How do 66 European Institutional Review Boards approve one protocol for an International Prospective Observational study on traumatic brain injury? Experiences from the CENTER-TBI study.

doi:10.21203/rs.2.18273/v2

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Research article

How do 66 European Institutional Review Boards approve one protocol for an International Prospective Observational study on traumatic brain injury? Experiences from the CENTER-TBI study.

https://doi.org/10.21203/rs.2.18273/v2

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published 12 May, 2020

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Background:The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency. Methods: We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe. Results:From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N=11, 61%) or locally (N=7, 39%) and primary IRB approval was obtained after one (N=8, 44%), two (N=6, 33%) or three (N=4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional central IRB approval was required in 55% of countries and increased duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75-224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p=0.0074). Conclusion:We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.

Medical Ethics

Neurology

Research Ethic Committees

European Union

Health-care Research

CENTER-TBI

Harmonization.

A Research Ethics Committee or Institutional Review Board (collectively referred to as IRB in the remainder of this manuscript) is appointed to review research protocols to ensure their compliance with ethical standards and national laws. IRBs have an essential role in (clinical) research to protect the dignity, fundamental rights, safety, and well-being of research participants and their formal approval is compulsory before a clinical study can start.[1] Although several international models exist to improve the harmonization of ethical principles, the functioning of IRBs are subject to national legislation and regulation, which refine their structure and function to better serve local needs and cultural preferences.[2-3] Approval of research protocols submitted to IRBs is subject to these differences, which may complicate the conduct of international research.

Managing variations in IRB procedures is important because of the increasing number of research initiatives which involve multiple European Union (EU) Member States.[4-6] Variation could be improved by harmonization of European law, which is the process of creating uniformity in laws, regulations and practices between countries. Regarding research and IRB procedures, lack of procedural harmonization 'leads to a complex and uncertain framework for ethical review and for participant information consent, resulting in numerous inefficiencies in observational studies'.[7] Greater procedural harmonization is generally considered desirable, because it could improve quality and efficiency of healthcare research by decreasing costs, increasing statistical validity,[8-10] optimizing data management,[10] allowing choice of relevant and generalizable outcome variables,[9] promoting uniform product safety regulations [8] and minimizing waste of resources due to inefficiencies.[8]

Although most IRBs have websites that describe the local submission process and provide access to submission guidelines and forms, up to date systematic information on IRB procedures and their level of harmonization in European health-care research is scarce. We are aware of only one previous meta-analysis on IRB procedures across European countries from 2005 to 2007 that was also related to research involving acutely mentally incapacitated individuals.[6] The Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study is a large observational study conducted in many countries across Europe that provides a unique opportunity to assess European IRB policies and procedures.[11]

This study aims to improve the efficiency of future research initiatives by quantifying the differences in IRB procedures through analyzing the procedural details, problems and challenges that researchers encountered in obtaining IRB approval for the general research protocol of the CENTER-TBI study.

Study setting

The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI, www.center-tbi.eu) Core study is a prospective observational study on traumatic brain injury (TBI), which was conducted between December 2014 and December 2017 in 63 neurotrauma centers across Europe and Israel.[11-12] The study included patients with TBI of all severities, and aims to improve characterization of TBI, in order to facilitate the development of precision medicine approaches and to identify best practices by using a comparative effectiveness research (CER) approach.[11-14] In the context of the project high-quality Personal Health related Data (PHD) were collected with repositories for neuro-imaging, DNA, and serum biomarkers. Prior to the study start and collection of clinical data, a uniform CENTER-TBI research protocol including all relevant documents was sent to all responsible IRBs to ensure its legal, ethical and statistical soundness and to obtain IRB approval.

A total of 68 centers from 19 countries initially submitted applications for IRB approval. Because this article focuses on IRB approval in Europe, two centers from Israel were excluded from our analysis. The 66 center that participated in this present study are from Austria (N=2), Belgium (N=5), Denmark (N=2), Finland (N=2), France (N=7), Germany (N=4), Hungary (N=3), Italy (N=8), Latvia (N=3), Lithuania (N=2), the Netherlands (N=7), Norway (N=3), Romania (N=1), Serbia (N=1), Spain (N=4), Sweden (N=2), Switzerland (N=1), and the United Kingdom (UK), (N=9). Sixty-one European centers were initiated and actively enrolled patients in the study.

Data collection and administration

All IRB submission documents, communication records and approval documents were collated per center by the Contract Research Organization, ICON plc (ICON), directly after final approval of IRBs. [15] ICON is a global company operating in the healthcare industry that was responsible for the clinical monitoring of CENTER-TBI data. The received IRB documents were obtained in 15 different languages (Danish, Dutch, English, Finnish, French, German, Hungarian, Italian, Latvian, Lithuanian, Norwegian, Romanian, Serbian, Spanish, and Swedish) and were partly translated before analysis. The authors contacted the principle investigators to obtain additional information to minimize the amount of unclear or missing data. Identifiable information was deleted to protect the privacy of stakeholders. This resulted in a final set of documents, that was analyzed for this study.

Analyses

We assessed the IRB review procedures by using the final set of documents and aimed to answer the following research questions in order to evaluate differences in obtaining IRB approval (1) Was the study considered to be observational or interventional? (2) Was the research protocol to be submitted to a central IRB or local IRB for primary IRB review and primary IRB approval? (3) Was additional IRB review required after primary IRB approval had already been obtained? If yes, to what extent? (4) How many review rounds were conducted before primary IRB approval was obtained? What were the reasons? (5) What was the time between protocol submission and obtaining the required IRB approval to start the study? The use of ‘primary’ in this context should be interpreted as first in an order and ‘additional’ as second in an order, without including a statement on importance.

To elaborate on the fifth question, we reconstructed six timeframes regarding the primary IRB review procedure: (1) time between protocol submission and primary IRB approval or first IRB reaction, (2) time between first IRB reaction and first reaction of researcher, (3) time between first reaction of researcher and primary IRB approval or second IRB reaction, (4) time between second IRB reaction and second reaction researcher, (5) time between second reaction researcher and primary IRB approval, and (6) total time between protocol submission and primary IRB approval. The existence of these timeframes naturally depended on the actual procedure. Data on any additional IRB review focused only on the duration of this particular review until the required IRB approval was obtained.

