Regulatory Science Symposium: Clinical Trials Hurdles Session 4 - Trial Master Files (2015)

• Phlexglobal Company Overview
  • Dedicated to trial master file 
  • Works with sponsors to provide compliant electronic trial master files (eTMFs)
• What is a Trial Master File (TMF)
  • Comprised of essential documents that allow for the evaluation of the conduct of a trial and the quality of data produced 
  • Demonstrate compliance with GCP standards
  • Must be able to stand on its own regardless of ICH, European Directive definitions 
  • High quality TMF is necessary for quality clinical trials 
• The relationship between the TMF and drug/device approval
  • Stages of drug discovery and development
  • Impact of inadequate TMF
  • Defining the TMF
    • ICH GCP chapter 8 has the minimum list of essential documents
    • Other trial-related records that permit evaluation of the conduct
    • Business records and supporting files are not included
    • TMF content-reference model
      • Standard contents, standard naming, standard structure, and standard metadata
      • Unofficial industry standard of how to compile a TMF and what documents to include and naming conventions
      • Not every company follows this model
        • The reference model consists of:
          • 11 zones based on clinical function
          • Pick a zone, find the artifact, and place document into the artifact
            • Ex. IRB zones include IRB and IRB-associated documents
• The clinical research professional role in TMF management
  • TMF contributors/consumers- 
    • Sponsor
      • Red= largest contribution and use of TMF project manager and clinical manager, make sure TMF is complete 
      • Green = regular contributions (ie. documentations of new sites) 
      • Blue = infrequent contributors or consumers 
    • Site
      • Obligated by federal regulations to maintain records at site for 3 years post-marketing
      • Documents per trial stage
        • Start-up (15%), conduct (75%), and close-out (10%)
        • Start-up and close-out is well defined
        • Conduct is when data may get muddled
        • Essential documents per study phase- start-up
          • Protocol
          • Informed consent 
          • Plans
          • Master file plan 
          • 1572s.
        • Essential Documents per study phase- study conduct
          • Present challenges: no idea about number or protocol amendments
          • Credibility issues
        • Essential documents per study phase – close-out
          • Final clinical study report
          • Final country visit reports 
          • Close-out visit report
• The challenges of TMF management
  • The number of documents in a TMF vary depending on type of study, number of sites, number of countries, and study duration
  • Impact of a clinical event
  • Protocol amendment etc. cause changes of documents 
  • Best to start collecting and storing documents properly from the beginning rather than wait until the end or before audit 
  • Timeliness
    • Maintain the TMF to know which sites to include for the next trial
    • Consistent data accrual means that a site is responsible and reliable and no one has to come out as often to check on them 
  • Everything in the TMF is subject to audits
  • Completeness
    • Systematic checks
    • Establish processes to react with conduct period 
    • Make sure everything required for the study is available
• Regulatory agencies (FDA, EMA, MHRA) expectations

Accompanying text created by Annie Ly | Undergraduate Research Associate and Provost's First Generation Research Fellow | lyannie@usc.edu