Recovery: The TMF Completeness Crisis

In our last post, we discussed the growing TMF completeness crisis. More often than ever, sponsors are discovering that upon closeout the TMF is woefully incomplete. Delays in TMF closure, as discussed in the last post, increase regulatory risk, derail regulatory submissions, and can endanger an entire project. Although a few key incompleteness mitigation strategies can reliably prevent a completeness crisis, what happens when a completeness crisis has already occurred? LMK’s top four post-initiation incompleteness mitigation strategies cut through the fog of misinformation, silence, indecision, and blame – guiding TMF stakeholders to most efficient path back to TMF health.

Reestablish the Dialogue

Recovery from a TMF completeness crisis means overcoming the behavior that enabled the crisis in the first place. Reflecting that a strained sponsor-CRO relationship is usually associated with TMF incompleteness, one must examine what aspects of a strained sponsor-CRO relationship are most damaging to TMF health. Usually, TMF avoidance behavior is to blame and this avoidance behavior is allowed to grow through lack of communication between sponsor and CRO. During protracted periods of silence, the condition of the TMF worsens and no party wants to address concerning trends. Therefore, in order to work towards a TMF health solution, CRO and sponsor must come together, ideally face-to-face (and perhaps for the first time), to discuss the TMF. Establishing a TMF dialogue may at first be uncomfortable or even emotionally charged, but once emotions are laid bare, the boundaries of the TMF completeness crisis can be located. The stress and frustration of a TMF health crisis can be greatly reduced simply by mutual recognition of the problem and a few tentative first steps made in good faith. For most, our imagination leads us to believe the health of the TMF is far worse than it actually is.

Regain Visibility

Sponsors are often tempted to delegate all TMF responsibility to a CRO. CROs, advertising themselves as one-stop-shops, are happy to provide their own TMF plans, TMF SOPs, TMF timelines, TMF system, and dedicated TMF staff. But, this one-stop-shop service allows the sponsor to conduct a clinical trial without ever seeing an essential document change hands—a true gap in oversight. Such a full-service arrangement, where a sponsor might not know how to (or even be able to) access his or her own TMF breeds the kind of TMF silence that prefaces a TMF completeness crisis. So, after establishing a dialogue with a CRO, discuss how best to achieve visibility of the TMF. Does the CRO have the ability to provide over the shoulder access to the TMF? Does this access provide contemporaneous information? If so, a trusted team member of the sponsor should fill the role of sponsor TMF expert.  If not, the discussion should focus on what kind of reporting will be provided to allow your team to map the completeness of and fully understand the areas of risk within your TMF. The inability to provide such access should strongly influence a sponsor’s decision to continue utilizing the CRO.

Adopt an Incremental Approach

Regaining visibility of the TMF, whether with over-the-shoulder access, or if necessary, through manually delivered reports, permits your team to break down the TMF’s completeness crisis into constituent parts. Adopting this incremental approach first requires appraising the TMF for completeness. It’s often best if the sponsor and CRO both conduct their own completeness assessment and discuss the result. From this discussion, a list of action items and/or missing documents can be developed. This list can be further reduced into components according to the TMF reference model, generally by level (trial, country, and site), and then assigned to the most knowledgeable stakeholders for resolution. Once the list is developed, it is best to calculate a rough estimate of resourcing requirements to resolve all items. From this estimate, a gap analysis can be conducted to determine if the budget or timelines must be adjusted. Again, one of the key features of this incremental strategy is securing buy-in from all parties. Only when the CRO, sponsor, and all other concerned parties agree on the list and share in one goal of TMF health will TMF health improve.

Complete the Cycle of Quality Control

In addition to having joint buy-in to the list of action items, a sponsor and CRO should also be in agreement about what constitutes action item closure. TMF quality control should be thought of as a cycle where expectation and reality are continuously aligned. In the case of TMF action items, closure should mean that the TMF is made whole, not just that a document has been located. For example, what if an action item is closed by one TMF stakeholder before others have the chance to evaluate the closure? What happens if the document does not conform to good document practices? What happens if the document reveals the existence of further missing documents? Answers to these questions should be communicated to all stakeholders to ensure any compliance trends obfuscated by incompleteness are identified and mitigated as the TMF becomes complete.  Although it is tempting to rush to completion, completeness is only one component of TMF health. Therefore, sponsor and CRO must not sacrifice true TMF quality control to shorten remediation timelines. 

Recovering an incomplete TMF requires healing both the relationships of TMF stakeholders and reorienting your team toward decisive and compliant TMF action. Last-minute TMF surprises can crumble an already strained sponsor-CRO relationship, further complicating the task of getting the TMF back on track. But, repairing a sponsor-CRO relationship is possible when dialogue is positive, the problem is well understood, and an actionable plan has been established and followed to completion.  Frustratingly, it takes far less effort to maintain TMF health than it does to bring a TMF back from the brink of a completeness disaster. However, despite our best efforts, not every clinical trial or TMF goes to plan. TMF completeness is best achieved through consistent and compliant trial execution, but sometimes grit and resiliency are just as important.