In order to assess regional variation, countries were grouped into six regions based on the United Nation geo-scheme: Baltic States (Latvia, and Lithuania), Eastern Europe (Hungary, Romania, and Serbia), Northern Europe (Denmark, Finland, Norway, and Sweden), Southern Europe (Italy, and Spain), the United Kingdom (UK), and Western Europe (Austria, Belgium, France, Germany, the Netherlands, Switzerland).[16] Incomplete data was marked ‘Missing’ (M) and all timeframes were reported in days.

To determine significant differences between the time from submission till approval of the research protocol between primary local IRBs and primary central IRBs, we performed a Mann-Whitney U test (continuous). Analyses were performed using R version 3.6.0. Finally, a descriptive analysis of questions, comments and answers from both IRB and researcher during the IRB review procedure was performed to summarize the problems and challenges that researchers encountered in obtaining IRB approval. IRB reactions were categorized and reported by their appearance: (1) Procedure, (2) Blood collection and biomarkers, (3) MRI, (4) Privacy and data security, (5) Other.

A total of 66 neurotrauma centers from 18 countries were included in this analysis. Most centers were located in Western Europe (N=26, 39%) and least in Eastern Europe (N=5, 8%) and the Baltic States (N=5, 8%). Most participating centers were from the UK (N=9), followed by Italy (N=8), The Netherlands and France (N=7) (Table 1). In all countries the local principal investigators were responsible to submit the general CENTER-TBI research protocol for IRB review and IRB approval.

Observational or interventional

The majority of countries (N=14, 78%) considered the study to be observational, while others judged it to be observational with diagnostic interventions (The Netherlands), interventional (France, Hungary) and observational and interventional (Serbia) (Table 1).

Primary central or primary local IRB review

Primary IRB review started directly after protocol submission and was considered ‘central’ when submitted to a central institution or an institution that was part of a national network (N=11, 61%). There were three options: (1) Primary central IRB approval had a national impact and applied to all participating centers within a country, without the need for additional IRB review (N=5; Denmark, Finland, France, Norway, Sweden). (2) Primary central IRB approval only allowed study start in the research centers associated with the approving IRB. Other participating centers in the country required approval after an additional extensive local IRB review. This involved the re-evaluation of the entire protocol and applicable ethics (N=4; Belgium, Germany, Hungary, Italy). (3) Primary central IRB approval only allowed study start in the research centers associated with the approving IRB. Other participating centers required additional approval after marginal local IRB review, mainly assessing local feasibility (N=2; UK, The Netherlands) (Figure 1).

Primary IRB review was considered ‘local’ when the protocol was submitted to an independent ‘local’ IRB. Obtained primary local IRB approvals only applied to the associated research centers and allowed study start without any additional requirements (N=7; Austria, Switzerland, Spain, Lithuania, Latvia, Romania, Serbia). Primary local IRB review could be performed simultaneously in each independent IRB (Figure 1).

For every protocol submission, there were two outcome options after IRB review: (1) the required (primary or additional) IRB approval had been obtained and the study could start, or (2) researchers were asked to answer questions or make protocol changes, which was followed by an extra IRB review round. This process varied between IRBs and was repeated until the required IRB approval was eventually obtained. None of the submissions in this study were rejected.

IRB review rounds

Eight countries (44%), including all countries from Eastern Europe and the Baltic State, obtained primary IRB approval in the first round after submission, while six countries (Austria, Belgium, France, Finland, Spain and UK) required one extra review round and four countries (Denmark, Germany, Norway and Sweden) required two extra review rounds (Figure 2). Extra review rounds were found in 73% of centers after primary central IRB submission and in 20% after primary local IRB submission.

Several IRBs commented on different aspects of the protocol: selection criteria (n=3, 38%), patient/proxy consent (n=4, 50%), and information forms (n=3, 38%). Also, specific questions were asked on possible non-standard care factors in particular MRI scans (N=4), blood sample collection (N=4). Four questions were asked about privacy and data security, mainly related to the period after study completion. All relevant information can be found in the supplementary files.
Duration from protocol submission to IRB approval

The median time from protocol submission until the required IRB approval was obtained to start the study was 114 days (IQR 75-224). The fastest required IRB approval was obtained after one day in Serbia and Romania, whereas the longest time was found in a center in the UK (535 days). Obtaining central IRB approval (138 days, IQR: 91-229) took significantly longer (p=0.0074) than obtaining local IRB approval (50 days, IQR: 29-102) (Table 2).

In Norway and Denmark, the majority of time from submission to primary central IRB approval was spent by researchers (67% and 69%, respectively), while in France (95%) and Hungary (71%) most time was consumed by IRBs. Regarding primary local IRB submissions, researchers only accounted for 12% of time in Spain and 21% in Austria (Figure 2).

Additional IRB review rounds after primary central IRB review were required in 55% of countries. An additional marginal (feasibility) review had a median duration of 104 days (IQR: 62-224), whereas an additional extensive IRB review took 189 days (IQR: 140-270) (Table 3).

Variation between centers within countries was least in Lithuania (31 to 47 days), Germany (288 to 312 days), Belgium (131 to 155 days), and Hungary (177 to 204 days), compared to Spain (69 to 349 days), the Netherlands (27 to 224 days), the UK (58 to 535 days), and Italy (65 to 288 days) (Table 3).

This study shows variation in IRB procedures between and within European countries, indicating a lack of uniform legislation and regulation, or inconsistencies in how such legislation or regulation were implemented. In some countries, a primary central IRB approval was sufficient for study initiation, while others required an additional IRB review at the participating site. Also, the number of review rounds, duration until IRB approval, and the nature of questions and comments from the IRBs varied. Not all IRBs considered the study to be observational, demonstrating a different way of understanding the study. The apparent lack of integration and harmonization in this context suggests that the efficiency of European research collaborations could benefit from improving knowledge on the existing differences, inefficiencies and moral values between and within countries.

