NEW YORK (GenomeWeb) – The Center for Genomic Interpretation (CGI), a non-profit that aims to improve the quality of genetic testing, released a statement earlier this month urging insurers to cover confirmatory testing for individuals with positive results from 23andMe's direct-to-consumer test for three BRCA1 and BRCA2 mutations.
The US Food and Drug Administration in March granted consumer genomics firm 23andMe authorization to sell a test that reports three mutations — BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT — which occur in around 2 percent of Ashkenazi Jewish women and significantly increase their risk of breast and ovarian cancer.
As part of the authorization, the agency noted that these mutations occur in about 0.1 percent of individuals from other ethnic populations, if at all, and while most people will not get a positive result from 23andMe's test, a negative result also doesn't mean that the person doesn't have one of thousands of other cancer-predisposing mutations in BRCA1, BRCA2, or other genes.
Importantly, the agency stated that consumers and health care professionals should not take medical actions based on 23andMe's test results, and that decisions about treatment and prophylactic surgeries to remove the breasts or ovaries require confirmatory testing.
The regulatory nuances of FDA's authorization of 23andMe's BRCA test have been controversial among genetics experts and healthcare providers, who fear that despite the agency's caveats, there is still a risk that patients who receive a negative result will be falsely reassured that they don't have a genetic risk for cancer and won't think to pursue more comprehensive screenings. For those who get a positive result, however, FDA's authorization has raised questions among genetic counselors and patients as to whether insurers will now pay for the confirmatory testing that agency has stipulated.
Now that consumers can order 23andMe's FDA authorized test online, CGI thinks payors should pay for confirmatory testing, as does the National Society of Genetic Counselors.
"The second that consumer got that positive result [from DTC testing], that very moment they switched from a consumer to a patient," said Julie Eggington, co-founder and CEO of CGI. Particularly in light of the FDA's guidance, "the next, natural step in that patient’s [care pathway] is to get a confirmatory diagnostic test."
CGI has been in discussion with payors it says are evaluating the possibility of covering confirmatory testing in this setting. The NSGC has also reached out to payors to educate them. "This is an issue that NSGC has been actively working on since the FDA BRCA [DTC test] authorization announcement was made," said NSGC President Erica Ramos, who is also on CGI's advisory board.
Specifically, NSGC is recommending that payors automatically authorize coverage for genetic counseling and confirmatory testing of BRCA variants reported by 23andMe. "These are ongoing conversations but so far payors have been very receptive to modifying their coverage to reflect this rapidly evolving testing landscape," Ramos said.
Historically, insurers have covered BRCA testing for patients who they deem to be at high risk for breast and ovarian cancer based on a personal or strong family history of these diseases. Consumers who seek out recreational genetic testing through companies like 23andMe then opt to learn their genetic risk for these diseases may not meet payors' coverage criteria.
"The original BRCA [test coverage] policies were created through deals between Myriad Genetics and payors in which they agreed to only pay for medical testing in certain high-risk populations," Charles Mathews, principal at ClearView Healthcare Partners, said in an email. Myriad's BRACAnalysis test was for nearly two decades the only commercial test for BRCA1/2 genes, and the company remains one of the leading providers of this testing.
"When you throw an FDA-approved [DTC] BRCA test into the mix, it upsets that balance by creating a new risk category (e.g., women testing positive on direct-to-consumer testing) that still need the full sequencing for confirmation," Mathews said.
According to Eggington, however, FDA's authorization of 23andMe's BRCA test has gotten the payor community thinking about how to manage the requests for covering confirmatory testing that will invariably come from 23andMe customers who receive positive results. Some payors have reached out to CGI given its expertise in adjudicating the clinical significance of genetic markers.
Eggington, who previously worked as a clinical variant specialist at Myriad, which maintains the largest database of BRCA variants, and then as 23andMe's director of variant classification science from 2015 to 2016, recently received a call from an insurance industry insider wondering if the 23andMe test was legitimate. "I said, 'Of course this is real,'" she recalled. "These are the three most famous mutations in BRCA."
In an effort to answer payors' questions about 23andMe's BRCA test, CGI requested the data that the consumer genomics company provided to the FDA. Then, one of CGI's volunteer statisticians reworked the data to verify the sensitivity and specificity of the assay. In its statement, calling on insurers to cover confirmatory testing for patients with positive results, CGI noted that studies that 23andMe submitted to the FDA comparing its test against DNA sequencing achieved 100 percent positive and negative agreement and yielded a false positive rate of less than 15 percent and a false negative rate of less than 16 percent, with 95 percent confidence.
Based on this, CGI issued a statement asking payors to cover confirmatory testing for those who receive positive results for the three variants 23andMe assesses and recommending that physicians and patients pick a "high-quality diagnostic test" for the confirmation. CGI did not receive any payment from 23andMe for this assessment, said Eggington, who started CGI in 2016 shortly after 23andMe ended a next-generation sequencing project and let go the scientists working on it, including her.
23andMe also did not ask CGI to issue its call to payors to cover confirmatory testing, Eggington said. However, she noted that 23andMe's willingness to share its data made it possible for CGI to do an independent assessment and make its recommendation.
