CS05 Trial Master File 05senttoSOPCom13June2016approvalDASP Trial Master File_05... · TMF plan should be agreed with and approved by the sponsor and will provide clear ... the Investigator’s

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STANDARD OPERATING PROCEDURE (SOP)

CS05 Trial Master File, version 05

Author: TFS

Authorised by:

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Alistair Bone, Executive Vice President Quality Assurance

Approved by: Date of authorisatio

Daniel Spasic, CEO

001\) Qz16 Approval Date:

) Effective Date

The contents of this document are confidential. Unauthorised use, disclosure or reproduction without prior written permission from TFS is prohibited.

Unofficial copy –not valid

Trial Master File

Standard Operating Procedure

Version: 05

Number: CS05

Effective date: 11 July 2016

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The contents of this document are confidential. Unauthorised use, disclosure or reproduction without prior written

permission from TFS is prohibited.

CONTENTS 1 PURPOSE ..................................................................................................................... 3 2 SCOPE .......................................................................................................................... 3 3 DEFINITIONS ................................................................................................................ 3 4 RESPONSIBILITY ......................................................................................................... 3 5 TRIAL MASTER FILE SET UP AND MAINTENANCE .................................................. 4 6 TRIAL MASTER FILE PLAN ......................................................................................... 4 7 HANDLING OF DOCUMENTS ...................................................................................... 4 8 TRIAL MASTER FILE .................................................................................................... 5 8.1 General File .................................................................................................................. 5 8.2 Country File .................................................................................................................. 5 8.3 Site Specific File ........................................................................................................... 5 8.4 Single Site File .............................................................................................................. 6 8.5 Files and Labelling ........................................................................................................ 6 8.6 Plastic Pockets, Staples, Paper Clips ........................................................................... 6 9 INDEX ............................................................................................................................ 6 10 SUBJECT CONFIDENTIALITY ..................................................................................... 7 11 DOCUMENT PROCESSING ......................................................................................... 7 11.1 Submitting Documents to the Trial Master File ............................................................. 7 11.2 Quality Control .............................................................................................................. 8 12 CORRESPONDENCE ................................................................................................... 8 12.1 Project Specific Email Folder ........................................................................................ 8 12.1.1 Structure of the Project Specific Email Folder ........................................................... 9 12.2 Filing of emails in the project specific email folder ....................................................... 9 13 FILING AND ARCHIVING ............................................................................................. 9 14 CHECKLISTS .............................................................................................................. 10 15 TRANSFER OF THE TRIAL MASTER FILE TO THE SPONSOR .............................. 10 15.1 Verification of Documents ........................................................................................... 10 15.2 Electronic Files ........................................................................................................... 10 15.3 Shipment of Trial Master File to sponsor .................................................................... 10 16 PROJECT FILE ........................................................................................................... 11 17 ARCHIVING OF INVESTIGATOR’S FILE ................................................................... 11


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1 PURPOSE This Standard Operating Procedure (SOP) defines company policy and procedures to be followed in the handling and filing of documents when a paper Trial Master File is used for all or part of the documentation generated in a clinical trial. 2 SCOPE If the Trial Master File is kept at the sponsor’s office only copies of documents required by the study team will be filed at TFS offices, and this SOP is not applicable. 3 DEFINITIONS Trial Master File (TMF) A file containing all essential documentation relating to a clinical trial. Investigator’s File The investigator’s file is a file of essential documents for the conduct of a clinical trial maintained at the investigational site. Working File A working file with copies of relevant trial documents necessary on a day to day basis to run the trial. 4 RESPONSIBILITY Project Manager

Preparing the Trial Master File Plan Managing the Trial Master File in compliance with this SOP Ensuring that All the required sections of the Trial Master File are maintained Ensuring that a project specific email folder is created for the project

Clinical Trial Assistant (CTA) Maintaining the Trial Master File Keeping the Trial Master File checklist up to date

