Details: Author: Louise Brook Clinical Trials Quality Monitor SOP Pages: 12 Version No. of replaced SOP: Effective date of replaced SOP: NA NA Approval: Version No: of the SOP being approved. Name of person approving this SOP. Date Signature of the person approving this SOP. 1.0 Professor Stephen Smye Director of R&I Leeds Teaching Hospitals NHS Trust 1.0 Clare Skinner Research Manager Faculty of Health and Medicine The University of Leeds Distribution & Storage: Distribution to Any Research Staff conducting or assisting with a CTIMP trial within Leeds Teaching Hospital NHS Trust Location of Document Paper: Electronic: Quality Assurance, Research and Development, Leeds General Infirmary I:\QA\1_SPONSOR_LEEDS_DOCUMENTS\SOPs/ R&I website V1.0 (131021) Page 1 of 12
Contents Page 2 Section A - Introduction Page 3 Section B - Applicability Page 3 Section C - Pages 4-11 1.0 - Setting up your Investigator Site File (ISF) / Trial Master File (TMF) Pages 4 2.0 - Filing and updating documentation throughout the trial Pages 4-10 3.0 - Documentation to be stored following trial closure Page 11 4.0 - General Trial Documentation Tips Page 11 5.0 - As an Investigator you must ensure the following Page 11 Section D - References Page 12 Section E - Definitions Page 12 V1.0 (131021) Page 2 of 12
Please note: This SOP should be used and followed in conjunction with other LTHT SOPs developed for researchers to support study set up and management. These can be found on the LTHT website or by contacting R&I directly. For clinical trials where Leeds is not the trial Sponsor you may use these SOPs as guidance, but refer to any Sponsor SOPs for further information. Section A Introduction 1.1 This Standard Operating Procedure (SOP) acts as a guide for all researchers to aid with TMF / ISF set up and maintenance when conducting a Clinical Trial of an (CTIMP) within Leeds Teaching Hospitals Trust (LTHT) and the University of Leeds (UoL). 1.2 This SOP should support standardisation and continuity between all members of staff working within research teams across LTHT / UoL and increase awareness as to how to maintain trial documents in accordance with Good Clinical Practice (GCP) and local procedure. 1.3 A Trial Master File (TMF) and/or an Investigator Site File (ISF) should be established at a beginning of a trial and contain all essential documents. It is the responsibility of the Investigator / delegated staff member to ensure the file is actively maintained and updated until trial closure. Filing documents with the investigator/institution and Sponsor in a timely manner can greatly assist in the successful management of the trial by the Investigator, Sponsor and Monitor (GCP E6 8.1). 1.4 ICH GCP section 8.1 states that the essential documents to be filed are those documents which individually and collectively permit the evaluation and conduct of a trial and the quality of the data produced. These documents serve to demonstrate compliance of the Investigator, Sponsor and Monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. Every trial is different and therefore the content of each TMF / ISF may vary. This SOP is designed to support researchers with decisions related to the set up and maintenance of an individual trial. 1.5 A template TMF index is available from the R&I Quality Assurance (QA) department and R&I website. This SOP will provide additional detail on various sections of the index, highlighting further information that may be relevant. At the end of the SOP you will also find general advice, tips and rules. Section B Applicability 1.1 All members of research staff involved in running CTIMP trials within LTHT including, but not restricted to: Chief and Principal Investigators (CI/PI), Research Nurses, Trial Coordinators / Assistants and Monitors. 1.2 The Investigator has ultimate responsibility for ensuring that all applicable site staff adheres to this SOP. V1.0 (131021) Page 3 of 12
1.3 Section C 1.0 Setting up your Investigator Site File (ISF) / Trial Master File (TMF): 1.1 The initial approvals, forms and supporting documentation submitted as part of the trial set up process must be retained and stored for future reference. It is therefore recommended you set up your Investigator Site File (ISF) at this time point. Guidance on the documents R&I require prior to granting NHS approval can be located on the R&I website. 