- Research article
- Open Open Peer Review
Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: the GenOSept experience
BMC Medical Ethicsvolume 20, Article number: 30 (2019)
During the set-up phase of an international study of genetic influences on outcomes from sepsis, we aimed to characterise potential differences in ethics approval processes and outcomes in participating European countries.
Between 2005 and 2007 of the FP6-funded international Genetics Of Sepsis and Septic Shock (GenOSept) project, we asked national coordinators to complete a structured survey of research ethic committee (REC) approval structures and processes in their countries, and linked these data to outcomes. Survey findings were reconfirmed or modified in 2017.
Eighteen countries participated in the study, recruiting 2257 patients from 160 ICUs. National practices differed widely in terms of composition of RECs, procedures and duration of the ethics approval process. Eight (44.4%) countries used a single centralised process for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%) required both. Outcomes of the application process differed widely between countries because of differences in national legislation, and differed within countries because of interpretation of the ethics of conducting research in patients lacking capacity. The RECs in four countries had no lay representation. The median time from submission to final decision was 1.5 (interquartile range 1–7) months; in nine (50%) approval was received within 1 month; six took over 6 months, and in one 24 months; had all countries been able to match the most efficient approvals processes, an additional 74 months of country or institution-level recruitment would have been available. In three countries, rejection of the application by some local RECs resulted in loss of centres; and one country rejected the application outright.
The potential benefits of the single application portal offered by the European Clinical Trials Regulation will not be realised without harmonisation of research ethics committee practices as well as national legislation.
The survey highlights the diversity in ethics assessment and approval procedures at national and local level across the EU for research involving genetic material and patients lacking capacity
The improvements introduced by the European Clinical Trials Regulation to limit the adverse consequences of such variation are unlikely to be realised if current national variations in interpretation of research ethics guidance persist
To improve the coherence and integration of ethics committees decision-making additional measures may be required to ensure consistent interpretation of national law across Europe
Sepsis has been described as “one of the oldest and most elusive syndromes in medicine” . Sepsis is a condition with high mortality risk. Many factors, such as genetics, age, gender, ethnicity, comorbid conditions, number of dysfunctional organs and temporal trends in markers of acute physiological derangement have been associated with sepsis outcomes [2,3,4,5,6,7,8,9].
The GenOSept project was conceived by the European Critical Care Research Network of the European Society for Intensive Care Medicine (ESICM) to investigate the potential impact of genetic variation on the host response and outcomes in sepsis. It was part-funded in 2004 for 4 years by the European Union 6th Framework Programme (https://www.esicm.org/research/trials/endorsed-trials/completed-projects-supported/). The collaboration has continued since through additional specific project funding. The aims of the project were to identify possible genetic determinants of outcome from sepsis in an international cohort of critically ill patients, and to build an intensive care medicine genetics collaboration between clinicians and scientists across Europe. GenOSept was launched in January 2005, with 18 countries and 160 intensive care units (ICUs) participating. Three genome centres (in Bonn, Paris and Oxford) supported the project. A total of 2257 evaluable patients were recruited between May 2006 and December 2008, providing important insights into the epidemiology and genetics of sepsis in Europe [10,11,12,13,14,15,16]. Collaborative analytical work continues using the samples which are stored in biobank facilities at the Wellcome Trust Centre for Human Genetics in Oxford.
European research: regulatory framework
A key component of the set-up phase of GenOSept was to determine the approval processes and outcomes of local and national ethics committees presented with a common protocol for genetic analysis in critically ill patients, many of whom would lack capacity. There are several European-level regulations of relevance to genetics research (Table 1). At the time GenOSept was conceived in 2004, clinical trials performed in countries within the European Union (EU) were required to adhere to the requirements of Good Clinical Practice described in the European Clinical Trials Directive 2001/20/EC (http://ec.europa.eu/health/human-use/clinical-trials/directive/index_en.htm), which was issued in April 2001 and transposed into the national laws of each EU member state by 2004. Individual institutions within EU countries are not permitted to introduce different research ethics legislation and are expected to adopt the principles of the EU Directive, by a process of “transposition”. Such process requires the EU member states to enforce the directive by passing appropriate legislative implementation measures. Individual nations within the EU may also adopt their own national ethical guidance, which may (or may not) be accompanied by a national review process (or a local review process based on national guidance).
While the aims of the Directive were commendable in terms of attempting to harmonise research processes and safeguard persons enrolled in clinical trials, the guidance posed certain challenges which hampered the conduct of clinical research. The Directive failed adequately to recognise the special circumstances of research conducted in emergency care when patients may lack capacity and surrogates can be unavailable, and made no provision for ‘observational’ research lacking direct potential benefit to the participant. The application of the Directive was associated with increased economic, bureaucratic and administrative burdens and, especially in the case of multi-national studies, delays in the approval process, related to the fact that each member state’s research ethics apparatus could interpret the principles of the Directive in different ways. Given variations in national regulatory pathways, this resulted in research applications involving patients lacking capacity being rejected in some countries and approved in others, as we detail below.
