Did the federal appeals court make the right decision in the Myriad case (which says that isolated gene sequences are not products of nature and are therefore patentable)?
69% No. Genes shouldn't be patented.
11% Eh, we'll see what happens next.
8% Yes. Any other decision would have been disastrous for biotech.
6% Yes. Myriad worked hard and deserves to keep those patents.
3% No. The court should have also upheld Myriad's method patents.
Read more!
By Turna Ray
"More than 200 healthcare professionals have signed a letter to Myriad Genetics requesting that the company incorporate in its Comprehensive BRACAnalysis test the capability to gauge large rearrangements in the BRCA 1 and BRCA 2 genes. The additional analysis may identify patients — particularly those of Latin American and Caribbean ancestry — who have variants that increase their risk for hereditary breast and ovarian cancer that would otherwise be missed by the standard BRACAnalysis test.
Myriad's $3,340 Comprehensive BRACAnalysis test includes complete sequencing of the BRCA 1 and BRCA 2 genes and detects five common large rearrangements in the BRCA 1 gene. Not included in the Comprehensive BRACAnalysis test is the so-called BRACAnalysis Large Rearrangement Test, or BART, launched five years ago, which gauges additional large rearrangements in the BRCA 1 and BRCA 2 genes.
Myriad offers BART as part of the Comprehensive BRACAnalysis test at no additional cost when patients "have an especially strong personal and family history of breast and ovarian cancer," the company states in a brochure for the test. For patients who don't meet Myriad's medical and family history criteria for BART, the firm charges an additional $700 to perform testing that would gauge these additional large rearrangements. In these instances, the additional analysis by BART is usually not covered by insurers because it is considered investigational.
After Myriad recently released data showing that a certain portion of deleterious mutations are missed by standard BRCA testing, a group of genetics professionals, surgeons, oncologists, and nurses led by the Yale Cancer Center wrote an open letter to the company urging it to incorporate this large rearrangement analysis into its Comprehensive test at no additional cost for all patients receiving Comprehensive BRACAnalysis, arguing that anyone eligible for full sequencing of the BRCA 1/2 genes should also receive BART.
"If Myriad included BART testing as part of their Comprehensive testing at the same cost, it means that every single patient would get this important test," Ellen Matloff, director of cancer genetic counseling at the Yale Cancer Center, told PGx Reporter. "The vast majority of patients do not meet Myriad's stringent criteria [for BART]; but every single patient who qualifies for Comprehensive BRACA testing also needs BART testing, and most do not get it."
Noting that Myriad’s revenue in the most recent quarter was $102.4 million, a 13 percent increase year over year, 209 healthcare professionals from 34 US states, Washington, DC, and Canada implored Myriad in the letter "to invest some of [its] earnings into incorporating BART analysis into standard BRACAnalysis" testing. The letter was addressed to Richard Wenstrup, Myriad Genetic Laboratories' chief medical officer.
Myriad said it has gathered the necessary outcomes data to begin the process of incorporating BART into professional society guidelines, which is necessary for insurers to start reimbursing for the test. According to a company spokesperson, in an effort to generate this data, Myriad has provided more than $20 million worth of free BART testing to many patients with a heightened risk of carrying a BRCA 1 or BRCA 2 genetic mutation.
The spokesperson noted, however, that Myriad hasn't yet determined if it will raise the price of its Comprehensive BRACAnalysis test if professional guidelines recommend BART for a subpopulation of patients and the company decides to offer this analysis as part of standard testing.
Prevalence Data
According to an internal analysis of 25,000 patients who met Myriad's eligibility criteria for complementary BART testing, the Comprehensive platform picks up 92.5 percent of all mutations in BRCA 1 and BRCA 2, while BART detects the remaining 7.5 percent of BRCA mutations associated with heightened risk of breast and ovarian cancer. The company estimates that less than 1 percent of patients who had deleterious mutations picked up by BART had negative test results by the Comprehensive BRACAnalysis test.
"Therefore, the chance of finding something with BART is a small fraction of the chance of finding something with the standard testing," Myriad explained in a recent clinical advisory.
However, Matloff and other healthcare professionals feel that the percentage of BRCA 1/2 large rearrangement mutations among high-risk patients are significant enough to justify providing BART as part of the Comprehensive platform. "Actually, if you look at their data," the number of patients with large rearrangements is "not a small percentage of patients," Matloff said. Myriad's analysis indicates that 7.5 percent of all patients positive for any mutation harbored rearrangements that could only be detected by BART, while another 2.4 percent had rearrangements detectable via the Comprehensive test.
Furthermore, healthcare providers in their letter to Myriad cite "data from other groups" — namely, a paper in press authored by a team of genetic counselors at the Center for Cancer Risk Assessment at Massachusetts General Hospital — which "suggests Myriad's 'high risk' criteria do not accurately predict which patients are likely to carry a BRCA rearrangement mutation."
Myriad said in its clinical advisory that it does not have much data on patients for whom BART was ordered separately from Comprehensive BRACAnalysis, but has found that "of all of the mutations that are found in lower risk patients, it does appear that a smaller percentage are detected with either the [rearrangement panel in the Comprehensive test] or BART."
