Additional risk minimisation measures in the EU - are they eligible for assessment?

Purpose: "Additional" risk minimisation measures (aRMMs) can be necessary to optimise the benefit-risk balance of a drug. Evaluation of effectiveness of these measures has become mandatory with the new European Union (EU) pharmacovigilance legislation in force since July 2012. The aim of this study was to classify the aRMMs in the EU with a special emphasis on the possibilities to analyse the effectiveness of these aRMMs in existing electronic healthcare databases (EHDs).

The role of Periodic Safety Update Reports in the safety management of biopharmaceuticals.

Purpose: To describe and assess the outcomes of Periodic Safety Update Report (PSUR) evaluations of biopharmaceuticals.

Methods: A cross-sectional analysis was performed of follow-up requirements of PSURs submitted for centrally approved biopharmaceuticals in the European Union between 1 July 2008 and 30 June 2010. A follow-up analysis on a subset of products that submitted multiple PSURs within the study period was also performed.

A cohort study exploring determinants of safety-related regulatory actions for biopharmaceuticals.

Background: The characteristics of biopharmaceuticals may require a tailored approach to their safety management. However, information on what tools and methods are employed to assess the safety of biopharmaceuticals post-authorization is lacking.

Objective: This study investigates determinants that contribute to the post-authorization management of biopharmaceuticals.

Risk minimization activities of centrally authorized products in the EU: a descriptive study.

Background: : Since the new legislation on risk management, which came into force in November 2005, an EU Risk Management Plan (EU-RMP) is a required part of the authorization dossier of innovative drugs licensed in the EU. The EU-RMP can include additional risk minimization activities (RMAs) to strengthen the benefit-risk balance of a drug. This study describes the additional RMAs of centrally authorized medicinal products authorized between 1 January 1995 and 1 January 2010.

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate.

Gene-environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip and/or cleft palate (CL/P). The P-glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CL/P offspring.

Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population.

Background: The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.

Methods: One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles).

Angiotensin-converting enzyme insertion/deletion polymorphism and risk and outcome of pneumonia.

Background: Recent studies have suggested involvement of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism in the susceptibility to and severity of community-acquired pneumonia (CAP) in Asian populations. We have explored the hypothesis that the ACE I/D polymorphism affects the risk and outcome of CAP in a Dutch white population.

Methods: This is a hospital-based prospective observational study including patients with CAP admitted between October 2004 and August 2006.

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer.

Purpose: As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN).

Methods: A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI).

The cholesteryl ester transfer protein I405V polymorphism is associated with increased high-density lipoprotein levels and decreased risk of myocardial infarction: the Rotterdam Study.

Background And Design: The effect of the cholesteryl ester transfer protein (CETP) I405V polymorphism on lipid levels, atherosclerosis and myocardial infarction (MI) was examined in 6421 participants from the Rotterdam Study.

Methods: Quantitative outcomes were studied with linear models; Cox models were used to assess MI risk.

Results: High-density lipoprotein cholesterol (HDL) increased by 0.

Effects of the renin-angiotensin system genes and salt sensitivity genes on blood pressure and atherosclerosis in the total population and patients with type 2 diabetes.

Most studies on the genetic determinants of blood pressure and vascular complications of type 2 diabetes have focused on the effects of single genes. These studies often have yielded conflicting results. Therefore, we examined the combined effects of three renin-angiotensin system (RAS) genes and three salt sensitivity genes in relation to blood pressure and atherosclerosis in the total population and type 2 diabetic patients.

Epistatic effect of cholesteryl ester transfer protein and hepatic lipase on serum high-density lipoprotein cholesterol levels.

Objectives: Polymorphisms in the hepatic lipase (LIPC -514C > T) and cholesteryl ester transfer protein (CETP I405V) genes affect high-density lipoprotein cholesterol (HDL-c) levels, but their relationship with cardiovascular disease and their combined effect is unclear. The objectives of the current study were to characterize the effect of the hepatic lipase variant, and its interaction with the CETP variant, in terms of cholesterol levels, atherosclerosis, and risk of myocardial infarction (MI).

Design: The study was conducted in the Rotterdam Study, a large single-center prospective cohort study in people aged 55 yr and older.

Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: a meta-analysis.

Several studies have reported an association between hyperhomocysteinemia, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and cleft lip with or without cleft palate (CLP), and congenital heart defects (CHDs). However, findings have been inconsistent. A meta-analysis was performed of published studies until September 2006 investigating these associations in both mothers and children.

Heritabilities, apolipoprotein E, and effects of inbreeding on plasma lipids in a genetically isolated population: the Erasmus Rucphen Family Study.