1.2 The file must contain all essential documents pertaining to the trial. A minimum list of essential documents which must be maintained and filed can be located in section 8 of the ICH GCP E6 document, together with a brief description (http://ichgcp.net/8- essential-documents-for-the-conduct-of-a-clinical-trial). Use this list as a checklist when constructing / maintaining your ISF, however please note it is not a definitive list 1.3 The ISF/TMF should be labelled with the trial title, R&I number and any other trial identifiers. You should label each file / box / binder with the volume number and sections contained e.g. ISF, Vol 1 of 2, Sections 1-7. 1.4 Each file should contain a site file index for easy navigation. Dividers can be used to clearly identify sub sections. 1.5 Local approval documents e.g., the R&I form, SSI form, Pharmacy Able to Support letter, evidence of approval from all support departments and correspondence between the research team / R&I and Sponsor should be filed within the ISF at the start of the trial. Additional documents are then added throughout the life of the trial. 1.6 Your study file should be located in a locked storage facility with access restricted to research staff. 1.7 Prior to commencing the trial please plan how much storage space will be required, taking into account the volume of paperwork likely to be generated (volume of CRFs etc.) 2.0 Filing and updating documentation throughout your trial: 2.1 Personnel and Key Contacts: 2.1.2 This section should list the main contact details for the research team including, where appropriate: The CI/PI, Sponsor, Trial Coordinator / Assistant, Data Manager, Lead Pharmacist. 2.1.3 This list must be updated by the member of staff delegated the responsibility of Site File Maintenance when any changes to the above contacts occur. V1.0 (131021) Page 4 of 12
2.2 Protocol (final and amendments): 2.2.1 The initial protocol and any amendments must be reviewed and agreed by the trial Sponsor prior to submitting the document to the Research Ethics Committee / Medicines and Healthcare Products Regulatory Agency (MHRA). 2.2.2 This section should include copies of all previously approved versions of the trial protocol used throughout the trial. If many amendments occur, superseded versions may be stored separately (or electronically) to save space in the main ISF (providing a file note is created documenting the alternate location. In these circumstances it is beneficial to store the signature page for the previous protocols in the ISF/TMF. 2.2.3 GCP (E6 section 8.2.6) states that the trial protocol must be signed to document Investigator and Sponsor agreement to the protocol / amendments, therefore please include a signature page for this purpose on the protocol. Complete a signature page for each new protocol held in the ISF / TMF after an amendment. 2.2.4 Please see the template protocol on the R&I website for guidance on protocol contents and format. 2.2.5 Version control all formal trial documents using the document footer. When an amendment is required update both the version number and date to allow amendments to be tracked (e.g. Protocol Version 1 (01/09/2013) would become Protocol Version 2 (12/09/2013) following an amendment.) 2.2.6 Superseded documents should always be marked as such to avoid accidental misuse. Strike a line through the front of the document and annotate as superseded. File in descending date order behind the current protocol or in a separate section if required (file note required if an alternate location is used.) 2.2.7 An Amendment Tracker Log should be implemented to record all amendments to trial documentation. This should include the version and date of the document, date of REC, R&I and MHRA approval (if applicable) and date implemented at site, allowing research teams to successfully manage version control to ensure the most current approved document is in use. A template amendment tracker log can be located on the R&I website for reference. 2.3 Blank Patient Information Sheet (PIS), Informed Consent Form (ICF) and GP letter (final and amendments) 2.3.1 Store copies of all template versions of the PIS/ICF and GP letter used throughout the trial in your ISF (marked as superseded where appropriate). 2.3.2 All information provided to the patient must be localised with the LTHT headers before use. V1.0 (131021) Page 5 of 12