Project Safety Representative, Project Data Manager and Project Statistician Ensuring that relevant sub-sections of the Trial Master File are maintained and

provided to the CTA at the end of the trial Monitor

Setting up the investigator’s file (this task can be delegated to a Clinical Trial Assistant)


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Ensuring that the investigator’s file is complete and updated when visiting the site. 5 TRIAL MASTER FILE SET UP AND MAINTENANCE The TMF should be established at the beginning of the trial. This means as soon as the trial is handed over to the TFS project manager. Before the files are set up it should be agreed with the sponsor, in writing, where originals/copies (for each paper document) will be filed e.g. at the investigator site or in the TFS TMF. The TMF should be maintained in an up-to-date state at all times. All essential documents should be obtained on an on-going basis from the relevant personnel (e.g. monitor, investigator) so that the file is always as up to date as possible. Documents should be sent and filed at regular intervals (e.g. every month or second month). 6 TRIAL MASTER FILE PLAN A Project Manager will use the TMF plan template to prepare a project specific TMF plan will be created at the beginning of the trial, before any documents are entered into the TMF. The TMF plan should be agreed with and approved by the sponsor and will provide clear guidance as to how the TMF will be managed. This will include, but not be limited to:

Users Index Filing conventions Naming conventions Workflow Location(s) for processing and storing any paper documents Procedures for transfer of the TMF

7 HANDLING OF DOCUMENTS Before, during and after a clinical trial, all essential documents for the conduct of the trial should be kept in such a way that they are protected against unauthorised access, as well as against damage by fire or theft. Documents shall be filed according to the TMF index and in consecutive order with the most recent document at the front. If documents are filed elsewhere a cross-reference shall be made in the index. At the end of the trial the project manager or delegate shall confirm that the trial master file is ready for archiving by carrying out the following:


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Removing duplicates and unnecessary copies Removing paper clips, plastic folders and staples Checking that the contents are indicated on the index (if any section is not applicable, this shall be indicated by writing “NA” in the index) Writing a file note to explain why any expected documents are missing or filed

elsewhere and filing the note to file in the appropriate section (Note: that this is only required when the index shows that the documentation is expected. File notes are not required for documents which do not exist at the time of the check or which will never exist)

When the file has been checked, an experienced monitor (who has worked for at least three years as a monitor) or another experienced person shall perform quality control (QC) check of the TMF. The QC check shall be documented on a separate copy of the TMF index and the document shall be filed in the TFS working file. 8 TRIAL MASTER FILE The Trial Master File will be divided into a number of different sections the contents of which are clearly defined in the indexes for the different files. 8.1 General File This file will contain common documents for all countries such as the Clinical Study Protocol, the Investigator’s Brochure, not site specific agreements and appropriate documentation from the Project File. 8.2 Country File The country files, one for each country, will each contain all documents relating to the applications to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) and Competent Authority in that country and other country specific documents. 8.3 Site Specific File Site specific files, one for each site, will each contain all the site specific documents for each investigator site, such as CVs for staff, site specific financial agreements etc. Each file above will consist of a number of different sections. Some sections in the Trial Master File such as:

Section 8: Drug Safety Section 10: Data Management Section 13: Statistics


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will be filed by the respective department and added to the TMF at the end of the trial. 8.4 Single Site File For single site studies the Single Site Index will be used. 8.5 Files and Labelling All documents in the TMF should be filed in identical files (colour and type) with dividers between sections. Files should be labelled on the back with the following information at a minimum: Trial title / name or identifier File number 8.6 Plastic Pockets, Staples, Paper Clips TFS does not recommend the use of plastic pockets, staples or paper clips in aTMF. 9 INDEX An official index is available on the TFS Intranet for each section and these should be used for all clinical trials. The index is mandatory and the existing headings and numbering may not be changed. However, new sub-headings may be added. When sub-headings are used they should be numbered consistently with the existing system in the index. This could be done in two different ways, either by adding a new number at the bottom of the list or by adding a sub-section. For example, to add a sub-heading under header 2.2 it is possible to add 2.2a, 2.2b etc. The sub-headings should be related to the topic in the heading. Original, Copy, NA The index templates contain columns to identify which type of document will be filed where. The options are: O = Original C = Copy NA = Not Applicable: this means that the document will not be available for this trial The grey fields indicate that it is not relevant whether the document is an original or copy. If a document will not exist for the trial then “NA” should be added to the grey field. The index template contains recommendations about the locations of originals and copies. These locations should be agreed with the sponsor. This agreement should be documented (by email or otherwise). The index should be modified to clearly identify where original documents should be filed according to the agreement with the sponsor.