Key ethical issues posed by the GenOSept project within this regulatory framework include the following:
The lack of capacity inherent in critical illness challenged the requirement to respect patient autonomy in obtaining consent.
The possibility of obtaining informed consent from surrogate decision-makers (‘legal representatives’) is much more difficult in the time-limited context of emergency care. This specific issue was mitigated by the possibility of obtaining blood for DNA testing for GenOSept at any time and patient data could be recorded retrospectively.
The European Clinical Trials Directive created a sematic confusion by referring to observational research as ‘non-therapeutic’, in the sense that such studies may have no direct benefit to the participants. However, they may benefit future patients or populations through enhanced scientific knowledge. The Directive did not acknowledge this important distinction.
Public concerns about the security and privacy of genetic data  appeared to conflict with the study’s methodological requirement to transfer human genetic material across national borders for analysis in the genotyping centres.
The requirement to respect confidentiality of personal data required a study design which preserved individual de-identification while retaining the capacity to link genotypic with phenotypic data. Linkage might also be necessary in the event that a participant were retrospectively to request the results of analyses performed on their samples. Preserving individual de-identification, while also retaining capability for data reconciliation where required, poses questions around the true sense and limitations of anonymization of data, as informatics technique evolve and the potential for databases to be combined, integrated and cross-referenced increases.
To study the approaches to these issues taken by the research ethics committees, we therefore undertook an analysis of the processes and outcomes of ethics reviews across the European countries participating in GenOSept.
A GenOSept project national coordinator was appointed in each country to identify and support ICUs to consent, recruit, and obtain a single set of blood samples from patients with severe sepsis or septic shock due to community acquired pneumonia (CAP), peritonitis, severe pancreatitis or meningococcal disease.
Individual de-identification was achieved while retaining the capability for data reconciliation, phenotypic integration and retrospective identification in the event of investigator enquiry, by using three coded numerical systems for clinical data, blood and DNA samples prior to the genomic analysis. A “linked anonymous” (de-identified) system involving a code specifying country ID (in letters e.g.UK), site ID (numerical) and patient ID (numerical) was used. This code was manually entered into the eCRF (electronic Case Report Form) and attached as a bar code to the blood samples and subsequently to the extracted DNA. Only the local clinician could link specific patients to their phenotypic data; the genome centres could only link the blood sample/DNA to the corresponding non-identified phenotypic data. The link between all three could only be made by an independent data Trustee, an academic lawyer from the UK with expertise in European legislation appointed by the project steering committee. It was stipulated that genetic information would not be made available to the patient.
Ethics and consent
The protocol included information about current European research legislation and a detailed description of the directives or position statements available at the time. The information sheet and consent form included a description of the project in non-medical terms which national coordinators were responsible for translating into their respective languages.
Following submission of the project to research ethics committees (RECs) in each country, national coordinators were subsequently invited to provide details of the submission process and outcome at study set-up, and then again following establishment of the European Regulation. The survey aimed at evaluating the following aspects for each participating European Country:
organisational arrangements (whether the approval procedure had been centralised at national level, or whether a local or regional process had to be followed)
the number of intensive care units involved within each participating nation
the form in which the application was made (whether via a web portal or in hard copy)
the usual composition of the REC (detailing the number of lay members and those with medical or legal expertise)
the month and year of submission for ethics approval and the duration of the process until approval
whether approval was granted to all units within each nation, some units only, or whether refused
the need for submission of further information to the REC
whether national guidelines existed for the conduct of research in critically ill patients
The survey explored both whether national ethics guidance existed, and whether a national review and approval process was in place. Data on the baseline characteristic of the submission process and ethics approval was reported using descriptive statistics with absolute and percentage values, median and interquartile ranges, as applicable and relevant to each result. Where comparisons between groups of countries were required (with regards to the presence or absence of a centralised approval process, and whether national guidance was available or not), inferential statistics were conducted in the form of linear regression analyses.
Results are summarised in Table 2.
Organisational setup, number of ICUs involved and format
Eighteen countries were willing to participate, incorporating 160 ICUs. The median number of ICUs involved in each country was 7 (interquartile range 2–12), the range being 1–28. Eight (44.4%) countries used a single centralised national or regional ethics committee for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%), Portugal, Spain and the Czech Republic, required submission to both a centralised and a local approval process. All countries used a paper-based application process except the UK, where a web-based system was in place. Results are summarised in Tables 2 and 3.
