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Exact Sciences Discusses Benefits of Taking Cologuard through FDA/CMS Parallel Review Pilot

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Originally published April 2.

In taking its colorectal cancer DNA screening test through the FDA and Centers for Medicare & Medicaid Services' parallel review pilot program, Exact Sciences has been able to shave off several years from the time it would have taken to garner regulatory approval and secure reimbursement for the diagnostic, according to CEO Kevin Conroy.

"This program was absolutely critical to our ultimate success," said Conroy during a March 20 webinar hosted by Avalere Health and The RPM Report on the early lessons learned from FDA/CMS' parallel review pilot. "It takes two years potentially off the time period from FDA approval to Medicare coverage. It saves us the cost of running a separate study for Medicare and for the Medicare population."

CMS and FDA's Center for Devices and Radiological Health launched the parallel review pilot in October 2011 in an effort to create a framework for conducting concurrent reviews of innovative devices that require premarket approval from the FDA and qualify for a national coverage determination – a six to nine month process by which CMS determines if it will pay for a product or service that it deems "reasonable and necessary" for the Medicare population. Through this pilot, which facilitates an overlapping review of clinical trial data by CMS and FDA, the agencies are hoping to reduce the time it takes a company to commercially launch a medical device and garner reimbursement coverage.

Exact Sciences voluntarily submitted its non-invasive Cologuard test to undergo parallel review in December 2011. The DNA test analyzes in patients' stool samples genetic alterations associated with colorectal cancer and pre-cancerous conditions. The company is evaluating Cologuard in the DeeP-C trial in which it has enrolled 10,000 men and women between ages 50 and 84 at average risk of developing colorectal cancer. The study aims to assess the ability of Cologuard to detect colorectal cancer and precancerous polyps compared to colonoscopy. Exact Sciences is planning to report results from the study later this year.

Though Cologuard is still undergoing parallel review, the pilot program already has made "a big difference" to the company, according to Conroy. "I would go so far as to say that I don't know how from an investment standpoint we could have done this without parallel FDA approval and Medicare coverage and payment," he said.

Conroy estimated that Exact Sciences' direct costs for the DeeP-C clinical trial total approximately $30 million. "So, running a second clinical trial is just really not an option," he said. "Early, innovative companies are going to look at this and say, 'Yeah, maybe I lose the benefit of being able to go and find a [Medicare Administrative Contractor] that will give me a favorable payment level, but what I get is a national decision and potentially get that faster and cheaper."

Nancy Stade, deputy director for policy at CDRH, noted during the webinar that most companies can realistically hope to peel off several months of review time, since even under the parallel review process FDA will review a PMA within a 180-day review clock and CMS will likely launch an NCD only after a joint-agency panel meeting with the test developer. Still, Exact Sciences' experience highlights the "real power of parallel review," said Stade, who advised sponsors taking tests through parallel review to consider from the outset how "one study [can] satisfy two different standards for review."

As previously reported by PGx Reporter sister publication GenomeWeb Daily News, Exact Sciences submitted a pre-PMA application with the FDA last year for Cologuard and subsequently held joint meetings with FDA and CMS. After factoring in the advice of both of the agencies, Exact Sciences decided on a modular submission path for Cologuard., Exact Sciences submitted the first module, the manufacturing module, with the FDA in December 2012; the firm submitted the second analytical module in February; and, after garnering top-line results from the pivotal DeeP-C trial in March, the firm has said it would file the final clinical module.

"One of the most significant inputs [from CMS] was making sure that the patient population for the clinical trial was powered sufficiently with Medicare patients," Conroy said. He indicated that CMS also provided other suggestions that the company incorporated into the trial design, but he did not elaborate. Exact Sciences did not respond to additional questions ahead of press time about how the DeeP-C trial design was changed based on the advice from the two agencies.

