Hélène Théophile

Causality assessment in pharmacovigilance: The French method and its successive updates

The methods for causality assessment of adverse drug reactions were developed in the 1970s and 1980s, alongside the development of pharmacovigilance. The French method is one of the earlier of these, following on from the pioneering works by Irey and Karch and Lasagna. Initially published in 1978, it was updated in 1985, and again in 2011. The main alterations to the original method are presented in tables annexed to this paper. The successive versions improved the presentation, provided more formalised definitions of the criteria for assessing causality, while at the same time ensuring the method remained easy to use. Causality assessment enables the causal link between a drug and the occurrence of an adverse reaction to be formalised and explained. It contributes to diagnosis, and to determining the action to be taken in case of an adverse drug reaction. It can contribute to the quality and the relevance of the data stored in pharmacovigilance databases.

Comparison of three methods (consensual expert judgement, algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre.

AbstractBackground: Different methods have been proposed for assessing a possible causal link between a drug treatment and an adverse event in individual patients. They approximately belong to three main categories: expert judgement, operational algorithms and probabilistic approaches. Objective: To compare, in a set of actual drug adverse event reports, three different methods for assessing drug causality, each belonging to one of the three main categories: expert judgement, the algorithm used by the French pharmacovigilance centres since 1985, and a novel method based on the logistic function. Methods: Fifty drug-event pairs were randomly sampled from the database of the Bordeaux pharmacovigilance centre, France. To serve as the gold standard, the probability for drug causation, from 0 to 1, was first determined for each drug-event pair by a panel of senior experts until consensus was reached. Causality was then assessed by members of the Bordeaux pharmacovigilance centre by using the French algorithm and the logistic method. Results expressed as a probability with the logistic method and as a score from 0 to 4 with the French algorithm were then compared with consensual expert judgement, as were the sensitivity, specificity and positive and negative predictive values. Results: Probabilities ranged from 0.08 to 0.99 (median 0.58; mean 0.60) for experts versus 0.18–0.88 (median 0.73; mean 0.67) for the logistic method. Consensual expert judgement was not discriminant (p = 0.50) in ten cases. For the algorithm, only three of five causality scores were found, doubtful scores being clearly predominant (74%) followed by possible (16%) and probable (10%) scores. Sensitivity and specificity were 0.96 and 0.42, respectively, for the logistic method versus 0.42 and 0.92 for the algorithm. Positive and negative predictive values were 0.78 and 0.83, respectively, for the logistic method versus 0.92 and 0.42 for the algorithm. Conclusions: Agreement between the three approaches was poor, and only satisfactory for drug events judged as drug-induced by consensual expert judgement. The logistic method showed high sensitivity at the expense of poor specificity. Conversely, the algorithm had poor sensitivity but good specificity. The comparatively good sensitivity and positive predictive values of the logistic method suggest that it may be more useful in the routine or automated assessment of case reports of suspected but still unknown adverse drug reactions. With a substantial rate of false positives relative to true negatives (low specificity), the logistic method does not replace, but can be complemented by, critical clinical assessment of individual cases in evaluating drug-related risk.

Updating the French method for the causality assessment of adverse drug reactions.

The Imputability Working Group (CRI) updated the French drug reaction causality assessment method. This tripartite group is made up of staff from the French network of regional pharmacovigilance centres, pharmaceutical companies, and the French National Agency for the Safety of Medicines and Health Products (ANSM). After reviewing the strengths and weaknesses of the previous method, several ideas for improvement were proposed: a better-worded and more discriminating scale for certain chronological and semiological criteria, a larger scale for the intrinsic score (increased from 5 to 7 levels), a new bibliographical scale to differentiate between expected and unexpected adverse drug reactions, and a new informativeness scale.