Usual composition of RECs
Ethics committees included lay members in 14 (77.8%) countries and legal expertise in 13 (72.2%). In four (22.2%) countries (Croatia, Greece, Hungary and Poland) the ethics committees were exclusively composed of medical doctors, with no patient or public (lay) representation.
Timing and duration of the approval process
Submissions for ethics approval were made, in the various countries, between May 2005 and November 2007. The median time from submission to final decision was 1.5 (interquartile range 1–7) months. In nine (50%) countries the application was approved within 1 month, while in six it took over 6 months; the duration was calculated as a “combined permissions process” (the times presented here were those including all regulatory and ethical steps between application submission and granting of permission to proceed). In Hungary the process of submission, initial rejection, and requests for clarifications and resubmission following appeal took more than 2 years before approval was granted, by which stage it was no longer possible to recruit centres.
Centralisation of approval did not confer greater efficiency. Median (Interquartile range) approval time in the countries with a centralised (national and/or regional) approval process was 1 (1–7) month, versus 2 (1–7) months in countries without such centralisation (linear regression analysis p = 0.57, r2 = 0.02).
If the nine countries with approval times of more than 1 month had been as efficient as those with approval times of 1 month or less, an additional 74 months of potential country or institution-wise recruitment would have been available in the first 2 years of the project.
Ethics applications were approved for all participating ICUs in 14 countries. In three countries (Germany, Italy and Israel) the local ethics committees at some hospitals rejected the application, hence the study could only proceed in the remainder. In particular, in Italy approval was obtained for 14 (63.6%) of the 22 ICUs willing to participate; in Israel only for 5 (55.6%) out of 9 ICUs, while in the case of Germany the proportion was 12 (80%) out of 15 ICUs. This clearly indicates different interpretations of the same Directive within the same national regulatory environment. Portugal was unable to participate at all because one local committee and the national committee rejected the proposal.
Reasons for rejection of the application were diverse. They included disagreement about the acceptability of performing genetic research in incapacitated patients and taking blood from an unconscious patient (Italy), concerns about sending blood samples out of the country (Israel), and doubts about security of anonymity, validity of assent from relatives or legal representative, inclusion criteria and selection of genes to be studied, and concerns about unauthorised use of genetic data. In Portugal the application was rejected primarily because of concerns about the commercial use of human tissue and genetic data, as one of the scientific partners was SIRS-Lab, a university spin-off company; approval could not be obtained despite clear agreements about the use of intellectual property and the fact that the EU encouraged such partnerships.
Need for submission of further information to the REC
In seven countries the applicants were required to submit additional information or modify the application. In Austria for example, the law required informed consent from the patient, thereby excluding patients without capacity; for this country the protocol was therefore modified to include only conscious patients capable of giving informed consent.
Data access requests
No patient included in the study requested access to their information; hence the Data Trustee’s adjudication was not required at any time.
Guidance at national level on the conduct of research in critically ill patients existed for 9 (50%) of the countries (Austria, France, Israel, Italy, the Netherlands, Poland, Serbia, Spain and the UK). Importantly, the fact that a country provides national guidance does not necessarily imply that there is a centralized review process to interpret such guidance. Indeed local institutions may interpret national guidelines in different ways. The existence of national guidelines was not associated with shorter time to approval, or with greater consistency in within-country decision making. Median (Interquartile range) approval time in the countries with existing national guidance was 1 (1–4) month, versus 2 (1–7) months in countries without guidance (linear regression analysis p = 0.91, r2 = 0.001).
We found substantial and persisting variations between EU member states in the organisation, structures, processes, efficiency, and decision-making of research ethics committees (RECs) in their assessments of an EU-funded observational study investigating the genetics of sepsis. In three countries decisions were inconsistent between individual centres, while one country did not allow any of its citizens to participate. The existence of national guidance was not always complemented by a centralized review process with uniform interpretation of such guidance. It seems paradoxical that, in two of the nine countries (Italy and Israel) where national guidance for ethics approval did exist, differential interpretation across the various local institutions led to approval being granted only for some of the centres willing to participate. In some centres delays in approvals and idiosyncratic requirements for protocol modifications hampered timely site initiation and patient accrual. If the nine countries with approval times of more than 1 month had been as efficient as those with approval times of 1 month or less, an additional 74 months of country or institution- level recruitment opportunities would have been realised in the first 2 years. Unnecessarily lengthy and laborious research ethics approval processes negatively impact on the perceived efficiency of the process, leading to increased dissatisfaction amongst academics . The responses from some of the RECs involved in assessing the GenOSept application suggests unwarranted and potentially paternalistic exclusion of patients lacking capacity , the consequence being that critically ill patients may be excluded from benefiting from research participation.
The lack of standardized membership requirements for RECs which we have identified, and the recognised lack of a common ethics training curriculum, could also contribute to variation in practices and outcomes .
