de Lange et al. BMC Medical Ethics (2019) 20:39 https://doi.org/10.1186/s12910-019-0373-y RESEARCH ARTICLE Open Access Huge variation in obtaining ethical permission for a non-interventional observational study in Europe Dylan W. de Lange1* , Bertrand Guidet2,3,4, Finn H. Andersen5,6, Antonio Artigas7, Guidio Bertolini8, Rui Moreno9, Steffen Christensen10, Maurizio Cecconi11, Christina Agvald-Ohman12, Primoz Gradisek13, Christian Jung14, Brian J. Marsh15, Sandra Oeyen16, Bernardo Bollen Pinto17, Wojciech Szczeklik18, Ximena Watson19, Tilemachos Zafeiridis20 and Hans Flaatten21,22 Abstract Background: Ethical approval (EA) must be obtained before medical research can start. We describe the differences in EA for an pseudonymous, non-interventional, observational European study. Methods: Sixteen European national coordinators (NCs) of the international study on very old intensive care patients answered an online questionnaire concerning their experience getting EA. Results: N = 8/16 of the NCs could apply at one single national ethical committee (EC), while the others had to apply to various regional ECs and/or individual hospital institutional research boards (IRBs). The time between applying for EA and the first decision varied between 7 days and 300 days. In 9/16 informed consent from the patient was not deemed necessary; in 7/16 informed consent was required from the patient or relatives. The upload of coded data to a central database required additional information in 14/16. In 4/16 the NCs had to ask separate approval to keep a subject identification code list to de-pseudonymize the patients if questions would occur. Only 2/16 of the NCs agreed that informed consent was necessary for this observational study. Overall, 6/16 of the NCs were satisfied with the entire process and 8/16 were (very) unsatisfied. 11/16 would welcome a European central EC that would judge observational studies for all European countries. Discussion: Variations in the process and prolonged time needed to get EA for observational studies hampers inclusion of patients in some European countries. This might have a negative influence on the external validity. Further harmonization of ethical approval process across Europe is welcomed for low-risk observational studies. Conclusion: Getting ethical approval for low-risk, non-interventional, observational studies varies enormously across European countries. Background against the potential harms for the patient. Interven- When doing medical research there is a potential dispar- tional trials should only commence if, at least, the min- ity between the interests of the researcher and the pa- imal legal, judicial and ethical standards are met. The tient who is going to be subjected to the medical European Union (EU) has issued a clinical trials directive research. For this reason, medical ethical approval has to (EU-CTD1) in 2001, which was implemented in the be obtained before research can be started. The medical member states in 2004 [1]. Since then, more than 10 ethical committees (ECs) or institutional review boards years have passed and a new clinical trials regulation has (IRBs) should weight the benefits of medical research now been implemented (EU-CTD2) [2]. In this process, all countries have streamlined the process of getting ap- * Correspondence: d.w.delange@umcutrecht.nl proval for medical research and have appointed national 1 Department of Intensive Care Medicine, University Medical Center, medical ethical committees for the analyses and approval University Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands of medical research. This is especially well regulated for Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Lange et al. BMC Medical Ethics (2019) 20:39 Page 2 of 7 studies with an intervention, like (randomized) interven- Definitions tional trials. Every country has its own procedure to judge medical However, observational research is generally consid- research protocols. We defined a “national medical eth- ered as having a minimal risk for the participants. In ical committee” as a committee that has the authority to many countries regulations have been developed to ei- judge an application for the entire country. A “regional ther exempt these studies from ethical review or provide medical ethical committee” has the authority to judge a the option of proportional review. These types of review medical research protocol for a particular region or state are often delegated to the chair or smaller group of the but not for the entire country. In many countries a local ethical committee as they do not usually require a full hospital ethical committee has to judge the medical re- board review [3]. However, up to date most of the re- search protocol as well. Their judgement can only be search on timeliness of the ethical review has focused on used as approval for that particular institute. We defined those traditional interventional trials that require full re- them as “institutional research boards” (IRBs). view. We recently performed a multinational, observa- tional study of very old critically ill patients (the VIP1- Ethical clearance study) [4]. The goal of the VIP1-study was to analyze The Regional