Taking clinical trials into the community

Article by Adam Green, freelance journalist

Reimagining clinical trials

Clinical trials are the engine of evidence-based medicine, showing whether a drug, device or medical strategy works and for whom. But they are difficult and expensive to run. Of all the logistical challenges, trial participation rates loom large. If trials do not recruit enough participants, or if they do not mirror who needs the treatment in the real population, the trial may fail to deliver.

Trials participants tend to be those patients who have more time, fewer commitments and are easier-to-reach, so are therefore not reflective of most patients with the condition being investigated. Geographic bias plays a role too, as trials tend to recruit from large hospital centres. If trials are built around those who can travel to hospitals, take time off work and navigate complex appointment systems, the evidence they generate may be less useful to the communities who experience the greatest burden of disease.

At the University of Birmingham, two researchers are spearheading projects that tackle trial participation challenges from different angles but with a shared goal: redesigning trials around real lives by moving activity out of already-stretched hospital and clinical settings and into the community and removing participation obstacles.

Professor Dipak Kotecha, professor of cardiology at the University of Birmingham, and NHS Consultant at the University Hospitals Birmingham NHS Foundation Trust, has built a trial platform, Dare2THINK, that can run large studies through GP surgeries across England using routinely collected NHS data, reducing workload and widening participation.

Professor Alex Sinclair, professor of neurology at the University of Birmingham, is leading a trial for a debilitating neurological condition by recruiting patients directly online, with postal medication, and high-street eye scans, relieving NHS bottlenecks and giving patients control.

Together, their work imagines a future in which research takes place where the participants actually are.

Kotecha’s response is to invert the usual trial process. Instead of asking patients to attend trial appointments in hospitals, research is brought to the patients. DaRe2THINK is a GP-based digital trials platform, developed in partnership with the Clinical Practice Research Datalink (CPRD; part of the UK’s medicines regulator). The trial platform can securely screen routine NHS primary care records for over 13 million patients, and is currently deployed in 500 English GP practices across England. The approach completely streamlines the ability to identify which patients may be eligible for a particular trial, supporting GPs, nurses and allied health professionals to invite people to take part in research to improve their health (often for the first time). Through co-design by patients and the public, DaRe2Think also makes it easy for people to join and stay in the trial without requiring any visits to their GP or hospital.

The first national deployment of DaRe2THINK is a trial comparing whether earlier use of a treatment already available in the NHS can prevent strokes, blood clots and dementia in patients with atrial fibrillation (AF), a very common heart rhythm disorder. Blood thinning medications (anticoagulants) are often prescribed to older people with AF at risk of stroke, and Kotecha has chaired international guidelines to ensure they are widely available. However, this is often too late to prevent vascular dementia, which Kotecha’s team have shown is a clear and pressing danger to younger patients with AF. The study will follow participants over a number of years, analysing GP and hospital records digitally, as well as self-reported data on memory, reaction times and quality of life.

For meaningful results, the study population must be large and representative, so the novel approach to recruitment and data collection is central to the study’s feasibility. Kotecha draws on an illustrative analogy. Traditional recruitment can feel like searching for needles in a haystack. Clinicians review lists, check eligibility criteria, and chase paperwork. Data-enabled recruitment is more like having a map that shows where those needles are in the first place.

In practice, the platform can screen patient records securely to inform NHS staff who might be eligible for a trial without disclosing their personal information. “Unlike other trials, in DaRe2Think the overstretched NHS nurses, doctors and pharmacists don’t actually have to fill in any information,” Kotecha says. “For example, they don’t have to put in the patient’s details, or the fact they had diabetes five years ago and a range of medications started last week. All of that effort has completely disappeared.”

The process is streamlined for participants too. An invitation from their GP arrives on a mobile phone, an information video by the patient and public team explains the study, and consent can be completed through the person’s own device. Follow-up can then be captured through linked NHS records, rather than relying on frequent in-person appointments.

The point is not simply speed, although faster recruitment matters. It also facilitates equity. Kotecha notes that “a quarter of our practices are in the most deprived areas, which are home to communities that have historically had fewer opportunities to benefit from advances in NHS care”. UK government data shows these inequalities are widening, limiting access to research and translating into worse health outcomes overall, particularly for chronic conditions. “For the first time, those people are able to access research, where they wouldn’t ever have had the chance to before.”

The approaches in DaRe2THINK have spearheaded other critical infrastructure to support healthier lives for all, with Kotecha and his team also working to embed health technologies in routine NHS care, and global partnerships to reduce health inequality.

Decentralising a complex neurological trial

If Kotecha’s work rethinks the logistics of large-scale cardiovascular trials, Professor Sinclair’s tackles a different problem: how to run complex intervention trials for a condition that can be debilitating, at a time when NHS capacity is stretched thin.

Sinclair is a consultant neurologist and Professor of Neurology working across the University of Birmingham and University Hospitals Birmingham. One area of her focus is idiopathic intracranial hypertension (IIH), in which rising pressure inside the skull leads to severe headaches and a sight-threatening swelling of the optic nerve (papilloedema). The condition disproportionately affects women of childbearing age living with obesity.

