The 2020 9th Annual TMF Summit placed proper emphasis on these three pillars of TMF management: Quality, Completeness, and Timeliness (real-time inspection readiness). Interestingly, 60% of attendees polled reported they were more concerned with completeness than quality.
The reasons given were:
Lack of support from other functional groups
Each study has different essential documents
Each study has various versions of documents
Overall tracking concerns on what is truly missing
Clinical personnel (CRAs, CTAs, etc.) who work closely with the TMF acutely understand the nuances of managing an eTMF and establishing the necessary strategy and processes. More and more, other functional groups within sponsor organizations are recognizing the importance of the TMF and associated processes and systems. With time, it has become clear that the TMF is not simply an archive; it is a complex and critical consideration in the success of a clinical trial.
The trend toward this TMF enlightenment across the entire sponsor organization needs to be encouraged in 2020 and beyond. The documents that ultimately end up in the TMF are specific to the conduct of the study itself. Documents like protocols, investigator's brochures, and informed consent forms, along with all documentation from your study start-up regulatory packet, including investigator CVs, financial disclosures, and so much more, must make their way through their initial authoring, review, and approval to be finally indexed correctly in the TMF/eTMF. These document processes involve many parties not specifically involved in managing the TMF and draw attention to the need for them to be captured completely so that all begin and end in the same system. There are stakeholders who influence study documentation but may never directly interact with the TMF and can impact the success of the organization’s TMF management. Organizations need complete buy-in on the document processes and approach to TMF management.
During the event, there were five key topics repeatedly highlighted:
Aside from the above-mentioned themes related to inspection readiness, remote inspections and training were also emphasized. Regulatory authorities are teaming up for joint inspections (e.g., MHRA and FDA for studies that extend across regions overseen by both). In scenarios where more than one regulatory agency is inspecting, remote access to the eTMF makes the entire process easier on everyone involved.
Furthering the need for enabling remote inspection, increasing numbers of inspectors are choosing to perform their audits remotely. This trend sometimes means requesting access for longer periods. Be sure to communicate with the inspector when the inspection is completed so that you can revoke access to the eTMF—not revoking their access in a timely fashion can, in itself, be a finding.
Inspectors also want to do as little TMF anthropology as possible since they deal with the main eTMF system regularly. While some inspectors might not want full training, it is still important to stay prepared. Every sponsor and study is different, so having a quick reference guide ready for the inspector on what is different about your TMF creates transparency and helps the inspector complete their audit more efficiently and quickly.
If you are familiar at all with our Division President, Michael Smyth, then you have likely heard him talk about real-time inspection readiness dating back at least ten years. Fast forward to 2020, and inspectors are looking at not only quality and completeness, but also the timing of when documents are filed. They check for incongruities with document filing timing. Specifically, whether there was an influx of documents submitted at the end of the trial and/or before inspection, as opposed to documents being filed as they become ready (on a more real-time basis). Sponsors must communicate with their document owners and CROs about the importance of timely indexing of documents to the TMF. Scheduling reports to run checks on document dates vs. submission dates is an effective way to maintain oversight.
Not only is the specific timing of document submissions important, but whether or not the documents were completed per the sponsor and/or CFO SOPs and plans. For example, the Monitoring Plan will list how soon after a site visit the visit report needs to be signed by the CRA. Some plans might also require additional oversight signatures, such as the CTM. In addition to the signature date, the visit report must be filed in the CTMS and/or eTMF within a certain time frame (e.g., 30 business days).
It was suggested during the summit that KPIs measured in the eTMF should be shared outside of the eTMF to appropriate team members for accountability. For example, one speaker discussed how his company posted the KPIs around the office to make every department stakeholder accountable. He noted this as an effective way to get the team’s attention. Being able to identify key trends as well as red flags like document errors or missing documents is critical. Keeping these in collective awareness is a good best practice. That practice requires providing the tools to be successful and learn from mistakes. There is a lot of talk in the industry about creating cultures of inspection readiness. Practices like the example above are where the rubber meets the road in terms of finding creative ways to actually make inspection readiness a mindful and daily practice.
Sponsors are using KPIs not only for inspection readiness but also to perform proper oversight of their CRO and vendor performance. These metrics can help the sponsor determine which of their CROs are performing well, where they need to increase training if there is high CRA turnover, and/or whether escalation is necessary regarding certain CRAs due to the trend identified (e.g., quality, completeness, and timeliness). In fact, more and more sponsors are hiring team members or consultants with the sole focus of internal and external performance analysis.
