Dorset Research Consortium. Research Governance: A handbook for Researchers in Dorset

Transcription

1 Dorset Research Consortium Research Governance: A handbook for Researchers in Dorset DRC Version 1 dated 25 th July 2012

2 Research Governance: The Basics... 4 What is Research Governance?... 4 The Research Governance Framework (RGF) Research Ethics Committee Approval... 5 What is Research Ethics Committee (REC) Approval?... 5 When do I need it?... 5 How do I know if my project is research?... 5 How do I apply?... 6 Proportionate Review... 7 How long does it take?... 7 R&D Approval (NHS Permission)... 8 When do I need it?... 8 How do I apply?... 9 What does the process involve?... 9 How long does it take? Dorset Research Consortium (main contact point following submission) Dorset County Hospital R&D Office Poole Hospital R&D Office Royal Bournemouth & Christchurch Hospitals R&D Office Research involving NHS staff Do I need REC approval? Do I need R&D Approval? Do I need to complete an R&D Form in IRAS? Sponsorship, Peer Review & Insurance What is a Sponsor? Who may act as a Sponsor? Will my Trust sponsor my research? What are the Sponsor s responsibilities? Can the sponsor delegate its responsibilities? Peer Review Insurance & Indemnity Other Approvals MHRA Clinical Trial Authorisation MHRA Declaration of No Objection Administration of Radioactive Substances Advisory Committee (ARSAC) Certificate

3 Ionising Radiation (Medical Exposure) Regulations 2000 (IRMER) Approval Human Tissue Authority (HTA) License ICH GCP What is ICH GCP? Why is ICH GCP important? Do I need ICH GCP training? How do I get ICH GCP Trained? NIHR Portfolio What is the NIHR portfolio? What are the NIHR portfolio eligibility criteria? How do I apply? What if my project is not adopted? Conducting your Research When can I start my Research? When do I need to get in touch with R&D? Amendments What are amendments? What are substantial amendments? What are non-substantial amendments? How do I make a substantial amendment? Why does the R&D office need to look at amendments? How long does review and approval take? Annual Progress Reporting What is Annual Progress Reporting? When are Annual Progress Reports required? How do I submit an Annual Progress Report? Can I continue with my research? Annual Safety Reporting What is safety reporting? How are events classified? What do I need to do? What else do I need to consider? Audit & Monitoring What is meant by auditing and monitoring? Monitoring

4 Auditing What triggers a Monitoring or Auditing Visit? Standard Operating Procedures Complaints Handling Reporting Recruitment Data Study Completion When is a project complete? What should I do when my project has completed? What should I do when my project has not completed on time? Research Governance Tips The R&D / DRC staff Royal Bournemouth & Christchurch Hospitals: Dorset County Hospital: Poole Hospital: The role of the Dorset Research Consortium Standard Operating Procedures Useful Links & Resources

5 1 Research Governance: The Basics What is Research Governance? Research Governance may loosely be defined as a range of regulations, principles and standards which exist to achieve and improve research quality across all aspects of health and social care. Research Governance aims to: Safeguard research participants Enhance ethical and scientific quality Protect researchers Monitor performance Minimise risk Promote good practice The Research Governance Framework (RGF) 1 The Research Governance Framework for Health and Social Care (RGF) is a Department of Health document which sets out the broad principles of good research governance. It ensures that health and social care research in England is conducted to the highest standards. The RGF acts as a key text, underpinning the conduct of research in the NHS; it is implemented and enforced by the Trust s Research and Development office (R&D office). The aim of the RGF is not to provide a single document that addresses all legislation, standards and good practice guidelines but to promote a quality research culture where excellence is promoted and where there is visible and strong research leadership and expert management. The RGF applies to all research, both clinical and non clinical, that is concerned with the protection and promotion of public health and which is to be undertaken in an organisation falling within the remit of the Secretary of State (NHS Trusts and Primary Care, for example). It also applies to research undertaken by industry (pharmaceutical companies), charities, research councils and universities that might have an impact on the quality of health and social care service. 1 Research Governance Framework for Health and Social Care: Second Edition, /DH_

