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

[SIZE=4][B]1. What is a Trial Master File (TMF)? [/B][/SIZE]

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.

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[SIZE=4][B]2. Is a TMF always required? [/B][/SIZE]

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.
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[SIZE=4][B]3. Can the sponsor and investigator TMFs be combined?[/B][/SIZE]

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.
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[SIZE=4][B]4. Can management of the TMF be subcontracted by the sponsor and what should be considered when using contract research organisations?[/B][/SIZE]

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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[SIZE=4][B]5. How should the TMF be organised?[/B][/SIZE]

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.
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[SIZE=4][B]6. Is it necessary to have SOPs and standard indices for the TMF?[/B][/SIZE]

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.

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[SIZE=4][B]7. How should the TMF be stored and who should have access?[/B][/SIZE]

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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[SIZE=4][B]8. Should the TMF be kept up to date?[/B][/SIZE]

The TMF must be kept up to date, with documents placed in the TMF in a timely manner as the UK legislation states that, [I]“The master file shall at all times contain the essential documents relating to that clinical trial”[/I] (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 [I]“inspection ready state”[/I]. This particularly applies to TMFs after the trial has completed, as these TMFs must be [I]“complete and legible”[/I] (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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[SIZE=4][B]9. What is regarded as an essential document?[/B][/SIZE]

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:

[I]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.[/I]

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:

[I]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[/I]

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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[SIZE=4][B]10. How should we deal with correspondence, in particular, emails?[/B][/SIZE]

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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[SIZE=4][B]11. Is it acceptable for the TMF to be electronic?[/B][/SIZE]

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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[SIZE=4][B]12. We scan our documents for inclusion in the TMF, is this acceptable and can the paper originals be destroyed?[/B][/SIZE]

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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[SIZE=4][B]13. Will access to the TMF be required during the inspection?[/B][/SIZE]

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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[SIZE=4][B]14. How long should the TMF be retained (archived) after the trial is completed?[/B][/SIZE]

Retention of the documents within the TMF (including the investigator site file) and the medical records of trial subjects is a legal requirement. The sponsor and the chief investigator must ensure that the documents contained, or which have been contained, in the TMF as well as the medical files of trial subjects are retained for at least 5 years after the conclusion of the trial (SI 2004/1031 [as amended] 31A, (7) and (8)). Trials where the data are used to support a marketing authorisation have further requirements as per Statutory Instrument 2004/3224 implementing Commission Directive 2003/63/EC. Here the documentation should be retained 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 EC (when there are no pending or contemplated marketing applications in the EC) or for at least two years after formal discontinuation of clinical development of the investigational product. Additionally, the sponsor or other owner of the data must retain all other documentation pertaining to the trial as long as the product is authorised. This documentation shall include the trial protocol (which must include the rationale, objectives and statistical design and methodology of the trial, with conditions under which it is performed and managed, details of the investigational product, the reference medicinal product and/or the placebo used), any standard operating procedures used for conducting the trial, all written opinions on the protocol and procedures, the investigator’s brochure, case report forms on each trial subject, final report and audit certificate(s), if available, and staff training records. Additionally, the final report shall be retained by the sponsor or subsequent owner, for five years after the medicinal product is no longer authorised.

Trial subject’s medical files must be retained for at least 5 years in their original format and in accordance with the maximum period of time permitted by the hospital, institution or private practice. Scanning or microfiching of patient notes is acceptable provided the process is validated such that the institution can demonstrate that it is an authentic copy of the original and is kept in a format that means that the data can be retrieved in the future. It is recommended that the notes of patients that have been involved in clinical trials are clearly identified to prevent premature destruction. Many UK hospitals attach stickers to the notes with a “do not destroy” or “retain until” date clearly marked.

