Title: Outcome Statement: Research Auditing and Monitoring Procedures Researchers in the Trust and research partners will be informed about the requirements and procedures involved in research audit and monitoring of approved research studies. Bonnie Teague, Research Manager Written By: Reviewed By: In Consultation With: Research Quality Lead, Research Audit Team Approved By and Date: V1.0 Research Governance Committee, 27 th September 2012 V2.0 Research Governance Committee, 26 th September 2013 V3.0 Research Committee, 27 th April 2017 References and Bibliography Associated Trust Policies and Documents: Applicable To: For Use By: Reference Number: Research Governance Framework 2 nd Edition, 2005. Medicine for Human Use (Clinical Trial) Regulations 2004 R&D005 Conducting Clinical Trials of Investigational Medicinal Products R&D008: Trial Management: Trial Master Files and Site-Specific Files R&D003: Research Integrity, Fraud and Misconduct All research staff involved in approved Trust research studies Research team members, Pharmacy, R&D, Sponsors, Auditors. R&D009 Version: 3.0 Published 1 st May 2017 Date: Review Date: April 2021 Equality Completed 27 th April 2017 Assessment: Implementation and Monitoring Routine distribution procedures (publication on the Trust intranet, email notification to identified researchers for distribution throughout the team plus distribution during Research training programme. Monitored through annual review of research auditing procedures by the research quality lead. Page 1 of 15
Review and Amendment Log Version Reasons for Development/Review Date Description of Change(s) V1.0 To ensure that research and clinical teams are aware of auditing requirements and procedures to be followed when a sponsor, R&D or regulatory authority audit is to be undertaken as required by the Research Governance Framework 2 nd Edition 2005 V2.0 Improve oversight of all research studies by introducing self-audit report options and 1 month monitoring visit. 27 th September 2012 26 th September 2013 N/A 1) Addition of self-audit report requirements. Addition of self-audit report template as Appendix 1. 2) Addition of initial monitoring visit within 1 month of approval of study. Addition of Monitoring report template as Appendix 5. 3) Addition of audit procedures required for study closedown/termination, to correlate with R&D013. Additional minor clarifications of language and meaning throughout the policy V3.0 Change 1 month monitoring visit delivery and remove appendices for use, to become advisory. 27 th April 2017 1) Changes to 1 month monitoring audit delivery. Removal of report appendices (Appendix 1,2,4,5), as to be used within guidance frameworks rather than policy. Page 2 of 15
1.0 Introduction A research audit is a systematic and independent examination of trial related activities and documentation, to determine that the research study is being conducted in accordance with the approved study protocol, sponsor s SOPs, regulatory requirements and Good Clinical Practice. Audits and Inspections performed by sponsor organisations or regulatory authorities have three primary functions: To assure participants rights, well-being and safety To assure integrity of clinical and research data To allow sound decision making regarding efficacy and safety of investigational product(s) or procedures The above functions are assessed through thorough checking of study and clinical documentation to ensure compliance with GCP guidelines and regulations, and ensure that monitoring responsibilities have been undertaken to a satisfactory level. A check is also made to ensure that data received by regulatory authorities can be verified/evidenced through source data at each site. 2.0 Purpose This document sets out the Trust systems to implement the aspects of the Research Governance Framework that deal with approval, monitoring and auditing of research within the Trust. These systems are designed to help minimise the risk of poor quality research, adverse incidents, research misconduct and fraud. 3.0 Definitions Clinical Trial of an Investigational Medicinal Product (CTIMP) A Clinical Trial of an Investigational Medicinal Product (CTIMP) is defined in the Medicines for Human Use (Clinical Trial) Regulations 2004 as any investigation in human subjects, other than a non interventional trial intended: To discover or verify the clinical, pharmacological or other pharmocodynamic effects of one or more medicinal products To identify one or more adverse effects of these medicinal products To study absorption, excretion or distribution of medicinal products with a view of ascertaining the safety or efficacy of such products. From May 2004, when the Trial Regulations came into force, CTIMPs have been regulated by the Medicines and Healthcare Products Regulatory Agency (MHRA) who needs to give explicit authorisation for a CTIMP to be conducted in addition to the standard approvals required for clinical studies. This is termed Clinical Trial Authorisation or CTA. EudraCT (European Union Drug Regulating Authorities Clinical Trials) is the European Clinical Trials Database of all clinical trials commencing in the European Union from 1 May 2004 onwards. The EudraCT database has been established in accordance with Directive 2001/20/EC. Each clinical trial with at least one site in the European Union receives a unique number for identification, the EudraCT Number. The EudraCT Number must be included on all Clinical Trial applications within the European Community and as needed on other documents relating to the trials (e.g. SUSAR reports). Page 3 of 15
