Four-year-old Zunaira is watching the animated children’s series Love Monster on an overhead TV screen as she lies in a hospital bed with six electrodes stuck to her body.
Her 10-year-old brother Zain is busy on his iPad on a chair next to her in the clinical research facility at Great Ormond Street Hospital (Gosh) in central London, whose white walls have been brightened with reproductions of children’s drawings of leaves. They are here for a study trialling a new drug to treat a rare genetic kidney disorder that can be fatal.
Electrocardiograms (ECGs) to measure the heart’s activity and blood tests are performed before both children are injected with lumasiran to treat primary hyperoxaluria type 1 (PH1). The rare condition is caused by the buildup of oxalate, a substance normally filtered through the kidneys and expelled in urine.
“She gets very excited when she comes to the hospital because she gets treated like royalty,” says Zunaira’s mother, Hafsah.
Zunaira has been given the drug, initially every month and now every three months, since she was three months old, as part of a clinical trial that involves just five children. The results were so good that her brother Zain is getting the same drug on a compassionate basis, a rare treatment option that allows an unauthorised medicine to be used outside trials.
Her treatment is novel for another reason: Zunaira is a participant in the increasingly rare field of commercial clinical trials in the UK.
The dwindling nature of such pilots has prompted leading health figures to warn of the risk to the UK’s ability to develop cutting-edge treatments and bring them to patients.
At the Gosh research facility, which is funded by the National Institute for Health and Care Research, lumasiran saved the children from needing a liver transplant – something their 13-year-old brother Amaan had to have aged six, after being diagnosed with PH1 the year before.
The family realised something was wrong when “he was sitting on the toilet and couldn’t pass urine”, Hafsah recalls. Amaan was also always tired and had bone pain – symptoms that his other two siblings escaped thanks to their treatment (Hafsah’s fourth child does not have PH1).
Amaan will have to take immunosuppressant drugs every day for the rest of his life. “So from having a child who had a transplant to having a child who just has an injection – there is a massive difference,” Hafsah says.
The lumasiran trial is funded by the drug’s US maker Alnylam Pharmaceuticals, a $26bn (£20.8bn) company based in Massachusetts, which is providing it for free in this case (the US list price is $61,451 for just 0.5ml). The treatment has recently been approved for use on the NHS by the body that scrutinises medicines’ value for money, the National Institute for Health and Care Excellence (Nice), which is thought to have negotiated a discount.
Gosh, a research hospital that specialises in rare and complex paediatric conditions, runs about 400 clinical trials a year – some sponsored by drug manufacturers, while others are funded by charities or government.
However, the UK has fallen behind other countries in conducting clinical studies, where new medicines are tested on volunteers to make sure they are safe and work, and to monitor any side effects. The Swiss pharma firm Novartis recently scrapped a large trial of a cholesterol drug in Britain.
The number of trials initiated in the UK fell by 41% between 2017 and 2021, with a similar drop in cancer trials, according to the Association of the British Pharmaceutical Industry (ABPI), which represents about 70 drugmakers. The decline has been made worse by the Covid-19 pandemic as NHS hospitals, which conduct much of each study, have been overwhelmed by frontline work; more than 7 million people are on waiting lists for surgery or specialist treatment, a new record.
“Delays in set-up and approval of clinical trials and the fact that research isn’t fully embedded in the NHS were already challenges prior to the pandemic, but they have been exacerbated with the added pressure of the pandemic and resulting backlog,” says Jennifer Harris, the ABPI’s director of research policy.
Tom Keith-Roach, the UK president of Britain’s biggest pharma company, AstraZeneca, says it has been forced to look overseas to host trials. “The number of patients it’s been possible to recruit into clinical studies in the UK, that’s been very challenging over the course of the last couple of years with the capacity constraints that exist in the frontline NHS. That’s meant a rebalancing of those clinical trial programmes into other hubs … places like Spain and Poland.” In a typical year, the company conducts more than 270 global clinical trials, involving more than 46,000 patients.
Gosh’s acting director of research and innovation, Dr Jenny Rivers, points to the “sheer complexity and volume of workload and competing NHS clinical pressures” and says staff shortages – especially in areas such as radiology – and other workforce pressures are “a huge issue” holding back research.
