STANDARD OPERATING PROCEDURE SOP 710 Good Clinical Practice AUDIT AND INSPECTION Version 1.3 Version date 27.02.2018 Effective date 3.03.2018 Number of pages 10 Review date February 2020 Author Role Approved by Role NNUH UEA Joint Research Office Julie Dawson Acting Research Services Manager Signature Date 2.03.2018 Authorised on behalf of NNUH and UEA by Role Professor Alastair Forbes Chief of Research & Innovation Signature Date 3/3/18 SOP 710 V1.3 Effective Date: 3.03.2018 Page 1 of 10
It is the responsibility of all users of this SOP to ensure that the correct version is being used. All staff should regularly check the NNUH R&D website for information relating to the implementation of new or revised versions of SOPs. Staff must ensure that they are adequately trained in the new procedure and must make sure that all copies of superseded versions are promptly withdrawn from use. The definitive versions of all Joint NNUH/UEA health care research SOPs appear online. If you are reading this in printed form please check that the version number and effective date is the most recent one as shown on the NNUH R&D website. TABLE OF CONTENTS 1 ABBREVIATIONS 3 2 INTRODUCTION 3 3 SCOPE 4 4 DEFINITIONS 4 5 RESPONSIBILITIES 4 6 PROCEDURES 5 7 RELATED DOCUMENTS 8 8 REFERENCES 8 9 APPENDICES 8 Appendix1: Examples of Study Personnel and Responsibilities List 9 Appendix 2: Change Control, Revision and Review Sheet 10 SOP 710 V1.3 Effective Date: 3.03.2018 Page 2 of 10
1 ABBREVIATIONS Joint Arrangements for Research AE CI CRF CRO CRTU REC GCP IB ICH MHRA NNUH PI R&D SOP SAE TMF UEA Adverse event Chief Investigator Case Report Form Contract research Organisation Clinical Research and Trials Unit Research Ethics Committee Good Clinical Practice Investigator Brochure International Conference for Harmonisation Medicines and Healthcare products Regulatory Authority Norfolk and Norwich University Hospitals NHS Foundation Trust Principle Investigator Research and Development Standard Operating Procedure Serious adverse event Trial Master File University of East Anglia 2 INTRODUCTION This SOP describes the procedures relating to the preparation required, prior to, during and after the conduct of a site audit and/or inspection by authorised internal and/or external regulatory body and/or a Sponsor. The organisation providing care is responsible for permitting and assisting with monitoring, audit and inspection by relevant authorities. Inspections performed by regulatory authorities such as the MHRA, are usually performed for three main reasons; (1) to assure integrity of clinical study data, (2) to assure subject s rights and safety, (3) to permit sound decisions regarding efficacy and safety. The main objectives of a regulatory inspection are to determine the compliance of Clinical Investigators with GCP guidelines and regulations, to assess if monitoring procedures have been satisfactorily implemented by a Sponsor or CRO and to assess whether data submitted to the regulatory authorities from specific studies are substantiated by appropriate records. The purpose of internal audit is to verify that: Participants rights and welfare are being adequately protected Assure regulatory compliance of the Trust as a Sponsor organisation Ensure integrity and quality of the clinical study data The audit can also assist in identifying training needs and correcting problem areas as well as providing suggestions to improve quality of clinical trials. SOP 710 V1.3 Effective Date: 3.03.2018 Page 3 of 10
3 SCOPE Joint Arrangements for Research 3.1 This SOP applies to all healthcare research sponsored by NNUH or UEA which falls within the scope of the UK Policy Framework for health and Social Care Research. Where additional legislation applies - for example the Medicines for Human Use (Clinical Trials) Regulations 2004 (and amendments) or the Medical Devices Regulations 2002 - required procedures will be indicated. External sponsors may require use of their own SOPs and this will be specified in site agreements. It is the responsibility of the local PI to ensure that study specific SOPs can be operated without conflicting with this SOP and in accordance with all organisational polices related to research. 