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Exact Sciences Readies Cologuard for Market; Lauds Parallel FDA, CMS Review Process

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NEW YORK (GenomeWeb) – After having gained regulatory approval and reimbursement backing under Medicare on the same day last week for its stool DNA-based colorectal cancer screening test, Exact Sciences is hoping to begin marketing its first commercial diagnostic with an 80-person sales team.

Last week, the US Food and Drug Administration approved Exact's Cologuard, a non-invasive test that gauges DNA and blood biomarkers and determines whether a patient has pre-cancerous polyps or cancer. Simultaneously, the Centers for Medicare & Medicaid Services issued a memorandum proposing to cover the test as a screening option once every three years for asymptomatic Medicare beneficiaries between ages 50 and 85 years who are at average risk for developing colorectal cancer. CMS is seeking comments on this proposal for 30 days and will issue a final decision after that.

Exact went through the so-called parallel review pilot project hoping to receive simultaneous decisions from the FDA and CMS regarding premarket approval and Medicare coverage, respectively. The company conducted a large, pivotal study involving 10,000 study participants, called DeeP-C, in order to convince the FDA that its screening test was safe and accurate and to sway CMS that the test was "suitable" for prevention or early detection of colorectal cancer in asymptomatic Medicare beneficiaries. In that study, Cologuard detected 92 percent of cancers and 69 percent of advanced precancerous polyps in average-risk patients.

According to Exact CEO Kevin Conroy, the company's 80-person sales force will initially target primary care physicians and large healthcare systems employing half of the primary care doctors in the US. By year end, Exact is hoping to grow its marketing team to around 100 people. The company has previously projected that if it is able to gain a 30 percent share of the colorectal cancer screening market, there stands to be a $1.2 billion US commercial opportunity for Cologuard.

An additional 10 sales reps are currently calling on large group practices and healthcare systems. "The value proposition to those large practices is that they can get more people screened in a cost-effective manner by utilizing Cologuard," Conroy told PGx Reporter. The company will further expand the sales team in 2015 as the need arises.

Additionally, the company will put resources behind educating private payors and patients about the test. "We have a significant digital campaign that we've kicked off for patients and physicians," Conroy said. "And with payors, we have a very concentrated effort to engage with the chief medical officers of the largest payors around the country."

Beyond the US market, Exact is planning to launch Cologuard in certain European countries by the first quarter in 2015, and introduce the test in Asian markets, such as China, Japan, and Korea, over a longer time frame.

Highlighting benefits of Cologuard

Conroy said he believes the results of the DeeP-C trial will help convince doctors to adopt the test for their patients. Exact is hoping that primary care docs will be impressed by the test's performance specifications published in the New England Journal of Medicine in April, showing Cologuard to have 92 percent sensitivity in detecting cancer Stages I-IV; 94 percent sensitivity for detecting early stage disease; and 87 percent specificity compared to 95 percent for fecal immunochemical testing (FIT).

During a review of the DeeP-C data in March by an FDA expert advisory panel, some experts pointed out that Cologuard had more false positives than FIT. However, most panelists were willing to accept this in light of Cologuard's improved accuracy in detecting true positives over FIT. The panel ultimately unanimously recommended FDA approve Cologuard. Conroy noted that additional studies will further investigate and compare Cologuard's false positive rate compared to FIT.

Sales reps will also be highlighting to doctors the non-invasive nature of stool-based testing compared to colonoscopy. Although colorectal cancer is preventable if caught early, often the invasive nature of colonoscopy – a standard procedure that allows physicians to look for signs of cancer by inserting a tube with a camera through the rectum and into the colon – deters patients from getting regularly screened. Conroy noted that studies have shown that 38 percent of patients whose doctors recommended only colonoscopy actually followed the advice and got screened within a year.

