Written by Nicole M. Palmer and John R. Nocero
Have you ever looked at dirty Trial Master File (TMF) data? I would be lying if I said, ‘No.’ That’s because I am a person with integrity. I like to follow the rules and your TMF should too. Let’s look at ICH GCP E6 R2 and see what it says regarding the guidelines to clean data,
” The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials.”
A risk-based approach starts on day 1 at the beginning of the trial to ensure the TMF data is clean. You can’t afford to wait. Your reputation is on the line, and you don’t want your TMF to appear unhealthy or begin to look out of shape if you decide to wait.
According to ICH GCP “5.18.7 Monitoring Plan The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial.”
To start, a robust plan must be in place documenting the procedures, and tasks assigned and the individuals responsible for the listed tasks (individuals must be properly trained). A key component to a robust plan is outlining how you are going to assess the risks of your essential documents and how often you are going to do quality checks and inspections.
Let’s look at what that process could be like using an eTMF system. First, it’s important to note, that if you are using an eTMF system, ensure that it has been validated. You just received a Protocol Signature Page (PSP), and you are assigned to do the initial review. Does this document meet good documentation practices? Your organization should have a detailed process in place with a minimum of the ALOCA-C principles. For example:
Attributable: Is the document identifiable? Missing pages, footers/headers? Is the document scanned incorrectly if a copy?
Legible: Is it clear who signed the PSP?
Contemporaneous: Is there a signature with a date?
Original: Do you have a wet signature, or can you identify the original matches the copy exactly?
Accurate: Is the information on the document, correct?
Complete: The document is compliant with all applicable guidelines/regulations.
Once you’ve decided that the protocol signature meets all requirements for good documentation practices you may upload the document and assign metadata to it. Now it’s time for a second review to ensure that the document does indeed meet good documentation practices and the metadata that was assigned to the document is accurate and complete prior to final filing.
Your eTMF system in conjunction with artificial intelligence should make it very easy to run reports to review the metadata of a document regarding the workflows, cycle times, and rejection of documents to assess the risk of a document.
When you are looking at a risk-based approach there are 3 main Key Takeaways to keep in mind when you are filing documents and assigning metadata:
-Subjects are always protected
-Data is complete and precise
-All guidelines, regulations, study plans, and protocol is always followed.
John, what are you looking for when it comes to keeping TMF data clean, happy, and healthy?
Nicole, Let’s unpack your three questions.
Clean – when I think of clean, I think “does the TMF have everything it is supposed to have?”? This is not always 100% clear if you don’t know the study. As an auditor/compliance professional going out to audit, it is your job to prepare – meaning, you need to look at the study and know what the TMF is supposed to contain, before you start auditing. It is not always as clear as going to the DIA reference model either.
Remember the TMF Reference Model “provides standardized taxonomy and metadata and outlines a reference definition of TMF content using standard nomenclature. The Model is not intended to be taken and used “off-the-shelf” but can be adapted to an electronic or paper TMF, and does not endorse, nor require, any specific technology for application.” Organizations are under no obligation to adopt the TMF Reference Model.
When I was first getting familiar with the model, I remember doing an early audit and not fully understanding it. It was new. I thought all TMFs were created equal. When I shared my findings with the project manager, they were like, “um John, we don’t have that. We are not supposed to have that.” I felt foolish, mostly because I did not prep. Remember – it is okay, if not imperative to meet with the PM team first before you start auditing to ensure you understand how they adopted the model to their study. I know – you are supposed to be impartial. Let me ask you something – if you are an internal auditor and looking at your studies, how are you supposed to be fully impartial? You are not. You have bias. That bias is protecting your organization. It is why you are there. So, reach out to your team and understand what is being kept and why it is being kept first, then audit, then share findings to match it up. That keeps it clean. Squeaky even.
Healthy – It is funny you mention healthy, Nikki. I am currently in the middle of a V shred since last December and I have my big, bad, Becky biceps back and popping. I can bang out 300 chin-ups a session again. My abs are almost in. Does this mean I am healthy, though? Not sure. I feel good. Think I am getting plenty of sleep and drinking enough water. But again, am I healthy? I give the appearance that I am, but I won’t know until I get bloodwork, or go to the doctor to get a checkup.
The TMF is the same way. You can crash prep for the day of the audit like you can crash diet, and on the day of, you get the appearance of looking healthy. But are you? Probably not. Healthy is the long game. I want a 30-year-old face on a 70-year-old body, aging like wine rather than milk. You should approach the TMF the same. If an auditor came in today, or any day, would the TMF look the same as it does on your audit day? No? well then, lay off the cheats (quick prep is the same as cake) and take your time and do it right. Regularly inspect like you monitor your weight. How do the docs fit? Are they good like your t-shirt? If not, you won’t be happy.
Happy – which leads right into happiness. Thanks for the Segway btw. What is a happy TMF? It is an audit-ready TMF. Many organizations think they are audit ready and it is a buzzword that gets tossed around, like sharing for amusement or evolving or growing vs dying (you know how I hate cheerleady buzzwords like I hate a matrix). But really they are not. And that is okay.
Look, your TMF audit readiness is dependent upon your organizational culture, communication between departments, willingness to admit mistakes, and a Q&A between subject matter experts. When you shore that up, that is where your TMF gets happy.
You know I am not the compliance guy who needs candy outside his office for people to come to talk to him. I pride myself on that. All should do the same. You know the saying happy wife = happy life? Not always true but it is catchy. How about happy TMF ensures you don’t die a regulatory death?
As always, if you have a question or want to leave a comment, please feel free- We are happy to help and love to hear from you.
Resources:
https://www.fda.gov/media/93884/download
Trial Master File Reference Model – (a Community Group affiliated to CDISC) (tmfrefmodel.com)
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