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Connected objects (CO), whether medical devices or not, are used in clinical research for data collection, a specific activity (communication, diagnosis, effector, etc.), or several functions combined. Their validation should be based on three approaches: technical and clinical reliability, data protection and cybersecurity. Consequently, the round table recommends that the typology of COs, their uses and limitations, be known and shared by all, particularly for implementing precise specifications. COs are used in clinical research during observational studies (assessment of the device itself or data collection), randomized studies, where only one group has a CO (assessment of its impact on patient follow-up or management), or randomized studies where both groups have a CO, which is then used as a tool to help with assessment. The benefits of using COs in clinical research includes: improved collection and quality of data, compliance of patients and pharmacovigilance, easier implementation of e-cohorts and a better representative balance of patients. The societal limits and risks identified relate to the sometimes intrusive nature of certain collected parameters and the possible misuse of data. The round table recommends the following on this last point: anticipation, by securing transmission methods, the qualification of data hosts, and assessment of the object's vulnerability. For this, a risk analysis appears necessary for each project. It is also necessary to accurately document the data flow, in order to inform both patients and healthcare professionals and to ensure adequate security. Anticipating regulatory changes and involving users starting from the study design stage are also recommended., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long-term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

Background: The aim of this study was to evaluate the analgesic efficacy and the safety of the association, paracetamol, opium prepared and caffeine, in two different dosages as compared to the conventional analgesic tramadol hydrochloride, on acute postoperative dental pain., Methods: We conducted a randomised, double-blind, multicentre, parallel-group clinical trial to test the efficacy and safety of single doses of two associations; paracetamol 500 mg, caffeine 50mg, opium prepared 25, and paracetamol 500 mg, caffeine 50mg, opium prepared 50mg, as compared to tramadol hydrochloride 100mg (called hereafter tramadol 100), and placebo, in the control of postoperative pain following the removal of 2 ipsilateral impacted third molars. The primary efficacy criterion was the sum of pain intensity differences as assessed every 30 minutes within 3 hours after the baseline assessment and administration of study treatment (SPID(0-3h))., Results: Of the 232 randomised patients, 228 (98%) completed the study. Analysis of the primary efficacy criterion (SPID(0-3h)) established: (i) the superiority of the 3 active study treatments vs. placebo (p<0.005); (ii) non-inferiority of paracetamol, caffeine, and opium 25mg, and paracetamol, caffeine, and opium 50mg vs. tramadol. Besides, both formulations of paracetamol, caffeine, and opium showed: (i) a faster onset of analgesic effect as compared to tramadol 100; (ii) a significantly stronger analgesic efficacy than tramadol 100, as measured 1 hour after the treatment intake; this superiority lasted all over the study duration for paracetamol, caffeine, and opium 50mg but not for paracetamol, caffeine, and opium 25mg. No unexpected safety concerns occurred, the two formulations of paracetamol, caffeine, and opium showed a good safety profile especially with paracetamol, caffeine, and opium 25mg as compared to tramadol., Discussion: This study evidenced the non-inferiority of the paracetamol, caffeine, and opium 25mg or 50mg vs. tramadol 100, and even though the strengths of the tested formulations were higher than that of the 2009, commercialised formulation of paracetamol, caffeine, and opium, efficacy was not offset by an alteration of the well recognised safety profile of the less strengthened formulation of the product being in use for decades., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

Objective: French law on biomedical research does not apply to non-interventional researches. A favourable advice of an IRB (Institutional Review Board) is required. This article describes the setting up of a Clinical Research Centers Ethics Committee., Methods: The Clinical Research Centers Ethics Committee (CRCEC) was created in November, 2006. To guarantee a better objectivity Grenoble's projects are reviewed in Clermont-Ferrand board and conversely. Recommendations are given according to the compliance of research with laws and regulations in effect in France., Results: Twenty eight projects were submitted to the CRCEC during a 18 months period, mainly observation studies in a hospital setting. Four projects were redirected towards a formal French Ethic Committees (CPP) submission. Requests of modifications concerned a lack of information relative to data confidentiality., Conclusion: This committee is useful but its voluntary and "unofficial" nature questions about its perpetuation. We suggest that non interventional research be submitted to official CPP.

The purpose of the clinical trial guidelines is to harmonise legislation in order to ensure consistency within Europe and thereby promote Europe's attractiveness for clinical research while maintaining or improving the protection of subjects who agree to participate. The French administrative system has hitherto been relatively favourable (with simple notification to a single Ethics Committee per study); it is thus important to maintain competitiveness in these respects, given that, in other areas (the time it takes to establish agreements, recruitment, etc.), other countries have the advantage. At the moment, this Directive has not been entirely transposed into French law. The pilot period established by the Afssaps (French drug agency) has made it possible to determine very quickly how to set things up. For Ethics Committees, the situation is more critical in that many points remain that need to be finalised (selection of members, internal rules, Competent Authority/Ethics Committee relationship, etc.). The Giens workshop issued a number of proposals and it hopes, through the Afssaps)/DGS (French agency of health in government)/LEEM Steering Group (French pharmaceutical companies association), to be able to help establish an efficient system which also correctly protect the patient.

