An FDA advisory panel has recommended approval of Grail’s Galleri blood test, which is designed to screen people 50 and older for multiple types of cancer from a single blood draw.
The test remains controversial because a massive British trial failed to meet its primary goal of significantly reducing the combined number of stage 3 and stage 4 cancers.
Supporters say Galleri could help find deadly cancers for which there is currently no routine screening, while critics say it remains unclear whether widespread testing will ultimately save lives.
A blood test that promises to detect dozens of cancers before symptoms appear has moved a significant step closer to approval by the U.S. Food and Drug Administration, even as researchers continue to debate whether the benefits justify widespread use.
The test, called Galleri and developed by Grail, is a multi-cancer early detection, or MCED, test. Rather than looking for one particular cancer, it analyzes patterns in DNA fragments circulating in the blood for signals associated with cancer and attempts to identify where in the body the cancer originated.
This week, an FDA advisory committee, on a 6-4 vote, determined that there is reasonable assurance Galleri is effective and voted unanimously that there is reasonable assurance it is safe. On the larger benefit-risk question, seven members voted that its benefits outweigh its risks, two voted no and one abstained.
The recommendation does not constitute FDA approval. The agency will make the final decision on Grail's premarket approval application and is not required to follow the committee's recommendation.
Already available without FDA approval
Adding to the unusual nature of the debate, Galleri is already commercially available in the United States.
Grail has been selling it as a laboratory-developed test, or LDT. The company said in a recent regulatory filing that Galleri has not been FDA cleared or approved and that FDA approval has not been required for it to market the test under the regulatory framework governing its laboratory-developed test.
Grail submitted the final portion of its FDA premarket approval application in January. The company says Galleri is intended to supplement — not replace — existing screening such as mammograms, colonoscopies and recommended lung and cervical cancer screening.
That distinction is important. A negative Galleri result does not mean a person is cancer-free.
Why Galleri is so appealing
The potential benefit is easy to understand. There are well-established screening programs for only a handful of cancers, while many deadly cancers are usually discovered after symptoms develop.
Galleri is designed to look for signals associated with numerous cancers simultaneously. If it could reliably identify cancers such as pancreatic, ovarian, liver or esophageal cancer before symptoms appear, doctors might have an opportunity to treat patients when their disease is more manageable.
Results from Grail's PATHFINDER 2 study involving more than 35,000 participants also provided encouraging evidence. Grail reported that adding Galleri to recommended screening increased the number of cancers detected, with 71% of the new cancers detected by Galleri found at stages 1 through 3.
But detecting more cancers is not necessarily the same thing as demonstrating that screening saves lives. That distinction lies at the heart of the controversy.
A major trial missed its primary target
The biggest challenge to Galleri came from the NHS-Galleri trial in England, involving more than 142,000 adults between ages 50 and 77.
The randomized study was designed to determine whether annual Galleri testing, added to normal care, would reduce the number of cancers diagnosed at stages 3 and 4.
It did not meet that primary endpoint. Researchers found no statistically significant difference in the combined number of stage 3 and stage 4 cancers between the Galleri group and the control group.
That result generated criticism because one of the central arguments for multi-cancer screening is that finding cancer sooner should shift diagnoses from later stages to earlier ones. There were, however, potentially important signals buried within the overall result.
Grail reported that annual testing reduced diagnoses of stage 4 cancers among 12 prespecified cancers by 22% in the second screening round and 26% in the third. The company also said adding Galleri increased stage 1 and 2 cancer diagnoses by 16% and reduced cancers first diagnosed through emergency presentations by 25%.
Those findings help explain why researchers and regulators can look at the same trial and reach different conclusions about Galleri's potential.
The early-stage problem
Another concern is sensitivity — the percentage of actual cancers the test successfully detects.
Galleri performs considerably better with some cancers and at later stages than it does with very early disease. That is potentially problematic for a product whose biggest promise is early detection.
FDA review materials highlighted questions about Galleri's performance for individual cancers and its ability to detect cancers at their earliest stages. Data from the British study showed particularly limited detection of stage 1 cancers.
That creates a paradox: the cancers that might benefit most from being discovered very early can also be among the hardest for a blood test to detect because small tumors may shed relatively little detectable material into the bloodstream.
There is also the issue faced by nearly every cancer screening test: what happens when the result is wrong?
A positive Galleri result does not diagnose cancer. It triggers additional medical investigation to determine whether cancer is actually present and where it is located.
That can potentially mean imaging, biopsies and other procedures for someone who ultimately turns out not to have cancer.
Galleri's relatively low false-positive rate is one argument in its favor, but even a low rate can become significant when a screening test is given to millions of healthy people.
False negatives carry a different risk. Someone receiving a negative result might incorrectly assume that other cancer screening or medical evaluation is unnecessary. That's why Grail and regulators emphasize that Galleri is intended to be used in addition to existing recommended screening rather than as a substitute.
Ultimately, the most important question is also the one researchers cannot yet answer definitively: Does screening healthy people with Galleri reduce cancer deaths? Further research will attempt to find an answer.