Small Pharmaceutical Companies
There were a few workshops specifically focused on small pharma. They discussed myriad topics from an explanation of the TMF and its importance to other departments to what small pharma companies should be looking for when forming a partnership. There was a lot of discussion on how small pharma could maximize productivity and efficiency. Smaller organizations need to find vendors that can help minimize stress on limited staff as well as a partner who can provide a complete, accessible platform to house the eTMF.
While the pharma industry is highly successful, start-ups are cash- and resource-limited. Even with investment capital, they are stretched to the limits to make sure every single dollar counts. They take on all of the risks to conduct research in hopes of successful trials that lead to new treatments that can eventually be brought to market. This process does not happen quickly. The money goes out and does not come back in for years and years.
Small pharma companies really need partners who understand what it means to support a start-up enterprise. There is a lot of talent in these organizations, but when you are a small company, you will inevitably have gaps in your available subject-matter expertise. You will also have the aforementioned constraints on the budget. These variables impact staff to lead, staff to administrate, and IT infrastructure and capability, to name a few essential aspects of operations. None of this means the future is bleak for small pharma companies. On the contrary, more than ever there are service and technology partners at the ready. In future content, we will discuss how smaller organizations can help themselves select the right partner.
The TMF Plan
Most people who work in the TMF know what the “TMF Plan” is; however, questions arise over who should be the document owner when working with CROs and vendors. The TMF Reference Model Committee informed attendees that the sponsor should have full ownership and the CRO should be added to certain sections (e.g., RACI) for alignment purposes. I raised the question, “Where do TMF services groups such as TransPerfect come into play?” The short answer: “We are in uncharted territory.”
Suggestions were made to create a vendor oversight plan and/or create another document for guidelines and be added to the sponsor TMF Plan RACI for clarity. The bottom line: Sponsors should have a TMF plan designed to tell the entire story of the TMF. In my experience, it is essential to set clear expectations on who is responsible for which action (sponsor vs. CRO vs. consultants vs. vendor). To future-proof potential gaps in your process, create an end-to-end workflow and include it in your plan. Between this workflow and the RACI outline, you will be on the right track to starting your study off on the right foot.
But wait…there’s more!
Some additional topics at the summit included the ever-growing intrigue around artificial intelligence, as well as discussions on archiving the eTMF and ongoing logs.
Artificial Intelligence (AI)
AI is on everyone’s mind for document filing. Three presentation topics involved what type of testing is being done, how AI can learn to file documents, and what we can expect from the future of AI in eTMF. Some of the AI challenges have been working with documents in foreign languages and non-streamlined templates. There will need to be a lot of testing and comparing of the AI filing locations vs. the human ones, as well as teaching the system to check for quality and PHI. It is an exciting time, and I cannot wait to see what the future of AI has to offer the eTMF world. We have some thoughts on that.
A 45-minute archiving panel discussion turned into a much longer conversation as, clearly, the attendees were interested in the topic. Many sponsors are currently updating their plans to include this final phase of the TMF. Hopefully next year there will be more sessions on this topic. Reading guidance on the topic is helpful to align with the declared expectations of regulatory agencies. We’ve summarized the EMA guidance, complete with a section on archiving. You can review the important points by downloading the white paper.
While the TMF is a repository for housing final documents, the question has come up with many sponsors on how to handle ongoing logs. Examples include the delegation of authority (DOA), drug accountability, visit records, and training logs.
In the past, these logs were collected during the COV and filed into the eTMF within six weeks after the COV; however, sponsors need the information on the logs long before closeout. For example, the sponsor may want the DOA list to verify who needs to have GCP certifications completed (as the full site staff is not listed on the 1572s) or to see if the CRA is using the visit log to track their visits or there are any issues with a site pharmacy distributing drug to the subjects.
A few presenters suggested filing these logs as they are collected, rather than waiting until closeout for all pages and signatures to be present. To track completeness, it was suggested to have each version supersede the last and add metadata such as “final” to the completed version.
The TMF Summit sends a great message to everyone in the clinical trial industry on the importance of maintaining a healthy and complete TMF. Karen Freid, from Merck, referred to the TMF as a book that should tell the entire story of the clinical trial from the beginning (pre-trial) to the end (closeout). If an inspector could not find a page (document or a literal page) or, even worse, a chapter (entire artifact), they would be lost in the story. I found this analogy to be both wonderful and accurate.
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