It is possible that RECs identified unique difficulties relating to cross-border genetics research which may have contributed to diversity in decision making. However, every REC received the same protocol for evaluation, and the critical care patients recruited to the various centres all met the same inclusion and exclusion criteria across the various EU countries. We therefore must conclude that the diversity in REC outcomes was attributable to non-clinical factors at an institutional, or national, level. Some of these factors must have been related to country-specific attitudes or legislation. Such diversity of decision-making between RECs is inconsistent with the principle of a harmonised approach to ethics across national borders. It is likely that attitudes amongst ethics committee members to genetics research in patients lacking capacity may have become modified in the years since the Human Genome project was completed.
Attempts to standardise the ethics of clinical research over many years [21, 22] have been hampered by the failure of the European Clinical Trials Directive 2001  to accommodate the particular challenges of research in emergency settings [23,24,25,26,27,28,29], by widely differing interpretations of ethical principles by national or local RECs, as well as variations in approval processes [21,22,23,24,25,26]. The absence of harmonised processes and standardised interpretation delays studies, creates additional costs, and may prevent citizens from participating in research, while failing to provide added protection for participants [30,31,32,33,34,35].
The European Clinical Trials Regulation (http://ec.europa.eu/health/human-use/clinical-trials/regulation/index_en.htm) is a welcome attempt to resolve these difficulties (anticipated implementation in 2019). It requires that research applications are processed by one member state with the outcomes applying to all. This measure resembles the approach of the US National Institutes of Health, which have recently mandated the use of a single Institutional review board for multi-centre clinical studies. However, while the Regulation requires member states to cooperate in assessing a request for authorisation of a clinical trial, it does not include cooperation on matters ‘of an intrinsically national nature, such as informed consent’(paragraph 6), though it does state that ‘ethics committees… should ensure the involvement of laypersons, in particular patients or patients’ organisations’. It remains to be seen whether the requirement to process approvals through a single member state will solve the issue of wide variation in national research ethics processes and outcomes. It is evident that the current trials regulations, combined with the absence of standardised proceedures and training of RECs have increased the complexity and burdens of research governance, and have reduced the opportunity for participation in research, without evidence of benefit to participating subjects .
Additional issues and challenges
An example of additional challenges faced by researchers in this area is provided by the UK. Here the Mental Capacity Act (2005) makes welcome provision for ‘non-interventional’ and emergency research; however, in the event of a consented person losing capacity during the research study, ‘advice’ must be obtained from the next of kin or equivalent consultee on whether the incapacitated person would have wished to continue with the study, even if the intervention has already occurred and that specific individual is now in the follow up phase . If the consultee is of the view that the patient would not have wished to continue in the study, the patient must be withdrawn and the data destroyed or de-identified, unless the patient specifically consented to continue in the study in the event of loss of capacity.
A further example is the case of patients consenting to participate provided there was no risk that an organisation related to the government could access their data. In such a situation, medical, nursing and research staff would be allowed to use the data for the purposes of the study, but a government regulatory authority would not be allowed to review the notes or the data, even in the context of an inspection.
Strengths and limitations
The GenOSept project began data collection over 10 years ago, and our survey demonstrates the challenges which continue to be faced by international researchers across member states involving genetic material and patients who lack capacity. Our findings show that efficient trans-European approval processes are possible. However, unexplained variation between some local and national ethics committees is having an undesirable effect on patient participation. While our survey did not allow for interaction with individual ethics committees to explore in greater detail the reasons for these variations in decision-making, we were able to use the information provided in the approval or rejection letters.
Our study highlights the diversity and adverse consequences of variation in ethics assessment and approval procedures at national and local level across the EU for research involving genetic material and patients lacking capacity. The improvements introduced by the European Clinical Trials Regulation will not be realised if current national variations in interpretation of research ethics guidance persist. The invaluable service provided by these committees to patients and the research community may require targeted support to develop a common interpretation of European legislation and the moral assumptions underpinning research in critically ill patients lacking capacity.
Community acquired pneumonia
Electronic Case Report Form
European Society for Intensive Care Medicine
- FP6 Sixth:
Framework Programme (European Commission)
Genetics Of Sepsis and Septic Shock
Intensive care unit
Multicentre Research Ethics Committee
Research Ethic Committee
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GenOSept National Coordinators:
The authors of this manuscript wish to thank all GenOSept Investigators, as listed in the supplement.
The GenOSept study was supported by the European Union and the 6th Framework Programme (European Commission Reference: LSHM-CT-2005-518226) and the Wellcome Trust Core Award (Grant Number 090532/Z/09/Z).
