Prevention and Remediation: The Completeness Crisis

With increasing frequency, TMF stakeholders face a completeness crisis at TMF close-out.  Delays in TMF closure increase regulatory risk, derail regulatory submissions, and can endanger an entire project. Sponsors, when asked about the growing trend of TMF incompleteness, are likely to cite a challenging relationship with a CRO. Regulators, however, have little sympathy for this excuse. Responsibility for the TMF, and indeed the whole trial, remain with the sponsor regardless of the use of a service provider. The TMF is a central part of trial oversight and despite the challenging dynamic of the sponsor-CRO relationship, the trend of TMF incompleteness must be reversed. Based on LMK’s experience, a TMF completeness crisis is best avoided by beginning a trial and the TMF on the right foot. A few key incompleteness mitigation strategies, coupled with a strong commitment to oversight, can prevent the last-minute shock of a fragmented TMF:

Incentivize TMF Health throughout the Trial Lifecycle

The relationship between sponsor and CRO is defined in a few key documents, most important among them the transfer of obligations documents and/or the master services agreement. Traditionally, these documents structure the CRO’s compensation to coincide with the completion of certain stage-gates, such as first patient first visit, last patient last visit, the achievement of certain enrollment milestones, and close out. If these key documents do not define TMF performance metrics or create TMF related stage-gates, your documents may provide incentive for your CRO to complete the TMF as quickly as possible—regardless of the completeness of the TMF. Structuring satisfactory TMF closure as a key CRO deliverable ensures that clinical trial resources and TMF health goals are aligned throughout the trial lifecycle.

Define and Communicate TMF Objectives from Day One

As part of incentivizing TMF health, one must clearly define the trial’s TMF objectives. Establishing these objectives begins with the creation of a TMF plan. Resist the temptation, however, to adopt a CRO’s TMF plan for the trial. Too often, these TMF plans are the same for every client and only describe the basic TMF SOPs of the CRO. An actionable TMF plan outlines the TMF quality system specific  to your trial. Defining TMF objectives, as an essential part of this TMF plan, includes establishing effective TMF performance goals. These completeness, correctness, and contemporaneousness objectives should all be measurable.

Once these objectives are defined, publishing them in the TMF plan is only the first step. TMF quality should be a centerpiece of your kickoff meeting, focusing specifically on areas of TMF risk. From this kickoff, the implementation of a training plan can ensure that TMF stakeholders have eTMF access, know how their roles intersect with the trial’s eTMF objectives, understand how their performance will be evaluated, and have the study-specific knowledge to succeed. Beginning a trial with clear expectations, coupled with the right training and tools, ensures TMF completeness from the start.

Accept Your Nontransferable Obligations

Remember, as the sponsor of the trial, regardless of the tasks delegated to a CRO or other partner, regulatory responsibility for the trial is nontransferable. Regulators view the TMF as one of the main oversight tools of the sponsor. An unhealthy TMF, therefore, causes regulators to question the oversight competency of the sponsor. Even considering the critical importance of the TMF, sponsors, especially those that have limited clinical trial experience, may not have the clinical operations experience in-house to closely monitor TMF health. Because of this ever-growing overlap between the TMF and sponsor oversight, sponsors must grow their own TMF expertise, either in-house or through TMF service providers, and should expect to be part of the cycle of TMF QC.  

There is a reason that completeness comes first in the three C’s of TMF health: complete, correct, and contemporaneous. A TMF’s purpose is to tell the story of a trial. An incomplete TMF is like a book with missing pages—even if the story is well written, it is inaccessible to any reader. But, by employing LMK’s top three incompleteness mitigation strategies, the narrative of your team’s hard work will shine through—and your oversight will never be called into question. But, in the event it is too late to implement these strategies, LMK has pioneered a completeness recovery strategy to restore harmony between sponsor and CRO as well as reenergize stakeholders to close out the trial with renewed purpose.  Check back for our next post where we will discuss how to begin to recover from a TMF completeness crisis.