Medical Device Daily

New colon cancer screening guidelines issued last week by the American Cancer Society (ACS; Atlanta) bode well for the fate of Exact Sciences (Marlborough, Massachusetts) stool DNA test, known as PreGen Plus. The company also said it is preparing for a 510(k) submission to the FDA, previously an unnecessary step for this type of test.

Both stool DNA testing and CT colonography were added to the ACS screening guidelines, which were developed in collaboration with the U.S. Multi Society Task Force on Colorectal Cancer and the American College of Radiology.

What differentiates this DNA test from other types of screening is that it is based on the molecular structure of the disease rather than appearance, as in a colonoscopy.

This represents achievement of a key catalyst for Exact Sciences in our mission to reduce colorectal cancer deaths, said Exact s president Jeffrey Luber during a conference call. The market for colon cancer screening is one of the largest diagnostic markets in history, with nearly 90 million people over the age of 50 who should be screened for the disease. But less than half of this population has been screened.

Exact s efforts to commercialize the test are an illustration of the changing tide at the FDA for tests that previously have fallen under home brew rules.

Recent guidance from the agency has indicated that the FDA wants a larger role in the regulation of these diagnostics. Exact received a warning letter last fall about their assay, which was previously covered under the Clinical Laboratories Improvement Act (CLIA), and regulated by the Centers for Medicare & Medicaid Services (Medical Device Daily, Nov. 13, 2007).

The Oct. 11 warning letter to Exact noted that data the agency obtained from the Centers for Medicare & Medicaid Services (CMS) regarding Exact s PreGen indicated it was used by commercialization partner LabCorp (Burlington, North Carolina) in both its main facility and in its plant in Burlington.

Use of the assay outside of Exact s plant evidently provided a red flag that sparked FDA s interest. Because the test was designed, developed, validated and marketed by Exact rather than LabCorp, the assay was outside the scope of lab-developed tests over which the agency has traditionally applied enforcement discretion.

And, because it is not PMA- or 510(k)-cleared, the FDA cited Exact for misbranding and adulteration.

Luber said Exact has recently met with the FDA regarding pending submission of a 510(k), and the FDA told the company that regulatory path, rather than a PMA, is feasible.

PreGen s DNA technology (sDNA) is based on the work of Bert Vogelstein, Kenneth Kinzler and colleagues at Johns Hopkins University (Baltimore) who discovered how colorectal cancer develops at the molecular level. Over time, cells lining the colon accumulate alterations and mutations in their DNA. Pre-cancerous lesions, such as adenomas, and colorectal cancers continuously shed cells into the stool. The altered DNA from these cells is released as the cells breakdown in the stool.

Exact s stool-based DNA technology was designed so that a stool sample could be collected in the privacy of one s home and shipped to a laboratory for testing. The laboratory isolates and amplifies the DNA from the sample, and analyzes it for DNA mutations and alterations that are known to be associated with colorectal cancer.

These updated guidelines are a major step forward for the millions of Americans over the age of 50 who have been unwilling or unable to use existing screening methods for detecting colorectal cancer, Luber said.

Because PreGen is a completely non-invasive approach that does not require bowel preparation, Luber said more people are likely to use the test.

The regulatory and reimbursement hurdles are not over yet.

Last month, CMS posted a proposed national coverage decision in which it agreed to examine the proposed coverage change last August from Exact for Medicare coverage of stool DNA testing for CRC screening in average risk individuals at every five years as an alternative to colonoscopy.

CMS s proposed decision is that it will not expand the colorectal cancer screening benefit to include coverage of this test, and cited the regulatory status of PreGen but indicated it will reconsider the matter if the product is cleared by the FDA (MDD, Feb. 12, 2008).

We believe news of the guidelines will also give us greater latitude with payers, Luber said.

Stool-based screening has now gained critical support and awareness, said Patrick Zenner, interim CEO of Exact. We believe with the backing of the ACS and other major medical organizations that we can affect a positive change in the current screening paradigm.

An analysis provided by the Agency for Healthcare Research and Quality on the cost-effectiveness of the PreGen DNA test, compared to the Hemoccult II fecal occult blood test, made by Beckman Coulter (Fullerton, California), said that the latter assay has been shown to reduce mortality by 15%-33%.

However, the AHRQ analysis, which used data provided by the Cancer Intervention and Surveillance Modeling Network consortium, indicated that the benefit of DNA screening measured in life-years gained compared with no screening, was lower than that of the annual Hemoccult II testing except for three-year testing.

The AHRQ report concluded that screening with PreGen does provide a benefit in terms of life-years gained compared with no screening, and that the DNA test will be cost effective only when significant improvements for the DNA stool test characteristics or relative adherence with DNA stool testing compared with other available options can be demonstrated.

Exact will be submitting PreGen Plus 1.1 for 510(k) approval, but version 2.0 is under development.

Version 2 will be submitted for FDA approval as well, Luber said. It s a more sensitive test and less complex to run than version 1.

The new ACS guidelines say some tests, which are typically more invasive, offer the best chance of preventing cancer because they can find colon growths (polyps) that can be removed before they become cancerous. Other tests are less likely to find polyps, but can still detect most cancers.