European survey on national harmonization in clinical research

Abstract 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. 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. is faster, and the results of the trial are more generally applicable. On the other hand, multinational clinical trials are significantly more complex to perform than national ones due in particular to the difficulties arising from the diversity of legal frameworks and operational practices. This is particularly true for the conduct of multinational trials initiated by academic institutions, which often do not have welldeveloped on-site management support. As a consequence, only 3% of academic trials are international (whereas 30% of industry trials are international). 1 In addition, the number of clinical trials, particularly those initiated by academic investigators, has been falling in recent years in many regions, including the European Union (EU). 2 In order to improve this situation, the EU adopted the Clinical Trial Regulation EU No. 536/2014 (CTR 3 ). Once in force, the CTR will lead to harmonized rules for conducting clinical trials throughout the EU. This will increase the efficiency of all trials in Europe with the greatest benefit for those conducted in multiple European Member States. It aims, among other things, to improve collaboration, information-sharing, and decision-making between and within Member States. 3  To what extent does harmonization of clinical research already exist in Europe? Through the Voluntary Harmonization Procedure (VHP), which was implemented in 2009 by the HMA, preliminary experience has been gained for the harmonization of clinical trial applications in particular (through mutual assessments). The CTR will further change and harmonize many processes related to multinational clinical trials, and these processes need to be adopted by existing "research infrastructures" and institutions. The term "research infrastructure" is used here to mean an organization that provides facilities, resources, or related services to researchers to enable toplevel scientific research; in the particular context of this article, we refer specifically to "infrastructures" that support multinational clinical research in Europe. We believe that these types of infrastructures, as well as existing harmonization processes (at national level), may be relevant for the implementation of the CTR (and beyond). As such, this paper aims to provide a snapshot of the current level of harmonization activities in clinical research; it also provides an overview of the current/potential role of infrastructures such as the European Clinical Research Infrastructure Network (ECRIN) to align harmonization processes between countries, in accordance with the expectations or requirements of the CTR (see also Appendix S1 for major changes under the CTR).
ECRIN is a public, nonprofit organization that links scientific partners and networks across Europe in order to facilitate multinational clinical research. 5 (Table 1). As per the ECRIN-ERIC statutes, the scientific partners must have developed shared tools, procedures, and practices to facilitate multicenter studies and have reached a "critical mass" in terms of competency. 6 ECRIN's scientific partners are involved in various harmonization activities at national level and beyond. To identify the scope of these activities, a survey was performed in ECRIN member and observer countries. The findings of the survey are also intended to support the identification of new fields of action for ECRIN to increase the quality and efficiency of multinational clinical research.

| RESEARCH INTERESTS
Research interests of the survey cover a status report on harmonization activities and the identification of possibilities to improve.

| METHODS
A survey was performed among ECRIN's national scientific partners in its member and observer countries (see Table 1) using a standardized, open-ended questionnaire.
Background information about ECRIN is given in Appendix S2.
In Table 2, basic data about the National Clinical Research Networks belonging to ECRIN are summarized.
Three rounds of data collection were performed between April 2018 and January 2019 to maximize completeness and comparability of the answers received. The detailed procedure of the data collection rounds is already described by Magnin et al. 7 The survey consisted of two parts, one dealing with national harmonization activities and the other with national training activities.
The results of the latter were published in the Trials Journal. 7 This report summarizes the results of the survey describing the harmonization of academic clinical research processes at national level. The questionnaire is included in Appendix S3.

| RESULTS
All ECRIN member and observer countries participated in the survey. Table 3 gives an overview of the responses on national harmonization activities, as provided by ECRIN's different scientific partner networks.

| Working groups
All but one of the scientific partners have established (or participate in national) working groups (WGs) in order to harmonize practices. In many cases, there is a systematic approach for collaboration.
Depending on the topic, collaboration may also be opportunity driven.
WGs (or initiatives) by country are as follows:

| Consulting
Consultation is provided in 10 countries and may be initiated by networks or asked for by national partners. In each country, this covers the following:

| Services
The

| Sharing templates/documents/ recommendations
All countries share templates/documents/recommendations developed in their network, except for Italy, which shares only within ECRIN-related studies. In addition, some countries provide external access upon request (Portugal), or on a cases-by-case basis (Germany), or for specific documents (Switzerland). Open and free access is provided by Ireland (with a disclaimer), and this will be the case for Norway, Slovakia, and Switzerland in the future.
Appendix S4 provides a noncomprehensive overview with useful links provided by the scientific partners. Furthermore, ECRIN harmonization activities and corresponding links are listed as well. To establish a more comprehensive future repository as planned by ECRIN, more conceptual work and resources are required, including a process to maintain the information (see also Section 5).

