research auditing and monitoring procedures · r&009 research auditing and monitoring...

Norfolk and Suffolk NHS Foundation Trust R&009 Research Auditing and Monitoring Procedures v2.0 of 24

Title: Research Auditing and Monitoring Procedures Outcome Statement: Researchers in the Trust and research partners will be informed about the

procedures involved in research audit and monitoring of approved research studies.

Written By: Bonnie Teague, Research Manager Reviewed By: In Consultation With: Research Quality Lead, Research Audit Team Approved By and Date: V1.0 Research Governance Committee , 27th September 2012

V2.0 Research Governance Committee, 26th September 2013 With Reference To: Research Governance Framework 2nd Edition, 2005.

Medicine for Human Use (Clinical Trial) Regulations 2004

Associated Trust Policies and Documents:

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 Policy

Applicable To: All research staff involved in approved Trust research studies

For Use By: Research team members, Pharmacy, R&D, Sponsors, Auditors. Reference Number: R&D009

Version: 2.0 Published Date: 27th September 2013 Review Date: October 2014

Impact Assessment: Completed 19th September 2013 Reason for Development/Review:

Development 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 2nd Edition 2005. Review v2.0:

1) Addition of self-audit report requirements. Addition of self-audit report template as Appendix 1.

2) Addition of initial monitoring visit within 28 days of approval of study. Addition of Monitoring report template as Appendix 5.

3) Addition of audit procedures required for study close-down/termination, to correlate with R&D013.

Additional minor clarifications of language and meaning throughout the policy

Implementation Routine distribution procedures (publication on the Trust intranet, email notification to identified researchers for distribution throughout the team) plus distribution during Research training programme.


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.

Since 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).

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.

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 site-specific 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 study-specific 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.


5.0 Guidance to Good practice 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 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 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 studies 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 can 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 a to-do list 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. 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 6 weeks prior to audit dates in the form of a letter (Appendix 3), 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 (Appendix 2). 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.

Immediate cessation of all study activities until findings have been resolved.

Major Findings

Breach of GCP. Could cause harm to participant or integrity of study data if unresolved in a timely manner.

Findings are required to be investigated and resolved within 2-3 months [A follow-up visit may be arranged].

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 4). 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 resolved. 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 (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 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 will 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. In particular, the following items will be looked at:

• Study Delegation Log completion • Trial Master File and/or Site File set-up • Presence of sponsor policies and/or additional study procedures • Highlighting any early concerns about conduct or delivery of the study.

The Research Office will complete a Research Monitoring report (Appendix 5) which will be placed in the site file/trial master file. A copy of the report will be sent to the Principal Investigator. 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. 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 close-down/termination. 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 a designated session in the “Research Trial Management Training” (Intermediate) course.


Appendix 1: Self-Audit Report

NSFT RESEARCH AND DEVELOPMENT: SELF-AUDIT REPORT

AREA OF AUDIT

QUESTION RESPONSE FURTHER COMMENTS

VERSION CONTROL

1 Where appropriate please identify the current version number and date for the following:

Version Date

Study Protocol

Participant Information Leaflet

• Minor

• Parent/Guardian

• Adult

• Staff

• Other (please specify)

Consent forms

• Minor

• Parent/Guardian

• Adult

• Staff

• Other (please specify)

•

2 Is the current version of the PIS referenced in the consent form?

Yes: � No: �

3 Do you receive any new versions of any of the above documents in a timely and efficient way?

Yes: � No: �

4 Who informs you of any new versions of study documents?

DATA PROTECTION

1 Who has access to confidential and participant identifiable data?

2 Do any participant identifiable data get transferred from NSFT to external sites (ie study team)?

Yes: � No: �

Study name /Acronym:

Principal investigator:

Name of Person completing questionnaire:

Research Role:

R&D/EuDRACT/MHRA CTA no:

Locality/Team:

Signature: Date: _ _ /_ _ /_ _

Study Type: Non CTIMP CTIMP – Non Commercial CTIMP - Commercial

Study Start Date: _ _ /_ _ /_ _ Study End Date: _ _ /_ _ /_ _ Recruitment Phase: Years _ _ Months _ _


AREA OF AUDIT


3 If Yes, what methods are used to transfer this information – both electronic and paper versions.

4 What measures are put in place for each transfer method to ensure protection of information?

5 Has confidentiality and data protection been fully discussed with potential participants?

Yes: � No: �

6 Has this discussion been recorded on the consent form?

Yes: � No: �

7 What systems are in place to store study materials within the dept/team/locality to comply with data protection and GCP standards?

