Lessons From the TMF Hotline: Inspection Readiness and The Power of the TMF QC Cycle

Thank you to all who attended LMK Clinical Research Consulting’s May 6th Inspection Readiness Day, hosted by LMK’s Founder and TMF trailblazer, Sholeh Ehdaivand! As those of you who attended the livestream event know, the purpose of Inspection Readiness Day is to provide every attendee with the real-world advice and battle-tested best practices necessary to prepare for a TMF inspection. To accomplish this, Sholeh spent an entire day manning the TMF Hotline, responding one-on-one to your most urgent TMF questions and concerns.

But what is TMF inspection readiness? TMF inspection readiness means that, during all stages of a clinical trial, a regulatory inspector would be able to immediately access your TMF and reconstruct the trial using only the documents and metadata present within. If an inspector cannot determine the story of your clinical trial from the TMF, serious regulatory consequences will likely follow. After all, your TMF is the most important deliverable of the clinical trial. Without a functioning TMF, regulators have no way of monitoring the quality of your clinical trial’s data and protecting the safety of the trial’s subjects and will act decisively to protect them both—even if it means halting a clinical trial for a promising treatment.

Although the concept of an inspection ready TMF may be simply described, inspection readiness is not easily achieved. At LMK, we know individual TMF stakeholders are often overwhelmed by the massive size and complexity of the average TMF and don’t know how they can individually advocate for the larger goal of organization-wide inspection readiness. Fortunately, TMF professionals have a powerful tool to achieve inspection readiness: the TMF quality control (QC) cycle. But what is the TMF QC cycle? And how can an individual TMF professional jumpstart the TMF QC cycle?

What is the TMF QC Cycle?

Too often an expected document checklist takes the place of a true TMF QC cycle. All TMF professionals are familiar these dreaded and time-consuming spreadsheets. These lists are often comprised of hundreds of rows of regulatory documents and a column full of checkmarks that supposedly confirm a document is present in the TMF. This kind of expected document checklist is not QC but rather a document inventory. A document inventory, although a valid component of a TMF QC system, is much like a list of the items that are already in your grocery cart. Unfortunately, when at the grocery store, what is really needed is the list of items that haven’t made it into your cart yet. An inventory cannot forecast trends, create placeholders for missing documents, or effectively tell the story of the trial. A better tool is needed, and that’s where all the other elements of the TMF QC cycle come in.

At its core, TMF QC is a complete cycle meant to continuously verify the current condition of the TMF in comparison to a predefined set of expectations. The TMF QC cycle is a process that moves with and against the flow of data (not just following the flow of documents from site to sponsor). A true TMF QC cycle consists of the following essential components, extending far beyond a list of documents:

  • Planning: The TMF has a clearly defined scope, a matrix of responsibilities, and prospective timelines.
  • Quality Thresholds: Clear error thresholds and pass/fail criteria are established.
  • Equipment: There are tools in place to capture and facilitate the QC cycle.
  • Continued Verification: TMF review is conducted continually based on the established expectations.
  • Corrective Action: Items identified during verification are resolved in a timely manner and tracked to completion.

With a true TMF QC cycle in place, you can be confident that your TMF always meets the expectations of regulators and is, therefore, always inspection ready.

How Do I Implement a TMF QC Cycle?

Modern TMFs are simply too big and too complicated for one person to manage on their own. This doesn’t mean, however, that you cannot be the TMF champion that revitalizes your organization’s TMF QC process.

If you are filling the role of TMF champion and are looking to establish or revitalize your organization’s TMF QC cycle, it is best to start with the basics well before a clinical trial begins. Before defining the scope, responsibilities, timelines, or metrics for your TMF, begin with mapping out the story your TMF needs to tell. Many of LMK’s most experienced TMF consultants and analysts recommend creating your own clinical trial storyboard, where you define the characters, events, challenges, and triumphs you expect to encounter throughout the narrative of your clinical trial. With the story of your clinical trial laid out before you and split into discrete milestones and stage gates, determining what regulatory documents you should expect in the TMF becomes a much less intimidating task.

For most TMF professionals, once the narrative of the clinical trial is elucidated and a list of expected documents is generated, the path to an effective TMF QC cycle becomes clear:

  • Periodic QC processes can be designed and established.
  • Resources can then be assigned to periodically review the completeness and quality of documents.
  • Reasonable quality thresholds can then be selected to trigger corrective actions in response to these periodic TMF reviews.
  • Finally, the completion status and effectiveness of corrective actions can be tracked and verified to completion.

In this manner, the cycle of QC, when fully implemented, becomes self-correcting and self-sustaining, ensuring that the TMF is complete, correct, and contemporaneous. When these “Three Cs” of TMF quality are consistently achieved, your TMF, by definition, is inspection ready.

Inspection Readiness Is a Worthy Pursuit

The motivation to achieve TMF inspection readiness is not abstract. Complete TMF failure has led to the rejection of regulatory submissions and the delay of the most promising treatment candidates. Even moderate TMF inspection findings may result in the need to create a Corrective and Preventative Action Plan (CAPA), which on average, costs an organization hundreds of thousands of dollars to implement.

The initial investment of effort to start up your organization’s TMF QC cycle, therefore, is well worth it and once underway, becomes less resource intensive. At LMK, we understand how challenging it can be for TMF professionals to secure the buy-in necessary to implement a TMF QC cycle that incorporates industry best practices. So, if you are a TMF professional looking for more real-world advice on how to jumpstart or revitalize your organization’s cycle of TMF QC, check out our extensive library of blogs, case studies, articles, and webinars, many of which discuss the individual elements of the TMF QC cycle in greater detail. If you’d like the full support of LMK’s experienced team of TMF experts to help you achieve enterprise-level TMF inspection readiness goals, reach out to us at hello@lmkcrc.com.