CT SOP version no 2.0

Changes from version 1.0: Updated according to ICH GCP R3. Details added regarding archiving of documents from CTIS application/approval/notifications, recommendations to use an eTMF/eISF if available, and requirement concerning naming of electronic documents. 

Sponsor has the overall responsibility for clinical drug trial documentation and must file all required documents, including any updated versions.

The sponsor may transfer any or all of the sponsor's trial-related duties and functions to a service provider but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf. Transfer of duties shall be specified in a written agreement.

The coordinating investigator should ensure that the Trial Master File (TMF) contains the essential documents to be archived by the sponsor. These documents are the property of the sponsor. It is the coordinating investigator’s responsibility to create, store and update the TMF. These tasks can be delegated. The delegation of tasks shall be documented.

If the trial is a multicentre trial involving more than one health facility/institution, the coordinating investigator will manage the TMF for the trial, which includes documents from each trial site (health facility/institution). In addition, there will be an ISF at each trial site.

Investigator’s Site File (ISF) contains the essential documents to be archived by the principal investigators (PI). The sponsor is responsible for providing the PI with an ISF, and the PI is responsible for creating, storing and updating the essential documents throughout the trial.

The sponsor institution and the institution where each PI is employed should maintain an overview of where the TMF/ISF(s) are located and ensure that they are retrievable, complete, legible and accurate during the entire archiving period. The sponsor institution should also ensure that any electronic systems used for study archiving are validated, and that the validation documentation is kept on file.

General principles

The trial documentation is divided into a sponsor part known as TMF and a site-specific part known as ISF. If the trial is a single centre trial, the essential documents in the TMF and the ISF may be filed together, which means that two separate files are not required.

The completeness of the study files will be reviewed during the monitoring visits and possibly during a GCP inspection from the authorities and/or audit by the sponsor.

Trial documentation can be paper only, a combination of paper and electronic documents, or only electronic. If using an electronic file, the system should be able to track who did what and when in the documents.

If an electronic TMF/ISF (eTMF/eISF) is used, the following requirements should be fulfilled:

• Permissions are based on features/roles.
• Access control (audit trail) should be in place to identify the date/time/user who has created, uploaded, approved and changed a document.
• The system should be validated, and validation documentation should be stored in eTMF/eISF.
• Users should be trained, and training should be documented and stored in the eTMF/eISF
• A standardised naming convention of documents, similar to naming of documents in CTIS, should be used 

When paper documents are scanned to be stored in an eTMF/eISF, the originals may be disposed of after scanning, but the following requirements must be met:

• The file name of the document must clearly describe the content, and contain the scan date and version number, if applicable (e.g. creation date, the document name, version).
• The image quality should be satisfactory.
• The number of pages must match the original.

These requirements must be checked for each scanned document before the original is disposed of. The same procedure can be used for scanning of wet-ink signatures.

Both the sponsor and the principal investigators should ensure data integrity by ensuring the data can be traced to its source, is easily readable, recorded at the time of the event, is the original record, is free from errors, complete, consistent, enduring and available.   

For trials using VieDoc™ as eCRF, a template for the eTMF/eISF is available. The research support unit or responsible data manager should be contacted to discuss implementation of this function in VieDoc™.

Contents

The nature and extent of records generated and maintained are dependent on the trial design, its conduct, application of risk proportionate approaches and the importance and relevance of that record to the trial. A guidance to the essential documents to be kept in TMF are those listed in Appendix C 3.3. of the Guideline for good clinical practice E6(R3).

The structure of the TMF has the following sections:

1. Trial Management
2. Central Trial Documents
3. Site Management

If essential documents are not kept in the ISF, a note describing where they are kept must be filed, see Location of Document if not in ISF.

Superseded versions of documents will be kept in the TMF. Superseded versions of documents provided by the sponsor (e.g. trial protocol, Investigators Brochure (IB)/ Summary of Product Characteristics (SmPC) and CRF data) should be present in the ISF in a manner to enable reconstruction without the need to access the TMF, with evidence of date of receipt (e.g. email or download from a web site), review and/or approval (when necessary) and date of implementation by the principal investigator.

To document approval in CTIS, the following documentation should be filed:

• The decision letter (vedtak) and documents the letter is referring to.
• The cover letter from the application and from answering RFIs.
• List of documents with version number that has been approved. This should have been included in the cover letters.

The TMF and ISF should be prepared by the coordinating investigator before the recruitment of the first trial participant. Table of contents templates for the Trial Master File (TMF) Table of Content Muliticenter Trial and the Investigator’s Site File (ISF) Table of Content for multi-centre trials, or if relevant the template for the combined TMF/ISF Table of Content Single Center Trial for a single centre trial, should be used.

There are templates for documents included in the TMF (see under section Attachments). It is recommended that these templates are used to ensure that essential documents are created according to ICH GCP.

The most important documents that should be filed in TMF/ISF. The ones with * (asterisk) should be filed before trial start. 

