Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: the GenOSept experience

  • 1Email authorView ORCID ID profile,
  • 2,
  • 3,
  • 2,
  • 4,
  • 5,
  • 6,
  • 7,
  • 5,
  • 8,
  • 9 and
  • 10
BMC Medical Ethics201920:30

https://doi.org/10.1186/s12910-019-0370-1

  • Received: 10 September 2018
  • Accepted: 22 April 2019
  • Published:
Open Peer Review reports

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

  • GenOSept
  • Genetic epidemiology
  • Research ethics
  • Decision-making
  • Human genetics
  • Intensive care

Key messages

  • 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

Background

Sepsis has been described as “one of the oldest and most elusive syndromes in medicine” [1]. 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 [29].

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 [1016]. 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).
Table 1

European regulations, position statements and advisory bodies affecting clinical research

Document

Source

Impact

Helsinki Declaration and the Universal Declaration on the human genome and human rights adopted by UNESCO (1997)

http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/human-genome-and-human-rights/

Need for legal representative or deferred consent, in the event of incapacity;

Genetic counselling;

Research should ‘contribute to the health benefit of other persons in the same age category or with the same genetic condition...

International Declaration on Human Genetic Data (2003)

http://www.unesco.org/new/en/social-and-human-sciences/themes/bioethics/human-genetic-data/

Recognition of ‘special status’ for human genetic data

The Charter of Fundamental Rights of the EU (2000)

http://www.europarl.europa.eu/charter/default_en.htm

Protection of personal data

European Directive on processing and free movement of personal data (Directive 95/46/EC)

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:HTML

Protection for individuals about the processing and free movement of personal data

European Group on Ethics in Science and New Technologies

https://ec.europa.eu/research/ege/index.cfm

An advisory body to the European Commission on ethical aspects of science and new technologies

European Clinical Trials Directive 2001/20/EC

http://www.eortc.be/Services/Doc/clinical-EU-directive-04-April-01.pdf

Requirement for prior informed consent from legal representative made emergency research impossible;

Semantic confusion of ‘therapeutic’ and ‘non-therapeutic’ research

The International Conference on Harmonisation Guidance on Good Clinical Practice (Topic E6) (CPMP/ICH/135/95)

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf

Principles of good clinical practice in clinical trials research

The Good Clinical Practice Directive 2005/28/EC

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:en:PDF

Supplementing the Clinical Trials Directive

European Clinical Trials Regulation 2014

http://ec.europa.eu/health/human-use/clinical-trials/regulation/index_en.htm

Improving coordination of the application process for trials involving multiple countries, with creation of single EU entry point and trials databank

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:
  1. I.

    The lack of capacity inherent in critical illness challenged the requirement to respect patient autonomy in obtaining consent.

     
  2. II.

    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.

     
  3. III.

    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.

     
  4. IV.

    Public concerns about the security and privacy of genetic data [17] appeared to conflict with the study’s methodological requirement to transfer human genetic material across national borders for analysis in the genotyping centres.

     
  5. V.

    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.

Methods

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.

Data protection

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

Results are summarised in Table 2.
Table 2

Characteristics of the application process for Ethical approval across the various European countries involved in GenOSept

Country

National coordinator

No of ICUs

Is the ethics approval process centralized or local?

In what form is the ethics application made?

Which of the following are usual members of the ethics committees?

Outcome of GenOSept application process: range of centres approved

Month/Year ethics application submitted & decision received

Additional info / modification

National guidelines for Research in ICU pts

National or Regional EC

Local EC

Paper application

Web-based Application

Lay

Medical

Legal

All units

Some units

Approval refused

Submitted

Approved or rejected

Interval (months)