6 2 Research Ethics Committee Approval What is Research Ethics Committee (REC) Approval? The Declaration of Helsinki (World Medical Association, as amended 2008), sets out the ethical principles for medical research involving human subjects including research on identifiable human material and data. It is perhaps the most important document in the history of research ethics. The role of Research Ethics Committees (RECs) is to safeguard the rights, safety, dignity and wellbeing of research participants by ensuring that research proposals have been designed and will be conducted in accordance with the Declaration of Helsinki. If they are satisfied that this is the case, they will offer a favourable opinion for the research (often referred to as REC approval ). RECs are entirely independent of NHS Trusts and investigators. When do I need it? As a general rule of thumb, all research taking place within the NHS re quires REC approval. REC review is not normally required for research involving NHS or social care staff recruited as research participants by virtue of their professional role. However, Research & Development (R&D) approval (NHS permission) is still required. Further information is available in section 4, below. How do I know if my project is research? Not all projects undertaken within the NHS are research. The term research has a specific meaning in the RGF and if a proposal does not fall within this definition it will not require review by a REC or approval by an NHS Research & Development (R&D) office. Activities which do not fall within the definition of research include: Clinical Audit Case Studies or Case Reports Service Evaluation Consensus Methods Patient & Staff Surveys 5

7 Applications for REC review may also be made on a voluntary basis for research tissue banks/ biobanks and research databases. The National Research Ethics Service (NRES) website has some useful guidance on categorising research proposals: If having considered the guidance you are still unsure whether your project is classified as research, the R&D office at your Trust should be able to help. If the R&D office is uncertain, then a summary of the research can be sent to the chair of a REC for review. How do I apply? Applications for REC approval and for other approvals necessary for a project (see below), can be made online via the Integrated Research Application System (IRAS), which can be accessed at: This system streamlines the process for seeking relevant approvals by ensuring that, as far as possible, details only need to be entered once for a single project and much of the form is then self-populated. Once you are ready to submit the forms in IRAS (i.e. the forms are ready to be signed by various parties and all supporting documentation outlined in the IRAS online checklist has been prepared), there are a number of methods for booking an appointment with a REC for review. It is highly recommended that you arrange a time when you can attend, to answer any queries the REC may have. When the booking process is completed, you will be given the name of the REC, a REC reference number and a submission date. The application should be submitted to the REC within 4 working days of making the booking. At the meeting of the REC, between 7 and 18 members will be present and will ask questions surrounding any ethical issues arising from your application. You should be prepared to clarify any ethical issues that may be raised. 6

8 Proportionate Review The aim of proportionate review is for studies which present minimal risk or burden for participants to be reviewed by a proportionate review REC sub-committee within 14 days of receipt of a valid application. If your research presents no material ethical issues, you may request that it be considered for ethical review under the proportionate review process. This option is available on the IRAS project filter. To check if your study is eligible for proportionate review, please visit: How long does it take? A REC is required to give an ethical opinion on an application within 60 calendar days from receipt of a valid application. Where further information is required to give an opinion, the REC may make a request in writing for further information. The clock will be suspended pending receipt of this information. A REC will typically issue an opinion within 10 working days after the meeting. 7

9 3 R&D Approval (NHS Permission) R&D Approval relates to the process of reviewing and checking applications for research to take place within an NHS organisation, prior to giving written permission. More recently, it is also frequently referred to as NHS Permission or Trust Approval. In most NHS organisations, an R&D office is responsible for carrying out these checks before permission is given by the research director or a delegated senior person. Across Dorset, the R&D departments are called the Research & Development (R&D) offices. When do I need it? Approval will be required from the R&D departments for each NHS organisation involved in the research, if the research proposal is to involve any one or more of the following: Patients and service users of the NHS; Individuals identified as potential participants because they are relatives or carers of NHS patients and services users; Patient data, organs and other bodily materials of past or present NHS patients; Foetal material and IVF involving NHS patients; Use of or potential access to NHS premises or facilities; and/or NHS Staff (whether as participants or research personnel) As a general rule, R&D approval will always be required if REC approval is required (see above). There may also be occasions where R&D approval is required when REC approval is not required (e.g. laboratory research on NHS premises, and studies interviewing NHS employees). 8

10 How do I apply? You can complete an application for R&D approval via the Integrated Research Application System (IRAS) which can be found at: This should be accompanied by a Site Specific Information (SSI) form outlining the various activities to be carried out at the Trust. Separate SSI forms can be generated for each organisation where the research will take place. A signed copy of the SSI form should be submitted to the relevant R&D office for your Trust. Electronic versions of the R&D form and SSI form generated within IRAS will then need to be submitted to the Dorset Research Consortium (DRC) with a number of other documents, depending on the nature of the project. Checklists for these documents can be found at: More guidance on the R&D submission process can be found on the Dorset Research website: What does the process involve? The RGF requires NHS organisations to ensure that before any research involving human participants, their organs, tissue or data commences: there are adequate arrangements and resources (finance, staff and facilities capacity) to meet the standards set out in the RGF through to project completion; an identified sponsor has taken on responsibility for the project; the project has received ethical approval (where required); there is a Clinical Trial Authorisation (CTA) in place for a clinical trial of a medicine; a Declaration of No Objection has been received for a clinical investigation of a medical device; other regulatory approvals are in place depending on the nature of the research; the allocation of responsibilities is agreed and documented; appropriate contractual arrangements are in place; and 9