2.3.3 The PIS,ICF and GP letter should be version controlled, with the version number and date updated each time the document is amended. 2.3.4 For information on how to construct a PIS and Consent Form and what information should be included, please see the template version located on the R&I website. 2.3.5 A template consent form can also be located on the NRES website. 2.4 Other Patient Related Documentation 2.4.1 Examples of documents to be stored in this section are; patient card, diary card, adverts, posters, dosing instructions, questionnaires. 2.4.2 Template versions of these documents should be stored in the TMF as master copies and be ethically approved versions. 2.5 Original Signed Consent Forms 2.5.1 Within LTHT it is recommended that the original signed consent forms be stored in the TMF/ISF (with a copy provided to the patient and a copy filed within the patients medical notes along with the PIS and GP letter). 2.5.2 Any member of staff obtaining consent for a clinical trial involving an Investigational Medicinal Product (IMP) must: - Complete the Trusts Informed Consent Workshop or the NIHR GCP Training (which incorporates the relevant Informed Consent Slides), - Be delegated to obtain consent by the CI/PI - Be appropriately qualified to undertake the task (e.g. research nurses are only permitted to obtain consent if this is clear in the trial protocol and REC application). 2.5.3 Whilst completing and / or filing any signed consent forms please check the following aspects: - All fields are complete and refer to the correct ethically approved PIS in use. - Investigator and patient sign the form on the same date (patient must personally sign and date their part of the form). - The member of staff obtaining consent is on the staff delegation log - All boxes are initialled by the patient (none left blank and none ticked rather than initialled.) 2.5.4 Errors in consent should be rectified if possible and explained via a file note. V1.0 (131021) Page 6 of 12
2.6 Contracts and Financial Agreements: 2.6.1 Contracts (signed copies) must be stored within the ISF / TMF to document agreements and financial arrangements between the investigator / institution, Sponsor and third party sub-contractors if applicable. 2.7 Sponsor Correspondence and Approvals: 2.7.1 Please file a copy of the Confirmation of Sponsorship letter and other relevant documents within the ISF for Leeds Sponsored trials. 2.7.2 The original R&I approval and approval of all substantial amendments must also be filed to provide a full audit trail of the documents used. 2.8 Regulatory Approvals and Correspondence: 2.8.1 The MHRA Clinical Trials Application, approval letters (initial and amendments) and correspondence (e.g. response to notification for grounds for non-acceptance) must be filed within the ISF for confirmation and audit trail purposes. 2.8.2 Notification of Substantial Amendment Forms and any other correspondence (including sponsor review forms) surrounding amendments must also be filed. 2.9 Research Ethics Approvals and Correspondence: 2.9.1 REC approval letters (initial and amendments) and associated correspondence (e.g. response to provisional/conditional approval letters, completed REC form) must be filed within the ISF to document that the trial has been subject to REC approval and granted favourable opinion. It will also identify which version numbers of documents are approved. 2.9.2 Notification of Substantial Amendment Forms and any other correspondence (including sponsor review forms) surrounding amendments must also be filed. 2.10 General Correspondence: 2.10.1 Relevant communication must be stored to document any agreements or significant discussions regarding the trial administration, protocol violations, potential serious breaches, trial conduct and adverse event reporting. 2.10.2 File any emails, letters, newsletters which contribute to the reconstruction of the trial. 2.10.3 Avoid duplication (e.g. chain emails) and file in date order with the most recent communication on top. V1.0 (131021) Page 7 of 12
2.11 Staff Authorisation Log / Delegation Log and CVs / GCPs: 2.11.1 The staff delegation log allows the PI/CI to delegate specific trial tasks to members of the research team. A template log can be obtained from the R&I website. This acts as a signature log allowing staff signatures to be cross referenced and verified when seen on trial documents e.g. Case Report Form (CRF) corrections/ entries made into medical notes. 2.11.2 The tasks assigned must be appropriate to the skills, experience and qualifications of the member of staff. Therefore signed and dated CVs and GCP training certificates must be filed for every member of staff listed. CVs and GCP training should be updated every two years. 2.11.3 The delegation log must be signed and dated by the CI/PI for each member of trial staff to confirm they are authorised to work on the trial. 