The Case-Population Study Design An Analysis of its Application in Pharmacovigilance

AbstractBackground: The case-population approach or population-based case-cohort approach is derived from the case-control design and consists of comparing past exposure to a given risk factor in subjects presenting a given disease or symptom (cases) with the exposure rate to this factor in the whole cohort or in the source population of cases. In the same way as the case-control approach, the case-population approach measures the disproportionality of exposure between cases of a given disease and their source population expressed in the form of an odds ratio approximating the ratio of the risks in exposed and notexposed populations (relative risk). Objective: The aim of this study was to (i) present the case-population principle design in a way understandable for non-statisticians; (ii) propose the easiest way of using it for pharmacovigilance purposes (mainly alerting and hypothesis testing); (iii) propose simple formulae for computing an odds ratio and its confidence interval; (iv) apply the approach to several practical and published examples; and (v) discuss its pros and cons in the context of real life. Methods: The approach used is derived from that comparing two rates expressed as person-time denominators. It allows easy computation of an odds ratio and its confidence interval under several hypotheses. Results obtained with the case-population approach were compared with those of case-control studies published in the literature. Results: Relevance and limits of the proposed approach are illustrated by examples taken from published pharmacoepidemiological studies. The odds ratio (OR) reported in a European case-control study on centrally acting appetite suppressants and primary pulmonary hypertension was 23.1 (95% CI 6.9, 77.7) versus 31 (95% CI 16.2, 59.2) using the case-population approach. In the European case-control studies SCAR (Severe Cutaneous Adverse Reactions) and EuroSCAR on the risk of toxic epidermal necrolysis associated with the use of medicines, the OR for cotrimoxazole was 160 and 102, respectively, versus 44.4 using the case-population approach. Similarly, these two case-control studies found ORs of 12 and 72 for carbamazepine versus 24.4 using the case-population approach, 8.7 and 16 for phenobarbital versus 21.9, 12 for piroxicam (analysed in the SCAR study only) versus 14.5, and 5.5 and 18 for allopurinol versus 3.4 using the case-population approach. Conclusions: Being based on the estimate derived from sales statistics of the total exposure time in the source population of cases, the method can be used even when there is no information about the actual number of exposed subjects in this population. Although the case-population approach suffers from limitations stemming from its main advantage, i.e. impossibility to control possible confounders and to quantify the strength of associations due to the absence of an ad hoc control group, it is particularly useful to use in routine practice, mainly for purposes of signal generation and hypothesis testing in drug surveillance.

Incidence of agranulocytosis in Southwest France.

Background: Updated knowledge of background event rates is fundamental to risk assessment. Objective: To estimate the incidence of agranulocytosis in the general population in Southwest France. Methods: All definite cases of acute non-cancer drug-related agranulocytosis in subjects aged more than 16 years were systematically retrieved weekly from Medical departments or labs in the catchment area (approximately 3.5 millions inhabitants). Event rates were compared to population figures from 1999 census data, and Poisson 95% confidence intervals computed. Results: From January 1st 1997 to December 31st 1998, 87 cases of agranulocytosis were identified, 58 being validated by an independent ad hoc panel of experts. The overall annual incidence rate was 9.2 per million inhabitants (95%CI: 6.9;13.0); 7.7 (95%CI: 4.8;11.7) per million in men, and 10.5 (95%CI: 7.2;14.8) per million in women. These rates of all-cause acute agranulocytosis can be used as expected background reference rate for specific risk assessment.