11 legislation relating to the research is followed within the organisation. In order for the R&D office to confirm that adequate resources are in place, it may be necessary to arrange a short meeting or telephone call with the Principal Investigator or delegated member of the research team. Given the resources required to conduct a clinical trial of an Investigational Medicinal Product (CTIMP), a feasibility meeting may need to be arranged to discuss a variety of matters. How long does it take? The length of time taken to obtain R&D approval varies depending on each individual project, the other approvals necessary (see below), and the R&D offices at different NHS organisations. We recommend that your application to the DRC is submitted at the same time as applying for REC approval (see above). If you provide us with all the documents required (see as early as possible, and are available to answer any further queries we may have, then this will help reduce the approval time. The DRC and the individual R&D offices are committed to reducing approval times across all forms of research. For tips on how you can help us to achieve this, please see section 13 below. You can contact the DRC directly, or your local Trust R&D department, regarding the progress of your study s review. Contact details are below and all contact details are available on the DRC website: Dorset Research Consortium (main contact point following submission) dorsetresearchconsortium@nhs.net Dorset County Hospital R&D Office Tel: Poole Hospital R&D Office Tel: Royal Bournemouth & Christchurch Hospitals R&D Office Tel: research2@rbch.nhs.uk 10

12 4 Research involving NHS staff Do I need REC approval? REC review is not normally required for research involving NHS or social care staff recruited as research participants by virtue of their professional role. However, the Research Ethics Service may accept an application for review of research involving staff if the proposal raises material ethical issues. This can be requested by the sponsor, chief investigator or host organisation. It is important to remember that ethics approval is required if the research involves any other activity that falls within the requirements for ethical review. Information regarding activity requiring ethical review is available on the NRES Website. Do I need R&D Approval? Yes. The Research Governance Framework for Health and Social Care still applies, and the research will continue to require R&D approval from each site involved. The process for obtaining R&D approval for research involving NHS staff remains the same as for any other research project. Further information about the process for obtaining R&D approval is available in section 3, above. Do I need to complete an R&D Form in IRAS? As R&D approval is still required for research involving NHS staff, you still need to complete an application for R&D approval via the Integrated Research Application System (IRAS) which can be found at: Within IRAS, it is possible to indicate in the Filter that a research project requires review by NHS R&D only. This will generate the necessary R&D application forms. 11

13 5 Sponsorship, Peer Review & Insurance What is a Sponsor? A sponsor is an organisation (or group of organisations) that accepts responsibility for ensuring that there are proper arrangements to initiate, manage, monitor and finance a project. The RGF requires that all research taking place in an NHS or social care context must have sponsor. It is a criminal offence to undertake a CTIMP without a sponsor. Evidence of sponsorship will be required by the R&D office before approval can be given. Who may act as a Sponsor? Any organisation that is a legal entity and which funds, initiates, hosts or employs staff involved in research may act as sponsor. While there is no official rule against individuals acting as sponsors, the Trusts will not indemnify research in these circumstances owing to the risks and legal liabilities involved. The sponsor will usually be: The Chief Investigator s (CI) employing organisation; A University, for student research projects; The lead organisation providing health or social care to participants (e.g. NHS Trusts); or The primary funder. Will my Trust sponsor my research? The Trusts are registered with the Department of Health as willing and able to act as a sponsor under the RGF. This does not mean that your Trust will accept sponsorship for all research requiring a sponsor. 12

14 Your Trust will consider accepting sponsorship where: The CI holds a substantive or honorary employment contract with the Trust; The research will only be carried out within the UK; The research does not pose significant legal, financial or reputational risks; The protocol is well designed and is scientifically and statistically sound. At RBCH, a request for the Trust to act as sponsor can be made by ing a copy of the research protocol and all other available information to Dr Robert Chapman at: robert.chapman@rbch.nhs.uk including Sponsorship Request in the subject line. This request should be made before completing the application through IRAS. At DCHFT, applicants should contact Dr Christopher Miller to apply for sponsorship on Tel: Christopher.miller@dchft.nhs.uk. At PHFT, applicants should contact Sarah Chessell to apply for sponsorship on Tel: sarah.chessell@poole.nhs.uk What are the Sponsor s responsibilities? The sponsor s primary responsibility is to safeguard the rights, safety, dignity and wellbeing of research participants. This responsibility prevails over the interests of science. In doing so, the sponsor will accept responsibility for securing the necessary arrangements to conduct the research and will ensure that all the necessary authorisations have been obtained before commencing. The sponsor is also responsible for monitoring the research to ensure it is conducted in accordance with applicable legislation and the Good Clinical Practice (GCP) Guidelines (see below). Can the sponsor delegate its responsibilities? Yes. The responsibilities which have been delegated by the sponsor to the CI or Principal Investigator (PI) will usually be set 13

