Trial Master FileDansk Selskab for Good Clinical Practice (DSGCP)

Philip Lange Møller og Lene Bjerring Bork

5. Februar 2020

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• The security of the cabinet• One key opens all

• Trial Master File

• Medical records

• IMP – Blinded period• Open labelled

• IMP – Returned (used)

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• SOPs for using electronic systems

• User Requirements Specification (URS)

• User Acceptance Tests (UAT)

• System release

• Control of access• Password• Role and rights

• Control of access to:• Building and rooms• Access to the server it self

• Server and maintenance• Firewall – updates• Platform – updates and patching• Programs – updates and patching• Intrusion detection and testing

• Audit trail• User friendly overview• Searching and listing tools

• Backup and Recovery

Paper based Electronic systems

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Electronic systems in clinical trials

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EMA inspection announcement letter

• You should ensure that you have identified ALL the trial documentation and its location that comprises the TMF and determined how this will be made readily available to the inspectors.

• Remember that the TMF may consist of trial relevant documentation held in files of various departments, e.g. pharmacovigilance, data management, statistics, R&D etc.

• ALL the documentation that comprises the TMF (that is the documentation that allows the inspectors to evaluate the conduct of trial) must be made available for direct access by the inspectors, including any electronic documentation (for example email correspondence). Any equipment and software etc. to access any electronic documentation will need to be provided by the organisation.

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TMF: basis for control

[GCP Directive 2005/28/EC: Chapter 4 Article 16]

The trial master file shall provide the basis for the audit by thesponsor’s independent auditor and for the inspection by thecompetent authority.

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Definition of inspection

[Regulation 536/2014, article 2, § 2 (31)]

“Inspection” means the act by a competent authority of conducting an official review of documents, facilities, records, quality assurance arrangements, and …..

….. that may be located at the clinical trial site, at the sponsor's and/or CRO facilities, or at other establishments which the competent authority sees fit to inspect.

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The Regulation regarding Trial Master File

[Regulation No 536/2014 preamble (52)]During the trial: In order to be able to demonstrate compliance with the protocol and with this Regulation, a clinical trial master file, containing relevant documentation to allow effective supervision (monitoring by the sponsor and inspection by Member States), should be kept by the sponsor and by the investigator. After the trial: The clinical trial master file should be archived appropriately to allow for supervision after the clinical trial has ended.

[Regulation (EU) No 536/2014 Article 57]The sponsor and the investigator shall keep a clinical trial master file. The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated, taking into account all characteristics of the clinical trial, including in particular whether the clinical trial is a low-intervention clinical trial. It shall be readily available, and directly accessible upon request, to the Member States.

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The TMF key message

• The TMF must be updated timely and must containing relevant documentation to allow effective monitoring during the trial conduct.

• It shall be readily available, and directly accessible upon request, to the Member States for inspection.

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Access during the inspection

• Individual access codes and passwords

• Read only access.

• Printing of documents must be possible.

• Audit trail must be available.

• The eTMF should allow review in an efficient manner, analogous to what is possible with paper TMFs.

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“Old” archiving of TMF

[Directive 2005/28 Articles 17 – 20]• The sponsor and the investigator shall retain the essential documents relating to a clinical trial for

at least five years after its completion. They shall retain the documents for a longer period, where so required by other applicable requirements or by an agreement between the sponsor and the investigator. Essential documents shall be archived in a way that ensures that they are readily available, upon request, to the competent authorities.

• Any transfer of ownership of the data or of documents shall be documented. The new owner shall assume responsibility for data retention and archiving in accordance with Article 17.

• The sponsor shall appoint individuals within its organization who are responsible for archives.

• Access to archives shall be restricted to the named individuals responsible for the archives.

• The media used to store essential documents shall be such that those documents remain complete and legible throughout the required period of retention and can be made available to the competent authorities upon request.

• Any alteration to records shall be traceable.

