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Agendia's MammaPrint Is First IVDMIA to Win FDA OK; Will New Imprimatur Be Advantageous?

The US Food and Drug Administration this week cleared Agendia’s MammaPrint molecular diagnostic, making it the first in vitro diagnostic multivariate index assay to win a green light since the agency issued a draft guidance describing such products last year.
MammaPrint was previously available as a homebrew test from April 2005 until August 2005. The test has been available in Europe since 2004.
Agendia, based in the Netherlands, expects that FDA approval will bolster product sales in the US and Europe. “We are exploring ways to make this product available in the US,” Agendia CEO Bernhard Sixt said in a statement. “We are also confident that the present FDA clearance of MammaPrint will help increase acceptance of this type of technology in clinical decision making for cancer in Europe.”
However, according to competitor Genomic Health, whose Oncotype Dx test was an early model for the new kind of diagnostic, the clearance does not necessarily guarantee the test will be adopted by the market.
“Ultimately we believe the physician adoption and payor reimbursement are the two really to cross over. And there is even some history in this space with HIV genotyping where tests that were approved by FDA didn’t necessarily break into the market over tests that were already available as [CMS’ Clinical Laboratory Improvement Amendments]-derived tests in labs,” Genomic Health CEO Randy Scott said during the company’s fourth-quarter earnings call this week.
“Sometimes there is a misperception that just because you have FDA approval means you will get reimbursement,” he added.
Overall, however, Scott noted that the approval of MammaPrint, which helps predict early-stage breast cancer recurrence, is good for the industry at a time when most players are looking to the FDA for more clarity in this area.
Fork in the Road
Currently, test manufacturers have two ways to bring their tests to market: through CLIA certification or through the FDA approval process. However, last fall the FDA issued a draft guidance in which it defined IVDMIAs and said that the agency, and not CLIA, should regulate them [see PGx Reporter 9-13-2006].
The document, called Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Assays, defines IVDMIAs as devices that use mathematical formulas to interpret gene and protein data to guide medical decision-making.
Genomic Health, whose CLIA-certified Oncotype Dx test may fall into this category, has repeatedly said that the guidance will not negatively impact the rate at which its test is adopted. Scott said that the company is continuing to discuss the regulatory details with FDA regarding Oncotype Dx, which tests for breast cancer recurrence and patients’ response to certain types of chemotherapy.
However, some diagnostic firms believe that by issuing the draft the FDA is trying to control how products similar to Oncotype Dx are developed and sold by labeling them as IVDMIAs and requiring them to obtain FDA clearance.
During an FDA conference call to announce the MammaPrint clearance, Steven Gutman, director of the Office of In Vitro Diagnostic Device Evaluation, explained that the agency has been clear in expressing its discomfort over the lack of federal oversight of IVDMIAs.
The FDA announced the clearance on Feb. 6, two days before the agency is scheduled to host a public meeting to discuss the regulatory issues surrounding IVDMIAs. Gutman insisted during the call that the agency is not trying to send any kind of a message by approving MammaPrint ahead of the public meeting.
“I wish I could tell you we were but we just aren’t that well organized,” Gutman quipped. “We took this as a serious submission … [but] we are just not that good to coordinate the way that people will probably read into it.”
Will FDA Clearance Help Adoption?
Genomic Health, which has had tremendous success getting payors to reimburse for Oncotype Dx, suggested that FDA clearance doesn’t necessarily guarantee success in the marketplace.
“What we have seen in the reimbursement world is really specific on a payor-by-payor basis,” Scott said. “[Payors] very much scrutinize the clinical data and evidence. I think every payor is different and they’ll have their own independent review boards, they’ll also set different criteria, but we’ve heard from day one that they want to see multiple peer-review publications, they want to know that your data and your test is changing physician practice.
“We’ve been working diligently to prove that to payors,” said Scott. “So I don’t think you can make sweeping conclusions about the field. You have to battle this out on a payor-by-payor basis and provide them with the evidence that they need to make key decisions.”
The pharmacy benefits manager Medco has said that payors will be looking for credible studies as well as a nod from the FDA to justify reimbursing for genetic tests [see PGx Reporter 12-06-06].
MammaPrint, cleared through an expedited de novo 510(k) process, is the first FDA-approved test that profiles gene activity patterns in multiple genes rather than looking at a single gene or mutational signals from multiple genes. It is designed to help predict the potential for breast cancer recurrence.
FDA contacted Agendia in April 2005 suggesting that MammaPrint might consider pursuing FDA clearance for MammaPrint rather than the CLIA path. An Agendia spokesperson told Pharmacogenomics Reporter this week that the company “proactively sought FDA clearance upon learning from them that they would be seeking oversight in the diagnostics arena.”
The agency similarly contacted Genomic Health in a Jan. 23, 2006, letter, requesting the company meet with the FDA “to discuss the nature and appropriate regulatory status of your technology, and the least burdensome ways that Genomic Health may fulfill any pre-market review requirements that may apply” [see PGx Reporter 11-08-06].
During the FDA call to announce MammaPrint’s approval, Gutman touted that the agency cleared the test after 12 “intense review days,” a fairly quick turn-around.
The entire approval process took 130 days from the time Agendia submitted its application on Sept. 6, 2006. According to Gutman, there were periods when the FDA put the submission on hold and requested additional information.
Data in Agendia’s FDA submission included a final validation study enrolling 302 patients at five European sites. Gutman noted that the positive predictive value of tumor recurrence in high-risk patients at five and 10 years is 23 percent and 29 percent, respectively. The negative predictive value in patients at low risk for recurrence is 95 percent and 90 percent, at five and 10 years, respectively.
As an IVDMIA, the MammaPrint test uses an algorithm to produce a score that gauges whether a patient is at low risk or high risk for distant metastases. The high-risk population is about twice as likely as the low-risk population to experience recurrence, Gutman said.
Once MammaPrint is prescribed, samples will be sent to Agendia’s facility in the Netherlands, where it will be analyzed. “With FedEx it’s quite feasible to send samples to Holland and it’s a very excellent turnaround,” Gutman assured. “They won’t be selling kits in the US. The plan is to use a single test site for operation.”
In a release, Agendia noted that FDA’s approval of its test “underscores the growing importance of personalized medicine.”
Genomic Health Welcomes Challenge
Genomic Health’s Scott, who said he views MammaPrint’s clearance as a positive for the industry, said that the “FDA, like many in the industry, believes that personalized medicine is the future.”
However, Scott also emphasized that Genomic Health expects competition for its Oncotype Dx test and welcomes the challenge from Agendia’s MammaPrint.
Oncotype Dx generated $8.1 million in revenue during the fourth quarter of 2006 compared to $1.9 million in the fourth quarter of 2005. Receipts for the full year increased to $27 million from $4.8 million in 2005. (See briefs for further details on financial performance.)  