15 out in a delegation of responsibilities document. These responsibilities can further be delegated among members of the research team provided this is recorded in a delegation of responsibilities log. Peer Review Peer review is a system where a research proposal or protocol is scrutinised by independent experts to promote quality research and prevent poorly designed research from taking place. While the RGF places responsibility for assuring the quality of research through peer review to the funder, this will sometimes be undertaken by the sponsor (if they are not the same organisation). The R&D office may require confirmation of peer review and in certain circumstances an independent peer review will be carried out. Insurance & Indemnity A key responsibility of the sponsor is to put in place arrangements for compensating participants if they suffer any harm as a result of their involvement in a project. For research sponsored by the Trust, the NHS Indemnity Scheme applies and provides unlimited cover for NHS staff, medical academic staff with honorary contracts and those conducting research for negligent harm. Non negligent harm (i.e. harm that has been caused through no fault of those conducting research) is not covered by this scheme, however ex gratia payments may be considered by the Trust in limited circumstances. For research sponsored by commercial companies, the arrangements for indemnity are covered in the agreement that the DRC and R&D office negotiates with the company. 14

16 6 Other Approvals MHRA Clinical Trial Authorisation Clinical trials of Investigational Medicinal Products (CTIMPs) are subject to strict legal requirements which are enforced by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. Determining whether a research proposal should be classified as a CTIMP can be complex and may require review by the MHRA before an application is submitted through the IRAS system. MHRA Declaration of No Objection A Declaration of No Objection is required for clinical investigations (trials) of medical devices. This includes non CE marked devices, CE marked devices which have been modified or are being used outside their intended purpose(s), non CE marked devices developed in house or off label use. Administration of Radioactive Substances Advisory Committee (ARSAC) Certificate An ARSAC certificate is required for any clinician (at each research site) who wishes to use ionising radiation or administer radioactive medicinal products (e.g. for bone scans) to human subjects. This does not apply to routine x rays or CT scans. Ionising Radiation (Medical Exposure) Regulations 2000 (IRMER) Approval If the research involves (or might involve) ionising radiation (diagnostic x rays, CT scans, DEXA scans, radiotherapy, radionuclide imaging), the proposal will need to be reviewed by the Trust s Radiology General Manager who will sign off on any use. Human Tissue Authority (HTA) License The storage of human tissue (or relevant material ) for research purposes will require a licence from the HTA in certain circumstances. 15

17 7 ICH GCP What is ICH GCP? The Good Clinical Practice (GCP) guidelines developed by the International Conference on Harmonisation (ICH) provide an international ethical and scientific quality standard for the design, conduct, recording and reporting of research involving human subjects. While these guidelines primarily relate to the conduct of clinical trials of Investigational Medicinal Products (CTIMPs), they are equally relevant and applicable to the conduct of all research. Why is ICH GCP important? The primary aim of the guidelines is to safeguard the rights, safety, well being and dignity of all research subjects. However, research that is conducted to GCP standards will be regarded as reputable and will assist in publication and international recognition of the research in the research community. Do I need ICH GCP training? If you are a Chief (CI) or Principal Investigator (PI) or a member of a research team that will be conducting a CTIMP, then ICH GCP training is a legal requirement. It is the policy across Dorset that this training should be completed every 2 years and a copy of your certificate must be provided to the DRC before R&D approval can be given. It is Dorset-wide policy that all Chief and Principal Investigators undertake this training, whether conducting a CTIMP or not. How do I get ICH GCP Trained? There are two options available: 1. Contact your local R&D office to obtain an online user account and activation code 2. If you are due to take part an NIHR Portfolio adopted project, you will be eligible to book a free place on the UKCRN ICH GCP training events. Details of these events are available through the DRC website. 16

18 8 NIHR Portfolio What is the NIHR portfolio? The National Institute for Health Research (NIHR) Portfolio is a national database of research, used to manage the allocation of service support funding to NHS organisations and supports the performance management of the NIHR Clinical Research Networks. A project which is included on the Portfolio is said to have been adopted. What are the NIHR portfolio eligibility criteria? Projects involving the NHS and which are funded by the Department of Health, other Government departments and non commercial NIHR Partners, are automatically eligible to be included in the Portfolio. NIHR Partners include those organisations that: Award research funds as a result of open competition and high quality peer review; Fund research that is of clear value to the NHS; and Have strategic direction for the research that they fund. Commercially sponsored projects, or those funded by industry which are led by an investigator (investigator led projects), may also be included on the Portfolio by undergoing the adoption process. How do I apply? The simplest method of applying is through the IRAS system when completing the various research applications. Question 5(a) of the Project Filter questions asks Do you want your application to be processed through the NIHR Coordinated System for gaining NHS Permission? By choosing YES to this question, you will be required to complete a short application form that will be sent electronically to you once your application has been submitted. What if my project is not adopted? Not all projects undertaken at the Trust will be eligible for adoption onto the NIHR portfolio. If your project is not adopted the main difference is that it means that ALL costs (research costs and service support costs) must be covered by the project grant or by your directorate. 17

