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Saint Denis, France

Drug evaluation is based on comparison. Thus, the choice of the comparator for any new treatment becomes a key issue, especially when there are great differences in medical practice and of use conditions of the comparators depending on the geographical zones and their evolution with time. The choice of the comparators must satisfy sometimes different expectations from the registration authorities and for insurance coverage. The universal comparator that allows answering all the clinical assessment questions does not exist. Placebo, when it can be used, remains a reference for the MA (marketing authorisation) application, but does not exclude the use of the reference drug available on the market and prescribed under optimal efficacy conditions. The reference treatment is sometimes a difficult choice due to the absence of validated therapeutic recommendations or if the recommendations vary depending on the countries. The expansion and international harmonization of prescription guidelines (clinical practice guidelines) would reinforce the robustness and efficiency of clinical research efforts with respect to the relevance of the comparison to reference treatments. This principle also applies to the use of a non-drug comparator when it has been recognized as the reference comparator in the treatment of the pathology in question. In as much as possible, the search for a consensus must also aim at defining in the clinical development recommendations significant thresholds for the size of evaluated effects. Optimization of the information made available after clinical trials could also be helped by the development of use of methodologies that allow assessing superiority on secondary criteria during a non-inferiority study on the main criterion. Finally, the development of early scientific consultations by the Haute Autorité de Santé (HAS, French Health Authority) would contribute to adapt phase III clinical trials better to questions concerning the assessment of the clinical added value of the medicinal products evaluated. © 2010 Société Française de Pharmacologie et de Thérapeutique. Source

Trenque T.,Reims University Hospital Center | Trenque T.,University of Reims Champagne Ardenne | Herlem E.,Reims University Hospital Center | Auriche P.,Afssaps | And 2 more authors.
Drug Safety

Background: Hyperprolactinaemia is a common endocrinological disorder that can be caused by a variety of physiological and pathological conditions, although in a large proportion of cases hyperprolactinaemia is drug-induced. Serotonin reuptake inhibitors (SRIs) are reportedly associated with hyperprolactinaemia; however, the number of published cases in the literature is limited. Objective: The aim of the study was to investigate the association between exposure to SRIs and the risk of reporting of hyperprolactinaemia in a spontaneous reporting database. Methods: All cases of adverse drug reactions (ADRs) involving hyperprolactinaemia spontaneously reported to the French Pharmacovigilance Database from 1985 to December 2009 were reviewed. Cases of hyperprolactinaemia in SRI users were described. In a case/non-case analysis, the association between reported cases of hyperprolactinaemia and the use of SRIs was assessed by calculating reporting odds ratios (ROR) with their 95% confidence intervals (CIs). Results: A total of 11 863 reports with SRIs were collected, of which 187 reported hyperprolactinaemia ADRs. Subjects were 39.7-13.5 years of age on average and mainly female (71%). We observed an increased risk of reporting of hyperprolactinaemia with the use of SRIs as antidepressants (overall ROR 3.3; 95% CI 2.8, 3.8), particularly with fluvoxamine (ROR 4.5; 95%CI 2.8, 7.2), citalopram (ROR 3.9; 95%CI 2.6, 5.8), fluoxetine (ROR 3.6; 95% CI 2.8, 4.7) and paroxetine (ROR 3.1; 95% CI 2.3, 4.2). Duloxetine, milnacipran and sertraline were not associated with an increased risk of reporting of hyperprolactinaemia. Conclusions: Treatment with SRIs is associated with an increased risk of reported hyperprolactinaemia. When investigating the aetiology of diagnosed hyperprolactinaemia, physicians should systematically enquire about treatment with SRIs. The risk of hyperprolactinaemia should be mentioned in the labelling of all SRI compounds. © 2011 Layton et al., publisher and licensee Adis Data Information BV. Source

Ahmed I.,French Institute of Health and Medical Research | Ahmed I.,University Paris - Sud | Ahmed I.,Imperial College London | Thiessard F.,University of Bordeaux Segalen | And 10 more authors.
Drug Safety