The duration from protocol submission to required IRB approval was highly variable and ranged from one day up to nearly one year. In literature, differences between IRB procedures were also reported and IRB review durations varied from weeks to several months. [6,17] The difference in total duration between primary central and primary local IRB approval could respectively be overestimated and underestimated by the short primary IRB review times in Serbia and Romania and the missing data of the first review round for the UK. The difference is not necessarily related to the number of review rounds, but might be more explained by the reason and nature (primary central/local review or extensive/marginal additional local review) of the extra review round(s), the accompanying amount of work and the working speed of both IRB and research team. The influence of the latter was substantiated by our data as responding to questions from the IRB seemed to account for an important part of time in several countries (e.g. Denmark and Norway), while the majority of time in other countries (e.g. Belgium, Spain and France) was accounted for by the time taken in primary evaluation by IRBs. The exact reasons for these ‘delays’ could however not be derived from our data and deserves further study. They might be caused by the difficulty of requirements or questions, although, according to the communication records, IRBs mainly requested extra explanation of research procedures. Based on the IRB information requests in this study, special attention should be given to the description of inclusion criteria, informed consent procedures, patient information forms, non-standard care procedures, privacy and data security. A quick response by investigators and agreeing on a maximal turnover time of 1 month to 2 months for IRBs could already minimize substantial delay. This is also in correspondence with literature, where IRB turnover time targets range from 30 to 60 days.[17-18]

The question whether CENTER-TBI was an observational or an interventional study did not appear to be a clear explanation for differences in number and duration of review rounds. Interventional studies are generally subject to a more extensive review process, where observational study reviews may be more marginal. Nonetheless, duration was short in France and long in the UK. CENTER-TBI is registered as an observational study, in which ‘the investigator is not acting upon study participants, but instead observing natural relationships between factors and outcomes’.[19] Two IRBs considered the study to be purely interventional. Interventional studies are studies ‘where the researcher intercedes as part of the study design’.[19] An explanation for this opposing classification is that the IRBs did and did not consider the following procedures to be standard-of-care: (1) Different amounts of additional blood draws at presentation and follow-up. (2) Neuropsychological assessments and outcome questionnaires up to a 24-month follow-up. (3) Additional MRIs at sites participating in the MRI sub-study.

Extra work without clear benefits delays projects and should be avoided when possible. An additional IRB review after primary central IRB approval is usually double work and could result in an extra delay of weeks to more than a year, without always having clear benefits over the already obtained primary approval.[17] Cancelling potentially unnecessary (extensive) additional IRB review procedures could not only reduce turnover time, but also reduce costs. The exact costs of European IRB review procedures are unfortunately unknown, but the direct costs of an IRB review and approval in the US have been calculated to be $107.544 ($82.610 in IRB fees and $24.934 in labor).[20]

Delays in obtaining IRB approval not only adversely affect study initiation, but are also associated with several other risks. Long procedures with many feedback rounds will delay study start, frustrate researchers and might even endanger meeting subsidiary demands. Researchers might attempt to speed up the process by changing the protocol or submitting the protocol to IRBs that are considered to be less strict but able to process the submission the quickest. This does not necessarily serve primary research objectives and might even hamper quality and generalizability of study results.

Optimization of IRB review procedures is urgently needed as multinational collaborations in healthcare research are increasing and even promoted by multiple European research grants.[4-5,21] Harmonization and adequate implementation of regulatory and ethical standards between European countries could improve the present situation.[7,22] The EU already aims to freely cooperate across borders by defining common standards and removing legal obstacles, but true harmonization of Member State laws in a research context has clearly not been established yet.[21-24] For example, the General Data Protection Regulation (GDPR) aimed to ensure a fair and transparent processing of personal data and aimed to improve patients’ control over their own data.[25] The implementation and use of the GDPR however showed the difficulty of harmonization in the protection of the EU citizens in this context. This was especially caused by the possibility for European countries to use their own national legislation in addition to the GDPR, which does not improve the desired harmonization.

Harmonization remains to be a highly complex process due to variation of national regulations that are based on national customs, culture, ethics, religion and other beliefs. [6] Harmonization of laws is designed to incorporate different legal systems under a basic framework. To overcome the highly complex process of harmonization in the area of research, it has been suggested to combine similarities between legislations and regulations of countries under a basic framework like a European research directive. A framework should acknowledge these local cultural or religious beliefs, as disregarding them is neither feasible nor desirable. While the desirable goal of harmonizing regulation will certainly benefit research in the future, both IRBs and researchers will have to put in efforts until that time. IRBs can accelerate the turnover by only requiring central IRB approval and researchers should respond quicker and more comprehensively to questions from IRBs, preventing the repetition of questions.

Strengths and limitations

The CENTER-TBI study provides a unique opportunity to provide comprehensive insight in the procedural differences between European IRBs. The study benefits from its large size and because the data acquisition process increased the quality and completeness of documents. Despite the quality of the documents, results were still dependent on the recorded information. Therefore, we could not always identify causal factors for variation, which is something to look for in future initiatives. The data on IRB review procedures in an observational study conducted with mentally incapacitated patients in neurotrauma centers might not be generalizable for other research settings.

This study shows variation between IRB procedures across Europe, which pose major challenges to large European research collaborations. Differences are likely caused by the lack of harmonization, integration and implementation of national legislations and regulations. To optimize efficiency for multinational European studies in context of obtaining IRB approval, the encountered differences and inefficiencies should be studied further and policymakers should evaluate the opportunities to optimize regulatory harmonization, while acknowledging the boundaries of national sovereignty and local cultural preferences.

EU	European Union
CENTER-TBI	Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury
CER	Comparative Effectiveness Research
GDPR	General Data Protection Regulation
ICON	ICON plc
IRB	Institutional Review Board
M	Missing
PHD	Personal Health related Data
TBI	Traumatic Brain Injury
UK	United Kingdom

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

There are legal constraints that prohibit us from making all data publicly available. Data could be identifiable because the limited number of centres per country that were included in this study. Readers may contact Dr. Erwin J. O. Kompanje ([email protected]) for reasonable requests for the data.

Competing interests

The authors declare that they have no competing interests.

Funding

CENTER-TBI was supported by the European Union 7^th Framework program (EC grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA) and from Integra LifeSciences Corporation (USA). David K. Menon was supported by a Senior Investigator Award from the National Institute for Health Research (UK).

Authors' contributions

MT and JD analyzed the data and drafted the manuscript and the supplementary tables. EV analyzed the data. All coauthors gave feedback on the manuscript. EJOK supervised the project. All coauthors were involved in the design of the study. All coauthors approved the final version of the manuscript.

Acknowledgements

Not applicable.