19 9 Conducting your Research When can I start my Research? Once the various approvals required for any project have been received and NHS R&D Approval has been granted, the research can proceed. It is a condition of any Research Ethics favourable opinion that NHS Management Approval is given for each NHS organisation participating in the research before commencing. For CTIMP projects a site initiation visit may be arranged to ensure that everything is in place and appropriately set up. When do I need to get in touch with R&D? It is important that you make contact with the R&D office in the following circumstances: Where approval is being sought for a substantial or non substantial amendment (see below); Where a research participant(s) suffers a Serious Adverse Event (SAE) or Suspected Unexpected Serious Adverse Reaction (SUSAR) (see below); Where the research has been suspended or terminated by the Sponsor or the authorities; Where a research participant dies in the course of a research project; Where there are concerns regarding research misconduct, a breach of GCP, or a breach of confidentiality or data protection laws; If you are having difficulties with patient recruitment; Submitting trial accruals information; Providing annual or periodic progress or safety reports to the R&D office, a REC or regulatory authority; When a project has closed to recruitment; When a project has completed (see section 15 for further information). You may also contact the R&D office if you have any queries or concerns or there is any information about your research that you think we would like to know about. 18

20 10 Amendments What are amendments? Amendments are changes made to research after a REC favourable opinion has been granted or, in the case of a CTIMP, MHRA Clinical Trial Authorisation has been granted. They can be substantial or non substantial. What are substantial amendments? Substantial amendments are defined as Amendments to the original REC application or to the protocol or any other supporting documentation that is likely to affect to a significant degree: The safety or physical or mental integrity of the subjects of the research; The scientific value of the research; The conduct or management of the research; The quality or safety of any Investigational Medicinal Product used in a trial. Examples of substantial amendments include (but are not limited to) changes to the design or methodology of a project, changes to procedures undertaken by participants or researchers, significant changes to patient documentation (information sheets, consent forms, letters to GPs etc.), addition of a new site(s) or appointment of a new Chief Investigator. A change of Principal Investigator will be a substantial amendment in the case of CTIMPs or where a site specific assessment (SSA) was requested by the REC which granted approval. The R&D office will need to grant approval for a change of Principal Investigator at the Trust. What are non-substantial amendments? Non substantial amendments are amendments that are unlikely to affect any of the above criteria. They do not need to be notified to the REC, but may be of interest to R&D departments. Examples of non substantial amendments include (but are not limited to) minor changes to protocol (contacts, errors, clarifications), changes to the research team other than the 19

21 Chief or Principal Investigator (as discussed above), changes in funding, changes in documentation used by the research team or extension to the duration of the project beyond the period specified in the application form. While extensions to the duration of the research project are regarded as non substantial, they must be notified to the R&D office in all circumstances. How do I make a substantial amendment? For local (in-house) studies, all amendments (substantial or minor) should be submitted to the R&D office. All substantial amendments need to be submitted to the REC that approved the project. Substantial amendments to CTIMPs must also be submitted to the MHRA. Regardless of whether the project is a CTIMP or non CTIMP, the same Notification of Substantial Amendment Form should be used. You should summarise the change(s) in the amendment and submit any documents that have been modified, showing both the previous and new wording. For studies where the Trust is a participating site only, forward a copy of the amended documents, REC correspondence & approval (and MHRA where applicable) sent by the lead site/ sponsor s representative to the R&D office for review. Why does the R&D office need to look at amendments? The R&D office needs to check if there are any significant implications of amendments to the Trust or its patients particularly financial and resources implications. This will be the case regardless of whether or not the Trust is sponsoring the research. NOTE: You must not implement any amendment without notifying the R&D office, unless urgent safety measures have been taken. 20

22 How long does review and approval take? The REC coordinator will confirm receipt of a valid notification within 5 days. Amendments are normally reviewed by a REC sub committee and an opinion issued within a maximum of 35 days from the date of receipt of a valid notice of amendment. If an unfavourable opinion is given, a modified amendment can be submitted and an opinion is usually issued within 14 days. The R&D office will usually review amendments once they are received, but will not be able to provide on-going approval for the research until a favourable opinion has been received from REC and/or the MHRA in the case of a CTIMP. Where there are financial implications associated with the amendment, it may be necessary to amend the clinical trial agreement to reflect this. The R&D office will notify you if this is the case. 21