Clinical engagement was gained through the Trials Group of the European Society of Intensive Care Medicine. National coordinators in each country provided their time to support the project. Additional support was obtained from the Wellcome Trust Centre for Human Genetics (Wellcome Trust grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070). ACG is funded by a National Institute for Health Research Clinician Scientist Fellowship award. German project management was partly funded by the Federal Ministry of Education and Research (0312617) and the Thuringian Ministry of Education (B309–00014). We thank the VASST and PROWESS investigators and Eli Lilly and Company for allowing us to access the genome-wide genotyping data and phenotypic information for patients recruited to these trials. We acknowledge the support of the National Institute for Health Research (NIHR), through the Comprehensive Clinical Research Network for patient recruitment in the UK and A. C. G. as an NIHR Clinician Scientist award holder.
The funding bodies did not contribute to the study design, the collection, analysis, and interpretation of data, nor in writing the manuscript.
Availability of data and materials
Reasonable requests to access the datasets analysed will be adjudicated by the GenOSept management committee.
Ethics approval and consent to participate
Written, informed consent for inclusion in the GenOSept study was obtained from all patients or a legal representative. Ethics approval was obtained either nationally and/or locally. The studies were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
List of ethical bodies that approved the studies
MREC, Multicentre Research Ethics Committee
The MRECs gave overall approval for the studies to be conducted in the UK
Scotland A Research Ethics Committee
Berkshire Research Ethics Committee
REC, Research Ethics Committee
|Ethikkommission Land Salzburg Ethik Kommission fur das Bundesland Salzburg||Ethikkommission für das Bundesland Salzburg Sebastian-Stief-Gasse 2 5020 Salzburg Postanschrift: Amt der Salzburger Landesregierung Ethikkommission für das Bundesland Salzburg Postfach 527 5010 Salzburg Austria|
|Comite d’Ethique ISPPC||Chu – Charleroi Boulevard Zoé Drion, 1 6000 Charleroi Belgium|
|Comite d’Ethique Hospitalo-Faculatiare de Liege||Centre Hospitalier Universitaire de Liège Domaine Universitaire du Sart Tilman Bâtiment B 35 B-4000 Liège Belgique Clinique Saint Pierre, Avenue Reine Faibiola, 9 1340 Ottignies Belgium|
|Research Ethics Committee Zagreb||University hospital Clinical Hospital Rebro Emergency and Intensive Care Medicine/Internal Medicine Kispaticeva 12 HR – 1000 Zagreb Croatia|
|Multicenter Ethics Committee Stanovisko multicentricke Eticke Komis Fakultni Nemoncnice U SV. Anny V Brno||Faculty hospital Brno Jihlavská 20 625 00 Brno Czech Republic|
|Ethics Committee of Faculty Hospital Hradec Kralove||Sokolaska 581, 500 05 Hradec Czech Republic|
|Ethics Committee of the University Hospital and Faculty of Medicine Palacky University in Olomouc||I.P. Pavlova 6, 775 20 Olomouc Czech Republic|
|Ethics Committee at University Hospital Ostrava||Ethics Committee Fakultní nemocnice s poliklinikou Ostrava 17. listopadu 1790, 708 52 Ostrava Poruba, Czech Republic|
|Ethics Committee Rozhodnuti Eticke Komise Fakultni Nemocnice Pizen||FN a LF UK Plzeň tř. Dr. E. Beneše 13 305 99 Plzeň Czech Republic|
|Ethics Committee of Masaryk’s Hospital Usti n.Labem||Socialni pece 3316/12 A 401 13 Usti n. Labem Czech Republic|
|Eticka Komise Nemocnice Znojmo||Nemocnice Znojmo, příspěvková organizace MUDr. Jana Janského 11 669 02 Znojmo Czech Republic|
|Ethics Committee for multicenter clinical trials County Hospital Liberec||Husova 10, Liberec, Czech Republic|
