European survey on national harmonization in clinical research.

BACKGROUND: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials throughout the EU. Existing harmonization initiatives and "research infrastructures" for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. METHODS: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardized questionnaire. Three rounds of data collection were performed to maximize completeness and comparability of the received answers. The survey aimed to describe the harmonization of academic clinical research processes at national level, to facilitate the exchange of expertise and experience among countries, and to identify new fields of action. RESULTS: Most scientific partners already have in place various working groups and harmonization activities at national level. Furthermore, they are involved in and open to sharing their know-how and documents. Since harmonization was mainly a bottom-up approach up until now, the extent and topics dealt with are diverse and there is only little cross-networking and cross-country exchange so far. CONCLUSIONS: Currently, the ECRIN member countries offer a very solid base and collaborative spirit for further aligning processes and exchanging best practices for clinical research in Europe. They can support a smooth implementation of the EU CTR and may act as single contact with consolidated expertise in a country.

[Questionnaire for assessing the risk of venous thromboembolism in hospitalized surgical and non-surgical patients in the 4th Hungarian antithrombotic guideline entitled "Risk reduction and treatment of venous thromboembolism"]. / Vénásthromboembolia-kockázati kérdôív kórházban kezelt sebészeti és nem sebészeti betegek részére "A thromboemboliák kockázatának csökkentése és kezelése" címu, 4. magyar antithromboticus irányelvben.

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.

Clinical research in Hungary. Infrastructure, organisation, legislation and framework. The situation in 2008.

The European Clinical Research Infrastructures Network (ECRIN) is designed to improve the capacity and quality of the clinical research in Europe and promote innovative pharmaceutical development. The regulation of the company-sponsored clinical trials is functionally acceptable, but other type of investigations (investigator initiated trials, trials of psychology, food supplements, devices, etc.) needs further harmonisation. Hungary joined ECRIN in 2005 and performed a lot of queries in regulation, legislation, monitoring, safety, pharmacovigilance, data management, quality assurance, etc., which are presently summarized in this paper in order to show the present situation of the complicated issues of clinical research in Hungary. This "country report" summarizes the present legislative and regulatory frames including the necessary issues being attached: organizing and setting-up the first representatives of clinical study centres into a network, which will facilitate the organisation and performance of multinational studies in various research areas.

[Cancer chemotherapy and anticoagulant prophylaxis]. / Az antikoaguláns profilaxis és a kemoterápia.

The modern pathobiochemical explanation of the old clinical finding, i.e. that the occurrence of the thromboembolic complications in cancer patients is significantly higher, starts to be clarified on the basis of recent knowledge regarding the role of cancer procoagulant, the expressed tissue factor and the changes in the clotting and fibrinolytic systems. Furthermore, the presently used chemotherapeutic agents have activating effects of the coagulation system as well. The details of these phenomena, the frequently used drugs and their pathobiochemical effects are detailed in this publication. Finally, it gives an outlook regarding the new adjuvant, beneficial effects of the direct anticoagulants in malignancies.

Investigation of Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in type 2 diabetes mellitus.

Increased levels of soluble P-selectin (sP-selectin) have been shown in a number of different disorders, e.g. diabetes mellitus (DM) and cardiovascular disease (CVD). Several studies have attempted to demonstrate the association of the most intensively examined variant of P-selectin gene polymorphism (Thr715Pro) with sP-selectin levels in healthy subjects and in CVD, but contradictory data have been reported. To clarify the effect of Pro715 allele on the sP-selectin levels in type 2 DM, we analysed this polymorphism in diabetic patients and compared these data with sP-selectin levels. Type 2 DM patients (n = 119), 48 BMImatched non diabetic individuals - consisting mostly of overweight subjects - and 57 healthy volunteers were included in the study. TheThr715Pro polymorphism was analysed by PCR-RFLP, while sP-selectin levels were measured by ELISA. Significantly elevated sP-selectin levels were found in both DM and in overweight subjects compared to healthy controls. We confirmed previous reports that in healthy Pro715 allele carriers lower sPselectin levels could be measured; however, this difference was only significant in case of lean subjects. No significant difference was detected in sP-selectin level among DM and overweight individuals according to this genotype. However, significant difference was observed in sP-selectin levels in older DM patients compared to younger ones, but these levels were not accounted for by the Thr715Pro polymorphism. We suggest that in type 2 DM individuals, the significantly elevated sP-selectin levels are not due to the Thr715Pro P-selectin gene polymorphism.

Serum levels of platelet released CD40 ligand are increased in early onset occlusive carotid artery disease.

OBJECTIVE: Soluble CD40 ligand (sCD40L) has been suggested as a key mediator between inflammation and atherosclerosis, and the CD40-CD40L interaction has a role in atherosclerotic lesion progression. We evaluated if platelet released serum sCD40L and sCD40 levels differ between patients with early onset occlusive carotid artery disease and age-matched controls. METHODS: sCD40L and sCD40 levels were measured in serum samples of 60 patients with occlusive carotid artery disease and 30 age-matched controls using ELISA. Degree of stenosis of the internal carotid artery (ICA), and intima-media thickness (IMT) in the common carotid artery were measured by high resolution ultrasound. Values are given as mean +/- SD. RESULTS: Mean age was 50.9 +/- 3.5 and 50.1 +/- 3.5 years in the patient and control groups. IMT was significantly thicker in patients than in controls (0.89 +/- 0.14 vs. 0.78 +/-0.12 mm, p=0.0003). Serum levels of sCD40L were significantly higher (6.9 +/- 5 vs. 4.5 +/- 3.0 ng/mL, p=0.038) in patients, whereas sCD40 did not differ significantly between patients and controls (85 +/- 56.9 vs. 79.3 +/- 18.7 pg/mL, p=0.34). IMT did not correlate with sCD40L or sCD40 levels (R=-0.03, p=0.77; and R=0.109, p=0.308, respectively). CONCLUSIONS: sCD40L but not sCD40 levels are significantly higher in patients with occlusive carotid artery disease. Platelet derived sCD40L may be a key mediator among inflammation, thrombosis and atherosclerosis.

