Afssaps

Saint-Léger-du-Bourg-Denis, France
Saint-Léger-du-Bourg-Denis, France
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Kireche M.,CNRS Strasbourg Institute of Chemistry | Peiffer J.-L.,AFSSAPS | Antonios D.,French Institute of Health and Medical Research | Fabre I.,AFSSAPS | And 4 more authors.
Chemical Research in Toxicology | Year: 2011

Formaldehyde and formaldehyde releasers are widely used preservatives and represent an important group of skin sensitizers. Formaldehyde is very often suspected to be the sensitizing agent of formaldehyde-releasers; however, many reported clinical cases of contact allergy to these molecules such as bronopol (2-bromo-2-nitropropane-1,3-diol) indicate negative skin reactions to formaldehyde suggesting a more complex mechanism. The aim of this study was to compare the chemical reactivity and biological activity of formaldehyde with those of two formaldehyde releasers: 2-bromo-2-nitropropane-1,3-diol and 1,3-dimethylol-5,5-dimethylhydantoin. A key step in the sensitization to chemicals is the formation of the hapten-protein antigenic complex via covalent binding between the chemical sensitizer and amino acids in proteins. The chemical reactivity of the three compounds was thus addressed using 13C NMR analysis of adduct formation upon incubation with a set of nucleophilic amino acids. The biological activity was measured in two in vitro models based on dendritic cells and a monocytic cell line (CD34-DC and THP-1 model) through monitoring of a panel of biomarkers. The results obtained show that 2-bromo-2-nitropropane-1,3-diol produces low amount of free formaldehyde in physiological buffers but that its degradation generates various molecules including 2-bromoethanol. In addition, 2-bromo-2-nitropropane-1,3-diol also generates adducts with amino acids, not observed with formaldehyde alone, that could be explained by the reactivity of 2-bromoethanol. In parallel, in a cellular approach using the human monocytic THP-1 cell line, 2-bromo-2-nitropropane-1,3-diol activates THP-1 cells at concentrations that are not correlated to simple formaldehyde release. This observation is confirmed in the more physiological model CD34-DC. Moreover, in the THP-1 model, the expression profiles of several biomarkers are specific to 2-bromo-2- nitropropane-1,3-diol. Finally, the use in the cellular model of the pure degradation products identified by NMR reveals the reactivity of bromonitromethane. In contrast, 1,3-dimethylol-5,5-dimethylhydantoin presents chemical and biological reactivities similar to those of formaldehyde. Taken together, these data suggest that 2-bromo-2-nitropropane-1,3-diol is an atypical formaldehyde releaser, releasing low amounts of formaldehyde at physiological conditions but producing multiple degradation products among which 2-bromoethanol and bromonitromethane are potential candidates for explaining the specific allergic reactions to 2-bromo-2-nitropropane-1,3-diol. © 2011 American Chemical Society.


The medicinal product from its conception to its launching is subject to numerous regulatory constraints. Faced with these demands, manufacturers must implement solutions to ensure production of small batches for clinical trials in compliance with GMP without ever knowing the characteristics (toxicity, allergenicity, etc.) of the products implemented. The results of this development will allow to understand the industrial production of the medicinal product. This presentation will review the revised annex 13 of the Good Manufacturing Practices on the manufacture of investigational medicinal products, as well as the deficiencies observed during inspections carried out by Afssaps in 2010.


Bodaghi B.,University Pierre and Marie Curie | Korobelnik J.F.,University of Bordeaux Segalen | Cochereau I.,Rothschild | Hajjar J.,Center Hospitalier General | And 2 more authors.
Journal Francais d'Ophtalmologie | Year: 2012

Intravitreal injections are very commonly performed in the daily practice of Ophthalmology and become a leading procedure in the management of age-related macular degeneration, diabetic retinopathy, infectious endophthalmitis or retinitis, uveitis and retinal vein occlusions. Based on the comments of a group of experts, including ophthalmologists, pharmacists and hygienists, the French Agency for the Safety of Health Products (AFSSAPS) edited a guide to good practice of intravitreal injections, revisiting those previously published in 2006. The overall experience accumulated during time is a valuable source of information to determine the most appropriate protocol. Therefore, the simplification of the procedure is reasonably proposed even though safety remains a major issue, in order to avoid complications, especially infections. © 2011 Elsevier Masson SAS.


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 | Year: 2012

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.


Chaintreau A.,Firmenich | Cicchetti E.,Firmenich | David N.,135 Avenue Charles de Gaulle | Earls A.,LGC Ltd. | And 7 more authors.
Journal of Chromatography A | Year: 2011

Previous publications investigated different data treatment strategies for quantification of volatile suspected allergens by GC/MS. This publication presents the validation results obtained on "ready to inject" samples under reproducibility conditions following inter-laboratory ring-testing. The approach is based on the monitoring of three selected ions per analyte using two different GC capillary columns. To aid the analysts a decisional tree is used for guidance during the interpretation of the analytical results. The method is evaluated using a fragrance oil concentrate spiked with all suspected allergens to mimic the difficulty of a real sample extract or perfume oil. At the concentrations of 10 and 100. mg/kg, imposed by Directive 76/768/EEC for labeling of leave-on and rinse-off cosmetics, the mean bias is +14% and -4%, respectively. The method is linear for all analytes, and the prediction intervals for each analyte have been determined. To speed up the analyst's task, an automated data treatment is also proposed. The method mean bias is slightly shifted towards negative values, but the method prediction intervals are close to that resulting from the decisional tree. © 2011 Elsevier B.V.


Babai S.,Center Regional Of Pharmacovigilance | Auriche P.,Afssaps | Le-Louet H.,Center Regional Of Pharmacovigilance
Therapie | Year: 2010

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.


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 | Year: 2011

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.


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.


Bamberger M.,Bristol Myers Squibb | Moore N.,Bordeaux University Hospital Center | Lechat P.,Afssaps
Therapie | Year: 2011

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.


Prigent J.,CEA Saclay Nuclear Research Center | Panigai L.,AFSSAPS | Lamourette P.,CEA Saclay Nuclear Research Center | Sauvaire D.,AFSSAPS | And 5 more authors.
PLoS ONE | Year: 2011

The Centers for Disease Control and Prevention have listed the potential bioweapon ricin as a Category B Agent. Ricin is a so-called A/B toxin produced by plants and is one of the deadliest molecules known. It is easy to prepare and no curative treatment is available. An immunotherapeutic approach could be of interest to attenuate or neutralise the effects of the toxin. We sought to characterise neutralising monoclonal antibodies against ricin and to develop an effective therapy. For this purpose, mouse monoclonal antibodies (mAbs) were produced against the two chains of ricin toxin (RTA and RTB). Seven mAbs were selected for their capacity to neutralise the cytotoxic effects of ricin in vitro. Three of these, two anti-RTB (RB34 and RB37) and one anti-RTA (RA36), when used in combination improved neutralising capacity in vitro with an IC50 of 31 ng/ml. Passive administration of association of these three mixed mAbs (4.7 μg) protected mice from intranasal challenges with ricin (5 LD50). Among those three antibodies, anti-RTB antibodies protected mice more efficiently than the anti-RTA antibody. The combination of the three antibodies protected mice up to 7.5 hours after ricin challenge. The strong in vivo neutralising capacity of this three mAbs combination makes it potentially useful for immunotherapeutic purposes in the case of ricin poisoning or possibly for prevention. © 2011 Prigent et al.

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