|Eticka Komise pro multicentricka hodnoceni Krajska nemocnice Liberec||Liberec, Husova 10 460 63 Liberec 1 Czech Republic|
|Ethics Committee on Human Research of the University of Tartu||TU Biomeedikum Room 3050 Ravila Str 19 51,014, Tartu, Estonia|
|REC Service de Réanimation Médicale||HOPITAL COCHIN 27, rue du Fbg St Jacques FR - 75,679 PARIS CEDEX 14|
|REC Service de Réanimation Médicale||HOPITAL BICETRE 78 rue du général leclerc FR - 94,275 LE KREMLIN BICETRE CEDEX|
|REC Service de Réanimation Médicale||HOPITAL BICETRE 78 rue du général leclerc FR - 94,275 LE KREMLIN BICETRE CEDEX|
|REC Service de Réanimation Médicale||HOPITAL BICHAT 46 rue Henri Huchard FR - 75,018 PARIS|
|REC Service de Réanimation Médicale||HOPITAL BEAUJON 100 Boulevard du Général Leclerc FR - 92,110 CLICHY|
|REC Service de Réanimation Médicale||HOPITAL GARCHES RAYMOND POINCARE 104 boulevard Raymond Poincaré FR - 92,380 GARCHES|
|REC Service de Réanimation Médicale||HEGP 20 rue Leblanc FR - 75,015 PARIS|
|REC Service de Réanimation Médicale||Hospital God Hotel Ap-Hp HOTEL DIEU 1 place du Parvis Notre Dame FR - 75,004 PARIS|
|REC Service de Réanimation Médicale||LOUIS MOURIER COLOMBES 178 rue Renouillers FR - 92,700 COLOMBES|
|REC Service de Réanimation Médicale||SAINT ANTOINE 184 rue du Faubourg St Antoine FR - 75,012 PARIS|
|REC Service de Réanimation Médicale||PITIE SALPETRIERE 47–83 bd Hôpital FR - 75,013 PARIS|
|REC Service de Réanimation Médicale||PITIE SALPETRIERE 47–83 bd Hôpital FR - 75,013 PARIS|
|REC Service de Réanimation Médicale||SAINT LOUIS 1 av. Claude Vellefaux FR - 75,010 PARIS|
|REC Service de Réanimation Médicale||TENON 4 rue de la Chine FR - 75,020 PARIS|
|REC Service de Réanimation Médicale||SAINT JOSEPH 185 rue Raymond Losserand FR - 75,014 PARIS|
|REC Service de Réanimation Médicale||ARGENTEUIL VICTOR DUPOUY 69 rue Lieutenant-Colonel Prudhon FR - 95,100 ARGENTEUIL|
|REC Service de Réanimation Médicale||EVRY LOUISE MICHEL Rue Pont Amar.Quartier Canal Coucouronnes FR - 91,014 EVRY|
|REC Service de Réanimation Médicale||COULOMMIERS CH RENE ARBELTIER Rue Gabriel PERI FR - 77,120 PALAISEAU|
|REC Service de Réanimation Médicale||LILLE 2 ALBERT CALMETTE Bd prof. Jules Leclerc FR - 59,037 LILLE CEDEX|
|REC Service de Réanimation Médicale||PONTOISE CH RENE DUBOS 6 av. Ile de France FR - 95,301 CERGY PONTOISE|
|REC Service de Réanimation Médicale||CHRU ANGERS 4 rue Larrey FR - 49,033 ANGERS CEDEX 01|
|REC Service de Réanimation Médicale||PELLEGRIN TRIPODE 1 Place Amélie Raba Léon FR - 33,076 BORDEAUX|
|REC Service de Réanimation Médicale||CHU BRETONNEAU 2 bld Tonnellé FR - 37,044 TOURS|
|REC Service de Réanimation Médicale||POITIERS JEAN BERNARD 350 av. Jacques Cœur FR - 86,021 POITIERS|
|REC Service de Réanimation Médicale||HOPITAL COTE DE NACRE av. Côte de Nacre FR - 14,300 CAEN|
|REC Service de Réanimation Médicale||CHU DE NICE Rte St Antoine Ginestière FR - 06200 NICE|
|REC Service de Réanimation Médicale||CHU PONTCHAILLOU 2 rue Henri-Le-Guilloux FR - 35,000 RENNES|
|REC Service de Réanimation Médicale||CHU NANCY 29 av. du Maréchal de Lattre de Tassigny FR - 54,000 NANCY|
|REC Service de Réanimation Médicale||CH SUD-FRANCILIEN 59 boulevard Henri Dunant FR - 91,106 CORBEIL-ESSONNES CEDEX|
|REC Service de Réanimation Médicale||SAINTE MARGUERITE 270 bld de Sainte Marguerite FR - 13,274 MARSEILLE CEDEX 9|
|REC Service de Réanimation Médicale||ROGER SALENGRO Boulevard du Pr Emile Laine FR - 59,037 LILLE|
|REC Service de Réanimation Médicale||GUSTAVE DRON 135 rue du Président Coty FR - 59,200 TOURCOING|
|REC Service de Réanimation Médicale||CHU MONTPELLIER 80 Avenue Augustin Fliche FR - 34,295 MONTPELLIER CEDEX 5|
