Healthcare databases in Europe for studying medicine use and safety during pregnancy.

PURPOSE: The aim of this study was to describe a number of electronic healthcare databases in Europe in terms of the population covered, the source of the data captured and the availability of data on key variables required for evaluating medicine use and medicine safety during pregnancy. METHODS: A sample of electronic healthcare databases that captured pregnancies and prescription data was selected on the basis of contacts within the EUROCAT network. For each participating database, a database inventory was completed. RESULTS: Eight databases were included, and the total population covered was 25 million. All databases recorded live births, seven captured stillbirths and five had full data available on spontaneous pregnancy losses and induced terminations. In six databases, data were usually available to determine the date of the woman's last menstrual period, whereas in the remainder, algorithms were needed to establish a best estimate for at least some pregnancies. In seven databases, it was possible to use data recorded in the databases to identify pregnancies where the offspring had a congenital anomaly. Information on confounding variables was more commonly available in databases capturing data recorded by primary-care practitioners. All databases captured maternal co-prescribing and a measure of socioeconomic status. CONCLUSION: This study suggests that within Europe, electronic healthcare databases may be valuable sources of data for evaluating medicine use and safety during pregnancy. The suitability of a particular database, however, will depend on the research question, the type of medicine to be evaluated, the prevalence of its use and any adverse outcomes of interest. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

The Clinical Practice Research Datalink for drug safety in pregnancy research: an overview.

Medicine use during pregnancy is common; however the safety of medicine use during pregnancy is largely unknown when a medicine comes to market. Electronic healthcare databases, including the Clinical Practice Research Datalink (CPRD), are increasingly being used for post-marketing surveillance in this field. The CPRD contains anonymised, longitudinal medical records routinely collected in primary care. Using CPRD data it is possible to identify medical records indicative of pregnancy, including pregnancy losses. Data on prescriptions issued can be used to determine maternal exposure and for about 80% of pregnancies it is possible to link the mother's medical record to the medical record of the child. Data in the medical records of the mother and child can then be used to identify adverse pregnancy outcomes, including congenital malformations. This paper describes some of the complexities involved in using CPRD data for pregnancy related research and discusses some of its strengths and limitations.

Identification of Pregnancy Adverse Drug Reactions in Pharmacovigilance Reporting Systems: A Novel Algorithm Developed in EudraVigilance.

INTRODUCTION: There is a need to strengthen the evidence base regarding medication use during pregnancy and to facilitate the early detection of safety signals. EudraVigilance (EV) serves as the primary system for managing and analysing information concerning suspected adverse drug reactions (ADRs) within the European Economic Area. Despite its various functionalities, the current format for electronic submissions of safety reports lacks a specific data element indicating medicine exposure during pregnancy. OBJECTIVE: This paper aims to address the limitations of existing approaches by developing a rule-based algorithm in EV that more reliably identifies cases that are truly representative of an ADR during pregnancy. METHODS: The study utilised the standardised MedDRA query (SMQ) 'Pregnancy and neonatal topics' (PNT) as a benchmark for comparison. Recognising that the SMQ PNT also retrieves healthy pregnancy outcomes, contraceptive failure, failed abortifacients as well as ADRs not associated with pregnancy, a novel algorithm was tailored to improve the accuracy of identifying suspected ADRs occurring during pregnancy. RESULTS: Upon testing, the algorithm demonstrated superior performance, correctly predicting 90% of cases reporting an ADR during pregnancy, compared to 54% achieved by the SMQ PNT. The implementation of the algorithm in EV led to the retrieval of 202,426 cases. CONCLUSION: The development and successful testing of the novel algorithm represents a step forward in pregnancy-specific signal detection in EV. Because signals associated with pregnancy may be diluted in a large database such as EV, this study lays the groundwork for future research to evaluate the effectiveness of disproportionality methods on a more refined subset of pregnancy-related ADR reports.

Smoking and delay to diagnosis are associated with poorer functional outcome in psoriatic arthritis.

