After a two day meeting, the Molecular and Clinical Genetics Panel of the FDA’s Medical Devices Advisory Committee ultimately voted to recommend.
After a two day meeting, the Molecular and Clinical Genetics Panel of the FDA’s Medical Devices Advisory Committee ultimately voted to recommend the approval of Epi proColon (Epigenomics AG) and Cologuard (Exact Sciences). Epi proColon and Cologuard are in vitro diagnostic tests for colorectal cancer (CRC).
Epi proColon is for the detection of methylated Septin 9 DNA in plasma derived from patient whole blood specimens. Methylation of the target Septin 9 DNA sequence has been associated with the occurrence of CRC. The test is indicated to screen patients for CRC who are defined as average risk for CRC by current screening guidelines.
Cologuard, on the other hand, is designed to analyze patients’ stool for detection of hemoglobin, multiple DNA methylation and mutational markers, and the total amount of human DNA. Cologuard is intended for use as an adjunctive screening test for the detection of colorectal neoplasia-associated DNA markers and for the presence of occult hemoglobin in human stool. A positive result may indicate the presence of CRC or premalignant colorectal neoplasia.
On Day one of the meeting, the Molecular and Clinical Genetics Panel voted by a narrow margin to recommend Epi proColon’s approval. The panel voted that the test is safe (yes-9, abstain-1), however the panel was split down the middle (yes-5 and no-5) on whether or not the test is effective. The panel chair, Ronald Przygodzki, M.D., voted to break the tie, making the final vote yes-5 and no-6. Regarding whether or not Epi proColon’s benefits outweigh its risks (and ultimately approving the product), the panel voted yes-5, no-4, and abstain-1.
These votes were primarily based on the discussion of two clinical studies. The first study (“Pivotal Clinical Study for Epi proColon Test”) compared the performance of the test to that of colonoscopy by evaluating archived specimens from a previous non-inferiority study. Not all of the pre-specified primary performance objectives were met in this study. For example, in the non-CRC group, the specificity was 78.8% (95% CI; 77%-81%), and did not meet the criterion that the test would demonstrate specificity of 85%. The second, supplemental clinical study compared the performance of Epi proColon and the fecal immunochemical test (FIT) to colonoscopy in blood and stool specimens from 290 patients. Epi proColon was found to be noninferior the FIT for sensitivity; however Epi proColon demonstrated lower specificity and resulted in a higher rate of false positives when compared with the FIT test.
Some panelists questioned the sensitivity of the test, saying it was too low for a screening test, which should ideally have a sensitivity of 80%-90%. They also expressed concerns about the high false-positive rate. “A sensitivity of about 70%, such that 30 out of every 100 people screened would be falsely negative, just seems too low as a screening test,” said panelist Dr. Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill. The results of the supplemental study also seemed to be a cause for concern with some of the panelists. “I’m uncomfortable with not clarifying that it should be an alternative for people who are not willing to take the FIT test,” said Dr. Weck. Despite the less-than-perfect clinical study results, not all of the panelists were against the approval of Epi proColon. Mary B. Mahowald, PhD, professor emerita at the University of Chicago in the Department of Obstetrics and Gynecology said that although she would like to see additional data, “There has been some documented effective use in patients who meet these criteria.”
In contrast, the panel unanimously affirmed the safety and efficacy of Cologuard on day two of the meeting. The panel agreed by a 10-0 vote that the benefits of the Cologuard test outweigh any risks. These favorable voting results were based primarily on data from the pivotal DeeP-C trial, which showed Cologaurd to have a significantly greater sensitivity for undiagnosed colon cancer, as compared with FIT. “We are pleased the committee strongly supported Cologuard’s approval,” Kevin T. Conroy, chairman and chief executive of Exact Sciences, said in a statement. “We look forward to continuing our work with the FDA to complete its review of Cologuard and remain committed to addressing the growing unmet needs in colorectal cancer screening.”
The agency is not obligated to follow its panel’s recommendation, but normally does so.
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