Our top 10 Q&A on Trial Master File
1. What is a Trial Master File (TMF)?
Each clinical trial comes with documentation of trial related activities, legal requirements and trial data. All trial related documents need to be collected, organised, managed and maintained in what is called the “Trial Master File” or Electronic Trial Master File (eTMF).
2. Why is a TMF needed?
A TMF is essential to enable the evaluation of the conduct of the clinical trial, the integrity of the trial data and the compliance with regulatory requirements. A TMF allows reconstruction of the trial activities undertaken, trial decisions made and trial data generated. A TMF is also indispensable to manage the
clinical trial as it permits involved individuals to access trial information.
3. Is a TMF always required?
Yes. Documentation from each clinical trial must be present and retrievable as it may be subject to, and should be available for an audit by the sponsor’s auditor and inspection by the regulatory authority. Documentation is indispensable to confirm compliance and integrity.
4. When is the TMF needed?
Trial master files should be established right at the beginning, maintained until the end and archived after the closure of each clinical trial.
5. Where is the TMF located?
The TMF is composed of 2 parts, held at different locations:
- a sponsor TMF, held by the sponsor organisation (or to whom this function is delegated), and
- an investigator site TMF, held by the investigator.
6. Can the sponsor and investigator TMFs be combined?
In most cases the sponsor TMF must be separated from the investigator TMF. This is firstly due to subject confidentiality issues, as the identify of study participants may not be revealed to the sponsor. Secondly, the investigator site file contains source data. Providing original source data to the sponsor would remove the investigator’s control on those data and jeopardise data integrity.
However, when the sponsor and investigator are essentially the same, the TMFs can be combined. This occurs often for trials sponsored by universities, where the investigator is an employee of the sponsor. The investigator is acting as a clinical investigator but also as a sponsor. The documentation typically held by the sponsor will need to be accessed by the investigator, thus the TMF can be a combined sponsor and investigator TMF.
7. Can the sponsor retain (archive) the investigator’s TMF?
The investigator should retain control of the documentation contained in the investigator site file. The investigator site file should never be sent to the sponsor organisation except in sponsor-investigator situations. This requirement does not mean that an external sponsor cannot arrange the archiving on behalf of the investigator, which is acceptable, subject to the following being implemented:
- The archive arrangements are formally agreed and documented between the sponsor and investigator or host institution
- A formal procedure is in place such that the documents are only released from the external archive with the approval of the investigator or host institution. Permission from the investigator or host organisation should also be required to permit access to the contents of investigator site archived materials at the
archive facility. It is recommended that this is tested for robustness.
- The records go directly between the investigator site and an archive facility independent of the sponsor, thereby ensuring that the Sponsor does not have uncontrolled access to the investigator files.
8. Can management of the TMF be subcontracted by the sponsor and what should be considered then?
Yes, the management of the TMF can be subcontracted to a contract research organisation (CRO). The CRO will then be generating documentation (to reside in the TMF) to clarify management, which should address:
- Who holds the official TMF, or which parts does each party hold when this is divided?
- How is documentation filed in the TMF during the active phase of a trial?
- What are access arrangements to enable trial management and oversight?
- What is the structure and index of the TMF?
- If an electronic TMF (eTMF) is being used, what are details of the e-system, processes to be followed, training requirements etc.?
- What are arrangements for managing correspondence?
- How would the TMF be made available for inspection?
- What are the archiving arrangements when the trial is completed?
- What are the exact applicable SOPs / applicable procedures/forms?
CROs may provide all the documentation back to the sponsor on completion of the trial, but if the CRO’s internal records are supplied to the sponsor, the CRO would need some assurance that internal records will be retained by the sponsor. These records are important in demonstrating that the CRO followed its own quality system.
Alternatively, internal CRO records could be retained and archived by the CRO, and such an arrangement would need to be clearly documented.
9. How are TMFs managed?
The sponsor must keep oversight to ensure that the correct documentation is being maintained. Sponsors must have quality systems in place to ensure oversight. In general guidelines and standard operating procedures (SOPs) are present to assist in handling, maintaining, monitoring and auditing TMFs.
Even if the sponsor has delegated the maintenance of the TMF to the CRO, there will still be a requirement for the sponsor to hold some trial documentation in order to undertake oversight of the conduct of the clinical trial. For example internal correspondence that may not be in the TMF of the CRO, but this
documentation must form part of the TMF of the sponsor.
10. How should the TMF be organised?
The organisation of a sponsor file can become quite complex when the trial is multi-country or multi-centre. Typically, documentation is organised in the sponsor file at three levels: global, country and investigator site. Although merging of the files may be suitable for example when a single country trial is being
performed, or when running a single site study (all three levels can be combined).
The sponsor organisation should identify where all of the potential documentation that should be filed in the TMF is located. It does not all necessarily need to be in the same location, but it should be clear where it is from TMF procedures/indices etc as the TMF must be readily available both during the trial and during the archiving retention period following the trial.
In large commercial organisations, the TMF could include documents from across a variety of different departments other than clinical operations, for example, Data Management, Statistics, Pharmacovigilance, Clinical Trial Supplies, Legal, Regulatory Affairs etc., as well as those provided or held by CROs. This contrasts with a small single centre non-commercial trial, where the documentation is likely to be much less and could be limited to just the investigator and pharmacy files.
In addition, some documentation may be non-study specific, for example the validation of a computer system that is used for numerous trials, but is still needed to demonstrate the quality of the trials.
Interested in learning more about the TMF? Our expert Marleen Verbeeck will tell you more in our Clinical Research Training for Clinical Trial Assistants (CTAs) course.
31/08/2018 by Marleen Verbeeck
FAQs for Trial Master Files (TMF) and Archiving http://forums.mhra.gov.uk
by Oliver Pearce on Document Management, eTMF https://blog.montrium.com/blog/10-faqs-about-trial-master-files-tmf-and-archiving-answered
Clinical Practice E6 (R2) Guideline http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html
Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content,
management, archiving, audit and inspection of clinical trials http://www.ema.europa.eu/ema/