OBJECTIVE: To identify predictors of poorer physical function in established psoriatic arthritis (PsA). METHODS: PsA patients with disease duration of ≥10 years were identified from the Bath longitudinal cohort. Physical function was assessed using the Stanford Health Assessment Questionnaire (HAQ). Sex, age at diagnosis, duration of symptoms prior to diagnosis, smoking, treatment and year of diagnosis were included in a multivariable regression analysis to identify associations with HAQ. RESULTS: 267 patients were identified for inclusion. The median age was 56 years (IQR 45-63), median disease duration was 13 years (IQR 10-18) and median HAQ score was 0.63 (IQR 0.13-1.25). The model predicted significant increases in HAQ related to smoking (0.23, 95% CI 0.04 to 0.42), age >50 years at diagnosis (0.27, 95% CI 0.03 to 0.51), symptom duration of ≥1 year before diagnosis (0.22, 95% CI 0.02 to 0.42), female sex (0.39, 95% CI 0.20 to 0.57) and history of treatment with an anti-TNF agent (0.63, 95% CI 0.32 to 0.93) at follow-up. CONCLUSIONS: Smoking, delay to diagnosis, older age at diagnosis, female sex and a history of anti-TNF treatment are associated with worse physical function in established PsA.

Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT).

PURPOSE: The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case-population study, named SALT (Study of Acute Liver Transplant), is documented here. METHODS: This was a multicentre, multinational retrospective case-population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005-31 December 2007). Cases were patients ≥ 18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals. RESULTS: The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy. CONCLUSION: The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.

Involvement of the European Medicines Agency in multi-stakeholder regulatory science research projects: experiences of staff members and project coordinators.

Background: The European Medicines Agency (EMA) interacts with many different stakeholders involved in the development of drugs, including academic researchers. In recent years, EMA has collaborated more closely with academia, inter alia by taking part in external research projects such as those set up under the Horizon 2020 program in general and the Innovative Medicines Initiative in particular. The aim of this study was to evaluate the perceived added value of EMA's involvement in these projects, both from the perspective of the Agency's participating Scientific Officers and of the coordinators of the consortia that undertook them. Methods: Semi-structured interviews were conducted with the coordinators of 21 ongoing or recently finalized projects in which EMA has participated, as well as with the Agency experts contributing to them. Results: In total, 40 individuals were interviewed, of whom 23 were project coordinators and 17 were EMA staff members. While most of the projects were reported to suffer from delays due to the SARS-CoV-2 pandemic, the consortia adapted to the circumstances and their members still expected to deliver on their objectives. EMA's input into the projects ranged from providing guidance by reviewing documents and attending meetings to creating project materials and disseminating them. The frequency of communication between EMA and the consortia varied widely. The projects generated a diverse set of outputs, which encompassed new or improved medicinal products, methodological standards, research infrastructures, and educational tools. All of the coordinators expressed that EMA's contributions to their projects had increased the scientific relevance of their consortium's work, and the EMA experts found that the knowledge and the deliverables produced by the projects were valuable, taking into consideration the time they had invested into them. In addition, interviewees highlighted some actions which could be taken to increase the regulatory significance of the project outcomes. Conclusion: EMA's engagement in external research projects benefits the consortia conducting them and supports the Agency's mission to foster scientific excellence and advance regulatory science.

Work disability in psoriatic arthritis: a systematic review.

OBJECTIVE: Work disability (WD) is an important functional outcome measure in arthritis. There is a large body of information on WD in rheumatic diseases such as RA and AS; however, until now factors that influence WD in PsA have not been systematically reviewed. Our objective was to perform a systematic and critical review of the current literature on WD and its measurement in PsA. METHODS: A systematic literature search was conducted using Medline, Embase and Cochrane databases. The search strategy was supplemented by a manual search of cited articles. All original English language publications in the form of meta-analyses, randomized controlled trials (RCTs), observational studies and publications in abstract form were included. A quality assessment was made of the articles published in full form. RESULTS: Nineteen publications (nine in abstract form) were identified. There is intermediate quality evidence that levels of unemployment (20-50%) and WD (16-39%) are high and associated with longer disease duration, worse physical function, high joint count, low educational level, female gender, erosive disease and manual work. There is sparse low-quality evidence that WD is worse in those with PsA than psoriasis alone. CONCLUSIONS: Disability at work in those with PsA is high; however, data on its associations are limited by the small number of reports and heterogeneity of data collected. Future work should focus on the validation of WD data collection tools for use in PsA.

