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

[MHRA Super Moderator]

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.

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[MHRA Super Moderator]

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)).

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[MHRA Super Moderator]

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.

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[MHRA Super Moderator]

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.

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[MHRA Super Moderator]

11. Is it acceptable for the TMF to be electronic?

Yes, either completely or a mixture of paper and electronic, provided this structure is sufficiently defined. There is an increasing use of eTMFs instead of paper based TMFs in the management of clinical trials and the same controls must be available for managing the eTMF as for a paper TMF in terms of security, control over unauthorised edits and access, ease of retrieval of documents etc.

Some eTMF are really the storage of documents within folders in a computer systems’ operating environment. Such systems have been typically shared areas where everyone has access in the organisation and documents could easily be moved, deleted, replaced etc and with a lack of version control so there is ambiguity over which is the current version and which is a superseded version. These systems would require appropriate controls and security to be in place, which would include role based permissions for activities being undertaken through the use of secure passwords. Accounts should be created and deleted within a formal approval process and in a timely manner. This is analogous to the paper system where the TMF is kept in a secure location, with restricted access. There should also be a back up of the system. A more acceptable solution is where the eTMF is a document management system containing further controls. For example, where the system is being used for approval of documents via a workflow system, password enabled electronic signatures should be used, the system must have an audit trail in place to identify date/time/user details for creation, uploading, approval and changes to a document. It would also be recommended that a system for locking documents or the entire eTMF is considered to prevent changes to documents, such as when the eTMF is archived. Finally, all members of staff involved in the conduct of the trial must receive training in using the system and this should be documented.

The eTMF could contain digital documents in their original format, potentially with digital signatures, or records that have been converted from another format (such as paper documents that have been converted to digital images, which may contain wet-ink signatures). Records that only exist in a digital format are often only printed onto paper at the time of an inspection as they normally are accessed in their digital form. This can result in loss of any version control applied in the computer system (e.g. dated filename). An example of this could be the “edit checks” specification used by data management. Such documents, when uploaded into the eTMF may also have the same potential issue which re-enforces the requirement that all documents should have clear version control which is maintained on transition from one media, or from one system, to another.

Unlike a paper TMF, documents loaded into the eTMF will require the addition of metadata to enable the document to be identified within the system. Metadata is that data that is associated with the document (but not the document itself) so typically would be identifying codes for the trial, site, protocol, product etc. The type of metadata is recommended to be formally defined to ensure consistency across all documents.

The eTMF will require validation to demonstrate that the functionality is fit for purpose, with formal procedures in place to manage this process and for change control. The validation of the system should follow previously published standards. The documentation for this process must be retained.

There is also the potential for the investigator site file, held by the principal investigator, to become electronic, with the system either provided by the sponsor, a vendor or by the host site organisation. The documentation in the investigator site file will contain source documents, for example, subject screening and identity logs, consent forms, drug accountability records etc, and the control of these must remain with the investigator unless specific consent had been obtained from trial subjects for their personal information to be released from the trial site. A situation where all the site records are sent to the external sponsor for uploading onto an eTMF system, which the investigator then accesses via a portal, would breach this requirement. The sponsor should consider the EMA GCP Inspectors Working Group Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials (EMA/INS/GCP/454280/2010), as the considerations and recommendations will have applicability to source documents contained in eTMFs.

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[MHRA Super Moderator]

12. We scan our documents for inclusion in the TMF, is this acceptable and can the paper originals be destroyed?

The use of eTMFs and electronic archiving generally require the scanning of some paper records to generate electronic copies of the documents. When original paper TMF documents are transferred to an electronic format (or other media) the system of transfer should be validated in order to ensure that the transfer of documents is without loss and to ensure that certifiable copies are made. Some eTMF systems require a review of each scanned document prior to it being approved within the eTMF, but all transfers should be certified for accuracy and completeness by someone with appropriate authority (e.g. trial manager), as part of the quality assurance system. This does not necessarily mean that the individual reviews every document, but that they have approved the validated system that is being used. The organisation should maintain records to demonstrate that the transfer system is effectively validated.
It is recommended that there is a formal process in place for regular checks of documents in the eTMF, usually on sampling basis, including escalation procedures where issues arise. This process could assess, for each document reviewed, one or more of the following:

• Accuracy of the metadata attributed to the document
• Quality of the image (e.g. readability)
• Whether it was the correct document (as expected)
• That the document had the correct number of pages
• The eTMF audit trail associated with the document (with a link to any changes)
• Chain of custody documentation and timeliness of uploading into the eTMF
• Approval process (where applicable)

Scanned images must be at appropriate resolution so that when viewed at actual size on the screen (as per the original) the image is clear and legible. Post-scan adjustments to the image to increase legibility are acceptable, provided the limits of what may be undertaken is clearly specified in a formal procedure. It is not acceptable to utilise the scanning process to remove or add material to the image, for example, to remove the header a fax machine has added, or undertake physical ‘cut and paste’ or ‘correction fluid’ activities on the original paper record. Documents within an eTMF must remain complete and legible in all aspects giving information about the way the document was prepared. This holds especially true for contracts and forms completed by hand. It would not be acceptable, therefore, to create a new electronic version of a form that had been completed by hand and then file that instead of the original (or the scanned, unaltered version of the original).

When a vendor is used for eTMF management, as with any vendor or subcontractor being used for clinical trials, appropriate pre-qualification checks should be undertaken prior to placing the contract. It is recommended that where TMF documents are moved from the sponsor to the vendor for scanning, a formal procedure is in place to ensure chain of custody records are maintained (e.g. use of a TMF record transmittal form).

There is a move towards scanning of patient medical records within the NHS and the same principles of ensuring authentic copies also applies to this situation, prior to any destruction of original source documents.

