Is your eTMF in a State of Control?

March 1, 2016

  • eTMF Best Practices

ICH Q10 defines “State of Control” as “A condition in which the set of controls consistently provides assurance of continued process performance and product quality.”  ISPE provides another definition: “A condition in which a pre-defined parameter is observed to remain within a pre-defined range of operation”.

These definitions provide a useful framework in which to examine the effectiveness of your eTMF.  The first essential concept is that of a “set of controls”.  What are the important measurements or metrics that will allow you to measure quality for an eTMF?

The most important measurement is TMF completeness – providing all of the documents needed to reconstruct the trial and ensure protection of the human subjects available for inspection.  The “set of controls” that support completeness is the set of placeholders representing what must be collected for the trial. For several reasons, defining the set of placeholders is not as simple as using a table of contents or template for defining what is expected.

Each TMF is unique, with the required contents determined by the type of study, the therapeutic area, the country or countries in which the study is being conducted, and many more factors.  Details that will affect the specific documents needed include the study design (blinded/unblinded, randomized, adaptive, etc.), the use of central vs. local ethics, the specific vendors and labs supporting the study, what documents are defined or re-defined at the study or site level, the need for translations, country-specific registrations and approvals, and much more.  Trying to define a set of templates for each combination of conditions is simply not possible, and heavy reliance on such templates will result in poor planning unless extensive manual editing of the resulting TMF index is done by a knowledgeable person (or persons).  Instead, a trial-specific set of conditions should be used to drive creation of the index.  Your eTMF should provide the tools to ensure an accurate plan is created – not just pick a plan from a small set of canned templates.

Each TMF experiences significant changes over time.  A perfectly planned TMF will most likely be obsolete a month into the trial unless it is maintained.  Changes may occur due to new sites or investigators, additional monitoring visits, protocol amendments, deviations, etc.  Unplanned documents such as correspondence and safety documents will need to be captured.  What does your eTMF provide to detect and plan for changes?  What processes do you have to handle hard to automate changes such as collecting the right set of correspondence?

If you have and maintain an accurate plan, then the next step is to monitor your adherence to that plan.  This is where you ensure that a “pre-defined parameter is observed to remain within a pre-defined range of operation”.  In other words, is your completeness consistently maintained at an acceptable level?  Most of Wingspan’s clients strive to be at least 96% complete at any point.  Escalations are generally triggered when completeness drops below the required level for some defined period of time.  Both the acceptable level and the escalation and resolution process are pre-defined.

Of course, there are other critical quality elements of an eTMF, such as document/image and indexing quality.  A well-designed QC process should ensure that, with few exceptions, final documents are fit for purpose.

Whether you already have an eTMF or are contemplating moving to a new eTMF, it’s worth asking yourself what combination of people, process and technology will demonstrate that your TMF is in a state of control.  Ultimately, that is what a health authority inspector will expect you to demonstrate.