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Thread: MHRA produced FAQs for Trial Master Files (TMF) and Archiving

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    MHRA produced FAQs for Trial Master Files (TMF) and Archiving

    1. What is a Trial Master File (TMF)?

    A TMF is the collection of documentation that allows the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP to be evaluated. It is also essential to allow the trial to be effectively managed by the sponsor as it allows the appropriate individuals access to the necessary trial documentation.

    The documentation contained within the TMF should be sufficient to adequately reconstruct the trial activities undertaken, along with key decisions made concerning the trial. Consideration should be given to the TMF being a stand-alone set of documentation that does not require additional explanation from the associated sponsor or site staff.

    Version 1: 17th December 2012

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    2. Is a TMF always required?

    Yes. The documentation from a trial of an investigational medicinal product must be filed in the TMF. This requirement is set down in both EU and UK legislation (2001/20/EC Article 15(5) and SI2004/1031 [as amended] 31A). The TMF forms the basis for an inspection to confirm compliance with regulatory requirements (Directive 2005/28/EC Chapter 4, Article 16). The TMF is normally composed of a sponsor TMF, held by the sponsor organisation (or to whom this function is delegated), and an investigator site TMF, held by the investigator. These files together are regarded as comprising the entire TMF for the trial and should be established at the beginning of the trial.
    Version 1: 17th December 2012

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    3. Can the sponsor and investigator TMFs be combined?

    In most cases it is essential to segregate those documents that are generated or held by the sponsor of the trial from those of the investigator. This requirement is firstly due to subject confidentiality issues, for example, the sponsor must not have documents such as consent forms and subject identification lists if the subject has not specifically consented to them holding this information. Secondly, where the investigator site file contains source documents, the case report forms (CRFs) contain source data or the CRFs are the investigator’s independent copy of the transcribed data, providing this to the sponsor would remove the investigator’s control.

    The segregation would be expected by MHRA GCP inspectors in all situations apart from where the sponsor and investigator are essentially the same. This can often occur for trials sponsored by NHS Trusts or Universities, where the Chief Investigator (CI) is an employee of the sponsor. In these situations, the CI is most likely to be acting as a clinical investigator in the trial and also, in many cases, has been formally delegated a number of sponsor tasks from the Trust research management function. This means that documentation typically held by the sponsor will need to be accessed by the CI, thus the CI file could be a combined sponsor and investigator TMF. GCP Inspectors have seen situations where the research management/governance department of the sponsor maintains the sponsor file upon the belief that this would be an expectation to comply with GCP. In reality it results in extensive and needless copying. In such a scenario it is perfectly acceptable for the management of the TMF to be delegated to the CI with the CI maintaining all the necessary documentation.

    The sponsor must still maintain an adequate level of oversight to ensure that the correct documentation is being maintained. One example of such oversight would be the availability of guidance or procedures within the organisation to assist the CI in maintaining the files together with monitoring and/or audit of the TMF and with the research management/governance department holding oversight documents, for example risk assessments, governance, CI questionnaire returns etc.
    Version 1: 17th December 2012

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    4. Can management of the TMF be subcontracted by the sponsor and what should be considered when using contract research organisations?

    Yes, the management of the TMF can be subcontracted.

    The complexity of the TMF is increased by the use of CROs in assisting in the management and/or conduct of the trial. In conducting allocated functions, the CRO will be generating documentation that will need to reside in the TMF and/or the CRO may have been delegated the task of managing the sponsor’s TMF. It is suggested that there is some documentation, e.g. a plan, to clarify the management of the TMF, for example, it could address:

    • Who holds the official TMF (or which parts each party holds when this is divided)
    • The process for filing documentation in the TMF during the live phase of a trial
    • The access arrangements for both parties to enable trial management and oversight
    • The structure and indexing of the TMF
    • Where an electronic TMF (eTMF) is being used, the details of the system, processes to be followed and training requirements etc.
    • Documents that both parties must retain
    • Arrangements for managing correspondence (i.e. so that there is not a huge amount of duplication)
    • How the TMF would be made readily available if either party was inspected
    • Arrangements for when the trial is completed
    • Lists/attachments of SOPs and applicable procedures

    Where a CRO is performing the functions of the sponsor, e.g. monitoring and management of the trial, they will also be generating documentation from following the CRO’s own SOPs. 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 these internal records will be retained by the sponsor, as GCP Inspectors have seen situations where these were not. These records are important in demonstrating that the CRO followed its own quality system. Alternatively, these internal CRO records could be retained and archived by the CRO and it is acceptable for the CRO to do so, but such an arrangement would need to be clearly documented.