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The CENTER-TBI participants and investigators:

Cecilia Åkerlund¹, Krisztina Amrein², Nada Andelic³, Lasse Andreassen⁴, Audny Anke⁵, Anna Antoni⁶, Gérard Audibert⁷, Philippe Azouvi⁸, Maria Luisa Azzolini⁹, Ronald Bartels¹⁰, Pál Barzó¹¹, Romuald Beauvais¹², Ronny Beer¹³, Bo-Michael Bellander¹⁴, Antonio Belli¹⁵, Habib Benali¹⁶, Maurizio Berardino¹⁷, Luigi Beretta⁹, Morten Blaabjerg¹⁸, Peter Bragge¹⁹, Alexandra Brazinova²⁰, Vibeke Brinck²¹, Joanne Brooker²², Camilla Brorsson²³, Andras Buki²⁴, Monika Bullinger²⁵, Manuel Cabeleira²⁶, Alessio Caccioppola²⁷, Emiliana Calappi ²⁷, Maria Rosa Calvi⁹, Peter Cameron²⁸, Guillermo Carbayo Lozano²⁹, Marco Carbonara²⁷, Simona Cavallo¹⁷, Giorgio Chevallard³⁰, Arturo Chieregato³⁰, Giuseppe Citerio^{31, 32}, Iris Ceyisakar³³, Mark Coburn³⁴, Jonathan Coles³⁵, Jamie D. Cooper³⁶, Marta Correia³⁷, Amra Čović³⁸, Nicola Curry³⁹, Endre Czeiter²⁴, Marek Czosnyka²⁶, Claire Dahyot‑Fizelier⁴⁰, Paul Dark⁴¹, Helen Dawes⁴², Véronique DeKeyser⁴³, Vincent Degos¹⁶, Francesco Della Corte⁴⁴, Hugo den Boogert¹⁰, Bart Depreitere⁴⁵, Đula Đilvesi⁴⁶, Abhishek Dixit⁴⁷, Emma Donoghue²², Jens Dreier⁴⁸, Guy‑Loup Dulière⁴⁹, Ari Ercole⁴⁷, Patrick Esser⁴², Erzsébet Ezer⁵⁰, Martin Fabricius⁵¹, Valery L. Feigin⁵², Kelly Foks⁵³, Shirin Frisvold⁵⁴, Alex Furmanov⁵⁵, Pablo Gagliardo⁵⁶, Damien Galanaud¹⁶, Dashiell Gantner²⁸, Guoyi Gao⁵⁷, Pradeep George⁵⁸, Alexandre Ghuysen⁵⁹, Lelde Giga⁶⁰, Ben Glocker⁶¹, Jagoš Golubovic⁴⁶, PedroA. Gomez⁶², Johannes Gratz⁶³, Benjamin Gravesteijn³³, Francesca Grossi⁴⁴, RussellL. Gruen⁶⁴, Deepak Gupta⁶⁵, JuanitaA. Haagsma³³, Iain Haitsma⁶⁶, Raimund Helbok¹³, Eirik Helseth⁶⁷, Lindsay Horton ⁶⁸, Jilske Huijben³³, PeterJ. Hutchinson⁶⁹, Bram Jacobs⁷⁰, Stefan Jankowski⁷¹, Mike Jarrett²¹, Ji‑yao Jiang⁵⁷, Faye Johnson⁷², Kelly Jones⁵², Mladen Karan⁴⁶, AngelosG. Kolias⁶⁹, Erwin Kompanje⁷³, Daniel Kondziella⁵¹, Evgenios Koraropoulos⁴⁷, Lars‑Owe Koskinen⁷⁴, Noémi Kovács⁷⁵, Ana Kowark³⁴, Alfonso Lagares⁶², Linda Lanyon⁵⁸, Steven Laureys⁷⁶, Fiona Lecky^{77, 78}, Didier Ledoux⁷⁶, Rolf Lefering⁷⁹, Valerie Legrand⁸⁰, Aurelie Lejeune⁸¹, Leon Levi⁸², Roger Lightfoot⁸³, Hester Lingsma³³, AndrewI.R. Maas⁴³, Ana M. Castaño‑León⁶², Marc Maegele⁸⁴, Marek Majdan²⁰, Alex Manara⁸⁵, Geoffrey Manley⁸⁶, Costanza Martino⁸⁷, Hugues Maréchal⁴⁹, Julia Mattern⁸⁸, Catherine McMahon⁸⁹, Béla Melegh⁹⁰, David Menon⁴⁷, Tomas Menovsky⁴³, Benoit Misset⁷⁶, Davide Mulazzi²⁷, Visakh Muraleedharan⁵⁸, Lynnette Murray²⁸, Ancuta Negru⁹¹, David Nelson¹, Virginia Newcombe⁴⁷, Daan Nieboer³³, József Nyirádi², Otesile Olubukola⁷⁷, Matej Oresic⁹², Fabrizio Ortolano²⁷, Aarno Palotie^{93, 94, 95}, Paul M. Parizel⁹⁶, Jean‑François Payen⁹⁷, Natascha Perera¹², Vincent Perlbarg¹⁶, Paolo Persona⁹⁸, Wilco Peul⁹⁹, Anna Piippo-Karjalainen¹⁰⁰, Matti Pirinen⁹³, Horia Ples⁹¹, Suzanne Polinder³³, Inigo Pomposo²⁹, Jussi P. Posti ¹⁰¹, Louis Puybasset¹⁰², Andreea Radoi ¹⁰³, Arminas Ragauskas¹⁰⁴, Rahul Raj¹⁰⁰, Malinka Rambadagalla¹⁰⁵, Jonathan Rhodes¹⁰⁶, Sylvia Richardson¹⁰⁷, Sophie Richter⁴⁷, Samuli Ripatti⁹³, Saulius Rocka¹⁰⁴, Cecilie Roe¹⁰⁸, Olav Roise^109,110, Jonathan Rosand¹¹¹, Jeffrey V. Rosenfeld¹¹², Christina Rosenlund¹¹³, Guy Rosenthal⁵⁵, Rolf Rossaint³⁴, Sandra Rossi⁹⁸, Daniel Rueckert⁶¹, Martin Rusnák¹¹⁴, Juan Sahuquillo¹⁰³, Oliver Sakowitz^{88, 115}, Renan Sanchez‑Porras¹¹⁵, Janos Sandor¹¹⁶, Nadine Schäfer⁷⁹, Silke Schmidt¹¹⁷, Herbert Schoechl¹¹⁸, Guus Schoonman¹¹⁹, Rico Frederik Schou¹²⁰, Elisabeth Schwendenwein⁶, Charlie Sewalt³³, Toril Skandsen^{121, 122}, Peter Smielewski²⁶, Abayomi Sorinola¹²³, Emmanuel Stamatakis⁴⁷, Simon Stanworth³⁹, Robert Stevens¹²⁴, William Stewart¹²⁵, Ewout W. Steyerberg^33, ¹²⁶, Nino Stocchetti¹²⁷, Nina Sundström¹²⁸, Anneliese Synnot^{22, 129}, Riikka Takala¹³⁰, Viktória Tamás¹²³, Tomas Tamosuitis¹³¹, MarkSteven Taylor²⁰, Braden Te Ao⁵², Olli Tenovuo¹⁰¹, Alice Theadom⁵², Matt Thomas⁸⁵, Dick Tibboel¹³², Marjolein Timmers⁷³, Christos Tolias¹³³, Tony Trapani²⁸, CristinaMaria Tudora⁹¹, Peter Vajkoczy ¹³⁴, Shirley Vallance²⁸, Egils Valeinis⁶⁰, Zoltán Vámos⁵⁰, Gregory Van der Steen⁴³, Joukje van der Naalt⁷⁰, Jeroen T.J.M. van Dijck⁹⁹, Thomas A. van Essen⁹⁹, Wim VanHecke¹³⁵, Caroline van Heugten¹³⁶, Dominique Van Praag¹³⁷, Thijs Vande Vyvere¹³⁵, Roel P. J. van Wijk⁹⁹, Alessia Vargiolu³², Emmanuel Vega⁸¹, Kimberley Velt³³, Jan Verheyden¹³⁵, Paul M. Vespa¹³⁸, Anne Vik^{120, 139}, Rimantas Vilcinis¹³¹, Victor Volovici⁶⁶, Nicole von Steinbüchel³⁸, Daphne Voormolen³³, Petar Vulekovic⁴⁶, KevinK.W. Wang¹⁴⁰, Eveline Wiegers³³, Guy Williams⁴⁷, Lindsay Wilson⁶⁸, Stefan Winzeck⁴⁷, Stefan Wolf¹⁴¹, Zhihui Yang¹⁴⁰, Peter Ylén¹⁴², Alexander Younsi⁸⁸, Frederick A. Zeiler^47,143, Veronika Zelinkova²⁰, Agate Ziverte⁶⁰, Tommaso Zoerle²⁷

