Clinical trials generate reams of documents. Many of these documents are produced for specific purposes or audiences. Many are subject to specific requirements that govern everything from the document’s format to the environment in which the document is produced.
As documents and their requirements proliferate, so does the burden on clinical trial and medical affairs teams to meet those requirements, track the documents and provide essential evidence demanded by regulators and other parties.
A Trial Master File has long served as the repository for necessary documents and logs. Today, an electronic Trial Master File or eTMF streamlines much of the work of document management, logging and compliance.
Improve Retention, Response Time and Reference
Before the digital revolution, a trial master file was maintained in physical format. Often, a specific physical space was set aside. Behind that locked door lay piles of binders and documents. To access the information, a member of the clinical trial or medical affairs team needed to be physically present in the space.
Healthcare information management has become more complex in recent years. “Today’s healthcare data management systems are facing key challenges in terms of data transparency, traceability, immutability, audit, data provenance, flexible access, trust, privacy, and security,” note Ibrar Yaqoob and fellow researchers in a 2021 article in Neural Computing and Applications.
These challenges appear in all aspects of healthcare, including clinical trials. Proliferating regulations, demands for transparency and complex trial challenges all generate a blizzard of documentation — and a corresponding avalanche of demands for access to that documentation. Analog TMF methods have been pushed beyond their limits.
An eTMF expands those limits without sacrificing the benefits of its physical predecessor:
- Retention of documents. Unlike a physical locked room or a three-ring binder, an eTMF doesn’t run out of space. Trial teams can generate as many documents as they need, with the corresponding signatures, metadata and related documents, without concerns about the use of physical space or resources.
- Response times. A physical TMF space raises immediate challenges when regulators demand a certain piece of evidence. Who is physically present to retrieve the paper document containing that evidence and also has the authority to do so? With an eTMF, physical presence is no longer a concern; an authorized party may access the platform from anywhere in the world in order to provide a prompt and complete response to regulatory demands.
- Reference for current and future trials. Documentation generated in a clinical trial can be a valuable source of information both during a trial and for future trial teams seeking to reproduce effective workflows or procedures. Storing documentation in physical form poses many of the same challenges as the physical TMF space. An eTMF helps resolve these issues. The eTMF makes information accessible for future reference and education, improving future trials.
In the past, locked rooms were necessary for security. Today, an eTMF can provide enhanced security and more refined control of access to information. The result is improved compliance as well as better access to necessary information.
The FDA’s good clinical practice (GCP) regulations provide the bedrock of the work reflected in a trial master file. Documentation must meet the ALCOA elements of good documentation:
- Attributable: We know who recorded or edited the information.
- Legible: We can easily read the information — both the original information and any subsequent edits.
- Contemporaneous: We know when the information was recorded and can check whether it was recorded at the time an event occurred.
- Original: The information is firsthand documentation, not a copy.
- Accurate: The information correctly records the content it is intended to express.
The International Council for Harmonization (ICH) E6(R2) addendum, adopted by the FDA in 2018, included a sixth element:
- Complete: The documentation contains all related information.
In practice, these elements often appear aspirational rather than essential. “One of the most common inspection findings in investigator site inspections is lack of reliable, accurate and adequate source documentation,” writes Chitra Bargaje in an article in Perspectives in Clinical Research.
An eTMF can boost teams’ efforts to meet each element of good documentation reflected in ALCOA-C. For example, an eTMF can:
- Automatically log user information whenever a user creates a document, enters information or edits an existing document.
- Maintain documents and related change or attribution logs in a consistent, easily readable format.
- Include automatic time and date stamps to identify when information was added or edited.
- Indicate whether information was added directly, or copied, pasted or uploaded from another source.
- Scan for discrepancies between documents when the documents should align.
- Require certain pieces of information to be included in a form or document.
An eTMF does not absolve team members from the responsibility of adhering to GCP standards, including the ALCOA-C elements. Rather, an eTMF provides necessary guidance, reminders and backups to help team members stay on track and guard against human error. Automated processes bring errors down and compliance up, notes Kimberly Kiner at 2K Clinical Consulting.
An eTMF makes it easier to ensure documents are available when needed, too. The ability to find and organize documents quickly may have profound effects on the success of regulatory submissions. As documents and the information they capture proliferate, getting the right information in the right format to the right regulators becomes more challenging — but it also becomes more vital.
For instance, “the key to submission success continues to be delivering a clear and effective integrated summary of safety (ISS) and efficacy (ISE) as quickly as possible,” write Craig McIlloney and fellow researchers in an article for Applied Clinical Trials. The same holds true for other documented evidence, such as evidence of proper training that may be demanded by the FDA or other agencies. An eTMF can help your team provide necessary documentation and evidence promptly.
Improved collaboration is often a natural side effect of eTMF implementation because effective use of the eTMF demands it. When information is not uploaded and shared in a timely manner, teams using the eTMF may struggle to complete essential tasks.
In a guest column for Clinical Leader, Biosceptre’s Brad Miller provides the following example. Suppose that the data management team completes user acceptance testing on the clinical database. The team promptly puts its findings into a report — but then procrastinates on uploading the report to the eTMF and sharing it with the appropriate parties.
When the report is finally added to the eTMF, the system provides a timestamp that reflects when the report was uploaded, not when it was created. The gap between the completion of the testing and the uploading of the report looks like a lag in completeness or timeliness, even when the work itself was done in a complete and timely manner.
“Your expectations of various functional teams are not mutually exclusive” when it comes to working together within an eTMF, notes Miller. When an eTMF is implemented effectively, the system boosts collaboration and provides instant feedback to users on how well they are holding up their end of the collective endeavor.
What’s the best way to choose an eTMF? Always put the goals of the clinical trial first, and choose your TMF software accordingly. “Using ECM [Enterprise Content Management] as a means, and not the end to building successful solutions will move your organization forward,” writes Laurence Hart, a director of consulting services at CGI Federal. When the project’s priorities are clear, the software can be deployed as a tool to meet those goals.