1. Introduction, purpose of this Standard Operating Procedure (SOP)

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1 Details Document Type Document name Ref # Version Effective from Review date Owner Prepared by Reviewed by Approved by Superseded documents Relevant regulations/legislation/guidelines/reference Standard Operating Procedure (SOP) ESA Clinical Trial Network - General Organisation and Principles SOP-CTN-001 v 1.1 dated 17/Dec/ /Dec/ /Dec/2015 ESA Clinical Trial Network, ESA Secretariat Brigitte Leva Sandrine Damster, ESA Research Committee (RC) Members: Wolfgang Buhre, George Shorten ESA RC Chair: Andreas Hoeft none 1* ICH Guidelines 2* CDISC : glossary of terms 3* DOH 4* EU Directives 5* HMSO 6* FDA Change History Date Version Number Change details Approved by 17/Dec/ Annual review, Andreas Hoeft typos Addition of DM 1. Introduction, purpose of this Standard Operating Procedure (SOP) The present standard operating procedure aims to define and clarify the general principles, organisation, and management of the (ESA) Clinical Trial Network (CTN) with written instructions to achieve uniformity. The SOP refers to the guidelines for Good Clinical Practice and regulations referenced above. The SOP describes the general roles and responsibilities of the CTN and its staff. This document describes the benefits of collaboration with the ESA CTN (financial support, CTN support package, and sponsorship). The present SOP further details the call for applications and application steps. 2. Summary The Clinical Trial Network provides an infrastructure for Institutions, clinicians and scientists allowing to work collaboratively across international borders to improve the care of patients in the field of Anaesthesiology, Intensive Care, Peri-Operative Medicine, Emergency Medicine and Pain Medicine. International networks all over the world have demonstrated the advantages of collaboration to address and answer clinically relevant research questions. Longterm collaborative relationships within research, education and clinical practice require dedicated resources and infrastructure enabling access to the entire clinical community. The aim of the ESA Clinical Trial Network (CTN) is to build such a collaborative network. 3. Glossary Standard Operating Procedures (SOP) are detailed written instructions to achieve uniformity of the performance of a specific function. SOPs form the basis on which Quality Systems and Processes are conducted and monitored against. (ref. 1* ICH) Page 1 of 7

2 Interventional Clinical Study: Clinical Study in which, a drug, device, therapy or process under investigation has an effect on an outcome of interest: e.g. quality of life, efficacy, safety, and pharmacoeconomics. (ref. 2* CDISC) Observational Clinical Study: Clinical Study without any intervention. Researchers observe participants and keep track of their health to measure individual and cohort outcomes. Specific drugs are not used in this type of study. Sponsor: - The EU Directive 2001 defines a sponsor as an individual, company, institution or Organisation which takes responsibility for the initiation, management and/or financing of a clinical trial. (ref. 4* EU-DIRECTIVE 2001/20). - UK Department of Health defines Sponsor as the Responsible for ensuring that arrangements are in place for the management, monitoring and financing of research (ref. 3* DOH 2001) - Definition of Sponsor by UK Her Majesty's Stationery Office (HMSO) is the person who takes responsibility for the initiation, management and financing (or arranging the financing) of that trial (ref. 5* HMSO, SI: ) - USA Food and Drug Administration in its Code of Federal Regulations Title 21 (ref. 6* FDA21 CFR 812.3) distinguishes the following: Sponsor: A person who initiates, but who does not actually conduct, the investigation, i.e., the investigational device is administered, dispensed, or used under the immediate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator (see next definition), and the employees are investigators. Sponsor-investigator an individual who both initiates and actually conducts, alone or with others, an investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator include both those of an investigator and those of a sponsor. Investigator an individual who actually conducts a clinical investigation, i.e., a person under whose immediate direction the investigational product is administered, dispensed, or used, provided that the investigation involves a subject. In the event of an investigation conducted by a team of individuals, the investigator is the responsible leader of that team. Page 2 of 7

