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. A TMF inspection is serious business: the fate of a clinical trial, billions of dollars of research and development, and the hard-won reputation of large pharmaceutical corporations and CROs are all on the line. Inspections are usually unannounced, so by nature they are unexpected. Inspections are dangerous in the sense that there are adverse consequences for negative inspection findings. If an inspection truly goes awry and shows evidence of gross negligence or fraud, fines and legal trouble could be the result.

Every TMF inspection, therefore, is a true emergency—but only for the unprepared.

Unfortunately, as regulatory expectations surrounding the TMF grow, the number of life sciences organizations unprepared for a TMF inspection is growing. Faced with rapidly increasing TMF inspection findings and growing concern and uncertainty from industry, EMA provided a reflection paper on what TMF inspection readiness should look like. While the sheer scope of the EMA’s expectations in this reflection paper can be overwhelming, Section 9, Problems found with trial master files from GCP inspections, a succinct bulleted list of the most common TMF emergencies that lead to EMA GCP inspection findings, is perhaps the most actionable to TMF professionals living the day-to-day realities of TMF management. This list doesn’t just exist to keep TMF professionals up at night; it also offers a great opportunity to learn from the most common inspection readiness failures, so they don’t happen to you.

In this blog post, we will consider the first common TMF inspection readiness emergency on EMA’s list. Watch for the next blogs in this series, as we consider the other TMF emergencies on EMA’s list and provide real-world advice that you can use to ensure your own TMF is inspection ready.

I Can’t Find My TMF

Item 1 on EMA’s list of problems found with trial master files from GCP inspections: “Organisation was unable to provide a full TMF (paper and electronic) for inspection purposes on the request of the GCP inspectors.

According to the EMA reflection paper, the primary purpose of the TMF is to allow, “auditors and inspectors to assess the compliance of the trial with legalization and guidance and by sponsors, monitors and investigators for the management of the trial.” Since having a TMF to inspect appears to be the most basic element of inspection readiness, one might first ask, “How does it even happen that an organization can’t provide a full TMF?” Surely, it’s obvious that some or all of the TMF is missing.

Sadly, the cause of this inspection finding is not as simple as it appears. The EMA reflection paper gives us some insight, noting:

“This is often as a result of the contents being restricted to the contents of Note for Guidance on Good Clinical Practice CPMP/ICH/135/95 Section 8 documents. The organisation should be aware of the locations within the organisation (and that includes all the global locations) of all the documentation that comprises the TMF and situations arise where there is complete lack of clarity on what constituted the TMF for the trial. This includes issues with the location of documents that are common across several clinical trials (for example, the investigator’s brochure).”

In other words, EMA is stating that this inspection finding does not mean life science organizations are not setting up a TMF or are losing parts of their TMF. Instead, this common inspection finding is the result of overwhelmed or disorganized study teams that are confused (or in denial) about what constitutes a complete and inspectable TMF.

EMA identifies two contributing factors to this kind of inspection finding:

  1. an incorrect understanding of what is considered an essential document, and
  2. foundational flaws with TMF’s structure, especially when that structure spans the globe and involves multiple clinical trials.

Both contributing factors generally take hold in a TMF that has started off on the wrong foot and incrementally devolves into compounded quality issues as the trial progresses.

Good Clinical Practice CPMP/ICH/135/95 Section 8, which is referenced by the EMA, lists the bare minimum essential documents, “which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.” EMA is, therefore, specifically stating in this reflection paper that restricting a TMF to the essential documents listed in Section 8 will lead to an uninspectable TMF. More broadly, EMA is confirming that there is no simple answer to the question, “What documents do I need to collect?” You need any and all documents that tell the most complete and accurate story of the clinical trial. The story changes every moment the study is conducted. Therefore, determining what must be filed in the TMF is, by definition, an ongoing pursuit.

Regarding the structure of the TMF, most modern, multicentered clinical trials span multiple organizations and countries. There could be dozens of trial sites, labs, and IRBs each filing unique document types in all types of file formats from countless informal repositories. Without proper pre-planning, it’s not hard to understand how small miscommunications across functional lines could result in EMA discovering a fragmented TMF of multiple conflicting repositories. Clinical trials are simply too big for one person to oversee, so answering the question, “Where is the TMF?” is not as simple as it would seem. On such a large scale and with such great complexity, development of basic TMF structure is a deceptively difficult task that requires careful and intentional coordination and collaboration between TMF stakeholders. The details need to be clear before the first documents are filed.

TMF Rescue

By the time the inspector has determined your full TMF, “is unavailable for inspection purposes,” it is too late to avoid a catastrophe. For those who have not been inspected yet, there’s some concrete actions you can take to prevent this inspection readiness emergency from happening to you.

Make a Complete TMF Plan

Every clinical trial is different, so every TMF plan should be different. Prospective pre-kick-off development of a TMF plan is your only opportunity to reorganize and refine your TMF oversight, structure, and content without undue risk to the trial. Making clear foundational choices like what eTMF system to use, who is responsible for the TMF, and where your TMF oversight will be located, ensures the worst inspection readiness emergencies cannot happen to you. The TMF Reference Model Community Group even has a great template available ( as a starting place for your own TMF plan. Just make sure you customize it appropriately!

Drop the Checklist Mindset

While a checklist of expected TMF documents can be a helpful tool, no checklist should be considered a complete list of TMF contents. Any checklist, no matter how complete, may give TMF stakeholders the incorrect message that ongoing critical thinking is not needed to achieve TMF completeness. TMF stakeholders should be engaged in a constant dialogue about the documents produced by your clinical trial’s processes. The essential documents you collect will inevitably change over time. It is critical to drop the checklist mindset so that your team can think freely about what documents best capture the ever-changing narrative of your clinical trial and can perform the right kind of quality control to achieve TMF health.

Adopt a Single Source of Truth:

eTMF technology offers many key advantages. When used correctly, the eTMF can be a single source of truth. Since anyone can access a cloud-based eTMF from anywhere, every clinical trial stakeholder has access to the exact same regulatory documents, all without the risk that comes from TMF documents held in uncompliant shared drives, unknown cloud providers, or email inboxes. If your eTMF, as the single source of truth, is complete, correct, and contemporaneous, there is little possibility of confusion surrounding the location, structure, and contents of the TMF. Adopting your eTMF as the single source of truth means all stakeholders (including inspectors) have an inspection-ready TMF available 24/7— all in one compliant, secure, and convenient repository.

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. Just give us a call, and we will rush to your TMF’s aid.

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 6th. 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.