By Turna Ray
This article has been updated to clarify comments made by Scientia Advisors' Patrick Terry.
BETHESDA, Md. — As far as XDx is concerned, it has jumped through all the right hoops to show the clinical utility of its AlloMap genomic heart transplant rejection test. But according to a company official, it hasn't seen the level of adoption it expected for the test because doctors don't have a monetary incentive to use it in place of cardiac biopsies.
Despite having published validation studies, garnered cost-effectiveness data, received approval from the US Food and Drug Administration, and gotten payor coverage for the gene-expression based test, the company believes it has hit a wall when it comes to physician adoption — a situation that it attributes primarily to financial considerations.
"Comparative effectiveness and strong clinical validation don't always ensure rapid and broad-scale adoption," Matthew Meyer, VP of corporate business development at XDx, said at a personalized medicine meeting here this week. "Financial incentives can often be very critical."
According to Meyer, since doctors get paid for performing endomyocardial biopsies to monitor whether heart transplant patients will reject their transplants, they have resisted adopting gene-expression testing to assess the risk of transplant rejection, since they do not get reimbursed in the same way for sending a patient's blood sample out for genetic analysis.
"Due to the fact that AlloMap is replacing biopsies, we're actually taking revenue away" from doctors, Meyer said. "It depends on each center and how physicians are compensated, but there is a revenue opportunity for physicians" when conducing biopsies. Endomyocardial biopsy (CPT Code 93505) has physician reimbursement rates ranging of around $200 to $300 per procedure.
AlloMap was launched in 2005 and was approved by the FDA as an in vitro diagnostic multivariate index assay in 2008. The test, in combination with clinical assessments, is meant to help doctors identify patients who have a low probability of rejecting their heart transplants.
In a study published in the New England Journal of Medicine last May, researchers led by Stanford University Medical Center's Michael Pham reported that AlloMap was noninferior to cardiac biopsies in monitoring whether patients who had received heart transplants at least six months prior were experiencing acute cellular rejection.
In the Invasive Monitoring Attenuation through Gene Expression, or IMAGE, study, participants who were profiled for the risk of transplant rejection by gene-expression testing, monitored clinically, and received echocardiographic assessments, had fewer biopsies and fewer adverse events than patients who were followed with just endomyocardial biopsies.
Endomyocardial biopsies are the standard method by which physicians track whether patients are taking to their new hearts. Requiring the resection of a small piece of the heart tissue, this procedure is extremely uncomfortable for the patient, and can lead to serious complications. After receiving a heart transplant, patients can require a dozen or more biopsies a year at a cost of tens of thousands of dollars per patient.
Following the publication of the IMAGE study, the International Society of Heart and Lung Transplantation included AlloMap in its guidelines. "Gene expression profiling (Allomap) can be used to rule out the presence of [acute cardiac rejection] of grade 2R or greater in appropriate low-risk patients, between six months and five years after heart transplant," the society recommended, giving the intervention a "B" for the level of evidence.
According to Meyer, the "B" grade is higher than the "C" grade that cardiac biopsy has received in this setting. There is no intervention that has received an "A" in heart transplant rejection.
Some insurers have taken notice of the positive news. XDx has signed contracts for Medicare coverage for the test, and several private payors, including Aetna, have agreed to pay for the test when patients have a medical need for it under their coverage criteria.
But despite all the nods of approval for AlloMap, doctors still aren't using the test in the numbers that XDx had hoped. "Even some of the investigators in that IMAGE study don't use the test," Meyer charged. "This is somewhat ironic to me because here you have some of the people who you think would be your advocates. The test results were pretty phenomenal, but they're not using the test."
Researchers involved with the IMAGE study could not be reached for comment before this article was published. However, the NEJM paper describing the study contains some clues as to why some doctors might have reservations about using AlloMap.
In the paper, the investigators noted that since study participants had received their heart transplants more than six months prior to enrolling in the trial, there was a bias toward enrolling patients with a low risk of transplant rejection.
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Furthermore, while the test is good at predicting which patients will not experience a rejection, it can't accurately predict which patients are likely to have one. As described in the NEJM paper, many of the episodes of transplant rejection in the gene-profiling arm were identified by observation of "overt symptoms of heart failure or echocardiographic evidence of graft dysfunction," not by gene expression patterns. Out of 34 transplant rejection cases in the gene-expression group ─ who were monitored observationally, by genetic testing, and by echocardiographs ─ only six were detected through profiling with AlloMap alone, according to the paper.