8 Are there any specific concerns regarding the secure storage and transfer of confidential and participant identifiable data?

Yes: � No: �

9 How long will participant identifiable data be stored at the end of the study?

10 Do you have access to the Trust Data protection SOP?

Yes: � No: �

SITE FILE

1 Where is the Study Site File held?

2 Who has responsibility for maintaining this?

3 Do you have free access to file when required?

Yes: � No: �

4 A) Has the delegation log been signed by all study team?

B) And, signed by PI?

Yes: � No: � Yes: � No: �

5 Have your team updated training certificates including GCP in Site File?

Yes: � No: �

CONSENT

1 Do the consent forms require initials for each statement?

Yes: � No: �

2 Have all participants completed a Consent Form prior to engaging in any research specific activity?

Yes: � No: �

3 Has the Informed Consent process been recorded including questions asked and outcome?

Yes: � No: �

4 Has “willingness to continue” been recorded ( where appropriate)

Yes: � No: �

5 Have you had to re consent anyone onto the study? (If Yes please give reasons)

Yes: � No: � N/A: �

AREA OF AUDIT



6 Have the reasons for non consent been sought and recorded. (If no please give reasons)

Yes: � No: �

PERFORMANCE MANAGEMENT

1 What are the target figures for the study?

2 Do you feel that you will meet the target figures in the required amount of time?

Yes: � No: �

3 If No, what main factors impede recruitment onto the study?

RESEARCH SITES/TEAM

1 Which other services/localities within the Trust are supporting this study?

2 Do you/Have you had regular contact with the teams?

Yes: � No: �

3 Have you had regular contact with the PI?

Yes: � No: �

4 Has the PI supported you in the roles delegated to you?

Yes: � No: �

ARCHIVING

1 Who is responsible for Archiving the study information?

2 How long should study information be stored for and where?

COMMUNICATION

1 Overall, In your opinion do you feel you get timely and sufficient communication/response from -

Main study team Yes: � No: �

R&D dept and Clinical Research Networks

Yes: � No: �

Clinical/Medical team Yes: � No: �

AUDIT

1 Have you had any monitoring visits, inspections or audits?

Yes: � No: �

2 If Yes, who by and when? (please identify all dates)

ADMINISTRATION

1 Were all approvals received prior to commencement of research activities?

Yes: � No: �

2 Do all research team members have current access permissions such as letters of access/honorary contracts/employment contracts?

Yes: � No: �

AREA OF AUDIT


TRAINING

1 Are there any Study related tasks that any team member does not feel competent or confident when

Yes: � No: � (please specify)


undertaking?

2 Have all team members received adequate training for the appropriate delegated study duties?

Yes: � No: �

3 Do all Study team members have up to date GCP training

Yes: � No: �

4 Who would you contact regarding any GCP related queries?

5 Have you ever had any GCP queries? And if so were they resolved?

Yes: � No: �

SAFETY REPORTING

1 Do you have a copy or have access to the safety reporting SOP for your study?

Yes: � No: �

2 Do you know what study related (S)AE/R’s require reporting?

Yes: � No: �

3 Are you confident in how to report adverse events for your study?

Yes: � No: �

4 Have any (S)AE/R’s been reported since commencement of the study?

Yes: � No: �

5 Have these been reported in accordance to protocol and SOP?

Yes: � No: �

6 Have any study related procedures or information been amended due to the Safety reporting?

Yes: � No: �

INTEGRITY

1 In your opinion do you believe that the study is being conducted in accordance with the relevant frameworks/legal & ethical legislation/SOPs?

Yes: � No: �

2 Are you aware of any incidences of fraud or misconduct in relation to the conduct of your study? (If yes, please refer to the Trust Research SOP)

Yes: � No: �

3 Are you aware of any complaints or concerns raised by study participants about the conduct of the study?

Yes: � No: �

PUBLICATIONS

1 Are you aware of any interim publications regarding the progress of the study?

Yes: � No: � N/A: �


Appendix 2: Audit Check-List

Component Present: yes/no/na

Comments Action required Auditor Initials

RN/CSO/AP Initials

Protocol & Associated Documents

Approved protocol and amendments

IRAS form

Approved Investigators Brochure/SMPC (Summary Of Medicinal Product Characteristics)

Approved Patient information leaflets

Sample Case Report Forms/QLQ Diary Cards

Approved consent forms

Completed consent forms

Approved GP Letter Approved publicity documents

Patient Identification form/Enrolment logs

Audit requested by whom and why:

Name of auditor: Name of RN/CSO/AP:

Date Audit Requested:

Locality/team: HIP Research Team

Study name /Acronym: R&D No/EuDRACT/MHRACTA: Date of Audit:




RN/CSO/AP Initials

Protocol & Associated Documents

Patient recruitment/screening form

Document tracking log

Any amended documents Study outcome measures/questionnaires.