Austria

Novak

1

02/07

09/07

7

a

Belgium

Damas

7

02/06

05/06

3

Czech Re

Sramek

8

07/05

07/05

< 1

Croatia

Gasparovic

2

11/07

3/08

4

Estonia

Sarapu

2

06/05

06/05

< 1

France

Chiche

8

10/05

10/06

12

Germany

Bloos

12

07/05

08/05

1

Greece

Armanagidis

2

04/06

04/06

< 1

Hungary

Bobek

10

10/05

09/07

24

Ireland

Ryan

7

03/06

10/06

7

Israel

Weiss

5

08/05

02/06

6

Italy

Cotogni

24

01/06

03/06

2

NL

Hazelzet

1

01/07

11/07

9

Poland

Mikstacki/Tamowicz

22

05/05

06/05

1

Portugal

Carneiro

0

08/05

08/06

< 1

Serbia

Surbatovic

2

07/06

07/06

< 1

Spain

Sirgo/Rello

19

07/05

08/05

1

UK

Hinds

28

03/06

04/06

1

Totals

18 countries

160

11

10

17

1

14

18

13

14

3

1

Median interval = 1.5 months

7

9

aAustria: the REC which received the application recommended inclusion only of those critically ill patients who had capacity to give consent

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.
Table 3

Characteristics of the RECs across the various European countries involved in GenOSept

Characteristic

Median (IQR) or n (%)

[Range]

No of ICUs per country

7 (2–15)

[1–28]

Countries with centralized (national/regional) REC only

8 (44.4%)

Countries with local REC only

7 (38.9%)

Countries with both centralized and local REC

3 (16.7%)

Countries with paper application process

17 (94.4%)

Countries with online application process

1 (5.6%)

Medical members of REC

18 (100%)

Lay and Legal members of REC

13 (72.2%)

Lay but no Legal members of REC

1 (5.6%)

Approval at all units within country

14 (77.8%)

Approval at some units within country

3 (16.7%)

No approval at country

1 (5.6%)

Application process duration (months)

1.5 (1–7)

[1–24]

Additional information or modification required

7 (38.9%)

Countries with National guidelines for research in critical care

9 (50%)

IQR inter-quartile range, n absolute number, % percentage

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.

Approval outcomes

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.

National guidelines

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).

Discussion

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 [18]. The responses from some of the RECs involved in assessing the GenOSept application suggests unwarranted and potentially paternalistic exclusion of patients lacking capacity [19], 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 [20].

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 [23] to accommodate the particular challenges of research in emergency settings [2329], by widely differing interpretations of ethical principles by national or local RECs, as well as variations in approval processes [2126]. 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 [3035].

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 [36].

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 [37]. 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.

Conclusions

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.

Abbreviations

CAP: 

Community acquired pneumonia

eCRF: 

Electronic Case Report Form

ESICM: 

European Society for Intensive Care Medicine

EU: 

European Union

FP6 Sixth: 

Framework Programme (European Commission)

GenOSept: 

Genetics Of Sepsis and Septic Shock

ICU: 

Intensive care unit

MREC: 

Multicentre Research Ethics Committee

REC: 

Research Ethic Committee

Declarations

Acknowledgements

GenOSept National Coordinators:

Jordi Rello.

jrello@crips.es

Gonzalo Sirgo.

gsirgoluanco@yahoo.es

Paolo Cotogni.

paolo.cotogni@unito.it

Apostolos Armaganidis.

aarmag@med.uoa.gr

Thomas Ryan.

tryan@stjames.ie

Frank Bloos.

frank.bloos@med.uni-jena.de

Ivan Novak.

novaki@fnplzen.cz

Vladimir Gasparovic.

vgasparovic111948@yahoo.com

Ilona Bobek.

bobekilona@gmail.com

bobeki@ogyik.hu

Adam Mikstacki.

mikstacki@lutycka.pl

Jan Hazelzet.

j.a.hazelzet@erasmusmc.nl

Yoram Weiss.

weiss@hadassah.org.il

Antonio Carneiro.

a.carneiro.ucip@hgsa.min-saude.pt

Silver Sarapuu.

silver.sarapuu@kliinikum.ee

Pierre Damas.

pdamas@chu.ulg.ac.be

Maja Surbatovic.

anes@EUnet.yu

Vladimir Sramek.

sramek@fnusa.cz

The authors of this manuscript wish to thank all GenOSept Investigators, as listed in the supplement.

Funding

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.

