From Reactive to Prospective: A TMF Transformation Case Study
How LMK’s TMF experts empowered a growing sponsor to take back the reins of their TMF
The Trial Master File (TMF) is the main deliverable of a clinical trial. If a clinical trial’s TMF fails, regulators will act swiftly to protect the safety of patients, and precious clinical data will be thrown into doubt. Despite the critical importance and high stakes of TMF health, sponsor organizations routinely delegate control of their TMFs to contract research organizations (CROs). As one clinical trial sponsor learned, however, it can be extremely difficult to gain this control back if circumstances change.
The Challenge: TMF Outsourcing Has Jeopardized Our Trial Oversight
A sponsor organization entered a rapid-growth phase after an initial marketing approval, which hastened the commercialization of several related compounds in their drug development pipeline. This explosive growth, while positive for the company, greatly increased the number of active clinical trials at the sponsor. It also presented a TMF compliance challenge as clinical trial management personnel struggled to keep up with the increased workload.
As a small but quickly expanding organization, the sponsor operated in a clinical outsourcing model since its inception. Most clinical functions, including TMF management, were outsourced to a large, multinational CRO. The benefits of this outsourcing arrangement were near-term, primarily the reduced cost and complexity of growing and managing clinical resources in house.
The sponsor was promised a full-service and hands-off clinical program by the large CRO. But after entering this explosive growth phase, expectations increased and timelines compressed. Suddenly the full-service solution provided by the CRO became decidedly hands-on. Critical study milestones were delayed due to TMF quality issues at the CRO preventing study closeout. Worse yet, when the sponsor’s leaders pressed for updates, reports from the CRO regarding TMF-related items became increasingly infrequent, and when the CRO’s reports were finally received, they were contradictory or out of date.
Even when some TMFs were finally closed, the process to migrate the TMF to the sponsor was time consuming, inconsistent, and unnecessarily complex. The worsening TMF quality issues finally became a crisis when the successful marketing application led to an in-depth inspection of the sponsor by the FDA. The inspection and its findings revealed serious trial oversight and TMF quality issues that needed to be urgently addressed with a corrective and preventive action plan (CAPA). The limited clinical staff at the sponsor were at a loss for how to proceed without interrupting their core business objectives.
The Solution: LMK’s Complete TMF Solution Puts the Sponsor in Control
After having little success addressing TMF quality issues with their CRO on their own, the sponsor sought out the TMF experts at LMK Clinical Research Consulting. LMK’s TMF consultants quickly assessed the scope and condition of the sponsor’s TMFs, performed a gap analysis against all applicable TMF regulation, and began the process of implementing the Complete TMF Solution.
The Complete TMF Solution combines the four domains for which LMK Clinical Research Consulting and TransPerfect have gained industry-wide recognition: innovative TMF education, deep expertise, powerful technology, and system-agnostic services. Uniting these domains into one values-driven organization offers clients a holistic model of TMF health unlike any other.
Leveraging the elements of the Complete TMF Solution, LMK’s TMF experts were confident that they could not only address the TMF quality issues and close out the CAPA but also build up the sponsor’s own internal capabilities to regain control of their TMFs. The deeper mission was to strengthen the sponsor’s overall trial management and oversight empowered by the TMF while still avoiding the cost, complexity, and expense of bringing TMF management completely in-house.
The Implementation: Incrementally Achieving Holistic TMF Health
Upon initial review, LMK’s consultants identified several key TMF quality issues, including:
- No study-specific TMF plan
- Differences between the observed TMF structure and the specified document index
- Failure to account for trial-specific documents in the document index
- Many missing, duplicate, or poor-quality documents
- Lack of contemporaneousness
These were further compounded by ongoing TMF process and TMF culture concerns expressed by the sponsor’s clinical operations team, including:
- Poor functional area engagement with the TMF
- Confusion surrounding use of sponsor or CRO standard operating procedures (SOPs)
- Inconsistent process for CRO filing of sponsor-generated documents
- No access to the live TMF or to TMF reporting functions
Fortunately, LMK’s TMF professionals were able to respond to the sponsor’s diverse array of TMF challenges by employing many elements of the Complete TMF Solution. From LMK’s initial consultation with the sponsor, it was clear that a hybrid-consulting approach was best based on the business objectives, size, and team culture. In this hybrid TMF management model, the sponsor would continue to outsource TMF administration to their existing multinational CRO but would, in parallel, develop greater in-house TMF expertise to improve overall clinical trial oversight and achieve a more collaborative business relationship with the CRO.