In addition to these retention times for the trial documentation, records relating to the full traceability of the IMP for Advanced Therapies have longer retention periods. These are 30 years after the expiry date of the product or longer if required by the clinical trial authorisation. This will include the relevant documentation contained in the sponsor and investigator files as well as the trial subjects’ medical records. Further information can be found in the EU detailed guidance on GCP for advanced therapy medicinal products, (2009).

It is the responsibility of the sponsor to inform the hospital, institution or practice as to when these documents no longer need to be retained. As such, the expectation would be that the retention requirements of the sponsor for the documentation and medical records held by the investigator should be agreed either in the protocol or a separate agreement. The sponsor would be expected to have systems in place to alert the investigator when the records are no longer required to be retained. The sponsor should notify investigators in writing when their trial records can be destroyed and up until that point the investigator or institution should take measures to prevent accidental or premature destruction of these documents. The ultimate responsibility for the documents to be retained by the investigator or institution resides with the investigator or institution. If the investigator becomes unable to be responsible for their essential documents (e.g. relocation, retirement etc) the sponsor should be notified in writing of this change and informed as to whom the responsibility has been transferred.

The EU Regulation on Medicinal Products for Paediatric Use 1901/2006, adopted in December 2006 and came into force in January 2007, enables the use of data from published literature for the application of Paediatric Use Marketing Authorisations (PUMAs). To this end, the archiving requirements should meet the requirement of Commission Directive 2003/63/EC. The data may not be used for a MAA when the TMF is only maintained for 5 years.

It is important that where an organisation has centralised records that may be relevant to a number of trials, for example, SOPs, staff training records or maintenance and calibration records for equipment used in the trial at a Phase 1 unit/NHS clinical research unit; that these are also considered in the arrangements for archiving and retention (including superseded versions or obsolete records for example training records of personnel who have left the organisation) as they may be required to be produced in addition to the TMF to demonstrate compliance.

The protocol or the formal procedures of the sponsor should contain details of the retention times for all the trial documentation as outlined above or the process used to determine how long particular documentation will be retained for and how this should be documented.

The requirements for the retention of sponsors’ records also apply to the records retained by CROs or other agents of the sponsor, unless arrangements have been made to transfer the documents to the sponsor. The details of the retention time of documents held by the CRO should be formalised in an agreement between the sponsor and the CRO or be clear within the CRO’s SOPs that will have been reviewed by the sponsor.

Investigators can retire, hospitals can close and CROs (some of which are also investigator sites, e.g. commercial phase 1 units) can go out of business or be acquired by other organisations. The sponsor should ensure that agreements cover such eventualities to ensure that the documentation remains available for inspection for the specified retention time. Sponsors outside of the UK should ensure that provision is made to make the archived documents for trials conducted in the UK available to the MHRA throughout the retention period, in particular for documentation held by CROs. This issue has occurred on several occasions in the UK when phase 1 units have closed and there has not been any contact with the trial sponsors to ensure the long term availability of their investigators files and data until the MHRA was informed.

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[SIZE=4][B]15. Can the sponsor retain (archive) the investigator’s TMF?[/B][/SIZE]

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. It is recommended that this is tested for robustness. 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
• 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.

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[SIZE=4][B]16. Are there any requirements for the archive storage conditions?[/B][/SIZE]

The storage area for the TMF records must be appropriate to maintain the documents such that they remain complete and legible throughout the required period of retention and can be made available to the competent authorities upon request. This should be assessed on a risk based approach. Where a sponsor is conducting many trials in support of a marketing authorisation, the requirement for long term storage in appropriate conditions will be higher than for a sponsor-investigator undertaking one small Type A category trial where its publication is not likely to affect prescribing practice. Adequate and suitable space should be provided for the secure storage of all essential records from completed trials. Thus, for an investigator storing a TMF or investigator site file the sponsor may consider that the office filing cabinet may provide a suitably secure environment for a 5 year retention period, whereas a large sponsor that is required to retain documents in excess of 15 years, may need more specialist facilities with sufficient level of controls. The areas to be considered when performing such a risk assessment include:

• Security – how accessible are the documents, are there locks in place on doors/cupboards, what is the risk of unauthorised access, are there windows on the ground floor etc?
• Location - what risks are there from water (burst pipes, flood), fire (what activities take place in the room next door/above/below), what runs in the ceiling/floor void etc?
• Size – is the archive facility large enough and have the appropriate off floor shelving to accommodate the expected documentation?
• Environmental – are there risks from excessive temperature, humidity, sunlight, contamination (dust, fumes, smoke etc)?
• Pests – are there risks from rodents, insects etc?

