Written by Nicole M. Palmer and John R. Nocero
You just received written notice that the Trial Master File (TMF) that you are assigned is being audited by your internal QA department. Now what?
Are you cool as a cucumber or sweating like you just ran a marathon?
Being inspection ready is a lot like running a marathon. It’s not something you can do overnight. It takes lots of preparation. An audit trail will easily tell us if we are scrambling last minute to try and pass the audit.
You may be thinking what will the QA team audit? Will it be IRB/IEC submissions? Monitoring Reports? Delegation of Authority Log also known as Site Signature Sheet? Good Clinical Practice training? Meeting minutes? Will they just pick one process zone? The quick answer to these questions is ESSENTIAL DOCUMENTS. They will audit the essential documents to ensure that the TMF is indeed in an inspection-ready state and will pass a sponsor audit.
Do you know what your Standard Operating Procedures/Working Instructions are for an internal audit? Or do you need to brush the dust off and review it?
Do you have a TMF plan and if so, what does it say? Can you recite it?
Do you know your local regulatory requirements?
Let’s take a look at our good friend ICH GCP E6 R (2)
Since we are using the word audit, let’s take a look at the definition:
1.6 “Audit A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s).”
In other words, when a sponsor comes to audit the TMF there shouldn’t be any gaps that lead them to ask questions. The essential documents that are filed in the TMF should tell the story of the trial from the beginning to the end. Telling the whole story. Remember the golden rule, if it wasn’t written down, and if the document wasn’t filed in the right location and in a timely manner, it didn’t happen.
Now that we got that covered, let’s take a look at the ICH GCP section:
5.1.1 “The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).”
So, the key takeaways are with ongoing preparation, if you follow and comply with:
-Compliance with the protocol
-Following Good Clinical Practice (GCP)
-Following regulatory requirements
Your TMF is most likely going to be in an inspection-ready state and will pass a sponsor audit.
John, from a QA’s perspective can you talk about why it’s important to have internal mock TMF inspections and what that looks like from your point of view?
Hi Nicole, at the granular level, it is all about audit readiness. I am a huge proponent of always thinking that an inspection can happen at any moment, and being ready to pass if it does. It is not about being flawless and having no findings; rather, it is about if the FDA or another auditor/inspector came in today and asked us to sit down with them, could we explain our processes in our book of business? Do we sound confident and coherent? Is what we are saying to them appropriate from a regulatory perspective and is it consistent with what we do? Can we show examples of our work that aligns with our processes and if we find anything that we did that wasn’t aligned with our processes, do we have an explanation?
Tell you a story – we had a situation yesterday that came up where we discussed a problem that had arisen that we discovered. We were not out of compliance per se; what happened was that people who previously completed this task were now gone, we had to complete it and we did not have any documented process on what they did to follow. So, we came up with a methodology and ran it against previous submissions. Numbers didn’t add up. Here’s what we did. We decided to go with our numbers and immediately document our process and what we did because we can justify it and we understand how that conclusion was drawn. That is a part of being audit-ready. If we get audited on it, we can explain it.
Great example, John! This happens a lot in clinical research. Oftentimes, we must pick up the missing pieces. There is a high turnover rate in clinical research and a common finding is a lack of accurate documentation of these staff changes. If we ask ourselves the questions you mentioned above, it can surely help us improve our processes.
Cheers to being confident at the next audit!
As always, if you have a question or want to leave a comment, please feel free- I am happy to help and love to hear from you.