2.11.4 The delegation log must be updated to include new members of staff and stop dates. No member of staff should commence trial related activities without first completing this log. 2.11.4 Remember to include the lead pharmacist to cover any pharmacy related tasks e.g. dispensing, drug accountability etc. 2.12 Screening Logs and Patient log: 2.12.1 A Trial Screening Log or Pre-Screening Log can be used to record patients who were approached/screened but not entered onto the trial e.g. they later declined to participate or failed pre-screening. Full names and identifiable information must not be recorded and stored in the ISF for any patient who has not consented to the trial (initials and date of birth are acceptable). 2.12.2 Capture the reason why a patient was not consented / randomised on the log to illustrate recruitment patterns or problems with the design of the trial e.g. numerous patients failing the same inclusion / exclusion criteria which may require a protocol amendment. 2.12.3 A Patient Identification Log must also be maintained and filed confirming which patients were enrolled. Typical fields include: patient name, patient trial number, consent date and randomisation date. 2.12.4 Patient logs must not be sent off the NHS site e.g. to the trial sponsor, so as not to breach patient confidentiality. 2.13 Phamacovigilance: 2.13.1 File blank Serious Adverse Event (SAE) Forms and SAE reporting procedures within the site file. Please ensure you have the most current version filed containing the correct sponsor contact/fax details. V1.0 (131021) Page 8 of 12
2.13.2 Your trial protocol must include a safety reporting section explaining how both Adverse Events (AEs) and Serious Adverse Events (SAE) are defined and reported. 2.13.3 It is useful to maintain an SAE log documenting the following points: - Description of SAE - Causality/seriousness - Start Date - Date reported to the trial sponsor - Date SAE resolved. 2.13.4 If an initial report is submitted, please ensure a follow up report is forwarded to the Sponsor once new information becomes available. SAEs should be followed up to resolution / stop date and the SAE must be fully documented within the patient s medical notes to enable source data verification. 2.14 (IMP) Accountability Logs, SPC and IBs 2.14.1 Pharmacy related documents e.g. drug accountability log, shipping records, disposal logs, dispensing procedures, temperature logs etc are often maintained in a separate pharmacy file held within the clinical trials pharmacy department you should check if this is happening. 2.14.2 Drug Accountability Logs must fully document what medication was received by the site, patient, when and where, as well as any medication returned to the Sponsor or destroyed. The running total of medication held at pharmacy is also recorded. 2.14.3 Pharmacy must maintain temperature records to confirm the IMP is stored within the correct parameters as instructed by the dispensing procedure, IB or SPC. However, if the IMP is to be stored with the research team separate temperature records must be maintained. Liaise with LTHT pharmacy for guidance. 2.14.4 Any equipment used i.e. temperature probes and fridges must be regularly serviced and calibrated for use. Please ensure all servicing and calibration records are stored within the file. 2.14.2 If your department is responsible for storing or dispensing the IMP (e.g. IMP is stored in clinic or theatre for the duration of the trial), separate accountability records should be maintained to ensure the whole IMP pathway is documented. 214.3 Investigator Brochures /Summary of Product Characteristic for all IMPs used in the trial must also be stored in the ISF/TMF and updated when necessary. Other documents such as Good Manufacturing Documents, Qualified Person Release, Certificate of Analysis, Manufacturing Authorisation and IMP License may also be required. V1.0 (131021) Page 9 of 12
2.15 Central Laboratory and Local Analysis of Biological Samples: 2.15.1 For any lab equipment used i.e. freezers and centrifuges please ensure all calibration records are stored within the ISF/TMF. 2.15.2 If external laboratories/analysis is used please ensure 3 rd party contracts are established with the organisation and that they are stored within the ISF. 2.15.3 Please store copies of the trial specific lab sample request forms in the ISF along with confirmation of sending/receipt. 2.16 Randomisation and Un-blinding 2.16.1 File randomisation and code break instructions, template unblinding form (if applicable), out of hours contacts and registration numbers / confirmation of randomisation faxes within the site file. 2.17 Case Report Form: 2.17.1 A blank template CRF should be stored in the site file. Only information requested on the CRF should be recorded, and it should not contain any patient identifiable information. 