NEW YORK (GenomeWeb) – The US Food and Drug Administration's clearance last week of 23andMe's Bloom syndrome test has created a more predictable path for the genomics firm to launch a direct-to-consumer (DTC) carrier testing offering in the near term.
As part of the authorization, the FDA said it is classifying carrier screening tests as class II, and intends to exempt similar devices from FDA premarket review.
FDA's action shows its regulatory flexibility as it is coming under significant criticism for its draft guidelines for regulating lab-developed tests (LDTs), a plan that lab industry players say will hinder diagnostics innovation and patient access to tests.
The agency has said it will regulate DTC genetic tests outside of its LDT regulatory framework. However, its handling of 23andMe's first 510(k) application – for a carrier test for a rare, autosomal recessive genetic disorder – shows its ability to lightly wield its regulatory authority for diagnostics that it finds pose intermediate risk (deemed class II in a three-class risk system) to patients.
The clearance also marks the first time the agency has cleared a genetic test being offered directly to consumers without going through a doctor. However, 23andMe stated that it would not immediately sell a stand-alone, DTC Bloom syndrome test, but that it would wait to commercialize "a more comprehensive product offering."
When 23andMe was offering health-related testing as part of the Personal Genome Service – before receiving an FDA warning letter in 2013 – it featured approximately 50 reports for carrier testing. The FDA warning letter asked 23andMe to stop marketing health-related test reports without the agency's approval or clearance. 23AndMe complied, offering ancestry reports and raw genomic data to new customers as it relaunched regulatory discussions with FDA regarding the Personal Genome Service.
The FDA accepted the first 510(k) application from 23andMe for Bloom syndrome last June, and announced its clearance seven months later. For 510(k) clearance, the FDA must deem the test "substantially equivalent" to a marketed device. However, according to FDA's decision letter, 23andMe filed for de novo classification of the test based on the determination that "there is no legally marketed device on which to base a determination of substantial equivalence."
After reviewing the data submitted by the company, the agency classified 23andMe's Personal Genome Service Carrier Screening Test for Bloom Syndrome in a Class II risk category under the generic banner of "autosomal recessive carrier screening gene mutation diagnostic system." The clearance was accompanied by "special controls," or requirements that 23andMe and other labs wishing to enter the DTC carrier testing space might follow to launch similar tests.
Among the requirements, labs will have to give consumers information about how to access a genetic counselor if the test is sold over the counter; use a saliva collection kit that has premarket approval or clearance from the agency; and include a "label" with a description of the device. The device description should explain the clinical performance of the test, including phenotype and genotype data from studies, information from the published literature, or guidelines recommendations; the type of biological sample the test analyzes; the probability that the test might fail; and procedures for managing risks.
23andMe didn't have to do clinical validation studies for the Bloom syndrome test because it is well known that mutations in BLM genes cause the disorder, according to the agency. Patients must inherit two copies of a BLM gene mutation, one from each parent, in order to get the condition, which results in short stature, skin that's sensitive to sunlight, and an increased risk for cancer. The prevalence in the overall population is unknown, but Bloom syndrome affects one out of 50,000 people of Central or Eastern European Jewish background and occurs most commonly among people of Ashkenazi Jewish descent.
However, 23andMe did do studies to prove to FDA that it could consistently run its test, by analyzing 105 samples without the BLMAsh variant across two lab sites. 23andMe also conducted an accuracy study comparing Personal Genome Service results for Bloom syndrome against sequencing using 65 saliva samples and five human cell line samples with known BLMAsh variant status. The results were in agreement for all 70 samples. In another study of more than 2,800 samples, 23andMe validated its lab procedures.
23andMe also conducted a user comprehension study to gauge how well people understood the carrier status test reports. In the study, which involved people representative of the US population answering questions about the test report, more than 90 percent of participants indicated they understood the test results, the company said. More detailed results of these validation studies will be posted by the FDA in the coming weeks.
In the decision letter, the agency also indicated that labs marketing carrier status tests DTC must label the tests to include information about its accuracy – the positive percent agreement and the negative percent agreement – compared to bi-directional sequencing or other methods that the agency deems appropriate. The label should also include information about the positive and negative predictive value of the test, reproducibility data, analytical specificity and sensitivity data, and information about device stability.
Since consumers will gain access to 23andMe's Personal Genome Service through the web, the test label information must be "prominently placed" and publicly accessible through a hyperlink from the ordering page, the FDA said in the decision letter for the Bloom syndrome tests. The FDA-cleared indication, which 23andMe will have to display on the test "label," notes it is to be used to gauge carrier status, but not to determine if a person has Bloom syndrome. The agency also said the test is intended "only for postnatal carrier screening in adults of reproductive age, and the results should be used in conjunction with other available laboratory and clinical information for any medical purposes."
Given the detailed regulatory framework laid out in the decision letter, 23andMe might be able to begin offering its several dozen other currently suspended carrier test offerings in a relatively quick timeline. "These are special controls that any manufacturer will need to follow in order to meet FDA requirements," FDA spokesperson Jennifer Corbett Dooren told GenomeWeb. "Future [carrier] tests would not be de novo and would be Class II exempt." The agency is planning to issue a notice in the federal register about these special controls and will be accepting public comments for 30 days.
According to 23andMe, it hasn't yet submitted any other review applications with the agency. This clearance doesn't offer much insight into the regulatory requirements 23andMe will need to meet for more complex disease predisposition tests, Dooren acknowledged.
Under the Personal Genome Service, 23andMe previously marketed numerous health-related test reports, which provided customers information on whether they had markers that could increase their risk for diseases, such as breast cancer and Alzheimer's. In its warning letter to 23andMe, FDA particularly expressed concerns about patient safety if the firm happened to provide wrong results for these serious, complex disorders. Given this history, it makes sense that 23andMe and FDA decided to tackle regulatory requirements for carrier testing first, since individuals carrying one copy of the mutation usually won't have health issues.
According to Dooren, the spit kit used by 23andMe as part of the Personal Genome Service is also now cleared for DTC use. The spit kit, manufactured by DNA Genotek, was previously cleared for "prescription use," she said, adding that the new clearance "does not mean that the Personal Genome Service is cleared."
Following the clearance, the Association for Molecular Pathology issued a statement bringing attention to the fact that it had recently changed its position on DTC marketing of certain types of tests. In 2007, AMP's position was that genetic testing should only be available through a doctor who orders tests from a lab certified to perform high-complexity testing. After revisiting the topic last year, the group now supports DTC offerings of genetic tests when the gene-disease association is backed by evidence, and when the lab has appropriate certifications, is transparent about the tests' limitations, and recommends consumers discuss results with genetic counselors or doctors.