The company attributes this to the observation that approximately 87 percent of large rearrangements are in BRCA 1. "Since the cancer risks associated with BRCA 1 mutations are higher than those associated with BRCA 2, there are more BRCA 1 mutations in patients with high risk clinical histories overall, and this is reflected in the higher proportion of mutations that are large rearrangements in BRCA 1," the company states in its note to physicians.
Myriad also found that the prevalence of large gene rearrangements is particularly high among patients of Latin American or Caribbean ancestry. In this group, Comprehensive BRACAnalysis testing identified 80 percent of all BRCA 1/2 mutations, while 20 percent of all mutations were identified using BART. "Since a higher percentage of mutations in this group are of the type that are detected only with BART, these patients are more likely to be [BRCA mutation] positive if BART is ordered," Myriad said.
The company notes that patients of Middle Eastern descent also appear to have a high percentage of mutations (19.5 percent) only detectable by BART. However, "the [patient] numbers in this group are so small that we can’t be sure if this is reliable information." The current data also don't support large rearrangement testing in patients of African descent, who had 8.1 percent of mutations only detectable by BART.
The Myriad spokesperson told PGx Reporter that the company has submitted its analysis on the prevalence of large rearrangement mutations picked up by BART to the National Comprehensive Cancer Network at NCCN's request.
Insurance Concerns
Now that there is data showing that large rearrangements in BRCA genes occur more often in certain minority populations in the US, Matloff said it's time for Myriad to incorporate BART into its standard testing procedures. "Since they're calling this a 'Comprehensive BRACAnalysis,' it's really false advertising," she said. "If they're going to claim to do comprehensive testing — that's [Myriad's] term — then that should include everything they offer in terms of looking for mutations in BRCA 1 and BRCA 2."
In their letter to Myriad, the healthcare providers note that charging extra for BART will make it inaccessible to the very population that the test stands to help most. The "Hispanic population is one of the most rapidly growing ethnic groups in the US and is disproportionately uninsured, underinsured, and at or below poverty levels," the signees pointed out. "Therefore, this population is less likely to be able to access and afford the necessary, expensive, additional BART testing."
Approximately 95 percent of patients at the Yale Cancer Center who are tested with Comprehensive BRACAnalysis do not get BART, "mostly because their insurance won't cover it," Matloff said.
For example, Aetna's coverage guidelines for BRCA testing state that if a woman is negative for founder mutations, then she must meet other criteria that place her at high risk for breast and ovarian cancer in order to qualify for reimbursement for Myriad's Comprehensive BRACAnalysis. However, Aetna notes that since there is insufficient data on the frequency of large BRCA rearrangements in US populations, retesting previously tested high-risk members with diagnostics such as BART would be "experimental and investigational."
Likewise, Cigna's guidelines state that the insurer will only reimburse for BART testing when the patient meets Myriad's high-risk criteria for complementary testing.
During a time when payors are demanding a high level of evidence showing clinical utility and cost effectiveness in order to pay for genetic tests, reimbursement for BART may not be as simple as convincing Myriad to include it in the Comprehensive BRACAnalysis panel — a move the company is unlikely to make without raising the cost of the test.
Furthermore, getting BART included in insurers' reimbursement policies may be particularly challenging since insurers are already wary of over-testing with BRACAnalysis. Several payors have instated prior-authorization schemes to ensure that the $3,000 BRCA test isn't being administered to those who don't meet the proper medical and family history criteria.
Some insurers have taken it upon themselves to gather the necessary data to inform their coverage policies around BRCA testing. Aetna is surveying de-identified data on 13,000 of its members who have received BRCA testing in order to gain greater understanding of how physicians are making testing decisions and figure out whether access to such tests is limited for women from lower socioeconomic and minority groups (PGx Reporter 09/22/2010).
Although Myriad hasn't publicly addressed the pricing repercussions of expanding its Comprehensive BRACAnalysis panel, the company is willing to discuss the clinical value of BART. "Currently, most payors do not provide reimbursement for BART as it is not included as a recommended test under guidelines like those from NCCN," the Myriad spokesperson said.
"We encourage medical professionals to provide feedback to NCCN and other relevant professional societies based on their assessment of [our] data. If guidelines are updated to incorporate a recommendation that BART be performed for every patient, we will diligently address the issue with payors."
A Question of Access
The request from healthcare providers to include BART as part of standard BRCA testing comes as Myriad is fighting a legal battle with researchers, doctors, and patients looking to invalidate its patents on isolated BRCA genes. In Association for Molecular Pathology et al. v. US Patent and Trademark Office et al., the Court of Appeals for the Federal Circuit last week upheld Myriad's patents on isolated genes but invalidated five method claims underlying its BRACAnalysis test (see related story, in this issue).
Although Yale Cancer Center has the capability to gauge mutations that aren't picked up by standard BRCA testing, the academic center cannot provide such services due to Myriad's IP position.
Before Myriad began offering BART, Yale Cancer Center had data showing that the company's Comprehensive test was missing a "significant percentage" of mutations in patients, according to Matloff, who is one of the plaintiffs in AMP v. USPTO.
"We asked for permission to offer the [large rearrangement] test to our patients until they had [their test] up and running and [Myriad] said, 'No,'" she recalled. "We didn't even get as far as purchasing a license."
Except for Harry Ostrer, a former New York University researcher, the appeals court deemed that all other researchers, patients, and healthcare providers, including Matloff, lacked sufficient grounds to challenge Myriad's patents in AMP v. USPTO."
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