1. TMF Quality Control: Is your TMF Inspection Ready?
Jackie Morrill, Executive Director of Clinical Operations
LMK Clinical Research Consulting

2. Today’s Agenda TMF Quality Control (QC) What is it? Why do we need it?
How do we do it?
Today’s Agenda
During this session we are going to talk about TMF Quality Control, better known as TMF QC. What exactly is it? Why do we need it? And how do we do it?
TMF Quality Control (QC)

3. About LMK
Before we dive into TMF QC, here’s a bit of information about LMK. We are TMF services company founded back in We are headquartered in Charlotte, NC and are the only TMF company to be certified by the Women’s Business Enterprise National Council (WBENC). We are eTMF agnostic and work with clients across North America who use many of the different eTMF platforms available on the market today. We take great pride in our team; all of whom are TMF University certified and provide their knowledge, guidance, and expertise to our clients to ensure continued inspection readiness from day one. We take a proactive approach to TMF management and oversight that makes clinical trial content quality and completeness a top priority through a clinical trial and not just pending an inspection or trial completion.
Inspection Readiness. Two words that can ignite worry, fear, and stress. At LMK, we work with our clients to alleviate those concerns and ensure that you are inspection ready from Day One. We believe that the clinical trial content is the foundation of every clinical trial, and a strong foundation is key to the overall health and stability of any clinical program. LMK takes a proactive approach and makes clinical trial content quality a top priority on an ongoing basis - from start through closeout - not just pending an inspection or trial completion.
Founded in 2013
HQ in Charlotte, NC
Only TMF company certified by WBENC
eTMF Agnostic company
All employees are TMF University Certified
Clients based in North America

4. What is TMF Quality Control (QC)?
So what exactly is TMF QC?
What is TMF Quality Control (QC)?

5. What is TMF Quality Control (QC)?
True TMF QC is a comparison of what’s present in the TMF, otherwise known as your TMF inventory, to what’s expected to be in the TMF at the time of QC. We often see clients, particularly those who’ve recently implemented an eTMF, generate and review an eTMF inventory report and assume they’ve completed a TMF QC. While a TMF inventory does give you some insights into your TMF, it doesn’t provide the full picture and reviewing it in a vacuum, without the context of study, can risk making you appear falsely complete.
Let’s say for example you have 5 versions of your protocol at the time when you pull your TMF inventory. If you have versions 1, 2, and 5 listed on your inventory, you would know that versions 3 and 4 are missing. But what about if you had versions 1, 2, and 3 listed on your inventory. If you didn’t know that 5 versions of your protocol were expected, you could look at that inventory and assume your TMF was complete when, in reality, you’re missing the most recent 2 versions (versions 4 and 5).
Expected
TMF QC
Present
TMF Inventory

6. How Do We Know What’s Expected?
Expected Documents
Trial Type
Indication
Phase
Milestones
Events
So how do we know what’s expected in the TMF for a particular study? There are many different factors that impact what types of documents you’ll expect to find in a TMF. This slides lists a few…
What type of trial are you running? Is it interventional or observational? Observation trials will have far less expected document types because you won’t need any of documentation associated with an investigation product or device.
What is the indication? Different indications have different assessments that will be called for in the protocol. Oncology studies often have a lot of imaging whereas something like a multiple sclerosis trial would include things like gait and neurological assessments.
What phase is the trial? Early phase trial will have documentation for healthy volunteers and dose escalation committees whereas later phases will not.
What milestones have you achieved for your study? Milestones are expected activities, such as Final Protocol Approval or First Subject First Visit, that occur throughout the life of a clinical trial. When we talk about milestones, what we’re really trying to understand is where we are in the clinical trial timeline. I’d expect to see a lot more documentation in the TMF if you’re approaching database lock rather than first site activated or first subject first visit.
What events have occurred on your study? Events are unexpected activities, such as protocol amendments or PI changes, that may occur throughout the life of a clinical trial. If you’ve had 3 protocol amendments, I would expect to see 4 versions of your protocol and all associated documents that needed to be updated with each amendment – this could include updated ICFs or IBs, new assessments, etc.
How Do We Know What’s Expected?

7. Ongoing QC of TMF content performed throughout the duration of the study
Performed at pre-defined intervals
Prospective
Required when ongoing QC has not been performed
Challenges: May not have sufficient resources or storyboarding information
Retrospective
Confirm TMF processes are being followed
Performed on the Sponsor or CRO TMF at pre-defined intervals
Oversight
Before we talk about why we need TMF QC, let’s talk a bit about a few different types of TMF QC.
The gold standard, and what all trials teams should be striving for, is prospective QC. This is ongoing QC of TMF content performed a prescribed intervals throughout the study as defined in the study-specific TMF Plan or TMF QC Plan. The QC should assess both TMF quality and completeness.
The next type of QC is retrospective QC and this is often what my team is called upon to perform on behalf of our clients. This type of QC is required when ongoing QC has not been performed throughout the study and is often performed at the end of a study or when an organization is notified of an inspection. This type of QC presents many challenges, particularly when it comes to determining the expected documentation for the study, since many of the people with that knowledge may have left the organization or moved onto new projects. This also makes it challenging to track down missing documents and to resolve document quality issues such as missing signatures.
The final type of QC we’ll discuss is oversight QC. The purpose of this QC is to confirm that your TMF processes are being followed. This could be QC of the sponsor’s internal TMF documentation by a centralized document management group or by an external third-party vendor or this could be a QC of the CRO’s TMF if the sponsor has outsourced any of the TMF management to their CRO. Oversight QC should also be performed at prescribed intervals outlined in the TMF Plan or TMF QC Plan.
Types of TMF QC

