FDA panel unanimously supports Cologuard colorectal cancer test

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.