Lowering the TMF temperature through quality reviews

We are thrilled to announce Season 2 of our exciting webinar program, Summer Shorts: TMF Excellence Edition! Avoid boring summer reruns and attend these fresh, informative sessions where our experts share the latest TMF best practices and guidelines to help ensure TMF health with less time and effort.

 Our “must-watch” topics include: 

• 30^th July – Document Processing: A New Hope – Register Here
• 6^th August – Risk-Based Quality Review: Inside Out – Register Here
• 13^th August – House of the Inspector – Register Here

Risk is part and parcel of conducting and managing clinical studies. It is embedded in trial master file (TMF) processes at any point during a study. But not all risks are equal and knowing when intervention is needed to lower the TMF risk temperature is key to avoiding major findings during an inspection.

As an inspection approaches, it’s more than likely that problems with the TMF have already occurred. The goal at this point is to lower the temperature and stop the issue from boiling over. It might be that your company has acquired a lot of studies and is struggling to manage the documentation. Or perhaps you are in the midst of a critical study and you’re seeing serious quality issues with it. Or maybe it’s your first inspection and you’re not sure how to deal with preparing your TMF.

There are a lot of different approaches to conducting a quality review to prepare for an inspection, depending on the issues faced.

What’s in a review?

First, though, it’s important to understand the difference between a quality check (QC) and a quality review. A QC largely focuses on a specific document, while a review looks at the TMF as a whole, providing a deep dive review at the document level across the study. Done properly, a quality review can offer insights to improve TMF health.

A quality review can be performed at intervals during the study, or in preparing for an inspection. The review might be carried out as a periodic risk assessment, perhaps checking a sample of documents from the TMF every few months, or an ongoing review to check new documents to mitigate issues before they arise. You should also be conducting an end of study review of the entire TMF to check for gaps.

During a quality review, you would be checking the completeness of the study. You would want to check specific documents, including the content in those documents, and perform cross checks. For example, when it comes to study monitoring reports, check the CVs of the principal investigator (PI) and sub investigators and cross check that information with visit logs or visit reports to ensure these documents match. That will flag issues such as if a new investigator name shows up on a visit log, but that person’s CV is missing from the TMF.

A risk-based approach to quality reviews might be to focus on a particular country or a set number of sites to gain deeper oversight of any issues. A quality review can also pinpoint some wildly unexpected issues. An example from our own experience was opening what should have been an FDA 1572 form^[1], which is the statement of investigator, to find a photograph of a duck! Those are the kinds of gaps and issues that could trip you up during an inspection if you haven’t conducted a quality review.

Where do we begin?

A common problem we encounter when companies begin their TMF review is knowing where to start. An inspection might be due and there are thousands of documents within the TMF, but not a lot of time. How do you adopt a risk-based approach to your quality review?

This is where what we refer to as a heat map can be helpful. The point of a heat map is to take a high-level view to determine the level of risk. A level one might be a missing questionnaire, so low risk, while level four and five risks would be documents such as safety documents, Institutional Review Board (IRB) approvals, and so on – documents that might result in a serious breach.

Heat maps can also be a proactive way to assess the risk and manage the TMF over a period of time. One company, for example, uses heat maps to measure the performance of the teams and the CROs they are working with. Since December 2019, they have performed 118 heat maps as a simple check on various issues, such as whether the quality with a CRO is improving.

Preparing for an inspection

A common issue with inspections is dealing with the known unknowns as well as the unknown unknowns. Starting with the known unknowns, these are the issues you are aware of but perhaps you’re not sure how to address them. An example might be you are missing a box, but you've at least identified there's a potential problem there and can put something in place to avoid or mitigate the risk.

The unknown unknowns are issues you have not thought about. A classic example is not planning for your TMF expert to be off sick a week before an inspection is due. It’s important to have a contingency plan. Have an understudy who can step up if needed.

One complete unknown unknown we experienced was during a mock inspection for a client in the UK. It so happened that the week of the mock inspection there was a major accident on the highway near the office, which resulted in massive traffic jams every day during the week of the mock inspection. To mitigate any potential issue in future, the company decided to put critical staff up on a nearby hotel in the week of an inspection to remove stress and make it easy for them to get to the office.

It’s not uncommon for sponsors to take a fatalistic view to inspections, assuming that once the study is over, there’s no way to remedy a problem. As experience has shown just because an inspector from a regulatory agency finds a critical issue doesn’t mean there’s no remedy. Often regulators will offer conditional approval if certain processes are put in place to address an issue. What’s important is to know what those issues are, seek ways to remedy them, be upfront with the agency about any problems and demonstrate that these issues don’t impact good clinical practice, patient safety or anything else that could be a serious concern for inspectors.

Going digital

While more and more companies are going digital, there are still issues with paper documentation. Certainly, COVID brought the issue of remote access to documentation to the forefront. Since then, there have been several examples that highlight the challenge paper presents.

During 2023 earthquake in Turkey one company’s office was destroyed. Fortunately, key documents could be recovered and digitized, but it was a significant challenge for the company. This example underscores the importance of digitizing documents and then, of course, conducting a quality review to make sure the documents are in good order.

Leveraging resources

Given the importance of conducting quality reviews, how do you make best use of your resources? While larger companies will often have a central TMF group to carry out reviews, smaller companies will need to consider a workaround. A QC can likely be handled by various people in the organization, who can check documents, ensure they have been filed correctly and that the metadata is correct.

For more extensive quality reviews, a best practice approach may be to outsource. And, in fact, regulators state that outsourcing is fine as long as the company maintains oversight and the outsourcing partner provides transparency.

Ultimately, a TMF quality review will vary depending on the situation, the state of documentation, results from periodic reviews, the number of documents involved and where the greatest risks lie.

This blog is intended to communicate PharmaLex's capabilities which are backed by the authors’ expertise. However, PharmaLex and its parent, Cencora, Inc., strongly encourage readers to review the references provided with this blog and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto as the blog may contain certain marketing statements and does not constitute legal advice.

^[1] Clinical Trial Forms, FDA. https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/clinical-trial-forms