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The digitisation of healthcare has brought new opportunities to complement and enhance the data traditionally utilized in regulatory decision-making. According to the EMA, real world evidence (RWE) has been defined as the information derived from analysis of routinely collected real world data (RWD) relating to a patient’s health status or the delivery of healthcare from a variety of sources other than traditional clinical trials. Before fostering the enormous potential presented by the use of routinely collected RWD (e.g. electronic health records, medical claims, insurance data etc.) several challenges need to be addressed: operational, technical, methodological and ELSI. Reusing RWD for research purposes in Europe and especially in a crossborder manner is hampered by the fact that health databases and registries are not easily discoverable and, even when they are, understanding what data they contain and their suitability for addressing a specific research question remains not trivial due to the lack of detailed data catalogues with adequate metadata (especially in English). The present report is entitled “D4.5 Public database inventorying the national health databases and registries and describing their access procedures for reuse for research purposes”. As the title indicates, the report delivers an inventory of national health databases and registries covering 15 European countries: Austria, Czech Republic, France, Germany, Hungary, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland. For each country the reader can find information on the national healthcare system, a list of health databases and registries, their description (or links to websites where this description can be found) and information on data access for research purposes. Although this deliverable was initially conceived as a “public database” in the form of a website, the EOSC-Life WP4 partners agreed that this would be unnecessary as the European Health Information Portal1 is already playing this role. Instead, this report will become publicly available through Zenodo and disseminated to relevant stakeholders working on similar issues (including the actors behind the Health Information Portal) as a way to “join forces” and complement each other’s work instead of duplicating efforts. In summary, we conclude that the picture across Europe is diverse and at times patchy as the health databases and registries are subject to different governance and sustainability models but also to different local laws and access rules. Interestingly, there is still, on a European level, great debate around the terms “anonymisation”, “pseudonymisation” and “de-identification” and when data can be considered anonymised and as such exempted from the GDPR. Additionally, even when the current barriers of discoverability and accessibility (that are the main focus of this report) are lifted, there remains the major question of whether such data sources are suitable for research, as concerns around their quality, completeness and structure (or lack of) are still to be addressed.

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.

BackgroundTreatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study MethodsA total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up ResultsThe cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively ConclusionsThe 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense

Background Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2nd stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use. Methodology In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2nd stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation. Principal Findings 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings. Conclusions/Significance In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up. Registration The trial is registered at ClinicalTrials.gov, number NCT00906880., Author Summary Sleeping sickness is a neglected tropical disease affecting people in Sub-Saharan Africa, most of them in poor, rural settings. If not treated, the disease usually progresses into a serious stage affecting the central nervous system, causing severe sleep disturbances, as well as other neurological and psychiatric disorders, coma, and death. Until recently, the only ways to treat 2nd stage gambiense sleeping sickness involved drugs that were either toxic (such as the arsenic derivative melarsoprol) or difficult to administer in resource-constrained settings (e.g. eflornithine). A new treatment, nifurtimox-eflornithine combination therapy (NECT), was developed and tested in clinical trials, and is now recommended as the treatment of choice for 2nd stage sleeping sickness. NECT is easier to administer than eflornithine, but more information needs to be gathered for its use in the field: logistical barriers must be overcome, health care staff must be well trained, and, importantly, the safety profile of the treatment in real-life conditions needs to be better evaluated. We report here the results of a study designed to gain better understanding of the clinical tolerability, feasibility and effectiveness of NECT in field conditions, and to gather data on its use in specific populations, such as children and pregnant women.

Treatment of human African trypanosomiasis (sleeping sickness) with the currently available drugs is unsatisfactory and new drugs and approaches are urgently needed. Despite being associated with severe adverse reactions and a long, complicated treatment schedule, melarsoprol (Arsobal®) is expected to remain the most used drug for the treatment of latestage sleeping sickness for the next decade because alternative treatments are too expensive and only at very preliminary stages of development. In the presented study, the overall effectiveness of an abridged application scheme of melarsoprol for the treatment of late-stage gambiense sleeping sickness was evaluated. In a first part, the long-term efficacy of the 10-day schedule was concluded based on the followup of the patients treated in a large-scale controlled clinical trial in Angola in 1998 (IMPAMEL I). In a second part, the overall effectiveness of this abridged treatment schedule was assessed in a multinational drug utilisation study (IMPAMEL II) that was executed under field conditions. Clinical effectiveness was shown by addressing specifically the usefulness in different settings, e.g. in different countries / centres and in children below 15 years of age. An economic appraisal was also done to assess the monetary benefit if switching from the standard treatment schedule to the short course of melarsoprol. 2800 patients from 16 different treatment centres ofAfrican countries endemic for T.b gambiense trypanosomiasis were treated with 10 daily doses of 2.2 mg melarsoprol/kg bodyweight on consecutive days. The short- and long-term efficacies of the 10-day schedule were good and comparable to the standard schedules found in the randomised, controlled clinical trial in Angola and in previous trials published in literature. However, poor follow-up is an inherent problem of sleeping sickness control and therefore highly variable attendance rates of the follow-up examinations could be anticipated. In our studies, they varied from acceptable in the controlled trial in Angola to rather low rates in many treatment centres of the multinational study. Highly variable outcomes were also found for the safety of the 10-day treatment schedule reported from the different treatment centres in the multinational evaluation. But nevertheless, the safety under field conditions proved to be well comparable to the findings of the clinical trial previously executed in Angola, the literature and the retrospective data from the participating treatment centres. No unexpected findings were reported. In addition, the tolerability and effectiveness of the abridged treatment schedule in children were assessed by reviewing all patients treated in the multinational study who were below the age of 15 years. There is evidence that the safety and efficacy profile of the 10-day schedule is similar in children and adults. The abridged treatment schedule was well tolerated by the children and we found only non-significant differences in the occurrence of adverse events compared to adults. Some of these differences could be explained by higher rates of concomitant parasitic diseases in children and the fact that some adverse events cannot be separated from common signs and symptoms of the disease, especially in younger children (e.g. headache). The cure rates were identical in the subpopulations. We found the 10-day treatment schedule to be more cost-effective than the standard treatment and a highly cost-effective treatment option for late-stage gambiense sleeping sickness in areas with scarce resources. The costs of treatment (diagnosis, hospitalisation and sleeping sickness specific treatment) were assessed in two rural treatment centres and compared to the benefits of the 10-day treatment and of the standard treatments, measured by the cost of treatment per DALY (disability-adjusted life-year) averted. The net benefit from switching from the standard (26 to 30 days hospitalisation) to the 10-day treatment schedule did reduce the costs per DALY averted by almost half of the costs calculated for the standard schedules and represented a “good value for money” option in the control of sleeping sickness. In addition, the 10-day schedule bears several advantages over the standard national treatment schedules: It reduces treatment duration, hospitalisation time, and total drug amount per patient, it is easier to implement in basic, rural treatment centres, and it increases the treatment centres’ capacity. Based on our findings and the experience of the sleeping sickness control programs in the respective countries, the abridged protocol was recommended by the 27th ISCTRC in late 2003 as the standard schedule for melarsoprol treatment of late-stage sleeping sickness due to T.b. gambiense. However, because of the different clinical nature and the high parasitaemia, the use of the 10-day schedule against T.b. rhodesiense is strongly discouraged until the necessary clinical evaluation will be conducted. Based on its simplified implementation, the 10-day schedule offers straightforward adaptation for combination therapy with other existing drugs, especially for melarsoprol refractory patients.