By, Simon Taylor, Principle KOL & European Strategy Lead @ Florence

The latest updates to the ICH R6 E3 that are currently out for public consultation contain some big changes in the way clinical research is run. In this blog, we’d like to run through a number of those changes, and in particular, the ones that relate to the current, and the future of site enablement – the most critical technology shift in Clinical research we have seen in a number of years.

“In the two decades since ICH E6 was first drafted, clinical trials have become more complex with respect to trial design, use of technology, the quantity of data collected and involvement of central testing facilities or other service providers.” ICH E6 (R3) Business Plan, 2019

Site Enablement is the focus on using technology to allow sites to get back to being with patients, so, to that end, how does the guidance help?

Focusing on trial design, involving patients in protocol decisions, and widening the types of researchers allowed to conduct research is the main change in trial design.

A less obvious but equally important change is the definition of an Investigator, relying less on the strict description of a physician/dentist and instead shifting towards a qualified healthcare professional responsible for providing and managing care. 

How does that benefit us in practice? One of the difficulties in site administration is keeping on top of people, and the documents needed to prove GcP Compliance – One of the bottlenecks is the reliance on certain medical professionals to gather documentation as well as sign those – Allowing more HCPs who are adequately trained to take more responsibility in a study, particularly when it comes to DCT’s, more community-based research and very tech-heavy studies, we will see that bottleneck come down as we stop over-relying on certain individuals and bring down that burden on key staff like our research coordinators.

As we have less intervention-heavy and technology-focused research, we can bring in experts in those fields to also search for important breakthroughs. This also allows research to diversify those able to conduct it. Traditionally, we have relied on those who have undergone extensive medical training to conduct research. Still, we can diversify those who conduct research to include all patients who need innovative therapies.

Patients’ safety, rights and well-being should always be our focus, but that principle should not limit how we treat them. Instead, we should let the best in their respective fields develop innovative medicines and engage patients as much as possible to make their experience as valuable as the results. This will naturally increase the diversity of people running research and those participating in it.

In Clinical Research, monitoring plays a key role in patient safety, both for ongoing monitoring of study conduct itself and as a mechanism for oversight we see so routinely utilised.

There has been a big change in the guidance with the addition of a specific section on Site Monitoring – previously; this was always treated more as an assumption rather than a reality.

A couple of key aspects for site enablement really stand out: 

1) The focus on Site Monitoring shows the shift in monitoring practices as a whole and the significance of sites within the monitoring process. 

2) Specifically calling out that Site Monitoring must consider site capacity and not add additional burden to the sites themselves is a nod to the capacity issues we see at sites day to day. Increasing Protocol Complexity, high staff turnover rates, population diversity and recruitment issues all contribute to the research gap that is so prevalent within the industry. 

Remote monitoring has always been a capability that has had obvious uses and benefits over traditional methods. Still, the guidance now encourages its use where possible within the monitoring plan – being truthful, we’d like to see the use of remote monitoring encouraged to be used as a first port of call over in-person methods, but perhaps the ICH will never go that far to recommend something so strongly – previously monitoring was to be used in ‘exceptional circumstances’, to this latest iteration where it is encouraged where appropriate, which sounds like a subtle language change. Still, it opens the door for really meaningful change.

The other aspect to take into consideration is the allowance of remote access to source records, so in the case of tasks like remote SDV, which has traditionally been a heavily in-person task, this will free up valuable time and space for sites and reduce the amount of time monitoring takes for sponsors.

Calling out site monitoring specifically does not add much text to the guidance itself, but calling it acutely reinforces the capacity crunch that exists and aims to take steps to help ease the burden on sites.

Quality & Risk Management are two of the cornerstones of research as we know it, and the R3 update is no exception to it; there are some large changes in tone in the recommendation, as well as bringing E6 much more in line with ICH E8.

‘Designing quality into Clinical studies’ is nothing new within E8. Still, its focus within E6 is intensified – The need for better trial design, both for patient experience, patient safety, and data quality, is as deliberate as it is important.

Risk has been emphasised more than ever, and not just concerning patient risk. Using risk as a decision-making tool across all aspects of the trial has been heavily encouraged, whether in the monitoring plan or within data governance; ensuring that risk levels are taken into account and proportionate responses taken is a real highlight.

So what does that mean for site enablement? Sites have always been at the forefront of trial quality, both from primary data collection and data handling; the use of electronic systems is heavily encouraged when it comes to handling data (Frankly, as it should be). There are a couple of aspects to this that will indirectly benefit sites, which will really help:

1. Sponsor/CRO Communication – Something we repeatedly hear from our sites is the lack of training regarding a protocol, and protocol amendments. The Guidance specifically calls out poor risk review when it comes to protocol amendments, and hopefully, the increased focus on making sure that quality is in focus will help out sites stay at the top of mind.
2. Audit proportionality – Interestingly, there is a call for auditors to perform their audits based on the risk level associated with the trial, so hopefully, sites being snowed under with paper and having to give up every ounce of spare meeting room space will also disappear. 

An easily missed change is the requirement for the investigator to be responsible for sufficient data handling, data capture methods and many others, which should open up the floodgates for sites to utilise the benefits of the technology available to them.

A change in the quality sections may not immediately seem like they have a direct impact on sites. How they do their work, but all of these changes add up to a reduction in the administrative burden on our sites – enabling them to return to being in front of patients.

Oversight peri and post-pandemic has been sharply brought into focus, and it’s hard. As a colleague of mine always says, ‘You have oversight until you don’t.’ So what is that tipping point, and what is the guidance doing about it?

Oversight will always be a thorn in our side. How to perform it appropriately is as open to interpretation as it is personal opinion, and we have seen over time the balance of what ‘good’ oversight looks like. The guidance emphasises the need for sponsors to assess any providers appropriately and maintain this as an ongoing process.

“So where does site enablement fit here? Surely this is a sponsor issue?” whilst Oversight is a sponsor’s responsibility, it is up to every provider involved in the trial to make that job easier. Sites can now utilise technology to provide adequate oversight, integrate into sponsor systems and develop their own ways of advertising their strengths and capabilities to take advantage of this. We must always respect the sponsor’s role in research, and instead of it being used as a tool to beat sites over the head, be proactive in how we approach it.

Andrew Fisher of the MHRA inspectorate sums it up well; ‘whilst activities can be delegated, responsibility cannot. Therefore they need to oversee the conduct of the trial.’

Oversight is nothing new – but the thing that changes Oversight to be a tool for good rather than for applying pressure downward will be collaboration – the better we communicate, the better we collaborate, and the more Oversight becomes a result of good research rather than a demanding request from a sponsor.

It would be naive to think that guidelines would ever go as far as mandating specific technologies to accelerate change. A cultural shift towards the use of technology for the good of patients and sites is recommended in the guidance, whether through more intelligent trial design, attracting a broader pool of investigators, or removing archaic monitoring practices that do little to improve study efficiency.

We hope it is not another two decades before we see guidances change to what modern research really entails, but for now, it’s a big step forward.

If you have any questions regarding how Florence can support relating to ICH E6 R(3), please reach out to info@florencehc.com.