|REC Service de Réanimation Médicale||HENRI MONDOR 51 av. Mar de Lattre de Tassigny FR - 94,000 CRETEIL|
|REC Service de Réanimation Médicale||CHU RANGUEIL 1, avenue Jean Poulhes FR - 31,403 CEDEX 04 TOULOUSE|
|REC Service de Réanimation Médicale||CHU PURPAN CHU Toulouse- Hôpital Purpan FR - 31,059 TOULOUSE CEDEX|
|REC Service de Réanimation Médicale||CH LYON SUD 165 Chemin du Grand Revoyet FR - 69,495 PIERRE-BENITE|
|REC Service de Réanimation Médicale||HOPITAL LA SOURCE BP6709 FR - 45,067 ORLEANS CEDEX|
|REC Service de Réanimation Médicale||CH VERSAILLES 177 rue de Versailles FR - 78,187 LE CHESNAY CEDEX|
|REC Service de Réanimation Médicale||CH BELFORT 14 rue de mulhouse FR - 90,000 BELFORT|
|Ethik Kommission Landesarztekammer Rheinland-Pfalz||Postfach 29 2,655,019 Mainz Germany|
|Ethik Kommission Arztekammer Mecklenburg-Vorpommern||Ernst Moritz Amdt Universitat Greifswald, Friedrich-Loeffler Str. 23d 17,487 Greifswald Germany|
|Ethik Kommission Bayerishe Landesarztekammer||Mühlbaurstr.16 D-81677 München Germany|
|Ethik commission Technische Universtat Dresden||Ethikkommission Technische Universität Dresden Fetscherstraße 74 01307 Dresden Germany|
|Ethik Kommission Univesitatsklinikum Rheinisch Westfalische Technische Hochschule Aachen||Universitätsklinikum Aachen Pauwelsstraße 30 52,074 Aachen Germany|
|Ethik Kommission Universitatslinikum Jena der Friedrich –Schiller||Bachstrasse 18, D-07740 Jena Germany|
|Ethik Kommission Schleswig-Holstein||Arnold-Heller-Straße 3 - Haus 18 24,105 Kiel Germany|
|Ethik Kommission for Arztekammer Hamburg||Humboldstrasse 67a – 22,083 Hamburg Germany|
|Ethik Kommission Universitat Heidelberg||Maybackstrasse 14–15, D68169 Mannheim Germany|
|Ethik Kommission Friedrich-alexander Universitat Erlangen-Nuremberg||Ethik-Kommission der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Krankenhausstraße 12 91,054 Erlangen Germany|
|Ethik Kommission Rheinische Friedrich-Wilhelms Universitat||Reuterstr. 2b 53,113 Bonn Germany|
|Ethik Kommission Universitat Ulm||Helmholtzstrasse 20 D-89081 Ulm Germany|
|Ethik Kommission Arztekammer des Saarlandes||Faktorestrasse 4 66,111 Saarbrucken Germany|
|Sismanoglio Geniko Nosokomeio||Sismanogliou 1 Marousi 151 26 Greece|
|REC||UNIVERSITY OF DEBRECEN Anaesthesiology and IC HU - DEBRECEN|
|REC||SZENT IMRE KAIBO Amerikai 57 HU - 1145 BUDAPEST|
|REC||JAVORSZKY ÖDÖN HOSPITAL KAIBO Argenti Döme tér 1–3 HU - 2600 VAC|
|REC||SEMMELWEIS UNIVERSITY Surgery 1St Ulloi Ut, 78 HU - 1082 BUDAPEST|
|REC||UZSOKI HOSPITAL ICU Uzsoki str., 29 HU - 1145 BUDAPEST|
|REC||COUNTY HOSPITAL ICU Megyei Korhaz Szentpéteri Kapu 72–76 HU - 3501 MISKOLC|
|REC||ST GEORGE COUNTY HOSPITAL General ITU Seregélyesi Street, 3 HU - 8000 SZEKESFEHERVAR|
|REC||UNIVERSITY OF PECS Anaesthesia and IC Ifjusag Ut, 13 HU - 7624 PECS|
|REC||OGYK HOSPITAL Intenzív Osztály Szabolcs u. 33–35 HU - 1135 BUDAPEST|
|REC||SZEGED UNIVERSITY Anaesthesiology and IC, Medical ICU Koranyi Fasor, 7 HU - 6720 SZEGED|
|REC||PANDY KALMAN COUNTY HOSPITAL ICU Semmelweis Street 1. HU - 5700 GYULA|
|Helsinki Ethics Committee||Kiryat Hadassah, POB 12000 Jerusalem, 91,120, Israel|
|Ethics Commission University College Cork, Ireland||Lancaster Hall, 6 Little Hanover Street, Cork, Ireland|
|Ethics Commission The Adelaide & Meath Hospital, Dublin||Tallaght, Dublin 24, Ireland|
|Ethics Commission Merlin Park Hospital, Galway||Unit 4, Merlin Park Hospital Galway Ireland|
|Comitato Etico dell’Azienda Sanitaria Ospedaliera “San Giovanni Battista” di Torino||Corso Bramante 88–90 10,126 Torino Italy|
|Comitato Etico Universita’ degli studi di Napoli Federico II comitato etico per le attivita’ biomediche||Via Sergio Pansini 5 80,131 Napoli Italy|
