Proactive TMF Management: Keeping Up with Regulatory Change and Multimodal Inspections

The trial master file (TMF) is the culmination of every clinical trial. The time, expense, and effort expended throughout the trial results in the TMF. Despite its importance, many organizations today focus more on achieving clinical study milestones. To ensure inspection readiness, organizations should include TMF requirements within broader clinical study milestones. Instead of “Do we have the first participant yet?” the question should be “Is the first participant in, do we have all the records needed to accompany that milestone, and are we ready to move forward?”

As protocols become more complicated and trial designs incorporate new approaches and technologies, it is vital that all study stakeholders understand how crucial the TMF record is, and what is needed to ensure that it is right the first time.

Over the past two years, improving TMF quality has become more challenging as the industry has adapted to trial complexity, remote and hybrid site inspections, regulatory changes, and new industry guidance. But change is probably the only thing we can count on in the future, and proactive strategies are needed to ensure that your TMF keeps pace. This post offers some tips for ensuring TMF quality despite changing regulations and practices.

Inspections and their impact on TMF

While hybrid and virtual inspections will continue, global regulators have been clear that they will never fully replace traditional on-site inspections. Companies should be prepared for inspections that can span very different modalities. This requires learning best practices from recent inspection experiences, recognizing how new regulations may affect TMF operations, and developing risk-based approaches to trial management, including TMF.

A report from the International Coalition of Medicines Regulatory Authorities (ICMRA)¹ offers health authority insights on the effects of remote and hybrid inspections. It confirms what many of us have already experienced: Virtual inspections require more preparation than traditional on-site formats and depend on strong technology support. In addition, there may be inspection interruptions due to staff availability, time zone differences, and travel or connectivity disruptions—meaning remote or hybrid inspections generally take more time to complete.

Over the past two years, traditional face-to-face inspections have also evolved. With social distancing policies in place, inspectors may have to tour certain parts of the facility alone. In addition, due to limits on how many people are allowed in each conference room, inspectors may not be able to meet with everyone on the team.

It’s clear that, for the foreseeable future, inspections may take place in many different modalities. Below are some suggestions for optimizing results:

• Schedule a dry run. Whether your inspection is virtual or hybrid, nothing beats holding a dry run (or mock inspection) to make sure your team is prepared. Be sure to test remote access platforms and support systems thoroughly.
• Have a backup plan in place. Regulators have asked for full technology support and backup, so be sure to have a failsafe plan and redundant technology in place in case it is needed.
• Seek insights and best practices from peers. Colleagues at your company or others you know from industry associations are often eager to share insights. Ask them for suggestions on how to ensure a smooth virtual inspection.
• Consider reaching out to the regulatory agency. Once you receive the inspection notice, contact the agency with any questions you may have. Health authorities are more open than ever to dialogue and informational exchanges.

Best practices for TMF quality

Before the inspection, you can control the quality of documentation and ensure a strong TMF by taking the following steps to meet the fundamental TMF requirements:

• Remember that timeliness is more critical than ever. Audit trails can quickly demonstrate gaps in timeliness. For example, a monitoring report completed in February but posted in July is an inspection red flag. Before an inspection, assess your system’s timeliness indicators, and take action if there are gaps.
• Ensure that records are accurate, and meet the ALCOA+C requirements for data integrity (i.e., that the data are attributable, legible, contemporaneous, original, accurate, and complete). Your organization can assess a sample—rather than every record—and take action if the accuracy is below your threshold.
• Close completeness gaps. Even with completeness indicators, your organization might be missing TMF records come inspection. Compile your team’s trial stories and independently confirm that the TMF records support them to close completeness gaps.

Consider the future regulatory impacts on TMF management

As you build your TMF practices, consider how industry changes and updated regulations might affect your approaches. For example, the TMF Reference Model² will affiliate with the Clinical Data Interchange Standards Consortium (CDISC) before the end of 2022, meaning the model will serve as an industry standard to improve and support clinical technology. Consider joining CDISC as a member, which isn’t required to access the model, but may be helpful to support future improvements.

Also, be sure to assess the new trial priorities set by ICH E8 Revision 1, which came out in October of 2021. Revision 1 requires a risk-management approach to protocol development, mandating that a quality by design (QbD) approach be used and that all factors critical to trial quality be assessed. ICH E6 Revision 3, a draft of which is expected in the third quarter of 2022, is also expected to emphasize risk management³. Regulators now require evidence in the TMF that both risk-based and QbD approaches are being used. It’s critical that every trial’s TMF can demonstrate risk-based trial management.

Risk-based TMF management

As regulators have demanded risk-based trial management, it is entirely appropriate to apply the same methods to TMF management. Putting a risk-based TMF plan into action may seem daunting, but approaching the task methodically will help simplify the process. Start by assessing and stratifying records and processes to identify those that are the highest risk. Next, determine how to measure those risks and the tolerance thresholds, as well as take action if thresholds aren’t met. You’re now ready to activate and test the risk approach.

Be sure to include change management tactics in your plan to help the teams understand the rationale, align to new methods and procedures, and become cheerleaders for risk-based management. Next, gather the data and measure the impacts of your risk-based assessments. Then, celebrate and share results with the team, recognizing wins and improvement opportunities. Apply those learnings to revise your plan, and start the cycle again.

It’s shortsighted to focus solely on achievement of trial milestones without accurate records. Set your team up for TMF success by ensuring that you are ready for inspections, whatever form they take, and that your documentation and tactics reflect the latest changes in regulation and guidance. Take advantage of a risk-based approach to TMF management to ensure continual improvement and good inspection results, everywhere, every time.

For more information on establishing a risk-based TMF management process, view the full session from the Veeva TMF Innovation Forum.

Fran Ross is an independent clinical trial consultant.