Authors’ contributions

AT conducted statistical analyses on the survey database, appraised the background literature, prepared the first draft of the manuscript and coordinated subsequent revisions; JB conceived the study, contributed to drafting and reviewing the manuscript and evaluating the survey database, contributed to the background literature appraisal; GMC contributed to revise the manuscript; ACG contributed to reviewing the manuscript; PH contributed to revise the manuscript; J-DC contributed to revise the manuscript; PAHH contributed to revise the manuscript; GHM contributed to revise the manuscript; FS conceived the study, contributed to reviewing the manuscript; CG conceived the study, contributed to quality assurance of the database, contributed to drafting and reviewing the manuscript; CH conceived the study, contributed to drafting and reviewing the manuscript. All authors read and approved the final manuscript.

Authors’ information

Not applicable.

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

Ethic Commissions/Bodies

 

Austria

 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

Belgium

 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

Croatia

 Research Ethics Committee Zagreb

University hospital Clinical Hospital Rebro Emergency and Intensive Care Medicine/Internal Medicine Kispaticeva 12 HR – 1000 Zagreb Croatia

Czech Republic

 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

Estonia

 Ethics Committee on Human Research of the University of Tartu

TU Biomeedikum Room 3050 Ravila Str 19 51,014, Tartu, Estonia

France

 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

Germany

 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

Greece

 Sismanoglio Geniko Nosokomeio

Sismanogliou 1 Marousi 151 26 Greece

Hungary

 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

Israel

 Helsinki Ethics Committee

Kiryat Hadassah, POB 12000 Jerusalem, 91,120, Israel

Ireland

 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

Italy

 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

Netherlands

 Ethische Commissie Erasmus MC Universitai Medisch Centrum Rotterdam

Postbus 2040 3000 Ca Rotterdam Netherlands

Poland

 Komisja Karol Marcinkowski University of Medical Sciences in Poznan

Collegium Maius Fredry 10 61–701 Poznań Poland

Portugal

 Not applicable: ethics approval declined

 Serbia

 Ethics Committee of Military Medical Academy

17 Crnotravska Serbia

 Ethics Committee of Clinical Center Kragujevac

CLINICAL CENTER KRAGUJEVAC Zmaj Jovina street 30 Kragujevac Serbia

Spain

 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

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis 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.

Authors’ Affiliations

(1)
Whiston Hospital, Prescot, Merseyside and Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
(2)
Imperial College, London, UK
(3)
Intensive Care Unit, John Radcliffe Hospital, Oxford, UK
(4)
University of Sheffield, Sheffield, UK
(5)
The Health Foundation, London, UK
(6)
Hospital Cochin, Paris, France
(7)
Department of Anaesthesiology and Pain Medicine, Bern University Hospital and University of Bern, Bern, Switzerland
(8)
Barts and the London Queen Mary School of Medicine, London, UK
(9)
Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
(10)
GenOSept National Coordinators, European Society of Intensive Care Medicine (ESICM), Rue Belliard, 19, B-1040 Brussels, Belgium