4. DEFINITIONS GCP site or study inspection - an inspection of an externally sponsored study hosted by NNUH, which involves a medicinal product. The MHRA, acting as the UK Competent Authority undertakes these inspections. GCP inspection of the sponsoring organisation Inspection conducted by the MHRA for studies involving medicinal product where the NNUH acts as a sponsoring organisation. The GCP inspection examines the systems used by the organisation to conduct clinical trial research. The inspectors will select a number of clinical trials to examine how the organisation s trial procedures are applied. Internal audit - An audit is a systematic and independent examination of trial related activities and documents that determines whether a trial or its related activities were conducted, and the data recorded, analysed and accurately reported according to the protocol, Sponsor s SOPs, GCP, and any applicable regulatory requirements. Internal Audit may be undertaken as a requirement of Research Governance where NNUH/UEA acts as Sponsor. In this case the R&D Offices of NNUH/UEA will undertake the audit, adhering to the principles of Research Governance and GCP. 5. RESPONSIBILITIES Auditor / Inspector: To conduct audit within agreed deadlines and to communicate and report findings with clarity and without prejudice. Auditee / Inspected: to cooperate with the audit / inspection requirements by expeditiously agreeing the timelines, providing staffing and documentary evidence to permit the efficient auditing or inspection of the NNUH sponsored & hosted studies. The local PI will have responsibility (supported by the R&D officers) for co-ordination of the Site/ Study inspection. All the information relating to the particular study at this site has to be made available to the inspectors. For sponsor specific MHRA inspection the R&D office will be responsible for co-ordination of the inspection process. All research within the organisation may be inspected. SOP 710 V1.3 Effective Date: 3.03.2018 Page 4 of 10
The MHRA inspectors have legal rights. These include the right to enter any premises involved in clinical trials of investigational medicinal products to carry out inspections, take samples, require the production of books and documents, and to take copies of, or copies of entries in such books and document and seize and detain substances, articles and documents. It is a criminal offence to obstruct this process. 5.1 The Audit/Inspection Timetable 5.1.1 In the first instance, the Auditor/Regulatory Authority will contact the PI directly to inform him/her that an audit/inspection is to take place, together with a suggested date and agenda. 5.1.2 In the case of audit by an external auditor/sponsor the PI/study co-ordinator should inform the R&D Offices of NNUH or UEA immediately that an inspection is to be undertaken. In the case of joint research, the R&D Offices of NNUH or UEA will notify the other of the audit/inspection and the NNUH R&D office will then notify any appropriate Trust departments with an interest in the audit. Both the R&D Offices of NNUH and UEA will also ensure that information is notified to appropriate NNUH and UEA management and governance functions. 6. PROCEDURES 6.1 Prior to the Audit/Inspection 6.1.1 The Investigator should notify all those personnel who need to be aware that an audit / inspection is to take place, e.g. Departmental director and/or UEA Head of School, Research Services Manager, Clinical Research Trials Unit Matron, R&D Offices of NNUH or UEA, Sponsor, REC, co-investigator(s), study coordinator, study administrator, research nurse, pharmacy, laboratory and technical departments (Radiology, Pathology, etc.) as appropriate and ensure that everyone is aware of the following: That there is to be an audit / inspection The purpose of the audit / inspection When the audit is to take place Who should be present, or be available if required 6.1.2 In the case of audit by an external auditor/regulatory Authority or external Sponsor of NNUH or UEA as a Sponsoring Organisation, the relevant R&D Office shall lead the preparation and arrangements for the audit itself; developing and agreeing clear timelines with the external party and clearly communicating the requirements to NNUH and UEA governance and management structures to individual Investigators and Research teams. 6.1.3 In the case of an audit of an individual externally sponsored study, the investigator and the study team should conduct a thorough review of the following prior to the audit: Study Procedures Study Protocol Case Report forms Source Data SOP 710 V1.3 Effective Date: 3.03.2018 Page 5 of 10