3 4. ESA Clinical Trial Network staff, overview of responsibilities ESA Data Manager ESA Research Commitee ESA Clinical Study Coordinator National Coordinators Study Chief Investigator Study Steering Committee Sponsor for Observational study = ESA Interventional Study = Institution of CI Local Coordinators Other Site staff (clinicians, nurses, etc.) ESA Research Committee (RC): The Research Committee may determine areas of particular scientific interest for a specific call and assumes responsibility for selecting studies through a competitive process, facilitates recruitment of centres (through the ESA CTN and personal contacts). If required, the RC may nominate a Data Safety Monitoring Board. Study Chief Investigator (CI): A Registered Physician who has overall responsibility for the Trial and who takes responsibility for: - Submission of a project to ESA RC including discussion of the literature, time-line and financial description. This submission is usually made on behalf of the Steering Committee. - Submission of the protocol for ethical approval and other necessary regulatory bodies for approvals. - Identification of centres willing to participate in the study. - Advancement of the project to successful conclusion including publication in a peer reviewed journal or journals. - Acknowledging ESA in all publications and presentations arising from the work. Study Steering Committee: A group of scientists which typically comprises at least five but no more than ten persons. The Committee actively contributes in the study design, conduct, data analysis and dissemination of study findings. Sponsor: An individual, company, institution, or Organisation which takes responsibility for the initiation, management, and/or financing of clinical trial. (ref. 1* ICH) See Glossary above and Sponsorship and collaboration section 6.3 for details. ESA Clinical Study Coordinator: The person, who handles most of the administrative responsibilities of a clinical study. The Clinical Study Coordinator is located at the ESA Secretariat Office established in Brussels and facilitates all aspects of trial administration, working in close collaboration with the Study Steering Committee to finalise the study documents and with the national co-ordinators and study centres to disseminate information. Data Manager (DM): This person is involved in discussions about data collection options and oversees development of data collection tools based on the protocol. Once enrollment begins, the data manager ensures that data is collected, validated, complete and consistent. At the completion of the clinical trial, DMensures that all data expected to be captured has been accounted for and that all data management activities are complete.the DM can be a senior Clinical Study Coordinator at the Page 3 of 7

4 ESA Secretariat Office in Brussels or appointed person by the Steering Committee from the Institution of one of the Steering Committee members. National Coordinator (NC): The person who is responsible for co-ordination of investigators and sites in different participating centres in his/her country. See guidance in section 8. Local Coordinator: Individual member of the study team designated and supervised by the principal investigator at a trial site (e.g. hospital) to perform study related procedures e.g. patient consent, randomisation, data collection, data return, etc. See guidance in section General Principles of the ESA CTN Aim Authorship Rules General Principles Patient Care Data Property 1. ESA CTN Aim The aim of the Clinical Trial Network is to facilitate, to integrate and to support clinical research conducted by members or research groups of the ESA or collaborating individuals or groups at an international level. The ESA CTN is managed by the ESA Research Committee, and its actions and activities are reported to the ESA Board by the ESA RC Chair. 2. ESA CTN for Patient Care Organisation committed to enhance patient care through research and education, and will help to raise the long-term objectives of the Society. All members of the ESA CTN agree to abide by the principles and obligations set out below. All contributors to and participants in the ESA CTN will agree to abide by the principles of ethical conduct in research and good clinical practice. They will act in the best interests of their patients and of the scientific community. 3. ESA CTN Studies Data Property The CTN is part of the ESA. For each Study, the study protocol will detail the Sponsorship and the data ownership policy. For ESA sponsored studies, the intellectual property of the data remains under the responsibility of the ESA/ESA RC. In case of collaborative studies with other societies (ESICM, etc.), the ownership of data should be decided upfront in the protocol. The Chief Investigator of the chosen trial is responsible for approval, monitoring, and financial issues of the research project. He/she reports to the chair of the ESA RC. If needed, an independent evaluation of feasibility of a large-scale project (and evaluation of adequacy of use of financial resources) will be requested from external reviewers experts in epidemiology or clinical trials. 4. ESA CTN Authorship Rules The Chief Investigator and the ESA RC agree on authorship order and/or criteria governing authorship in advance. This must be described in the study protocol. For each study all efforts should be made with the Journal editor to include the name of the Page 4 of 7

5 network in the list of authors. Including all members of the project Steering Committee is not mandatory. Collaborators responsible for recruitment of the greatest number of patients and those who contribute at each step of the project (design-inclusion-analysis-writing) should be prioritised. 6. Clinical Trial Network benefits Financial Sponsorship Benefits Administrative Coordination The ESA offers the following benefits for a period of at least 1 year to Research investigators and Research groups/steering Committee. 1. Financial support A CTN grant up to 30,000 is provided for Study costs. This grant is used for electronic data capture, statistical advice, publication, to support traveling costs, or reimburse other costs study related (to be agreed with ESA in advance). For meetings, ESA Committee procedures are followed with agenda and minutes recorded. Meetings should occur at reasonable costs, mainly at the ESA Brussels Secretariat or at other ESA meetings such as Euroanaesthesia Congress. The ESA is responsible for covering the costs of the hosting facility, if needed. In this respect, the ESA can also facilitate video conferencing platforms. For details see GUI- CTN-004: CTN Cost Reimbursement Guidelines 2. Administrative and Coordination support package Support includes: - Access to the ESA members database; potential partner centres that constitute the first core of the ESA CTN (access via the ESA Secretariat); - Entitlement to display the ESA CTN logo together with the following sentence: the Clinical Trial Network of the on their documentation, s and websites. The ESA Board and the ESA RC must be informed of any promotional material embedding the ESA CTN logo; - Dedicated section on the ESA website for study description, study documents and communication between researchers; - Facilities of the ESA Headquarters for meetings of the Chief Investigator with the study Steering Committee and National coordinators (if needed); - Space in the ESA newsletter for promoting the study; - Annual Congress: Provision of a meeting room during the ESA Annual Congress, subject to space availability, opportunity to promote the project and display documentation at the ESA booth whenever available; - Teleconference calls (number and extent to be defined upon study); - Study Coordination: ESA Staff dedicated to study coordination will support the Chief Investigator in: Page 5 of 7