Colorectal cancer incidence on the General Practice Research Database.

PURPOSE: The General Practice Research Database (GPRD) contains longitudinal patient medical records collected within UK primary care. This study aimed to identify incident cases of colorectal cancer on the GPRD and to compare incidence rates for 2007 with those reported by the UK cancer registries. METHODS: Algorithms were created to identify incident cases of colorectal cancer on the GPRD and cases were required to have additional medical codes to support the diagnosis. Age-specific and sex-specific incidence rates for 2007 were calculated using the GPRD data and compared with those reported by the cancer registries. RESULTS: Trends in colorectal cancer by age and sex were similar for the two data sources; however, the incidence of colorectal cancer on the GPRD was lower than that of the registries, particularly when supporting evidence was required: 57.0 compared with 70.2 per 100 000 per year for men and 42.0 compared with 56.6 per 100 000 per year for women. Inclusion of cases without supporting evidence still resulted in lower rates but increased the GPRD rates to 63.7 and 48.4 for men and women, respectively. The largest discrepancy was observed in the older age groups. CONCLUSION: Colorectal cancer rates on the GPRD were lower than those reported by UK cancer registries, especially when requiring supporting evidence in addition to a diagnosis code. It appears that the requirement of supporting evidence on the GPRD for colorectal cancer identification may result in some true cases being excluded, particularly in the very elderly. Copyright © 2012 John Wiley & Sons, Ltd.

Administrative complexities for a European observational study despite directives harmonising requirements.

PURPOSE: For pharmacoepidemiological studies in Europe, accessing data should require only authorisation by the relevant data protections committees, as expected from the 1995 Data Protection Directive (95/46/EC). Our experience from a multinational observational study across seven European countries shows that this is certainly not the case. METHODS: The study was a multicentre, multinational, case-population study in European liver transplant centres in seven countries, retrospectively evaluating a 3-year period. Before data collection started, the procedures to obtain the necessary authorisations for the participating countries were defined. REMARKS: In France, a single opinion from a single data protection committee was enough to start the study. In Italy, Portugal, Greece and the UK, there was a national authority, but the hospitals requested the approval by their local committees/bodies irrespective of whether the authorisation of the national committee came after or before that of local ones. In Ireland, only one hospital participated, and the opinion of its ethics committee was sufficient. In the Netherlands, the opinion of the institutional review board of the local coordinating centre was necessary to obtain the opinions from the institutional review boards of the other hospitals. The information requested by the different committees and the time to obtain the approvals varied, even within the same country. CONCLUSION: This degree of complexity and disharmony, and resulting cost, was observed in a simple retrospective study. Regulators will need to be aware that these time-consuming, expensive and useless complexities must be factored in when estimating the time and cost of a study.

The incidence of primary glomerulonephritis worldwide: a systematic review of the literature.

BACKGROUND: Little is known about the worldwide variation in incidence of primary glomerulonephritis (GN). The objective of this review was to critically appraise studies of incidence published in 1980-2010 so that an overall view of trends of these diseases can be found. This would provide important information for determining changes in rates and understanding variations between countries. METHODS: All relevant papers found through searches of Medline, Embase and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. RESULTS: This review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada, Australasia and the Middle East. Rates for the individual types of disease were found to be in adults, 0.2/100,000/year for membrano-proliferative GN, 0.2/100,000/year for mesangio-proliferative GN, 0.6/100,000/year for minimal change disease, 0.8/100,000/year for focal segmental glomerulosclerosis, 1.2/100,000/year for membranous nephropathy and 2.5/100,000/year for IgA nephropathy. Rates were lower in children at around 0.1/100,000/year with the exception of minimal change disease where incidence was reported to be 2.0/100,000/year in Caucasian children with higher rates in Arabian children (9.2/100,000/year) and Asian children (6.2-15.6/100,000/year). CONCLUSIONS: This study found that incidence rates of primary GN vary between 0.2/100,000/year and 2.5/100,000/year. The incidence of IgA nephropathy is at least 2.5/100,000/year in adults; this disease can exist subclinically and is therefore only detected by chance in some patients. In addition, referral policies for diagnostic biopsy vary between countries. This will affect the incidence rates found.