23 11 Annual Progress Reporting What is Annual Progress Reporting? When are Annual Progress Reports required? Research Ethics Committees (RECs) are required to monitor research that has received a favourable opinion. Therefore, researchers must submit Annual Progress Reports in order to inform REC of the progress of the research. The information required in an Annual Progress Report relates to research conduct, recruitment, amendments, and safety. A Progress Report should be submitted to the REC which gave the favourable opinion (approval) 12 months after the date on which the favourable opinion was given. Annual Progress Reports should be submitted thereafter until the end of the study. How do I submit an Annual Progress Report? It is the responsibility of the Chief Investigator to complete and submit Annual Progress Reports for their research project. Annual Progress Report Forms are available on the NRES website at: There are separate forms for submitting Annual Progress Reports, depending on the type of research: Annual Progress Report Form for Clinical Trials of an Investigational Medicinal Product (CTIMP). Annual Progress Report Form for All other research. A paper copy of the Annual Report Form should be sent to the main REC, and a copy sent to the R&D office. The REC office will acknowledge receipt of the Annual Progress Report, and it will be reviewed. If necessary, the Chief Investigator may be invited to attend a meeting of the main REC or a sub committee to discuss the progress of the research. 22

24 In cases where the Trust is a participating site only, copies of annual progress reports sent to the REC should be requested from the coordinating centre. Can I continue with my research? The main REC does not need to re confirm its favourable ethical opinion each time an Annual Progress Report is received. It is generally assumed that the opinion applies for the duration of the research, although the REC may review its opinion at any time. 23

25 12 Annual Safety Reporting What is safety reporting? Safety reporting involves relaying to the appropriate bodies within the required timescales, the occurrence of any harm, suffering or death by a research participant in the course of research. This will permit an assessment of the safety of the research so that measures may be put in place to prevent it happening again. In the most severe cases, the research may be suspended or even terminated. Safety reporting is vital for all research projects; however there are strict legal requirements to be satisfied in the case of CTIMPs. How are events classified? There are four main levels of events: Adverse Events (AEs) & Adverse Reactions (ARs) are any unfavourable and unintended signs, including abnormal laboratory results, symptoms or a disease associated with treatment. These must always be recorded in a Case Report Form (CRF) or on the patient s medical notes. Serious Adverse Events (SAEs) & Serious Adverse Reactions (SARs) are defined as any untoward medical occurrence(s) that at any dose results in death, hospitalisation or prolongation of existing hospitalisation, persistent or significant disability/incapacity or a congenital anomaly or birth defect. These events must be reported immediately to the sponsor. Suspected Serious Adverse Reactions (SSARs) are any ARs considered consistent with information available about an Investigational Medicinal Product (IMP). They must be reviewed at regular intervals to see if the profile of any IMP has changed and a record made of this. Suspected Unexpected Serious Adverse Reactions (SUSARs) are any events suspected to be caused by an IMP, but which are not consistent with information about the IMP. These are the most serious of events and are subject to expedited reporting procedures. 24

26 What do I need to do? The process for safety reporting varies depending on whether or not the research is a CTIMP and on the procedures of the Sponsor of the research. However the general process below should be followed in all research: 1. RECORD The event should be reported in the subject s medical records, and on the Case Report Form (CRF) or on a Safety Reporting form provided by the Sponsor. 2. ASSESS An assessment should be undertaken by the Chief or Principal Investigator to evaluate seriousness, causality, intensity and expectedness. 3. REPORT Based on the conclusion from step 2, the event should be reported in the form and within the timescales required. What else do I need to consider? There are a number of issues to consider at each stage and the timescales depend on the nature of the event for example a fatal Suspected Unexpected Serious Adverse Reactions (SUSAR) must be reported immediately to the Sponsor (within 24 hours), followed up in writing within 48 hours, and reported to the MHRA and REC no later than 7 days after the Sponsor becomes aware of the reaction. The procedure is much more straightforward for non CTIMPs, including clinical investigations of medical devices. Please refer to SOP ref: RES/009 Adverse Event, Serious Adverse Event and Suspected Unexpected Serious Adverse Reactions Reporting for the detailed procedures. In addition to safety reporting, progress reports are required to be sent to the REC which gave the favourable opinion for the project every 12 months after the date on which the opinion was given. These must be forwarded to the R&D office for information also. 25