Validation and Reproducibility of the Updated French Causality Assessment Method: an Evaluation by Pharmacovigilance Centres & Pharmaceutical Companies

OBJECTIVE Assess the validity and reproducibility of the updated version of the French causality assessment method in conditions approaching real-life use. METHODS A random sample of 31 drug-event pairs from the French pharmacovigilance database was assessed by the consensual judgement of three experts (gold standard). Separately, a team from a pharmacovigilance centre (PhVC) and another from a pharmaceutical company assessed these pairs using the current method, then with the updated method. To test the inter- and intra-rater reproducibility, two seniors and two juniors from a PhVC and a pharmaceutical company assessed the pairs twice with the updated method. A weighted kappa coefficient was used to measure the agreement of the two causality assessment methods with the consensual expert judgement (validity) as well as the agreement of the updated causality assessment over time (intra-rater reproducibility) and between evaluators (inter-rater reproducibility). RESULTS Agreement between the current method and consensual expert judgement was fair for the PhVC team (weighted kappa [Kw] 0.33) and moderate for the pharmaceutical company team (Kw 0.41). For the updated method, agreement was better for both the PhVC (Kw 0.58) and the pharmaceutical company (Kw 0.52) teams. The inter- and intra-rater reproducibility of the updated method based on the intrinsic imputability was satisfactory overall (Kw 0.30-0.91). Discrepancies between evaluations from PhVC and pharmaceutical companies were observed with the updated method. CONCLUSION The updated method performed better than the current one for drug causality assessment, suggesting that it should be used in routine pharmacovigilance.

Communication in Drug Safety

Public communication on safety concerns over medicines and advice on how to preventmedicineinduced patient harm is a decisive challenge for the overall success of those responsible for pharmacovigilance. It was in this spirit that the topic of communication in drug safety was put on the agenda of the 10th Annual Meeting of the International Society of Pharmacovigilance (ISoP) in Accra, Ghana, on 5 November 2010, as a follow-up to the sessions on communications at previous annual meetings. The informal environment chosen this time was different and unusual but ideal for the topic at stake: an interactive debate involving all participants in the session with the objective of understanding the characteristics of effective communication. Around 30 participants from all over the world came together and presented views from their various perspectives: community and hospital pharmacy, academia, pharmacovigilance centres and regulatory agencies, as well as international bodies. Much is known in theory about good communication practices, particularly with regard to the need for clear messages targeted at different populations. But how to achieve this in practice? Reciprocity was defined as the starting point: an exchange of information based on mutual respect and shared interest. Two crude communication levels are to be distinguished: one-to-one communication between patients and healthcare professionals, versus mass communication – with smaller or larger audiences – by those investigating and regulating medicines. Independently of the level, the principles of reciprocity and interaction should apply, not least in the research and planning stage, before communication takes place. The interactive debate was a free-flowing discussion where almost all participants took the floor and presented examples, bringing the principles and challenges of their application to life. Patients’ misunderstandings as to the indication and adverse effects of medicines seem frequent. This was illustrated by examples, including one on women’s fears over adverse effects resulting in infertility and termination of pregnancy. The introduction of a communication protocol for thoroughly informing the women concerned in the presence of a third-party witness or supporter has solved the problem in the setting presented. Other examples related to communication over counterfeit medicines, another difficult area given that many people feel they do not have the financial means for, or easy access to, quality-assured products. MEETING REPORT Drug Saf 2011; 34 (10): 881-882 0114-5916/11/0010-0881/

Relative risks from case-population data.

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Patterns of Laxative Use in Self-Medication

