Nalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO ...2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication.
Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane's Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI 0.08; 2.01) and 1 y (RR = 0.98, 95% CI 0.04; 23.95) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI -0.32; 2.01; SF-36 mental component summary score: MD = 1.01, 95% CI -1.33; 3.34) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = -1.65, 95% CI -2.41; -0.89) and at 1 y (MD = -1.60, 95% CI -2.85; -0.35) and total alcohol consumption at 6 mo (SMD = -0.20, 95% CI -0.30; -0.10). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI 2.02; 6.63) and 1 y (RR = 7.01, 95% CI 1.72; 28.63). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used.
The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption.
Transparency and reproducibility are expected to be normative practices in clinical trials used for decision-making on marketing authorisations for new medicines. This registered report introduces a ...cross-sectional study aiming to assess inferential reproducibility for main trials assessed by the European Medicines Agency.
Two researchers independently identified all studies on new medicines, biosimilars and orphan medicines given approval by the European Commission between January 2017 and December 2019, categorised as 'main studies' in the European Public Assessment Reports (EPARs). Sixty-two of these studies were randomly sampled. One researcher retrieved the individual patient data (IPD) for these studies and prepared a dossier for each study, containing the IPD, the protocol and information on the conduct of the study. A second researcher who had no access to study reports used the dossier to run an independent re-analysis of each trial. All results of these re-analyses were reported in terms of each study's conclusions, p-values, effect sizes and changes from the initial protocol. A team of two researchers not involved in the re-analysis compared results of the re-analyses with published results of the trial.
Two hundred ninety-two main studies in 173 EPARs were identified. Among the 62 studies randomly sampled, we received IPD for 10 trials. The median number of days between data request and data receipt was 253 interquartile range 182-469. For these ten trials, we identified 23 distinct primary outcomes for which the conclusions were reproduced in all re-analyses. Therefore, 10/62 trials (16% 95% confidence interval 8% to 28%) were reproduced, as the 52 studies without available data were considered non-reproducible. There was no change from the original study protocol regarding the primary outcome in any of these ten studies. Spin was observed in the report of one study.
Despite their results supporting decisions that affect millions of people's health across the European Union, most main studies used in EPARs lack transparency and their results are not reproducible for external researchers. Re-analyses of the few trials with available data showed very good inferential reproducibility.
https://osf.io/mcw3t/.
Different methodological choices such as inclusion/exclusion criteria and analytical models can yield different results and inferences when meta-analyses are performed. We explored the range of such ...differences, using several methodological choices for indirect comparison meta-analyses to compare nalmefene and naltrexone in the reduction of alcohol consumption as a case study.
All double-blind randomized controlled trials (RCTs) comparing nalmefene to naltrexone or one of these compounds to a placebo in the treatment of alcohol dependence or alcohol use disorders were considered. Two reviewers searched for published and unpublished studies in MEDLINE (August 2017), the Cochrane Library, Embase, and ClinicalTrials.gov and contacted pharmaceutical companies, the European Medicines Agency, and the Food and Drug Administration. The indirect comparison meta-analyses were performed according to different inclusion/exclusion criteria (based on medical condition, abstinence of patients before inclusion, gender, somatic and psychiatric comorbidity, psychological support, treatment administered and dose, treatment duration, outcome reported, publication status, and risk of bias) and different analytical models (fixed and random effects). The primary outcome was the vibration of effects (VoE), i.e. the range of different results of the indirect comparison between nalmefene and naltrexone. The presence of a "Janus effect" was investigated, i.e. whether the 1st and 99th percentiles in the distribution of effect sizes were in opposite directions.
Nine nalmefene and 51 naltrexone RCTs were included. No study provided a direct comparison between the drugs. We performed 9216 meta-analyses for the indirect comparison with a median of 16 RCTs (interquartile range = 12-21) included in each meta-analysis. The standardized effect size was negative at the 1st percentile (- 0.29, favouring nalmefene) and positive at the 99th percentile (0.29, favouring naltrexone). A total of 7.1% (425/5961) of the meta-analyses with a negative effect size and 18.9% (616/3255) of those with a positive effect size were statistically significant (p < 0.05).
The choice of inclusion/exclusion criteria and analytical models for meta-analysis can result in entirely opposite results. VoE evaluations could be performed when overlapping meta-analyses on the same topic yield contradictory result.