The use of an eTMF would be considered as a prerequisite to the sponsor being able to destroy paper records and reduce storage requirements. The UK legislation does not consider the transfer of documentation to other media, but does require the documents to be readily available, complete, legible and contain traceability of any changes made (SI 2004/1031 [as amended] 31A (2), (6) and (7)). Volume 10 guidance requires that sponsors should ensure that essential documents are not destroyed before the end of the required retention periods; however, transfer of the document to an eTMF repository could enable earlier destruction of the paper original. The eTMF system would need to have all the characteristics as defined above such that MHRA GCP Inspectors would have confidence that the eTMF is complete and the documents are authentic copies. Experience of eTMFs to date has not yet provided sufficient evidence that inspectors would not need to request some original paper records for inspection and thus early, complete destruction of such records is not currently recommended or should only be undertaken on a risk based approach. A duplicate paper TMF need not be retained; the reasons for this include the following:

• A document may only have existed and been used in an electronic format (e.g. a spreadsheet used for QC of edit check programs)
• A paper document may be a copy of an original located elsewhere (e.g. investigator’s signed CV)
• Documents that do not have wet ink signatures, thus the electronic version is an exact copy of the paper version that has been in the TMF (provided there are no additional annotations made, handwritten or otherwise, for example, receipt stamps, fax machine header etc)

This indicates that the eTMF would contain some documents that are more likely to have the original paper copy requested than others, such as, agreements with wet ink signatures, signed letters etc. The current recommendation is to undertake a risk assessment so as to decide which documents do not need to be retained on paper, particularly focussing on whether the paper version could be obtained or not upon request (e.g. reprinted or obtained from another location)

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[MHRA Super Moderator]

13. Will access to the TMF be required during the inspection?

Yes. The TMF is the basis of inspection for the MHRA conducting GCP inspections in the UK (and elsewhere). As indicated previously GCP inspections in the UK require, according to the UK legislation, the TMF for the trial to be readily available and for the TMF to be produced at any reasonable time by the organisation during the trial conduct and for at least 5 years after the trial completion (SI 2004/1031 [as amended] 31A, (2) and (7)). The requirements and logistics of TMF provision will be discussed with the organisation prior to the inspection and this is where the benefit of planning the arrangements for the TMF at the trial start can be beneficial, especially in complex trials with CRO involvement. Organisations should have considered how to make the TMF available to the inspectors should an inspection be announced. MHRA GCP Inspectors will be clear about the levels of the TMF they wish to review, which is usually the whole of the country level and the site level documents. For the latter, specific sites may be requested during the inspection if there are many to choose from. There will also be a requirement to view some documentation from the trial level TMF, for example, the investigator brochure. The inspectors will not expect to have to request documentation individually for a trial as the whole TMF should be provided if asked for.

The inspectors will require direct access to the TMF, which means reviewing the TMF as used by those conducting the trial. Inspectors have in the past been provided with an ‘artificial TMF or ‘snapshot’ which consisted of a copy of the official TMF being used and led to issues with documentation not being consistent with that of the official TMF.

The organisation must be aware of the locations of all the documentation that comprises the TMF as there have been inspections where only the clinical operations files have been provided that contain the ICH GCP section 8.0 documentation.

The MHRA GCP inspectors will not wish to be supervised during the review of the TMF. Documents will not be removed from the site without the organisation being made aware and inspectors make every effort to ensure that the documents remain as provided (for example returning documents to their original position in the file). This usually means that inspectors will flag documents using sticky labels for later review or to identify documents that require clarification or discussion with appropriate representatives of the organisation. Such identifiers should not be removed until the inspection is completed. In the UK the GCP Inspectors do have the right under the Medicines Act to seize the TMF.

MHRA GCP Inspectors are not averse to reviewing an eTMF during a GCP inspection. The legislation does not differentiate between paper and eTMFs therefore all the requirements are the same; however, the use of an eTMF at an inspection presents additional challenges to both the inspector and the organisation.

The GCP Inspectors’ expectation is that the eTMF should adequately replicate the paper based system that it is replacing. There have been issues when reviewing eTMFs during an inspection and this has resulted in organisations receiving major inspection findings and/or an increased number of inspector days on site. The organisation is recommended to consider that the requirements for inspectors will also reflect the requirements of any auditors and the system should be designed and developed or purchased with this requirement in mind.

While it is acknowledged that some training or familiarisation for an eTMF will be required, it is recommended that this is very brief (taking no more than an hour, otherwise additional inspection days will be required) which implies that the system should be user friendly. MHRA GCP Inspectors will require direct access to the eTMF system (not a copy), without reliance on an eTMF ‘super-user’, so the system should ideally facilitate a read-only ‘inspector or auditor view’ access.

The eTMF will require the use of suitable equipment for the inspector to view the documents. It is recommended that this equipment facilitates the presentation of the documents at actual size, which in most cases would be A4 paper, and the size should not be reduced due to other areas on the screen, for example, directory/index structure, toolbars etc. The organisation should not expect the inspectors themselves to provide suitable equipment to view the eTMF.

It is anticipated that the time taken to review documents in the eTMF system would be similar as the time to review them on paper, otherwise additional days may be required to conduct the inspection (at a cost to the organisation) or reference made back to the original paper records. This issue has occurred on occasion during the UK statutory routine GCP inspection programme. It is recommended that the system has an efficient speed of access and does not require the use of a nomenclature document or require time spent opening non self-evident named files to determine their content. The system and equipment would ideally be akin to flipping the pages of a book with a system tool available to mark documents for subsequent retrieval and examination as well as the ability to compare documents side by side.

Finally, inspectors may have to copy and retain documents from the eTMF and it is recommended that the organisation have facilities to do this.

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