Xavier Kurz

Bridging Differences in Outcomes of Pharmacoepidemiological Studies: Design and First Results of the PROTECT Project

Background: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. Purpose: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. Methods: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. Results: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. Conclusion: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

Evaluation of the effectiveness of risk minimization measures

Before the introduction of risk management planning (RMP), pharmacovigilance was usually considered a series of process steps starting with data collection through signal detection, risk evaluation, action to protect public health, communication, and then evaluation of the effectiveness of the actions taken (a process step that was only rarely taken in practice). The introduction of RMP has ensured greater proactivity to pharmacovigilance and postauthorization benefit risk management. The final and perhaps most difficult step is the introduction of systematic evaluation of the effectiveness of risk minimization measures (RMM), thereby demonstrating public health protection.1

Autoimmune disorders after immunisation with Influenza A/H1N1 vaccines with and without adjuvant: EudraVigilance data and literature review

All suspected autoimmune disorders (AID) reported as adverse reactions to EudraVigilance from 1 October 2009 to 31 December 2010 for adjuvanted (Celtura™, Fluval P™, Focetria™ and Pandemrix™) and non-adjuvanted (Cantgrip™, Celvapan™ and Panenza™) pandemic Influenza A/H1N1 vaccines were analysed to determine whether adjuvanted vaccines were associated with higher reporting of AID than non-adjuvanted ones. AID were identified based on the corresponding MedDRA High Level Group Term. Reports of type 1 diabetes mellitus and multiple sclerosis were also included in the analysis. Causality was assessed based on WHO causality assessment for adverse events following immunisation and Brighton Collaboration criteria for Guillain-Barré syndrome (GBS), idiopathic thrombocytopenic purpura and acute disseminated encephalomyelitis. Of the 50,221 adverse reactions received in EudraVigilance for A/H1N1 vaccines (adjuvanted: 46,173, non-adjuvanted: 4048), 314 were AID (adjuvanted: 276, non-adjuvanted: 38). GBS was the AID with the highest number of reports (125, adjuvanted: 109, non-adjuvanted: 16). Reporting ratios as calculated by the percentages of AID amongst all reported adverse reactions were 0.60% (95% CI: 0.53-0.67) and 0.94% (95% CI: 0.64-1.24) for adjuvanted and non-adjuvanted vaccines, and were 0.26% (95% CI: 0.22-0.31) and 0.37% (95% CI: 0.18-0.56) in a restricted analysis based on diagnostic certainty, causal relationship and plausible temporal association. Reporting rates for all reports of AID using the estimated number of vaccinees as denominator were 6.87 (95% CI: 6.06-7.68) and 9.98 (95% CI: 6.81-13.16) per million for adjuvanted and non-adjuvanted vaccines, and 3.01 (95% CI: 2.47-3.55) and 3.94 (95% CI: 1.95-5.94) per million in the restricted analysis. These results do not suggest a difference in the reporting of AID between adjuvanted and non-adjuvanted A/H1N1 vaccines. In a literature review performed on 31 August 2011, GBS was also the AID the most frequently discussed in association with A/H1N1 vaccination; reporting rates were generally within expected background rates.

Reliability Study of the Leg-O-Meter, an Improved Tape Measure Device, in Patients with Chronic Venous Insufficiency of the Leg

The objective of this study was to evaluate the inter-rater reliability of the Leg-O-Meter, an instrument designed to measure the ankle or calf circumference. The Leg-O-Meter consists of a tape measure fixed to a stand attached to a small board on which the patient is in standing position. For this study the tape measure of the Leg-O-Meter was fixed at 10 cm from the board in order to standardize all measurements. Informed consent to participate in the study was obtained from 39 patients consulting the phlebology clinic of Hôpital St-Michel, Paris, France. Participants were asked to enter a closed room where four independent and blinded observers consecutively took measurements of both legs with the Leg-O-Meter. The order of the observers was randomized between patients. Under the assumption of a two-way random effects model an intraclass correlation coef ficient (ICC) was used to determine the reliability or reproducibility of a measure with the Leg-O-Meter. The overall reliability coefficient calculated by the ICC for the right and left leg were estimated at 97.09% [95.52%;100%] 950,o and 97.08% [95.86%;100%]95%, respectively. The authors conclude that the Leg-O-Meter gives a standardized and reliable measure of the circumference of the ankle. Furthermore, it is not invasive or costly.