GCP: Good Clinical Practice. Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subjects. [Definition from EU Directive 2001/20/EC, article 1, clause 2] Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible and accurate. Investigational Medicinal Product (IMP) A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form. [EU 2011/C 172/01] MHRA: Medicines and Healthcare Products Regulatory Authority. The MHRA's Good Clinical Practice (GCP) Inspectorate is part of the Inspection, Standards and Enforcement Division of the MHRA. The function of the GCP Inspectorate is to assess the compliance of organisations with UK and EU legislation relating to the conduct of clinical trials in investigational medicinal products. This is achieved through carrying out inspections of sponsor organisations that hold clinical trial authorisations (CTA) or organisations that provide services to clinical trial sponsors (host organisations). Trial Manager: A representative of the main research team (within the sponsor organisation or contracted partner) who has received delegated management duties from the Chief Investigator for the conduct of the trial across all research sites. Research Integrity Officer: The Research Integrity Officer has defined responsibility for instigation of an inquiry and investigation into research practices in the Trust. They, or their nominated delegate, are responsible for the investigation of any allegations of research fraud or misconduct in line with the Trust s policy on Research Integrity, Fraud and Misconduct. 4.0 Duties Sponsor: The organisation with overall responsibility for the conduct of the clinical trial. The sponsor will arrange for indemnity, regulatory and R&D approvals to be in place by the start of the study, will set-up and provide full trial documentation and study training to local research teams, will ensure that appropriate emergency reporting procedures are in place, will provide study medication to be sent to local Pharmacy sites where required, will perform comprehensive monitoring and audit functions throughout the study by arrangement with local teams. CI Chief Investigator: The lead researcher with responsibility for the conduct of the clinical trial across all research sites, including but not limited to the following areas. 1. Qualifications and agreements (Good Clinical Practice (GCP) Training, delegation of trial-related duties) 2. Adequate Resources to conduct the overall study time, funding, demonstrate ability to recruit (via pilot etc) 3. Medical care of trial subjects: A qualified clinician, who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical decisions 4. On-going communication with Ethics/MHRA/R&D throughout trial (amendments, annual reports etc) 5. Ensure full compliance with protocol and document deviations and submit amendments to Ethics and R&D. Page 4 of 15
6. Investigational Product (if applicable) - responsible for IMP accountability at site/s (can be assigned to appropriate pharmacist) Investigational devices are also the responsibility of the CI. 7. Randomization Procedures and Unblinding responsible for following trial s randomization and blinding/unblinding procedures (if applicable) 8. Informed consent responsible for following GCP guidelines on informed consent 9. Records and Reports follow GCP guidelines on Case Report Forms and source documentation, maintenance of trial documentation such as the Trial Master File, financial agreements and archiving 10. Progress Reports provide written summaries to Ethics (annually or more frequently if requested) and sponsor and Ethics and R&D regarding substantial changes to trial 11. Safety Reporting: Responsible for ensuring all Serious Adverse Events (SAEs) are reported to sponsor and approving and regulatory committees as required, and suitable guidance is in place for recording of adverse events. 