Requesting conflicts of interest declarations from the European Medicines Agency: 3-year follow-up status.

AIMS: We have previously described the European Medicines Agency's (EMA) and the US Food and Drug Administration's guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. METHODS: We submitted Freedom of Information requests in February 2020 to access EMA's lists of committee members (and their declared conflicts of interest) involved in drafting the 13 'Clinical efficacy and safety' guidelines available on EMA's website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). RESULTS: After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%-44% declared any interests and we judged 14%-18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. CONCLUSIONS: After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the 'Clinical efficacy and safety' guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Dental Research Waste in Design, Analysis, and Reporting: A Scoping Review.

Research waste is highly prevalent across biomedical investigations. We aimed to assess the evidence on the extent of research waste in dental research. We performed a scoping review of empirical evaluations of dental studies assessing the prevalence and impact of limitations in design, conduct, analysis, and reporting of research. PubMed was searched using specific terms to retrieve studies dealing with design, conduct, analysis, and reporting of studies in dentistry, with no year or language restrictions. Of the 1,807 publications identified from the search and from manual searches, 71 were included in this review. The topic and article selection was based on the expert opinion of the authors. The existing evidence suggests that, although there are improvements over time, substantial deficiencies in all areas (design, conduct, analysis, reporting) were prevalent in dental research publications. Waste in research is a multifaceted problem without a simple solution. However, an appreciation of optimal research design and execution is a prerequisite and should be underpinned by policies that include appropriate training in research methods and properly aligned incentives.

The role of meta-analyses and umbrella reviews in assessing the harms of psychotropic medications: beyond qualitative synthesis.

á½ φελέειν, á¼¢ µá½´ ßλάπτειν (Primum non nocere) - Hιppocrates' principle should still guide daily medical prescribing. Therefore, assessing evidence of psychopharmacologic agents' safety and harms is essential. Randomised controlled trials (RCTs) and observational studies may provide complementary information about harms of psychopharmacologic medications from both experimental and real-world settings. It is considered that RCTs provide a better control of confounding variables, while observational studies provide evidence from larger samples, longer follow-ups, in more representative samples, which may be more reflective of real-life clinical scenarios. However, this may not always hold true. Moreover, in observational studies, safety data are poorly or inconsistently reported, precluding reliable quantitative synthesis in meta-analyses. Beyond individual studies, meta-analyses, which represent the highest level of 'evidence', can be misleading, redundant and of low methodological quality. Overlapping meta-analyses sometimes even reach different conclusions on the same topic. Meta-analyses should be assessed systematically. Descriptive reviews of reviews can be poorly informative. Conversely, 'umbrella reviews' can use a quantitative approach to grade evidence. In this editorial, we present the main factors involved in the assessment of psychopharmacologic agents' harms from individual studies, meta-analyses and umbrella reviews. Study design features, sample size, number of the events of interest, summary effect sizes, p-values, heterogeneity, 95% prediction intervals, confounding factor adjustment and tests of bias (e.g., small-study effects and excess significance) can be combined with other assessment tools, such as AMSTAR and GRADE to create a framework for assessing the credibility of evidence.

Overlapping network meta-analyses on the same topic: survey of published studies.

Background: To assess how common it is for a published network meta-analysis (NMA) to have other published overlapping NMAs, and to evaluate these overlaps. Methods: A total of 88 NMAs of randomized controlled trials evaluating the comparative effectiveness of health interventions were randomly selected. For each of these, we searched for NMAs on the same topic. A random sample of 40 pairs (an index NMA and one of its overlapping NMAs) was selected to assess the overlap in terms of nodes, treatments and references. The topic with the largest number of overlapping NMAs was described in depth. Results: In all, 68 of the 88 index NMAs had at least one overlapping NMA: 77% [95% confidence interval (CI), 69-86%]. We identified 515 pairs of overlapping NMAs. Among the 40 randomly selected pairs, 73% (95% CI, 58-88%) of nodes, 79% (95% CI, 72-86%) of treatments and 48% (95% CI, 37-59%) of references included in the index NMAs were also found in the respective overlapping NMAs. Efficacy of biologics in rheumatoid arthritis had the largest number of overlapping NMAs, with 28 NMAs published between 2003 and 2014. Differences in selection and definition of nodes of treatments resulted in different network geometries. There were also differences in both the direction and the statistical significance of effects. Conclusions: Published NMAs exhibit extensive overlap and potential redundancy. Erratic retrieval of eligible trials, and lack of consensus on the range of interventions to be considered and how they might be merged or split in different nodes, may cause confusion.

Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses.

Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearman's correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.

Antiretroviral therapy for initial human immunodeficiency virus/AIDS treatment: critical appraisal of the evidence from over 100 randomized trials and 400 systematic reviews and meta-analyses.