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10 SUBJECT CONFIDENTIALITY Under the EU Data Protection Directive and USA Health Insurance Portability and Accountability Act (HIPAA), and in order to protect their legal right to confidentiality of personal information, TFS cannot accept any documents which contain the following information on a trial subject:

Name Postal address (other than state/county, city/town) Telephone number Fax number Email address Social Security Number or equivalent Insurance Certificate number Driver’s License number Vehicle ID / Serial number Personal URLs IP address Full face or comparable images Medical record number Prescription number Health plan beneficiary number Bank account numbers Medical device identifiers and serial numbers Biometric identifiers Fingerprints Voiceprints Passport number

Any documents with any of these attributes received by TFS will be handled as described in the TFS Data protection SOP. 11 DOCUMENT PROCESSING 11.1 Submitting Documents to the Trial Master File Monitors and other TFS personnel who collect and/or generate essential paper documents are responsible for submitting documents to the CTA (or the person responsible for filing) on a regular basis (at least every 2 months). It should be clearly identified in the TMF plan how documents can be sent to the Trial Master File.


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Senders are responsible for ensuring: The shipment includes a document which identified the documents sent The quality of the documents

Readability check, reproduction of colour, quality of wet ink signature or annotations and handwriting in general

Confirmation that the document has the correct number of pages Confirmation that all applicable signatures and dates are present

11.2 Quality Control After the document has been received the following QC activities should be performed as a minimum:

• Confirmation that it is the correct document • Readability check, reproduction of colour, quality of wet ink signature or annotations

and handwriting in general • Confirmation that the document has the correct number of pages • Confirmation that all applicable signatures and dates are present

QC may be performed by the CTA, or other person to whom this task has been delegated. A quality control plan should be included in the TMF plan. 12 CORRESPONDENCE Any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, and adverse event (AE) reporting will be documented and filed in compliance with ICH E6 GCP 8.3.11 which requires that the following correspondence should be filed: Relevant communications other than site visits - letters - meeting notes - notes of telephone calls It is important that sufficient documents are filed to be able to identify what decisions have been made and why. However, not all correspondence has to be filed in the paper TMF. 12.1 Project Specific Email Folder All project related emails should be kept in a project specific email folder.


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During the start-up phase of a project the Project Manager will request TFS IT to create a project specific email folder in Outlook. The Project Manager will inform TFS IT who should be given access to this email folder. The Project Manager will inform TFS IT to change the access rights if there is a change in staff. Once the trial is complete and the TMF is being prepared for shipping to the sponsor all emails will be transferred to suitable media for inclusion in the TMF.

12.1.1 Structure of the Project Specific Email Folder

The project specific email folder should include the following sub-folders at a minimum: - Sponsor - Project Manager - Separate sub-folders for all departments involved in the project: data management,

statistics, medical writing, regulatory affairs, drug safety. If a lead is assigned for each department, a lead-sub-folder for each department should also be created.

- For clinical operations, several sub-folders should be created: lead sub-folder; separate sub-folders for each country and/or each site, as applicable for the trial; sub-folders for IEC/ IRB

- A sub-folder for each sub-contractor/vendor involved in the trial - Internal 12.2 Filing of emails in the project specific email folder Any TFS employee who sends an email which meets the above definition of relevant should copy the appropriate email folder address. For emails received from a person outside TFS the first addressee should file the email in the project specific email (sub-) folder, unless otherwise agreed. 13 FILING AND ARCHIVING During an ongoing trial the TMF should be stored in locked cupboards or a storage area with restricted access. The cupboards or storage area should be fire resistant or fireproof and there should be adequate fire prevention in the facilities. This means there should be smoke detectors and sprinklers or fire extinguishers. If sprinklers are in place a risk assessment should be performed to ensure that there is no unnecessary risk for damage by water. Smoke detectors should be connected to the fire brigade or other 24 hour a day, 7 days a week service to ensure that immediate action is taken in the event of a fire.