Background: 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 (PRR 02.5), the 2.5% quantile of the Information Component (IC 02.5) or the 5% quantile of the Gamma Poisson Shrinker (GPS 05). 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 PRR 02.5, GPS 05 and IC 02.5 with two FDRbased methods derived from the Fisher's exact test and the GPS model (GPS pH0 [posterior probability of the null hypothesis H 0 calculated from the Gamma Poisson Shrinker model]). Secondly, restricting the analysis to GPS pH0, 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 GPS pH0 in terms of both number of detections of true signals and time to detection. Additionally, based on an FDR threshold of 5%, GPS pH0 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. © 2012 Springer International Publishing AG. All rights reserved. Source

Babai S.,Center Regional Of Pharmacovigilance | Auriche P.,Afssaps | Le-Louet H.,Center Regional Of Pharmacovigilance

Background. Since donepezil and memantine are currently used for treating Alzheimer's disease, it is interesting to analyse, reassess and compare their safety profile in order to promote a better use. Methods. All spontaneous reports of suspected serious adverse drug reactions with donepezil alone and with memantine alone recorded in the French Pharmacovigilance Database during 6 years were retrospectively analysed. Results. The most frequent adverse drug reactions with donepezil alone and memantine alone were respectively: bradycardia (10% versus 7%), weakness (5% versus 6%) and convulsions (4% versus 3%). Conclusion. The most adverse drug events with donepezil and with memantine are associated with elderly people, even if they do not receive any other treatment. Donepezil and memantine have an acceptable safety profile but physicians should take special care when they prescribe any drug known to cause bradycardia or to reduce the epileptogenic threshold. © 2010 Société Française de Pharmacologie et de Thérapeutique. Source

Bamberger M.,Bristol Myers Squibb | Moore N.,Bordeaux University Hospital Center | Lechat P.,Afssaps

Based on the observation that over the last 30 years the cost of development has risen regularly as the number of new chemical entities reaching the market has fallen, how can "savings" be made in terms of clinical development, the objective being more rapid access to a drug for medical needs that are not covered? Several instruments exist to enable innovative products to be made available more quickly: temporary use authorisations, which are not concerned by this work (ATUs), conditional marketing authorisations (MAs) and MAs under exceptional circumstances. These aspects have been taken up in the European medicines agency (EMA)'s "Road Map", which states "A key issue for Regulators will be if a more "staggered" approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more "real life" data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations." The rules of procedure of the Transparency Commission for their part provide for the notion of preliminary examination: in order to prepare as best as possible the examination of dossiers of products assumed to be innovative and to limit delays, the office can undertake a preliminary study as soon as the dossier has been filed at the Committee for medicinal products for human use (CHMP). It may, at this time, request the firm to provide further information and may call on external experts. The implementation of this preliminary study does not exonerate the firm of the obligation of filing a complete dossier. The post inscription studies requested by the Transparency Commission (ISPEP - public health benefit and post-marketing studies) are usually requested in the case of hesitations regarding the level of improvement of the medical benefit (ASMR) [level II/III or IV/V]. Such requests mainly concern uncertainties regarding the transposability, the patient profile or correct usage in real life. Among the studies whose results were provided, in 15 cases the results were in line with expectations, in 6 cases they resulted in downward re-evaluations and the final 3 cases were inconclusive. The final recommendations of the round table were: Defining the medical need that is not covered by working in consultation (Industry and Health Authorities); Providing a Complementary Investigations Plan (PIC) after the MA at a very early stage to reinforce the early MA, and/or HTA (health technology assessment) preparation and monitoring (possible constraining actions); Enhanced use of modelling techniques and their transposability; "Intussusception" of phases to optimise the development of a complete dossier; Early "scientific opinions" (EMA, French Health Products Safety Agency [Afssaps], French Health Authority [HAS]); Raising the awareness of the authorities, industry, doctors and patients with regard to controlled observational studies; Developing the use of public data bases. © 2011 Société Française de Pharmacologie et de Thérapeutique. Source

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