The trial master file (TMF) is the collection of essential documents which allows the conduct of a clinical trial to be reconstructed and evaluated. It is basically the story of how the trial was conducted and managed. This blog highlights some of the issues which have been experienced by sponsors and inspectors attempting to manage and review the large amounts of documentation that exist in support of a trial.
What needs to be filed in the TMF?
A common misunderstanding is that only those documents listed in section 8 of International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) good clinical practice (GCP) are required to be filed. This is incorrect and the documents listed in section 8 only provide half of the story, as a number of key areas are not included such as documentation associated with data management and Qualified Person (QP) certification.
Another common area on documentation is correspondence associated with key decision making and trial conduct. We all use email as a key method of communication yet the correspondence section in the TMF is often very sparse or lacks the relevant emails. When as an inspector we say that we will raise a deficiency against a problem, it’s often the case that a number of emails can be provided to explain the issue but its unclear why they were not present in the TMF in the first place
The next significant issue is that for commercial sponsors, the most frequent major finding is in relation to record keeping and essential documents and we have had to (on more than one occasion) add extra inspector days in order to complete the inspection due to problems with access to and provision of the TMF. While it may be feasible in UK inspections to conduct a return visit (with all of the logistical issues this may also raise for the sponsor), for an inspection requested by the Committee on Medicinal Products for Human use (CHMP) as part of a marketing authorisation application, this can be problematic. If the inspected sponsor site is outside of the European Union (EU), the ability to add additional days is very limited and therefore problems with the provision of the TMF could result in the rejection of an application due to the inability to fully evaluate the compliance of the trial with GCP requirements.
Neither the legislation, or the expectations of MHRA have changed in relation to the TMF, however the way in which the TMF is now presented for inspection by organisations has changed significantly. We believe this is due to 2 factors. Firstly, the increased globalisation of clinical trials, with huge TMFs containing essential documents that are spread across the globe and shared between different organisations such as the sponsor, contract research organisations, investigator sites, laboratories etc. Secondly (and probably in response to the first point), TMFs are now becoming electronic.
The move to electronic systems
TMFs are not alone in becoming electronic (eTMF); we all work electronically, for example the clinical trial approvals from the MHRA clinical trial unit are now electronic, and the digital world is most definitely upon the clinical trial world with the advent of electronic case report forms (CRFs), electronic patient reported outcomes, electronic data capture etc. There are many advantages to the use of eTMFs such as ease of access, traceability and the ability of staff throughout the world to input into, access and manage the same repository of information. The other significant advantage is the ability to reduce the paper mountain associated with each trial. But with the advent of new technologies there also comes the need to ensure that the systems function as required and can deliver additional benefits when compared to the systems that they replace.
Currently we are seeing a transition between paper and electronic systems. This, and the ongoing development of suitable eTMF platforms, means that inspectors have been spending a lot of time on GCP inspections in discussion with the organisation to determine what their TMF consists of and exactly where it all is. For example there may be an electronic system that houses the majority of trial-related essential documents, which is usually presented to inspectors as the eTMF. However in addition to this, we usually discover that there are paper documents that are not provided as part of the TMF, and also that there are electronic systems that store essential documents that are also not considered by the organisation to be part of the TMF.
While we don’t expect that the TMF is a single system that holds every document and we are happy to review a number of systems on inspection, it is expected that the organisation identifies all of these systems and has a clear understanding of the content of the TMF and where all of the essential documents are located. A simple way to achieve this is to have an overarching mapping document that lists all the essential documents and where they are located. As part of this exercise, organisations should also determine how this can be accessed by the inspectors; for example is a specific type of read-only access required? It is typical that consideration has not been given to providing suitable access for the inspection team to the various components of the TMF and fulfilling our expectation that we can navigate the TMF ourselves. It is common that the organisation being inspected provides expert users to navigate the inspection team around the eTMF. This should not be necessary following some basic training and an awareness of the eTMF structure; if you relate this back to the paper TMF we would not require someone to help us turn the pages of a folder once the various files have been relocated to the inspection room. We often ask the question to quality assurance personnel as to how they would access the TMF during one of their audits, as surely the same type of access would be needed?
In general we have found that eTMFs have been designed as a repository for documents, but access to and retrieval of those documents is equally as important for managing clinical trials. We have conducted inspections where the eTMF ‘expert’ in the organisation has been unable to easily retrieve documents due to the manner in which they have been named or filed. It is clear that the technology is available to facilitate an eTMF that can comply with the regulations both from an inspection point of view but also as a tool to allow for the retention of essential documents, but the various requirements necessary to facilitate this needs to be part of the design and user requirement specification stage of the build of the system. Issues we have seen on inspection generally relate to poor system design rather than changing expectations of the inspectors. If we return to the paper TMF vs eTMF example then the implementation of an eTMF should enhance the management, retention and review of essential documents rather than making it more cumbersome.
Talk to your inspector!
Prior to an inspection, the inspector will send out a clear request in relation to expectations of the TMF, and will be happy to discuss the requirements and how the TMF will be provided. It is your opportunity to clearly describe how you intend to supply the documentation required to support the inspection and you should state what system access will be provided if multiple platforms are used. It’s important to take advantage of this opportunity to go over these requirements, not only could it save you from a critical finding on inspection, but if the inspection is in relation to a marketing authorisation application, it could prevent the refusal of the application on the grounds that the integrity of the data and compliance with GCP cannot be verified.
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Check out our guidance on good practice for information on the inspection process and staying compliant.