IIH is best understood by picturing the skull as a rigid box. Inside are the brain, blood, and cerebrospinal fluid (CSF), the clear fluid that cushions the brain and spinal cord. Because the skull cannot expand, the balance between brain tissue, blood and cerebrospinal fluid (CSF) is tight. Small shifts in brain pressure cannot be accommodated as the rigid skull cannot expand. Increased brain pressure termed intracranial pressure (ICP) can compress the optic nerve which can cause blindness and headaches.

IIH is strongly associated with body weight, and substantial weight loss reduces ICP. Fat is not an inert tissue. It is biologically active, influencing hormones, inflammation and blood flow, and these signals can affect the pressure in the brain. Previous studies suggest that significant weight loss can reduce ICP and improve symptoms.

Sinclair’s team is exploring whether a new generation of weight loss medicines such as Mounjaro might help reduce ICP. These so-called GLP-medications act at the choroid plexus, a network of vessels that drive CSF. Sinclair explains this mechanism through a plumbing metaphor: if the choroid plexus is the tap, it may be possible to pharmacologically “turn down” the flow and relieve pressure.

In an earlier Phase 2 clinical Trail, the IIH Pressure Trial the team showed that ICP was significantly reduced for those receiving GLP-1 treatment. However, there is a further question. If the drug helps, we also need to know what might happen when people stop taking it. “As with most weight-loss medications, we would expect that when treatment stops, weight may increase again,” Sinclair says. But if these drugs act directly on CSF regulation, they could represent a targeted treatment for raised ICP, in addition to a metabolic or weight-modifying approach. This led to Sinclair’s current trial, which will evaluate weight loss driven by Mounjaro in adults with IIH and papilloedema (both on and then off the drug).

But even the best-designed clinical trials can stall if the system cannot absorb them. Sinclair describes how site set-up times have ballooned, for instance. At the hospital, what used to take “three months to open” can now take “18 months to three years”, because the staff and infrastructure needed to support research, such as research nurses, pharmacy input, specialist testing, are all under increasing pressure.

For IIH trials, one pinch point is ophthalmic testing. “The equipment that we need to do the eye tests is really, really restricted,” she explains, often already booked for routine clinical care. Her response is to step outside the usual model. “To avoid placing extra demands on NHS services, we made the decision to run the trial independently of the NHS,” Sinclair says.

Instead, the University of Birmingham acts as a central hub. Participants recruit themselves having watched engaging, easy-to-follow informational videos (often via social media), giving electronic consent via video link, and then receiving medication through the post.

All follow up visits are run by the Birmingham medical team via video link so the patients can be at home. Even sample collection is decentralised: stool, urine, saliva, and blood can be collected using home kits and mailed back for analysis, and the specialist eye scans move to the high street. Through a collaboration with Specsavers, a UK community optician chain, participants can attend their local optician for standardised OCT (optical coherence tomography) scans.

“We’ve stepped outside of the NHS, and we’ve put the patient right at the front,” says Sinclair. This is a design choice that treats time, travel, and access as scientific variables, because the demographics of participants shape the evidence that a trial produces.

Trust, access and digital exclusion

Both researchers are realistic about risks of novel and alternative trial design and logistics. “Digital” does not automatically mean “fair”. Done badly, technology can widen inequality by concentrating benefits among people who are already connected, confident, and well-served. “I think up to this point, technology has largely worsened health inequality”, says Kotecha, “but there is now an opportunity to actually improve it.”

Kotecha’s team is now thinking beyond the GP surgery to community hubs and partnerships with trusted local leaders to reach people who may not routinely engage with healthcare. He points to an example from COVID-19: Birmingham City Council asked community groups affiliated with Citizens UK to help improve the uptake of vaccines across different cultures and religions by leveraging their community leaders. The ambition is to use similar, trust-based approaches to identify people who could benefit from preventive treatment earlier.

For example, tens of thousands of people attend every Birmingham City football match. With the right approach and technology, we can deliver prevention through the club's vast existing infrastructure, reaching out into the community and delivering health messages in a familiar non-judgmental environment, says Kotecha. The University of Birmingham and Birmingham City Football Club have a strategic partnership to make this happen in the future.

It is tempting to see these as standalone innovations: but both Kotecha and Sinclair argue that the place they arise in matters. Birmingham’s population is large and diverse. Sinclair emphasises that the city’s mix of ethnicity and socio-economic catchments is key for research, because it’s important to include diverse populations "so that our results truly reflect, and can benefit, people across the UK.” There is also the practical advantage of the close-knit relationship between the University of Birmingham and NHS partners in the region as part of Birmingham Health Partners, which is delivering ground-breaking research and improving patient care.

If trials can be run with less burden, better representation, and lighter reliance on hospital attendance, they can answer questions that matter faster, and more fairly. For Sinclair, that means unblocking research projects that might be stymied by limited equipment and overstretched services. For Kotecha, it means building a patient recruitment pipeline that can involve practices in deprived areas and rural regions, so that studies reflect all of the people the NHS serves.

Beyond their clinical value, these innovative trial approaches could help the UK improve its global standing in delivering life sciences research. The government’s Life Sciences Competitiveness indicators show that a strong research environment depends not just on scientific excellence but on the ease with which complex trials can be delivered, the ability to recruit large numbers of participants at pace, and the importance of the resulting evidence.

The UK government is eyeing a greater role for the country as a leading global hub for clinical research. Designing innovative trials can simultaneously reduce reliance on NHS services, expand research capability and help the UK ascend to its rightful place in the global life sciences research landscape.