Close-out of a clinical trial raises many questions about responsibility and management of the trial master file (TMF). According to ICH E6 (R2), final close-out can only occur when the monitor – or clinical research associate (CRA) – “has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files”i.
As experience shows, however, this is not what happens; rather, responsibility for close-out – especially as it relates to completion of the Trial Master File – often falls to TMF teams. Regardless of what phase a trial is in, the complexities of the protocol design, how many sites or countries the study has been conducted in, a lot of work goes into making a trial successful. As complex as the trial is, so too is the close-out process, and it’s vital that it is carefully planned to meet ethics and regulatory requirementsii.
To create a clearer pathway for the TMF close-out, we have developed a five-part game plan: the closure trigger, quality reviews, record completeness, system tasks and finally, TMF lock and archive.
The Closure Trigger
The first stage is the closure trigger. These are the organizational triggers for closing out the TMF, for example, a specific milestone, last patient visit, database lock, clinical study report, among others. Regardless of the phase, protocol or product type, the process for closing down a study should be consistent and documented.
Integral to this consistency is having work instructions to support the close-out. This can help to keep teams focused and on track with the trial closure process, especially those who have had less experience finalizing a trial.
We advise staying on top of milestones so you can predict the closure trigger. A well maintained TMF will provide clues as to how the study is progressing and if close-out visits are taking place. Managing these steps and making sure all key stakeholders are informed will help you to meet timelines. Finally, as the person or team responsible for the TMF, be prepared to take charge and keep people informed and accountable at this stage, since other stakeholders will likely be moving onto other projects and trials.
Quality Reviews
Next is quality review, which requires having all the study-related documentation at your fingertips. While a quality review can be overwhelming, at this point in the study there should be plenty of documentation from previous reviews – whether performed by your team or others involved in the study.
Look at the findings from the interim reviews. Check to see if issues have been remediated and, if not, add these to your risk-based review checklist. At this point in the study, you know where the issues lie. Did you have data integrity issues? Were sites terminated early? Or were some sites never enrolled? What types of serious adverse events were documented during the trial? And what remediation efforts were identified? These findings can serve as a starting point for the review.
While these interim reviews are valuable source documents, when it comes to the final review, there isn’t much leniency for remediating findings since more often than not sites have closed and there is no longer access to the data. It’s important, therefore, to set target deadlines for remediation and understand the associated timeframes to meet any deadlines. Consider ways to improve oversight and complete remediation efforts. That should include clear documentation on remediation steps taken, documents reviewed, and the end result of the quality review.
Understand also that there may be issues that can’t be remediated, meaning you will need to consider other ways to move forward. We have worked with customers that have had difficulty getting the information they need. That might be because their engagement with a contract research organization (CRO) has ended but documents are missing and can’t be updated or an old monitoring visit is lost. Sometimes a note in the file might suffice, but there may be an issue that can’t easily be dealt with. Planning for such eventualities can help to stem later problems.
Alternatively, you may be able to leverage information from a sister study that is using the same principal investigators and sites. Adopting a flexible approach can be invaluable during a quality review.
Record Completeness
A good starting point for addressing record completeness is to check that all the site documentation from close-out visits has been shared and is in the system. Check all your inventories. Are there lists that can help you determine what is missing from previous visit? Is there a site that has failed to respond to your emails?
Consider using senior CRAs who have handled multiple close-outs. Are there issues they have seen in the past and what steps have they taken to mitigate these? This can help you to avoid those missteps in your close-out. Collaboration and transparency will not only help to stem gaps in records but also keep everyone moving toward the same objective, which is record completeness from your CRO and vendor.
Whether you have been involved in the study from the outset or have recently been assigned, there are ways to better understand who your CRO and vendors are. Do you have a vendor list and a vendor management plan? Do you have insight into the types of services your vendors provide? This will help to support documentation requirements.
It’s likely that you will have multiple functional areas that have some kind of responsibility when it comes to the TMF. It’s important to verify the completeness of their documentation. If one function is responsible for overseeing a vendor, confirm that they know what that vendor is doing and that all vendor documentation has been properly uploaded.
All these steps are key to achieving record completeness.
System Tasks
Our fourth step, system tasks, gets you closer to finalizing your close-out. At this point, all of your TMF close-out deliverables should be met. This is where the final review to verify completion of all system tasks should be conducted.
You should determine at this point the types of functionalities your system has and any quality issues that need to be raised. Make sure you oversee the remediation of these quality issues. Which stakeholders are responsible for closing those out? Are they aware of those issues? Have you informed them of your deadline for close-out and remediation?
While, ideally, these gaps should have been addressed before this point, there are always stragglers. Now is the time to go back in and verify that these have been closed. Manage expected documents. Confirm that your placeholders have been fulfilled and the associated expected document lists are aligned with that. And check for workflow glitches.
These are issues that we often see. Documents may have been uploaded months ago but a system issue meant they got stuck, or someone went away and forgot to approve a task. Check for these and pull particular reports that can give you more information on what may be stuck and what may need to be raised. You may be able to fix the problem yourself, depending on access, or you may need to reach out to other stakeholders to address the gap.
Another often overlooked step is to check access controls. Once your third-party vendors have completed their responsibilities, make sure you revoke their access. And, importantly, do not give inspectors access before they are due to come in. In one notable example, a one company gave the inspector access on Friday afternoon before a scheduled Monday morning inspection. The inspector took the opportunity to carry out the inspection over the weekend and by Monday had a list of issues for the company to address!
Lock and Archive
The first step is fairly obvious: make sure that everything is locked. A lot of systems have the ability to automatically lock everything down and make the TMF read-only. Part of this is enabled by the removal of access but make sure no further changes can be made to the TMF at this point.
The final part of the five steps of close-out is archiving. That means securing the TMF and controlling it for the long term. An important consideration is the required retention period. Each region has slightly different requirements. The EU announced in article 58 of the EU Clinical Trial Regulation 536/2014 (CTR) that data collected in the context of research with a medicinal product must be retained for 25 years from when the trial finishesiii. Meanwhile, Canada has reduced its record retention requirements to 15 years under the Food and Drug Regulations and Natural Health Products Regulationsiv.
Nevertheless, sponsors will need to retain data for the longer period if they have products in the EU, irrespective of Canada’s requirements.
A thorough Overview
A well-managed TMF close-out requires careful planning, consistency, proper oversight and fully leveraging knowledge of all key stakeholders across the trial. Have your game plan from the start of trial close-out, address gaps in data and documentation, and prepare to think outside the box to tackle issues as they arise in order to achieve a successful TMF inspection.
How many TMF close-outs have your conducted? What are some of the big gaps you have found in your close-outs? If you’re new to close-outs, what are you most concerned about? Reach out to us with any questions you may have or anecdotes you would like to share.
[i] Guideline for good clinical practice E6(R2), EMA, Dec 2016. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-good-clinical-practice-e6r2-step-5_en.pdf
[ii] Booth, G. (2022). End of Trial and Close Out of Data Collection. In: Piantadosi, S., Meinert, C.L. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52636-2_41
[iii] Regulation (EU) No 536/2014, European Union. https://eur-lex.europa.eu/eli/reg/2014/536/2022-12-05
[iv] Notice: Period reduced for keeping clinical trial records for drugs and natural health products, Government of Canada. https://www.canada.ca/en/health-canada/services/clinical-trials/notice-period-reduced-keeping-records-drugs-natural-health-products.html
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