|Comitato Etico Azienda Ospedaliiero Universitaria Ospedali Rhuniti, Ancona||VIA CONCA 71 60,126 ANCONA (Ancona) Italy|
|Comitato Etico Azienda Ospedaliera Universitaria Careggi, Firenze||Viale Peiraccini 28 50,139 Firenze Italy|
|Comitato Etico Azienda Ospedaliera San Gerardo, Monza||Via Pergolesi 33 20,053 Monza (MI) Italy|
|Comitato Etico Azienda Ospedaliero Universitaria Di Ferrara||Via A.moro 8 Cona (FE) Italy|
|Ethische Commissie Erasmus MC Universitai Medisch Centrum Rotterdam||Postbus 2040 3000 Ca Rotterdam Netherlands|
|Komisja Karol Marcinkowski University of Medical Sciences in Poznan||Collegium Maius Fredry 10 61–701 Poznań Poland|
|Not applicable: ethics approval declined|
|Ethics Committee of Military Medical Academy||17 Crnotravska Serbia|
|Ethics Committee of Clinical Center Kragujevac||CLINICAL CENTER KRAGUJEVAC Zmaj Jovina street 30 Kragujevac Serbia|
|Comite Etico de Investigacion Clinica del Hospital General Universitario de Alicante||Hospital General Universitario de Alicante Pintor Baeza, 12, 03010 Alicante, Spain|
|Comite Etico Hospital Universitario Dr. Peset||Av. de Gaspar Aguilar, 90, 46,017 València, Valencia, Spain|
|Comite Etico de Investigacion Clinica del Hospital de Bellvitge Barcelona||Feixa Llarga, s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain|
|Comite Etico Hospital Universitario Puerta Del Mar||Av. Ana de Viya, 21, 11,009 Cádiz, Spain|
|Comite Etico Hospital Universitario de Gran Canaria||Calle Dr. Alfonso Chiscano Díaz, 338 35,010 Las Palmas de Gran Canaria, Las Palmas, Spain|
|Comite Etico Hospital Universitario de La Princesa Madrid||Calle de Diego Leon, 62, 28,006 Madrid, Spain|
|Comite Etico Hospital General Universitario Reina Sofia de Murcia||Av. Intendente Jorge Palacios, 1, Murcia, Spain|
|Comite Etico Hospital Virgen de la Victoria Malaga||Campus de Teatinos, s/n, 29,010 Málaga, Spain|
|Comite Etico Hospital De Mataro, Consorci Sanitari del Maresme||Carrer Prolongació Cirera, s/n, 08304 Mataró, Barcelona, Spain|
|Comite Etico Hospital Clinico San Carlos||Profesor Martín Lagos, S/N Madrid - 28,040 Spain|
|Comite Etico Hospital Universitari De Tarragona Joan XXIII||C/ Dr. Mallafrè Guasch, 4, 43,005 Tarragona, Spain|
|Comite Etico Hospital de Sagunto||Avenida Ramón y Cajal, S/N, 46,520 Sagunt, Valencia, Spain|
|Comite Etico Centro Medico Delfos||Av. de Vallcarca, 151, 08023 Barcelona, Spain|
|Comite Etico Hospital Universitari Joan XXIII de Tarragona||C/ Dr. Mallafrè Guasch, 4, 43,005 Tarragona, Spain|
|Comite Etico de investigacion Clinica De Aragon (CEICA)||Avenida Gomez Laguna 25 planta 3 50,009 Zaragoza Spain|
|Comite Etico Hospital de Basurto||Montevideo Etorb., 18, 48,013 Bilbao, Vizcaya, Bizkaia, Spain|
|Comite Etico Hospital Santa Maria del Rosell||Paseo de Alfonso XIII, 61, 30,203 Cartagena, Spain|
|Comite Etico Hospital Universitario Arnau de Vilanova de Lleida||Avenida Alcalde Rovira Roure, 80 25,198 Lleida Spain|
|Comite Etico Hospital Universitario de Burgos||Avda. Islas Baleares, 3, 09006 Burgos, Spain|
|Comite Etico Hospital Universitario Puerto Real||Carretera Nacional IV, km 665, 11,510 Puerto Real, Cádiz, Spain|
|Comite Etico Hospital Universitari de Girona Doctor Josep Trueta||Avenida França, s/n, 17,007 Girona, Spain|
|Comite D’Etica d’Investigacio Clinica Consorci Hospitalari de Vic||Av. de França, s/n 9a planta A -Despatx 913 17,007 – Girona Spain|
For individual recruitment centres, chief and principal investigators, national coordinators and contributors see relevant lists in the Additional file 1.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
List of Contributing Centres and Investigators. (DOC 121 kb)