Assuring Access to Safe Medicines in Pregnancy and Breastfeeding.

Scientists and regulators in Europe and the United States continue to seek methods and strategies to improve knowledge on rational use of medicines for pregnant and breastfeeding populations, an important subset of women's health. Regulatory agencies have made strides toward improvement, but much more is needed. Recognizing the importance of international collaboration, we have begun to consider how to address these important public health issues more globally. The health of the child begins with the health of the mother.

Strengthening regulatory science in academia: STARS, an EU initiative to bridge the translational gap.

Truly disruptive medicine innovation and new treatment paradigms tend to start in non-commercial research institutions. However, the lack of mutual understanding between medicine developers and regulators when it comes to medicine development significantly delays or even prevents the access of patients to these innovations. Here, we outline what regulatory-related barriers hamper the translational development of novel products or new treatment paradigms initiated in academia, and propose key steps towards improved regulatory dialogue among academia, funding bodies and regulatory authorities. Moreover, we briefly describe how the STARS (Strengthening Training of Academia in Regulatory Science) project aims to reach out to medicine innovators in academia to bridge the regulatory knowledge gap and enhance this dialogue to facilitate the implementation of academic research findings in clinical practice.

The incidence of myasthenia gravis: a systematic literature review.

BACKGROUND: A systematic review of literature published between 1980 and 2007, on the incidence of myasthenia gravis, was undertaken. METHODS: All relevant papers found through searches of Medline, Embase and Science Direct were critically appraised and an assessment was made of the reliability of the reported incidence data. RESULTS: Thirty-one studies were included in the review, the majority of which investigated populations in Europe. The incidence rates reported were between 3.0 and 30.0/1,000,000/year. However, it is thought that the rates at the upper end of this range, reported by the prospective studies, provided the most accurate estimates. Overall, incidence rates have increased over time owing to a greater awareness of the disease and improved methods of diagnosis. CONCLUSIONS: The most accurate estimate of incidence of myasthenia gravis was around 30/ 1,000,000/year. The incidence in children and adolescents aged 0-19 years was found to be between 1.0 and 5.0/ 1,000,000/year. The rates presented in this review are likely to be an underestimate of the true incidence rates, as mild cases will have been missed and cases in the elderly will have been misdiagnosed.

The epidemiology of Guillain-Barré syndrome worldwide. A systematic literature review.

BACKGROUND: This systematic literature review of the epidemiology of Guillain-Barré syndrome (GBS) identifies trends in incidence rates by age, study method and cause of disease. It is important to have a reliable estimate of incidence to determine and investigate any changes: no previous systematic reviews of GBS have been found. METHODS: After critical assessment of the reliability of the reported data, incidence rates were extracted from all relevant papers published between 1980 and 2008, identified through searches of Medline, Embase and Science Direct. RESULTS: Sixty-three papers were included in this review; these studies were prospective, retrospective reviews of medical records or retrospective database studies. Ten studies reported on the incidence in children (0-15 years old), and found the annual incidence to be between 0.34 and 1.34/100,000. Most studies investigated populations in Europe and North America and reported similar annual incidence rates, i.e. between 0.84 and 1.91/100,000. A decrease in incidence over the time between the 1980s and 1990s was found. Up to 70% of cases of GBS were caused by antecedent infections. CONCLUSIONS: Our best estimate of the overall incidence of GBS was between 1.1/100,000/year and 1.8/100,000/year. The incidence of GBS increased with age after 50 years from 1.7/100,000/year to 3.3/100,000/year.

The incidence of autoimmune thyroid disease: a systematic review of the literature.