12. Premature Termination or Suspension of Trial Responsible for ensuring trial subjects, institution sponsor, Ethics and R&D are promptly informed if trial ends prematurely or is suspended 13. Final Report and End of Study Notification ensure that final report provided to institution, Ethics and R&D, regulatory authorities and sponsor The CI will be responsible for the integrity of the study protocol and publications resulting from the study PI: The lead researcher with delegated responsibility for the conduct of the clinical trial aligned with the responsibilities of the chief investigator (listed above) across the local site only. The PI will report any adverse events or serious adverse events to the sponsor/ci, will be responsible for the set-up and conduct of the study at the local site and ensure that all trial documentation (such as set-up of sitespecific files) and appropriate training has been received and passed onto the study team. Duties will include set-up and maintenance of trial documentation, patient identification and recruitment, patient follow-up, arrangement and collection of prescribed study medication from Pharmacy and ensuring that the study is being conducted to study protocol, trust policy and GCP standards Local Research Team: The local research team, as named on approval documentation, have delegated duties from the CI and PI to conduct the clinical trial at the local site. Duties will include set-up and maintenance of trial documentation, patient identification and recruitment, patient follow-up, arrangement and collection of prescribed study medication from Pharmacy and ensuring that the study is being conducted to study protocol, trust policy and GCP standards. Pharmacy: To ensure that drug prescribing for clinical trials is performed in a way which is consistent with study protocol GCP regulations, legislation and trust policies, and that full records are maintained and kept accurate by the Trial Pharmacist. R&D/Research Office: To conduct thorough research governance checks of a study prior to commencement in the Trust, and ensure that the trial is being conducted to be compliant to approved protocol, GCP and Trust policies, and undertake local research audits of clinical trials where appropriate. The host NHS organisation is required to have procedures in place for conducting the trial in accordance with Good Clinical Practice and the Clinical Trials Regulations, including: Adequate training for all site staff and adequate training records covering research and studyspecific training; Ensuring clarity of roles and responsibilities (e.g. contracts and agreement, delegation log) Appropriate knowledge of the trial and quality systems in all peripheral departments (e.g. laboratories, radiology, medical records); Ensure systems and facilities are fit for purpose (e.g. computer systems, equipment) Conducting the trial in accordance with the protocol, including: informed consent; reporting of adverse events / reactions as per protocol (and urgent safety measures); unblinding procedures; and IMP accountability at the trial site; and Adequate trial documentation and archiving of trial documentation. Page 5 of 15
5.0 Research Audit Requirements 5.1 Determination of audit priority The NSFT, in its role as sponsor of non-ctimp research studies and host of clinical research studies adhering to Good Clinical Practice guidance and Clinical Trial Regulations, will undertake research audits of at least 10% of its approved and active studies each year. Which studies to audit is determined by the overall risk of conducting the study, and is determined by the following criteria: High Priority: Studies sponsored by the NSFT, Industry studies and CTIMPs, especially where there are no formal existing arrangements in place by sponsor representatives to conduct monitoring or auditing visits. Additionally, any studies where concerns are reported to the Research Manager or Research Integrity Officer about the conduct of the study by R&D officers or other Investigators will be classified as high-risk. Medium-priority: Any non-ctimp interventional study being undertaken in the Trust where the sponsor has not established its own monitoring or auditing schedule, or indicates that it does not intend to come onto site to audit. Low-priority: Any other non-interventional study. 5.2 Self-Audit Report Each research team is encouraged to complete a self-audit report periodically to identify gaps in trial management processes and documentation and highlight any concerns about the conduct of the study. The Research office will also request completion of a self-audit report annually as part of the progress report procedures. This report should be completed by a designated member of the research team, a copy kept on file and a copy sent to the Research Office. 5.3 Pre-Audit Preparation Meetings NSFT Research and Development may offer research teams the opportunity to undertake a pre-audit preparation meeting, which is designed to be a facilitative and educational process to prepare teams for formal audits by sponsors, R&D or regulatory authorities. The Research Quality Lead will contact research teams undertaking studies classified as high- and medium-priority and will offer to visit their area. This meeting will look at study information to ensure that comprehensive study information is present, that documentation is correct and being used as approved, and that site-files are set-up in accordance with Trust or sponsor policy. This is recorded on the NSFT Audit check-list (Appendix 2). The Quality Lead will write an actionlist for research teams, and will follow-up on the initial meeting within 6 months to ensure that all action points have been resolved satisfactorily. The team is expected to keep a copy of the action plan and to place a copy in their research site file. During this time, research teams will be informed of formal auditing procedures so they are aware of the requirements if/when a formal audit is then undertaken by the Trust. Page 6 of 15
