Clinical 101 – TMF Basics

Why do organizations maintain a TMF?

When I was consulting, I was often asked why we had so many projects helping clients improve their Trial Master File (TMF) management abilities. While I like the think that there was so much demand for Electronic Trial Master File (eTMF) consulting because people genuinely are excited about eTMF, the real answer was an obvious one – Sponsors must maintain a TMF and make that TMF available to regulatory inspectors in order to bring a therapy to market.

What do the regulations dictate?

That brings us to the question = “why do we need to have an eTMF?”

The answer is that Good Clinical Practice mandates that an organization demonstrate its compliance with GCP. The previous sentence may sound like circular logic, but an organization must be able to provide evidence that the trial satisfied the following requirements:

  • The protocol was followed during the execution of the trial
  • The safety of patients was the primary and core concern of all study personnel
  • The data being submitted to garner approval of the safety and efficacy of the treatment was appropriately collected and can be trusted
  • Both the Sponsor and the Investigator have the documentation/evidence that proves the three prior requirements.

What do some inspectors expect?

In addition to the explicitly defined requirements for an eTMF, there is a generally understood expectation that the inspectors have for an eTMF. This expectation is that the TMF can be stand-alone; that is, the TMF should tell the whole story of the study without supplemental information or narration from a study team member. An inspector should be able to discern from the documentation what happened during the study and when events occurred, who was part of the situation, how did they respond, and how timely the response was.

What Do TMFs Require for Inspection? 

So now that we know the overall expectations for a TMF, how do we satisfy those requirements? We can think about three main categories of focus to help drive inspection readiness for a TMF (regardless of it being paper or electronic).

TMF Control

  • There needs to be a defined and comprehensive lifecycle for a Trial Master File – you need to have a plan and procedures covering from the instantiation of the TMF to the closure/archiving of the TMF. This is usually documented in a TMF Plan for the study.
  • There should be a defined and reasonable structure that defines how content is arranged – this often aligns to the TMF Reference Model, but that is not required. This is usually documented in a TMF Index as an attachment to the TMF Plan.
  • There needs to be controlled access to the TMF – ranging from a locked file room to controls in an electronic system. Inspectors want to have confidence that only appropriately delegated team members can impact the TMF.
  • Investigator control their own files – a site maintains their Investigator Site File (ISF). While the content may overlap with the eTMF, the site is responsible for “owning” their content and must have control over it.
  • Chain of custody and proper processes must be in place during transfer of the TMF from a CRO (or other vendors) to a Sponsor

TMF Execution and Processing

  • There must be a rigorous process to review content to drive finalization. This does not mean each document needs to go through an 8-step review process to get approved, but there needs to be a defined approach to how content gets to a finalized state.
  • There needs to be a process for building Quality Assurance and/or Inspection Readiness into the TMF. The study team (or delegate) should have a process to review the holistic TMF and drive improved quality, timeliness, and completeness.
  • There needs to be a process for the Sponsor to evaluate/oversee the TMF when a 3rd party (CRO, vendor, etc.) is managing it since the Sponsor is ultimately responsible for the TMF.

Alignment with “Standards”

  • TMF content should comply with good record keeping best practices – that is aligned with the principles of ALCOAC
    • Attributable – you know who created and modified the document/record
    • Legible – the document/record can be read easily
    • Contemporaneous – activity on a document (approval, signature, filing) should be as close to real-time as possible
    • Original – the document/record in the system is recognized as being the source (or certified as an accurate copy when converting from paper to electronic)
    • Accurate – the document and the metadata around it should be real and complete/accurate
    • Complete – the document and the metadata around it should be comprehensive enough to support recreation of the events surrounding it

What Do eTMFs Require for Inspection?

So, the expectations for a TMF managed electronically (in an eTMF) are a clarification of the above plus alignment with applicable predicate rules (FDA Part 11/Annex 11, EMA), which define expectations for security, audit trails, electronic signatures, etc.