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“Old” long term archiving

[Directive 2003/63 Annex 1, section 5.2 (c)]

• Marketing authorisation holders must arrange for essential clinical trial documents (including case report forms) other than subject’s medical files, to be kept by the owners of the data:

• for at least 15 years after completion or discontinuation of the trial,

• or for at least two years after the granting of the last marketing authorisation in the European Community and when there are no pending or contemplated marketing applications in the European Community,

• or for at least two years after formal discontinuation of clinical development of the investigational product.

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Future archiving of the TMF

[Regulation 536/2014 , Article 58]

• Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial.

• However, the medical files of subjects shall be archived in accordance with national law.

• The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

• Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

• The sponsor shall appoint individuals within its organisation to be responsible for archives. Access to archives shall be restricted to those individuals.

• The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

• Any alteration to the content of the clinical trial master file shall be traceable.

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TMF guidelines

EudraLex Volume 10, Chapter V: Recommendation on the content of the trial master file and archiving July 2006

EMA/INS/GCP/856758/2018 : Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)

NEW GUIDANCE

2018

EU GCP Inspectors Working Group - Subgroup

Additional guidance:

EMA Q&A: Good clinical practice (GCP)Paragraph: GCP matters – bullet 12 and sub-bullets.

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Guideline on GCP compliance in relation to trial master file (paper and/or electronic)

EMA Q&A: Good clinical practice (GCP)

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Trial Master File (TMF)

• The Regulation does not differentiate between paper and electronic TMFs therefore all the requirements are the same for both formats.

• The investigators TMF must be used by PI and relevant site staff.

• The CRO TMF must be used by relevant CRO (and sponsor) staff

• The sponsor TMF must be used by relevant sponsor (and CRO) staff

• The TMF is used by monitors, auditors and inspectors to assess whether the sponsor, CRO(s) and the investigator(s) complies with the Regulation, the principles and guidelines of GCP and with any other applicable regulatory requirements.

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TMF content and index

• The sponsor and the investigator should identify and make a record of the location(s) of all of the potential documentation that is considered to form the TMF, even if several locations, departments, country organisations and systems are involved, so that it is effectively organised.

• The investigator/institution is responsible for and should therefore have control of all essential documents and records generated by the investigator/institution before, during and after the trial.

• Some documents may be pertinent to more than one clinical trial; such as the Investigator Brochure or documents that are stored in a centralised system, for example central training records, SOPs and delegation logs, documentation demonstrating the validation of computer systems that are not trial-specific.

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Archiving of investigators TMF

• The sponsor can arrange long term archiving for the investigator.

• Investigator must continue to have control over their TMF and data.

• Retrieval of archived files and documents must never cross the sponsor or be in their hands at any time.

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Use of a portal

• Where a portal is used to provide documents to the investigator, if this is not part of the investigator TMF there needs to be a mechanism to ensure such documentation is filed in the official investigator TMF.

• Also, consideration should be given to provision of an audit trail to demonstrate investigator access to documents in the portal at the appropriate time.

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Timeliness of the TMF update

• The TMF shall be up to date.

• In trials with multiple parties involved, the timescales for submission and filing of documents to the TMF should be defined.

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Essential documents

The index of the TMF in chapter 8 of the CPMP/ICH/135/95 (ICH GCP) defines the minimum number and types of documents that usually is considered essential for any given trial.

This can not always be considered exhaustive list.

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Electronic TMF (eTMF)

• Formalized procedures for user and password management

• User accounts: Individual and function limited

• Role based privileges and access rights (e.g. blinded / unblinded);

• Secure passwords for users and password complexity requirement;

• Audit trail that identifies date/time/user details for creation, uploading, approval and changes to a document;

• Procedure for checks of audit trails

• Procedure for locking and protecting individual documents to prevent accidental changes to documents (including long time archiving);

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Validation of an eTMF

• The eTMF should be validated in accordance with published standards to demonstrate that the functionality is fit for purpose, with formal procedures in place to manage this process.