¹ Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden

² János Szentágothai Research Centre, University of Pécs, Pécs, Hungary

³ Division of Surgery and Clinical Neuroscience, Department of Physical Medicine and Rehabilitation, Oslo University Hospital and University of Oslo, Oslo, Norway

⁴ Department of Neurosurgery, University Hospital Northern Norway, Tromso, Norway

⁵ Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway, Tromso, Norway

⁶ Trauma Surgery, Medical University Vienna, Vienna, Austria

⁷ Department of Anesthesiology & Intensive Care, University Hospital Nancy, Nancy, France

⁸ Raymond Poincare hospital, Assistance Publique – Hopitaux de Paris, Paris, France

⁹ Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy

¹⁰ Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands

¹¹ Department of Neurosurgery, University of Szeged, Szeged, Hungary

¹² International Projects Management, ARTTIC, Munchen, Germany

¹³ Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria

¹⁴ Department of Neurosurgery & Anesthesia & intensive care medicine, Karolinska University Hospital, Stockholm, Sweden

¹⁵ NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK

¹⁶ Anesthesie-Réanimation, Assistance Publique – Hopitaux de Paris, Paris, France

¹⁷ Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino - Orthopedic and Trauma Center, Torino, Italy

¹⁸ Department of Neurology, Odense University Hospital, Odense, Denmark

¹⁹ BehaviourWorks Australia, Monash Sustainability Institute, Monash University, Victoria, Australia

²⁰ Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia

²¹ Quesgen Systems Inc., Burlingame, California, USA

²² Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia

²³ Department of Surgery and Perioperative Science, Umeå University, Umeå, Sweden

²⁴ Department of Neurosurgery, Medical School, University of Pécs, Hungary and Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Hungary

²⁵ Department of Medical Psychology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

²⁶ Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

²⁷ Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy

²⁸ ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia

²⁹ Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain

³⁰ NeuroIntensive Care, Niguarda Hospital, Milan, Italy

³¹ School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy

³² NeuroIntensive Care, ASST di Monza, Monza, Italy

³³ Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands

³⁴ Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany

³⁵ Department of Anesthesia & Neurointensive Care, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK

³⁶ School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia

³⁷ Radiology/MRI department, MRC Cognition and Brain Sciences Unit, Cambridge, UK

³⁸ Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany

³⁹ Oxford University Hospitals NHS Trust, Oxford, UK

⁴⁰ Intensive Care Unit, CHU Poitiers, Potiers, France

⁴¹University of Manchester NIHR Biomedical Research Centre, Critical Care Directorate, Salford Royal Hospital NHS Foundation Trust, Salford, UK

⁴² Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK

⁴³ Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium

⁴⁴ Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy

⁴⁵ Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium

⁴⁶ Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia

⁴⁷Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

⁴⁸ Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

⁴⁹ Intensive Care Unit, CHR Citadelle, Liège, Belgium

⁵⁰ Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary

⁵¹ Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark

⁵² National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand

⁵³ Department of Neurology, Erasmus MC, Rotterdam, the Netherlands

⁵⁴ Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway

⁵⁵ Department of Neurosurgery, Hadassah-hebrew University Medical center, Jerusalem, Israel

⁵⁶ Fundación Instituto Valenciano de Neurorrehabilitación (FIVAN), Valencia, Spain

⁵⁷ Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/school of medicine, Shanghai, China

⁵⁸ Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden

⁵⁹ Emergency Department, CHU, Liège, Belgium

⁶⁰ Neurosurgery clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia

⁶¹ Department of Computing, Imperial College London, London, UK

⁶² Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain

⁶³ Department of Anesthesia, Critical Care and Pain Medicine, Medical University of Vienna, Austria

⁶⁴ College of Health and Medicine, Australian National University, Canberra, Australia

⁶⁵ Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical Sciences, New Delhi-110029, India

