. Most research focuses on the vic-tims of cyber dating abuse, however, we focused on the factors that predict perpetration of cyber dating abuse. We explored whether aggression (verbal aggression, physical aggression, anger and hostility), romantic jealousy (emotional, cognitive and behavioral jealousy), and gender predicted perpetration of cyber dating abuse (n = 189). We found that hostility, behav-ioral jealousy and gender significantly predicted perpetration of cyber dating abuse. The findings of this study contribute to our understanding of the psychological factors that drive cyber dating abuse in romantic relationships

A phase II study of high dose epirubicin in unresectable non small cell lung cancer.

Epirubicin (EPI), a doxorubicin analogue, is reported to have equal antitumour activity with lower cardiac and systemic toxicity. Recently, the maximum tolerated dose of this drug has been revised upwards with reported increased response rates in several malignancies. We initiated a phase II study of high-dose EPI as initial treatment for patients with advanced non-small cell lung cancer (NSCLC) (stage III and IV). Between May 1988 and November 1989, 25 patients were entered. The starting dose of EPI was 135 mg m-2, with dose attenuations and escalations of 15 mg m-2 based on mid-cycle evaluation of toxicity. Treatment was repeated every 3 weeks. Nine partial responses (36%, 95% CI: 18-57.5%) and 11 patients with disease stabilisation (44%) were observed. Median (range) time to progression was 19 (3-70) weeks. Median (range) survival is 32 (9-116+) weeks. There were no treatment related deaths. Major side effects were leukocytopenia WHO grade III/IV (23% of courses) and mucositis WHO grade II/III (15% of courses). In two patients left ventricular ejection fraction decreased greater than 15% compared to baseline values after a cumulative Epirubicin dose of 435 mg m-2, and therefore went off study. In none of the patients clinical signs of congestive heart failure were observed. We conclude from our data that high-dose EPI, contrary to previous negative studies using lower doses of EPI, ranks amongst the most active regimens against advanced NSCLC. Toxicity of high-dose EPI is moderate. Further evaluation of this compound in combination regimens is recommended