While Eggington and Ramos said that discussions are ongoing with payors about the prospect of covering confirmatory testing for individuals with positive 23andMe BRCA test reports, GenomeWeb was unable to confirm this directly with insurers, despite reaching out to several of the largest players in this space.
Some reimbursement experts who closely follow payor trends in the molecular diagnostics space noted that while insurers may be interested in understanding the impact of DTC genetic testing on their business, they questioned whether they would ultimately pay for confirmatory assessment following consumer-initiated testing for individuals that don't meet coverage criteria for medical history or family history. Importantly, private payors have been looking for ways to rein in their spending on genetic testing. Several large commercial insurers have enlisted genetics-benefit management firms and instituted prior authorization programs to more tightly control spending and utilization of tests that don't meet coverage criteria.
Even if some payors don't institute specific policies in this regard, given the nature of the three BRCA mutations 23andMe tests for, a genetic counselor could convince an insurer to pay for confirmatory testing for those who get positive results, said Scott Weissman, founder of Chicago Genetic Consultants.
"These three mutations are founder to the Ashkenazi Jewish community and some Eastern European populations, which means it is highly unlikely anyone would develop one of these mutations de novo," Weissman observed. "I think I could use an ICD-10 code, [describing diseases, symptoms and special circumstances,] indicating that there is a family history of a BRCA1 or BRCA2 mutation to get the testing covered, without actually knowing that one of the parents is positive."
Despite a difficult reimbursement climate for genetic tests, some payors are indeed mulling how to address greater consumer access to BRCA testing, said Gillian Hooker, VP of clinical development at Concert Genetics, a health technology company that works with labs, hospitals, clinicians, and insurers, to make the genetic testing market more efficient and transparent. "Payors are being thoughtful and recognizing that ways of ascertaining BRCA mutation carriers in the population are changing and can be done a number of ways and [DTC testing] is one of them," she said.
The debate over consumer access to 23andMe's limited BRCA test also comes at a time when many prominent geneticists and testing firms are advocating for population screening for pathogenic mutations in BRCA1/2 for all women starting age 30. Companies like Color, which charges around $250 for its hereditary cancer panel, for example, believes that such a population screening strategy is becoming feasible from a cost standpoint.
Earlier this year, British researchers published a study in the Journal of the National Cancer Institute, modeling the cost-effectiveness of screening 27 million women in the UK and 100 million women in the US over age 30 for a panel of hereditary risk genes, including BRCA1/2, and reported that it would prevent 80,000 and 300,000 breast and ovarian cancers in these countries, respectively. Using a $250 price point, the researchers of this study concluded that population-based hereditary cancer panel testing "is the most cost-effective strategy" compared to the current policy based on clinical and family history.
Other cost-effectiveness assessments, using different metrics, have arrived at somewhat different conclusions. A 2015 study published in JAMA Oncology, for example, found that a universal screening program from BRCA1/2 genes would not be cost effective ― assuming that clinical diagnostics (that are more widely adopted than Color’s test) cost several thousand dollars. This analysis, however, found that BRCA1/2 screening was much more impactful for Jewish women (with an average 16-fold higher life expectancy gain), since mutations are more prevalent in this community. And, importantly, the authors wrote that universal screening of BRCA1/2 could become cost effective if more companies like Color price tests at around $250.
"There's a lot of discussion happening right now … about population-wide screening and at what price do things like that start to make sense," Hooker said. And as the cost of sequencing continues to get more affordable, "that changes the way these things look to payors."
According to Eggington, however, in conversations with the payors who have reached out to CGI about 23andMe's BRCA test, she hasn't had to educate them on the cost-benefit of covering confirmatory testing, but rather they've been more concerned about whether this was a "legitimate assay," and whether these three variants are the right variants to test for.
Insurers have similar questions about the clinical validity of other genetic tests on the market, too, given the rapid expansion of the market. According to the latest estimate from Concert, there are 74,000 commercially available genetic tests in the US and 14 new tests enter the market daily.
Recognizing this growing challenge for insurers, CGI will roll out an effort in coming weeks, called ElevateGenetics to help labs garner the test quality data that insurers want to see when deciding coverage or granting a lab in-network status. Labs can request an independent review from CGI of the methodologies that impact test quality. If the labs pass muster under CGI's review, which will be based on metrics issued by professional society guidelines and in the published literature, they will receive a quality award that they can then use to negotiate coverage with payors.
Genetic lab benefit managers, and other groups such as CureOne and Blue Cross Blue Shield Association's web-based evidence review platform Evidence Street are also working to decipher, and to bring more predictability and transparency around the evidence payors want to see on genetic tests.
"Genetic diagnostic testing has become an incredibly complex area, and there are many different angles from which to view quality," said Eggington, who sees ElevateGenetics as a complementary but distinct effort from these others. She did not specify how, other than to say that CGI's program will evaluate lab-based methodologies with an eye toward ensuring that patients get "accurate and relevant genetic test results, no matter what the hereditary disease." CGI plans to make its evaluation metrics publicly available once the effort gets underway.