Site Personnel

Contact Details

Headed Paper

Current CV’s signed and dated

Confidentiality forms

Delegation and signature log

Training logs

Study processes Instructions for handling trial medication and trial related materials

Shipping materials Randomisation details Completed outcome measures/questionnaires etc




RN/CSO/AP Initials

Ethics Ethics application form

Ethics approval letter

Regulatory Regulatory authorisation ie CTA for the UK

Regulatory Application

Sponsorship Letter of acceptance of sponsorship

Delegation of sponsorship responsibility

NHS Trust R&D Approval Letter

Progress Report

Contracts & Agreements/Finance/Indemnity

Funding agreements

Others e.g. IMP Supplier

Cheque Request Forms/Invoices

Indemnity (if not covered in the agreement)




RN/CSO/AP Initials

Safety Reporting Detailed description of how to report SAE’s and SUSAR’s clearly denoting appropriate time scales.

Serious Adverse Events Reports (SAE)

Suspected Unexpected Serious Adverse Event Reports (SUSAR)

Annual safety reports Procedures for randomisation and blinding/code break (If applicable)

Code break envelopes

Blank SAE envelopes

Monitoring Monitoring plan

Site initiation visit report (or equivalent)

Monitoring visit reports/logs

Study Close or Visit Report




RN/CSO/AP Initials

Subject Logs and Consent forms

Subject screening/Enrolment Log and Identification code list

Signed informed consent forms

Equipment Calibration certificates

Related correspondence

Contact details of authorised equipment support/suppliers

Details of programme of equipment maintenance

Audit Audit report/certificate Audit Correspondence

Pharmacy

Delegation of authority and signature form.

Pharmacy agreement

Cheque request forms/invoices

Documentation of shipment

Sample of labelling Instructions for handling of IMP




RN/CSO/AP Initials

Pharmacy Notification of Unblinding Retrieval of code-break envelopes

Drug accountability Pharmacy correspondence

Local Laboratory

Contract laboratory form

Laboratory agreement

Normal ranges

Accreditation

Sampling Instructions/protocol

Laboratory correspondence

Other local service providers. Contracts

Study report /publication. Study report /publication

General correspondence. Correspondence

Communication log




RN/CSO/AP Initials

Post- trial documentation. Investigational product(s) accountability at site.

Documentation of investigational product destruction.

Completed subject identification code list.

Audit certificate

Final trial close – out monitoring report

Treatment allocation and decoding documentation.

Final report by investigation to IRB/IEC where required and where applicable to the regulatory authority.

Clinical study report Other study specific

documentation.

File Notes.

Signature (Auditor):

Signature (RN/CSO/AP):

Date: (In Full)

Date: (In Full)


Appendix 3: 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 Norfolk and Suffolk NHS Foundation Trust, 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 4: Notification Of Formal Audit Findings NAME AND ADDRESS OF INVESTIGATOR

DATE OF LETTER

Dear NAME OF INVESTIGATOR,

Re: NAME OF STUDY Notification of Audit Findings The Norfolk and Suffolk NHS Foundation Trust, 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.

Immediate cessation of all study activities until findings have been resolved.

Major Findings

Breach of GCP. Could cause harm to participant or integrity of study data if unresolved in a timely manner.

Findings are required to be investigated and resolved within 2 months [A follow-up visit may be arranged].

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)

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, RESEARCH INTEGRITY OFFICER RESEARCH MANAGER/AUDIT TEAM LEAD


Appendix 5: R&D Monitoring Check-list: Set-up of study

Monitored Item Present: yes/no/na

Comments Action required Monitor Initials

Researcher Initials

Trial Master File/Site File set-up.

Study team CVs and training logs in place.

Delegation Log – present in file and signed.

Sponsor policies/procedures in place and distributed to team members.

Clear contact list for

study team.

Any other early areas of concern highlighted in the following areas: Recruitment of Participants

Delivery of Study Procedures

Safety of Participants

Other Areas:

Study name /Acronym: Date of NSFT Study approval:

Name of Research Office Monitor: Name of Local Researcher:

R&D #:

Signature (Research Monitor): Date: (In Full)

Locality/team: Date of Monitoring Visit: