Carmen Kreft-Jais

Antipsychotics‐induced ischaemic colitis and gastrointestinal necrosis: a review of the French pharmacovigilance database

First‐ and second‐generation antipsychotics commonly cause mild gastrointestinal hypomotility. Intestinal necrosis may be a consequence of such gastrointestinal perturbations.

Bayesian pharmacovigilance signal detection methods revisited in a multiple comparison setting

Pharmacovigilance spontaneous reporting systems are primarily devoted to early detection of the adverse reactions of marketed drugs. They maintain large spontaneous reporting databases (SRD) for which several automatic signalling methods have been developed. A common limitation of these methods lies in the fact that they do not provide an auto-evaluation of the generated signals so that thresholds of alerts are arbitrarily chosen. In this paper, we propose to revisit the Gamma Poisson Shrinkage (GPS) model and the Bayesian Confidence Propagation Neural Network (BCPNN) model in the Bayesian general decision framework. This results in a new signal ranking procedure based on the posterior probability of null hypothesis of interest and makes it possible to derive with a non-mixture modelling approach Bayesian estimators of the false discovery rate (FDR), false negative rate, sensitivity and specificity. An original data generation process that can be suited to the features of the SRD under scrutiny is proposed and applied to the French SRD to perform a large simulation study. Results indicate better performances according to the FDR for the proposed ranking procedure in comparison with the current ones for the GPS model. They also reveal identical performances according to the four operating characteristics for the proposed ranking procedure with the BCPNN and GPS models but better estimates when using the GPS model. Finally, the proposed procedure is applied to the French data.

Adverse drug reactions in patients with Alzheimer's disease and related dementia in France: a national multicentre cross‐sectional study

To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimers disease (AD) or other dementia in France.

Isotretinoin exposure during pregnancy: assessment of spontaneous reports in France.

AbstractBackground: In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study. Objective: To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands. Methods: All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: ‘conception <1 month after isotretinoin discontinuation’, ‘conception during isotretinoin treatment’ and ‘patient already pregnant when isotretinoin was started’. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of child-bearing age treated with isotretinoin. Results:Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. ‘conception <1 month after isotretinoin discontinuation’ (23%), ‘conception during isotretinoin treatment’ (61%), and ‘patient already pregnant when isotretinoin was started’ (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999–2002. Conclusions:We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.

Early detection of pharmacovigilance signals with automated methods based on false discovery rates: a comparative study.

AbstractBackground: Improving the detection of drug safety signals has led several pharmacovigilance regulatory agencies to incorporate automated quantitative methods into their spontaneous reporting management systems. The three largest worldwide pharmacovigilance databases are routinely screened by the lower bound of the 95% confidence interval of proportional reporting ratio (PRR02.5), the 2.5% quantile of the Information Component (IC02.5) or the 5% quantile of the Gamma Poisson Shrinker (GPS05). More recently, Bayesian and non-Bayesian False Discovery Rate (FDR)-based methods were proposed that address the arbitrariness of thresholds and allow for a built-in estimate of the FDR. These methods were also shown through simulation studies to be interesting alternatives to the currently used methods. Objective: The objective of this work was twofold. Based on an extensive retrospective study, we compared PRR02.5, GPS05 and IC02.5 with two FDR-based methods derived from the Fisher’s exact test and the GPS model (GPSpH0 [posterior probability of the null hypothesis H0 calculated from the Gamma Poisson Shrinker model]). Secondly, restricting the analysis to GPSpH0, we aimed to evaluate the added value of using automated signal detection tools compared with ‘traditional’ methods, i.e. non-automated surveillance operated by pharmacovigilance experts. Methods: The analysis was performed sequentially, i.e. every month, and retrospectively on the whole French pharmacovigilance database over the period 1 January 1996–1 July 2002. Evaluation was based on a list of 243 reference signals (RSs) corresponding to investigations launched by the French Pharmacovigilance Technical Committee (PhVTC) during the same period. The comparison of detection methods was made on the basis of the number of RSs detected as well as the time to detection. Results: Results comparing the five automated quantitative methods were in favour of GPSpH0 in terms of both number of detections of true signals and time to detection. Additionally, based on an FDR threshold of 5%, GPSpH0 detected 87% of the RSs associated with more than three reports, anticipating the date of investigation by the PhVTC by 15.8 months on average. Conclusions: Our results show that as soon as there is reasonable support for the data, automated signal detection tools are powerful tools to explore large spontaneous reporting system databases and detect relevant signals quickly compared with traditional pharmacovigilance methods.

