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Navigating Robotic Process Automation, ICH E6(R3) Changes, and Outsourcing in Clinical Trials

Applied Clinical Trials Online

With ambitious goals to accelerate clinical trials, increase efficiency, and lower costs, many leading life sciences companies are prioritizing transformation initiatives. Still, challenges persist with managing risk-based approaches, meeting new and changing regulatory requirements, and improving the relationship between sponsors and sites. Advancing trial master file (TMF) processes can help move the industry forward and help companies manage change more seamlessly.

I sat with some of the top minds in TMF to understand the trends shaping their strategy and discuss what the very near future will look like in clinical operations. Here are the six trends that will significantly impact TMF and the future of clinical trials.

1. Automation to reduce manual or high-volume activities

The industry is turning to bots and robotic process automation (RPA) to enable automation of high-volume manual processes. These bots typically don’t eliminate tasks requiring human review, action, or processes subject to inspection findings but drive critical efficiencies for TMF functions.

To complete tasks like document classification, quality review, and reconciliation, a top 20 biopharma deploys a fleet of more than 10 bots. “We call them digital workers,” says the company’s head of TMF. “They have their own user IDs and system access privileges. Each bot has a TMF ‘manager’ for training and performance measurement.”

These human and digital workers are both seen as integral parts of the company’s TMF strategy. “The digital workers take care of standardized, transactional tasks while human workers focus on decision-making, defining strategy, and managing stakeholders.” Over four years, the company estimates successfully automating more than 1,000,000 transactions with its fleet of bots and saving 200,000 hours of work for its TMF team.

2. Snapshot views of TMF health becoming a reality with comprehensive study scores

More companies are adopting risk-based approaches for TMF management. These approaches can improve TMF quality by focusing effort on the highest-risk documents. For example, a company following risk-based practices can allot more time to the quality control of documents critical to inspection readiness—like a site’s training record and qualifications—than to lower-risk activities, like site email communication.

A large biopharma, for example, implemented risk-based reviews and created a weighted formula to assess its TMF health holistically. The formula combined quality, timeliness, and completeness metrics into a single study health score.

Now, the company can compare study health across its studies and partner contract research organizations (CROs). It also helps compliance managers engage more effectively with study managers, improving TMF health.

“We’ve seen a broader embrace of the importance of TMF,” says one of the top 20 biopharma’s TMF business operations lead. “Our compliance manager is not a traffic cop who points out everything wrong with the TMF. Instead, they provide solutions.”

Since piloting this program, the company has improved the starting TMF health score average for new studies by 180%. This demonstrates the effectiveness of combining a risk-based approach with study health scoring.

3. Increasing focus on risk-based TMF to meet ICH E6(R3)

ICH E6(R3) is imminent and expected to be finalized later this year. The new regulation will require TMF teams to approach data integrity, systems, and retention rules differently. Key changes include:

  • Guidance so companies can take a more thoughtful, risk-based approach to TMF management.
  • Expectations for essential or “potentially essential” records, with the types of records now listed as potentially essential influenced by a broader range of factors related to specific trials. This means sponsors and CROs must collaborate to define what “essential” really means.
  • Introduction of the role of digital systems in clinical trials explicitly. Now, investigator sites must ensure that their software systems are “fit for purpose.”
  • Reference to local laws for document retention. This will likely mean that inspection sites will shift most of this responsibility to sponsors. Companies will need to adapt to local regulations and develop new processes to manage retention.

4. TMF inspections are now remote, hybrid, and multi-agency

Remote and hybrid inspections are standard practice, and the FDA is beginning to team up with other global agencies, such as the EMA and MHRA. The collaboration includes attending each other’s inspections, understanding their approaches, and sharing learnings. While the insights shared can improve efficiency, the multi-agency approach increases complexity for sponsors.

Inspectors are also asking biopharmas to map the document lifecycle across sites, CROs, and their systems. To improve document identification, some companies are reviewing and reducing their alternate filing locations. This heightened scrutiny emphasizes the importance of updating inspection-readiness processes, including audit trails.

5. Outsourcing strategies are evolving as biopharmas consider tradeoffs

Organizations are insourcing areas such as medical monitoring, data management, and vendor oversight to increase their control and data ownership. This comes amid the industry’s pendulum shift toward insourcing.

Considering a cost-benefit analysis is beneficial to ensure the right operating model because CRO integration and training in sponsor systems can create inefficiencies. Depending on the outsourcing strategy, biopharmas will also adapt internal staffing numbers.

One top 20 biopharma has insourced 95% of its TMF management, deploying a team of over 60 clinical documentation associates (CDA) to work directly with study teams and conduct quarterly meetings. “The CDAs need to think critically about what documents are needed and influence study team members to drive outcomes,” said the biopharma’s associate director of TMF.

In contrast, another large biopharma outsources significant portions of its TMF management to CROs and consulting vendors. To drive TMF health, they aim to resource one TMF lead for every 10 trials, site-dependent.

“The role of the TMF lead is like the canary in the coal mine,” says the pharma’s associate director of TMF. “They help identify trends but are not responsible for the content. We’re pushing to have TMF leads identify trends and empower business functions to address those issues.”

Fast-growing biotechs may consider combining insourcing and outsourcing—including adapting their operating model on a study-by-study basis—to drive compliance while conserving resources.

6. Standardization of TMF data grows

The TMF Reference Model is now affiliated with the Clinical Data Interchange Standards Consortium (CDISC), signaling the ongoing industry shift toward standardization and uniformity in how eTMF systems are set up, including metadata expectations.

“We’re very excited about this change,” says one CDISC TMF Reference Model steering committee member. “One of the biggest efforts will be bringing the TMF Reference Model out of the spreadsheet and into the CDISC library.”

Standardization will drive improvements in how sponsors manage TMF, especially for companies automating processes across connected eTMF and CTMS. This creates consistency across sponsor environments, streamlining processes for CROs as well.

Advancing TMF for speed and agility

Arthur Conan Doyle wrote, “There is nothing more deceptive than an obvious fact.” In the case of clinical research, the documentation in the eTMF proves facts and serves as the backbone of studies. Leaders should understand the strategic importance of how the eTMF fits in the bigger picture as they evolve processes, optimize the trial operating model, and implement new technologies for greater speed and efficiency.

The industry can move toward more connected and efficient clinical trials by establishing a strong foundation for TMF management that enables connections across the study ecosystem. This is the future of drug development, and forward-looking companies are leading the way by driving positive change.