⁶⁶ Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands

⁶⁷ Department of Neurosurgery, Oslo University Hospital, Oslo, Norway

⁶⁸ Division of Psychology, University of Stirling, Stirling, UK

⁶⁹ Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK

⁷⁰ Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands

⁷¹ Neurointensive Care , Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK

⁷² Salford Royal Hospital NHS Foundation Trust Acute Research Delivery Team, Salford, UK

⁷³ Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

⁷⁴ Department of Clinical Neuroscience, Neurosurgery, Umeå University, Umeå, Sweden

⁷⁵ Hungarian Brain Research Program - Grant No. KTIA_13_NAP-A-II/8, University of Pécs, Pécs, Hungary

⁷⁶ Cyclotron Research Center , University of Liège, Liège, Belgium

⁷⁷ Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK

⁷⁸ Emergency Department, Salford Royal Hospital, Salford UK

⁷⁹ Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany

⁸⁰ VP Global Project Management CNS, ICON, Paris, France

⁸¹Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France

⁸² Department of Neurosurgery, Rambam Medical Center, Haifa, Israel

⁸³ Department of Anesthesiology & Intensive Care, University Hospitals Southhampton NHS Trust, Southhampton, UK

⁸⁴ Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and Sportmedicine, Witten/Herdecke University, Cologne, Germany

⁸⁵ Intensive Care Unit, Southmead Hospital, Bristol, Bristol, UK

⁸⁶ Department of Neurological Surgery, University of California, San Francisco, California, USA

⁸⁷ Department of Anesthesia & Intensive Care,M. Bufalini Hospital, Cesena, Italy

⁸⁸ Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

⁸⁹ Department of Neurosurgery, The Walton centre NHS Foundation Trust, Liverpool, UK

⁹⁰ Department of Medical Genetics, University of Pécs, Pécs, Hungary

⁹¹ Department of Neurosurgery, Emergency County Hospital Timisoara , Timisoara, Romania

⁹² School of Medical Sciences, Örebro University, Örebro, Sweden

⁹³ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

⁹⁴ Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

⁹⁵ Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

⁹⁶ Department of Radiology, University of Antwerp, Edegem, Belgium

⁹⁷ Department of Anesthesiology & Intensive Care, University Hospital of Grenoble, Grenoble, France

⁹⁸ Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy

⁹⁹ Dept. of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Dept. of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands

¹⁰⁰ Department of Neurosurgery, Helsinki University Central Hospital

¹⁰¹Division of Clinical Neurosciences, Department of Neurosurgery and Turku Brain Injury Centre, Turku University Hospital and University of Turku, Turku, Finland

¹⁰² Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique, Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France

¹⁰³ Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Barcelona, Spain

¹⁰⁴ Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania

¹⁰⁵Department of Neurosurgery, Rezekne Hospital, Latvia

¹⁰⁶ Department of Anaesthesia, Critical Care & Pain Medicine NHS Lothian & University of Edinburg, Edinburgh, UK

¹⁰⁷ Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK

¹⁰⁸ Department of Physical Medicine and Rehabilitation, Oslo University Hospital/University of Oslo, Oslo, Norway

¹⁰⁹ Division of Orthopedics, Oslo University Hospital, Oslo, Norway

¹¹⁰ Institue of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

¹¹¹Broad Institute, Cambridge MA Harvard Medical School, Boston MA, Massachusetts General Hospital, Boston MA, USA

¹¹² National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia

¹¹³ Department of Neurosurgery, Odense University Hospital, Odense, Denmark

¹¹⁴ International Neurotrauma Research Organisation, Vienna, Austria

¹¹⁵ Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany

¹¹⁶ Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary

¹¹⁷ Department Health and Prevention, University Greifswald, Greifswald, Germany

¹¹⁸ Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg, Austria

¹¹⁹ Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, the Netherlands

¹²⁰ Department of Neuroanesthesia and Neurointensive Care, Odense University Hospital, Odense, Denmark

¹²¹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway

¹²² Department of Physical Medicine and Rehabilitation, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

¹²³ Department of Neurosurgery, University of Pécs, Pécs, Hungary

¹²⁴ Division of Neuroscience Critical Care, John Hopkins University School of Medicine, Baltimore, USA

¹²⁵ Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK

¹²⁶ Dept. of Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands

¹²⁷ Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy

¹²⁸ Department of Radiation Sciences, Biomedical Engineering, Umeå University, Umeå, Sweden

¹²⁹ Cochrane Consumers and Communication Review Group, Centre for Health Communication and Participation, School of Psychology and Public Health, La Trobe University, Melbourne, Australia

¹³⁰ Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland

¹³¹ Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania

¹³² Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands

¹³³ Department of Neurosurgery, Kings college London, London, UK

¹³⁴ Neurologie, Neurochirurgie und Psychiatrie, Charité – Universitätsmedizin Berlin, Berlin, Germany

¹³⁵ icoMetrix NV, Leuven, Belgium

¹³⁶Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK

¹³⁷ Psychology Department, Antwerp University Hospital, Edegem, Belgium

¹³⁸ Director of Neurocritical Care, University of California, Los Angeles, USA

¹³⁹ Department of Neurosurgery, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