The British Standard BS 5454:2000 [I]“Recommendations for the storage and exhibition of archival documents”[/I] is a standard for commercial archive facilities and sponsors may refer to this for consideration in maintaining purpose built archive facilities as well as taking it into account when assessing potential contract archiving companies.

It is essential that sponsors make a documented assessment of the storage conditions at the investigator site for the investigator site file and that the investigator provides this information. The importance is illustrated by a UK investigator site where the archive facility was inspected and found to contain an automatic water pump to extract flood water, together with numerous decorating products stored above the investigator site files. The inspector outlined the risks to the documentation, but this was not acted upon as a subsequent serious breach report was received of water damage to the investigator files when the pump failed to operate during a river flood.

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[SIZE=4][B]17. How should electronic documents/data be archived?[/B][/SIZE]

The use of electronic systems for such activities as data management, statistical analysis, reporting, trial management systems and eTMFs means that electronic documentation and data is likely to need to be retained. The data may be on a server or on transportable media, e.g. USB drives, CDs, tapes etc. It is recommended that more than one copy of the data is retained, for example where the data is archived in a specific server, this should be subject to back up, with the back up media stored in a separate location. Consideration may be given to storing the data in differing formats on different types of media or even on the same media from different manufacturers.

Access to archived data must be suitably restricted, either by user access levels to the archive area of a server or by controls to access the storage area where the media are retained (as for paper). Additionally, the electronic documents or data that have been archived must be protected from unauthorised changes to maintain authenticity.

It is important that future access to records and data is maintained. This could include maintaining the system (hardware and software) to access the data in its original format or the use of a new system to emulate the old software or migration of the data into a new format to ensure continual access with new software. This issue should be addressed by the organisation via formal procedures.

Media used to store the data may potentially deteriorate or become obsolete, for example, during a recent inspection a paper file contained a 3.5” floppy diskette containing the randomisation schedule. At the current time, PCs with ability to use such media are rare and future potential access would not be guaranteed, thus transfer to an alternative would need to be considered. The media should be stored under appropriate conditions. The transfer of data to new media as technology advances would need to be considered by the organisation. It is also recommended that periodic test retrieval or restores are undertaken to confirm that ongoing availability to the data is being maintained.

Where data is required to be migrated to new media or a new format, then the transfer should be validated and fully documented, so that it can be subject to audit, to ensure and demonstrate that there has been no loss, changes or corruption to the data or meta data and that authenticity is maintained.

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[SIZE=4][B]18. Is there a need for an Archivist?[/B][/SIZE]

It is a legal requirement that the sponsor appoints a named individual within the organisation to be responsible for archiving the documents which are, or have been, contained in the TMF and that access to these documents shall be restricted to those appointed individuals and auditors or inspectors (SI 2004/1031 [as amended] 31A, (9)). There can be more than one such person named and the requirement can be met by either having specific archivist role(s) or person(s) in another role may also have the specific archiving duties, but either way there should be clear documentation to support the appointment(s) and appropriate training provided. The named individual responsible must have a clear legal link to the sponsor, in that they are the sponsor/co-sponsor themselves or employed or contracted by the sponsor/co-sponsor (SI 2004/1031 [as amended] 31A, (11)). Whilst an investigator site institution is not required to have a named individual (unless they are a sponsor in their own right), where the organisation has many trials, a person responsible for this activity would be recommended.

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