OBJECTIVE: To undertake a systematic review of literature published between 1980 and 2008 on the incidence of autoimmune thyroid disease. DESIGN: All relevant papers found through searches of Medline, EMBASE and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. RESULTS: The reported incidence of autoimmune hypothyroidism varied between 2.2/100 000/year (males) and 498.4/100 000/year (females) and for autoimmune hyperthyroidism, incidence ranged from 0.70/100 000/year (Black males) to 99/100 000/year (Caucasian females). Higher incidence rates were found in women compared to men for all types of autoimmune thyroid disease. The majority of studies included in the review investigated Caucasian populations mainly from Scandinavia, Spain, the UK and the USA. It is possible that nonautoimmune cases were included in the incidence rates reported here, which would give an overestimation in the incidence rates of autoimmune disease presented. CONCLUSION: To our knowledge this is the most comprehensive systematic review of autoimmune thyroid disease conducted in the past two decades. Studies of incidence of autoimmune thyroid disease have only been conducted in a small number of mainly western countries. Our best estimates of the incidence of hypothyroidism is 350/100 000/year in women and 80/100 000/year in men; the incidence of hyperthyroidism is 80/100 000/year in women and 8/100 000/year in men.

Data resources for investigating drug exposure during pregnancy and associated outcomes: the General Practice Research Database (GPRD) as an alternative to pregnancy registries.

Pregnancy registries are the most commonly used data resource for the post-marketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literature review identified further observational data sources that monitor pregnancy outcomes for future evaluation. Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for a range of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry. Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.

Reanalysis of two studies with contrasting results on the association between statin use and fracture risk: the General Practice Research Database.

BACKGROUND: Two recent case-control studies by Meier et al. and van Staa et al. used the UK General Practice Research Database (GPRD) to examine the association between the use of statins and the risk of fractures, with different results. The objective of the present study was to examine methodological explanations for the discrepant results. METHODS: We created two datasets, which mimicked the previous study designs: a 'selected population' (SP) case-control dataset, with fracture cases matched to controls nested within a selected cohort (Meier et al.), and an 'entire population' (EP) case-control dataset, with both cases and controls sampled from the total GPRD population (van Staa et al.). Cases and controls were matched by gender, age (year of birth or 5 year age bands), and general practice. RESULTS: The study included 131 855 fracture cases. The crude odds ratio (OR) for hip fracture in statin users was 0.37 (95% CI 0.27-0.52) in the SP and 0.54 (95% CI 0.39-0.74) in the EP dataset. This difference was reduced when matching by year of birth, rather than by 5 year age bands: crude ORs were 0.58 (95% CI 0.43-0.79) and 0.61 (95% CI 0.44-0.88), respectively. In the SP dataset, 37% of the cases could be matched by year of birth, while this was achieved for 99% in the 'EP' dataset. The exposure time-window, the selection of confounders, and exclusion of high-risk patients also influenced results. CONCLUSION: Residual confounding by a matching variable and different definitions of the exposure time window explained differences in results. In case-control studies of drug use and fracture risk, broad matching criteria for age should be avoided and the selection of the time-window for exposure should be carefully considered.

Hormone replacement therapy and risk of acute myocardial infarction : a review of the literature.

Many animal studies and studies on intermediate clinical endpoints have shown hormone replacement therapy (HRT) to be associated with both favourable and unfavourable cardiovascular effects. We reviewed the literature regarding HRT and the distinct endpoint of acute myocardial infarction (AMI) in peri- and postmenopausal women. Searches of the MEDLINE and EMBASE databases were conducted. Fifty papers were identified as eligible for inclusion: eight randomised controlled trials, 18 cohort studies, 23 case-control studies and one case-control and cohort study. The single large primary prevention randomised controlled trial on HRT and the risk of AMI in generally healthy women (Women's Health Initiative trial) reported a small yet significantly increased risk of AMI in postmenopausal women receiving combined HRT. This contrasts with a large number of observational studies that suggested a protective effect, although in many of these studies the results were not statistically significant. Inconclusive evidence on the effect of duration of use does not support the notion that a possible protective association is causal. Detection bias and residual confounding are alternative explanations for the associations observed in the randomised controlled trial and observational studies. No studies on groups of women with existing cardiovascular disease or with diabetes mellitus, including the only large secondary prevention trial (Heart and Estrogen/Progestin Replacement Study), reported a significant change in AMI risk between HRT users and non-users. There is insufficient evidence to suggest that HRT is associated with a change in the risk of AMI in the majority of women. However, certain subgroups of women with specific genetic polymorphisms may be more susceptible to a change in the risk of AMI with HRT use.