27 13 Audit & Monitoring What is meant by auditing and monitoring? Research conducted within the NHS is subject to scrutiny to ensure that it is being conducted, recorded and reported according to the protocol, standard operating procedures (SOPs), ICH GCP and the applicable regulatory requirements. Monitoring Monitoring is a quality control procedure undertaken by a representative of the Sponsor which will sometimes be the Trust. The purpose of monitoring is to verify that the rights, safety and well being of participants are being protected and that the trial data are accurate, complete and verifiable. The monitor will also look to see if the trial is being conducted in compliance with the approved protocol, with GCP and the applicable regulatory requirements. The monitor may also visit pharmacy, for CTIMPs, to review the pharmacy site file and accountability logs. Auditing Auditing is a quality assurance procedure undertaken by a representative of the Sponsor which is independent of and separate from routine monitoring. The purpose is to evaluate trial conduct and compliance with the protocol, SOPs, GCP and applicable regulatory requirements. Following an audit or monitoring visit, a follow up letter will be sent to the PI and project team explaining the findings, whether they are major, moderate or minor, and make recommendations about how to overcome any negative findings. What triggers a Monitoring or Auditing Visit? It is DRC policy to monitor 100% of all CTIMPs and Device investigations for which a Trust is the sponsor, at least annually. A percentage of other projects for which the Trust acts as sponsor will also be monitored. As a host organisation, we aim to audit 20% of CTIMPs and Device investigations for which a Trust within the DRC is not the Sponsor. In addition the DRC will monitor any 26

28 trust sponsored project which reports a SUSAR, and audit any commercial project withdrawn prematurely for reasons other than safety, unless recently monitored by the Sponsor. Audit and monitoring visits may take place at any time, although adequate notice will be given. It is important that the project documentation is well maintained and accessible at all times. In the case of projects that are externally sponsored, the follow up letters for any audit and monitoring visits must be forwarded to the R&D office for information. The regulatory authorities may also conduct an official review (inspection) at any time. If you are advised of an inspection taking place for your research, you must inform the R&D office. Similarly, the R&D office will notify you in advance of any inspection in which your project will be assessed. Standard Operating Procedures Detailed guidance on every aspect in this Handbook is available in a comprehensive set of SOPs. The SOPs are available on the QPULSE document management system (please contact your local R&D team to arrange training and access), and upon request via . It is recommended that the SOPs relating to a particular project are retained in hard copy on the Trial Master File or Project File for reference. Complaints Handling Given the consensual nature of research, there must be a way for patients to make complaints, whether in relation to the conduct of the research on the whole, or their individual experience. Similarly, research staff might also want to make a complaint if they feel that there is no other option available to them. Where the participant is making the complaint, the Trust s Complaints Procedure must be followed. If a member of staff has any concerns or complaints, they should feel able to discuss this with the Principal Investigator. However if they are not happy to do this, the R&D office are able to help and will escalate matters confidentially. 27

29 14 Reporting Recruitment Data Reporting recruitment data relates to the number of participants enrolled/consented onto any research project. This information is recorded for two separate reasons: 1. For safety monitoring purposes it is necessary for Trusts to be aware of how many patients are taking part in different types of projects; 2. Projects adopted onto the NIHR portfolio generate income for the Trust to help us support research. The amount of income is based on a formula which is number of patients recruited x the average cost of that type of project. Accurate data is required to ensure sufficient income can be obtained from the NIHR Comprehensive Local Research Network (CLRN) to support that research. Recruitment data for all projects should be ed to your hospital s R&D office monthly. 28

30 15 Study Completion When is a project complete? The completion of a project should be defined in the protocol. In most cases, completion will be the date of the last patient s last visit (LPLV) or the completion of any patient follow up and data collection. In CTIMPs, it is important to note that closing to recruitment is not the same as completion. What should I do when my project has completed? 1. Communicate completion to relevant bodies and authorities For all projects, a Declaration of End of Study form must be completed and sent to the REC that granted a favourable ethical opinion for the project. This form can be found online: For CTIMPs, a Declaration of End of Trial form must be completed and sent to the MHRA: The R&D office should be forwarded a copy of these notifications in all cases. 2. Final analysis of data and locking of the project database (if applicable) 3. Complete all financial obligations Any outstanding invoices payable or to be raised should be dealt with and arrangements in place for providing medications or treatment to participants after completion (if agreed). 4. Writing of final project reports, dissemination and publication of findings 5. Archiving of documentation What should I do when my project has not completed on time? Occasionally projects do not finish recruiting or following up patients within the time specified in the REC approved protocol. An extension to the study end date is considered by NRES and the MHRA (for CTIMPs) to be a non substantial amendment. While formal approval is not needed from the REC, the MHRA require notification (in no prescribed form) for CTIMPs and it is good practice to write to the REC for information purposes only. In all cases, you must inform the R&D office of this change. 29