References

  1. Angus DC, van der Poll T. Severe Sepsis and septic shock. N Engl J Med. 2013;369:840–51.View ArticleGoogle Scholar
  2. Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ. 2007;335:879–83. https://doi.org/10.1136/bmj.39346.495880.AE.View ArticleGoogle Scholar
  3. Rosenthal GE, Kaboli PJ, Barnett MJ, Sirio CA. Age and the risk of in-hospital death: insights from a multihospital study of intensive care patients. J Am Geriatr Soc. 2002;50:1205–12 http://www.ncbi.nlm.nih.gov/pubmed/12133014. Accessed 28 Apr 2014.View ArticleGoogle Scholar
  4. Angele MK, Pratschke S, Hubbard WJ, Chaudry IH. Gender differences in sepsis: cardiovascular and immunological aspects. Virulence. 2014;5:12–9. https://doi.org/10.4161/viru.26982.View ArticleGoogle Scholar
  5. Plurad DS, Lustenberger T, Kilday P, Zhu J, Green DJ, Inaba K, et al. The association of race and survival from sepsis after injury. Am Surg. 2010;76:43–7 http://www.ncbi.nlm.nih.gov/pubmed/20135938. Accessed 27 Nov 2017.Google Scholar
  6. Flores C. Host genetics shapes adult sepsis survival. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70307-8/fulltext, vol. 3; 2015. https://doi.org/10.1016/S2213-2600(14)70307-8.View ArticleGoogle Scholar
  7. Paugam-Burtz C, Dupont H, Marmuse J-P, Chosidow D, Malek L, Desmonts J-M, et al. Daily organ-system failure for diagnosis of persistent intra-abdominal sepsis after postoperative peritonitis. Intensive Care Med. 2002;28:594–8. https://doi.org/10.1007/s00134-002-1250-5.View ArticleGoogle Scholar
  8. Tridente A. Sepsis 3 and the burns patient: do we need Sepsis 3.1? Scars, Burn Heal, vol. 4; 2018. p. 205951311879065. https://doi.org/10.1177/2059513118790658.View ArticleGoogle Scholar
  9. Oltean S, Ţǎţulescu D, Bondor C, Slavcovici A, Cismaru C, Lupşe M, et al. Charlson’s weighted index of comorbidities is useful in assessing the risk of death in septic patients. J Crit Care. 2012;27:370–5. https://doi.org/10.1016/j.jcrc.2011.08.021.View ArticleGoogle Scholar
  10. Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche J-D, et al. Variants in the mannose-binding lectin gene MBL2 do not associate with Sepsis susceptibility or survival in a large European cohort. Clin Infect Dis. 2015;61:695–703. https://doi.org/10.1093/cid/civ378.View ArticleGoogle Scholar
  11. Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, et al. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med. 2014;40:202–10.View ArticleGoogle Scholar
  12. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, et al. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med. 2015;3:53–60. https://doi.org/10.1016/S2213-2600(14)70290-5.View ArticleGoogle Scholar
  13. Tridente A, Clarke GM, Walden A, Gordon AC, Hutton P, Chiche J-D, et al. Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort. Crit Care. 2015;19:210.View ArticleGoogle Scholar
  14. Walden AP, Clarke GM, McKechnie S, Hutton P, Gordon AC, Rello J, et al. Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care. 2014;18:R58. https://doi.org/10.1186/cc13812.View ArticleGoogle Scholar
  15. Scherag A, Schöneweck F, Kesselmeier M, Taudien S, Platzer M, Felder M, et al. Genetic factors of the disease course after Sepsis: a genome-wide study for 28Day mortality. EBioMedicine. 2016;12:239–46. https://doi.org/10.1016/j.ebiom.2016.08.043.View ArticleGoogle Scholar
  16. Tridente A, Bion J, Mills GH, Gordon AC, Clarke GM, Walden A, et al. Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis. Ann Intensive Care. 2017;7:96.View ArticleGoogle Scholar
  17. Majumder MA, Cook-Deegan R, McGuire AL. Beyond our Borders? Public resistance to global genomic data sharing. PLoS Biol. 2016;14:e2000206. https://doi.org/10.1371/journal.pbio.2000206.View ArticleGoogle Scholar
  18. Pehboeck D, Hohlrieder M, Wenzel V, Benzer A. Submission of clinical studies to ethics committees or clinical trials registers: the authors’ point of view. Intensive Care Med. 2009;35:713–6. https://doi.org/10.1007/s00134-009-1434-3.View ArticleGoogle Scholar
  19. Shepherd V. Research involving adults lacking capacity to consent: the impact of research regulation on “evidence biased” medicine. BMC Med Ethics. 2016;17:55. https://doi.org/10.1186/s12910-016-0138-9.View ArticleGoogle Scholar
