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Case study: FOCUS4 - Foundations for fighting COVID-19

The NIHR research infrastructure, embedded in the NHS, has been supporting the delivery of novel, complex and innovative clinical trials for over a decade.

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Flagship clinical trial

As FOCUS4 prepares to report findings at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021, we take a historical look at how this groundbreaking trial has helped shape the future of clinical trial delivery in the UK. We talked to Tim Maughan, Chief Investigator and Professor of Clinical Oncology at the University of Oxford, to explore how experience gained from delivering FOCUS4 has helped the UK to rapidly answer questions of global importance about the treatment of COVID-19.

FOCUS4, one of the UK’s flagship precision medicine cancer trials, opened back in 2014. It is a randomised trial investigating treatments for colorectal cancer using a complex adaptive methodology which is known as Multi-Arm, Multi-Stage (MAMS) design. Such trials, also called umbrella or platform trials, allow for multiple treatments to be tested simultaneously against the standard of care (the control). However, FOCUS4 has the added complexity of stratified medicine, which requires that all eligible patients undergo genome sequencing to identify genetic biomarkers relating to their cancer. Patients are then matched to the trial arm/treatment to which they are most likely to respond.

Watch a video of Professor Tim Maughan on NIHRtv (YouTube) explaining why FOCUS4
was needed, how it was set up, and what results have come from the study so far

This new way of working emerged following a rapid increase in the number of new cancer treatments being developed by life science companies which needed a systematic approach to quickly understand which treatments worked against which cancers. Professor Maughan explains:

“The adaptive, multi-arm, multi-stage approach provided a more efficient way of working compared to traditional back-to-back randomised clinical trials which only test one treatment at a time. Not only does it avoid the delays and costs of setting up a new trial for each new drug candidate, it also makes the screening process more efficient. Patients are screened for a match to all the drugs being trialled and have a higher probability of being able to join the trial and access a cutting-edge treatment. But more importantly - and this is where the adaptive bit comes in - new arms can be added to the trial platform as new drugs become available. Equally, where drugs are showing no benefit, that arm of the trial can be closed and the patients can be switched to a different treatment.”

The FOCUS4 trial design was considered groundbreaking when it opened in 2014 as it was one of the first large-scale, molecularly stratified, MAMS cancer trials in the UK. It successfully enrolled 1,434 patients from 88 hospitals. Prior to this the FOCUS3 study, opening in February 2010, sought to establish the feasibility of this approach, recruiting 240 patients at 24 centres.

However, the UK’s experience of MAMS trials can be tracked back further to the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) Trial which opened in the UK in 2005. This trial is ongoing, has recruited over 11,500 participants, and has produced practice-changing results in the treatment of prostate cancer. Although STAMPEDE commenced much earlier than FOCUS3 or FOCUS4, Professor Maughan says it is important to note:

“STAMPEDE is less complex in that it does not involve molecular stratification. This is a significant difference in the complexity of the trial delivery and why trials like FOCUS4 and the National Lung Matrix are world-renowned, despite opening a number of years after STAMPEDE.”

Fast forward to 2020 and the COVID-19 pandemic. The emergency situation necessitated a systematic approach to quickly understand which treatments worked against the novel coronavirus. Sound familiar?

Collaborative research culture

Speed and agility are imperative in a pandemic situation. This caused a seismic shift in attitudes towards developing new ways of working in areas such as streamlining the trial approval process.

Rapid trial set-up and delivery are also crucial. Thankfully, as we’ve established, the UK already had experience and understanding of implementing large scale, adaptive, Multi-Arm, Multi-Stage clinical trials. This existing knowledge and ability to collaborate on a national scale certainly seems to have underpinned our rapid COVID-19 research response seen in trials like RECOVERY (Randomised Evaluation of COVID-19 Therapy). Professor Maughan said:

“FOCUS4 lies in this historic development of complex innovative designs. It builds first of all on the establishment of the research infrastructure through the Clinical Research Network, which is integral to the support of all these major UK national trials. Secondly, it builds on the adaptive statistical methodology, which was first developed in STAMPEDE - the Multi-Arm, Multi-Stage approach.

“The RECOVERY trial is built on the same adaptive statistical model and also the fact that there was this fantastic research delivery infrastructure in the UK, which enabled it to move very fast and recruit these huge numbers of patients in a very short period of time. The success of RECOVERY and other MAMS trials in recent years is testament to the 20 years of investment in clinical research delivery culture in the NHS and the collaborative working across the industry in the UK.”

The world-leading RECOVERY trial does, indeed, use the MAMS trial design to test emerging treatments for the novel coronavirus and was established during the early stage of the pandemic when there were no proven treatments available. Within three months, it generated clinical evidence resulting in dexamethasone becoming the world’s first proven drug to reduce mortality for the most seriously ill patients. It also showed that hydroxychloroquine, once considered a promising therapeutic candidate for COVID-19, has no clinical benefit for hospitalised patients and this arm of the trial ceased immediately.

The PRINCIPLE (Platform Randomised trial of INterventions against Covid-19 In older peoPLE) and REMAP-CAP (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) trials also utilise an adaptive platform approach. These flagship trials, building on the foundations of STAMPEDE, FOCUS4 and Lung Matrix, are likely to accelerate uptake and acceptance of the adaptive platform approach in clinical trial delivery in future years as the global drive for faster and more efficient clinical trials intensifies.

Watch a video on NIHRtv (YouTube) of Professor Tim Maughan explaining how experience gained from delivering
FOCUS4 has helped the UK to rapidly answer questions of global importance about the treatment of COVID-19.

Forthcoming findings

It seems quite pertinent then for FOCUS4 to be on the cusp of publishing new findings in the wake of the pandemic. Professor Maughan looks back at some of the previously published results of the trial:

“Our first molecular cohort showed comprehensive negative results, and we were able to close it after only 32 patients had been accrued to FOCUS4-D - one arm of the FOCUS4 trial. That was published back in 2017 and you'll see in many platform designs that a number of negative results come out. That's important because we're showing that things don't work as well as the things that do work.

“The trial closed to recruitment in October 2020, after conducting three molecularly targeted sub-trials and one non-molecularly stratified trial in six years, and has generated some interesting results. I will be presenting some of these at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021 and we are in conversation with journals about publications.

“When we embarked on FOCUS4 we knew it would be a challenge, and we have learnt a huge amount along the way. It’s really important now that we share this learning and continue to improve the way we do clinical trials in the future.”

Professor Maughan also recognises that complex trials like FOCUS4 require the right ingredients to enable successful delivery. He emphasises the importance of the UK’s unique clinical research landscape:

“The whole complex research ecosystem of the UK presents an unparalleled opportunity for complex and innovative trials. We have the NHS as a single health care provider, the NIHR Clinical Research Network as a coordinated research delivery organisation, the collective work of the funders, forward-thinking regulators, and the National Cancer Research Institute. All this facilitates a really collaborative clinical research culture within the UK where organisations don’t have to compete with each other for patients, for example. Not a lot of countries in the world that can replicate that same environment.

“We have also shown that our research infrastructure can be adapted to an emergency situation and this is thanks to the NIHR Clinical Research Network and the trained research workforce who are based in every hospital and primary care setting in the UK. I think the real challenge now is ensuring that we learn from the COVID-19 crisis to improve the way we do things normally, in the clinical research setting, outside of the pandemic.”

Further information about FOCUS4

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