There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

Replication and meta-analysis of TMEM132D gene variants in panic disorder.

A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

First-trimester ductus venosus screening for cardiac defects: a meta-analysis.

BACKGROUND: Heart defects are the most common congenital abnormalities. OBJECTIVE: We aimed to evaluate in a meta-analysis the screening performance of abnormal ductus venosus (DV) Doppler waveform for detection of congenital heart disease (CHD) in chromosomally normal fetuses. SEARCH STRATEGY: Studies were retrieved from a search of MEDLINE, ISI, SCOPUS and EMBASE (from 1999 to March 2011) using the keywords 'ductus venosus', 'DV', 'chromosomal abnormalities', 'congenital heart disease' and 'nuchal translucency'. SELECTION CRITERIA: We considered all studies that examined the diagnostic performance of DV in the first trimester for CHD in chromosomally normal fetuses. We included studies that were limited to fetuses with increased nuchal translucency (NT), normal NT, and studies that examined fetuses regardless of NT status. DATA COLLECTION AND ANALYSIS: Seven studies (n = 50,354) regardless of the NT status, nine studies (n = 2908) with increased NT and seven studies (n = 47,610) with normal NT were included in the meta-analysis. We drew hierarchical summary receiver operating characteristic (HSROC) curves using the parameters of the fitted models. MAIN RESULTS: In populations including participants regardless of NT status, the summary sensitivity and specificity of DV for detecting CHD were 50 and 93%, respectively. In participants with increased NT, the summary sensitivity and specificity were 83 and 80%, and in those with normal NT, they were 19 and 96%, respectively. AUTHORS' CONCLUSIONS: The estimated performance of DV assessment for detection of CHD in chromosomally normal fetuses can be considered in evaluating the potential use and limitations of this screening test.

Polymorphisms in the 5' flank of COL1A1 gene and osteoporosis: meta-analysis of published studies.

UNLABELLED: A meta-analysis of studies was conducted involving 24,511 participants with 7,864 fractures in which polymorphisms in the 5' flank of COL1A1 (rs1107946, rs2412298, and rs1800012) were related to osteoporosis phenotypes. Polymorphisms of all three sites were associated with BMD, and rs1800012 was associated with fracture but effect sizes were modest. INTRODUCTION AND HYPOTHESIS: Polymorphisms in the 5' flank of COL1A1 gene have been implicated as genetic markers for susceptibility to osteoporosis, but previous studies have yielded conflicting results. METHODS: We conducted a meta-analysis of 32 studies including 24,511 participants and 7,864 fractures in which alleles at the -1997G/T (rs1107946), -1663in/delT (rs2412298), and Sp1 binding site polymorphisms (rs1800012) of COL1A1 had been related to bone mineral density (BMD) or fracture. RESULTS: For the Sp1 polymorphism, BMD values in TT homozygotes were 0.13 units [95% CI, 0.03 to 0.24] lower at the spine (p = 0.01) and 0.16 units [0.10 to 0.23] lower at the hip (p = 1 x 10⁻6) than GG homozygotes. Clinical fractures were 1.31-fold [1.04-1.65] increased in TT homozygotes (p = 0.02) and vertebral fractures were 1.34-fold [1.01-1.77] increased (p = 0.04). We also observed associations between spine BMD and allelic variants at the -1997G/T (p = 0.05) and the -1663indelT (p = 0.009) sites. We found no association between alleles at the -1997G/T or -1663indelT sites and fracture but power was limited. CONCLUSIONS: The COL1A1 Sp1 polymorphism is associated with a modest reduction in BMD and an increased risk of fracture, although we cannot fully exclude the possibility that the results may have been influenced by publication bias. Further studies are required to fully evaluate the contribution of the -1997G/T and -1663in/delT sites to these phenotypes and to determine if they interact with the Sp1 polymorphism to regulate susceptibility to osteoporosis.

EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD). METHODS: A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force. RESULTS: Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. CONCLUSION: Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Vaccination in adult patients with auto-immune inflammatory rheumatic diseases: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases.

OBJECTIVES: To present the systematic literature review (SLR), which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for vaccination in adult patients with auto-immune inflammatory rheumatic diseases (AIIRD). METHODS: AIIRD, vaccines and immunomodulating drugs, as well as eight key questions were defined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A SLR was performed using MedLine through October 2009 and including data from meta-analyses, systematic reviews, randomized trials, and observational studies, excluding case series with ≤ 5 participants. Articles in English and regarding patients ≥ 16 years of age, were eligible. RESULTS: Several vaccine-preventable infections (VPI) occur more often in AIIRD-patients and most vaccines are efficacious in AIIRD-patients, even when treated with immunomodulating agents, except rituximab. There does not appear to be an increase in vaccination-related harms in vaccinated patients with AIIRD in comparison with unvaccinated patients with AIIRD. However, these studies are underpowered and therefore not conclusive. CONCLUSION: Based on the current evidence from the literature, recommendations for vaccination in patients with AIIRD were made. However, more research is needed in particular regarding incidence of VPI, harms of vaccination and the influence of (new and established) immunomodulating agents on vaccination efficacy.