5.4 Formal Audit Procedures The below procedures detail state the process for R&D compliance audits or audits undertaken by the NSFT when it is acting as sponsor on a research study, however a similar procedure will be undertaken by all sponsoring organisations and external auditing authorities (see Sections 5.4 and 5.5). 5.4.1 Notification and set-up of full research audits Audits will be performed by persons in the Research & Development who are qualified through training and/or experience through their employment to undertake a fair and comprehensive audit of research study files held in the Trust and/or in a partner organisation. Audit reports, outcomes and letters will ultimately be authorised by the Research Integrity Officer. The NSFT Research Audit team will inform local investigators of their intention to conduct an audit at least 4-6 weeks prior to audit dates in the form of a letter (Appendix 1), although prior discussion to inform suitable dates may take place before formal notification. It is expected that investigators, including the Principal Investigator will be on-site and available for the audit on the dates agreed. Investigators will be asked to ensure that a suitable room is booked for the auditors for the times specified at each site and make available all study-related documentation (Trial Master File, source data, supporting files/docs). All information provided should be accurate and up-to-date. Each team member should be aware of their areas of responsibility on the study when questioned, supported by the information provided in the study documentation. 5.4.2 Conduct of research audit NSFT Research Audit team members and Research Investigators should allow 1-3 days for the conduct of a research audit. Audit team members will review all documentation provided, against known Governance approval documentation held in the R&D office, and will record any findings or discrepancies on the Audit Check-list (Guidance Document). Investigators may be questioned by the Audit team about study procedures, or may be asked for further information/data if it cannot be found in the provided study documentation. 5.4.3 Classification of Audit Findings The findings from sponsor audits for all studies are categorised in the following manner: Category Implication Action required Critical Findings Major breach of GCP. Causes harm or increased immediate risk to study participants and/or affects the integrity of the study data. resolved. Major Findings Breach of GCP. Could cause harm to participant or integrity of study data if unresolved in a timely Page 7 of 15 Immediate cessation of all study activities until findings have been Findings are required to be investigated and resolved within 2-3 months [A follow-up visit may be arranged].
manner. Minor/Other Findings Low risk to participants but requires resolution before end of study. Findings are required to be resolved by the next audit (12 months) 5.4.4 Notification of Audit Findings Within 14 days of an audit taking place, the research team will be informed of the findings of the study by a formal letter detailing each point raised (Appendix 2). Where required or requested, a face-to-face meeting with the lead local investigator will also be arranged. A suggested action plan is provided by the Audit Team for each point. A date may be arranged at this point for a follow-up meeting to ensure that any Critical and Major findings have been actioned. 5.4.5 Follow-up procedures for Audit Findings The R&D Audit team will conduct a follow-up visit of the initial formal audit if critical and major findings have been found. The follow-up visit will follow the pattern of the initial audit visit, but will concentrate specifically on the resolution of the findings, rather than a full audit being undertaken. Critical findings require immediate action and all study activity across all sites should be suspended until the finding has been resolved. Major findings require urgent action, and although study activity can continue, resolution of findings should be given priority. The follow-up visit for major findings will be scheduled to be conducted within 2-3 months of the original audit. Minor findings will be expected to be resolved by the next scheduled audit if applicable (usually within 12 months). 5.4.6 Escalation of Findings If, during the follow-up visit, it is found that Major or Minor findings have not been resolved and/or satisfactory steps have not been taken towards resolving the finding, the finding may be escalated to the next level i.e. Major findings will be reclassified as Critical, Minor findings will be classified as Major, at which point the appropriate action will be implemented. The research team will be informed in writing if the escalation procedure is implemented. 5.4.7 Recording of Audit Outcomes A copy of all audit-related documentation, including initial notification and the list of Findings, should be placed in each site file and archived with study documentation at the end of the study. 5.5 External Auditing by Regulatory Authorities The regulatory or UK competent authorities, such as the MHRA, have the legal right to enter premises involved in the conduct of CTIMPs or Medical Device trials to undertake inspections, take samples or copies of research materials and seize research documents. It is a criminal offence to obstruct this process. Once an investigator or R&D officer has received notification of an upcoming audit/inspection by the Competent authority (commonly referred to as a site or study inspection), they should notify all local Page 8 of 15