¹⁴⁰ Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA

¹⁴¹ Department of Neurosurgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

¹⁴² VTT Technical Research Centre, Tampere, Finland

¹⁴³ Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Åkerlund	Cecilia	[email protected]
Amrein	Krisztina	[email protected]
Andelic	Nada	[email protected]
Andreassen	Lasse	[email protected]
Anke	Audny	[email protected]
Antoni	Anna	[email protected]
Audibert	Gérard	[email protected]
Azouvi	Philippe	[email protected]
Azzolini	Maria Luisa	[email protected]
Bartels	Ronald	[email protected]
Barzó	Pál	[email protected]
Beauvais	Romuald	[email protected]
Beer	Ronny	[email protected]
Bellander	Bo-Michael	[email protected]
Belli	Antonio	[email protected]
Benali	Habib	[email protected]
Berardino	Maurizio	[email protected]
Beretta	Luigi	[email protected]
Blaabjerg	Morten	[email protected]
Bragge	Peter	[email protected]
Brazinova	Alexandra	[email protected]
Brinck	Vibeke	[email protected]
Brooker	Joanne	[email protected]
Brorsson	Camilla	[email protected]
Buki	Andras	[email protected]
Bullinger	Monika	[email protected]
Cabeleira	Manuel	[email protected]
Caccioppola	Alessio	[email protected]
Calappi	Emiliana	[email protected]
Calvi	Maria Rosa	[email protected]
Cameron	Peter	[email protected]
Carbayo Lozano	Guillermo	[email protected]
Carbonara	Marco	[email protected]
Castaño-León	Ana M.	[email protected]
Cavallo	Simona	[email protected]
Chevallard	Giorgio	[email protected]
Chieregato	Arturo	[email protected]
Citerio	Giuseppe	[email protected]
Ceyisakar	Iris	[email protected]
Coburn	Mark Steven	[email protected]
Coles	Jonathan	[email protected]
Cooper	Jamie D.	[email protected]
Correia	Marta	[email protected]
Čović	Amra	[email protected]
Curry	Nicola	[email protected]
Czeiter	Endre	[email protected]
Czosnyka	Marek	[email protected]
Dahyot-Fizelier	Claire	[email protected]
Dark	Paul	[email protected]
Dawes	Helen	[email protected]
De Keyser	Véronique	[email protected]
Degos	Vincent	[email protected]
Della Corte	Francesco	[email protected]
den Boogert	Hugo	[email protected]
Depreitere	Bart	[email protected]
Đilvesi	Đula	[email protected]
Dixit	Abhishek	[email protected]
Donoghue	Emma	[email protected]
Dreier	Jens	[email protected]
Dulière	Guy-Loup	[email protected]
Ercole	Ari	[email protected]
Esser	Patrick	[email protected]
Ezer	Erzsébet	[email protected]
Fabricius	Martin	[email protected]
Feigin	Valery L.	[email protected]
Foks	Kelly	[email protected]
Frisvold	Shirin	[email protected]
Furmanov	Alex	[email protected]
Gagliardo	Pablo	[email protected]
Galanaud	Damien	[email protected]
Gantner	Dashiell	[email protected]
Gao	Guoyi	[email protected]
George	Pradeep	[email protected]
Ghuysen	Alexandre	[email protected]
Giga	Lelde	[email protected]
Glocker	Ben	[email protected]
Golubović	Jagoš	[email protected]
Gomez	Pedro A.	[email protected]
Gratz	Johannes	[email protected]
Gravesteijn	Benjamin	[email protected]
Grossi	Francesca	[email protected]
Gruen	Russell L.	[email protected]
Gupta	Deepak	[email protected]
Haagsma	Juanita A.	[email protected]
Haitsma	Iain	[email protected]
Helbok	Raimund	[email protected]
Helseth	Eirik	[email protected]
Horton	Lindsay	[email protected]
Huijben	Jilske	[email protected]
Hutchinson	Peter J.	[email protected]
Jacobs	Bram	[email protected]
Jankowski	Stefan	[email protected]
Jarrett	Mike	[email protected]
Jiang	Ji-yao	[email protected]
Johnson	Faye	[email protected]
Jones	Kelly	[email protected]
Karan	Mladen	[email protected]
Kolias	Angelos G.	[email protected]
Kompanje	Erwin	[email protected]
Kondziella	Daniel	[email protected]
Koraropoulos	Evgenios	[email protected]
Koskinen	Lars-Owe	[email protected]
Kovács	Noémi	[email protected]
Lagares	Alfonso	[email protected]
Lanyon	Linda	[email protected]
Laureys	Steven	[email protected]
Lecky	Fiona	[email protected]
Ledoux	Didier	[email protected]
Lefering	Rolf	[email protected]
Legrand	Valerie	[email protected]
Lejeune	Aurelie	[email protected]
Levi	Leon	[email protected]
Lightfoot	Roger	[email protected]
Lingsma	Hester	[email protected]
Maas	Andrew I.R.	[email protected]
Maegele	Marc	[email protected]
Majdan	Marek	[email protected]
Manara	Alex	[email protected]
Manley	Geoffrey	[email protected]
Maréchal	Hugues	[email protected]
Martino	Costanza	[email protected]
Mattern	Julia	[email protected]
McMahon	Catherine	[email protected]
Melegh	Béla	[email protected]
Menon	David	[email protected]
Menovsky	Tomas	[email protected]
Misset	Benoit	[email protected]
Mulazzi	Davide	[email protected]
Muraleedharan	Visakh	[email protected]
Murray	Lynnette	[email protected]
Nair	Nandesh	[email protected]
Negru	Ancuta	[email protected]
Nelson	David	[email protected]
Newcombe	Virginia	[email protected]
Nieboer	Daan	[email protected]
Nyirádi	József	[email protected]
Oresic	Matej	[email protected]
Ortolano	Fabrizio	[email protected]
Otesile	Olubukola	[email protected]
Palotie	Aarno	[email protected]
Parizel	Paul M.	[email protected]
Payen	Jean-François	[email protected]
Perera	Natascha	[email protected]
Perlbarg	Vincent	[email protected]
Persona	Paolo	[email protected]
Peul	Wilco	[email protected]
Piippo-Karjalainen	Anna	[email protected]
Pirinen	Matti	[email protected]
Ples	Horia	[email protected]
Polinder	Suzanne	[email protected]
Pomposo	Inigo	[email protected]
Posti	Jussi P.	[email protected]
Puybasset	Louis	[email protected]
Rădoi	Andreea	[email protected]
Ragauskas	Arminas	[email protected]
Raj	Rahul	[email protected]
Rambadagalla	Malinka	[email protected]
Rehorčíková	Veronika	[email protected]
Rhodes	Jonathan	[email protected]
Richardson	Sylvia	[email protected]
Richter	Sophie	[email protected]
Ripatti	Samuli	[email protected]
Rocka	Saulius	[email protected]
Roe	Cecilie	[email protected]
Roise	Olav	[email protected]
Rosand	Jonathan	[email protected]
Rosenfeld	Jeffrey	[email protected]
Rosenlund	Christina	[email protected]
Rosenthal	Guy	[email protected]
Rossaint	Rolf	[email protected]
Rossi	Sandra	[email protected]
Rueckert	Daniel	[email protected]
Rusnák	Martin	[email protected]
Sahuquillo	Juan	[email protected]
Sakowitz	Oliver	[email protected]
Sanchez-Porras	Renan	[email protected]
Sandor	Janos	[email protected]
Schäfer	Nadine	[email protected]
Schmidt	Silke	[email protected]
Schoechl	Herbert	[email protected]
Schoonman	Guus	[email protected]
Schou	Rico Frederik	[email protected]
Schwendenwein	Elisabeth	[email protected]
Sewalt	Charlie	[email protected]
Skandsen	Toril	[email protected]
Smielewski	Peter	[email protected]
Sorinola	Abayomi	[email protected]
Stamatakis	Emmanuel	[email protected]
Stanworth	Simon	[email protected]
Kowark	Ana	[email protected]
Stevens	Robert	[email protected]
Stewart	William	[email protected]
Steyerberg	Ewout W.	[email protected]
Stocchetti	Nino	[email protected]
Sundström	Nina	[email protected]
Synnot	Anneliese	[email protected]
Takala	Riikka	[email protected]
Tamás	Viktória	[email protected]
Tamosuitis	Tomas	[email protected]
Taylor	Mark Steven	[email protected]
Te Ao	Braden	[email protected]
Tenovuo	Olli	[email protected]
Theadom	Alice	[email protected]
Thomas	Matt	[email protected]
Tibboel	Dick	[email protected]
Timmers	Marjolein	[email protected]
Tolias	Christos	[email protected]
Trapani	Tony	[email protected]
Tudora	Cristina Maria	[email protected]
Vajkoczy	Peter	[email protected]
Valeinis	Egils	[email protected]
Vallance	Shirley	[email protected]
Vámos	Zoltán	[email protected]
van der Naalt	Joukje	[email protected]
Van der Steen	Gregory	[email protected]
van Dijck	Jeroen T.J.M.	[email protected]
van Essen	Thomas A.	[email protected]
Van Hecke	Wim	[email protected]
van Heugten	Caroline	[email protected]
Van Praag	Dominique	[email protected]
van Wijk	Roel	[email protected]
Vande Vyvere	Thijs	[email protected]
Vargiolu	Alessia	[email protected]
Vega	Emmanuel	[email protected]
Velt	Kimberley	[email protected]
Verheyden	Jan	[email protected]
Vespa	Paul M.	[email protected]
Vik	Anne	[email protected]
Vilcinis	Rimantas	[email protected]
Volovici	Victor	[email protected]
von Steinbüchel	Nicole	[email protected]
Voormolen	Daphne	[email protected]
Vulekovic	Petar	[email protected]
Wang	Kevin K.W.	[email protected]
Wiegers	Eveline	[email protected]
Williams	Guy	[email protected]
Wilson	Lindsay	[email protected]
Winzeck	Stefan	[email protected]
Wolf	Stefan	[email protected]
Yang	Zhihui	[email protected]
Ylén	Peter	[email protected]
Younsi	Alexander	[email protected]
Zeiler	Frederick A.	[email protected]
Ziverte	Agate	[email protected]
Zoerle	Tommaso	[email protected]