2.17.2 The CRF should directly match the protocol and only request information which is specifically required. More detailed guidance on how to construct a CRF can be obtained from the QA department / R&I website (CTGN 44) 2.18 Quality Assurance / Audit / Inspections and Monitoring: 2.18.1 Please keep a record of any monitoring visit or audit reports within the site file. 2.18.2 For Leeds Sponsored trials this will include a site initiation visit report and any routine monitoring visit action reports. 2.18.3 Store both the Monitoring Action Reports and completed responses showing what corrective action was implemented at site for confirmation purposes. 2.21 TSC / DMC Correspondence 2.18.1 Trial Steering Committees usually meet on an annual basis (more frequent for high risk studies please consult your trial protocol). Meeting minutes and significant discussions must be stored within the ISF. 2.22 Database and Data Record Logs 2.22.1 A blank copy of any trial database and any associated documentation i.e. validation and management, should be filed within this section. V1.0 (131021) Page 10 of 12
2.23 Statistical Analysis Plan 2.23.1 A copy of the statistical analysis plan or relevant section of the protocol describing the statistical considerations of the trial must be filed within the ISF. 2.24 Safety Reporting: 2.24.1 Copies of the annual Development Safety Update Reports (DSUR) sent to the MHRA and executive summary sent to the REC must be filed within the ISF including the SAE line listings. For older trials any annual progress reports / safety reports must also be filled together with the associated MHRA/REC correspondence. 3.0 Documentation to be stored following trial closure: 3.1 Trial Closure 3.1.1 Please complete and file the declaration of end of trial form and close down monitoring visit report within the ISF. The Sponsor close down visit will ensure the ISF / TMF is complete and fit for archiving. 3.2 Publications 3.2.1 Once data from the trial has been published any relevant documentation must be filed within the ISF. 3.3 Archiving 3.3.1 Please refer to the archiving section of your trial protocol or the separate archiving SOP available from QA / R&I website. 4.0 General Trial Documentation Tips: File documentation within the ISF subsections in date order with the most recent document on top. Documents can be stored electronically e.g. copies of the IB/superseded protocols to save space within the ISF however this must be referenced within the ISF via a file note and all documentation must be printed out as hard copy prior to archiving/requested by the sponsor/mhra. When new trial documentation is approved for use do not discard previous versions Instead mark the old copies as superseded by striking a single line across the front of the document and annotating as superseded. When creating and updating trial documents please include version control e.g. version 1.0 (01/01/2013). When the document is amended please update BOTH the date and version number in the footer (e.g. version 2 (01/02/2013)) V1.0 (131021) Page 11 of 12
5.0 As an Investigator you must ensure the following: A site file is made for each CTIMP containing all essential documents, complete with a contents list for easy navigation. The file will be constructed at the start of the trial and be updated in a timely manner A staff authorisation log / delegation log will be created and maintained detailing all staff working on the trial. Training documentation will be updated every two years, or where applicable. All formal trial documents (including the information provided to the patient) must receive the necessary approvals e.g. Sponsor/R&I/REC/MHRA prior to implementation, including any substantially amended documents. The site file will not contain patient identifiable detail (such as sections of the medical notes or correspondence naming the patient.) Section D References MHRA Good Clinical Practice Guide 2012 E6 Guideline for Good Clinical Practise version 2.1 August 2011 Section E CI CRF CTIMP DMC DSUR GCP GP IB ISF ICF LTHT MHRA PI PIS QA R&I REC SAE SOP SPC SSI SUSAR TSC UoL Definitions Chief Investigator Case Report Form Clinical Trial of an Data Monitoring Committee Development Safety Update Report Good Clinical Practise General Practitioner Investigator Brochure Investigator Site File Informed Consent Form Leeds Teaching Hospitals Trust Medicines and Healthcare products Regulatory Agency Principal Investigator Patient Information Sheet Quality Assurance Research and Innovation Research Ethics Committee Serious Adverse Event Standard Operation Procedure Summary of Product Characteristics Site Specific Information Suspected Unexpected Serious Adverse Reaction Trial Steering Committee University of Leeds V1.0 (131021) Page 12 of 12