Is there a cake in the fridge?? – ICH E6 Rev 2 blog part 2

Why do I think that the imminent arrival of ICH E6 Rev 2 is the most significant change in thinking within the global clinical trials arena in 20 years?

I believe the importance is that it encourages all of us to re-consider how we design and run our trials. Rather than a quick fix of bolting-on a few new SOPs, we will all need a change of mind-set (much harder to achieve in practice) to challenge, refine and focus our current working practices and templates. Also as traditional roles change we will need to acquire new skills. Nowhere is this more true than for the role of ‘monitor’.

Traditionally, (I was a CRA in the mid-1980s), monitors were hired for their extrovert, inquisitive personalities, their scientific background and for excellent interpersonal communication skills. Over the intervening years and with the introduction of technologies like IXRS, eCRFs, eTMFs, on-line access to laboratory data and even electronic medical records, some might argue that being computer-savvy is the first pre-requisite. Being constantly available by mobile phone, whilst populating the CTMS and filling your timesheet mean the ability to multi-task is fundamental. But what of the future, with the potential divergence of centralised and roving monitor roles?


The emerging new role of the monitor

ICH E6 Rev 2 details that centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on site monitoring and indicates some methods that may be used. So Central Monitors should be skilled at data review, identifying and questioning missing or inconsistent data, looking for deviations, outliers, or an unexpected lack of variance in submitted data. Monitors have often ‘dabbled’ in these pastimes, but rarely to this point has it been the main focus of their role. Probably more important than the skill necessary to do this, will be the inclination or interest in playing with and analysing datasets. Central Monitors will still need good interpersonal communication skills. They will need to interact closely with expert data-managers and statisticians (without treading on their toes?), as well as explaining to others what trends or patterns they believe they may be seeing in those data.

Quite probably the Central Monitor will be briefing the site monitors on what they should be focusing on during their on-site visits. This interaction will require wisdom on both sides. The Central Monitor has seen the data and may think they know what that is telling them, but they cannot know if the data is real, accurate or gives the whole picture. That is where the skills of the On-site Monitor come to the fore – they need to play detective and like all good detectives they have to keep an open mind. We’ll return to this theme soon.

In our brave new world sponsors and CROs have the unenviable job of working out how to appropriately resource variable monitoring requirements across multicentre, multi-country studies. One thing we can be sure of, is that this is likely to drastically reduce the likelihood of the scenario where a monitor was responsible for a few sites with whom they could build-up close working relationships (even friendships) by visiting every 4-6 weeks. Far more likely is that we’ll have pools of monitors who go where they are required, as the need arises. The consequence (for the monitor) is that they may be arriving at a site for the first time in order to investigate some aspect(s) of the data submitted by the site staff. How they approach this will be key to the success or failure of this kind of monitoring.


The mindset of the monitor

Those ‘outlier’ data points could be a simple recording or transcription error, but they could also be valid and the start of an important safety signal about the effects of your drug/ device. Being able to differentiate these correctly is crucial and lies at the heart of risk-based management of quality.

Our On-site (detective) Monitors need to ask a lot of questions: Is it real? Is it accurate? What does that tell me? What other explanations might there be? What else do I need to look at as a consequence? They should be ready to test any hypothesis proposed by the Central Monitor to confirm or refute it, based upon the evidence available, before drawing any conclusion and making decisions.

Some readers may detect that this sounds just like the way an auditor/inspector thinks and works, and you’d be quite correct. My co-founder in Wider Perspectives, Bev Mehentee was challenged at a QA conference several years ago when she suggested that monitors would need to work like auditors in future, but this now seems self-evident.

Like auditors, the new ‘roving’ site monitor may find themselves having to establish relationships with site staff very quickly and potentially at their first meeting with that site.  They will have to maintain their focus on the assigned quest, whilst being observant for other information or intelligence to inform the situation.  Keeping an open mind at the same time as developing the terrier-like instincts as well as the tact and diplomatic skills that auditors are so well known for will serve them well – (Well ok, they are good and bad auditors, like any other role).

The other key element of being an open-minded On-site Monitor, is the need to keep your eyes and ears open for information that can never be accessible to the Central Monitor. You may have been asked to investigate one issue, but there may be other, more or less important, items to be discovered. A real-life example follows.

About a decade ago, I was auditing a phase 2 study at a prestigious university medical centre in north east USA on behalf of a small biotech. The investigator was highly motivated and engaged in the trial and the clinical and laboratory data were as near flawless as an auditor likes to see. After verifying the accuracy of the IMP accountability (zero remained), the courteous chief pharmacist offered me (a fellow pharmacist) a guided tour of the impressive new clinical trials pharmacy. Ten years after this event, I can still recall vividly the look of absolute shock and horror on her face when, at the end of the tour, she opened the large (IMP) refrigerator wide to reveal a spectacularly large birthday gateaux nestled in between the variety of IMP for other studies. I was confident upon leaving the site that the shamefaced (new) pharmacy technician who appeared shortly thereafter, would never make the same mistake again. As I’m only an auditor (and not usually involved in proposing CAPA) I leave you to determine whether this was signal or noise!

If monitors are going to be acting like auditors in future, what will auditors do now? It seems that we will all be needing to learn some new skills for the brave now world. But remember even if you become a skilled pastry chef in your spare time, a clear separation from your clinical trial day job is advisable.


Mr. Peter Brummitt