We have been on a journey you and me, we started off by understanding the purpose of a clinical trial and the multiple phases to get products to market. We then looked at the Trial Master File and how one trial can produce hundreds and thousands of documents, all of which need to be collected, organized, and retained throughout, and after, the trial. Finally, we covered the days of paper and how electronic TMFs have changed our lives forever.
Now, in the last blog I dropped a little spoiler. I touched on three things that all studies try to achieve with their TMF, and how the accelerated usage of the eTMF helps to both manage and meet these. So, let’s get into it, let’s talk about the TMF Trinity.
We often refer to the state of your studies Trial Master File as TMF Health. It’s a way of understanding the state of your TMF, getting a view on what is going well, and what needs improvement. The idea is that if you maintain good TMF Health, your study will be ready for an inspection regardless of the notice you get. To achieve TMF Health though you need something to work towards, that is where the TMF Health Zones enter the picture. There are three specific measurements (the TMF Trinity, get it?) that can be used to warn you early of upcoming problems, and give you assurances that things are going well without having to do 100% reviews every day.
Below we are going to go into each of the areas, why they are important and how we measure them. It is also worth mentioning here, and I will repeat it at the end, TMF Health, Inspection Readiness, call it what you want, it is not something you “achieve” and then move on. It is something you must maintain from the very first day of the trial to the very last. Each day is just as important as the last or the next, remember that while you read on as it will help you understand the importance and size of the tasks.
Tick Tock, Tick Tock
Time, it is the perfect unit of measurement, it is universal across the entire planet, it is understood and known by just about everyone. Even my dogs understand the passage of time, or at least they know when it is time for them to be fed.
Timeliness is our first of the three points of this trinity, its measurement is a key indicator of the state of your TMF and could be argued the easiest to keep track of. The measurement here is the time taken from a document being ready to file in the TMF to the point that it is available in the TMF. Normally, “ready to file” would be defined as when a document is signed off and approved, or perhaps the date at which correspondence is received, or maybe when a visit occurred. Each artifact type will have a different assumption of “ready to file” however the TMF Reference Model has a good guide on what is generally accepted. “Available in the TMF” is a little trickier, just because someone has submitted content to the TMF does not mean it is available. Usually, the content has to go through some sort of process, either to assign to the correct location or to get a check by a second person to ensure both its location and metadata are correct. For this reason, saying its available once submitted is not very accurate, a better end point is to say once the content has passed all initial processing and is in a “Final” state. At this point it is accepted that the content is complete and is usually made available to all users with access to that study.
Now, the reason we measure this is it can be an early indicator of problems, if it is taking too long for the content to be available to the study team, how can you be assured, they are making the best decisions? How can the study team, actually, make any decisions without referring to the most current TMF content? This is one of those red flags that can be problems an Inspector can uncover relatively easily, and it can question the management of your TMF, and, furthermore, the whole trial. If you can keep your Timeliness in check, you have already won half the battle, the data is at least in the TMF.
Anything worth doing is worth doing right first time
Quality can sometimes be a very subjective thing, my idea of a quality movie, like 1999’s Deep Blue Sea, may be different to yours. In this instance you would be objectively wrong, but you get the point.
Quality in this instance is very objective, did the content submitted pass through processing within your eTMF and become Final, Approved or whatever else you describe it as? The basics here are to check three things: s the content in the correct location? Has the metadata that is assigned to this content correct? and is the content itself actually final and of good quality? The first is self-explanatory, if you have a Principal Investigator’s CV, has it been filed to the correct artifact within the study? additionally has it been filed to the correct country and site? Secondly you would check if the correct metadata has been entered to match the content, but generally you are checking if , have things like the document date have been entered correctly, if there is an expiry date, is that there, and what about version numbers? Finally, is it generally a good submission? If it’s a scan, is it legible or did someone move the page halfway through scanning, are there any blank pages or redundant information in the content, that sort of thing.
If any of these checks fail, the submission should be flagged and follow up should be performed to correct the issues. Sometimes all that means is changing a date in a metadata field, other times you will need to re-upload content in its entirety. Keeping track of how many documents do not pass through processing first time can be incredibly helpful. If you start to see the number of quality issues increasing, it could be an indicator of bigger problems. Do you need to retrain people, is there an issue with the original source of the content, are your processes confusing. Measuring Quality enables you and your team to take a more proactive approach and mitigate problems before they become too big.
You complete me
Completeness is not about having everything you need but having everything you need at that moment in time, my Pokémon card collection, for example, was complete late 2000, but then they released a whole new Pokédex! set!
In the TMF, Completeness is a measurement of what you have versus what you are expecting at that moment in time. We discussed before about how an eTMF can be used to plan out what artifacts will be required and how many, so even on day one, before you submit a single document, the eTMF can let you know that you are expecting 546 separate pieces of content. Systems do this by helping the team to understand what information will be required to complete the trial, many of them can also update to manage changes over the course of the trial. The thing is though is not every artifact needs to be fulfilled on day one, some won’t even need to be fulfilled on day 101 but rather right at the end of the trial. If you were to measure Completeness based on the total number of expected documents versus the actual number of submitted documents, you would always be at less than 100% until the last submission was made.
It is this reason that Completeness is performed throughout the trial and measured against where you are in the trial right now, if you have just reached a study milestone like first patient first visit (this is where the very first patient has the first visit to a site and is considered an incredibly important moment in the trial), you would measure completeness against the documents that are required to be there in order to actually meet the milestone, things like protocol signature pages, Investigator CVs, etc. Measuring that can give you a result of 100% as you would have all the content you need in that moment.
It is also worth mentioning that a document isn’t usually counted in completeness until it is available in the TMF and has passed through processing, which is why you need both Timeliness and Quality to achieve Completeness.
Use your imagination
In the previous blog post Electronic vs Paper, why it is more than a DMS I touched on how the eTMF suddenly allowed us to deal with more than just the document, we could look at metrics, reports, trends. Think about the three points above, and just imagine, how would you track these in a paper world? How would you measure them, compare them? And more importantly how would you do it in a timely manner, there is no point in knowing your submissions were over 30 days late, 60 days ago. Or, that the new CRA you hired has the highest number of quality issues, after the site they oversee has closed. And there is certainly no point in being able to tell people you were at 100% completeness last week, the day before a new country approval was received, a protocol amendment was issued and a close out monitoring visits were held at five of your sites.
I said it at the start, and I will say it again, TMF Health is not something you work towards, achieve, and then stop. You need to maintain it every day and you need to make sure that the data you have available to you is as current as it can be. This will mean that you can act accordingly and give you and your teams the best chance.
This is not Goodbye, but See You Soon
It goes without saying but thank you. Thank you for taking time to read through these blogs, even if you have skipped to the part of interest, or read just one of them, thank you.
I have loved doing these and I hope that you found them helpful as well. This post wraps up our Clinical Trials and the TMF 101 blogs, to wrap up the whole series please join us at our Ask An Expert session on October 19th where I’ll be joined by some of our TMF experts here at Phlexglobal and we’re there to answer all of your TMF related questions. You can register here.
So what’s next? If there is interest perhaps, we will do a new series, graduate to Sophomores, and tackle a few other topics like Oversight, Quality Review, and Inspection Readiness or CRO Selection.
Until then you know the drill, reach out to me here if you liked this blog or have any questions, I have had a few emails and loved each and every one of them. Make sure you keep checking back to see what other content we release and sign up for our webinar series, we always have something interesting going on.
Until next time
Watch the Clinical Trials and the TMF 101 series webinar on demand and read the previous series blogs: