Modelling and Clinical Trials in Paediatrics

Clinical trials are more difficult to conduct in children, but they are even more necessary than in adults – their scarcity is an ethical scandal. Mathematical models can be built that can describe both the disease process and the mechanism of action of drugs. These models can then be used to simulate the outcome of clinical trials. Inspection of the simulated results then facilitates optimisation of the trial design and proposed methods of analysis. Validation is a crucial issue for the good practice of modelling and simulation. The participants of Round Table No. 6 recommend: (i) that modelling be systematically employed; (ii) that all the required professional personnel be involved, at all phases; (iii) that all data needed are made accessible; (iv) that clinicians be trained; (v) that specialists develop training tool kits; and (vi) that universities provide appropriate training

Modélisation et essais cliniques en pédiatrie

Les essais cliniques sont plus difficiles à réaliser chez l'enfant, mais ils sont encore plus nécessaires que chez l'adulte : leur rareté constitue un véritable scandale éthique. La modélisation est une représentation fondée sur la logique et les mathématiques, applicable aux mécanismes des maladies et des médicaments. La simulation permet de manipuler des objets comme les essais cliniques. La prédiction de résultats simulés permet l'optimisation du plan expérimental et du plan d'analyse. La validation est une étape cruciale de la modélisation et de la simulation. Les participants de la Table Ronde recommandent : (i) d'envisager systématiquement le recours à la modélisation ; (ii) d'impliquer toutes les compétences requises, à toutes les étapes ; (iii) que toutes les données soient rendues accessibles ; (iv) que les cliniciens soient formés ; (v) que les spécialistes mettent au point des kits de formation ; (vi) que les universités proposent une formation adéquate

Pharmacological characterization of the human P2Y13 receptor

The P2Y13 receptor has recently been identified as a new P2Y receptor sharing a high sequence homology with the P2Y12 receptor as well as similar functional properties: coupling to Gi and responsiveness to ADP (Communi et al. 2001). In the present study, the pharmacology of the P2Y13 receptor and its differences with that of the P2Y12 receptor have been further characterized in 1321N1 cells (binding of [33P]2-methylthio-ADP (2MeSADP) and of GTPgamma[35S]), 1321N1 cells coexpressing Galpha16 [AG32 cells: inositol trisphosphate (IP3) measurement, binding of GTPgamma[35S]) and Chinese hamster ovary (CHO)-K1 cells (cAMP assay)]. 2MeSADP was more potent than ADP in displacing [33P]2MeSADP bound to 1321N1 cells and increasing GTPgamma[35S] binding to membranes prepared from the same cells. Similarly, 2MeSADP was more potent than ADP in stimulating IP3 accumulation after 10 min in AG32 cells and increasing cAMP in pertussis toxin-treated CHO-K1 cells stimulated by forskolin. On the other hand, ADP and 2MeSADP were equipotent at stimulating IP3 formation in AG32 cells after 30 s and inhibiting forskolininduced cAMP accumulation in CHO-K1 cells. These differences in potency cannot be explained by differences in degradation rate, which in AG32 cells was similar for the two nucleotides. When contaminating diphosphates were enzymatically removed and assay of IP3 was performed after 30 s, ATP and 2MeSATP seemed to be weak partial agonists of the P2Y13 receptor expressed in AG32 cells. The stimulatory effect of ADP on the P2Y13 receptor in AG32 cells was antagonized by reactive blue 2, suramin, pyridoxal-phosphate-6-azophenyl-2',4'disulfonic acid, diadenosine tetraphosphate, and 2-(propylthio)-5'-adenylic acid, monoanhydride with dichloromethylenebis (phosphonic acid) (AR-C67085MX), but not by N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate (MRS-2179) (up to 100 microM). The most potent antagonist was N6-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-5'-adenylic acid, monoanhydride with dichloromethylenebis (phosphonic acid) (ARC69931MX) (IC50 = 4 nM), which behaved in a noncompetitive way. The active metabolite of clopidogrel was unable to displace bound 2MeSADP at concentrations up to 2 microM.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Exclusion of documents due to the tax authority’s audit

