The days of scrambling to get ready for an audit are gone. The FDA requires every clinical trial sponsor to be inspection-ready at any time. There’s no longer an option to find missing items, remediate duplicates or correct errors – but how can you ensure your team is maintaining its study data and content in an organized, error-free manner? How you can achieve inspection readiness?
This was the topic of the CenterWatch webinar: 5 Steps to TMF Inspection Readiness. Agatha’s head of North American Operations, Ken Lownie, and Janine Penman, CEO of JPScientific, an industry expert and consultant, explore what it means to be inspection-ready and take you through what you need to do to ensure your TMF content and data is ready whenever the auditors come.
TMF Inspections are Changing
Inspection readiness traditionally meant spending days, weeks, or even months getting ready. But things are different now. Penman explained there was a time when most audits were planned and announced; not always – there were also the unplanned audits that occurred, especially when there was a cause. But today, planned audits are the exception, not the rule.
“The ICH guidelines are changing to recognize the fact that running a good quality clinical trial, according to good clinical practice, doesn’t necessarily come through in the spirit of scrambling at the last minute to put your documentation together.”
She said inspection-readiness is the idea that you’re always ready for an audit and the ICH has started to word their guidelines in such a way you should always be ready for an audit; you shouldn’t scramble at the last minute.
That means inspection readiness is a regulatory requirement now. COVID may have brought the issue to the surface faster, but it’s not the direct cause.
What Does Inspection Readiness Mean?
Inspection readiness refers to the requirement to ensure that all clinical trial documentation and systems are up to date at all times. That means that every day, systems are updated, inspected, and maintained in a state that is ready for an external auditor to access the systems and conduct an inspection.
As Lownie described it, it means that at any point during a clinical trial all documentation and processes are ready for inspection audit.
“It means your documents are up to date, deduped and organized, and your processes are in place. That means no notification, not “getting ready” for the audit…instead, it means you are ALWAYS ready. The result is higher quality and lower costs.”
Or as Penman put it:
“Inspection readiness in its true spirit looks like the FDA showing up at my window in the middle of the night and all I have to do is log into a system, give them read-only access and go back to bed.”
We often talk about inspection-readiness as it relates to the electronic trial master file application (eTMF) but Penman explained that there is much more to the TMF story. She talked about clinical site data, clinical data, regulatory data, connected data (including data from watches or monitors); this data is stored in many different applications, including a Clinical Trial Management System (CTMS), which may or may not connect to the eTMF.
Inspection-Readiness is Not a One Time Effort
Penman described inspection readiness as a continuum, not a one-time event that you prepare for.
“It’s not a state of being where you just tick a box and say, yes, we’re inspection ready – good to go.”
“I think there are very few sponsors who live in a state of more than 80% inspection ready at all times. Right now, with the announcement of an audit, they get there and some get there more quickly than others. But the idea of inspection readiness isn’t to find out about an audit and then get there. The idea is to just live there; it’s the place we live. And so I think very few sponsors are doing that and that’s why you know, and that’s why we need to talk about it.”
The other point Penman made is that you don’t have to get 100% inspection-ready to reap the benefits of inspection readiness. She said that even at 60-70% you can see a reduction in stress, manpower and resources, and costs. There’s also a reduction in risk, Lownie added.
Lownie also shared that when sponsors give inspectors direct access to the eTMF application (which is something several Agatha eTMF customers do), with their own access rights to go in and inspect documents, it’s a very different experience for the inspectors.
“It’s a huge confidence and credibility-building experience for the inspector because they’re seeing your system live through their inspector’s lens with the right access controls.”
The Role of Technology in TMF Inspection Readiness
While it is true that there are sponsors and CROs who try to maintain inspection readiness without the use of a fit-for-purpose eTMF application, Penman said that a validated eTMF is business-critical. A validated eTMF provides functionality that other applications or manual processes don’t:
- An audit trail for all documents. Document control is a requirement for a system that manages essential documents for a trial.
- It follows the TMF reference model. Other systems might be organized similarly but in most cases, you’ll spend a lot of time setting up your folders and recreating the TMF model. With a fit-for-purpose eTMF (like Agatha), the DIA reference model is there by default and you can modify it if needed to support your processes.
