A blood test promising to detect more than 50 types of cancer – currently being trialled in large numbers of people in England – is facing mounting evidence against its implementation as a screening tool for early cancer, with experts saying it has been “overhyped” and calling the current trial “unethical”.
Big promises have been made for the Galleri blood test, which its maker, Californian biotechnology company Grail, says is capable of detecting more than 50 types of cancer.
Harpal Kumar, president of Grail Europe, described the test as a “groundbreaking and potentially life-saving advance that could have a tremendous human and economic benefit”, reports The BMJ.
The NHS is currently running a £150m trial of the test, involving more than 100 000 participants, and depending on results, plans to roll out a further pilot involving up to 1m tests.
If effective, the test would help the NHS meet its target to diagnose 75% of cancers at an early stage by 2028. Trial success would also hand Grail a lucrative deal: although contract details remain confidential, a single test in the US currently retails for $950.
Multi-cancer early detection tests likes Galleri are touted as game changers. Instead of screening for one disease at a time, they can potentially test for dozens of cancers from just one blood sample.
However, concern is mounting over why this particular test has been selected, how it is being evaluated, and whether the bar to success has been set too low.
New evidence
Documents leaked to The BMJ indicate that the criteria being used, unpublished until now, are unsuitable to justify a new national screening programme aimed at saving lives.
They show that even Mike Richards, the chair of the independent UK National Screening Committee, has privately voiced “serious concerns” to Amanda Pritchard, NHS England’s chief executive, about the trial and its ability to provide sufficient evidence “on whether the benefits of testing outweigh potential harms and at reasonable cost”.
Other documents detail the deal between the NHS and Grail, raising questions about whether it is too industry-friendly. As well as agreeing to buy 1m tests after satisfactory completion of the first trial stage, the NHS has committed to buying 5m more tests by 2030 if the test fulfils certain criteria, show the documents.
In return, Grail would build a “new state-of-the-art test processing and sequencing facility in the UK once the NHS commits to purchasing minimum annual volumes, keeping the UK at the global forefront of clinical application of genomics”.
Richard Sullivan, director of the Institute of Cancer Policy at King’s College London, says the deal is a “clear cut case of public risk and private profit”.
“It is following a pattern established in this country over the past decade where the regulatory or evidential bar is being set lower and lower in favour of the private sector, with the public sector (taxes) taking all the risk.”
Added to these concerns, it emerged in June that Grail is facing a class action lawsuit in the US, where embittered investors, faced with steep losses, claim the company exaggerated Galleri’s effectiveness to increase its share price.
The plaintiffs claim it was “false and misleading” that the roll-out would “save tens of thousands of lives”. A Grail spokesperson said they “don’t comment on ongoing litigatiom”.
NHS trial: a mistake?
Experts also say it is unclear why an NHS trial is being done of a test that showed so little promise in earlier trials.
The test is one of several multi-cancer detection blood tests, or “liquid biopsies”, on the market, and uses sequencing technology to analyse DNA fragments circulating in the blood, also known as cell free DNA (cfDNA). These cfDNA fragments from cancer cells have specific “methylation patterns”.
Grail said that Galleri checked more than 1m methylation sites in DNA, using machine learning and artificial intelligence to detect whether someone is harbouring a cancer.
NHS England claims the test can identify many cancers that “are difficult to diagnose early”, like head and neck, ovarian and pancreatic cancers.
But some eight months before the NHS Galleri trial was announced in 2020, Grail published data showing that in patients already known to have cancer, the test detected only 43.9% of stage 1-3 cancers.
In 2021, another Grail-funded study in Annals of Oncology found that the test sensitivity for stage one cancers was only 16.8%. Many of the authors declared fees, patents, or stock holdings with the company.
These results are “strikingly low,”, said Clare Turnbull, professor of cancer genetics at London’s Institute of Cancer Research.
“A good screening test would typically be anticipated to have high sensitivity for early stage cancers, as these are usually the cancers for which surgery would offer the patient a high likelihood of cure (or long term remission).”
Paul Pharoah, professor of cancer epidemiology at the Cedars-Sinai Medical Centre-LA, agreed: “I don’t think the evidence was sufficiently strong to warrant the trial.” “With a sensitivity for stage one disease of less than 20% overall and only 44% for all stage 1-3 cancers diagnosed through other tests, I don’t think a trial is ethical.”
It was unclear why “a trial of a test with such little promise” was done, he added.
Some clues can be seen in emails obtained by The BMJ through freedom of information requests.
