Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis

OBJECTIVES: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA.METHODS: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).RESULTS: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates.CONCLUSION: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. OBJECTIVES: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA.METHODS: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE).RESULTS: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates.CONCLUSION: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs.SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014014842

Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries

<p>Abstract</p> <p>Background</p> <p>In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe.</p> <p>Methods</p> <p>We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries.</p> <p>Results</p> <p>Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised.</p> <p>Conclusion</p> <p>The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.</p

Testing the Effect of Relative Pollen Productivity on the REVEALS Model : A Validated Reconstruction of Europe-Wide Holocene Vegetation

Reliable quantitative vegetation reconstructions for Europe during the Holocene are crucial to improving our understanding of landscape dynamics, making it possible to assess the past effects of environmental variables and land-use change on ecosystems and biodiversity, and mitigating their effects in the future. We present here the most spatially extensive and temporally continuous pollen-based reconstructions of plant cover in Europe (at a spatial resolution of 1° × 1°) over the Holocene (last 11.7 ka BP) using the 'Regional Estimates of VEgetation Abundance from Large Sites' (REVEALS) model. This study has three main aims. First, to present the most accurate and reliable generation of REVEALS reconstructions across Europe so far. This has been achieved by including a larger number of pollen records compared to former analyses, in particular from the Mediterranean area. Second, to discuss methodological issues in the quantification of past land cover by using alternative datasets of relative pollen productivities (RPPs), one of the key input parameters of REVEALS, to test model sensitivity. Finally, to validate our reconstructions with the global forest change dataset. The results suggest that the RPPs.st1 (31 taxa) dataset is best suited to producing regional vegetation cover estimates for Europe. These reconstructions offer a long-term perspective providing unique possibilities to explore spatial-temporal changes in past land cover and biodiversity

Status of Planned and Ongoing Paediatric Trials Investigating COVID-19 Vaccines:A Cross-Sectional Study of Paediatric Clinical Trials Planned in Agreed PIPs and/or Registered in Clinical Trial Databases

BACKGROUND: The immune system matures throughout childhood; therefore, evidence about the safety and efficacy of vaccines for the prevention of COVID-19 in the paediatric population is important. Efficacy and safety have not been established for COVID-19 vaccines in a large part of the paediatric population at the time of the initial approval for use in adults. This study aims to provide an overview of planned and ongoing paediatric clinical trials investigating the safety and/or efficacy of COVID-19. METHODS: We identified all paediatric clinical trials investigating the safety and/or efficacy of COVID-19 vaccines in clinicaltrials.gov and clinicaltrialregister.eu, as well as all clinical trials planned in agreed PIPs (Paediatric Investigational Plans) as of 11 June 2021. Information about the study design, the paediatric age groups that they included, and the primary and secondary safety and efficacy outcomes were collected, together with expected timelines for the studies. RESULTS: 21 clinical trials were identified through the clinical trial registries and 19 clinical trials were specified in 6 agreed PIPs, 5 of these trials were also in the trial registers. All PIPs stipulated development of the COVID-19 vaccines for the full paediatric population, with a deferral. The earliest expected completion date of a PIPs is March 2024. The majority (14/21) of registered trials are randomised double-blinded studies. All investigated safety, 20 have a surrogate efficacy outcome (immunogenicity), of these 7 also measure clinical efficacy (COVID-19 infections). 18 studies were initiated, of these, all but one is still ongoing and one in adolescents has been finalised. CONCLUSION: Even though several trials have been planned in agreed PIPs, the registered paediatric clinical trials identified are most often not part of a PIP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43441-021-00356-y

Tuberculosis medicines for children in Europe: an unmet medical need

The availability of first-line medicines for the treatment of drug-susceptible tuberculosis (TB) is inconsistent across European countries. This is particularly worrisome for child-friendly medicines. There are reported examples of physicians being forced to adapt and/or combine formulations intended for adults to treat children with TB. Reduced compliance, unknown effects on treatment outcomes and unpredictable toxicity are potential consequences of resorting to these suboptimal treatment options. Furthermore, the use of these alternatives may increase the risk of drug-resistant TB. This study analysed the availability and use of TB medicines in the European Union (EU)/European Economic Area, with a particular focus on child-friendly formulations. We sought to carry out a full review of the situation by means of a survey involving the EU regulatory network. Countries were asked to confirm marketing status of anti-drug-susceptible-TB medicines, ways used to overcome their absence in their territory and the general difficulties they face to treat children with TB. Results confirmed that rifampicin suspension is the only child-friendly formulation available in Europe, approved in just 10 member states. Overall, 24 countries out of 30 considered the lack of adequate drug-susceptible TB medicines an unmet medical need. To overcome this, countries confirmed that they resort to importation or use adapted formulations. The joint forces of European institutions and pharmaceutical industry are crucial for the development of paediatric formulations and contribute to better compliance and health outcomes

Prescribing patterns and safety monitoring of duloxetine using the Danish Register of Medicinal Product Statistics as a source

Background: The safety and pattern of use of a medicinal product cannot be fully studied prior to its marketing. In Denmark, the Danish Health and Medicines Authority (DHMA) monitors marketed drugs. An available source is the Register of Medicinal Product Statistics (RMPS), which can possibly be used for these purposes. Objective: To investigate utilisation and potential safety issues of relatively new antidepressants containing the active ingredient duloxetine (Cymbalta® and Xeristar®) by using dispensing data available in the RMPS. Methods: A retrospective study using dispensing data was designed to estimate the size and composition of the user population and patterns of use of the antidepressants Cymbalta® and Xeristar® (active ingredient: duloxetine) in the period from 1 January 2005 to 31 December 2010. Data were retrieved from Epikur, a register subset of the RMPS. Results: Both women and men in different age groups used duloxetine for depression. Some users switched to another antidepressant. Prescription of the drug for persons below the age of 18 years revealed a potential safety issue. Concomitant treatment with Cymbalta® or Xeristar® and fluvoxamine, isocarboxazid, Yentreve®, or ciprofloxacin also revealed potential safety issues. Conclusions: The present study indicated that the RMPS is applicable in monitoring the pattern of use and potential safety issues related to duloxetine when it is prescribed for depression. Switching to other antidepressants could reflect some potential safety issues. Use of duloxetine for persons below the age of 18 years and its concomitant use with contraindicated drugs also indicated potential safety issues. </jats:p

Access to innovative oncology medicines in Europe

This article intends to give an overview about developments in European Regulatory and Health Technology Assessment (HTA) of new cancer drugs. As background information, it will refer to an overview article by Bergmann et al. [1], which pointed out the status and the limitations of the current system. The authors discussed possible steps to improve the interface between regulators and HTA bodies but stated that this alone will not be sufficient to overcome heterogeneous HTA assessments between HTA agencies. Major issues and challenges for the foreseeable future will be to overcome the heterogeneity of patient access decisions of pharmaceutical payers across Europe which is due to (i) considerably different scientific approaches and methodology to the more or less formal evaluation of cost-effectiveness; (ii) differing health priorities across the countries that reflect historically developed cultural differences and values or different unmet medical needs and (iii) different economic strengths among nations, regions and locales that necessarily drive health care budgetary decisions. The authors consider that this needs a science-based common position on methodology, greater commitments by politicians and health care decision makers to ensure equal access for patients across the EU to anti-tumour medicines. ..