- It provides the reporting capabilities that are essential for inspection readiness.
“And spoiler alert, eTMFs are not priced so high that they’re incomparable with things like Box or Ignite, you actually might find as a sponsor that you save money by getting a fit-size validated TMF rather than thinking you’re saving all this money just by going with folders for now.”
One point that Lownie made is that by storing TMF documents in a non-compliant application, or file shares, it’s impossible to meet all the documentation requirements of other parts of FDA regulations around signatures, version management, and audit trials. A validated eTMF application needs to be 21 CFR Part 11 compliant.
“You know, in our industry, there’s an interesting thing. A lot of people start in Big Pharma and end up in smaller Pharma. And I think what happens is when they do that, they say, oh, at Big Pharma, you know, we use Viva, Open Text, Documentum, etc. So the perception they have is built back in those big companies. And they think, well, we don’t have hundreds of 1,000s of dollars to do it the way we did it at Big Pharma X. And that’s what you said, spoiler alert, that there are systems like Agatha. But there are others that are not measured in those dollars at all. These are subscription-based, ready-to-use models that are much, much easier.”
Shopping for an eTMF? Here are the Most Important Requirements
Lownie and Penman shared what they see as the key requirements for an eTMF application. They also asked the listeners. Here’s what they came up with:
- A fourth-generation product: cloud-based and ready-to-use. “It’s not something you’re going to spend weeks or even months doing workshops on your requirements. You’re going to say, we all know what a TMF is. There’s a reference model, it has to have version control, check-in, check out, audit trails, be 21 CFR compliant.”
- Fit-for-purpose: it’s right-sized for your company. But it also means that your company can use it. “If people don’t know how to use this system, they won’t use the system. And if the system doesn’t get used, you’re not inspection ready.”
- Ready to use: “When I say a ‘ready to use application’, what I mean is, you’re near ready to use. It should still be configurable. You still have to adjust workflows, you might have parts of the reference model you need or don’t need. But it should be fundamentally very close to a complete app ready to use.”
- Follows the DIA reference model but is configurable: “I would even go so far as to say you do need to take a look at your reference model when you start your study. If there are things that are not applicable, folders that are not applicable, you need to hide or delete them. Because having a bunch of empty folders hanging out there is just red herrings for auditors.”
- A full audit trail: Including versions of a document, all reviews, and approvals, all access to the system.
- The ability to see what’s missing: “The expected document index is exactly what we choose against. And if you work with a services team having an up-to-date expected document index is business-critical.”
- A quality control function: One that not only identifies if a document is quality checked, but provides a reconciliation workflow that identifies what is going to happen next to that document.
- Reporting dashboards and metrics: See not only what’s missing, but where documents are in the processes (eg. in a holding room, a queue for a QC workflow), what folders have missing documents, and what folders have fully approved documents.
- A connection between the Investigator Site File (ISF) and the TMF: “If you have an inspection-ready TMF it probably means you have some level of investigator site documents already funneling into your CMS. Knowing the status of each of your sites is very important for the TMF. Usually, the site level is a big black hole. Sponsors do very well at the study level and at the country level. It’s at the site level where they usually don’t know what status the documents are in or they’re usually missing a lot.”
Getting Inspection-Ready: 5 Things to Do
Penman offers a list of things you should do today to start preparing your TMF for inspection.
- Plan ahead. Don’t wait for a letter from the FDA with an inspection date.
- Dedicate resource(s). If you are a small sponsor who does everything in-house, then you need to dedicate one or more people, like the CTM or a clinical trial assistant who is familiar with the documents and what’s required for GCP compliance.
- Create a process. “If you already have a process for managing your documents in Dropbox, fantastic. Take that process and morph it into something that is going to help you migrate and maintain documents in a compliance system.”
- Select an eTMF that is right-size for you today. Find out what modules or features it has that you need and ask the vendor how long it will take to implement the application. Do a trial to test the application out and see if it does work for you, the way you need it to.
- If you need help implementing the eTMF and getting your TMF set up, talk to vendors who provide these services and can help you get set up quickly.
You can watch the full webinar here.