    Where the sponsor has delegated the maintenance of the TMF to the CRO as well as many other trial conduct functions, 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. In this situation, many of the documents will be copies of those held in the TMF of the CRO. However, there will also be documentation that demonstrates the oversight of the sponsor, for example internal correspondence that may not be in the TMF of the CRO, but this documentation must eventually form part of the TMF. In GCP inspections of sponsor’s where virtually all the trial conduct functions have been subcontracted, it would be expected that the sponsor provides documentation to demonstrate oversight of the trial conduct. In such situations the quality system of the sponsor should reflect its oversight functions and this would include procedures for the handling of trial documentation that demonstrates this is taking place. This may take the form of sponsor oversight files and defining what needs to be maintained. It is recommended that sponsor oversight can still be demonstrated if the files of the sponsor are amalgamated with the CRO TMF at the end of the trial. One common problem is that the oversight is done extensively be email, for example demonstrating review and approval of key trial documents, but these emails are not made available to the inspectors.
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    5. How should the TMF be organised?

    The organisation of a sponsor file can become quite complex such as 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. This is a recommended approach to take as it allows particular sections of the TMF to be made available upon request, although amalgamation of the files may be a more suitable approach to take if, for example, a single country trial is being performed (with combination of global and country level files) or when running a single site study, where 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. For example, it may be appropriate for an organisation to determine that SAE cases will all be retained in the PV department, including the SUSAR receipt confirmation rather than printing it off the PV database and filing in the TMF. This detail, may, dependent upon its complexity require formal documentation in a procedure (e.g. SOP). 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. 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.
    Version 1: 17th December 2012

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    6. Is it necessary to have SOPs and standard indices for the TMF?

    The extent of the potential distribution of TMF documentation and the number of trials a sponsor conducts should inform the decision as to whether a formal procedure is necessary to document the locations of all records associated with the TMF as well as the content of the TMF (e.g. standard indices) or whether the protocol providing an overview of the TMF arrangements together with a trial specific index in the TMF is sufficient. The use of a formal procedure, such as a SOP, and a standard indexing system (rather than creating “study specific” indices repeatedly) in organisations sponsoring several trials is recommended as it tends to facilitate compliance.

    It is essential to have a suitable indexing system in place for the TMF. This ensures that the documentation is appropriately sorted and filed, which facilitates audit, inspection and trial management. It is recommended that the documentation is filed in date sequential order to enable a clear audit trail of, for example, communications with sites, REC and Regulatory Authorities.

    Investigator site files are typically indexed and organised by the trial sponsor and maintained with the assistance of the trial monitor. As a result an investigator who is working with several sponsors may have several different files organised in slightly different ways. Some non-commercial trials may not provide investigator site files and in such circumstances the investigator will need to organise the filing themselves. In such cases, if the host organisation (NHS Hospital) has a standard indexing system available for use, this would prove useful to the investigator.

    Version 1: 17th December 2012

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    7. How should the TMF be stored and who should have access?

    The sponsor’s TMF is the repository of all the information that is necessary to reconstruct the trial and therefore its security and maintenance is vitally important. The arrangements for who should access the TMF in order to add or remove documentation are important points to consider and must be controlled on a risk based approach. The two key factors that influence risk are:

    • Number of trials the organisation is conducting (creation of a specific department to manage TMFs may be appropriate compared with an investigator maintaining their own TMF in their office).

    • Use of the trial data (if the trial is to be used to support a marketing authorisation or will be important in determining treatment via its publication).

    The investigator’s TMF should be stored securely such that only study staff (and monitors, auditors and inspectors) can gain access to the documentation.

    Some organisations have controls in place for placing or removing documentation from the TMF whilst the trial is in progress. It can take the form of formal submission of TMF documents with some form of TMF tracking. For example generation of a submission record or a simple signature and date on the index of the file. Some organisations may archive the documentation on an ongoing basis to prevent loss, particularly where eTMFs are in use. The risk of a lack of control would obviously be missing documentation at the end of the trial. It is recommended that this risk and the implications of the loss should be evaluated before the implementation of additional paperwork or systems to track or manage the placing of documents in the TMF.

    Version 1: 17th December 2012

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    8. Should the TMF be kept up to date?

    The TMF must be kept up to date, with documents placed in the TMF in a timely manner as the UK legislation states that, “The master file shall at all times contain the essential documents relating to that clinical trial” (SI 2004/1031 [as amended] 31A, (3)). This can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. The contemporaneous nature of the TMF may vary in trials and could be more anachronistic in trials that have more complex TMF arrangements with multiple parties involved. In this scenario it may be useful to define the timescales for submission and filing of documents to the TMF in procedural documents or TMF plans. Documentation in the TMF that is relied upon for subsequent activities should be in the TMF prior to the activity taking place, for example, monitoring visits rely on the information in the previous report, so the previous report should be completed and filed in the TMF prior to the next visit. MHRA GCP inspectors would raise concerns if the TMF appeared out of date such that the ability to manage and oversee the trial conduct was questionable. It should be remembered that MHRA GCP inspections can be unannounced or performed at short notice and even routine inspections may not contain a notification of the trials to be inspected until a short period prior to the inspection, thus the TMF must be maintained in an “inspection ready state”. This particularly applies to TMFs after the trial has completed, as these TMFs must be “complete and legible” (SI 2004/1031 [as amended] 31A, (7)).