Study Documentation/Trial Master file/site file (see SOP Creating a Trial Master file ) i.e. patient s notes, pharmacy and drug records, signed financial documents/receipts, pharmacy agreements, documentation relating to doses/dispensing etc. For audits of CTIMPs or Medical Device Trials, the R&D Offices of NNUH or UEA shall discuss the review findings with the investigator and study team and shall identify appropriate actions to be taken to ensure that the documents listed in 5.2.2 are available. 6.2 Preparation for the Audit /Inspection 6.2.1 The investigator and the study team should check that suitable facilities are booked for the Auditors / Inspectors. The Auditors / Inspectors will need to have an office or a quiet area in which to work, meet people and examine records. Access to a photocopier may also be a necessary requirement. Ensure that all the requested documentation is available for the Auditor / Inspector. Note: any missing data or forms should be covered by appropriate signed and dated file notes. 6.2.2 The investigator and the study team should ensure that all required study team personnel will be available on the day of the audit / inspection either in person, by pager, or telephone. The investigator(s) and the study team(s) should ensure the following are available and current/up-to-date for each Study being audited/inspected: A copy of the most up to date Investigator s Brochure A signed copy of the final protocol including any protocol amendments. The letter of approval from the Research Ethics Committee, NHS Trust and/or Competent Authority. Check that it refers to the final version of the protocol for the study. Approved Protocol amendments. Copies of REC and Trust approval letters in place, with dates of implementation of each protocol amendment recorded. Dates of implementation must not supersede the dates of approval. Signed copies of agreements relating to the Study (Drug Supply, Technical, Laboratory Services, Collaborate; Materials Transfer, etc). Documentation to confirm that any other information required by the REC and Trust has been supplied e.g. notification of Serious Unexpected Adverse Events. Up-to-date list of study personnel and delegation log which accurately reflects all personnel who have been involved in the study, no matter how minor their roles. Curriculum Vitae on file for anyone undertaking assessments, completing CRFs or obtaining informed consent. A training log documenting all relevant training for study staff. An up to date log of subjects enrolled in the study. Screening logs and records of patients withdrawn from the study should also be in place. Completed informed consent forms, and any anomalies noted with a signed and dated file note. The date of consent should be prior to any study related procedures. Review of eligibility criteria for all subjects who have entered the study. Any anomalies should be accompanied by a signed and dated file note. SOP 710 V1.3 Effective Date: 3.03.2018 Page 6 of 10
Joint Arrangements for Research CRF fully completed, signed and dated, with checks made to ensure that all data are legible. CRFs checked for inconsistencies regarding medical history, diagnoses, concomitant medications and dates of visits. Any anomalies should be accompanied by a signed and dated file note. For each subject in the study, all files and records checked for evidence of Adverse Events (AEs) and to ensure that details of all Adverse Events have been recorded in the CRF. Determine whether or not the AEs observed are defined as serious. Refer to the protocol for AE definitions and ensure that all SAEs have been reported according to the agreed SOPs and within appropriate timelines. Confirm that there is no outstanding documentation relating to any AEs and check that all events have been followed up adequately. If drug accountability is being undertaken by the Investigator, check that all medication packs are accounted for. A high return of unused material in patient supplies is expected. If the pharmacy is dealing with this aspect, visit the pharmacy and ensure that dispensing and return records are available. Ensure that Investigator and each member of the study team are aware that the Auditor will be looking for evidence that each person dealing with the study, particularly the Investigator, can clearly identify the extent of their knowledge and degree of participation throughout the whole study. 