“We’ve demonstrated through Covid that we can set studies up extremely rapidly. The Recovery trial, which opened first in adults, was open to recruitment of children less than a week after we had the paediatric protocol approved,” Rivers says, referring to the world’s largest Covid-19 drug trial that opened in late March 2020. “The trouble is when you look at scale and you’re trying to open multiple studies of high complexity at the same time.”
The decline in clinical trials raises questions about Britain’s ability to drive innovation, and about benefits to patients, the NHS and the economy. Last week, a report by the Academy of Medical Sciences warned the future of the UK’s health research was at risk, and suggested that the hospitals that did such studies “have better patient outcomes overall”.
Access to new treatments through clinical research is particularly important for the 3.5 million people with rare diseases in the UK. Declining trials also mean less revenue for the NHS, as drugmakers pay on average £9,000 per patient recruited on to one. That brought in £355m to the health service in 2018-19.
Successive prime ministers have identified the pharmaceutical industry as a key pillar of the economy. ABPI estimates that increased investment in research and development could generate an additional £68bn over the next 30 years.
With the government’s vision of turning the UK into a “life sciences superpower” under threat, ministers have commissioned a review into clinical trials, conducted by James O’Shaughnessy, which is expected to report on 25 May.
Emma Walmsley, the chief executive of Britain’s second biggest drugmaker, GSK, says the review will “get into the real details of what is blocking, which can tend to be coordination, pace, execution of agreements, along with technology. We need to see … some concrete action to get a pivot return to recovery and competitiveness in allocation from the world to UK-based clinical trials.”
In the later stages of drug development, known as phase III, pharmaceutical companies run large trials across several countries, involving thousands of volunteers, in parallel.
“What we see in some of our global competitors, is that not only are other countries such as Spain able to get their clinical trials approved by the regulator and set up at the site really quickly, they are also able to really reliably recruit patients. It’s a challenge,” says Harris.
This matters to patients too. “If we’re not able to recruit patients into the trial, that’s hindering their access to those innovative new medicine and vaccines – and for some patients, particularly for those living with rare diseases, a clinical trial can be their only option,” Harris says.
She notes that when a clinical trial is stuck in the approval and set-up phase, it cannot open for patient recruitment, and calls for faster approval and set-up.“If you’re doing a global clinical trial and you have other countries recruiting their cohorts, the UK risks falling behind global timelines that companies need to stick to.”
In the UK, it takes an average of 247 days to get a study from being approved by the regulator to the first patient receiving a dose of the drug, an increase of 25 days since 2018. In Spain, there are targets for rapidly approving clinical trials and setting them up. As a result, trials there are approved and start recruiting 50 days faster than those in the UK, while the US, Australia and Germany are also faster.
The UK drugs regulator is undergoing the biggest overhaul of clinical trial regulation in 20 years. One important change the new regulation will include came from a pilot in which the regulatory and ethics reviews of clinical trial applications were combined. That led to a halving of the approval times for studies and cut the period from application to recruiting a first patient by 40 days.
Another hurdle is pharma firms having to sign contracts with dozens of hospitals or trusts to set up a trial. To tackle this, NHS England introduced a standardised approach last October, with model contracts and a single national price list for the costings, such as nurses’ time and samples taken.
The ABPI says it understands that half of clinical trials in England now use this approach. Scotland also operates a single price price model for industry research; however, there is no standardised approach across the four UK nations.
Lord O’Shaughnessy’s review is likely to recommend ringfencing time for research for clinicians, and to address trial governance processes. Rivers says it is vital that “research is seen as a crucial part of optimal care and can’t be seen as a separate commitment”. She is also calling for closer partnership working between hospitals and drugmakers earlier on, and with patients, to design the protocols for trials that detail how they will be conducted.
Experts also say it needs to be easier for the public to participate in the studies. Half of GP practices were involved in research in 2020-21, for example by giving patients questionnaires or wearable devices, but many family doctors lack dedicated research time.
“There is no silver bullet to this,” says the ABPI’s Harris. “We need to see action across the board.”
Back at Gosh, Zunaira and Zain retreat to the play area before their injections. Their mother says she is “very happy” that the PH1 drug has now been made available on the NHS, and the children can live relatively normal lives.
