The vital part of each Clinical Trial conduct is management of Essential Documents.
According to established Good Clinical Practice (GCP) guidelines “Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the Investigator, Sponsor and Monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.”.
The various Essential Documents are grouped in three sections according to the stage of the Clinical Trial during which they will normally be generated:
- before the clinical phase of the trial commences,
- during the clinical conduct of the trial, and
- after completion or termination of the trial.
GCP provides descriptions of the purpose of each Essential Document, and whether it should be filed in either the Investigator/Institution or Sponsor files, or both.
Trial Master Files (either paper or electronic, hereinafter referred to as “(e)TMF”) should be established at the beginning of the trial, both at the Investigator/Institution’s Site (usually referred to as “Investigator Site File”) and at the Sponsor’s office. A final close-out of a trial can only be done when both Investigator/Institution and Sponsor files are reviewed and it is confirmed that all necessary documents are filed appropriately.
This article aims to briefly describe the management of Trial Master File in Clinical Trials.
Essential Documents should be collected and filed in the (e)TMF according to:
- Drug Information Association (DIA) TMF Reference Model
- Sponsor’s requirements
- Approved TMF Management Plan
- Regulatory requirements.
Essential Documents must be provided to the Sponsor and/or Regulatory Authorities representatives at first request. These documents must be always audit ready and available for review during the Clinical Trial conduct and within the defined by Sponsor/local Regulatory timelines archiving period.
The essential role in (e)TMF management of Clinical Trials lies within “TMF Coordinator” job role (at CRG it is a separate role, but in different companies it could be embedded into other clinical trial roles).
Typical responsibilities of TMF Coordinator are:
- Collection of Essential Documents for (e)TMF from Project Team members
- Renaming of Essential Documents according to TMF Naming Conventions specified in corresponding TMF Management Plan
- Timely submission of collected Essential Documents to (e)TMF:
- by directly uploading them to electronic TMF or filing them to paper TMF
- by separately sending them to the Sponsor/TPV’s TMF Specialist via previously approved TMF distribution list of e-mails/mailing addresses along with the corresponding completed transmittal forms.
In execution of the above responsibilities TMF Coordinator (blinded or unblinded, if applicable) closely cooperates with the rest of CRG Project Team.
Usually, the (e)TMF consists of the Trial File, Country File and Site Files:
- Trial File – documentation applicable to the trial level
- Country File – documentation applicable to the country level (in case more than one country participate in the Clinical Trial)
- Site File – documentation applicable to the site level, including Pharmacy File, if applicable.
The TMF Index is usually based on the DIA TMF Reference Model (version is agreed on a project-by-project basis). It is used to transmit final documents to their appropriate filing location and contains relevant information about TMF expectations for the Clinical Trial.
TMF Index according to the DIA TMF Reference Model is broken into several sections: Trial Management, Central Trial Documents, Regulatory, Investigational Review Board/Independent Ethics Committee and other Approvals, Site Management, Investigational Medicinal Product and Trial Supplies, Safety Reporting, Centralized Testing, Third Parties, Data Management, Statistics.
Depending on the activities being carried out, many Clinical Trials require additional documents not specifically mentioned, therefore the additional sections as part of the TMF Index might be included that will facilitate reconstructing and evaluating of the clinical trial conduct.
Filing of documents into (e)TMF
All responsible Clinical Trial Project Team members are required to ensure that the Essential Documents are submitted/uploaded to (e)TMF in a timely manner.
Essential Documents filed into (e)TMF should be checked prior to submission/uploading by applicable Project Team members, so they satisfy Good Documentation Practices.
Essential Documents should be checked against the next parameters (non-exhaustive list):
- Documents titled in compliance with the requirements of approved TMF Naming Conventions
- Version of document in line with the related SOPs/Work Instructions/Clinical Study Project Plans/applicable templates
- Document format – PDF is preferred document format for electronic TMF upload
- Document included in the correct section in a Transmittal Form for electronic TMF upload (if applicable)
- Originals or Certified Copies
- Translations if required and availability of corresponding Certificate of Translation Accuracy.
When a certain document is missing or is incomplete a “Note to File” Form should be completed, dated, and signed by the responsible Project Team member. Its purpose is to explain clearly and explicitly the reason of why the document is missing or is incomplete. It should be filed in (e)TMF replacing the missing document or clarifying any document-related issue(s).
Unblinded (e)TMF management
In case the Clinical Trial consists of blinded and unblinded components, at the beginning of the Clinical Trial unblinded Project Team is assigned. Unblinded Project Team is responsible to manage unblinded Essential Documents (these are usually related to Investigational Medicinal Products) and their filing to unblinded (e)TMF. Unblinded Essential Documents are located in corresponding Pharmacy File at Clinical Trial Sites.
Unblinded Essential Documents are managed only by unblinded Project and Site Teams similarly to blinded Essential Documents and this should be clearly reflected in TMF Management Plan.
(e)TMF retention and archiving
The retention and/or destruction procedures will be agreed with the Sponsor or applicable Third Party Vendor and described in corresponding TMF Management Plan. The retention period is to be adhered to and in accordance with the current country laws and regulations.
Carpathian Research Group capabilities
CRG as a CRO has extensive experience in management of (e)TMF and with our expertise Sponsors could be confident on (e)TMF inspection/audit readiness at any moment of Clinical Trial lifecycle.
Information on all other Clinical Trial services that we provide could be found at www.crg.global
You can contact us at email@example.com