8. Poll Question
Do you currently have a TMF QC process in place?
Yes No

9. Poll Question
I agree that TMF QC is important, but we struggle because:
It takes too much time
It takes too many resources
We do not have a process
We have a process, but we are not compliant

10. Why Do We Need TMF QC?

11. Inspection Readiness Reconstruct Trial Conduct Review of… To evaluate…
Compliance with Regulations and GCP
Protection of Subject Rights and Safety
Reliability of Data
Review of…
Documentation
Data
Metadata
Reconstruct Trial Conduct
We need TMF QC to ensure continued inspection readiness. What do we mean when we say inspection ready? Being inspection ready means to be prepared for an inspector to reconstruct the clinical trial conduct via a review of any and all documentation, data, and metadata to evaluate the compliance with the applicable legislation and Good Clinical Practice (GCP) all in an effort to confirm that patient rights and safety have been protected and the data is reliable. But not all TMF documentation is created equal…
Inspection Readiness

12. Complete Quality Timely TMF Trifecta Inspection Readiness
To achieve true inspection readiness, your TMF must meet all 3 criteria included in what we call the TMF trifecta:
First, your TMF must be complete and contain all expected documentation in order to paint an accurate picture of how your trial was conducted. We often say that the TMF tells the story of your clinical trial and how good can a story be when it’s missing several chapters?
Second, your TMF must be of quality. Even if you have all the necessary documents in place, if the documents are difficult to read or inaccessible then it’s as if those documents don’t exist at all.
Third, your TMF must be kept up to date and maintained in a timely fashion. Since inspections and audits can occur at any time during a trial, to be truly prepared you must ensure that all documents are present at all times.
TMF QC will help you identify issues in all three of these areas so that you can track down missing documents and correct any quality issues before too much time passes.
TMF Trifecta

13. So now we know what TMF QC is and why it’s important but how do we actually perform a meaningful TMF QC?
How Do We Perform TMF QC?

14. Six Key Elements of TMF QC1.
Careful Planning 2.
Desired Level of Quality 3.
Proper Equipment 4.
Verification 5.
Continued Inspection 6.
Corrective Action
We like to break it down to the 6 key elements of TMF QC, which are:
Careful planning
Defining your desired level of quality
Leveraging proper equipment
Performing a true verification of TMF content against expectations
Ensuring continued inspection throughout the life of the study and
Corrective action
Six Key Elements of TMF QC

15. Element 1: Careful Planning
To identify what’s missing, you must know what’s expected!
Earlier when we talked about what TMF QC is, we said that true TMF QC is a comparison of what’s present in the TMF to what’s expected to be in the TMF at the time of QC. A large part of the planning phase, before you start any TMF QC, is to determine what documents are expected for your study at that point in time. There are several resources that may be helpful for this:
We recommend that every study maintain a storyboard. A storyboard is a centralized place to maintain and track pertinent information about a study such as the projected milestones dates, actual milestone days, the list of study countries and corresponding languages, the site list, which countries have central IRB and which sites use them, important study events – PI changes, protocol amendments, etc.
Some eTMF platforms allow study teams to generate an expected document list for their study that will track the different versions of key study documents. This list can also be generated manually in something like Excel. The important thing to remember for both your expected document list and your storyboard are that they must be kept up to date in order to be helpful so regular reviews and updates should be included as part of ongoing study upkeep.
You will of course want to review your key study reference documents such as your protocol, IB, and study plans. For example, a review of your study’s monitoring plan will indicate how frequently monitoring visits occur. When you go to do your QC, this information will allow you to flag potentially missing visit reports if too much time has passed from when the last report was filed.
At the most basic level you can refer to the list of ICH-GCP Section 8 essential documents, which includes the minimum requirements for documentation before the study starts, during study conduct, and after a trial ends. The TMF Reference Model is a more comprehensive list of expected documents but neither of these resources are study-specific so they are a good starting point but will not give you any insights into your study-specific expectations.
The key takeaway – to identify what’s missing, you must know what’s expected!
Storyboard
Milestones
Study Events
Document Versions
Update as required
Expected Document List
Study Start
Updated based on Study Events and Milestones
Study Reference Documents
Protocol IB
Monitoring Plan
Essential Documents
ICH-GCP Section 8
TMF Reference Model
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

