TMFs are Like Snowflakes… No Two Alike

January 6, 2015

  • eTMF Resources

Most companies have standardized on the TMF Reference Model, with or without modifications, to describe the types of documents in their Trial Master Files. The types of documents needed for each individual trial is drawn from that list.

Therefore, it might initially seem simple to build a standard Table of Contents, or Index, from that list, and then use it as a template for each trial. At first, that approach might seem attractive – although most people would conclude that several templates would be needed – maybe to account for drug trials vs. device trials, or for different phases of studies.

Upon digging in a little deeper, it starts to become obvious that a “template” approach to planning the TMF is woefully inadequate.  Take a look at some of the factors that influence the contents of the TMF at the study, country, and site levels (and this is far from a complete list):

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Study Level Factors

  • Is the trial for drugs or devices (or for a combination product)?
  • What is the blinding and randomization design?
  • What types of non-IP supplies are being used and what documentation is needed for them?
  • Will this trial include an investigator meeting?
  • What committees will be needed?
  • What documents will be provided to, or collected from, subjects?
  • What study level vendors are being used and which documents are being collected for each type of vendor?
  • What placebos and/or comparators are being used in addition to the IP?
  • Will CRFs be eCRFs, paper CRFs, or a combination?

Country Level Factors

  • What submissions and approvals are needed in this country?
  • Which documents will require country-specific versions?
  • Which documents will require translations, and what components are required for each (translation, back translation, certificate of translation, etc.)
  • What licenses are needed in this country?
  • Does this country have a central IRB/IEC?
  • What documents does this country require for each investigator or sub-investigator?
  • What country level vendors are being used and which documents are being collected for each type of vendor?

Site Level Factors

  • Which site-level documents will require translations, and what components are required for each (translation, back translation, certificate of translation, etc.)
  • Does this site have local EC/IRB submission or approval?
  • Will this site have a site specific Informed Consent form (or other site-specific documents required by a local ethics committee)?
  • How many sub-investigators does this site have?
  • What site level vendors are being used and which documents are being collected for each type of vendor?

For CROs, these questions may be even more complex as, depending on their contractual obligations, they may perform some services resulting in the creation or collection of documents for some trials and not others.

When all of these factors affecting the TMF contents are understood, it becomes obvious that a one size fits all planning template is a crude tool at best.  For sponsors and CROs planning a trial without benefit of an eTMF, a knowledgeable person needs to consult references and experts in order to document what is needed (usually in spreadsheet form).    For those using an eTMF, the eTMF should provide a mechanism to actually define the initial contents of the TMF based on all key factors specific to the trial – not just create thousands of placeholders, many of which are not relevant to the study.

And finally – this discussion talks about defining the TMF at the beginning of the trial, but no trail stays static for its duration, and likewise the TMF must be adjusted (usually expanded) as the trial unfolds.  For ideas on keeping the TMF up-to-date, see Study Events: Keeping your Trial Master File Up-To-Date as Your Trial Evolves on the Applied Clinical Trials website.