NADPH oxidase activity is associated with cardiac osteopontin and pro-collagen type I expression in uremia.

International audienceCardiovascular disease is a frequent complication inducing mortality in chronic kidney disease (CKD) patients, which can be determined by both traditional risk factors and non-traditional risk factors such as malnutrition and oxidative stress. This study aimed to investigate the role of oxidative stress in uremia-induced cardiopathy in an experimental CKD model. CKD was induced in Sprague-Dawley rats by a 4-week diet supplemented in adenine, calcium and phosphorous and depleted in proteins. CKD was associated with a 3-fold increase in superoxide anion production from the NADPH oxidase in the left ventricle, but the maximal activity of mitochondrial respiratory chain complexes was not different. Although manganese mitochondrial SOD activity decreased, total SOD activity was not affected and catalase or GPx activities were increased, strengthening the major role of NADPH oxidase in superoxide anion output. Superoxide anion output was associated with enhanced expression of osteopontin (×7.7) and accumulation of pro-collagen type I (×3.7). To conclude, the increased activity of NADPH oxidase during CKD is associated with protein modifications which could activate a pathway leading to cardiac remodelling

Polyphenols decreased liver NADPH oxidase activity, increased muscle mitochondrial biogenesis and decreased gastrocnemius age-dependent autophagy in aged rats

International audienceThis study explored major systems of reactive oxygen species (ROS) production and their consequences on oxidative stress, mitochondriogenesis and muscle metabolism in aged rats, and evaluated the efficiency of 30-day oral supplementation with a moderate dose of a red grape polyphenol extract (RGPE) on these parameters. In the liver of aged rats, NADPH oxidase activity was increased and mitochondrial respiratory chain complex activities were altered, while xanthine oxidase activity remained unchanged. In muscles, only mitochondrial activity was modified with aging. The oral intake of RGPE decreased liver NADPH oxidase activity in the aged rats without affecting global oxidative stress, suggesting that NADPH oxidase was probably not the dominant detrimental source of production of O(2)·(-) in the liver. Interestingly, RGPE supplementation increased mitochondrial biogenesis and improved antioxidant status in the gastrocnemius of aged rats, while it had no significant effect in soleus. RGPE supplementation also decreased age-dependent autophagy in gastrocnemius of aged rats. These results extended existing findings on the beneficial effects of RGPE on mitochondriogenesis and muscle metabolism in aged rats

The European “Clinical Trial” Regulation; Relationship with the Jardé Act: a Giens Workshop

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency. Abbreviations: see end of article

Le règlement européen «essais cliniques» : articulation avec la loi Jardé : un atelier de Giens

Le Parlement et le Conseil de l’Union Européenne ont publié en mai 2014 un nouveau règlement relatif aux essais cliniques de médicaments, destiné à remplacer la directive 2001/20/CE. Sa mise en application n’interviendra pas avant 2016. Néanmoins, il est essentiel de se préoccuper dès à présent de l’articulation de ce texte avec la législation nationale, c’est-à-dire de la loi Jardé dont la mise en œuvre a été retardée, précisément dans l’attente de la publication du règlement européen. L’atelier de Giens a listé et étudié les différents problèmes que cette articulation ne manquera pas de poser. Ont été particulièrement abordés : les modalités d’évaluation de la méthodologie des essais, l’articulation fonctionnelle entre l’Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) et les Comités de Protection des Personnes (CPP) pendant cette phase d’évaluation des demandes d’autorisation, l’évaluation des études post-autorisation/inscription des médicaments et des dispositions médicaux, la transparence des données. Abréviations : voir en fin d’article

The European “Clinical Trial” Regulation: Relationship with the Jardé Act: a Giens Workshop

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency. Abbreviations: see end of article

Les essais plateformes

International audienc

Platform trials

International audienceFor the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is par-ticularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investiga-tion. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities

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

How the new European data protection regulation affects clinical research and recommendations?

International audienceClinical research on human subjects or their data is confronted with conflicting requirements with, on one hand, the principle of open science (transparency and data sharing), the possibilities offered by big data and the reuse of healthcare or research data, and on the other, changes to the regulatory and legislative framework, including the general data protection regulation (GDPR). A roundtable was organized in Giens, France in October 2018 to identify problem areas, the need for clarification and streamlining, and to make recommendations to promote clinical research while ensuring a high level of patient protection. After details were given about these developments, the roundtable participants were able to propose recommendations, primarily (1) to clarify: what is considered anonymized data, and what is "public interest" within the meaning of the GDPR; (2) for the French data protection authority (CNIL) to continue preparing reference methodologies to simplify the approval system; (3) to promote the secondary use of data by making it easier to inform patients and obtain broad patient consent, by specifying the circumstances under which their withdrawal and opposition rights apply, so as to limit the risk of bias; (4) to facilitate access to data warehouses by providing technological and methodological aids. The roundtable also recommends increasing discussions between authorities in Europe on research topics, encouraging French authorities to contribute to the preparation of codes of conduct and setting up a voluntary harmonization procedure to coordinate the opinions of data protection authorities, while ensuring that key documents are available in English

Des études mono-bras aux études de comparaison externe. Considérations méthodologiques et recommandations

National audienceLes études mono-bras sont parfois utilisées comme études pivots mais elles présentent des limites méthodologiques qui ne leur permettent pas d’obtenir un niveau de fiabilité élevé comme peut l’être celui de l’essai contrôlé randomisé qui reste le standard de l’évaluation des nouveaux traitements. L’objectif de cette table ronde était de discuter des limites de ces études, d’analyser les solutions disponibles et acceptables afin de proposer des recommandations pour leur réalisation et leur évaluation. Les études mono-bras proprement dites sont intrinsèquement inadaptées pour démontrer le bénéfice d’un nouveau traitement car il est impossible de déduire ce bénéfice à partir d’une valeur sous traitement sans connaître ce qu’elle aurait été en l’absence du nouveau traitement. Une comparaison avec d’autres données est alors implicite. Cependant, cette comparaison est limitée par (1) le choix post-hoc de la référence de la comparaison, (2) le biais de confusion qui nécessite impérativement une approche d’ajustement, et (3) les autres biais, de mesure et d’attrition entres autres. La prise en considération de ces limites devrait conduire, avant tout, à la réalisation d’essais à contrôle externe (« externally controlled trial ») à la place des essais mono-bras comme le propose la dernière version d’ICH E10. Par ailleurs, la comparaison externe doit être formalisée dans le protocole de l’étude avec un choix a priori de la référence de comparaison ainsi que la méthode de comparaison formelle : test par rapport à une norme, ajustement avec des données individuelles, groupe contrôle synthétique ou « matching-adjusted indirect comparisons (MAIC) ». Finalement, l’essai de comparaison externe doit être réservé aux situations où la randomisation est irréalisable. Pour être acceptable, ces études doivent pouvoir donner la garantie d’absence de biais de confusion résiduelle, ce qui n’est vraiment recevable que si l’effet observé est extrêmement important et l’évolution de la maladie fortement prévisible