[Microcirculatory changes in patients with chronic venous and lymphatic insufficiency and heavy leg symptoms before and after therapy with procyanidol oligomers (laser-Doppler study)]. / Krónikus vénás-lymphás elégtelenség következtében kialakult "nehéz láb" tünetegyüttesben szenvedo betegek mikrocirkulációjának változása flavonoid-származékkal (procyanidol oligomerek) végzett kezelés hatására (lézer-Doppler módszer alkalmazása).

INTRODUCTION: To study the efficacy of venotonica and medicaments having anti-edema effect is very actual. AIMS: Patients suffering from venous-lymphatic insufficiency were treated with procyanidol oligomers in an open, prospective study. The effective substance of this medication protects the fibrous connective tissue protein, thus improving the function of the venous and lymphatic capillaries. METHODS: For three months, the daily dose was 2 x 150 mg 30 patients were included into the study. The efficacy of the treatment was evaluated by statistical methods analysing the changes of the clinical symptoms and the satisfaction of the patients. For the first time, laser-Doppler method was used to determine the pathological condition of the dermal microcirculation before and after 3 months of treatment. The laser-Doppler tests used as indicators of the functional changing of the microcirculations were as follows: venoarterial response, reactive hyperemic response, and thermal stimulation response. The authors established the standard values and compared the measurement scores to those. According to the resulting scores, the status before and after the treatment can be compared by statistic analysis. Subjective complaints of the patients such as pain, heaviness of the leg, nightly muscle cramps were estimated by a visual analog scale. RESULTS: The treatment (procyanidol oligomers) significantly reduced lymphedema (p < 0.001) in the "heavy leg" syndrome. Symptoms as pain, heaviness of the leg, muscle cramps, improved significantly (p < 0.001) after treatment. The microcirculatory status was pathologic before treatment. After treatment, there was no significant improvement in the laser-Doppler results. CONCLUSIONS: The study revealed that in venous-lymphatic insufficiency, the arterial-capillary system is also damaged. The authors bring to attention that the disorder of the dermal arteries playing a role in the pathogenesis of venous-lymphatic insufficiency first detected in this study needs to be further investigated.

[Conclusions of consensus development conferences on the prevention and treatment of venous thromboembolism]. / A vénás thromboemboliák megelózéséról és kezeléséról tartott konszenzus konferenciák tapasztalatai.

An education program for hospital physicians and family doctors including up to date knowledge on diagnosis, prevention and treatment of venous thromboembolism has been elaborated, chiefly within the framework of hospital consensus conferences. Postgraduate consensus meetings led by representatives of specialities interested in prophylaxis of venous thrombosis have been held in 64 hospitals all over the country during the years 1996 to 2002, with a total number of more than 10,000 doctors working in hospital or general practice. In contrast to descriptive reports offered so far on drugs, the aim was a comprehensive clinical review of the problem, according to the principle of "disease management". By this way not only new diagnostic, therapeutic and prophylactic methods were presented but we managed to shape a new attitude based on new pathophysiological findings. As a result of the conferences the incidence and mortality of venous thromboembolism has decreased both on hospital and national levels. The consensus meetings acting as local interdisciplinary postgraduate forums have been supported by the Hungarian Thrombosis and Haemostasis Society and the haemostasis workshops of the country (Budapest, Debrecen, Pécs, Szombathely). Shaping the principles and methods for prophylaxis and therapy of venous thromboembolism can be regarded as a model which can subsequently be adapted to the problems of arterial thrombosis as well.

D-dimer as a potential prognostic marker.

Malignant tumors are often accompanied by increased risk for procoagulant activity, thrombosis and embolism. As a marker indicating such disturbancies is D-dimer, a product of fibrinolysis. In this retrospective study almost 300 patients with malignant tumors were evaluated. During LMWH treatment (as thromboprophylaxis) the highest frequency of VTE with worst prognosis occurred in pancreatic cancer (partly due to the late discovery) followed by ovarian, colonic and breast cancers. Also, increased D-dimer level correlated with progression (stages) and high mortality rate. Furthermore, D-dimer showed very similar or better prognostic activity than the clinically widely used classic tumor markers and suggested to use it as an additional value..

Typical investigational medicinal products follow relatively uniform regulations in 10 European Clinical Research Infrastructures Network (ECRIN) countries.

BACKGROUND: In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe. METHODS: We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries. RESULTS: Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised. CONCLUSION: The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.

Compassionate use of interventions: results of a European Clinical Research Infrastructures Network (ECRIN) survey of ten European countries.

BACKGROUND: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. METHODS: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). RESULTS: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. CONCLUSIONS: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.

The effect of LMWH (Nadroparin) on tumor progression.

Recent clinical studies on patients with malignancies, who were treated with UHF and LMWHs raised the possibility, that these agents may possess an inhibitory effect on tumor progression. Further studies supported that this effect is independent from the anticoagulant and antithrombotic action. In this retrospective study oncological patients with an increased risk for thromboembolism were choosen, who received prophylactic treatment with an LMWH (nadroparin) at least for 6 months. Comparing with the control group, in some subgroups (T3 and T4, as well as M1) the LMWH-treated patients showed a significantly increased survival.

Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN).

BACKGROUND: Thorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states. METHODS: In order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey. RESULTS: The ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising. CONCLUSION: The list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.