Abstract The tax authority has an obligation to ensure that all tax cases are adequately investigated according to 40:1 SFL. In order to fulfill this obligation the tax authority has a number of investigation options. The most common form of investigation is so- called desktop investigations, which means that the tax authority will send written inquiries or injunctions to taxpayers. The most intrusive and resource-intensive form of investigation is audit. The general rule is that the tax authority’s auditor may examine all accounting records and other documents related to the business. Since an audit decision cannot be appealed, the revised may request that certain documents should be excluded from the audit, 47:3 SFL. There are three possibilities for excluding documents according to 47:2 SFL. The first reason applies to documents that may not be seized and the second reason applies to documents that are not covered by the audit. The third and last possibility for exclusion applies to documents with a significant protective value. The last mentioned possibility may only be exempted if the protective value outweighs the importance of the tax authority’s control. If the tax authority doesn’t agree that the document should be excluded the county’s administrative court must decide the case on the basis of the documents contents and the revised evidence. This essays first purpose is to examine which documents can be excluded from a tax authority’s audit and therefore to investigate the legal situation. To fulfill the first purpose, a legal dogmatic method has been used. Analyzing court cases has concluded the following. Documents may not be seized if there is a confidential relationship between a lawyer and a client. It is therefore not the content of document, but the fact that the document has been entrusted to a lawyer that is the reason for exclusion. The confidential relationship has also been considered to include a third party in some specific situations. However, certain information in documents has not been considered as information entrusted by a lawyer in his profession. This information relates to clients identity, lawyers fees and other expenses. The question regarding documents that should be excluded because they are not covered by the audit is not completely clear. This is due to the absence of precedence. The documents that can be excluded on this basis are if the documents do not refer to the taxation or if they are not of importance in the business. Documents may also be excluded because of its significant protective value if they contain sensitive personal information, qualified tax advice or industrial secrets. It also requires that the tax authority’s need to control is relatively low. This essay also aims to examine how the legal rules of exclusion of documents relate to the rule of law. The aspects of the rule of law that has been considered are: integrity, predictability, the principle of legality and the principle of equal treatment. To fulfill the second purpose, a legal political method has been used. The following has been determined by an analysis of the legal rules of exclusion in relation to the rule of law. Audit is a form of control that ensures a high efficiency. The rules of exclusion of documents increase legal certainty in an acceptable way for the revised. That is because the rules strengthens the integrity, are acceptably predictable, are legislated and fulfill the principle of equal treatment. Therefore the rules of exclusion do not require any change in relations to the rule of law.

Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcS-crizotinib trial

International audienceBackground: The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK ALCL). Methods - ALK ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks.Results: Twenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3-not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23-59%) and 63% (95% CI: 43-79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients.Conclusion: Crizotinib shows efficacy and an acceptable safety profile in ALK ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation

From single-arm studies to externally controlled studies. Methodological considerations and guidelines

International audienceSingle-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment. The implication is that comparison with other data is necessary. However this comparison has limitations due to (1) the post hoc choice of the reference used for comparison, (2) the confusion bias for which an adjustment approach is imperative and, (3) the other biases, measure and attrition among others. When these limitations are taken into account this should, first and foremost, lead to the conduct of externally controlled trials instead of single-arm trials as is proposed by the latest version of ICH E10. Moreover, the external control must be formalised in the study protocol with a priori selection of both the reference control and the formal method of comparison test in relation to a standard, adjustment on individual data, a synthetic control group or matching-adjusted indirect comparisons (MAIC). Lastly, externally controlled studies must be restricted to situations where randomisation is infeasible. To be acceptable, these studies must be able to guarantee freedom from residual confusion bias, which is only truly acceptable if the observed effect is dramatic and the usual course of the disease is highly predicable