Table 1: Baseline study information
Region Country	Centers (N)	Central or local IRB review	IRB decision on study type
Baltic States	5
Latvia	3	Local^a	Observational
Lithuania	2	Local	Observational
Eastern Europe	5
Hungary	3	Central	Interventional
Romania	1	Local	Observational
Serbia	1	Local	Observational and Interventional
Northern Europe	9
Denmark	2	Central	Observational
Finland	2	Central	Observational
Norway	3	Central	Observational
Sweden	2	Central	Observational
Southern Europe	12
Italy	8	Central	Observational
Spain	4	Local	Observational
United Kingdom	9
United Kingdom	9	Central^b	Observational
Western Europe	26
Austria	2	Local	Observational
Belgium	5	Central	Observational
France	7	Central	Interventional
Germany	4	Central	Observational
Netherlands	7	Central	Observational with diagnostic interventions
Switzerland	1	Local	Observational

^a Latvia has a local review procedure, but, after approval had been obtained for the first center, other centers did not require additional approval.

^b In the UK, the research protocol had to be submitted to an external national committee that was not associated to the submitting center. After primary approval by this national committee, all centers (including the submitting center) required additional IRB approval.

Table 2.
	Duration (days)*	Centers (N)	Missing (N)
All centers	114 (75-224)	58	8
Local review	50 (29-102)	10	4
Central review	138 (91-229)**	48	4
- Central (1)	98 (94-114)	16	0
- Central (2)	189 (140-270)	17	3
- Central (3)	104 (62-224)	15	1

Table 2
Title: Duration of protocol submission until required IRB approval before study start.

Legend:

*Duration was reported in median number of days (IQR).

**Group difference between local and central review were significant (P=0.0074, Mann-Whitney U).

Local review: Obtained primary local IRB approvals only applied to the associated research centers and allowed study start without any additional requirements

Central (1): Primary central IRB approval with national impact, applying to all center within a country, without the need for additional local IRB review.

Central (2): Primary central IRB approval only allowed study start in the research centers associated with the approving IRB. Other participating centers required approval after additional extensive local IRB review.

Central (3): Primary central IRB approval only allowed study start in the research centers associated with the approving IRB. Other participating centers required approval after additional marginal local IRB review.

Table 3. Duration from submission to required IRB approval before study start per country and study center.
Country	Central or local IRB review	Duration in days
		Centre
		1	2	3	4	5	6	7	8	9
Denmark	Central (1)	114	114
Finland	Central (1)	75	75
France	Central (1)	98	98	98	98	98	98	98
Norway	Central (1)	233	233	233
Sweden	Central (1)	83	83
Belgium	Central (2)	131	138	141	257	M
Germany	Central (2)	288	296	312	M
Hungary	Central (2)	177	200	204
Italy	Central (2)	65	70	139	141	155	261	273	288
Netherlands	Central (3)	27	46	91	209	223	224	M
United Kingdom*	Central (3)	58	61	63	84	104	157	229	282	535
Austria	Local	52	M
Latvia	Local	113	M	M
Lithuania	Local	31	47
Romania	Local	1
Serbia	Local	1
Spain	Local	69	179	349	M
Switzerland	Local	28

Table 3.

Central (1): Primary central IRB approval with national impact, applying to all center within a country, without the need for additional local IRB review to start study.

*In the UK, the research protocol had to be submitted to an external national committee not associated to the submitting center. After primary approval by this national committee, all centers required additional IRB approval.

Local review: Obtained primary local IRB approvals only applied to the associated research centers and allowed study start without any additional requirements

M = Missing

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published 12 May, 2020

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How do 66 European Institutional Review Boards approve one protocol for an International Prospective Observational study on traumatic brain injury? Experiences from the CENTER-TBI study.

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