The trial master file: a case for change
The TMF is the definitive source of clinical trial documentation that provides evidence that patient rights and safety have
been protected and that the integrity of the trial data, study analysis, and study conclusions are credible. While the TMF
is the primary source of information needed to reconstruct and demonstrate the conduct and validity of a clinical trial, the
underlying process of managing and maintaining the TMF for clinical trials is often broken and fragmented. TMFs today, which
consist of both electronic and paper document formats, are generally scattered across a large and complex network of clinical
trial systems and document repositories. An average clinical trial easily generates 10,000 documents with larger trials producing
more than 100,000 documents. This means that a large global pharmaceutical company's TMF can contain millions of documents.
With the vast amount of data stored in multiple locations, locating documents becomes particularly challenging, time consuming,
and subject to frequent procedural errors. In addition, TMF users and contributors often span different geographies, locations,
and functions, making standardization of the TMF processes even more challenging, particularly as pharmaceutical companies
begin to heavily outsource their clinical trial execution activities. Finally, with the rapidly changing regulatory landscape
and introduction of new requirements, pharmaceutical companies are struggling to maintain compliance with regulatory expectations
and requirements for the TMF.
In recent inspections across a number of pharmaceutical companies, regulatory health authorities, including the MHRA, EMA,
and FDA, have placed a higher level of scrutiny on the TMF as supporting evidence that appropriate procedures were being followed
during a clinical trial. Pharmaceutical companies and CROs alike have struggled to maintain regulatory compliance and have
often been cited for inability to provide a full TMF for inspection. As a result, the industry is making a concerted effort
to address these challenges and meet regulatory requirements. One notable example is a multi-year effort led by a Drug Information
Association working group that established a common TMF reference model. This group, comprised of participants from more than
150 pharmaceutical companies including Pfizer, as well as regulatory agencies such as the FDA and MHRA, has helped drive standardization
across the industry. The discussion and activity around the TMF continue to gain momentum, as evidenced by a number of industry
conferences focused specifically on the TMF this year, which has more than tripled compared to two years ago.
Pfizer addressed the challenges it faced with the TMF by overhauling its processes and technology systems. The decision to
utilize the QbD approach rather than other standard process improvement methodologies was based on the desire to achieve "zero
defects" in its TMF by building quality into the process. In the specific application of QbD to Pfizer's TMF process, the
TMF was treated as the "end product," with a focus on designing the process to reduce the number of defects, i.e. missing
or incorrect documents. Though the premise of building quality into the TMF process and routinely monitoring it to enable
consistent quality may seem simple and even basic, it is a paradigm shift for the industry. For many companies, the TMF has
traditionally been a "graveyard" repository of clinical trial documents filed as an afterthought and relatively forgotten
until the time of an audit or inspection. In an effort to reduce the overall cost of poor quality, Pfizer has developed a
dynamic solution which enables active contribution, organization, maintenance, and monitoring of TMF documents. As part of
the solution, Pfizer has built the necessary controls and measures to proactively manage quality in real time.
TMF process redesign effort included four key steps.