Characteristics of drugs safety signals that predict safety related product information update

Purpose: Investigation of drug safety signals is one of the major tasks in pharmacovigilance. Among many potential signals identified, only a few reflect adverse drug reactions requiring regulatory actions, such as product information (PI) update. Limited information is available regarding the signal characteristics that might predict PI update following signal evaluation. The objective of this study was to identify signal characteristics associated with PI updates following signal evaluation by the European Medicines Agency Pharmacovigilance Risk Assessment Committee during 2012 to 2016. Methods: A comparative study was performed based on data from 172 safety signals. Characteristics of signals were extracted from the European Pharmacovigilance Issues Tracking Tool database. Multivariable logistic regression analysis was used to assess the relationship between signal characteristics and the decision to update the PI. Results: Multivariable logistic regression analysis showed that the presence of evidence in multiple types of data sources (adjusted odds ratio [OR] 7.8 95% CI [1.5, 40.1]); mechanistic plausibility of the drug-event association (adjusted OR 3.9 95% CI [1.9, 8.0]); seriousness of the event (adjusted OR 4.2 95% CI [1.3, 13.9]); and age of drugs ≤5 years (adjusted OR 3.9 95% CI [1.2, 12.7]) were associated with the decision to change the PI (P < 0.05). Conclusions: This study identified 4 characteristics of drug safety signals that have shown to be associated with PI changes as outcome of signal evaluation. These characteristics may be used as criteria for selection and prioritization of potential signals that are more likely to necessitate product information updates

The Application and Implications of Novel Deterministic Sensitivity Analysis Methods

Deterministic sensitivity analyses (DSA) remain important to interpret the effect of uncertainties in individual parameters on results of cost-effectiveness analyses. Classic DSA methodologies may lead to wrong conclusions due to a lack of or misleading information regarding marginal effects, non-linearity, likelihood and correlations. In addition, tornado diagrams are misleading in some situations. Recent advances in DSA methods have the potential to provide decision makers with more reliable information regarding the effects of uncertainties in individual parameters. This practical application discusses advances to classic DSA methods and their implications. Three methods are discussed: stepwise DSA, distributional DSA and probabilistic DSA. For each method, the technical specifications, options for presenting results, and its implications for decision making are discussed. Options for visualizing DSA results in incremental cost-effectiveness ratios and in incremental net benefits are presented. The use of stepwise DSA increases interpretability of marginal effects and non-linearities in the model, which is especially relevant when arbitrary ranges are implemented. Using the probability distribution of each parameter in distributional DSA provides insight on the likelihood of model outcomes while probabilistic DSA also includes the effects of correlations between parameters. Probabilistic DSA, preferably expressed in incremental net benefit, is the most appropriate method for providing insight on the effect of uncertainty in individual parameters on the estimate of cost effectiveness. However, the opportunities provided by probabilistic DSA may not always be needed for decision making. Other DSA methods, in particular distributional DSA, can sometimes be sufficient depending on model features. Decision makers must determine to which extent they will accept and implement these new and improved DSA methodologies and adjust guidelines accordingly

Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands

Aim The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. Methods A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. Results In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). Conclusions Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity

Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: The Rotterdam Study

Background: In The Netherlands, costs of HMG-CoA reductase inhibitor (statin) use have recently increased sharply compared with costs of other drugs. However, several studies have established both undertreatment and non-guidelines-indicated treatment with statins, suggesting a suboptimal use of resources. Objective: To estimate the drug costs associated with non-guidelines-indicated treatment and undertreatment with statins in an elderly population. Patients and setting: Data were obtained from the Rotterdam Study, a population-based prospective cohort study which began in 1990 with 7983 participants aged ≥55 years. Subjects with a history of cardiovascular disease (CVD) were excluded. Pharmacy records were used to assess patterns of medication use in daily medical practice. Main outcome measure: Non-guidelines-indicated treatment and undertreatment with statins were established in relation to Dutch cholesterol management guidelines for all participants. We calculated the costs of statin therapy associated with non-guidelines-indicated treatment, and the