| Local/national certification programs for clinical research
The majority of countries offer no local/national certification pro-  Table 4.
It should be noted that there is some diversity of interpretation and use of terms related to certification (see Section 5).

| Influence on national harmonization regarding clinical research
A broad spectrum of ratings of the influence of ECRIN scientific partners on harmonization of clinical research in their country was observed. The influence was rated as "high" in three countries, "moderate" in two countries, "low" in three countries, and "very low" in one country. One country reported "low" in harmonization but "very high" in structuring and one "moderate to high." One country that rated the influence as "low" stated that more governmental support is needed for the implementation of harmonization. Another rating was "moderate" because the network is only 3 years in operation; however, it is Germany Audits for new KKS members are a prerequisite for membership. Also teaching curricula certification. Target group: within network.

Hungary
No. The National Institute of Pharmacy and Nutrition (OGYÉI) is the authority: they offer and perform the local certification program. Consortium members organize professional conferences, where it is possible to complete the GCP course for all interested (external and internal) parties. As the part of the HRDOP project (Education development subproject) we are also working on curriculum development. The teaching materials developed for clinical trial staff (study coordinator, study nurse, investigator, sub-investigator) will be available not only within the universities but also externally.

Ireland
Yes, on completion of the Mutual Recognition Scheme for QMS, the centers are issued a letter of completion (mutual recognition) from HRB-CRCI. ICH GCP training for Investigational Medicinal Products (IMPs) and medical devices is carried out by the Clinical Research Facilities and Centers (CRF/C's) in the network and certificates of completion are issued by the centers. The target groups for these courses are the CRF/C's and their staff as well as the investigator teams running the trials from the hospitals engaged with the CRF/C's for clinical research. Individual centers offer a range of different clinical research training courses in addition to those listed above.

Italy
Certification is required for clinical research organizations (CROs) (for any kind of study) and for clinical sites only if involved in phase I studies. In both cases they self-certify their activities. Inspections by the Italian Competent Authority will follow. We do not offer any certification programs.

Norway
Planned: certification program for study nurses/coordinators. In discussion: certification "light" for early phase units. already collaborating with the major stakeholders. In the country with a rating of "moderate to high," the national network has become a recognized stakeholder for academic research; however, so far, there was little involvement in the legislative process.

| Perception as facilitator for clinical research
All of ECRIN's scientific partners are perceived as facilitators rather than an additional source of bureaucracy. Three countries added that CTUs might be perceived as increasing administrative workload, since they continue to ask researchers to comply with the regulations (for the sake of quality but resulting in more paperwork). • Closer collaboration with other "research infrastructures" could be an aim for the certification of biobanks, for example.

| DISCUSSION
• Collaboration with different international registries for clinical trials in order to align content and improve comparability (eg, to better identify funding sources and data ownership). 20 • Transnational implementation of the Erasmus + CONSCIOUS project on innovative educational methodology will provide a new tool for many countries to standardize clinical trials and increase their efficiency at EU level and worldwide.
• ECRIN national scientific partners need to work towards more visibility at national level to foster quality and efficiency of multinational clinical research. 21 • Collaboration and agreements to facilitate cross-border data sharing through harmonized processes and best practices (citation: "The more broadly adopted standards (for data, metadata, models, and terminology), the easier the sharing of data and communication of meaning along with that data"). 22 • A similar survey performed on a regular basis will make it possible to evaluate the "structuring effect" of ECRIN over time.

| Limitations of the survey
Data collection was limited to 11 ECRIN member and observer countries through the coordinating units of the national scientific partners.
The ECRIN partners served as a convenient and representative sample. However, we cannot exclude other harmonization activities not known to the networks. In addition, the national networks of the member/observer countries are all organized differently, ranging from few units providing services nationwide to a network of up to 30 CTUs across the country. 23 As a consequence, the information is very heterogeneous and may not be complete in all cases and thus may not be representative for the entire EU.
In addition, diversity of interpretation and use of terms was identified in the survey as, for example, the "process of certification." Does it mean a very rigorous process like ISO certification or does it refer to the simpler process of getting, for example, a certificate for training? Also "consultancy" was interpreted differently: consultancy as a core business of CTUs for researchers vs acting as experts for different bodies and authorities. For future surveys, such expressions should be better defined or provided in closed-ended questions.
Nevertheless, the survey has been performed in three rounds with stepwise improvement of the information and face-to-face discussions between the survey participants and thus gives a good overview on harmonization activities in the participating countries. Just recently, Poland joined ECRIN as an observer, and hence, future updates will be even more comprehensive.