Their ISF is Your TMF

In a business niche as highly critical, closely scrutinised and heavily regulated as pharmacovigilance it remains a puzzle why clinical development organisations struggle so often with the “end of process task” of distributing Safety Reports*. These are commonly known as Suspected Unexpected Serious Adverse Reaction or SUSARs. Timely safety report distribution is important because of its part in improving patient safety but also due to the compelling regulatory obligation to distribute this material promptly.

A Pharmacovigilance Process Summary

  1. Site reports Serious Adverse Reaction (SAR) within 48 hours.
  2. Sponsor determines if SAR is unexpected or not.
  3. Sponsor reports SUSAR to relevant regulators within days (for EMA within 7 days and typically 15 days for the FDA).
  4. In parallel to step 3 the sponsor has a responsibility to promptly inform other sites once the matter is identified as a safety issue. While there is some scope for interpretation here, “promptly” is normally interpreted as meaning a number of days and not some longer period of time. Typically sponsors will aim to distribute safety reports within 15 days.

For reference here is how the FDA explain things – p16 of FDA Guidance Safety Reporting Requirements for INDs and BA/BE Studies.

The reality is that this end of process task sounds simple to define but it is in fact pretty complex and time critical. In addition – organisations are often so blindly addicted to using email that alternative, more dynamic and reliable means of information distribution are strangely alien and fantastical. But why not use distribution means that allow for active information distribution, with real-time dynamic readership information? In an age where audience behaviour is closely tracked, isn’t it time you knew who has read your latest Safety Report, and more crucially who has not?

Like so many of us, I’ve spent a good chunk of time in recent months on industry webinars - it’s so good to hear of the new ideas and innovations happening in many places. It also helps one reflect on the assumptions present in one’s own world that aren’t necessarily obvious to others.

One example is the distinction between the Investigator’s Study File and the Sponsor’s Trial Master File. Clearly these are separate, real entities - the core requirements of GCP is on each of the Investigator and the Sponsor to create, curate and archive these in turn. Too often it seems that this distinction serves to emphasise how different the ISF is from the TMF. However a huge amount of the content of one is also required in the other. This is not some small, occasional overlap on the edges of a childhood Venn diagram - the overlap is such that a substantial majority of the content in any given ISF needs to also appear in the TMF. To a large extent their ISF is your TMF.

Why then is it so rare for study teams to make it easy for these 2 related, overlapping filing systems to cohabit in some common electronic space?

Think for a moment on the options that would be available.

  • The site coordinator could load regulatory package documents for their site straight into your TMF
  • When the next version of the protocol comes along wouldn’t it be great to swap out ALL the old versions and insert the new version in all the places where study staff will reach for the protocol?
  • And why not eliminate the onerous end of study task of document reconciliation between the ISF and TMF?

This last point about document reconciliation between what is at site and what the sponsor / CRO have in their files is often not given the attention it deserves. Experienced monitors estimate that end of study document reconciliation can easily take more than a day per site. The issues are mundane, time consuming and not the stuff of high science. Lost documents; misplaced documents; wrong versions of documents; documents physically filed in the wrong location.

In a common electronic space like myClin it is simply impossible for sites to lose documents that you give them access to. Monitors report that end of study document reconciliation is reduced to practically zero. Conservatively this could save you $1,500 in end of study monitoring effort per site. 

Your eTMF shouldn’t be some static filing repository. In 2021 the expectation now is for this to be a living, collaborative place where your whole study team executes the trial. When sites are able to post content to your TMF so the TMF is much better placed to capture the true story of your study. You are also able to code and index content as you go along - it's clear that such contemporaneous filing activity is more accurate that mass indexing at study close out, and has the major benefit of flushing out quality and compliance issues early so preventing small issues becoming big problems later.  

ISF Reference Model

It's worth being aware that the indexing taxonomies that sites use can quite reasonably be different to those that the sponsor uses - such as the TMF Reference Model. In 2020 for example 2 new, but different, ISF coding taxonomies were proposed - one by MAGI (here courtesy of MedPoint Digital) and one by Veeva
Handily a tool like myClin allows for highly collaborative document sharing and coordination WITHOUT imposing the taxonomy of one organisation on the other, e.g. a site can use any of the emerging ISF Reference Models or even one of their own while the sponsor can continue to use the TMF Reference Model (or another).

A common electronic space like this has other benefits too for the sponsor:site relationship. Site staff report that the sponsor can get credit for providing a tool that actually helps sites in their daily tasks, rather than simply transferring a sponsor task to site as EDC is sometimes perceived. You are directly helping them organise their site files in a better way. Helping them in turn helps you .

As for the idea that sites don’t directly access and contribute to your TMF - that sounds positively twentieth century.