In the end the markets had it pretty much correct. This week’s clash of the colorectal cancer screening titans – or wannabe titans – before a US advisory panel came down clearly in favour of Exact Sciences.
This rewarded the faith of investors who had pushed the group’s market cap close to $1bn, and justified the caution of those backing its rival, Epigenomics, worth barely a tenth of this amount. It cannot be denied that Exact’s Cologuard assay could now alter the screening landscape, though delicate arguments around pricing and practical use have yet to play out.
Exact has been rewarded for taking a risky decision to run the 10,000-patient Deep-C trial, the largest truly prospective study of colorectal cancer screening ever conducted.
The adcom was satisfied with Cologuard’s 92% sensitivity (ability to pick out actual cancers) and 87% specificity (accuracy in ruling out cancer), and the only minor quibble in the review was the suggestion that patients who had been incorrectly cleared might decide to forgo routine colonoscopy.
Colonoscopy is the current gold standard, and is extremely accurate but expensive. Faecal immunochemical testing (FIT) is far less accurate, but – crucially – it is much cheaper. It is the FIT segment that both Epigenomics’ Epi proColon blood assay and Exact’s Cologuard, a stool-based test, are fighting for, and like FIT both need confirmation with colonoscopy.
Ultimately, the Cologuard adcom turned into a whitewash, with unanimous backing of the test's safety, effectiveness and benefit/risk. The agency does not have to follow an adcom’s advice, but it would be extremely unusual if it went against such an overwhelming verdict.
For Epigenomics, however, the outcome was bleak. The panel backed Epi proColon’s safety unanimously, but went against it on efficacy, and a five to four vote for benefit over risk is the type of scrape likely to result in an FDA rejection. Surprisingly, though, Epigenomics remains hopeful of approval in summer.
Relatively poor specificity had dogged both tests, since given colorectal cancer’s incidence a figure below 90% implies around 20 false positives for each actual cancer case correctly identified.
But interestingly this alone did not seem to trouble the Epi proColon panel as much as the combination of its 81% specificity with poor sensitivity (72%). Epigenomics has argued that its test is non-inferior to FIT, which in a head-to-head trial showed 68% sensitivity at 97% specificity.
This will probably cut little ice with the FDA, as will Epigenomics’ argument that low sensitivity is a non-issue because in any case all its test is doing is driving more people to comply with colonoscopy screening (Event – Epigenomics and Exact await tough panel screening, March 6, 2014).
The panel’s key doubt centred on lack of long-term data. In contrast to Cologuard, Epi proColon has only been subjected to case-control studies, or variations on this theme; even its 8,000-subject Presept trial had selected a sample of colonoscopy-confirmed cases, and thus did not represent a real-world setting.
In any case, where an entrenched competitor is not given a knockout blow – and neither Epi proColon nor Cologuard truly does this to FIT – there is another key consideration, and one that is out of the FDA’s remit: cost. Versus FIT’s $30, Epi proColon costs roughly $140 per patient, and Cologuard $300.
The sustainability of this in addition to colonoscopy will only become apparent in the market. The German firm now plans a 1,500-patient longitudinal study of its test in a screening situation that it hopes will address the panel’s concerns, but proposes to run this as a post-approval commitment.
It would be disastrous if the FDA now told it to run this before granting approval, though the company insists that it does not consider this likely. Quite apart from the cost, a delay of several years could see Epi proColon coming to a market segment by then dominated by Exact.
True, apart from the pharmacoeconomic subtlety, Cologuard might also face problems in practical use, since it basically involves a patient mailing a stool sample through the post.
But the potential for it to target people currently unwilling to undergo colonoscopy, coupled with its benefit in detecting precancers – much lower than Exact had touted, but still apparently relevant – could help Cologuard overcome the fact that it is basically a very expensive solution to some of the shortcomings of a slightly worse product.
Unfortunately for Epigenomics, this is a criticism that Epi proColon has yet to shake off.