As system-agnostic service providers, LMK’s consultants have decades of experience with many eTMF platforms, including the large CRO’s eTMF platform. After advocating for access to the CRO’s sponsor portal on behalf of the sponsor, LMK’s document analysts were able to independently and efficiently inventory all existing TMFs. With this inventory, LMK’s TMF consultants developed a custom-tailored document index, TMF plan, and TMF quality control cycle for each clinical program. These deliverables directed the TMF remediation process with the large CRO.
LMK’s TMF consultants and TMF support analysts were then flexibly integrated into the sponsor’s clinical team to assist in both closing TMF queries and processing the bolus of document processing activity associated with the remediation. LMK’s TMF consultants regularly provided up-to-date reporting with clear performance indicators. These reports allowed the sponsor’s clinical team to easily monitor LMK’s progress and accurately communicate this progress to the sponsor’s leadership. As the remediation activities progressed, LMK’s TMF consultants also helped author, and ultimately close, the inspection-related TMF CAPA promised to regulators.
In the months that followed, the sponsor’s management worked closely with LMK’s TMF consultants to develop new TMF SOPs and processes that aligned with their objectives and strengthened their clinical trial oversight. This included the implementation of scalable document processing and QC solutions from TransPerfect and LMK Clinical Research Consulting, as well the adoption of tailored performance metrics for the sponsor’s CRO to ensure ongoing TMF health.
Finally, LMK’s TMF experts also directly sought to revitalize the sponsor’s TMF culture through a fully customized TMF training program as part of implementation of the new SOPs and processes. This training program introduced learners from all functional areas to experience-appropriate TMF scenarios using the in-use eTMF platform and simulated regulatory documents based on the sponsor’s own regulatory documents.
The Outcome: LMK Transformed the TMF Into a Prospective Trial Management Tool
For LMK’s client, the Complete TMF Solution rapidly restored TMF inspection readiness. The Complete TMF Solution also provided a clear, incremental path that reimagined the sponsor’s eTMF as a prospective clinical trial management tool and competitive advantage.
Practically speaking, the results were even more profound for the sponsor’s clinical trial managers who regularly interacted with the TMF and the sponsor’s CRO:
“The TMF is a subject people are willing to discuss again. My peers in other functional areas no longer avoid requests for documents and can even upload them without my help. I know we have a repeatable process for creating, starting up, and closing TMFs on-time.”
“Our CRO has provided over-the-shoulder access to the TMF and knows TMF quality is important to us. Inspection readiness is the expectation. Our new service contract includes the TMF performance metrics that LMK helped us develop. I know if we get inspected, we’re ready. I have the reports to prove it.”
As a prospective clinical trial management tool, the sponsor’s now complete, correct, and contemporaneous TMFs provided a wealth of knowledge and insight to the organization’s leadership and decision-makers. These actionable insights empowered new approaches to staffing, clinical monitoring, clinical supply, and investigator selection that were not possible before their TMF transformation.
When asked if their relationship with LMK would inspire the sponsor to take their TMF and perhaps other aspects of their clinical functions in-house, a key decision-maker reflected on their transformative TMF experience with LMK:
“I’m not exactly sure what our long-term plans are for TMF management. It will depend on our growth. I am confident, though, that our relationship with LMK makes us certain that no matter what happens, we will be on the right side of TMF process, technology, and regulation. In retrospect, it was a smart decision to invest in my team’s TMF expertise rather than waiting for days for a reply email about the status of the TMF. I would recommend LMK to any team struggling to manage their TMFs.”