INFLUENCE OF AGING ON PAIN: Although pain affects a large majority of the elderly population living in the community and in institutions, our knowledge of the evolution of pain experience with age is poor. Results of clinical surveys and experimental pain studies are contradictory, showing no change, an increase, or a decrease of pain with age. Many results suggest a decrease of pain perception with age that could be explained by peripheral and central neuroanatomical aging and psychological changes of the aging patient towards pain., Influence of Age on the Pharmacology of Analgesics: Biological aging added to multiple pathologies and polymedication explains the pharmacological changes of analgesics. Among pharmacokinetic changes that are globally well known, vigilance must focus on renal excretion of analgesics and their metabolites and on the increased risk of side-effects and drug interactions. Information on pharmacodynamic changes of analgesics are scarce in aging patients who are susceptible to drugs and which demographical trend increases., Perspectives: A better fundamental knowledge of the evolution of pain with age could help to improve care in the elderly with pain, especially in very old subjects with cognitive impairment and loss of communication skills, where pain evaluation is particularly difficult. Also, more research is needed on the pharmacodynamics of analgesics in older subjects, with a view of a decreased iatrogenic risk, a better pain treatment and quality of life of the elderly.

The assessment of the clinical properties of analgesics is not easy. Some of the difficulties are due to the multiplicity of the aetiologies involved in the pain process, to the complexity of pathophysiological mechanisms modulating the nociception and to the subjectivity of painful sensation. All of these explain the fairly high variability of the criteria available for assessing pain level or pain relief. As a consequence, that variability directly interferes with the pharmacological effect of analgesics to be assessed in clinical trials. Furthermore, the lack of consensus concerning the evaluation criteria does not facilitate the choice of a study design or the comparison of data collected from different clinical trials. Clinicians have to choose between testing the analgesics in healthy volunteers (experimental pain) or in patients suffering from painful disease (spontaneous pain). These two approaches are often complementary for assessing the pharmacological profile of new analgesic compounds. Whatever the choice, the investigators have to pay attention to the methodological aspects to avoid pitfalls and bias in this difficult field of therapeutic research.

Objective: High altitude pulmonary oedema can be successfully treated and prevented by calcium channel blockers. Moreover, calcium entering in the cells could explain the congestive phenomena of acute mountain sickness (AMS). These findings led us to study the action of a calcium channel blocker, isradipine, in the prevention of non-complicated AMS., Methods: In a double blind randomized study, 20 healthy volunteers received 5 mg of isradipine (n = 6) or placebo (n = 6) for 8 days. After 5 days of treatment in normoxia, the subjects were rapidly transported to an altitude of 4350 m. The efficiency of the treatment was then estimated by the AMS symptom score, haemodynamic parameters and renal function., Results: The administration of isradipine did not significantly modify AMS symptom score nor most of other parameters measured in high altitude hypoxia. Heart rate was an average of 15 b/min lower in the isradipine group, probably because of a direct action of isradipine on the sinus node. Otherwise, the effects of hypoxia were similar in both groups and were in accordance with the literature. There was no clear explanation for the increase in cardiac output and stroke volume when the subjects moved from supine to standing position. Renal blood flow, measured by Doppler or para-aminohippuric acid clearance was not modified by hypoxia. Cerebral blood flow was elevated, due to the direct vasodilator effect of hypoxia. However this increase did not seem to be the main mechanism responsible for the congestive phenomena. On the other hand, the increase in capillary permeability (demonstrated by the increased transcapillary escape rate of albumin, and albuminuria) appeared to play a major role in the pathogenesis of AMS and high altitude cerebral oedema. Isradipine had no protective effect on these phenomena and its use should be restricted to the treatment of high altitude pulmonary oedema.

The authors report the case of a 15-year old boy with Tangier disease characterized clinically by grossly enlarged tonsils, liver and spleen. Blood counts showed signs of hypersplenism, and blood lipid assays disclosed hypercholesterolaemia with moderate hypertriglyceridaemia and very low levels of high density lipoproteins. The diagnosis was confirmed by biopsies of the liver, spleen, rectal mucosa, tonsils and bone marrow, all tissues which contained foamy histiocytic cells staining like adipose cells. Following splenectomy, the child developed an unexplained, persistent (6 months) fever, then died suddenly of digestive haemorrhage. A genetic study showed a high degree of inbreeding, with 2 deaths probably due to Tangier disease. The authors contrast the surprising severity of this case with the apparent benignity of the disease as described in other publications.