research team members involved in the study across all sites as soon as possible. This notification should include the date, duration and nature of the prospective audit/inspection. The local research team, led by the Principal Investigator, should conduct a thorough review of all study materials to ensure compliance prior to the audit/inspection. This review should include, but not limited to, Study protocol Study procedures Trial Master File/Site File including. Patient-specific documentation and Pharmacy arrangements/records. Source Data Case Report Forms The local research team should inform R&D of the pre-audit review, who will support review preparation and arrangements. Any findings of the review which require corrective action will be clearly documented by the research team and R&D, with a clear and timely management plan put in place where required. A copy of the actions and plan should be placed in the site files, with a copy being sent to the sponsor organisation. The competent authority also has the right to conduct inspections of sponsoring organisations, where all research in the Trust may be conducted. In the case of these inspections, Research & Development will co-ordinate set-up of the visit and inspection process. In the case of an inspection of a sponsoring organisation, the Trust will also be required to submit a dossier of information to the regulatory authority detailing relevant studies, personnel and departments involved in the conduct of research. It is expected that research and clinical teams will support the Trust to complete this dossier and this process should be considered to be high-priority. 5.6 Internal Host Organisation Monitoring Within one calendar month of a research study being approved in the NSFT, the Research Office may arrange a short monitoring visit with the NSFT research team to check that trial management activities are in place, or are in the process of being set-up. If a meeting is not arranged, the named study coordinator will be sent a short online survey to complete on behalf of the study, to confirm that trial management activities have been set-up. In particular, the following items will be looked at: Study Delegation Log completion and authorisation Trial Master File and/or Site File set-up Presence of sponsor policies and/or additional working study procedures Highlighting any early concerns about conduct or delivery of the study i.e. Performance Management. Any issues raised from the Early monitoring or survey completion will be communicated to the research team, and they will be supported to complete study set-up within the following month. 5.7 External Sponsor Monitoring According to the ICH-GCP framework, the purpose of study monitoring is to verify that: The rights and well-being of research participants is being protected. Reported trial data is complete, accurate and verifiable from source data. The conduct of the trial is compliant with the current protocol, regulatory authority regulations and GCP guidelines. A monitoring visit conducted by a representative of the Sponsor involves source data verification to compare the case report form entries with information available from source documents i.e. patient notes, files and test results. Page 9 of 15
The monitor should inform the research team about the visit in advance, including details about the monitoring schedule for the study and the expected duration of the visit. The research team and Monitor should jointly find a suitable location for the conduct of the Monitoring visit. The research team should make all study documentation and source data available to the monitor for the duration of the visit, and any supporting departments contacted in advance. After the visit, the Monitor will complete the study Monitoring Report Form and make a copy available to the PI/CI stating what has been reviewed, and the findings of the visit, including information about any areas which need corrective action. The research team should file a copy of the Monitoring Report Form in the study file, plus document any corrective action or subsequent communication about the findings. 