Given that a large portion of the colorectal cancer population in the US qualifies for Medicare, Cologuard was a particularly appropriate test for parallel review by CMS and FDA. Conroy estimated that Medicare spending accounts for approximately 75 percent of the $14 billion the US spends annually on treating colon cancer. Furthermore, he noted that Medicare patients are about just under half of the overall intended use population for Cologuard.

"We think Medicare coverage … will trigger private payors to pay for our test," Conroy added. Overall, at 30 percent market penetration, Exact Sciences is hoping for a $1.2 billion US commercial opportunity for Cologuard.

When CMS and the FDA first proposed their intention to launch the parallel review pilot, industry players expressed concerns about whether simultaneous review by two agencies may be more risky for sponsors, particularly if one body arrives at a negative decision on the product. Tamara Syrek Jensen, deputy director for CMS's coverage and analysis group, explained that the joint FDA/CMS panel meeting during the parallel review process can help CMS decide when to open an NCD on a test and garner key data that wouldn't otherwise be available for a new, investigational product.

"CMS sees the panel meeting as something that really helps us support a positive NCD, and we will probably rely on what happens in that panel more so than what we may have done in the past," Jensen said. "Because it is a new, innovative device, there won't be any more data out there except for [what's discussed] in that panel. So, that will be a very important part for us."

The differences between FDA and CMS's review protocols present some unique issues for sponsors to consider before pursuing parallel review. For example, a product being reviewed by the FDA remains confidential unless the sponsor makes it public. However, once CMS initiates an NCD on a test, it becomes an open process and can make public certain information about the product under review.

Jensen pointed out that the parallel review is a voluntary process and the test sponsor can withdraw a request for an NCD from CMS. "Once [sponsors] do ask us [for an NCD], they can withdraw their request … up to the date we post a tracking sheet," Jensen said. "Once we make it public that we have opened up the NCD, there really isn't any turning back from there."

While there may be risks in taking a test through parallel review, there are also significant efficiencies sponsors can achieve through the process. As an example, Jensen highlighted that optimally CMS could open an NCD tracking sheet the day FDA approves a test with a "proposed decision," which shaves six months off the statutory time frame for a regulatory determination from CMS. The sponsor can then expect a final NCD decision within 90 days. "Those are some very good conversations that you likely don't get unless you're part of parallel review," Jensen said.

Shortly after CMS and FDA announced the launch of the parallel review pilot, Louis Jacques, director of CMS's coverage and analysis group, said at a conference that most sponsors may be reluctant to go through a process where two agencies with very distinct mandates, seeking different evidentiary requirements, will be in the same room (PGx Reporter 12/7/2011).

However, given Exact Sciences' experience, Conroy advocated in support of the parallel review process. "When FDA and CMS come together and put together an innovative program, it's incumbent upon us to praise those efforts if we want to encourage that type of innovation," Conroy said during the webinar. "We can't as an industry complain when things don't go the way we would like to see them to go."

In Conroy's view, simultaneous input from the FDA and CMS lowers the risk that a sponsor will experience late-stage delays because the agencies want more information on the product. During the webinar, he advised companies to evaluate early on whether they need to go through an NCD for a particular test or if it would be more beneficial to garner coverage through local Medicare contractors.

Since Cologuard is a screening test, it made strategic sense for Exact Sciences to pursue an NCD, which then made the test appropriate for parallel review. "So, if you look at this innovative new program, it is really a no brainer for us," Conroy said.

For the time being, only medical devices under the regulatory purview of CDRH are eligible for parallel review, but not drug/test combination products that involve multiple FDA divisions or tests that already have an NCD issued on them. "We did say during the initial pilot program that we would consider down the road whether this is something that should be expanded to other [FDA] centers," Stade said, adding that the agencies' experience with the pilot over the last two years certainly doesn't suggest that the program should be terminated.

"I think as the program becomes better understood and there are some successes that come out of the program, more and more companies are going to see that there is a potential to significantly streamline the [regulatory and reimbursement] process, and potentially reduce costs and the need for a second study," Conroy said.

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