How do you determine Essential Documents for a Clinical Trial?

June 11, 2013

  • eTMF Best Practices

The regulatory basis for the establishment and maintenance of a Trial Master File (TMF) is well-documented.  The ICH “ GUIDELINE FOR GOOD CLINICAL PRACTICE  E6(R1)” states “Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor’s office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.  Furthermore, EU COMMISSION DIRECTIVE 2005/28/EC of 8 April 2005 states that

“…the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated. Those documents shall show whether the investigator and the sponsor have complied with the principles and guidelines of good clinical practice…”.  But what are the essential documents?

 

The UK Medicines and Healthcare products Regulatory Association (MHRA) reports that they often encounter the attitude with sponsors that if a document is not listed in the ICH GCP or EudraLex Volume 10 as an essential document, then it need not be contained in the TMF.  In fact, their definition of the TMF is broader and less specifically defined:

 

A TMF is the collection of documentation that allows the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP to be evaluated. Therefore, the documentation contained within it should be sufficient to adequately reconstruct the trial  activities undertaken, along with key decisions made concerning the trial.

 

To understand this concept, it’s useful to think about several examples cited by MHRA of documents needed to reconstruct a trial that are not part of ICH E6 or EudraLex Volume 10:

  • Qualified Person (QP) Certification
  • Regulatory green-light to release and ship Investigational Medicinal Product (IMP)
  • Database Lock Documentation

 

 

 

 

 

The team working on the TMF Reference Model has invested a very significant effort in developing a master list of TMF documents.  This list is a highly useful reference to use in establishing essential documents.  However, two questions remain even when working with the reference model.

What trail specific information might be missing?

Even when using the TMF reference model, the specific details of a trial might result in the need for additional documents to allow conduct or reconstruction of the trial.  The best place to determine this is when conducting the trial’s risk assessment before the trial begins.

What documents are not needed?

Both E6 and the TMF Reference Model contain many documents that may not be needed for a specific trial.  For example:

  • Device-specific documents are not needed for a non-device trial
  • Trials not using EDC or IVRS don’t require documents specifically associated with those systems
  • Depending on the nature of the trial, subject advertisements may be used to recruit subjects at some or all sites, with favorable opinions on those advertisements then needed from the IRB/IEC

In addition, the risk level of the trial should dictate to some extent which documents are needed.  A trial assessed as category Type A (No higher than the risk of standard medical care) that uses an IMP in the same manner as per normal clinical practice may not require monitoring of temperature during storage.

It’s a best practice to establish a standard for how the nature of the trial dictates the required content of the TMF.  Establishing a series of questions tied to TMF Model document types (or the sponsor’s equivalent) will result in a repeatable process and provide a mechanism for maintaining and improving the ability to pre-define the exact contents of each TMF.

Summary

Knowing the exact documents required for a specific trial is key to establishing and maintaining a TMF that supports the conduct and reconstruction of a trial.  The three elements to determining the essential documents are:

  • A high quality master list based on the TMF model or the sponsor’s own standards
  • A risk assessment that identifies additional key documents for the specific trial
  • A repeatable, question-driven process for determining which documents from the master list are needed based on trial specifics