TMF Control

  • The eTMF system must have proper procedures and capabilities to ensure security – that only the appropriate team members can perform the appropriate activities
    • Training on the system must be provided to users
    • Different permission/security levels within the system
    • Ability to add/remove users from a study
  • The eTMF system must have an audit trail that allows inspectors to easily understand how the study and content was managed)

TMF Execution and Processing

  • The system should help provide content clarity by allowing the addition of metadata to augment the document contents – this helps the team, and inspector, understand the context of the content
  • The system should provide mechanisms (workflows, electronic signatures, etc.) to allow users to document their activities within the system.

TMF System Management

  • The system should be managed/supported in a robust manner
    • During implementation, the system must be validated to ensure the satisfaction of requirements (and underlying regulations)
    • Post-implementation, the system must have a backup and disaster recovery plan in place. Some of this is handled by a vendor, but the organization running the eTMF must have business continuity plans in place as well.

Common TMF Findings

Now that we have outlined the expectations for trial master files (both in paper and electronic systems), we can probably guess the findings that commonly arise from TMF inspections. Thankfully we don’t have to think too hard as the MHRA has documented trends around inspections.

  • Not surprisingly, completeness is the most common finding. Without access to the entire universe of content, an inspector will be hard-pressed to holistically evaluate the study. Lack of completeness arose both from poorly defining the content expectations as well as simply not collecting content that was expected.
  • Ancillary systems received focus from inspectors because frequently, the scope of TMF documentation includes multiple systems (think contract management systems, safety systems, etc.), and sometimes Sponsors forget to include these systems in their definition of the study TMF.
  • Timeliness is a more common finding now that electronic systems support enhanced evaluation of content by inspectors – no longer can we just slide in a piece of paper into the three-ring binder right before inspectors walk in the door.
  • Oversight findings are more common now that ICH E6 R2 came out and reinforced Sponsor expectations – no longer can the Sponsor be a passive recipient of the TMF at the end of the study.

How to drive inspection readiness

Now that we know what the expectations are, and where organizations tend to fall short, we can focus on ensuring that your organization fares better during an inspection. As we reviewed in my post on selecting an eTMF system, I defined the high-level processes for managing a TMF as follows:

TMF High-level Process Flow

Planning the TMF

As part of planning the TMF, you should focus on ensuring that your process supports:

  • Defining how the study is going to be run via a formal TMF Plan
  • Defining your content expectations via a TMF Index (often an appendix to the TMF plan)
  • Controlling how team members get added to the study (system- and training-wise)

Processing Content

To support improved content processing outcomes, you should focus on:

  • Driving contemporaneous collection/filing by empowering team members to file content directly
  • Ease document filing by having a standard structure and metadata schema
  • Leverage workflows to drive finalization of content:
    • automates documentation of activities 
    • allows qualified team members to provide input/make decisions proactively

Understanding Progress

To help improve inspection outcomes leverage system reporting whenever possible:

  • Reports can tell us the status of content in the system and guide activity against content that needs to be reviewed or remediated
  • Reports (when combined with defined content expectations) can guide our understanding of completeness and help us fill gaps in the TMF
    • Note that the defined content expectations are a critical aspect that does require rigor
  • Reports can help us understand the performance of team members (timeliness of activity as well as the level of satisfaction), which can help drive process improvement or increased focus to prevent issues.

Preparing for and Supporting Inspections

To help improve inspection outcomes, leverage system reporting whenever possible:

  • Inspection prep/quality review workflows can improve the quality of content as well as provide evidence of oversight by the study team
  • Provide direct inspector access to the TMF with appropriate security restrictions in-place

Conclusion

As you can see, there are lots of expectations for having an inspection-ready eTMF. Thankfully the industry has a pretty good understanding of the expectations – now it is just a matter of being able to dedicate the resources to get there. As a Sponsor, you have your choice of partners to help drive inspection readiness (eTMF vendors, CROs, and consultants) and they are great resources to tap into. If you need assistance choosing a partner or have additional questions, please get in touch with me, and I will do my best to help you out.