Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

Value of Post-Registration Studies for Reimbursement Renewal

Post-registration studies describe parameters of real-life clinical practice such as the treated population, conditions of treatment initiation, treatment duration, adherence, associated benefits/risks as well as the impact on treatment strategies, healthcare procedures and on public health. The results of these studies are used in particular for re-evaluation, re-registration or in applications for reimbursement. Since 1997, 134 requests for post-registration studies have been made either by the French Transparency Committee (CT) and/or the Committee for Pricing of Healthcare Products (CEPS) and the results of these studies were taken into account in the re-evaluation of Actual Benefit (AB) or Improvement in Actual Benefit (IAB). During the roundtable discussion on this subject at the National Clinical Pharmacology Meeting held at Giens (France), the difficulties in performing such studies were identified and proposals were made to predict and anticipate requests for these studies but also for the training of physicians

Études post-AMM : apport dans la réinscription des produits

Les études post-inscription documentent, en situation réelle, les conditions de mise sous traitement, les populations réellement traitées, les durées de traitement, l'observance, les bénéfices des traitements, l'impact du traitement sur les stratégies thérapeutiques, l'organisation des soins et l'impact de santé publique, ... Leurs données sont utilisées notamment lors d'une réévaluation anticipée ou lors du renouvellement d'inscription au remboursement. Cent trente quatre demandes de la Commission de la Transparence (CT) et/ou du Comité Économique des Produits de Santé (CEPS) ont été faites depuis 1997 et leurs résultats sont pris en compte et participent à la réévaluation du Service Médical Rendu (SMR) et de l'Amélioration du Service Médical Rendu (ASMR) anticipés. Au cours de cette table ronde des Rencontres Nationales de Pharmacologie Clinique de Giens, les difficultés de réalisation des études post-inscription médicaments ont été identifiées et des propositions ont été formulées dans les domaines du dialogue autour de la demande, de la prévisibilité et de l'anticipation des demandes et de la formation des médecins

How to Improve the Clinical Development Paradigm and its Division into Phases I, II and III

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)

Comment faire évoluer le paradigme du développement clinique et son découpage en phases I, II, III

Partant de la constatation que depuis 30 ans, le coût du développement augmente régulièrement à mesure que le nombre de nouvelles entités chimiques atteignant le marché décroît, comment faire des « économies » en termes de développement clinique, l’objectif étant un accès plus rapide au médicament, pour les besoins médicaux non couverts ? Plusieurs instruments existent pour permettre une mise à disposition plus rapide de produits innovants : les autorisations temporaires d’utilisation ou ATU (qui ne sont pas concernées par ce travail), les autorisations de mise sur le marché (AMM) conditionnelles, les AMM sous circonstances exceptionnelles. Ces éléments sont repris dans la « road map » de l’Agence européenne du médicament, (European Medicines Agency ou EMA), qui dit : « 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. » Le règlement intérieur de la Commission de transparence pour sa part prévoit la notion d’examen préliminaire : afin de préparer au mieux l’instruction des dossiers des produits présumés innovants et de limiter les délais, le bureau peut engager une étude préliminaire dès le dépôt du dossier au Comité des spécialités pharmaceutiques humaines (CHMP). Il peut à cette occasion solliciter de la firme des éléments d’information et faire appel à des experts externes. La mise en œuvre de cette étude préliminaire n’exonère pas la firme de l’obligation de déposer un dossier complet. Les études post inscription demandées par la commission de transparence (ISPEP) le sont souvent dans le cas d’hésitations sur le niveau d’amélioration du service médical rendu ou ASMR (niveau II/III ou IV/V). Ces demandes concernent essentiellement des incertitudes sur la transposabilité, le profil patient ou le respect du bon usage. Parmi les études dont les résultats ont été rendus, dans 15 cas les résultats sont en conformité avec les attentes, dans 6 cas elles ont abouti à des réévaluations à la baisse, enfin dans 3 cas elles étaient non conclusives. Les recommandations finales de la Table Ronde étaient : définition du besoin médical non couvert à travailler en concertation (industriels et autorités de Santé)

Direct Cost-Modeling of Rheumatoid Arthritis According to Disease Activity Categories in France

International audienceObjective. The objective of this cost-of-illness study was to assess the use of direct medical resources, excluding drug costs, by patients with rheumatoid arthritis (RA) in France, and to construct cost estimates according to level of disease activity. Methods. Three categories of RA disease activity were defined according to Disease Activity Score 28-joint count (DAS28) thresholds: remission (DAS28 3.2). Eight resource utilization items were defined: medical visits, laboratory tests, hospitalization, imaging, physiotherapy, nursing, adaptive aids, and transportation. Resource utilization and unit costs from the national-payer perspective were estimated through expert opinion and simulated using distribution ranges for each item. Cost distributions were computed by Monte-Carlo simulations estimating overall costs per 6 months over a 2-year period. Results. For patients achieving remission, costs were estimated at a mean of (sic)771 (SD 199) for the first 6 months and at (sic)511 (SD 162) for each subsequent 6-month period. For patients achieving LDAS, costs were estimated at (sic)905 (SD 263) for the first 6 months and (sic)696 (SD 240) for each subsequent 6-month period. For patients in MHDAS, costs were estimated at (sic)1215 per 6 months (SD 405). Conclusion. This cost-of-illness assessment provided current estimates of direct medical costs for RA according to disease activity in France. The findings suggest that achieving remission or LDAS is associated with substantially lower medical costs for RA versus being in MHDAS. (First Release Dec 1 2010; J Rheumatol 2011;38:439-45; doi:10.3899/jrheum.100589

Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

International audienceAutoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS , FASLG , and FADD , all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS

The cost of treating high blood pressure in general practice in France

Hypertension, Cost, Family practice, I12,