5.8 Study Close-down/termination of the study All studies in the NSFT may be subject to a final close-down audit at the end of the study. This will be performed by the Sponsor, Regulatory Authority and/or NSFT Research office upon notification of the close of the study. The audit will be arranged within 28 days of initial notification of closedown/termination if the study is selected for a Close-down audit. Each research team is encouraged to conduct an internal self-audit of the study prior to the final R&D audit. A self-audit toolkit is available from the Research and Development office and should be conducted and signed off by the trial coordinator, principal investigator or other named person delegated the duty for undertaking study file management at the local site. A signed copy of the toolkit should be placed in the front of the Trial Master file or Study File and a copy sent to R&D for their records. If there are any significant findings or actions required as a result of the self-audits or any outstanding findings from previous audits conducted by the Research Office, sponsor or regulatory authority, it is expected that the study will not be archived until the identified issues have been resolved. 5.9 Training NSFT Research teams and investigators are offered the opportunity to undertake training in Research audit and monitoring procedures and preparing for research audits through designated sessions in the Research Training Programme. Page 10 of 15
Monitoring Statement Aspects of the policy to be monitored Compliance of research audit team to adhere to procedures. Monitoring method Annual review of audit procedures Individual/Tea m responsible for monitoring Research Quality Lead Frequency Annually, of all research studies formally audited and reviewed receipt of self-audit reports/surve ys. Findings: Group/Commi ttee that will receive the findings/moni toring report NSFT Research Committee. Action: Group/Commi ttee responsible for ensuring actions are completed NSFT Research Committee. Page 11 of 15
Appendix 1: Formal Audit Notification letter TITLE AND ADDRESS OF INVESTIGATOR DATE OF LETTER DEAR PRINCIPAL INVESTIGATOR, Re: NAME OF STUDY: Notification of Sponsor Audit Please be advised that the, in their role as study sponsor, will be conducting an audit of NAME OF STUDY study files to ensure compliance with Good Clinical Practice regulations and the Research Governance Framework. The dates of the audit will be: DATES AND LOCATION Please ensure that a suitable room is booked for the auditors for the times specified at each site. Make available all study-related documentation (Trial Master File, source data, supporting files/docs). All information provided should be accurate and up-to-date. Each team member should be aware of their areas of responsibility on the study when questioned, supported by the information provided in the study documentation. Please also ensure that relevant members of the study team are available on site on the days of the audit, either in person or via telephone, to answer any questions during the on-going audit. Your auditors will be: R&D AUDIT TEAM MEMBERS We may be required to discuss findings with yourself at the end of the audit, so please ensure that you are available to meet the auditors at the end of the second day for this purpose. An audit report and monitoring schedule (if required) will be sent to you within 14 days of the audit. Yours sincerely, RESEARCH INTEGRITY OFFICER/R&D DIRECTOR APPENDIX 2: Notification Of Formal Audit Findings NAME AND ADDRESS OF INVESTIGATOR DATE OF LETTER Dear NAME OF INVESTIGATOR, Page 12 of 15
Re: NAME OF STUDY Notification of Audit Findings The, in their role as study sponsor/site, undertook a first audit of the NAME OF STUDY on the DATES OF AUDIT SUMMARY OF OVERALL AUDIT IMPRESSION. The findings from sponsor audits for all studies are categorised in the following manner: Category Implication Action required Critical Findings Major breach of GCP. Causes harm or increased immediate risk to study participants and/or affects the integrity of the study data. Major Findings Minor/Other Findings Breach of GCP. Could cause harm to participant or integrity of study data if unresolved in a timely manner. Low risk to participants but requires resolution before end of study. Immediate cessation of all study activities until findings have been resolved. Findings are required to be investigated and resolved within 2 months [A follow-up visit may be arranged]. Findings are required to be resolved by the next audit (12 months) The critical and major findings for the NAME OF STUDY are as follows and require action. A full list of Minor/other findings will be made available by the follow-up meeting on the DATE OF FOLLOW-UP MEETING: Category Study Findings Suggested Action required Critical Findings Major Findings If you have any queries about these findings, or the action to be taken, please contact the NSFT R&D office on EMAIL ADDRESS or TELEPHONE NUMBER. We will provide a full list of findings to the CHIEF/PRINCIPAL INVESTIGATOR on DATE OF FOLLOW-UP, after which we will arrange a follow-up visit in 2-3 months to ensure that major findings have been resolved. If any major findings have not been resolved satisfactorily in this time, they will be escalated to a critical finding. Yours Sincerely, Page 13 of 15
RESEARCH INTEGRITY OFFICER RESEARCH MANAGER/AUDIT TEAM LEAD Page 14 of 15
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