6.2.3 Where the audit/inspection is of NNUH or UEA as a Sponsor organisation, a nominated individual in the relevant R&D Office shall prepare the dossier of information, involving relevant investigators as needed. The individual shall ensure that all required R&D personnel, investigators and research study team personnel will be available on the day of the audit / inspection either in person, by pager, or telephone. 6.3 During the Audit / Inspection 6.3.1 The investigator, the study team and the management team should ensure that suitable facilities are made available for the Auditor / Inspectors. 6.3.2 The investigator and the study team should ensure that the appropriate study site personnel are available on the day of the audit / inspection in person, by pager, or telephone to answer any questions during the on-going audit / inspection. 6.3.3 The investigator and the study team should ensure the following: Details of the study team responsibilities are listed and available in the Trial Master File (refer to Appendix 1 for an example list). They are familiar and confident about their areas of responsibility in order to answer questions by the auditor/inspector. They can provide up to date and accurate information to the auditor/inspector in a timely manner. Unsupported information should not be offered. They seek clarification if they do not fully understand any questions raised by the auditor/inspector. SOP 710 V1.3 Effective Date: 3.03.2018 Page 7 of 10
They do not answer questions if they are not the correct person to give a proper answer. 6.4 After the Inspection The Auditor / Inspector will, according to their own guidelines inform the necessary persons of the result of the findings. The NNUH R&D office must receive a copy of any findings in order to send the completed report to the Joint Research Governance Committee. 7. RELATED DOCUMENTS All approved study documents All SOPs, as Auditors will audit against the SOPs in place at the site. 8. REFERENCES Research Governance Framework (2005) MHRA: Risk-based inspection programme for good practice inspections https://www.gov.uk/guidance/good-clinical-practice-for-clinical-trials#inspections-under-the-riskbased-compliance-programme 9. APPENDICES Appendix 1: Example of a Study Personnel and Responsibilities List Appendix 2: Change Control, Revision and Review Sheet SOP 710 V1.3 Effective Date: 3.03.2018 Page 8 of 10
Appendix 1. Example of a Study Personnel and Responsibilities List Title Name and details Responsibilities Chief/Principal Investigator Co-Investigator CRC Technician Pharmacist Statistician Data Manager Doctor Smith, MD Tel No. Dr. Tall, MD Tel No. Nurse Green, RN Tel. No. Mr./Ms. Quick, BS Tel No Mr./Ms. Right, Pharm. D Tel No. Mr./Ms Number PhD Tel No Mr./Ms Database, Tel No Overall supervision of study. Sponsor and IRB communications conduct weekly meetings to discuss study progress. Subject screening and enrolment. Performs clinical evaluations, document, and report and follow-up adverse events. Explains study procedures to subject/patient; obtains informed consent; schedules follow-up appointments; collects clinical data; performs day to day study procedures. Process, store and arrange transport for blood and urine specimens. Receive trial medication. Dispensing trial medication to subjects. Maintain trial medication logs. Store returned drugs from subjects/patients. Meet with monitors Design of data analysis Design, acceptance and maintenance of electronic data management systems SOP 710 V1.3 Effective Date: 3.03.2018 Page 9 of 10
Appendix 2: Change Control, Revision and Review Sheet CHANGE CONTROL, REVISION AND REVIEW SHEET: SOP 710 Version No Change Date Reason for Change 1.1 28/6/2010 Addition of responsibilities for the UEA R&D Office. 1.2 01/01/2014 Minor corrections to text, addition of agreements to list of documents in 5.2, addition of requirement to submit completed audit report to the Joint Research Governance Committee, correction of version numbering and combining of control and revision sheets. Reviewer: Lisa Chalkley Designation: Industry Manager CLRN Signature and Date: L Chalkley 16 th December 2013 1.3 27.02.2018 Change of name from Research Governance Framework to UK Policy Framework for health and Social Care Research. Reviewer: Basia Brown Designation: Research Governance Co-ordinator Deletion of reference to UEA for GCP MHRA inspections (site and Sponsor). Updates to Hyperlink for MHRA website Minor formatting changes. Signature and Date: 27.02.2018 Reviewer: Designation: Signature and Date: SOP 710 V1.3 Effective Date: 3.03.2018 Page 10 of 10