© 2013 Lippincott Williams & Wilkins www.epidem.com | 935 The case-population ratio is perpendicular to the RR: rather than the ratio of case rates among exposed and unexposed, it is the ratio of exposure rates among cases and population. In the usual two-by-two table (Table), where a is the number of exposed cases, b the number of exposed noncases, c the number of unexposed cases, and d the number of unexposed noncases, RR is (a/a+b)/ (c/c+d), OR is a/c/b/d (or ad/bc), and case-population ratio is (a/a+c)/((a+b)/ (a+b+c+d)). The analysis population may come from a representative population sample with a known sampling rate or from representative samples with unknown sampling rates (eg, the UK Clinical Practice Research Datalink). In that case, case-population ratio could be expressed as (a/(a+c))/((e/e+f)), where e and f are the exposed and unexposed in the sample, which may or not include the cases. If cases are rare, case-population ratio can be simplified to ad/bc/ ((1−Pexp)/(1−Cexp)), where Pexp is the population exposure to the drug of interest (b/b+d), and Cexp is the case exposure to the drug of interest (a/a+c). The smaller the population and case exposures, the better case-population ratio (CPR) approximates the OR. The OR estimates the RR when the event is rare, so the lower the exposure in cases and in the general population, and the rarer the event, the better the CPR approximates the real RR of the association of exposure and event. We built a table of CPR for various RR and population exposures (eTable, http://links.lww.com/EDE/A718). When population exposure is below 1%, the difference between case-population ratio and actual OR or RR is less than 1%. Above 1%, CPR underestimates RR above 1 and overestimates RR below 1. We tested this in a case-population study of liver transplantation in Europe for which drug utilization was the exposure of interest.3–5 In this study with exhaustive case identification, and full description of the country’s drug utilization over the same period and in the same population of patients, we computed the actual Relative Risks from Case-Population Data Kathrin Wolf Regina Hampel Susanne Breitner Alexandra Schneider Stephanie von Klot Josef Cyrys Helmholtz Zentrum München German Research Center for Environmental Health Institute of Epidemiology II Neuherberg, Germany

Rhabdomyolysis after co‐administration of a statin and fusidic acid: an analysis of the literature and of the WHO database of adverse drug reactions

TO THE EDITOR: Laxatives have long been a typical example of selfprescribed medicines. However, in 2002, the Food and Drug Administration required removal of 2 stimulant laxative ingredients (aloe and cascara) from over-the-counter drugs, as these products were not generally recognized as safe and effective.1 The European Medicines Agency stated in 2007 that, without medical supervision, the stimulant laxatives cascara, aloe and senna should only be used on a short-term basis,2 which was already the case in France for stimulant laxatives, all recommended for a maximum of 8 to 10 days. The purpose of this study was to evaluate patterns of laxative use in self-medication in actual practice. Methods. A cross-sectional study was conducted in a random sample of community pharmacies in the Bordeaux area, in southwestern France, in accordance with the requirements of the Regional Ethics Committee. All sales of laxatives without prescription were identified during a 2week period. Characteristics of users and patterns of use were collected during a face-to-face interview by using a structured questionnaire filled out by the pharmacist for each purchase of laxative without prescription. Results. A total of 137 users of laxatives in 29 pharmacies (19% of sampled pharmacies) were identified during the study period. The mean number of self-medicating laxative users was 2.4 per pharmacy per week (range 0–10); 86.1% were female, 64.2% were known customers of the pharmacy, and the median age was 64 years (interquartile range, 46–75 y). Among individuals in the study population, 18.3% purchased more than one brand and 40.9% purchased more than one box of laxatives. Table 1 summarizes patterns of laxative use in self-medication. Laxatives were used for the purpose of weight loss by 8.0% of the study population and chronically (ie, daily and for ≥1 y) by 31.4%. Stimulant laxatives, which were the most commonly used, were used chronically (31.8%) to the same extent as other types of laxatives (30.8%). Discussion. The participating pharmacy rate was rather low but concordant with that found in other studies using no follow-up or fee.3 This study confirms data in the literature showing that laxatives are used primarily by women and the elderly.4 Although notable, the proportion of laxatives used for weight loss among the population studied could have been underestimated, since such nonapproved use is often denied. The finding that stimulant laxatives were used chronically, contrary to the current guidelines and recent regulatory decisions, highlights the poor impact of leaflet warnings. The daily use of these laxatives may be based on the erroneous concept that a daily bowel evacuation is necessary for good health. Motola et al.5 made the same observation in their study, conducted among 70 pharmacies in southern Italy. Almost half of the studied population used laxatives because they considered themselves to be constipated, despite evacuating 3 or more times per week. A large education campaign for patients regarding constipation and the proper use of stimulant laxatives would certainly be appropriate.