• The procedures should describe system installation including functionality testing, system maintenance, system security measures, change control, data backup, recovery, contingency planning, decommissioning and, if applicable, transition to a new system.

• All members of staff involved in the conduct of the trial and using the system should receive appropriate training.

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Transferral of documents

The process for transferring documents should be robust and should be validated (i.e. there should be a demonstrable 1:1 mapping between the content of the two systems).

Verification that any audit trail has been transferred.

Example could be the CRO eTMF system uploads documents into the sponsor eTMF system.

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Version control and prints from the eTMF

• Version control should be applied to electronic documents in the system.

• If the document is printed to paper the same version control should be apparent on the printed version.

• Expiry timeline for printed documents should be considered.

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Backup and migration

• There should be a regular back-up of the eTMF with the back-up stored in a separate location and/or media.

• Any migration of data and documents to new media or a new format should be validated to ensure long-term readability.

• There should be periodic test retrieval or restores to confirm the on-going availability of the data.

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Scanning or transfers to other media

• The media used to archive the content of the clinical TMF shall be such that the content remains complete and legible throughout the retention period.

• Particular attention should be paid when records are stored on electronic, magnetic, optical or other non-permanent media. In such cases suitable controls should be implemented to ensure that these records cannot be altered without appropriate authorisation and the creation of an audit trail.

• Digitised documents in the eTMF should be a certified copy of the original (through a validated procedure).

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The digitisation process

• The use of eTMFs and electronic archiving generally requires the digitisation of original paper records to generate electronic copies.

• The digitisation process of transfer should be validated in order to ensure that certified copies are made to ensure that information will not be lost or altered.

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Certified copy

• A certified copy is a paper or electronic copy of the original record that has been verified (e.g. by a dated signature) or has been generated through a validated process to produce a copy having the exact content and meaning of the original.

• The ICH addendum:• A paper or electronic copy of the original record that has been verified (e.g.,

by a dated signature) or has been generated through a validated process to produce an exact copy having all of the same attributes and information as the original

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The SOP for the digitisation process

• approval for digitisation;

• transportation of the records to the location of digitisation;

• preparation and digitisation of the records;

• indexing and assignment of metadata;

• import of the digitised records into the eTMF system;

• quality control;

• destruction of the paper records;

• access to the eTMF system;

• changes to documents and metadata;

• migration of digitally hosted/archived records;

• deletion of digitally hosted/archived records.

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The SOP cont.

• The organisation should maintain records to demonstrate that the digitisation is effectively validated.

• As part of the validation a formal process should be in place for regular QC checks of digitised and indexed documents in the eTMF. This would usually be undertaken on a sampling basis, including escalation procedures where errors occur beyond a pre-defined Acceptance Quality Limit (AQL). The sponsor is responsible for deciding the AQL. The AQL may vary for different sets of documentation on a risk based approach.

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Document quality control

• accuracy of the metadata attributed to the document;• quality of the image (suitable resolution, readability, legibility,

reproduction of colour - where the colour has meaning, the quality of wet ink signature or annotations and handwriting in general etc.);

• whether it is the correct document (as expected);• that the document has the correct number of pages;• that a page or document was added as new to the digital archive and not

marked as a corrected version of an already-existing page or document;• the eTMF audit trail associated with the document; • chain of records transfer documentation;• approval process (where applicable);

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Destruction of digitised copies

• Taking into account the implications for providing legally recognized evidence and after consultation with its liability insurer, the sponsor as well as the investigator should decide whether documents legally requiring a signature (e.g. written informed consent of trial participants, contracts) should be sorted out and retained in the original form instead of being destroyed.

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Philip Lange Møllerplm@dadlnet.dk+45 2094 7016

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Lene Bjerring BorkGCP-krav@dkma.dk+45 4488 9595