Where Should I Begin?

February 4, 2021

Experience in various roles within clinical research greatly helps with having an understanding of the Trial Master File (TMF) but it’s not always necessary to have decades of experience in clinical research to be an effective TMF Analyst or Auditor. The most important thing to keep in mind when performing a TMF Quality Control (QC) review is that the TMF is meant to tell the story of the clinical trial; a story that should be complete, accurate, and clear. From study start up through the end of the study, the TMF must paint a picture of how the study progressed. This includes things that may have gone wrong (as they inevitably do), who participated in the study (both study subjects and study personnel), and all changes that were made along the way.

So where does a TMF Analyst, Auditor or Specialist begin? Let’s take a look at some things we have learned over the years, as well as some examples, and hopefully you will be able to use or adapt some of the methods for your own process.

For this blog,  we will use a “hypothetical” site as an example. You have just been assigned a site to perform TMF Quality Control (QC) review. Within the site file, you will find multiple subfolders with documents.  We always like to think of a site as a collection of related documents for a single site that need to be cross-referenced to both the TMF Index and other documents in the site file.

Let’s use a large category like Institutional Review Board (IRB) documentation as an example. This section contains documents like IRB approvals, submissions, membership rosters, compliance documentation, etc. The first question to ask is, “What part of the clinical trial story are these documents supposed to tell?” The answer for the IRB is to demonstrate mandatory oversight while the study is active at this location. The IRB is responsible for confirming that appropriate steps have been taken to protect subjects’ rights and safety while they are participating in the trial.

The first step is to determine whether the site is using a Central IRB or a Local IRB, which can be determined by cross-referencing the Food and Drug Administration (FDA) Form 1572. Locating the name of the IRB that is listed on the 1572 will tell you which documents you should be looking for when performing your QC review.

The next step is to determine if the study is still active/ongoing at this site. There are several ways you can go about this. You can start by reviewing any background information such as a “Storyboard” that may have been provided. If this type of information has not been provided, then you must piece it together from a review of the TMF content. Start by looking in the IRB documentation section for the IRB Closure Letter/Submission. If this is not present, you can look at the Monitoring Visit Reports (MVRs). When a study has been closed out at a site, there will be a Close Out Visit (COV) Report filed. If a COV report is filed, then you know the study has been closed at the site. If a COV report has not been filed, there is still a chance that the COV has occurred, but the report has not been filed yet. It’s a good idea to use the Delegation of Authority (DOA) log as a second reference. At the COV, the Clinical Research Associate (CRA) or Monitor will have the PI initial the end date or stop date for each person listed and sign off on the final DOA log. If the DOA has not been signed off on by the PI, then you can continue under the assumption that the study is still active/ongoing at this site.

Now that we have this information, we want to piece the rest of the story together. For each IRB Submission, there should be a corresponding IRB Approval. Plus, if there were requests by the IRB for further information between the Submission and Approval, you would also need to have these questions and the site’s responses recorded/filed. Always remember that we are telling a story and it must be complete, accurate, and clear.

Here is a sample of what to look for and the cross-checks to perform when reviewing a few of the IRB artifacts (to stay organized, it’s helpful to take notes along the way):

  1. Initial IRB Submission:
    • Does it have a corresponding approval?
    • Does the PI’s name on the document match the 1572 and DOA log?
    • What documents were included on the initial submission?
      • Which protocol version was submitted? This should be cross-referenced against the Protocol Signature Page artifact.
      • Were consent forms included with this submission? Each will need to be cross- referenced with what is filed in the informed consent form [ICF] artifact.
      • Were any subject advertisements submitted? If so, there is an artifact for advertising documentation that needs to be cross-referenced.
      • What other locations was the study conducted at? This will need to be verified against the 1572.
    • Were there any subsequent requests from the IRB for clarification on the initial submission? If so, the letter requesting this information should be filed as well.
    • If there was a request for clarification, is the site’s official response to the IRB filed?
  1. Amendment Submissions:
    • Were there consent form update? If so, each will need to be cross-referenced with what is filed in the ICF artifact.
    • Were there any protocol updates? If so, these should be cross-referenced against the Protocol Amendment Signature Page artifact.
    • Was there a change of staff? If so, this should be cross-referenced with the DOA log or 1572 depending on the personnel’s role within the study.
  2. Continuing Review:
    • Was the continuing review completed at the correct time point? In most cases, the initial approval will show an expiration. The continuing review approval should be on or before that date.
    • Is there a corresponding approval letter?
    • Were there any subsequent requests by the IRB for clarification on the continuing review? If so, the letter requesting this information should be filed as well.
    • If there was a request for clarification, is the site’s official response to the IRB filed?
    • Were there any additional amendments included with the Continuing Review? If so, these need to be cross-referenced (see #2 above).

This is just one example of how to approach a few of the artifacts in the IRB section, but you can use the same logic to review the other artifacts (IRB rosters, compliance documentation, etc.) to ensure TMF completeness. While TMF QC reviews can be tedious and time-consuming, we hope you will also find the process to be rewarding and interesting. Your TMF QC reviews are ultimately what ensure that the clinical trial story is complete and accurate.