NCHR Testifies at the Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee Meeting on Shield Guardant Health

We thank you for the opportunity to share our views on Shield Guardant Health cf-DNA blood test for colorectal cancer (CRC) screening with the Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee.

The National Center for Health Research is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work and have no conflicts of interest.

Currently, only approximately 60% of eligible Americans are up to date with their colorectal cancer screening, leaving over 40 million people unscreened according to the recommended screening schedule. There is a lack of adherence with annual fecal immunochemical tests (FIT) and many patients wish to avoid colonoscopy altogether due to bowel preparation, sedation, and/or time required away from work. For these reasons, the cf-DNA blood-based test for CRC screening offers a potential for a practical and easily accessible screening test.

However, there are several important factors to consider regarding the use of cf-DNA blood-based tests for CRC screening:

1. The sensitivity of the cf-DNA blood test was high in patients with Stage I-III CRC 87.5% (95% CI 75-94) with 42 of 48 individuals with Stage I-III CRC had a positive cf-DNA blood test. Yet the sensitivity for Stage I CRC was only 65% (95% CI 41-83) and 11 of 17 individuals with Stage I CRC had a positive cf-DNA blood test. Further, the cf-DNA blood test had an even lower sensitivity among patients with advanced adenomas of 13.2% (95% CI 11-15) with 147 of 1,116 individuals with advanced adenomas having a positive cf-DNA blood test, which has also been highlighted by FDA scientists as a major concern since most CRCs arise from advanced adenomas. Ultimately, these data show that the test is ineffective at detecting CRC across the spectrum of the disease.
2. When comparing the sensitivity of the cf-DNA blood test to other non-invasive CRC screening tools such as the multi-target stool DNA test, the cf-DNA blood test is inferior. The widely available, new multi-target DNA test has a sensitivity of 92.7% (95% CI 85-97) for Stage I-III CRC and a sensitivity of nearly 44% for patients with advanced adenomas. Thus, we recommend that you consider whether this screening test is appropriate for FDA approval since other available alternative screening tests have demonstrated a superior sensitivity.
3. The investigators recommend screening every three years with the cf-DNA blood-based test. Yet, it is unclear how that time interval was determined, and more data are needed to establish the appropriate time interval between screenings. We urge the advisory committee to require investigators provide evidence that would support a three-year screening interval prior to FDA approval.

1. Approximately 10% of the average-risk individuals screened with cf-DNA had a positive result with a normal colonoscopy. It is important to note that other solid-tissue tumors may release abnormal cf-DNA fragments and investigators provide no discussion on how these results are to be interpreted and if any additional screening or diagnostic testing should be performed in these cases. Thus, we strongly recommend that the advisory committee consider the impact of such results on patients as a positive blood test followed by a normal colonoscopy represents a true risk and may lead to additional unnecessary invasive testing. Accordingly, we recommend the advisory committee require an evidenced-based guidance from investigators on how these results should be followed up prior to FDA approval.

We commend the investigators for expanding the science of CRC screening. But ultimately the cf-DNA blood test has a relatively low sensitivity for Stage I CRC, very poor sensitivity for advanced adenomas, is inferior in sensitivity compared to other available CRC screening alternatives, and there are a lack of data regarding the time interval needed between screenings and how to advise patients with a positive cf-DNA result and normal colonoscopy. Accordingly, we are concerned that this test risks missing many early CRC diagnoses and may provide patients with false reassurance or, alternatively may subject patients to more invasive testing if a positive result is detected but their colonoscopy is negative.

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