16. Element 2: Desired Level of Quality
There is no such thing as a perfect TMF.
Sholeh Ehdaivand, LMK Founder and CEO
Once we know what documentation we expect to find during our QC, we need to define what our acceptable level of quality is for our TMF. Of course, we all want to have a perfect TMF but as our LMK Founder and CEO Sholeh says, there is no such thing as a perfect TMF! If we can’t achieve 100% quality, then what are we willing to accept?
It’s important to consider the risk and consequences for different documents. Certain document types, such as consent forms or IP accountability, carry a much higher risk of an inspection finding if they are missing or illegible.
Define thresholds and escalation pathways. For example, you could say that if 20% of documents reviewed fail QC then a broader sample of documents needs to be reviewed or if you find that a certain uploader appears to have a higher rate of quality issues with documents they’ve uploaded then you may need to schedule a retraining or escalate to their line management.
Define…
Thresholds
Escalation Pathways
Consider…
Risk
Consequence
Document Type
What are you willing to accept?
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

17. Element 3: Proper Equipment
Moving onto the third element – now that we know what documents we expect to see and what level of quality we must achieve, what tools are we going to use to support and document our QC review?
We recommend developing a QC checklist that outlines the pass/fail criteria for different document types. Some criteria such as legibility will apply to all documents whereas other criteria such as confirming all signatures are complete will only apply to a subset of documents. You can also list completeness cross-checks on your QC checklist. These checks including things like confirming that everyone listed on a 1572 has a CV and financial disclosure filed or that every document listed in an IRB submission is filed in its respective section. Your QC checklist promotes consistency across reviewers by ensuring that everyone is holding documents to the same standards and performing the same cross checks to confirm completeness.
Performing your QC review is only half the battle. Documenting it is the other, which is where your QC tracker comes in handy. Your QC tracker shows which documents were reviewed as part of each QC and what the findings were. It should also be used to track remediation of all issues through to resolution. If you are using an eTMF, you may be able to leverage functionality within the system to document and track QC. Alternatively you can create a standalone QC tracker in something like Excel or SharePoint.
QC Checklist
Outlines pass/fail criteria
Promotes consistency
QC Tracker
Evidence of QC checks performed
Leverage eTMF functionality
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

18. Element 4: Verification
With the proper tools in place, we can now move onto the fourth element which is where we perform the QC review and verify that what we expect to see is actually present in our TMF. Performing true TMF QC is like peeling an onion and not just because it makes us want to cry. Like an onion, there are many different layers to TMF QC. We start at the surface with a review of the documents that are present. We review these documents to confirm they meet all applicable quality standards. From there we start peeling back the layers as we dig deeper and assess our TMF completeness by looking for documents that are not present based on our expectations.
Present
Expected
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

19. Element 5: Continued Inspection
TMF QC is not something that we perform once and move on. To be truly inspection ready, we must have continued inspection of our TMF throughout a study. Timing of your QC reviews may be based on milestones. In this case, reviews are performed when certain key milestones, such as first site activated, are achieved. Or your reviews may be performed on designated calendar intervals – such as every 3 months or every 6 months. The study phase may also have an impact on QC timing. QC performed quarterly on a phase 3 study may be spaced out too much for a shorter phase 1 study. QC may also be performed ad hoc based on certain risk factors such notification of an inspection or when your desired level of quality has not been met in previous reviews.
Whatever the timing of your QC reviews is, it should be defined in your TMF Plan!
TMF QC Timing
Milestone based
Calendar based
Phase based
Risk based
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

20. Element 6: Corrective Action
The final element of QC is closing the loop by taking corrective action on all issues that have been identified during QC. At LMK we take a find it, fix it approach and try to close out all issues within 30 days of identification. The longer issues are left open, the more challenging it can become to close them out. If you identify a missing signature and don’t address it for 6 months, the individual who needs to sign may have left the organization or moved into a new role. To facilitate quicker resolution, it’s important to assign owners who are accountable for resolution of each issues. These owners should be documented in your QC tracker so it’s clear who is working on what and nothing slips through the cracks.
When closing out issues, use note to files with caution. Very rarely is it appropriate to use a note to file to close out an issue and often when we see clients try to do this, their note to file simply states the issue and that it could not be resolved. These note to files add no value to your TMF and cannot replace the due diligence that should be untaken when trying to close out each issue.
FIND IT
FIX IT
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action
Timely resolution of issues
LMK Recommendation: Within 30 days of identification
Accountability for resolution of issues
Use Note To Files with caution

21. Key Takeaways – TMF QC What is it?
Comparison of what’s present to what’s expected
Expected documents vary by study
Why do we need it?
To ensure continued inspection readiness
Confirm TMF meets quality, completeness, and timeliness requirements
How do we do it?
Careful Planning
Desired Level of Quality
Proper Equipment
Verification
Continued Inspection
Corrective Action

22. Questions?

23. Thank you Jackie Morrill Executive Director of Clinical Operations

24. Conclusion
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