The Current Status of European and National Financial Sources for Clinical Research and Their Impact on Paediatric Non-commercial Clinical Trials: A Case Study of the Czech Republic.

INTRODUCTION: Paediatric non-commercial interventional clinical trials (NICTs) are crucial for healthcare provision. In spite of the fact that current regulations and initiatives try to enhance the quantity and quality of paediatric NICTs, there are still shortcomings that need to be addressed in order to accelerate the conduct of relevant clinical trials in children. To improve the current landscape of paediatric clinical research, it is necessary to identify and analyse the main trends and shortcomings, along with their impact on national performance in paediatric NICTs and this is the aim of this work. METHOD: A retrospective systematic search of paediatric NICTs was performed on four international clinical trials registries. Entries were filtered by date from 01/01/2004 to 31/12/2017. Each identified paediatric NICT was screened and analysed for sponsors, funders, type of intervention, therapeutic area, design characteristics and associated publications. RESULTS: The search identified 439 unique NICTs. When stratifying the trials by enrolment ages, 86 trials were found involving the paediatric population. Most trials investigated the use of medicinal products and were focused on cancer or cardiovascular diseases. The most common sources of the funding were non-profit organizations. Furthermore, from the total number of completed trials, only half of them already published their results. CONCLUSION: The main shortcomings-specifically, ethical, methodological and, in particular, economic obstacles were identified. There is a continual need for greater support and collaboration between all major stakeholders including health policymakers, grant agencies, research institutions, pharmaceutical industries and healthcare providers at the national and international level.

Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR).

PURPOSE: Bioavailability of clopidogrel in the form of crushed tablets administered via nasogastric tube (NGT) has not been established in patients after cardiopulmonary resuscitation. Therefore, we performed a study comparing pharmacokinetic and pharmacodynamic response to high loading dose of clopidogrel in critically ill patients after cardiopulmonary resuscitation (CPR) with patients scheduled for elective coronary angiography with stent implantation. METHODS: In the NGT group (nine patients, after cardiopulmonary resuscitation, mechanically ventilated, therapeutic hypothermia), clopidogrel was administered in the form of crushed tablets via NGT. Ten patients undergoing elective coronary artery stenting took clopidogrel per os (po) in the form of intact tablets. Pharmacokinetics of clopidogrel was measured with high-performance liquid chromatography (HPLC) before and at 0.5, 1, 6, 12, 24 h after administration of a loading dose of 600 mg. In five patients in each group, antiplatelet effect was measured with thrombelastography (TEG; Platelet Mapping) before and 24 h after administration. RESULTS: The carboxylic acid metabolite of clopidogrel was detected in all patients in the po group. In eight patients, the maximum concentration was measured in the range of 0.5-1 h after the initial dose. In four patients in the of NGT group, the carboxylic acid metabolite of clopidogrel was undetectable and in the remaining patients was significantly delayed (peak values at 12 h). All patients in the po group reached clinically relevant (>50 %) inhibition of thrombocyte adenosine diphosphate (ADP) receptor after 24 h compared with only two in the NGT group (p = 0.012). There was a close correlation between peak of inactive clopidogrel metabolite plasmatic concentration and inhibition of the ADP receptor (r = 0.79; p < 0.001). CONCLUSION: The bioavailability of clopidogrel in critically ill patients after cardiopulmonary resuscitation is significantly impaired compared with stable patients. Therefore, other drugs, preferentially administered intravenously, should be considered.