TMF 911, What’s Your Inspection Readiness Emergency?

A fire. A flood. A heart attack. These are all considered emergencies.

Emergencies take a myriad of forms but share some core characteristics: They are consequential and serious events. They are unexpected and dangerous, requiring immediate action to prevent loss of life, property, or both.

In the life sciences industry, the word “inspection” fits these same criteria. Every TMF inspection, therefore, is a true emergency—but only for the unprepared.

In the last post in this series, we discussed an EMA reflection paper that outlines some of the most common TMF inspection readiness emergencies. We paid special attention to the first item on EMA’s list of common problems found during TMF inspections, “Organisation was unable to provide a full TMF (paper and electronic) for inspection purposes on the request of the GCP inspectors”, and gave real-world advice on how to prevent your own TMF from being found uninspectable.

In this blog post, we will consider another common TMF inspection readiness emergency on EMA’s list. Watch for the next blogs in this series, as we consider the remaining TMF inspection readiness catastrophes on EMA’s list and share more actionable steps for securing TMF inspection readiness.

My TMF is Fake

Item #3 on EMA’s list of common TMF inspection readiness findings is below:

“The sponsor provided an ‘artificial TMF’, thus failed to provide adequate direct access.”

In practical terms, this means EMA’s inspector observed large inconsistencies between regulatory documents, performed an initial investigation, and found that the TMF you’ve presented isn’t the true document repository of the clinical trial.  This is a big problem for several reasons, most notably because presenting an artificial TMF could give the appearance of a premediated effort to mislead the inspector. But, as in our last post, this TMF inspection readiness emergency is not as simple as it appears. EMA gives us more insight into how an organization could present an artificial TMF without directly intending to mislead:

“Inspectors have, in the past, been provided with an ‘artificial TMF’ or ‘snapshot’ which consisted of a copy of the official TMF being used and led to issues with documentation not being consistent with that of the official TMF.”

Through this quote, EMA suggests that even well-meaning, but misguided, attempts to achieve inspection readiness can lead to a fake TMF. EMA also summarizes the three signs suggesting that the presented TMF has become ‘artificial’:

1. Dividing or compartmentalizing the working document repository used to hold essential documents from the repository presented to an inspector.
2. Creating and archiving multiple copies of essential documents with conflicting information about a distinct event or events.
3. Failing to present the full progression of the TMF over time or not presenting the essential document repository as it is presently.

But what exactly does ‘artificial’ mean in the context of the TMF? In our opinion, EMA has designated an artificial TMF as one that fundamentally contravenes the three pillars of a healthy TMF: Completeness, Correctness, and Contemporaneousness.

In fact, upon closer examination, it’s clear that each of the signs of an artificial TMF noted by EMA directly violate one or more of the pillars of TMF health:

• A partition between the working TMF and the artificial TMF is by nature incomplete.
• An artificial TMF likely contains essential documents that directly contradict the true TMF. These contradictory documents and the entire artificial TMF itself are inaccurate and incorrect.
• An artificial TMF that is a ‘snapshot’ in time is not contemporaneous with the real TMF or the true narrative of the clinical trial.

We call Completeness, Correctness, and Contemporaneousness the three pillars of TMF health because each one is critical to supporting the narrative within the TMF. If any one of these pillars is missing, then the narrative within the TMF will come crumbling down, and the conduct of a trial and the quality of the data produced cannot be truly evaluated. Without the ability to use your TMF to evaluate the conduct of a trial and the quality of the data, regulators will act decisively and aggressively to ensure that subject safety and data integrity are not jeopardized.

TMF Rescue

By the time the inspector has determined your real TMF is elsewhere, it is too late to avoid serious consequences. For those who have not yet been inspected, there’s some concrete actions you can take to ensure your TMF doesn’t accidently become a poor facsimile of the real thing:

Be Wary of Copies

As discussed in our last post, the TMF should be a single source of truth, meaning that it is the sole source and repository for all the essential document data generated by a clinical trial. This is for good reason, as many TMF quality issues originate or are worsened with the creation of duplicates and unauthorized or accidental copies of original essential documents. It is the easy ability to copy documents via electronic document and eTMF technology that, in part, makes the creation (accidental or otherwise) of an artificial TMF feasible.