First French Experience of ADR Reporting by Patients After a Mass Immunization Campaign with Influenza A (H1N1) Pandemic Vaccines

AbstractBackground: Available data concerning the contribution of patient adverse drug reaction (ADR) reporting in practice are scarce. Few studies have compared patients’ reports with reports from healthcare professionals (HCPs). During the 2009–10 mass immunization campaign with A (H1N1)v2009 pandemic influenza vaccines, a reinforced pharmacovigilance plan was introduced in France according to European Medicines Agency recommendations. For the first time, patients were offered the opportunity to report suspected ADRs to pandemic vaccines directly to regional pharmacovigilance centres. Objective: The aim of the study was to compare the characteristics of patient and HCP ADR reports in order to assess the qualitative and quantitative contribution of patient reporting to the French Pharmacovigilance System. Methods: All spontaneous ADRs registered into the French Pharmacovigilance Database from 21 October 2009 to 15 June 2010, in which either one of the most frequently administered pandemic vaccines (i.e. Panenza® or Pandemrix®) was involved, were analysed. ADRs were classified as ‘serious’, ‘medically serious’ and ‘non-serious’. This study focused on ‘serious’ and ‘medically serious’ ADRs. An ADR was ranked as ‘medically serious’ when it required medical intervention or hospitalization within less than 24 hours. In each level of seriousness, frequency of ‘unlabelled’ ADRs, ADRs of ‘special interest’, imputability scores and category of ADRs according to Medical Dictionary for Regulatory Activitives (MedDRA®) primary System Organ Class were compared between patient and professional reports. Results: Among the 4746 reports received during the study period, 1006 (21.2%) originated from patients. HCPs reported significantly more ‘medically serious’ or ‘serious’ ADRs than patients (15.1% [565/3740] vs 8.4% [85/1006], respectively; p < 0.001). No difference was found in ‘unlabelled, serious’ ADRs between patients and HCPs (56.5% [n= 13] vs 56.7% [n= 136], respectively). Conclusions: In this first French experience of formal patient participation to ADR reporting, patient contribution to the total number of ADRs reached 21.2%. This study revealed no major qualitative difference between patient and HCP reports. ADR profiles reported by patients appeared to be consistent with those from professionals. Further investigations are necessary to assess the intrinsic quality of notification forms coming from non-professional reporters. However, this study is of particular interest in the context of publication of the first governmental decree that will formally integrate patient participation to the current French ADR reporting scheme.

Association between concomitant use of several systemic NSAIDs and an excess risk of adverse drug reaction. A case/non-case study from the French Pharmacovigilance system database

AimsTo examine whether the risk of some selected adverse effects increases with the number of systemic non-steroidal anti-inflammatory (NSAID) drugs.MethodsThe French Pharmacovigilance database was examined for an association between drug reaction reports and the exposure to one and two or more NSAIDs using a case/non-case study design. In the analysis, 54,583 spontaneous reports of adverse drug reactions were included, consisting of 2270 reports of hepatic injury, 994 reports of acute renal failure, 194 reports of gastrointestinal bleeding and 525 reports of angioedema, among others.ResultsUse of NSAIDs significantly increased the risk of hepatic injury, gastrointestinal bleeding, acute renal failure and angioedema. The odds ratios tended to increase with the number of NSAIDs for hepatic injury, gastrointestinal bleeding and acute renal failure but not for angioedema. In comparison with reports that did not mention any use of NSAIDs, the odds ratios associated with the use of a single NSAID and two or more NSAIDs were respectively 1.2 (95%CI: 0.9–1.5) and 2.2 (95%CI: 1.3–3.8) for hepatic injury, 7.3 (95%CI: 4.9–10.9) and 10.7 (95%CI: 2.9–40.2) for gastrointestinal bleeding, 3.2 (95%CI: 2.5–4.1) and 4.8 (95%CI: 2.6–8.8) for acute renal failure. For angioedema, the odds ratios were roughly similar when a single NSAID (OR=2.7; 95% CI: 2.2–3.4) or two or more NSAIDs (OR=2.0; 95%CI: 0.7–6.0) were used. The risk of severe ADRs (hepatic injury and acute renal failure) was six- to sevenfold higher in reports mentioning concomitant use of two NSAIDs or more than in those that did not.ConclusionThis study shows that concomitant use of two or more NSAIDs was associated with an excess risk of adverse effects such as hepatic injury, acute renal failure and gastrointestinal bleeding. Although simultaneous use of several systemic NSAIDs has no pharmacological justification, this may raise a serious public health problem with the increasing use of over-the-counter non-steroidal anti-inflammatory agents.