31 16 Research Governance Tips Inform us immediately if you have been contacted directly to undertake any research Be sure to include the REC reference number on all correspondence with the R&D office Feel free to phone the DRC office if you have not received a confirmation that your application is being processed, or you want to check on the progress of your application Allow 5 working days from submitting your application before following up on progress If you are asked for further information or documents, provide these as soon as possible For large projects, it is preferable to provide a single point of contact The R&D office operates a paperless system and all documents other than wet signed CV s, SSI Forms and R&D forms must be submitted electronically Submit your application to a REC at the same time as submitting your application to us Where attachments are too big to send by , please forward on a CD/DVD When ing your R&D and SSI Forms in IRAS, do so in both PDF and XML formats this will help us to process your application more efficiently (guidance on retrieving these is available at: Throughout the process and after approval, it is recommended that all versions of project documentation are saved, including track changes Always communicate to the R&D office anything that may be of interest (i.e. competitive recruitment, patients waiting for treatment, excess treatment costs) Providing a valid submission in the first instance will help us to process and review your application more efficiently (guidance on valid submissions is available at: 30

32 16 The R&D / DRC staff Royal Bournemouth & Christchurch Hospitals: Dr Robert Chapman Head of Research (RBCH) Mat Davis IT Specialist (RBCH & DRC) Caroline Jamieson-Leadbitter Research Governance Manager (RBCH) Finance Negotiator & Lead on applications for the DRC Chair of the DRC Laura Purandare Research Monitor (RBCH) Research Governance Facilitator for the DRC Dorset County Hospital: Dr Christopher Miller Research Coordinator (DHFT) Contracts Manager for the DRC Rosemary Reader Research Management & Governance administrator (DHFT) CSP lead for the DRC Poole Hospital: Sarah Chessell Clinical Audit & Research and Development Manager (PHFT) Rhona German Research Governance Administrator Jayne Smith Research Governance Facilitator (PHFT) Applications Facilitator for the DRC Margaret Younger Senior Project Manager (PHFT & DRC) The role of the Dorset Research Consortium The function of the DRC is to provide a single process for registration, approval and maintenance of research trials within Dorset, including set up, approvals, monitoring, auditing and archiving. We operate as a single research management and governance team responsible for Trust wide compliance with regulatory requirements such as the Research Governance Framework, Medicines for Human Use, Standards for Better Health, GCP & EU Directive and MHRA. We are continually developing Consortium strategy in line with stakeholders' requirements. 31

33 17 Standard Operating Procedures Standard Operating Procedures (SOPs) provide detailed guidance on all aspects of study management from design through to completion. This guidance is relevant for all Chief and Principal Investigators, Research Nurses and other research personnel. A comprehensive set of SOPs for the conduct of research in Dorset is available via the QPULSE document management system (please contact your Trust s R&D team to arrange training and access). Please contact the DRC (dorsetresearchconsotium@nhs.net) or your R&D department for further information. Below is a list of the current approved SOPs for conducting research in Dorset: Reference RES/001 RES/002 RES/003 RES/004 RES/005 RES/006 RES/007 RES/008 RES/009 RES/010 RES/011 RES/012 RES/013 RES/014 RES/015 RES/016 RES/017 RES/018 RES/020 RES/021 RES/022 SOP Title Preparation, Review, Approval and Issue of Standard Operating Procedures and other documents Study Team Definition of Responsibilities Data Protection Study Files and Filing Archiving Monitoring Visits Case Report Form (CRF) Completion Informed Consent Adverse Event, Serious Adverse Event and Suspected Unexpected Serious Adverse Reactions Reporting Blinding: Codes and Code Breaking Randomisation and Stratification Gaining approvals to start studies Review and validation of the protocol Estimation of Patient Numbers, Patient Recruitment and Intention to Enrol Pre study Monitoring visits Performing and Documenting Training for Research Staff Recording & Reporting of Deviations, Violations, Potential Serious Breaches, Serious Breaches and Urgent Safety Measures Research Protocol Amendments Investigators Brochure The conduct of GCP monitoring visits (internal audit) The handling of dry ice You will be automatically notified by when a new SOP is added, or changes are made to an existing SOP by Q-PULSE. 32

34 18 Useful Links & Resources Dorset Research Consortium website Clinical Trials Research Toolkit toolkit.ac.uk Data & Tissues Research Toolkit toolkit.ac.uk Experimental Medicine Research Toolkit toolkit.ac.uk Human Tissue Authority Integrated Research Application System (IRAS) MHRA Clinical Trials Homepage ex.htm MHRA Medical Devices Homepage NIHR Learning Management System NRES Applications Guidance NRES After Ethical Review Guidance 33