Because of the common occurrence of copy-related inspection findings, an important update of ICH GCP E6(R2) includes the definition of a “certified copy” to help end confusion about what is considered an original essential document in an eTMF. We discuss the concept of certified copies in greater detail in a previous blog post, but to summarize, regulators now expect that every organization has written processes ensuring that only “exact copy[ies] having all of the same attributes as the original” are filed in the TMF. Any copy of an essential document other than a certified copy is no longer acceptable and should be replaced with a certified copy as soon as possible via your ongoing TMF quality control cycle.

Banish Shadow Repositories

The existence of an artificial TMFs begs the question, “Where is the real TMF?” In most cases, the answer is that the real TMF lies in other shadow repositories. Shadow repositories are created when, for whatever reason, the official TMF or eTMF repository is not being used as the primary essential document repository by stakeholders in a favor of a system that better suits their needs (at least in the short term).  Without the right features and oversight, shadow repositories like email inboxes, shared drives, personal cloud storage websites, and desktop folders can easily become a de facto TMF.

Usually, TMF stakeholders using shadow repositories have every intention to catch-up the official TMF later. Unfortunately, though, if an inspector arrives before the TMF is caught up or if stakeholders fall hopelessly behind, complete TMF failure and/or serious inspection findings can result. For this reason, TMF leaders must prevent the use of shadow repositories both by keeping TMF stakeholders accountable through effective quality control measures and by making sure that any barriers to efficient eTMF use are immediately addressed.

Inspection Readiness Is an Ongoing Process

EMA notes that a TMF can also be artificial if is a ‘snapshot’ of the true TMF. ‘Snapshot’ implies that the artificial TMF presented for inspection is caught at a certain timepoint and isn’t contemporaneous.  Given the clear importance of a contemporaneous TMF, what’s the point of creating an outdated snapshot if it’s ultimately going to lead to a catastrophically failed inspection?

The creation of an artificial TMF snapshot often comes from the desire to cram before a TMF inspection like you would the night before a final exam. Let’s consider a scenario where a TMF is primarily held in shadow repositories. What would you do to try and salvage your reputation when given a few weeks’ notice of an inspection? Most in this situation assemble a team of hastily trained administrators to upload as many documents as possible into the ‘correct’ TMF before the inspection occurs. The problem with this strategy is, of course, that you haven’t fixed the real TMF. Instead, you’ve made a fake TMF that is lagging weeks or months behind the actual TMF. Even if this crash TMF looks complete, the eTMF’s audit trial will ultimately tell the inspector the true story.

There are simply no shortcuts to TMF health. Much like clinical trial informed consent, inspection readiness is an ongoing process that begins well before the investigator meeting and continues well after clinical trial close out. The highest performing clinical teams don’t just care about the TMF when an inspection is announced, they are proactively following a continuous quality control cycle that is constantly comparing the condition of the TMF to regulators’ expectations and systematically closing any gaps as soon as possible after they develop.

It’s OK to Call for Help

When an emergency happens outside of the TMF, we call 911. The purpose of 911 is to quickly ensure anyone and everyone has access to the emergency services they need. But what about a TMF emergency? Is there a TMF 911?

That’s where LMK Clinical Research Consulting and TransPerfect come in with The Complete TMF Solution. The Complete TMF Solution combines the four domains that LMK Clinical Research Consulting and TransPerfect have gained industry-wide recognition for: innovative TMF education, deep expertise, powerful technology, and system agnostic services. Uniting these domains into one values-driven organization offers our clients a holistic model of TMF health that can quickly rehabilitate any TMF to inspection-ready condition.

If you have a TMF inspection emergency and are looking for expert support, be sure to attend LMK’s upcoming TMF Inspection Readiness Day on May 6^th. Sholeh Ehdaivand, Founder of LMK Clinical Research Consulting will be manning the TMF Hotline, ready to respond to your most urgent TMF concerns with experience-based advice and battle-tested best practices.