6 The preparation and review of key study documents: Study protocol, patient case report form, study guidelines and forms Administrative follow up: filling of applicable Ethics approval and documents Preparation of technical facilities for Data capture as well as electronic Case Report Form (CRF) Follow up of participants: Call for centres, sending information letters to the sites (pre, during, post recruitment). For details on call for centre process, please refer to GUI- CTN-001 in section 8. Data handling and data cleaning support Study Report and archiving support 3. Sponsorship and collaboration: - Current regulations require that an Investigator-driven clinical trial (IDCT) has a single sponsor an agency or organisation that takes legal responsibility and liability for the trial. Many Organisations are unwilling to undertake the role of sponsor at a pan- European level for multinational trials. Widely varying regulations and laws on liability between countries makes sponsorship difficult to define. This is one main difference in Europe between academic and pharmaceutical companies, the latter being able to take pan-european sponsorship, while for the former it is extremely difficult. - In addition there is no consistent approach to the sponsorship of trials that are not investigating IMPs (Investigational Medicinal Products) in Europe. - In view of the above consideration the following has been decided for ESA CTN: - For observational studies, the ESA can act as legal sponsor. It depends on the individual study and will be documented in the study protocol. In the case that ESA is acting as Sponsor, the ESA Study Coordinator will ensure study registration. In the case that the local academic institution of the Chief Investigator would be sponsor, the CI will ensure that the study is registered and updates provided through the clinicaltrials.gov website. - For Interventional studies, the ESA cannot act as the sponsor; in this case the sponsor will be the local academic institution of the CI and ESA will act as a funding collaborator. - If required, the ESA can facilitate contacts with potential partners, and will also support fund raising if appropriate (i.e. collaboration with national funding agencies and industrial partners). - If required, the ESA can support in grant applications and assist with preparation of applications to the European Commission or to other funding bodies. 7. Call for Studies Application Process: Who can submit an Application? Selection Steps Application Process What kind of project can be submitted? Application Steps 1. Who can submit an Application? Every physician can apply for support by the ESA CTN. Non ESA members health care professionals are entitled to present proposals. Page 6 of 7

7 2. What kind of project can be submitted? The ESA CTN targets scientific and educational research activities, which are of interest in the field of Anaesthesiology, Intensive Care, Emergency Medicine and Pain Medicine. There are no restrictions with respect to the scale of a study. The ESA actively promotes observational and interventional studies which benefits from a large population. Sub-studies: In principle, applications for sub-studies within a main study are possible and can be done by every participating centre. The Chief Investigator and the Steering Committee are responsible if a sub-study is feasible or not. The ESA RC must be informed in case of sub-study is performed. 3. Application Steps Call for Studies proposals is open when agreed by the ESA RC members during the Research Committee meetings. A Call for Study proposals is published on the ESA website, Newsletter and enews etc. at least 3 months before the deadline for application. Full application is done using the ESA Call For Study Proposal Form. Research Grants. The chief investigators will present their study proposal. The study proposal will be sent to the ESA Research Secretariat. Late applications will not be accepted. 4. Selection Steps Evaluation and selection of proposals will be carried out by the ESA RC. The ESA RC is responsible for communication with successful applicants. One to two members of the RC are selected for in depth evaluation of the proposal (literature review, evaluation of methods, relevance of study endpoints, plausibility of study expected effects and power analysis). During the RC meeting, the proposals are discussed in depth by all members, after presentation of critical analysis by 2 pre-selected members. A decision is taken (agreement / rejection / postponed and need for further information). As deemed appropriate, one or more research projects will be recommended for grant. The ESA Board must ratify the grant and approve the final budget before the grant is awarded. After approval by the Board, the Chief Investigator of the successful proposal will be required to become an ESA member in order to receive the ESA CTN grant. 8. Related documents and checklists 8.1 GUI-CTN-001 Call for Centres Guidelines 8.2 GUI-CTN-002 Local Coordinator Role Guidelines 8.3 GUI-CTN-003 National Coordinator Role Guidelines 8.4 GUI-CTN-004 CTN Cost Reimbursement Guidelines 8.5 Call For Study Proposal Form 8.6 How to Fill in the Call For Study Proposal Form Page 7 of 7