"These observations raise the possibility that clinical observation may detect the majority of serious rejection episodes," the study authors pointed out, adding that most transplant centers in the US still perform biopsies since there hasn't been a comparison of patient outcomes when transplant rejection is monitored by biopsy versus clinical observation.
In the end, the authors of the IMAGE trial concluded that AlloMap may offer a "reasonable alternative to routine biopsies" in patients at low risk of rejection. "However, the study had limited power to allow for a firm conclusion to be reached regarding the use of gene-expression profiling as a substitute for the performance of biopsies," the authors wrote. "A larger trial with a narrower noninferiority margin and a longer follow-up period would be necessary to definitively resolve this issue."
Similarly, while AlloMap received a positive grade in ISHLT's guidelines, the recommendation restricts the test's use in a limited population of heart transplant patients at low risk of rejection.
"The assay has been proven as an independent predictor in elucidating the probability of acute cellular rejection, but has not been designed to be informative about other forms of rejection, such as antibody-mediated rejection, cardiac allograft vasculopathy, or chronic mediated rejection," Patrick Terry, the head of the pricing, reimbursement and market access practice at life sciences consulting firm Scientia Advisors, told PGx Reporter. "As such, there are clear clinical rationales that biopsies remain a very important tool to ascertain the stability of the transplant organ and for managing treatment regimes for individual patients."
In Terry's view, it is the test's demonstrated clinical evidence to date that is limiting its adoption rather than physicians' financial motives. "Simply stated, the AlloMap test is an additive procedure rather than a replacement of existing invasive procedures at this stage of the evidence paradigm for both physicians and payors," Terry said.
Terry stressed in a subsequent statement that his comments were intended to illustrate what a hypothetical physician or payor might argue concerning the test and do not reflect the opinion of Scientia Advisors.
Meyer did not discuss these outstanding issues with the IMAGE study and AlloMap, but noted that XDx is continuing to conduct additional studies involving the test.
In the meantime, the company is attributing the adoption lag for AlloMap squarely on the fact that doctors lack the financial incentive to change the standard of care. "Physicians, of course, want to do what's best for their patient, but at the same time, when there is a revenue issue, there are also going to be challenges in terms of adoption," Meyer said.
Although doctors may not acknowledge "the elephant in the room" trotted out by XDx, the company has nonetheless become proactive about trying to remove this adoption barrier. For example, it is trying to make a case for AlloMap by reaching out to hospital administrators, nurse coordinators, advocacy organizations, and patient groups.
It is in XDx's favor that patients, when given the choice between AlloMap and cardiac biopsies, will easily choose the genetic test. In the IMAGE study, patient satisfaction was higher among those monitored via AlloMap than those receiving biopsies.
The company is using social networking channels such as Facebook and YouTube to raise patient awareness of AlloMap. Referencing the pharmaceutical industry's success in selling drugs through direct-to-consumer advertising, Meyer pointed out that when patients go to their doctors and ask specifically for a drug, "more often than not, they get it."
XDx is also having conversations with doctors, trying to convince them that by forgoing biopsies in favor of AlloMap, they can free up their labs for procedures that are more profitable than biopsies. "In addition, creating a reimbursement code for AlloMap score interpretation is something we're looking at, too, [in order] to give them some incremental revenue for ordering an AlloMap," Meyer added.
The company is making a cost-effectiveness argument to payors, who are eager to contain healthcare spending by backing preventative strategies and lowering adverse events.
"Payors are an ally in the management of lower-cost care. This makes perfect sense for them, because in addition to the absolute cost savings in relation to AlloMap, the long-term outcomes are better because you don't have these side effects that are occasionally going to occur with biopsy patients," Meyer said. "If you have a heart valve damaged during a biopsy, the costs to repair that are going to be huge."
With a price tag of $3,400, AlloMap can be significantly cheaper than having multiple cardiac biopsies, which can range from between $4,000 and $10,000 each time.
"The test is growing substantially, so it's not all gloom and doom," Meyer said. "But the ramp-up we were expecting has slowed."
XDx did not disclose the number of AlloMap tests it has performed to date, or provide any specifics on how sales have fallen short of expectations. As of October 2009, the company reported that 16,000 AlloMap tests had been performed, and more than 6,000 patients had been tested. According to XDx's Facebook page, which likely reflects more recent data, more than 7,000 patients across 100 transplant centers have been tested with AlloMap.
XDx is currently seeking CE marking for AlloMap in order to launch the test in Europe. Meyer said the company is hoping to get that certification by the end of the month. In Europe, the reimbursement landscape "is much brighter," he said, since doctors aren't paid on a per-procedure basis.
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