• Protocol* and all protocol amendments, dated and signed by Sponsor
• Investigator's Brochure* or Summary of Product Charateristics*
• Patient information sheet and informed consent forms (all approved versions)*
• Example of the blank CRF*
• Source Data List *
• Contact Information Study Team, including the Delegation Log
• CVs and documentation of ICH GCP-training for investigators (Investigator Curriculum Vitae) and for other study personnel (Non-investigators Curriculum Vitae), dated and signed
• Insurance certificate ( for Norway: Drug Liability Association, Legemiddelansvarsforeningen)*
• Approvals, applications and correspondence through CTIS with competent authorities (e.g. Norwegian Medical Products Agency (DMP)) and independent ethics committees (IEC, e.g. Regional Committees for Medical and Health Research Ethics (REK)) and internal approvals* etc.
• Institutional Review Board/ Independent Ethics Committee composition (list of members and qualifications)* 
• Investigational Medicinal Product (IMP) documentation (e.g. preparation, management)
• Reference values, e.g. laboratory and technical procedures.
• Trial initiation report*, dated and signed
• Agreements and contracts*, dated and signed
• Relevant correspondence allowing reconstruction of important trial activities and decisions, or that contains other significant information
• Written study specific procedures for laboratory, imaging, etc. and documentation of certification/accreditation of facilitites 

And in the TMF only:

• Data Management Plan (DMP)
• Statistical Analysis Plan (SAP)
  • For blinded trials, it should be finalised before database lock
  • For open trials, it should be written before study start. The protocol may satisfy the requirements for being the first version of the SAP. 
• Monitoring plan
• Safety plan: If the Transcelerate protocol template is used, the protocol may serve as the safety plan together with SOP Safety planning and SOP Safety Reporting.

Randomisation lists should be kept with restricted access based on roles to ensure that the randomisation and/or the blinding of the trial are kept. 

And in the ISF only:

• The Screening Log and Identification & Enrollment Log
• IMP Accountability Form, different variations available as templates,  choose one that is fit for the purpose and adapt as necessary (IMP Accountability Form Common Stock Unnumbered, IMP Accountability Form Different Manufacturers, IMP Accountability Form with kit or ID-number)
• Laboratory Sample Storage Log 

The contents of the TMF and ISF must be updated each time a change occurs in the documents on file. Any change in the documents should be traceable. The documents to be filed/updated in the TMF are reflected in Checklist Conduct of Clinical Trial - Sponsor, similarly in Checklist Conduct of Clinical Trial - Centre for ISF.

The Sponsor should keep unblinded adverse event data with restricted access based on roles to ensure that the randomisation and/or the blinding of the trial are kept.

It is important to keep the TMF/ISF updated thought out the study. The monitor will check the completeness of the TMF/ISF during monitoring visits.

Storage

Review the "General Principles" section.

The TMF/ISF, both electronic and paper documents, should be kept secure and with restricted access by the Sponsor/coordinating investigator/PI.

Only trial team members, monitors, auditors and inspectors should have access to the TMF/ISF. The Identification & Enrollment Log and any other documents (e.g. informed consent documents) identifying trial participants should be kept separate from the collected data (CRF/eCRF). 

Any copies of patient records must preferably be shredded after monitoring visits.

Important emails/communication should be stored with information about sender, recipient, and date. It is recommended to have a specific folder in the email system for emails that should be printed out and filed  or archived electronically in the TMF/ISF.

Close-out

Review the "General Principles" section.

At the end of the trial the TMF/ISF must be updated before long-term archiving. See also SOP Completion, Reporting and Archiving.

Any copies of patient records must be shredded at the end of the trial and not included in the archived TMF/ISF.

Important emails/communication should be stored in the TMF/ISF with information about sender, recipient, and date.

Duplication of documentation should be avoided.

The medium chosen for archiving (i.e. paper or electronic) should be documented on the tables of content of the TMF/ISF by putting a check mark in the appropriate column. If an electronic system is chosen, paper documents should be scanned as described under the section "General Principles". The certification of the scanning should be documented at the end of the tables of content of the TMF/ISF.

Only trial team members, monitors, auditors and inspectors should have access to the TMF. The Identification & Enrollment Log and any other document (e.g. informed consent documents) identifying trial participants should be kept separate from the collected data (CRF/eCRF).

Sponsor/PI will archive the TMF/ISF for at least 25 years after the trial is completed, in accordance with reg. 536/2014. For advanced therapy trials the documentation should be stored for 30 years, please refer to SOP Advanced Therapies. There is no requirement for documentation to be archived on-site, however the TMF shall be archived in a way that ensures it is readily available and accessible upon request to the sponsor, auditor and monitor.

The Sponsor/PI/Coordinating investigator shall ensure there are procedures to protect the documents throughout the archiving period.

• Checklist Conduct of Clinical Trial - Sponsor - Template
• Checklist Conduct of Clinical Trial - Centre - Template
• Trial Master File (TMF) Table of Content Muliticenter Trial - Template
• Investigator’s Site File (ISF) Table of Content - Template
• TMF/ISF Table of Content Single Center Trial - Template
• Location of Document if not in ISF - Template
• Informed Consent Form Version Tracking Log - Template
• Protocol - Template
• Protocol Version Tracking Log - Template
• Contact Information Study Team - Template
• Meeting Participants List - Template
• Prescreening Log - Template
• Screening Log - Template
• Identification & Enrollment Log - Template
• Laboratory Sample Storage Log - Template
• Source Data List - Template
• Pharmacy File Table of Contents - Template
• Delegation Log - Template
• Training Log - Template
• CV for Investigators - Template
• CV for Non-investigators - Template
• Data Management Plan - Template
• Statistical Analysis Plan - Template
• Monitoring Plan - Template