This study was registered on October 19, 2016, in the Open Science Framework (OSF, protocol available at https://osf.io/7bq4y/ ).
In very preterm infants, cardio-respiratory events and associated hypoxemia occurring during early postnatal life have been associated with risks of retinopathy, growth alteration and ...neurodevelopment impairment. These events are commonly detected by continuous cardio-respiratory monitoring in neonatal intensive care units (NICU), through the associated bradycardia. NICU nurse interventions are mainly triggered by these alarms. In this work, we acquired data from 52 preterm infants during NICU monitoring, in order to propose an early bradycardia detector which is based on a decentralized fusion of three detectors. The main objective is to improve automatic detection under real-life conditions without altering performance with respect to that of a monitor commonly used in NICU. We used heart rate lower than 80 bpm during at least 10 sec to define bradycardia. With this definition we observed a high rate of false alarms (64%) in real-life and that 29% of the relevant alarms were not followed by manual interventions. Concerning the proposed detection method, when compared to current monitors, it provided a significant decrease of the detection delay of 2.9 seconds, without alteration of the sensitivity (97.6% vs 95.2%) and false alarm rate (63.7% vs 64.1%). We expect that such an early detection will improve the response of the newborn to the intervention and allow for the development of new automatic therapeutic strategies which could complement manual intervention and decrease the sepsis risk.
Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the ...European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis.
Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods.
The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI 0.64-0.99) and the absence of difference for overall survival (HR: 1.25, 95% CI 0.95 - 1.62). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results.
EMA's approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.
After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (C blood )-guided ...therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI C blood within the therapeutic range. Other pharmacokinetic parameters, such as the intragraft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intragraft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR).
In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intragraft concentrations of CNI (C EMB ). C blood and the concentration inside peripheral blood mononuclear cells, (C PBMC ), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the 3 matrices were compared between patients with and without biopsy-proven acute rejection (BPAR).
Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. C blood , C EMB , and C PBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6%) from 26 patients (76.5%), all except one was of low grade. None of the PK parameters (C blood , C EMB , C PBMC , C EMB/blood , and C PBMC/blood ) was associated with BPAR.
In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters, including C blood , with the occurrence of BPAR. However, a trend was noticed for the C EMB and C EMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of C EMB and C PBMC for CNI TDM in HTR.
Women are under-represented in senior academic and hospital positions in many countries. The authors aim to assess the place and the evolution of all appointed female and male health practitioners' ...working in French public Hospitals. Data of this observational study were collected from the National Management Centre (Centre National de Gestion) from 2015 up to January 1, 2020. First, the authors described demographic characteristics and specialties of all appointed medicine, pharmacy, and dentistry doctors' working as Hospital Practitioners, Associate Professors, and Full Professors in French General and University-affiliated Hospitals in 2020. Then, they retrospectively reported the annual incidence of new entrance according to gender and professional status from 1999 to 2019 thanks to the appointment date of all practitioners in activity between 2015 and 2020. In 2020, 51 401 appointed practitioners (49.7% of female) were in activity in French public hospitals with a large majority being medical doctors (92.4%) compared to pharmacists (6%) and dentists (1.6%). Women represented 52.5% of the Hospital Practitioners, 48.6% of the Associate Professors, and 22.0% of the Full Professors (p < 0.001). There were disparities between the rates of female Full Professors in medicine (20.6%), pharmacy (36.1%), and dentistry (44.3%, p < 0.001). Women were appointed Hospital Practitioners and Associate Professors earlier than men (respectively 37.1 versus 38.8 years, p < 0.001 and 36.1 versus 36.5 years, p = 0.04), and at a later age among Full Professors (43.7 versus 41.9 years, p < 0.001). Compared to men, the annual proportion of appointed women varied significantly between 1999 and 2019 from 47.6% to 60.4% for Hospital Practitioners, from 50.0% to 44.6% for Associate Professors, and from 11.2% to 33.3% for Full Professors (p < 0.001 for trend). Although more and more women occupy positions in French hospitals, there is still a gender gap regarding access to Full Professor status in medicine and pharmacy, but not in dentistry. The disparity in numbers makes comparison difficult. Despite a trend towards gender equality during the last twenty years, it has not yet been achieved regarding access to the highest positions.
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