Committee for Medical and Health Re- whether frailty was associated with poor outcome in this search Ethics, Western-Norway was asked to judge elderly patient group. Performing this research provided whether sending out a questionnaire on the ethical us with an opportunity to explore how differently ethical process to the NCs needed ethical committee review. approval processes are working in various countries. The They judged that sending out such a questionnaire was VIP1-study is prototypical for low-risk observational re- exempted from ethical review. search. In short, in this study we included 5021 patients over 80 years old from 311 ICUs. We looked at reasons Results for admission, severity of disease, frailty, treatments dur- Half of the countries (n = 8/16) needed apply to only ing ICU (e.g. mechanical ventilation, renal replacement one national medical ethical committee (national EC), therapy, and vasopressor treatment), limitations in life while the others had to apply to the national ECs and sustaining therapy and outcome at 30 days. The data was subsequently to the individual hospital institutional re- collected in central online database and apart from age, search boards (IRBs) (question 1). gender and study number no other data was collected The most frequent body to be approached (question 2) that could lead to identification of the patients. National was a local hospital institution review board (IRB) (67%), Coordinators (NCs) were to apply for national ethical followed by a regional EC (33%) and a national EC (25%) approval at the appropriate EC. We aimed for a waiver . In one country all participating hospitals had to send of informed consent but various countries demanded individual applications to their respective IRBs since written informed consent prior to inclusion. For a more there was no national medical ethical committee. Most detailed description of the methods and definitions we hospitals had to provide more specific information re- refer to the publication of the VIP1-study [4]. garding the upload of data (question 5) to a central data- Here, we describe the differences in the processes to base abroad (n = 14/16). One country had to apply for obtain ethical clearance in the participating European this at a separate EC, because the national EC was not and EU affiliated countries and the opinions of the Na- allowed to judge data collection in a foreign country. In tional Coordinators about the medical ethical approval n = 4/16 the NCs had to ask additional ethical approval process. to keep a local subject identification code list to de- pseudonymize the patients to be able to answer queries from the coordinating center (question 6). In 11 coun- Methods tries this was not necessary and in one country there Originally, it was planned to get ethical approval from was a separate application for this, resulting in two sep- the participating countries in the first 6 months of 2016. arate ethical approval rounds to the central EC. The first center in Europe to apply for ethical approval The time from application until the first national ap- for the VIP1-study started in May 2016. The last proval (question 3) is shown in Fig. 1. The time-to- country started with this procedure in October 2016. approval ranged from less than a week to more than Each country had a designated National Coordinator 300 days. (NC), who was responsible for the process of getting In n = 9/16 informed consent from the patient was not national ethical approval. In February 2017 an online deemed necessary (question 4), and in n = 7/16 informed questionnaire concerning the experience of getting consent was prospectively required from the patient or ethical approval with 11 questions was sent out to 16 the relatives or retrospectively from the patient. In 5 European NCs (Table 1). countries consent from the patients was necessary in de Lange et al. BMC Medical Ethics (2019) 20:39 Page 3 of 7 Table 1 The questionnaire to the national coordinators Question Answer possibilities Q1 Did you have to apply to more than one body in order to get approval for the study? … yes … no … other, please specify Q2 If Yes on Q1: Which bodies (committees) did you apply for consent? … a national committee/body … a regional committee/body … a local hospital intitutional research board … other, please specify Q3 How long was the application process from start to decision (weeks)? …. weeks Q4 Did you have to get informed consent for this study? … yes, from the patient … yes, from the family … yes, but in retrospect from the patient … No, not deemed necessary Q5 Is there a specific regulation when you send data electronically to a common … no database in another country? … yes, it must be specified in detail on the application … yes, there is a seperate body and an independent application Q6 Did you have to seek allowance to have your own (local) file/database with names … yes of the included patients from your unit? … no … never thought of it Q7 If YES from patient or family on Q4, how often was consent denied? … never … occasionally … sometimes … frequently Q8 Do you consider (personal opinion) it necessary to have informed consent for such a … yes study? … no … uncertain … other, please