Despite considerable progress in unravelling the genetic basis of dyslipidemias, most findings are based on families with extreme phenotypes. We studied lipid levels in an extended pedigree ascertained irrespective of phenotype from the population of a recent genetic isolate in the Netherlands. Heritabilities of plasma lipid measures were examined; this analysis also included estimates of the proportion of variance attributable to ApoE genotype.

IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes.

Objective: Previously we observed that non-carriers of the most common alleles of an IGF-I promoter polymorphism have low circulating IGF-I levels and an increased risk of developing myocardial infarction (MI), particularly in patients with type 2 diabetes.

Design: We investigated whether this IGF-I promoter polymorphism is associated with survival of type 2 diabetes in a Caucasian population aged 55 years and older.

Methods: The study was embedded in the Rotterdam Study, a prospective population-based cohort study.

The alpha-adducin gene is associated with macrovascular complications and mortality in patients with type 2 diabetes.

We examined the association between alpha-adducin 1 (ADD1) gene polymorphism (Gly460Trp) with macrovascular complications and mortality in type 2 diabetes in a Caucasian population aged >or=55 years. The study was part of the Rotterdam Study, a prospective population-based cohort study. ADD1 polymorphism was determined in 6,471 participants, including 599 patients with type 2 diabetes at baseline.

Interleukin 6 -174 g/c promoter polymorphism and risk of coronary heart disease: results from the rotterdam study and a meta-analysis.

Objective: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Interleukin (IL) 6 has many inflammatory functions, and the IL-6 -174 G/C promoter polymorphism appears to influence IL-6 levels. Findings of previous studies on the relation between this polymorphism and risk of cardiovascular diseases are inconsistent.

Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk.

Background: The renin-angiotensin system plays an important role in homeostasis and lately, its main effector, angiotensin II, has been attributed with angiogenic and growth factor actions in the breast tissue. Previous studies have shown that the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for the variability of ACE plasma concentrations. The use of ACE inhibitors and the ACE I/D polymorphism may be linked to breast cancer risk.

The association between angiotensin-converting enzyme gene polymorphism and coronary calcification. The Rotterdam Coronary Calcification Study.

Background: An insertion/deletion (I/D) polymorphism in the gene encoding angiotensin-converting enzyme (ACE) has been associated with serum ACE levels. The association between the ACE I/D polymorphism and coronary heart disease is unclear. Electron-beam-computed tomography (EBT) is a technique to non-invasively quantify the amount of coronary calcification.

The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis.

Background: We conducted a meta-analysis to re-evaluate the role of the dopamine D4 receptor gene 48-base-pair- repeat (DRD4) polymorphism in mood disorders.

Methods: DRD4 allele frequencies were compared between 917 patients with unipolar (UP) or bipolar affective disorder (BP) and 1164 control subjects from 12 samples, using the Cochrane Review Manager.

Results: An association was found between all mood disorder groups and DRD4.

The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.

Investigations of the -514 C-->T single nucleotide polymorphism (SNP) in the hepatic lipase (HL) gene promoter region (LIPC) have yielded contradictory results regarding its association with changes in plasma lipids. The current study is a meta-analysis of 25 publications on this SNP, comprising over 24,000 individuals, and its relationship with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and HL activity. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype [weighted mean difference (WMD), -5.

Angiotensin-converting enzyme gene polymorphism and common carotid stiffness. The Rotterdam study.

The insertion/deletion (I/D) polymorphism of the ACE gene may be involved in structural arterial changes. Aim of the present study was to assess the relationship between the ACE I/D gene and vessel wall stiffness among older adults. The study was conducted within the Rotterdam study, a population-based cohort study including subjects aged 55 years and older.

Smoking-dependent effects of the angiotensin-converting enzyme gene insertion/deletion polymorphism on blood pressure.

Background: Studies on the role of the angiotensin-converting enzyme (ACE) gene in the development of hypertension have yielded conflicting results. Recent studies suggested that this gene might have smoking-dependent effects on the development of cardiovascular disease.

Objective: To study the relationship between the ACE insertion/deletion (I/D) polymorphism, blood pressure and risk of hypertension in current, former and non-smokers in a population-based cohort.

Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta-analysis.

Background And Purpose: Many studies have investigated the association between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and carotid artery intima-media thickness (IMT); however, most studies were small and conducted in selective samples. The aim of this study was to evaluate this association by performing a meta-analysis on published articles.

Methods: We searched Medline for articles studying the association between the ACE I/D polymorphism and carotid IMT.