The life sciences industry has been evolving towards the use of electronic Trial Master Files (eTMFs) to manage the documentation associated with clinical trials.  The promise of enhancing process efficiency, improving access to studies for increasingly global and virtual teams, and providing timely access to the TMF for internal and agency audits has proven attractive, especially to Tier 1 Pharma and large CROs.   Smaller organizations have begun to express interest as well.  However, progress was accompanied by lingering concerns about the expectations of regulatory agencies around the management and auditing of eTMFs and the records they contain.

In 2012, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) included a discussion of TMF/eTMF in their published Good Clinical Practices (GCP) Guide.  The Guide discussed issues such as security, records management and audit access.  It provided significant clarification and was viewed as a bellwether for the practices of other agencies.  Recently, the European Medicines Agency (EMA) issued a draft “Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials”.   This paper is the first published framework for eTMF for an entire region.   EMA states that the paper is provided in response to the numerous questions they have been receiving regarding TMF / eTMF, as well as in response to inspection findings.

EMA states that the aim of the paper is to “set out the requirements for the TMF as covered in directives and guidance and to give recommendations to assist organisations in maintaining a TMF that facilitates trial management, GCP compliance and inspection. The paper also addresses archiving of the TMF, clarifying retention times and gives some recommendations regarding destruction of paper documentation.”  Although it answers many of the questions posed by industry, it also raises some additional questions.  Industry will have a chance to provide comment until the end of April 2013.

This article will examine the most significant portions of the paper and their impact on people, processes and technology. 

Organization and Control

The paper emphasizes the differences between the sponsor TMF and investigator TMF (investigator site file).  Although ICH Good Clinical Practice CPMP/ICH/135/95 provides details on which documents are required for each TMF, confusion is not uncommon and presentations have been made suggesting that a common archive could manage both files.  This is not clearly acceptable:

• In organizing the TMFs, it is essential to segregate some documents that are generated or held by the sponsor from those of the investigator and vice versa as some documentation held by the investigator should not be provided to the sponsor, for example those documents that would result in breach of subject confidentiality.
• Exceptions are possible only when the sponsor and the investigator are the same organization, for example when the sponsor is a hospital/health institution.

The role of the CRO also impacts the organization and control of the TMF.  The sponsor remains responsible for the trial and needs to maintain – and document - oversight. Sponsors should ensure that the role of the CRO is formally defined and documented, including specific details around TMF/eTMF structure, filing processes, access, applicable procedures and documents, and audit.  For an eTMF managed by a CRO, the CRO will either have to provide access to the sponsor or determine how TMF documents will be provided without direct access.  Details in the refection paper can serve as the basis for contract review.

Structure

The sponsor should identify the location of all of the potential documentation that is part of the TMF.  In large organizations, the TMF could include documents from across a variety of different departments and systems other than clinical operations, for example, Data Management, Statistics, Pharmacovigilance, Clinical Trial Supplies, Pharmacy, Legal, Regulatory Affairs, etc.    These documents need not be physically present in the TMF/eTMF, but if they are not, access to them by auditors during inspection is necessary no matter where they reside.
EMA also stresses that sponsors should establish a common TMF structure used across trials regardless of location, with unnecessary sections deleted from the master structure for each trial.  Investigators may use a sponsor’s structure if they wish.

Essential Documents

EMA emphasizes that any documentation which has been created during the trial and that helps reconstruct and evaluate trial conduct must be filed in the TMF, irrespective of whether it is explicitly listed in published guidelines.   Superseded documents must be retained in the TMF so that trial activity can be reconstructed for any point in the trial.   Any quality record produced from following a quality system procedure must be retained in the TMF to demonstrate compliance.
Specific guidance on trial correspondence includes:

• Electronic correspondence (emails) may be retained electronically, provided the requirements for eTMF and electronic archiving are considered. Emails should be saved to ensure that the associated metadata is retained, for example as .pst files rather than pdf documents or being printed and signed.
• Correspondence (paper and emails) should be effectively organized and filed in chronological order in an appropriate section in the file.
• Duplication of any documentation in the TMF is recommended to be avoided, but this often occurs with email correspondence and with attachments.
• Sections including correspondence must be complete, that is, both sent and received correspondence must be included.

The TMF should to be up to date, with documents placed in the TMF in a timely manner with the aim to maintain the TMF “inspection ready”.
The overall implication is that sponsors and CROs will need to review their TMF master lists to see if they are really complete or if they have been including only documents listed in guidance.  Specific procedures for handling correspondence and quality records should be reviewed to ensure that documents are collected in a timely manner and contain all of the information expected during an inspection.

Inspection

As expected, EMA emphasizes the need for the sponsor and investigator TMFs to be readily available for inspection at any time during a trial.  Direct access is required for all systems comprising the TMF.  A new consideration for sponsors is whether they would be willing to provide remote eTMF access to agency auditors – EMA has expressed interest in this capability but sponsors would need to determine how comfortable they would be in offering remote access as it is not currently required.

The eTMF

Acceptability of an eTMF depends on the practices around its implementation and use.  Storage of TMF documents within folders in a file system is unlikely to be considered a substitute for a true eTMF due to lack of controls around security and accessibility.
Good practices expected for an eTMF include:

• Version control applied to electronic documents
• Control over timely creation and deletion of user accounts, and password-controlled access
• Protection of documents against unauthorized modification
• Regular backups
• Formal change control and validation
• Documented training

EMA has not yet seen the use of eTMF at investigator sites, but it would be permissible.  However, 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 the requirement that the records stay under the control of the investigator.
When agency auditors examine an eTMF, they expect to be able to work with it after no more than an hour’s training.  To facilitate review, the organization should provide adequately sized monitors and ideally provide tools to compare and mark documents.

Scanning

EMA provides a set of detailed requirements for quality control (QC) of scanned images. Sponsors and CROs should review these requirements to ensure they are complying.   A certified copy of a paper document can replace the original paper record.  Although 100% QC is not required, justification is needed for lower levels of QC, including following a validated process.

Record Retention

EMA summarizes a variety of records retention requirements and their impact on TMF.  Factors that influence retention include the type of record (medical record, study report, IMP document, etc.), the status of the product (approved, marketed, or retired) and national retention requirements that may override EC directives.  After reviewing these complicated requirements, it’s clear that a record retention schedule should be established by a records management expert.  A named individual must be responsible for an archived TMF, and regulations and risks studied closely before destroying paper documents transferred to an eTMF.

Conclusion

The reflection paper provides a specific set of requirements that every sponsor or CRO responsible for TMFs should review in detail, as they will serve as the basis for any agency inspection.  For those organizations using an eTMF, a self-audit is in order; for those contemplating eTMF, a clearer picture of the process requirements should assist in determining project scope and organizational readiness.