From breakthroughs to patient benefits: inside the ICR’s Clinical Trials and Statistics Unit

Image: Dispensing medicines for a clinical trial (Jan Chlebik for the ICR, 2014)

“The best way to turn pre-clinical science into benefits for patients is through high quality clinical trials,” says Professor Judith Bliss.

As the Founder-Director of the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, and a National Institute for Health Research (NIHR) Senior Investigator, she is passionate about clinical trials and their continued value in modern medicine.

Judith and her colleagues at the ICR-CTSU are currently managing 65 trials at different stages from set-up to reporting, focusing on breast, urological and head and neck cancers, and also other rarer cancer types including melanoma, sarcoma and ovarian cancer.

ICR-CTSU is part of a network of 53 academic clinical trials units, called the UKCRC Registered CTU Network, and one of 15 with a specialist interest in cancer clinical trials as designated by the National Cancer Research Institute (NCRI). Eight of those, including ICR-CTSU, receive core funding from Cancer Research UK.

“ICR-CTSU was first accredited in 2007, at a time when the formalisation of clinical trials units was beginning to take a leap forward via the creation of the CTU networks,” Judith said. “We were pioneers in that sense.”

A partnership between clinician and clinical trials unit

Now, the Unit is made up of almost 100 members of staff and works closely with clinical chief investigators from across the UK to support the development of clinical trials, conduct, analyse and interpret the data from them.

“Any large scale clinical trial project will always be a partnership between a clinical lead and a clinical trials unit which has expertise in statistical analysis and trial management,” Judith explained.

The ICR-CTSU is driven by the expertise of its staff: statisticians, data scientists, IT programmers, trial managers, data managers, quality assurance experts and administrators, who work together to conduct complex scientific experiments, ensuring design quality and efficiency and then recruiting patients from 250 hospital sites across the UK.

Developing the research question and defining the design

Dr Nuria Porta is a principal statistician, her role involves working on the statistical development, oversight and analysis of several trials.

“I am heavily involved from the beginning, at the concept stage and design of the trial, and preparing grant applications to obtain funding for the trials,” she told me. Nuria works closely with trial chief investigators, clinical and lab co-investigators and other ICR-CTSU colleagues to develop the research question and define the design.

“The past few years have been very exciting for the unit, as we are developing and implementing novel and complex designs, particularly in the early phase arena. For instance, biomarker-driven platform trials – a type of trial with a single protocol where multiple treatments are evaluated simultaneously – permit answering several research questions at the same time, thus enabling quicker qualification of promising new treatments.”

Choosing an efficient trial design

“It is crucial to choose an efficient trial design that will best answer the research question. This is often a balance between finding the best statistical properties and the feasibility of implementing a complex intervention in an NHS setting,” Nuria explained. “For instance, we have recently secured NIHR funding to evaluate an ICR developed software that processes whole body MRI images and quantifies extent of bone disease, enabling objective assessment of treatment response.”

“During peer-review of the project, led by Professor Dow-Mu Koh, a cluster-randomised design – where centres, not patients, are randomised to the two strategies under evaluation – was suggested by reviewers. We successfully pushed back their suggestion by understanding the potential biases of each design considered, and their barriers to implementation.”

“There are many aspects to define upfront, so design is a very important step in the process,” she continued. “How we will measure the outcome, how many patients we need… Too few patients, and we won’t be able to answer the original question. But treating more patients than needed may be unethical or unsafe.”  

Towards the end of the trial, Nuria works together with the trial statistician to analyse the results and prepare the output, and contributes to writing the manuscript which will become the primary publication, the first full report of the results of a study, which undergoes rigorous peer-review before being published in a scientific journal.

“Work does not finish here, though. Statisticians will also drive secondary analyses of trial data, so we can learn as much as we can from our trials,” she explained.

Innovative new trials

Katy Jarman is a data manager, responsible for all things data during the trial lifecycle: from designing and testing the clinical database during the set-up of a trial, to monitoring data collection during the running of a trial, to final checks and cleaning of the data during trial closure. 

“Generally, the trials we run are getting more innovative and complex,” Katy told me. “It’s really exciting to be involved in new innovations, and it is great because it means we can better target treatments to patients. It used to be that patients were randomised to either receive a new treatment or standard-of-care control in the majority of trials, but now it can be much more complicated, as each new trial has a quirk or special feature we haven’t come across before.

“For example, one of the trials I am working on, called POETIC-A, has a two-part registration and randomisation element: if eligible, patients are registered, then have a biopsy taken at surgery, and the sample is sent to the central lab for analysis, and they are testing for the value of a particular marker called Ki67, that indicates whether a cell is growing and dividing normally.”

Ki67 is one of a number of markers that are widely used as prognostic and diagnostic markers in some cancers.  

“Depending on whether the patient’s Ki67 levels are above or below a threshold level, they can, or can’t proceed to the randomisation phase,” Katy continued. “If the patient reaches the threshold and wishes to proceed, the lab then needs to carry out further analysis before the patient can be entered onto the trial. So there are quite a few different steps involved in the trial even before the randomisation part begins.

“It is logistically challenging in terms of data management, and we are constantly having to adapt. We often reach out to colleagues in the Unit or wider trials community to ensure we are using the best practices, and developing the most efficient processes.”