  20. Hernandez R, Cooney M, Dualé C, Gálvez M, Gaynor S, Kardos G, et al. Harmonisation of ethics committees’ practice in 10 European countries. J Med Ethics. 2009;35:696–700. https://doi.org/10.1136/jme.2009.030551.View ArticleGoogle Scholar
  21. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Washington, DC: U.S. Department of Health and Human Services; 1978. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html. Accessed 22 Dec 2015Google Scholar
  22. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects – WMA – The World Medical Association. 1964. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 2 Mar 2018.
  23. Clinical trials - Directive 2001/20/EC - European Commission. https://ec.europa.eu/health/human-use/clinical-trials/directive_en. Accessed 2 Mar 2018.
  24. Sterz F, A Singer E, Böttiger B, Chamberlain D, Baskett P, Bossaert L, et al. A serious threat to evidence based resuscitation within the European Union. Resuscitation. 2002;53:237–238. http://www.ncbi.nlm.nih.gov/pubmed/12062833. Accessed 31 Mar 2016.View ArticleGoogle Scholar
  25. Lemaire F, Bion J, Blanco J, Damas P, Druml C, Falke K, et al. The European Union directive on clinical research: present status of implementation in EU member states’ legislations with regard to the incompetent patient. Intensive Care Med. 2005;31:476–9. https://doi.org/10.1007/s00134-005-2574-8.View ArticleGoogle Scholar
  26. Bosch X. Europe’s restrictive rules strangling clinical research. Nat Med. 2005;11:1260. https://doi.org/10.1038/nm1205-1260b.View ArticleGoogle Scholar
  27. McMahon AD, Conway DI, Macdonald TM, McInnes GT. The unintended consequences of clinical trials regulations. PLoS Med. 2009;3:e1000131. https://doi.org/10.1371/journal.pmed.1000131.View ArticleGoogle Scholar
  28. Liddell K, Kompanje EJO, Lemaire F, Vrhovac B, Menon DK, Bion J, et al. Recommendations in relation to the EU clinical trials directive and medical research involving incapacitated adults. Wien Klin Wochenschr. 2006;118:183–91. https://doi.org/10.1007/s00508-006-0577-2.View ArticleGoogle Scholar
  29. Liddell K, Chamberlain D, Menon DK, Bion J, Kompanje EJO, Lemaire F, et al. The European clinical trials directive revisited: the VISEAR recommendations. Resuscitation. 2006;69:9–14. https://doi.org/10.1016/j.resuscitation.2005.12.004.View ArticleGoogle Scholar
  30. Frewer LJ, Coles D, Champion K, Demotes-Mainard J, Goetbuget N, Ihrig K, et al. Has the European clinical trials directive been a success? BMJ. 2010;340:c1862 http://www.ncbi.nlm.nih.gov/pubmed/20382668. Accessed 3 Aug 2015.View ArticleGoogle Scholar
  31. Hearnshaw H. Comparison of requirements of research ethics committees in 11 European countries for a non-invasive interventional study. BMJ. 2004;328:140–1. https://doi.org/10.1136/bmj.328.7432.140.View ArticleGoogle Scholar
  32. Stamer UM, Naef N, Porz R, Stuber F, Leva B, Meissner W, et al. Ethical procedures and patient consent differ in Europe. Eur J Anaesthesiol. 2015;32:126–31. https://doi.org/10.1097/EJA.0000000000000206.View ArticleGoogle Scholar
  33. Møller AM. Ethical requirements in Europe: different legislations, different traditions, the Danish perspective. Eur J Anaesthesiol. 2013;30:53–4. https://doi.org/10.1097/EJA.0b013e32835af2af.View ArticleGoogle Scholar
  34. Rikkert MGMO, Lauque S, Frölich L, Vellas B, Dekkers W. The practice of obtaining approval from medical research ethics committees: a comparison within 12 European countries for a descriptive study on acetylcholinesterase inhibitors in Alzheimer’s dementia. Eur J Neurol. 2005;12:212–7. https://doi.org/10.1111/j.1468-1331.2004.00980.x.View ArticleGoogle Scholar
  35. Sherwood ML, Buchinsky FJ, Quigley MR, Donfack J, Choi SS, Conley SF, et al. Unique challenges of obtaining regulatory approval for a multicenter protocol to study the genetics of RRP and suggested remedies. Otolaryngol Head Neck Surg. 2006;135:189–96. https://doi.org/10.1016/j.otohns.2006.03.028.View ArticleGoogle Scholar
  36. Duley L, Antman K, Arena J, Avezum A, Blumenthal M, Bosch J, et al. Specific barriers to the conduct of randomized trials. Clin Trials. 2008;5:40–8. https://doi.org/10.1177/1740774507087704.View ArticleGoogle Scholar
  37. Mental Capacity Act - Health Research Authority. https://www.hra.nhs.uk/planning-and-improving-research/policies-standards-legislation/mental-capacity-act/. Accessed 21 Jan 2018.

Copyright

© The Author(s). 2019

Advertisement