“Sometimes there is a misperception that just because you have FDA approval means you will get reimbursement.”

Revenues were largely driven by increased adoption and reimbursement. “We entered 2006 with just over 10 million lives covered; now, in early 2007, nearly 100 million lives are covered for Oncotype DX,” Scott said in a statement announcing Genomic Health’s fourth quarter and full-year 2006 financial results.
Despite the test’s success in the marketplace, Genomic Health said it has been factoring the introduction of competing tests into its models. “We believe we have a great package with Oncotype Dx, with four major clinical validation studies, over 2,600 patients, both recurrence and chemotherapy benefit, as well as the tamoxifen benefit. So we think we have a solid product.
Oncotype Dx is indicated for use in women with Stage I or Stage II estrogen receptor-positive, node-negative breast cancer who were taking tamoxifen. The 21-gene assay analyzes a tumor to determine a recurrence score, a number between zero and 100 that corresponds to a person’s likelihood of breast cancer recurrence within 10 years of the initial diagnosis.
Oncotype Dx can also determine the likelihood that a patient will benefit from certain types of chemotherapy.
MammaPrint is also indicated for early-stage, node-negative breast cancer. But unlike Oncotype Dx, MammaPrint cannot claim testing for chemotherapy benefit, but gauges patients’ risk of breast cancer recurrence at 5 and 10 years.
For the most part, during the earnings call, Genomic Health officials tried to avoid comparing Oncotype Dx and MammaPrint. However, the company did suggest that Oncotype Dx’s use of paraffin-embedded tissue over fresh frozen tissue samples, as is required for MammaPrint, might help adoption.
According to Genomic Health, the company designed Oncotype Dx to use paraffin-embedded tissue “to facilitate … what is routine practice of pathology and surgery.”
“Certainly in community hospitals what is routine is to prepare tumor blocks in paraffin. So we adapted our technology to meet their needs,” said Genomic Health Chief Medical Officer Steve Shak during the call.
“I am sure [Agendia] will explain how to [work with fresh frozen tissue samples] in clinical practice as they introduce the test. But, as you know, most hospitals are very busy in their practices, they have a lot of work that they do already to deliver care to their patients,” Shak added.
Genomic Health is conducting studies this year to expand Oncotype Dx’s indication into node-positive breast cancer. If the studies are successful, the company expects to launch a product in 2008.
The company is also conducting studies to evaluate the clinical utility of individual Oncotype Dx genes. Upon successful completion of the test “the company plans to include single gene results for estrogen receptor and progesterone receptor gene expression by the end of 2007,” Genomic Health said.
IVDMIA Story to Continue
FDA’s Gutman emphasized during the call that while MammaPrint is “biologically very meaningful” it is “not a perfect test.”
“Very few of them are and we haven’t found a perfect test yet, but we’ve only been in business for about 30 years,” Gutman noted. “It’s a first step toward having improved personalized molecular medicine as a tool for making better treatment decisions for patients.”
Though he declined to specifically discuss FDA’s regulatory intentions regarding IVDMIAs ahead of the public meeting, Gutman noted that MammaPrint is an example of a genetic test that displays “the kind of novelty and complexity that our entire risk-based structure would flag as something that does have an impact on public health.”
The MammaPrint clearance was precedent-setting from a regulatory standpoint, however. Historically, FDA has elected to review only those tests developed at multiple sites. Tests developed at a single lab have been typically overseen by CLIA regulations.
“FDA has clearly made a public signal with the IVDMIA guidance … [and] suggested that we’re not comfortable with that enforcement decision about this subset of tests, and we’ve made a suggestion that enforcement discretion for that subset of tests may not be such a good idea,” Gutman said.
FDA approval and CLIA certification are two distinct pathways, with the main difference being that CLIA regulations evaluate labs after a diagnostic has entered the market, whereas FDA reviews a test for approval before market entry. Additionally, while CLIA assesses the quality control of the laboratory for the assay, it does not require clinical validation of the test. In contrast, FDA approval has analytical and clinical validation requirements, and has reporting systems in place to ensure patient safety issues can be addressed.
Although the FDA has made strong signals of its intention to require FDA approval for IVDMIAs, Gutman maintained that the entire regulatory issue with IVDMIAs is not yet settled.
“What I can’t predict for you is the end of the story,” he said, noting that stakeholders will discuss the pros and cons of FDA’s regulatory authority over IVDMIAs on Feb. 8.

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