specify Q9 All in all: How satisfied are you with the ethical clearance process for this study? … very satisfied … satisfied … neutral … unsatisfied … very unsatisfied … other, please specify Q10 What is your opinion of having a common EU regulation on research ethics, and that … I am in favour of this acceptance in one country will bind the rest (similar to drug-approval regulations) … I am not sure … I am against this … Other, please specify Q11 The name of your country … advance, and in one country survivors had to consent in Discussion retrospect and only then was it allowed to use their data. International observational studies of consecutive pa- One country allowed for consent by the family (proxy) tients can reveal important differences in admission pol- without confronting the patient. Only n = 2/16 of the icies, treatments and outcomes of certain subgroups of NCs agreed that informed consent was necessary for ICU patients. Such observational studies often collect such an observational study (question 8). pseudo-anonimized or coded patient information and no Overall, n = 6/16 of the NCs were satisfied with the particular treatment or intervention is imposed upon the entire process of ethical approval, n = 8/16 were (very) subjects of the study. The potential harm to the subjects unsatisfied with the process and n = 2/16 were neutral is, therefore, negligible and most would claim none. One (time consuming but necessary) (question 9)(Fig. 2). could assume that these observational studies are However, there was no clear correlation between the assessed by the national ethical committees in an identi- time-to-approval and being dissatisfied (p = 0.622). N = cal swift modus and the need for informed consent is 11/16 would welcome a European central EC that would waived. On the contrary, here we describe that this judge observational studies for all European countries, process went from smooth to such a prolonged period while n = 5/16 were “not sure” fearing “more bureau- that one country could not even enter the study before cracy” in the ethical approval process (question 10). the proposed end date [5]. de Lange et al. BMC Medical Ethics (2019) 20:39 Page 4 of 7 days Portugal 300 Denmark 231 Slovenia 120 Ireland 119 Italy 115 Sweden 90 UK 82 Belgium 72 Germany 51 Norway 50 Switzerland 50 Spain 45 Poland 28 France 23 Greece 7 Netherlands 7 0 75 150 225 300 Fig. 1 Time between application and first approval. Time between application and first approval to start or rejection from national Ethical Committee(s) or Institutional Research Board(s) In this survey, covering 16 European countries, we “approval time” are not solely the responsibility of the have demonstrated that there is very large variety of the ethical committees. Sometimes insufficient information ethical processes and outcome from either national ECs’, in the protocol is reason for additional queries. This will regional ECs’ or IRBs’ approval with regard to an identi- lead to additional delay and the majority of ICUs needed cal study protocol. In most countries, more than one additional time between start of the national EC proced- level of ethical approval had to be approached. Often a ure and the final local IRB approval [9]. Moreover, after national EC needed to assess the research protocol and, this study was performed most of the European coun- once approved, the local IRBs needed to consent with tries that have participated in our research have imple- the protocol as well. The time from applications to deci- mented the new General Data Protection Regulation sion was unexpectedly large and only a few countries re- (GDPR) which has had a major impact on the collection ceived feedback within a month from their national EC of observational data [10]. [6–8]. After a national EC has cleared the study local Another major disparity between countries was the IRBs need to assess whether the study can be performed need for informed consent. A basic requisite for medical at their institution. Sometimes local IRBs are stricter research is that every patient has the right to decide than their national ECs and sometimes these IRBs whether or not he/she will participate in medical re- needed additional information that was lacking from the search. However, if the patient is unable to consent be- original study protocol. Clearly, the differences in cause of severe illness informed consent could be asked Very unsatisfied Unsatisfied Neutral Satisfied Very satisfied 0 2 4 6 8 Fig. 2 Overall satisfaction with the ethical approval rate. There was no obvious relation between being satisfied/very satisfied and the length of the approval process or a concordance between satisfaction and wanting centralized EU approval de Lange et al. BMC Medical Ethics (2019) 20:39 Page 5 of 7 retrospectively. However, some patients might not be We have learned that we need to allow for up to one able to give informed consent afterwards (because they year to get all the countries to approve such a study [15, are deceased or cognitively impaired). Leaving these pa- 16]. Not incorporating this “waiting time” in study pro- tients out of the analyses might hamper the external val- tocols will lead to loss of