Safety monitoring of Influenza A/H1N1 pandemic vaccines in EudraVigilance

The 14,543 spontaneous reports of suspected adverse reactions received in EudraVigilance from 1 November 2009 to 30 April 2010 for three centrally authorized Influenza A/H1N1 vaccines marketed in the European Economic Area (Celvapan, Focetria and Pandemrix) were extracted to evaluate the effectiveness of recommendations to strengthen pharmacovigilance systems during the pandemic and illustrate methods of signal detection used by the European Medicines Agency in this context. The number of vaccinees on 30 April 2010 was estimated to be at least 37,166,000 with a reporting rate of 391 per million vaccinees. 81.4% of reports were received in a period of 2 months ending 31 December 2009. Reports for A/H1N1 vaccines had fewer missing values for date of birth, age, case narrative, vaccination date and reaction onset date than reports involving human papilloma virus vaccines in a pre-pandemic period but more missing batch numbers (46.6%), with earlier notification by health care professionals to national authorities (median of 7 days since reaction onset date) and by national authorities to EudraVigilance (4 days). The network of European pharmacovigilance centers and the Agency was effective for monitoring the safety of A/H1N1 vaccines during the 2009-2010 influenza pandemic and coped with a sudden increase of the number of reports. Areas to be reinforced in order to improve the response to a future pandemic and to strengthen vaccine pharmacovigilance systems in general are highlighted. Observed-to-expected analyses were affected by uncertainties regarding the numbers of vaccinated individuals and age-specific background incidence rates. Imbalance analysis used by the Agency may overcome some of these limitations but needs further development. A multinational vaccine health outcome resource is needed to assess the burden of vaccine preventable diseases and the epidemiology of potential adverse outcomes, and to quickly evaluate safety signals, estimate the utilization, benefits and risks of vaccines and evaluate the effectiveness of public health measures.

Increasing scientific standards, independence and transparency in post‐authorisation studies: the role of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), an initiative coordinated by the European Medicines Agency, aims to build capacity for and increase trust in post‐authorisation studies to further support medicine decision making.

New approaches to strengthen pharmacovigilance

Until recently, pharmacovigilance was mainly based on spontaneous reports, which provide low evidence of risks associated with medicines. Today, the importance of the full spectrum of the evidence hierarchy is recognised. This article reviews new approaches and data sources used in pharmacovigilance and shows that individual case safety reports, observational data, clinical trials and meta-analyses have unique characteristics that complement each other for the overall benefit–risk evaluation of medicines.

Calcium channel blockers and cancer : A risk analysis using the UK Clinical Practice Research Datalink (CPRD)

Objective The evidence of an association between calcium channel blockers (CCBs) and cancer is conflicting. The objective of the present study was to evaluate the risk of cancer (all, breast, prostate and colon cancers) in association with exposure to CCB. Methods This is a population-based cohort study in patients exposed to CCBs from across the UK, using two comparison cohorts: (1) patients with no exposure to CCB (non-CCB) matched on age and gender and (2) unmatched patients unexposed to CCB and at least one other antihypertensive (AHT) prescription. Cancer incidence rates computed in the exposed and the two unexposed groups were compared using HRs and 95% CIs obtained from multivariate Cox regression analyses. Results Overall, 150 750, 557 931 and 156 966 patients were included, respectively, in the CCB, non-CCB and AHT cohorts. Crude cancer incidence rates per 1000 person-years were 16.51, 15.75 and 10.62 for the three cohorts, respectively. Adjusted HRs (CI) for all cancers comparing CCB, non-CCB and AHT cohorts were 0.88 (0.86 to 0.89) and 1.01 (0.98 to 1.04), respectively. Compared to the AHT cohort, adjusted HRs (CI) for breast, prostate and colon cancer for the CCB cohort were 0.95 (0.87 to 1.04), 1.07 (0.98 to 1.16) and 0.89 (0.81 to 0.98), respectively. Analyses by duration of exposure to CCB did not show excess risk. Conclusions This large population-based study provides strong evidence that CCB use is not associated with an increased risk of cancer. The analyses yielded robust results across all types of cancer and different durations of exposure to CCBs.

Multi-centre, multi-database studies with common protocols: Lessons learnt from the IMI PROTECT project

To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases.

Measuring the impact of medicines regulatory interventions – Systematic review and methodological considerations

Evaluating the public health impact of regulatory interventions is important but there is currently no common methodological approach to guide this evaluation. This systematic review provides a descriptive overview of the analytical methods for impact research.