On 15 October 2020, Illumina, the then parent company of Grail, emailed Nadhim Zahawi, a minister in the Department for Business, Energy & Industrial Strategy, requesting a meeting to discuss “this revolutionary technology” that could have “an incredibly positive impact on UK patients and …the economy”.
The email referred to links that Grail and Illumina already had in the UK. Illumina’s “world-leading sequencing technology was invented in the UK”, and Grail had a significant clinical trial programme with centres in London, it said.
It added: “We will continue to build on that foundation, and our other collaborations with the NHS, Genomics England, industry and academia to help realise the promise of the UK’s recently published genomic strategy.”
A government aide suggested that a meeting should be granted as “they are a big company that makes machines… it ticks the industry box”. The deal, with a press release signalling the launch, occurred six weeks later.
NHS England didn’t respond to questions about why it didn’t put a contract out to tender. Instead, a spokesperson said: “At the time of the agreement in 2020, Galleri was the only test for which a company was in a position to do a trial at sufficiently large scale.”
Behind closed doors
The £150m NHS trial began screening participants in mid-2022, but its details have been marked by secrecy. It is generally considered good practice to have the trial protocol available for scrutiny before a trial starts and is publicly registered, with full details of how the trial will be conducted and the outcome measures.
Clinicaltrials.gov records the start date of the trial as August 2021, but trial details were not uploaded until more than a year later: October 2022.
Funded by Grail, this prospective randomised controlled trial aimed to recruit 140 000 asymptomatic patients between 2021 and 2026. Participants make three visits to a mobile clinic over two years, with half having a Galleri test and half in the control group.
The primary outcome measure was the absolute numbers of stage three and four cancers diagnosed.
Interim results of the trial were published in an NHS England blog at the end of May, saying that NHS England “did not find them compelling enough” to proceed directly to the planned large scale pilot programme in July 2024. Full details were not published.
Instead, NHS England will wait for the final trial results, expected in 2026, before making any further roll-out decision.
Documents obtained by The BMJ outline for the first time what the “success criteria” are that the trial needs to meet. The NHS has committed to buying 1m tests if the Galleri test produces a positive predictive value (the proportion that gives true positives) of more than 30%, a 30% reduction in stage IV cancers in the intervention arm, compared with the control arm, and a 75% higher number of cancers detected by Grail than in the control group.
Would these criteria mean “success” for patients?
Turnbull says that just demonstrating a shift in the distribution or proportion of cancers presenting at different stages does not tell us whether or not this multi-cancer early detection tool is improving survival in patients with those cancers.
She cites a recent meta-analysis across screening studies for various cancers showing that stage distribution largely does not predict survival.
“Galleri’s own data have shown that survival stage-for-stage is poorer for cancers detected by the Galleri-MCED (multi-cancer early detection) than for those not detected.”
This is crucial, she said, because it may be that the supposedly early stage cancers detected by Galleri are ones that have already metastasised – and that the technology is demonstrating that it is better than imaging at detecting early metastasis.
Pharoah agreed. “There is the whole question of what would be the appropriate endpoint. With a multi-cancer detection test (multi-harm opportunity from overtreatment) I cannot see that anything other than all-cause mortality is sufficient.”
When such a large section of the population is exposed to screening, even a small proportion of false positive testing can have a large effect on demand for imaging and diagnostic investigations, costs, and waiting lists, he added.
There are other warnings that the Galleri test might fail to deliver on its promises.
A 2023 Lancet study suggests that the test’s sensitivity is even lower in a screening population than in previous trial populations. In the Pathfinder study, on asymptomatic patients in North America, 1.4% had a positive test, but 62% of these results turned out to be false positives.
Warning
In February 2024, when NSC Chair Richards wrote to Pritchard with “serious concerns” , he said that if the trial led to a roll-out of a “million tests” the committee recommended the need for a control group, with research ethics approval, but “unfortunately, those responsible within NHSE for this phase of the programme have declined to take our advice on this”.
As a result of all these failings, Richards said, the UK NSC might be unable to make a recommendation about the roll-out of Galleri at the end of the project.
An NHS England spokesperson, however, said that they believed that Grail was “now being subjected to one of the largest and most rigorous investigations done in any healthcare system worldwide”, that no decision had been made, and no further details were available.
By contrast, an NHS England source speaking to The BMJ under the condition of anonymity said: “The clinical or scientific data doesn’t stack up, but that should have come first. This is not the way to do a trial – it should be done transparently. It’s not been thought through at all.”
NHS England article – An update on the ongoing NHS-Galleri trial (Open access)
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