    There should be a process to ensure that any documents that have been, or are currently contained, in the TMF have traceability of any changes made to them to comply with UK legislation (SI 2004/1031 [as amended] 31A, (6)).

    Version 1: 17th December 2012
    Last edited by MHRA Super Moderator; 17th Dec 2012 at 02:31 PM.

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    9. What is regarded as an essential document?

    Any documentation that facilitates evaluation that the trial has been conducted in accordance with EU/UK legislation and guidance documents must be retained in the TMF. Often encountered on inspection is the view that if a document is not listed in ICH E6 guidance as being an ‘essential document’ then it need not be contained in the TMF. This is not the expectation of GCP inspectors. Firstly, the UK legislation (SI 2004/1031 [as amended] 31A) defines essential documents as follows:

    The essential documents relating to a clinical trial are those which (a) enable both the conduct of the clinical trial and the quality of the data produced to be evaluated; and
    (b) show whether the trial is, or has been, conducted in accordance with the applicable requirements of Directive 2001/83/EC, the Directive, the GCP Directive and Commission Directive 2003/94/EC.


    Two of the principles of GCP, which are a UK legal requirement (SI 2004/1031 [as amended] Schedule 1, Part 2, (4) and (9)) are:

    The necessary procedures to secure the quality of every aspect of the trial shall be complied with.

    All clinical information shall be recorded, handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of records of the trial subjects remains protected


    These principles and definitions together can be interpreted to mean that all records created from following trial procedures as well as those listed in guidance relating to the conduct the trial should be retained to demonstrate compliance. The documentation listed in section 8 of ICH GCP and section 3 of the Volume 10 TMF guidance is a useful guide for the minimum documents that are considered essential, but it is not comprehensive, examples of documents that are essential to reconstruct the trial but that are not contained include, QP certification, the regulatory green light document to release and ship IMP and the database lock documentation. The ‘essential documents’ list can therefore be regarded as a minimum subset of the potential documentation that could be regarded as essential for reconstruction of the trial conduct. This list should not be used as a definitive checklist for TMF content. It is important to note some documentation listed in ICH GCP or Volume 10 may be inappropriate, such as a randomisation schedule, or have been replaced for a particular trial, such as an investigator’s brochure for trials of marketed product where the SPC is being used. Where a risk adaptive approach is being followed, some documents listed may not be in the TMF, for example IMP temperature storage records, IMP accountability, laboratory reference ranges etc. and the rationale for this would be in the trial risk assessment.

    Additionally, during inspections, verbal information provided during interview, particularly at investigator sites, reveals activities that occurred that were not transparent from the documentation in the file, such as the training that the principal investigator provides to his/her team members. It is therefore recommended that an assessment of all activities is undertaken to determine whether they need to be documented to enable reconstruction of the trial conduct from the paperwork alone. This is an important point to consider, because if a trial needs to be reviewed by the regulatory authority some years after its completion, personnel involved may no longer be available, therefore the TMF must be a robust record of all aspects of the clinical trial.

    Version 1: 17th December 2012

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    10. How should we deal with correspondence, in particular, emails?

    The conduct of a clinical trial can generate large of amounts of correspondence such as emails, letters, meeting minutes and telephone call reports, which may be internal within an organisation (e.g. sponsor, vendor or investigator site) or between organisations (e.g. sponsor and CRO, sponsor and investigator). Correspondence is an important component in reconstructing the trial conduct with some CRO organisations relying solely on email correspondence to confirm sponsor approval of processes, documents, and decisions. Only relevant correspondence that is necessary for reconstruction of key activities and decisions (for example the medical monitor allows an ineligible subject to remain in the trial) or that contains other significant information must be retained. If some correspondence is not retained (particularly certain emails which may not add any value by being retained, such as, email correspondence between investigator site staff and the trial monitor discussing holidays or suitable hotels to stay in near the site), then there should be a formal process to assist individuals in the evaluation of whether it contributes to the reconstruction of the trial or not. Electronic correspondence may be retained electronically (see question concerning eTMF).

    It is recommended that correspondence is effectively organised, for example, it could be segregated into topic area (e.g. protocol development). It is essential that some correspondence is filed in an appropriate section in the file (for example, correspondence with MHRA, REC etc). It is also recommended that correspondence is always filed in chronological order and that duplication of documentation (e.g. chain emails) is avoided. Electronically attached documents that are not present elsewhere within the TMF must be included where necessary for reconstruction (for example reports/data reviewed in dose escalation meetings).

    Sections including correspondence must be complete. During GCP inspections it is often seen that only copies of letters received rather than those sent out and received are filed (such as those sent from the sponsor to REC or investigator to REC), such that the TMF only contains half of the audit trail.

    For emails, these could be printed on to paper or retained electronically as a pst file (preferable) or a pdf. See also FAQ numbers 11 and 17.

    Version 1: 17th December 2012

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