FDA Panel Recommends New Colon Cancer Test by Narrow Margin

Troy Brown, RN

March 26, 2014

An FDA advisory panel voted by a narrow margin to recommend premarket approval for the Epi proColon (Epigenomics AG) colorectal cancer (CRC) test today.

The Molecular and Clinical Genetics Panel of the FDA's Medical Devices Advisory Committee voted that the test is safe (yes-9, abstain-1). Regarding whether or not the test is effective, the panel voted yes-5 and no-6. Regarding whether or not its benefits outweigh its risks, the panel voted yes-5, no-4, and abstain-1.

The Epi proColon test is a qualitative in vitro diagnostic test for detecting methylated Septin9 DNA, which has been associated with the occurrence of CRC, in plasma obtained from patient whole blood specimens.

The company is requesting FDA approval of the Epi proColon test for the indication of CRC screening for patients with average CRC risk as defined by current screening guidelines. The test is not intended to replace CRC screening by colonoscopy, and patients with a positive Epi proColon test result should be referred for diagnostic colonoscopy. Test results are intended to be used in conjunction with the physician's assessment of patient history, other risk factors, and professional guidelines.

The vote follows a discussion of data from 2 clinical studies. The study (VAL0018) — "Pivotal Clinical Study for Epi proColon Test" — compared the performance of the test to that of colonoscopy by evaluating archived specimens from 1623 participants in a previous study (SPR006) "Prospective Evaluation of Septin9 Performance in CRC Screening" (PRESEPT).

The supplemental clinical study (SPR002) compared the performance of Epi proColon and the fecal immunochemical test (FIT) to colonoscopy in blood and stool specimens from 290 patients.

Not all of the prespecified primary performance objectives were met in the pivotal study. The sensitivity of Epi proColon was 68.2% (95% confidence interval [CI]; 53%-80%), which was within the prespecified criterion that the test would demonstrate sensitivity for CRC of 65%, but the 95% CI lower bound was below the targeted point estimate of 65%, at 53.4%.

In the non-CRC group in the pivotal study, the specificity was 78.8% (95% CI; 77%-81%), and did not meet the criterion that the test would demonstrate specificity of 85%. The 21% false positive rate was higher than expected, and indicated that more individuals than anticipated would be recommended to undergo follow-up diagnostic testing, such as colonoscopy, that would be negative.

Lower Specificity Than FIT Test

In the supplemental study, the Epi proColon test demonstrated noninferiority to a fecal immunochemical test (OC FIT-CHEK, Polymedco) for sensitivity, but the test had lower specificity and resulted in a higher rate of false positives when compared with the FIT test.

The test is associated with false positive results in patients with chronic gastritis, lung cancer, and also in pregnant women.

Several panel members voiced concern about using the test for screening, especially when the test failed to perform better than the FIT test.

"I'm uncomfortable with not clarifying that it should be an alternative for people who are not willing to take the FIT test," said voting panel member Karen E. Weck, MD, professor and director of the Molecular Genetics Laboratory, University of North Carolina, Chapel Hill.

"False Sense of Security" with False Negative Results

Some panel members were worried that patients who have negative results would be less likely to comply with colonoscopy recommendations.

"I'm more concerned about false negatives," said Dr. Weck. She said patients with false test results might have a false sense of security. "I don't see a compelling argument that it's really an effective screening test,"

Voting panel member Mary B. Mahowald, PhD, professor emerita at the University of Chicago in the Department of Obstetrics and Gynecology, MacLean Center for Clinical Ethics, and the Committee on Genetics, said that although she would like to see additional data, "There has been some documented effective use in patients who meet these criteria."

The voting panel members have disclosed no relevant financial relationships.

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