FDA Paves a Path for Some DTC Genetic Tests; Challenges Others

At the same time that 23andMe (Mountain View, Calif.) received U.S. Food and Drug Administration (FDA) approval to launch a revamped direct-to-consumer (DTC) genetic test that includes reports on 60 carrier status, wellness, trait, and ancestry findings, the agency kept up its scrutiny of DTC genetic testing, issuing letters to three manufacturers of DTC genetic tests questioning their marketing of specific tests.

23andMe’s late October launch of its overhauled test comes nearly 2 years after the FDA ordered the company to stop providing its health risk assessment test. The revamped test costs $199 for 35 carrier status reports for autosomal recessive conditions including cystic fibrosis, sickle cell anemia, and hereditary hearing loss; four wellness reports including assessments related to caffeine consumption, lactose intolerance, alcohol flush reaction, and muscle composition; and more than 19 trait reports on hair, facial features, and taste and smell preferences. Notably, the new product lacks disease risk testing and pharmacogenomic evaluation.

In the Oct. 27 Federal Register, the FDA issued a final order confirming its earlier statements in February about autosomal recessive carriers screening tests and explaining how labs can legally commercialize carrier screening tests that are 510(k) exempt. The agency classifies an autosomal recessive carrier screening gene mutation detection system as a class II medical device with special controls. The device is assigned the generic name “autosomal recessive carrier screening gene mutation detection system,” and the FDA defines this over-the-counter test as “qualitative in vitro molecular diagnostic system used for genotyping of clinically relevant variants in genomic DNA” and says they are not intended for copy number variation, or cytogenetic or biochemical testing.

That final order set forth the FDA special controls which require, among other things, the device manufacturer provide information about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre-and post-test counseling; specific labeling about the gene and associated variants tested along with evidence of “scientifically established clinical validity;” and the manufacturer must conduct a study that assesses user comprehension of the device’s labeling and test process, with a minimum of a 90 percent or greater overall comprehension rate. Additionally, the manufacturer must provide warnings recommending consultation with a health care provider, particularly for positive results.

The FDA also issued a Notice in the Federal Register requesting comment regarding its intent to exempt from the premarket notification requirements autosomal recessive carrier screening gene mutation detection systems, subject to certain limitations.

The FDA explained that the special controls described above mitigated the risks of false positives and false negatives of the testing. The special controls requiring scientifically established clinical validity and public posting of that information lowered the risk of false and misleading claims “for autosomal recessive inheritance.” The FDA also explained that the diseases tested for are very rare and only reveal the carrier status of the

person tested. Further, information about both parents is needed to determine risk for future children. Thus risks due to false positives are limited, the FDA explains—i.e., not just one parent but both must receive false positive test results to affect the course of action taken and even in the unlikely event that both parents receive false positive results, a potential child still only has a 25 percent chance of having the tested disease. Additionally, the controls requiring the tested individuals comprehend the limitations of the testing, and be advised how to access counseling from board-certified clinical molecular geneticists or equivalent professionals about the testing, also reduce the risks of false positives. Risks created by false negatives were mitigated by the special controls imposing labeling requirements and performance specifications and because of inherent limitations in the testing—i.e., not every potential mutation is known and tested for and thus “there will be a proportion of carriers who will not be detected.” Finally, the likelihood of inaccurate testing is reduced by Clinical Laboratory Improvement Amendment requirements, requirements regarding collection devices used and other controls regarding analytical performance. Thus, the FDA concluded that the special controls “reasonably assure that a legally marketed device of this type will have the characteristics necessary for its safe and effective performance without the need for premarket notification.”

FDA Issues Letters to DTC Genetic Test Makers
While providing the exemption discussed above, the FDA continues to question DTC test makers about their products. DTC DNA4Life (Mandeville, La.) received a letter from the FDA questioning the company’s marketing of an unapproved genetic test. The test, which predicts response to 120 commonly prescribed medications based on analysis of 12 genes tied to drug metabolism, is being marketed as an unapproved medical device, the FDA says. The agency said it is unable to identify any FDA clearance for the company’s test and requested either a clearance number or the reasons DNA4Life believes that FDA clearance is not required for its test.

The company believes it is filling a need for affordable pharmacogenomics information, given the high rates of adverse drug reactions. Richard Zimmer, DNA4Life’s CEO, told Reuters that he and his advisors don’t believe the test needs to be approved by the FDA, as it is a laboratory-developed test. In addition to its recent history of issuing warning letters to direct-to-consumer genetic testing companies, the FDA has indicated its intent to expand its oversight and regulate high-risk, laboratory-developed tests, which would likely include pharmacogenetic testing.

In addition to the DNA4Life letter, the FDA also issued a letter to DNA-Cardiocheck, Inc. noting that its direct-to-consumer test, DNA-CardioCheck, which tests for DNA genetic markers relating to cardiovascular disease, deep-vein thrombosis and stroke is a device for which no FDA clearance has been sought. It also sent a letter to Interleukin Genetics Inc. regarding three separate genetic tests which detect predisposition for increased risk to heart attack and diabetes and other obesity related conditions. Those letters made the same claim that these tests appear to be devices subject to FDA regulation and there’s no record of FDA clearance being granted. The FDA advised both companies to either provide a clearance number or advise why the company believes no clearance number is required.

Takeaway: While genetic testing is gaining ground in passing FDA scrutiny, the FDA is unrelenting in its oversight of direct-to-consumer genetic testing.