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Original documents should be stored in a manner which ensures that the risk for accidental destruction by fire or otherwise is minimised. If this cannot be achieved by storing them in a separate fireproof area, then documents should be shipped to the sponsor. 14 CHECKLISTS A checklist (to be found on the TFS Intranet) with details of all the documents in the Trial Master File (version numbers etc.) should be maintained and updated throughout the trial. This document will be forwarded to the sponsor at the end of the trial and will act as confirmation of all documents in the file. 15 TRANSFER OF THE TRIAL MASTER FILE TO THE SPONSOR At the end of the trial the Project Manager should contact the sponsor and agree on how and when the Trial Master File should be shipped to the sponsor. This will normally be done after the clinical study report has been written but should be no later than 3 months after the database lock meeting. 15.1 Verification of Documents All the files should be reconciled and the documents in the TMF should be verified against the checklist. 15.2 Electronic Files Data Management clinical data / databases will be copied to CD, or other suitable media) preferably as SAS files, or other formats agreed with the sponsor Project-specific email folders and sub-folders (including the emails) can be copied to suitable media) and sent to the sponsor. The contents of the media should be verified and it should be documented in a file note that they contain the trial documents. 15.3 Shipment of Trial Master File to sponsor The entire TMF together with the electronic files should be shipped to the sponsor with the TMF checklist, together with an official transfer letter which will require confirmation that all documents have been safely received. If a confirmation of receipt is not received, within 20 working days, then the Project Manager will contact the sponsor to confirm receipt. It should be agreed with the sponsor when and how the TMF should be transferred. It is recommended that a courier such as UPS is used.


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16 PROJECT FILE The Project Manager should maintain a Project File which should contain, amongst other documents: Project Plan (first approved version and updates) Project team lists COSMOS plan Internal project meeting minutes Deviation logs Project specific training logs Handover forms Change orders List of trial specific SOPs All reports submitted to the sponsor, such as status reports QC checklists Transfer letter 17 ARCHIVING OF INVESTIGATOR’S FILE The investigator/institution should maintain the trial documents as specified in ICH E6 GCP Section 8 Essential Documents for the Conduct of a Clinical Trial and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents. Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained. (Reference: ICH E6 GCP 4.9.5) It is the responsibility of the monitor to inform the principal investigator of the need to take measures to prevent accidental or premature destruction of the trial documents in the Investigator’s File. The Principal Investigator shall be instructed that if he/she moves or retires he/she shall nominate someone in writing to be responsible for the record keeping. The Principal Investigator must inform the sponsor about this.


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Upon request of the sponsor, TFS will assist in arranging for archiving in a third party archive.


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DOCUMENT HISTORY

Version No Effective Date Brief Description of Change New training required

Yes No

01 1 February 2002 New SOP 02 10 September 2006 General update to harmonise

TFS and CDC SOPs

03 17 December 2010 Minor updates to improve the SOP

04 29 May 2013 Update re set up and maintenance of the Trial Master File

05 11 July 2016 Replacing study with trial. Using the term trial master file (TMF). Limiting scope to paper TMF, managed by TFS. Re-definition of responsibilities. Addition of subject confidentiality process section and a section on emails. Other minor changes.

EXTENSION WITHOUT CHANGES

Review date Extension valid to QA Approval

9 September 2009 11 September 2010 Approved directly on the SOP 10 September 2010 10 March 2011 Approved directly on the SOP

25 April 2016

25 April 2017 Extension in section Extension without changes in version 4