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs.

OBJECTIVES: To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. METHODS: The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. RESULTS: Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence > 5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1-5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. CONCLUSIONS: Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

Validation of the Greek translation of the Dundee Ready Education Environment Measure (DREEM).

CONTEXT: The educational environment makes an important contribution to student learning. The DREEM questionnaire is a validated tool assessing the environment. OBJECTIVES: To translate and validate the DREEM into Greek. METHODS: Forward translations from English were produced by three independent Greek translators and then back translations by five independent bilingual translators. The Greek DREEM.v0 that was produced was administered to 831 undergraduate students from six Greek medical schools. Cronbach's alpha and test-retest correlation were used to evaluate reliability and factor analysis was used to assess validity. Questions that increased alpha if deleted and/or sorted unexpectedly in factor analysis were further checked through two focus groups. FINDINGS: Questionnaires were returned by 487 respondents (59%), who were representative of all surveyed students by gender but not by year of study or medical school. The instrument's overall alpha was 0.90, and for the learning, teachers, academic, atmosphere and social subscales the alphas were 0.79 (expected 0.69), 0.78 (0.67), 0.69 (0.60), 0.68 (0.69), 0.48 (0.57), respectively. In a subset of the whole sample, test and retest alphas were both 0.90, and mean item scores highly correlated (p<0.001). Factor analysis produced meaningful subscales but not always matching the original ones. Focus group evaluation revealed possible misunderstanding for questions 17, 25, 29 and 38, which were revised in the DREEM.Gr.v1. The group mean overall scale score was 107.7 (SD 20.2), with significant differences across medical schools (p<0.001). CONCLUSION: Alphas and test-retest correlation suggest the Greek translated and validated DREEM scale is a reliable tool for assessing the medical education environment and for informing policy. Factor analysis and focus group input suggest it is a valid tool. Reasonable school differences suggest the instrument's sensitivity.

Synopsis of preterm birth genetic association studies: the preterm birth genetics knowledge base (PTBGene).

AIM: Our goal wasto produce a field synopsis of genetic associations with preterm birth and to set up a publicly available online database summarizing the data. METHODS: We performed a systematic review and meta-analyses to identify genetic associations with preterm birth. We have set up a publicly available online database of genetic association data on preterm birth called PTBGene (http://ric.einstein.yu.edu/ptbgene/index.html) and report on a structured synopsis thereof as of December 1, 2008. RESULTS: Data on 189 polymorphisms in 84 genes have been included and 36 meta-analyses have been performed. Five gene variants (4 in maternal DNA, one in newborn DNA) have shown nominally significant associations, but all have weak epidemiological credibility. CONCLUSION: After publishing this field synopsis, the PTBGene database will be regularly updated to keep track of the evolving evidence base of genetic factors in preterm birth with the goal of promoting knowledge sharing and multicenter collaboration among preterm birth research groups.

Industry sponsorship and selection of comparators in randomized clinical trials.

BACKGROUND: Most clinical trials on medical interventions are sponsored by the industry. The choice of comparators shapes the accumulated evidence. We aimed to assess how often major companies sponsor trials that involve only their own products. METHODS: Studies were identified by searching ClinicalTrials.gov for trials registered in 2006. We focused on randomized trials involving the 15 companies that had sponsored the largest number of registered trials in ClinicalTrials.gov in that period. RESULTS: Overall, 577 randomized trials were eligible for analysis and 82% had a single industry sponsor [89% (166/187) of the placebo-control trials, 87% (91/105) of trials comparing different doses or ways of administration of the same intervention, and 78% (221/285) of other active control trials]. The compared intervention(s) belonged to a single company in 67% of the trials (89%, 81% and 47% in the three categories respectively). All 15 companies strongly preferred to run trials where they were the only industry sponsor or even the only owner of the assessed interventions. Co-sponsorship typically reflected co-ownership of the same intervention by both companies. Head-to-head comparison of different active interventions developed by different companies occurred in only 18 trials with two or more industry sponsors. CONCLUSIONS: Each company generates a clinical research agenda that is strongly focused on its own products, while comparisons involving different interventions from different companies are uncommon. This diminishes the ability to understand the relative merits of different interventions for the same condition.

EULAR points to consider for conducting clinical trials in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions. DESIGN: ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE. METHODS: The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE. RESULTS: The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications. CONCLUSIONS: Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.