countries and will, therefore, idation of the research. In such cases the researchers can diminish the external validity of the findings for the apply for a waiver of informed consent to the EC. The European population. We presume more delay in ap- EC can grant such a waiver provided that the research proval for studies with a higher potential of harm for pa- poses important societal value and the research poses no tients (like interventional studies or even patient more than minimal risk to the participants. We think questionnaires) [17, 18]. this applies to observational studies in critically ill, eld- Obviously, this analysis has limitations. We only asked erly patients. The majority of countries were allowed to the national coordinators of the VIP1-study to provide perform this study without any informed consent from us with their ethical approval experiences. After the na- the patient, but in a substantial amount of countries tional coordinators had gained ethical clearance many such permission had to be sought before inclusion of the local researchers needed to go through a similar experi- patient [11]. If a patient is, for medical reasons, not able ence at their local IRBs. A swift approval at a national to consent (e.g. unconscious, sedated, etc.) and subse- level may not be followed by a similarly swift approval at quently dies, this will create potential loss in patient re- a local level, or vice versa. Such data were not incorpo- cruitment subsequently leading to a selection bias and rated in this analysis. Obviously, the results from our this may diminish the validity of the study [12]. A poten- study are not necessarily transferrable to other studies tial solution is to accept that survivors may claim their (limited external validity). data to be removed (retrospective consent) but allow in- clusion of data from deceased patients, despite the bias Conclusion that also this option can introduce on the final results We conclude that further harmonization between Euro- [13, 14]. However, only one country used this method pean countries in ethical clearance for observational, and from the 226 included patients only one patient non-interventional studies and registries is desirable. opted for removal of his data. The majority of national However, these differences between European countries coordinators (n = 14/16) judged this observational study need to be considered and incorporated in the research as having such a low potential of harm to the subjects plan in order to prevent missing important contributors. that they would not need informed consent for this study. However, this leaves n = 2/16 that are convinced Acknowledgements This study was supported in kind (but not financially) by the European that consent is necessary even for anonymous observa- Society of Intensive Care Medicine (ESICM). tional registries. Half of the national coordinators were not satisfied Authors’ contributions with the process. There was no obvious concordance be- DL has made substantial contributions to the conception and design of the work; has aided in the acquisition, analysis and interpretation of data and tween the time needed to get the study approved by the has drafted the work and substantively revised it. He also has approved the national EC and satisfaction. However, the countries in submitted version (and any substantially modified version that involves the which the verdict was received swiftly were invariably author’s contribution to the study) and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions satisfied with the entire process. Clearly a swift approval related to the accuracy or integrity of any part of the work, even ones in process leads to higher satisfaction. Especially in coun- which the author was not personally involved, are appropriately investigated, tries with a very prolonged EC process the national co- resolved, and the resolution documented in the literature. BG has made substantial contributions to the conception and design of the work; has ordinators were dissatisfied and more willing to accept a aided in the acquisition, analysis and interpretation of data and has drafted centralized European ethical clearance entity for non- the work and substantively revised it. He also has approved the submitted interventional studies/registries. At present, a new clin- version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or ical trials directive (EU-CTD2) is being implemented. integrity of any part of the work, even ones in which the author was not However, this directive particularly focuses on interven- personally involved, are appropriately investigated, resolved, and the tional trials (that, indeed, have a high potential risk of resolution documented in the literature. FA has aided in the acquisition and has drafted the work and substantively revised it. He also has approved the harm for the medical subjects). This leaves a gap in submitted version and has agreed both to be personally accountable for the international legislation for pseudo-anonymous observa- author’s own contributions and to ensure that questions related to the tional registries. The majority of the national coordina- accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the