Quality Control in the Trial Master File

Written by Nicole M. Palmer and Nina Apfelbaum

?The trial master file (TMF) is one of the single most important things in a clinical trial. If you want to know anything about a trial it will be in the TMF. This is why it’s so important that your documents are complete, accurate, and filed in real-time.? Nina and I will share with you why TMF quality control is so important and how it relates to being in an inspection-ready status.

First, let’s see how the guidelines define Quality Control. Per ICH GCP section 1.47 Quality Control (QC) is defined as, “The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.”

Now that we know this, who is responsible for Quality Control? I’m glad you asked! Ultimately, it is the sponsor. A sponsor may delegate trial-related tasks to a Contract Research Organization (CRO), however, it is still the sponsor’s responsibility to oversee quality control. As TMF professionals we have to do our due diligence with the TMF at the micro and macro level.

Let’s start by breaking down document QC:

Document Completeness- Is every document that needs to be in the TMF in there? ?Such as the protocol, informed consent form, IRB approvals etc. Are there duplicates? Are documents missing? If so, these are going to be red flags and you better have some good answers ready!

Accuracy and Consistency- Is all the information correct? Are the dates in the right format?

Legibility- Are all scanned pages accounted for and easily readable?

Timeliness- All of the documents that need to be in the TMF must be filed in real-time. We don’t want to be going on a wild goose chase looking for a document.

Why are Crosschecks Important?

?Establish that all documents are in place by performing TMF crosscheck also known as quality control. After running reports on all Sponsor Plans (TMF Plan, Project Management Plan, Communications Plan, etc.,) and ensuring the latest version is accounted for; double-check the naming convention and CTMS, as well as the dates to verify that they’re accurate and in the correct format. When you are performing a crosscheck this is where you need to think about your TMF is telling the story of a clinical trial. You will want to double-check that every related document is included and accounted for. For instance, refer to the examples provided below:

Protocol (linked documents):

·??????? Financial Disclosures

·??????? IRB Approval

·??????? Registration

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1572 (linked documents):

·??????? Financial Disclosure Form

·??????? Names of PI and Sub-Is

·??????? Medical License for PI and Sub-I

·??????? CV for PI and Sub-I

·??????? Names and addresses of medical schools, hospitals, research facilities, and clinical laboratory facilities

·??????? Name and address of IRB

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IRB Approvals (linked documents)

·??????? Protocol Approvals/Amendments

·??????? ICFs

·??????? Trial Application

·??????? Request for Waiver

·??????? Informed Assent

·??????? Data Collection

·??????? Vulnerable Population Form

·??????? Site Permission Letters

·??????? Formal Agreements

·??????? Data Safety Monitoring Plan

·??????? Supplemental Information

Importance of a TMF QC Strategy

Now that we have gone over QC on a micro and macro level, let’s break it down on why having a TMF QC strategy is important. Firstly, it’s important to have your process documented in an SOP/Working Practice. Everyone should know how to do it and who should be performing it. Secondly, your team is going to need to be trained on this process. This doesn’t mean they read the SOP/WI and they are trained. Training goes beyond the SOP. Without a documented process in place, this could jeopardize the integrity of your TMF leading to inconsistencies. Consistency is critical for maintaining the quality and integrity of the TMF. Following your QC strategy is important from a regulatory perspective because you want to ensure that you are in compliance. Having a TMF that is in compliance builds trust and credibility.

Conclusion

It’s important to remember that quality control checks are not one-and-done. It’s a continual process. Establishing a clear QC strategy ensures a high-quality TMF for all stakeholders (Sponsors, CRO Partners, Vendors, Regulatory Authorities, and Site Personnel). This strategy builds on Inspection Readiness Reviews which identify missing or duplicate documents. To always be prepared for an inspection, this strategy and others should be reviewed, practiced, and updated on a timely basis.

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