A collaborative and inclusive ethos

The collaborative nature of the Unit is one aspect that sets ICR-CTSU apart from other trials units, according to Professor Charlotte Coles, who is Professor of Breast Cancer Clinical Oncology and NIHR Research Professor at the CRUK Cambridge Centre, and has been working with ICR-CTSU for almost 20 years.

“I first became involved with ICR-CTSU when I was a trainee, working in Cambridge,” Charlotte said. “It just goes to show how open and collaborative the group is, that I was able to get involved as an external trainee. I got more and more involved to such a stage that I became Chief Clinical Coordinator, a new post that was a kind of Deputy Chief Investigator. I learnt a lot from Professor John Yarnold and Professor Judith Bliss as mentors.”

Charlotte is now the chief investigator for four ICR-CTSU trials focusing on different aspects of breast cancer radiotherapy.

“The ICR-CTSU is so experienced in terms of radiotherapy trials, and they have almost three decades of experience to build upon, and strong links with sites across the UK,” she said. “Their expertise, and their collaborative and inclusive ethos is what sets them apart for me and why I choose to work with the ICR-CTSU on these highly specialised trials.”

The impact of FAST-Forward

Charlotte is also a member of the Trial Management Group for the NIHR-funded FAST-Forward trial, which looked at a one-week course of radiotherapy for breast cancer, delivered in five doses, or fractions, compared with the previous standard of care that took three weeks. The FAST-Forward trial built upon experience gained by the FAST trial, led originally by Professor John Yarnold.

“I would say FAST-Forward is the most influential trial worldwide in breast radiotherapy in about the last 20 years,” Charlotte said. “It is a really high quality study that has had a huge impact and changed clinical practice internationally. Though it wasn’t a Covid trial, it has been particularly important during Covid times as rapid adoption of evidence-based five-fraction radiotherapy helped to rapidly reduce the footfall in radiotherapy departments, ensuring safety of patients and staff.”

Early last year, the FAST-Forward trial reported its results.

“The trial data was due to be analysed in 2020, but the timescale was condensed due to Covid, as we were being contacted by people across the world asking how to safely deliver breast cancer radiotherapy in five fractions,” Judith recalled. “Therefore, ahead of the paper coming out, we made the protocol available online so the technical aspects of the new treatment could be safely delivered.”

“Though we would not usually change practice until results were published, these were exceptional circumstances and publishing the protocol allowed patients worldwide to be treated in five days rather than three weeks, or even longer in some places. We followed up with the paper in The Lancet within the month. That felt like a real achievement.”

Pushing the boundaries to improve the efficiency of trials

Clinical trials are highly regulated and have complex governance and oversight structures with a high administrative burden, so running them can be challenging, and results are not always delivered as quickly as they were for FAST-Forward. It’s Claire Snowdon’s job, as a Deputy Director and Operations Director in ICR-CTSU, to overcome that administrative challenge.

Claire oversees the non-statistical staff within the Unit, including trial management, data management, research administration and IT. And as Operations Director, Claire represents ICR-CTSU in operations groups across networks of CTUs.

“Everybody wants trials to happen more quickly, whilst maintaining scientific integrity and regulatory compliance,” Claire explained. “I look at processes, and question whether they can be changed. What are the benefits versus the risks, do these processes have any impact on patient safety or the quality of the science? Along with other operation leads in the national network of CTUs, I spend a lot of time pushing the boundaries and trying to reduce the level of bureaucracy, in order to make trials more efficient, pragmatic and risk adapted.”

“If there was work to be done, we were able to do it”

As with every workplace, when Covid-19 hit and the UK went into lockdown, the ICR-CTSU had to move to full remote working very quickly. Luckily, efficient systems for remote working were already in place.

“It was complex, but relatively straightforward to move the Unit online overnight, and we had no hiatus in the work of the Unit,” Judith said. “If there was work to be done, we were able to do it. The challenge was that the work dried up somewhat, when NHS research staff were rightly redeployed to tackle the immediate threat of Covid.”

The research activity at sites is now rebuilding, with the support of CTUs such as ICR-CTSU.

“We’re conscious and aware that staff at hospital sites have had a very difficult year, and many people will be feeling burnt out,” Judith said. “We recognise that we are asking people to go above and beyond, it is easier to treat someone with the standard-of-care, than spend half an hour talking to them about a clinical trial. Equally we know how important research is to patients.”

Covid-19 and the importance of clinical trials

The pandemic has illustrated the importance of clinical trials.

“Over the past year we have seen some drugs promoted as effective against Covid in the lay media, which proved to have no effect at all when tested in trials,” Judith said. “Without evidence from clinical trials, you don’t know who to treat, what dose to use, what order to treat patients in. There has to be robust evaluation of the effectiveness of new treatments.”

The backlog of patients waiting for cancer diagnosis and treatment caused by the pandemic makes improving cancer treatment in the near future more important than ever especially where the focus of research is on risk adaptation of treatment, sparing patients unnecessary treatment where it is safe to do so. Clinical trials will be imperative in helping to advance cancer research and benefit patients now, and in the coming years – clinical trials units like ICR-CTSU will have a central role in ensuring these trials are as impactful as possible.

Thank you to Professor Judith Bliss, Claire Snowdon, Professor Charlotte Coles, Dr Nuria Porta, Katy Jarman and Katie Goddard for their valued contributions to this article.