Inspection Readiness Begins with the Trial Master File (TMF)

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Donna Dorozinsky, RN, MSN, CCRC, Barnett International

PAID MESSAGE – The Trial Master File (TMF) is held by the sponsor and represents the story of the study of the study. The Investigator Site File (ISF) is held by the site and represents the story of the study at the site. These documents are the cornerstone of inspection readiness, and it is essential that both the sponsor and site organizations employ strategies for insuring that their TMF/ISF are prepared for a potential health authority inspection from the beginning of every study.

This becomes even more critical as many European agencies conduct routine inspections during an active study. Organizations can ensure not only that the documentation is available and complete, but that the documentation tells the story of a study that was conducted in adherence to the protocol using principles of Good Clinical Practice (GCP). Ensuring that your ISF and TMF are built in a way that the complete documentation tells the story of the study will ensure that you are ready come inspection day.

Some frequently asked questions about the TMF include:

Q. If a sponsor is utilizing an eTMF, do all clinical trial records need to be kept within that eTMF?

A. No. Some sponsors determine that the safety reporting documentation should be maintained by the Pharmacovigilance department with all of the SUSAR/CIOMS reporting retained in one location for that compound. In many cases, sponsors hold TMF content in different systems. As long as these systems are compliant with the requirements for maintaining electronic records (i.e., 21 CFR, Part 11 & Annex 11) and there is a method for the long-term archive within these systems, then it is acceptable to leave them in this location. In these situations, it is helpful if the sponsor maintains a map that documents the location of the different records that comprise the TMF. This will facilitate the timely retrieval of records in the event of a regulatory inspection. The TMF content must be readily available during the life of the study as well as archived following the completion of the trial. If content is held outside the eTMF, then the functional group holding the content must be accountable for the completeness of that portion of the TMF. It is important that there is a plan for providing a health authority inspector access to all locations where the TMF content is retained. Additionally, some documentation may be non-trial specific. For example, the TMF validation documentation will be held outside the TMF.

Q. Will a regulatory inspector expect access to our eTMF?

A. During a health authority inspection, the TMF is the basis of the inspection. These inspectors will expect that the TMF be readily available to them. Delays in MHRA being provided access to information within the TMF could result in the issuing of a critical finding if the delay results in an increase in the number of days required to conduct the inspection. Recently, the FDA has requested direct access to the sponsor’s eTMF as part of its inspection. If a sponsor is holding TMF content in another validated system, then the sponsor should have a plan in place for providing the regulatory inspector access to that system as part of the inspection process.

Q. Must the TMF be kept up to date or is it acceptable to organize the TMF at the end of the study?

A. Regulatory authority expectation is that the TMF be maintained in a constant state of inspection readiness. This requires that records are filed within the TMF in a timely manner. Each organization should define timeliness within its procedural documents or TMF Plan. Maintaining an up-to-date TMF helps in providing oversight to the clinical trial. If the sponsor waits until the end of the trial to ensure the TMF is complete, it is much more difficult and sometimes impossible to obtain records that are complete. When utilizing an eTMF, timeliness becomes very transparent because records are time and date stamped when they are added to the TMF.

Q. Is a TMF plan required for each study?

A. There are no regulatory requirements for preparing a TMF Plan. However, a TMF Plan can be valuable when a sponsor and CRO will both be contributing content to the TMF and both parties will have some responsibility in the maintenance of the TMF. In some cases, both parties prepare their own TMF Plan and in other cases one plan is prepared to support both organizations. The TMF Plan generally includes details regarding the following:

  1. The system(s) where the official TMF or record of source is held.
  2. Reference to procedural documents that support the management of the TMF.
  3. The processes that are used for filing the TMF content during the trial. This includes the process for getting the records from the site monitor into the TMF in a timely and secure manner.
  4. The process for managing access and training on the TMF.
  5. The structure of the TMF.
  6. The process for adding content to the TMF.
  7. References to existing procedural documents that support TMF activities.
  8. The formal archive plan.

Sponsors, CROs, and Investigator sites are all too aware of the stress of preparing for a health authority inspection, and the key to a successful inspection is preparing at the start of the study.

Learn more about TMF requirements and challenges through the following resources and presentations:

Good Clinical Practice: A Question and Answer Reference Guide 2018 (published by Barnett International and includes a full chapter on the Trial Master File)

Trial Master Files: Why there are Important and How to Organize Them (Barnett International Workshop)

TMF/eTMF Audit Strategies (Barnett International Course)

TMF/eTMF Regulatory Agency Expectations, Inspections and Findings (Barnett International Course)

Inspection Readiness – Beginning with the End in Mind (Presentation for ACRP 2019 in Nashville)

Donna Dorozinsky, RN, MSN, CCRC, is a Senior Trainer with Barnett International with more than 25 years of experience in study operations, including clinical operations, safety, data management, biostatistics, clinical supply management, and TMF management. Donna works with sponsor companies, academic centers, regulatory agencies, CROs, and investigator sites across all areas of clinical compliance, TMF management, and inspection readiness.

For more information about Barnett, contact us at + 1 781 972 5400, +1 800 856 2556 or