tors would welcome a central European ethical resolution documented in the literature. AA has aided in the acquisition and organization for observational studies which would has drafted the work and substantively revised it. He also has approved the speed up national and local approvals. The general con- submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the sensus was that such a non-interventional study should accuracy or integrity of any part of the work, even ones in which the author not take prolonged periods to be approved. was not personally involved, are appropriately investigated, resolved, and the de Lange et al. BMC Medical Ethics (2019) 20:39 Page 6 of 7 resolution documented in the literature. GB has aided in the acquisition and was not personally involved, are appropriately investigated, resolved, and the has drafted the work and substantively revised it. He also has approved the resolution documented in the literature. TZ has aided in the acquisition and submitted version and has agreed both to be personally accountable for the has drafted the work and substantively revised it. He also has approved the author’s own contributions and to ensure that questions related to the submitted version and has agreed both to be personally accountable for the accuracy or integrity of any part of the work, even ones in which the author author’s own contributions and to ensure that questions related to the was not personally involved, are appropriately investigated, resolved, and the accuracy or integrity of any part of the work, even ones in which the author resolution documented in the literature. RM has aided in the acquisition and was not personally involved, are appropriately investigated, resolved, and the has drafted the work and substantively revised it. He also has approved the resolution documented in the literature. HF has made substantial submitted version and has agreed both to be personally accountable for the contributions to the conception and design of the work; has aided in the author’s own contributions and to ensure that questions related to the acquisition, analysis and interpretation of data and has drafted the work and accuracy or integrity of any part of the work, even ones in which the author substantively revised it. He also has approved the submitted version and has was not personally involved, are appropriately investigated, resolved, and the agreed both to be personally accountable for the author’s own contributions resolution documented in the literature. SC has aided in the acquisition and and to ensure that questions related to the accuracy or integrity of any part has drafted the work and substantively revised it. He also has approved the of the work, even ones in which the author was not personally involved, are submitted version and has agreed both to be personally accountable for the appropriately investigated, resolved, and the resolution documented in the author’s own contributions and to ensure that questions related to the literature. accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the Funding resolution documented in the literature. MC has aided in the acquisition and This study did not receive any funding. Not applicable. has drafted the work and substantively revised it. He also has approved the submitted version and has agreed both to be personally accountable for the Availability of data and materials author’s own contributions and to ensure that questions related to the The datasets used and/or analyzed during the current study are available accuracy or integrity of any part of the work, even ones in which the author from the corresponding author on reasonable request. was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. CAO has aided in the acquisition Ethics approval and consent to participate and has drafted the work and substantively revised it. He also has approved Before publication of the data we asked the Regional Committee for Medical the submitted version and has agreed both to be personally accountable for and Health Research Ethics, Western-Norway whether asking the national the author’s own contributions and to ensure that questions related to the coordinators their experiences and using these data for a scientific accuracy or integrity of any part of the work, even ones in which the author publications needed ethical approval. The Regional Committee for Medical was not personally involved, are appropriately investigated, resolved, and the and Health Research Ethics, Western-Norway exempted sending out the resolution documented in the literature. PG has aided in the acquisition and questionnaire and using the information for a scientific publications from has drafted the work and substantively revised it. He also has approved the ethical review (30.08.2017). submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the Consent for publication accuracy or integrity of any part of the work, even ones in which the author Not applicable. was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. CJ has aided in the acquisition and Competing interests has drafted the work and substantively revised it. He also has approved the The authors do not have competing interests concerning this study. submitted version and has agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the Author details accuracy or integrity of any part of the work, even ones in which the author 1 Department of Intensive Care Medicine, University Medical Center, was not personally involved, are appropriately investigated, resolved, and the University Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands. resolution documented in the literature. BM has aided in the acquisition and 2 Hôpitaux de Paris, Hôpital Saint-Antoine, Service de Réanimation Médicale, has drafted the work and substantively revised it. He also has approved the 75012 Paris, France. 3Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, submitted version and has agreed both to be personally accountable for the Institut Pierre Louis d’Epidémiologie et de Santé Publique, 75013 Paris, author’s own contributions and to ensure that questions related to the France. 4INSERM, UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de accuracy or integrity of any part of the work, even ones in which the author Santé Publique, Paris, France. 5Department of Anesthesia and Intensive Care, was not personally involved, are appropriately investigated, resolved, and the Møre and Romsdal Health Trust, Ålesund Hospital, Ålesund, Norway. resolution documented in the literature. SO has aided in the acquisition and 6 Department of Circulation and Imaging, Faculty of Medicine, NTNU, has drafted the work and substantively revised it. He also has approved the Norwegian University of Science and Technology, Trondheim, Norway. submitted version and has agreed both to be personally accountable for the 7 Department of Intensive Care Medicine, CIBER Enfermedades Respiratorias, author’s own contributions and to ensure that questions related to the Corporacion Sanitaria Universitaria Parc Tauli, Autonomous University of accuracy or integrity of any part of the work, even ones in which the author Barcelona, Sabadell, Spain. 8Laboratory of Clinical Epidemiology, GiViTI was not personally involved, are appropriately investigated, resolved, and the Coordinating Center, department of Public Health, IRCCS – “Mario Negri” resolution documented in the literature. BB has aided in the acquisition and Institute for Pharmacological Research, Ranica (Bergamo), Italy. 9Unidade de has drafted the work and substantively revised it. He also has approved the Cuidados Intensivos Neurocríticos, Hospital de São José, Centro Hospitalar de submitted version and has agreed both to be personally accountable for the Lisboa Central, Lisbon, Portugal. 10Department of Anaesthesia and Intensive author’s own contributions and to ensure that questions related to the Care Medicine, Aarhus University Hospital, Aarhus, Denmark. 11Department accuracy or integrity of any part of the work, even ones in which the author Anaesthesia and Intensive Care Units, IRCCS Istituto Clinico Humanitas, was not personally involved, are appropriately investigated, resolved, and the Humanitas University, Milan, Italy. 12Department of Anaesthesiology and resolution documented in the literature. WS has aided in the acquisition and Intensive Care, Department of Clinical Intervention and Technology, has drafted the work and substantively revised it. He also has approved the Karolinska University Hospital, Huddinge, Sweden. 13Clinical Department of submitted version and has agreed both to be personally accountable for the Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana, author’s own contributions and to ensure that questions related to the Ljubljana, Slovenia. 14Division of Cardiology, Pulmonology and Vascular accuracy or integrity of any part of the work, even ones in which the author Medicine, University Hospital Düsseldorf, Heinrich-Heine-University, was not personally involved, are appropriately investigated, resolved, and the Düsseldorf, Germany. 15Department of Surgery, Mater Misericordiae resolution documented in the literature. XW has aided in the acquisition and University Hospital, Dublin, Ireland. 16Department of Intensive Care Medicine, has drafted the work and substantively revised it. He also has approved the Ghent University Hospital, Ghent, Belgium. 17Division of Anaesthesiology, submitted version and has agreed both to be personally accountable for the Department of Anaesthesiology, Clinical Pharmacology and Intensive Care author’s own contributions and to ensure that questions related to the (APSI), Geneva University Hospitals, Geneva, Switzerland. 18Division of accuracy or integrity of any part of the work, even ones in which the author Intensive Care and Perioperative Medicine, 2nd Department of Medicine, de Lange et al. BMC Medical Ethics (2019) 20:39 Page 7 of 7 Jagiellonian University Medical College, Krakow, Poland. 19Intensive Care, 17. Ahmed AH, Nicholson KG. Delays and diversity in the practice of local Kingston Hospital, Kingston, UK. 20Intensive Care Unit, General Hospital of research ethics committees. J Med Ethics. 1996;22:263–6. https://doi.org/10. Larissa, Larissa, Greece. 21Department of Anaesthesia, Haukeland University 1136/jme.22.5.263. 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