Complications of BCG vaccine SSI® recent story and risk management plan: the French experience.

As of January 2006, the BCG vaccine SSI® became the only BCG vaccine available for tuberculosis vaccination in France. The use of this vaccine led to significant changes in vaccination technique which were accompanied by a rapid increase in the number of adverse reactions (ADRs) reported. A national pharmacovigilance follow‐up began in February 2006, and a risk management plan (RMP) was put in place in April 2006, made of three phases (carried out in June 2006, July 2006 and September 2006) with risk minimisation measures.

Safety surveillance of influenza A(H1N1)v monovalent vaccines during the 2009–2010 mass vaccination campaign in France

In June 2009, the World Health Organization declared a pandemic due to A(H1N1)v 2009 influenza virus. In France, a mass vaccination campaign started following European Medicines Agency (EMA) recommendations, and a Pharmacovigilance plan was launched. The aim of this study was to describe safety data collected from 21 October 2009 to 15 June 2010 for Pandemrix® (ASO3 adjuvant vaccine, indicated in adults and children >9 years) and Panenza® (a nonadjuvant vaccine primarily administered to children <9 years old and pregnant women), the two most frequently used vaccines in France. The French Pharmacovigilance system consists of a network of 31 regional centres and is based on mandatory spontaneous reports of “serious” and/or “unexpected” adverse events (AEs) [1]. However, it is well known that spontaneous notifications suffer from underreporting, the magnitude of which varies between 82% and 98% [2]. For the 2009–2010 vaccination campaign, French health authorities heightened awareness to extensive notifications with online health practitioner and patient reports via the regional centre concerned. All

Adverse drug effects in patients with Alzheimer's disease or another dementia: PEIMA study

was predictive of acetylcholinesterase inhibitors (AChEI) response in patients with Alzheimer’s disease (AD), but few examined the effect of education level. This study was aimed to identify whether the effect of baseline cognition on AChEI response was modified by education level. Methods: A total of 257 mild to moderate AD patients, who received AChEI, were recruited from the neurology clinics of three teaching hospitals in northern Taiwan from 2007 to 2010. Mini-mental status examination (MMSE) was performed at baseline and at months 6 and 12 after the initiation of AChEI. The education level was classified as lower education ( 6 years) or higher education (> 6 years). Responders to AChEI treatment were defined as the improvement of MMSE score equaled to two points or greater between baseline and 6 months. Logistic regression was used to explore the association between baseline MMSE and AChEI response by education level (higher and lower). Results: About 90% patients completed 6 months while 72% completed 12 months of AChEI treatment. A significant improvement was observed at the 6 months in both AD patients with low and high education (mean MMSE change 1⁄4 0.9 6 2.6, 0.5 6 2.6, respectively). At the 12 months, a sustained improvement in MMSE score was observed among those with low education (12 month MMSE-baseline MMSE 1⁄4 0.99 6 3.12, p 1⁄4 0.0014). In contrast, among those with higher education, MMSE increased at 6 month and then decreased to slightly lower than baseline at 12 month (12 month MMSE-baseline MMSE 1⁄4 0.35 6 3.8, p 1⁄4 0.415). A lower baseline MMSE score was associated with better response to AChEI in those with higher education, after adjustment for age, gender, and apolipoprotein E (APOE) e4 status [odds ratio (OR) 1⁄4 0.82, 95% confidence interval (CI) 1⁄4 0.72-0.92]. Patients with the lowest quartile of baseline MMSE were 7 times more likely to be responders as compared with those in the highest quartile (95% CI 1⁄4 2.36-20.5). Education level alone was not predictive of AChEI response. Conclusions: AD patients with low education level have more sustained response to AChEI. Baseline MMSE is a useful predictor of AChEI treatment, especially in those with high education.