According to the National Cancer Institute, there were an estimated 143,000 new cases of colorectal cancer last year, and more than 50,000 patients died from the disease. Exact further cited data that around 23 million Americans between 50 and 75 aren't getting screened as recommended by guidelines. However, early screening could help detect colorectal cancer earlier and lead to a greater than 90 percent five-year survival rate. Moreover, according to US Centers for Disease Control estimates, if everyone age 50 or older got screened for colorectal cancer according to recommendations, 60 percent of colorectal cancer deaths may be avoided.

While Exact is hoping that doctors will want to improve screening compliance and test accuracy by adding Cologuard to their armamentarium, the test is not intended as a replacement for colonscopy, which is considered a gold standard screening tool for colorectal cancer. "A positive result may indicate the presence of colorectal cancer or advanced adenoma and should be followed by diagnostic colonoscopy," the FDA-approved indication for Cologuard states.

"We think physicians will offer both colonoscopy and Cologuard to their patients, and patients who are disinclined to undergo colonoscopy will go for Cologuard," Conroy said. "Our goal as a company is to ensure that a patient gets screened either by colonoscopy or Cologuard."

Further helping Cologuard's adoption will likely be the much lower price tag compared to colonoscopy. Cologuard's list price is just under $600, while colonoscopy can run several thousands of dollars. Conroy noted that Exact has proposed a discounted price to CMS of $502, and is expecting a decision with regard to pricing in August or September. Exact's proposed pricing for Cologuard is based on Medicare pricing for tests gauging mutations in the KRAS gene, fecal hemoglobin testing, and RAR-alpha genetic testing for leukemia.

As for patients, Exact is betting that they will particularly like the privacy that Cologuard testing offers them. After a physician orders the test, Exact mails a stool collection kit to the patient's home, and the patient can send the sample to Exact for analysis. The turnaround time for the test is around two weeks and results indicate whether a patient's stool sample is either positive or negative for the presence of precancerous polyps or cancer.

Exact is also finalizing the protocol for a five-year post-marketing study to gather additional evidence on how Cologuard testing every three years impacts longer-term outcomes. "Programmatic modeling will indicate to the guidelines committees what the right testing interval is" for Cologuard, Conroy said. During the review by FDA's advisory panel, several experts were interested in seeing evidence supporting annual Cologuard screening, instead of every three years.

A critical component of driving adoption of Cologuard will be to get guidelines bodies to recommend the test for screening and indicate the interval at which it should be performed. The most recent American Cancer Society guidelines mention stool DNA testing, but don't recommend a screening interval. Exact is also hoping for a mention of Cologuard in the US Preventative Services Task Force and the Multi Society Task Force on Colon Cancer Screening guidelines.

"It will take some time for the various guidelines committees to opine on the appropriate [screening] interval," Conroy said. "But we think the starting point will be [every] three years" as discussed by the FDA expert panel.

Parallel review payback

Cologuard is the first medical device to be reviewed under the FDA-CMS parallel review pilot project. While Conroy shied away from recommending parallel review to other companies, he noted that Exact could very well pursue the pathway again for some of its other tests. While Cologuard is Exact's first commercial product, the company is also developing tests for pancreatic, esophageal, and stomach cancers.

"I can't speak for other companies, because everybody has to do their own homework. But for us, [parallel review] has been exceedingly positive," Conroy said. "It enabled us to do something that has never been done in history, which is to get FDA approval and get a proposed CMS national coverage decision [NCD] on the same day."

In the past, Conroy has estimated that Exact's direct costs for the DeeP-C clinical trial totaled approximately $30 million. "So, running a second clinical trial is just really not an option," he said last year during a webinar hosted by Avalere Health and The RPM Report. "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."

During the webinar, Conroy also opined that the parallel review process helped guide a small diagnostic shop like Exact toward garnering an NCD for its test more easily. "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," he said.

Louis Jacques, former director of CMS' coverage and analysis group, has spoken in the past about industry players' reluctance to pursue parallel CMS and FDA review. One factor potentially discouraging participation, according to Jacques, is the misconception that parallel review automatically compels the test developer to seek an NCD – a scary prospect for some given the risk that a negative determination would mean the test is not covered at all in the US.

"Because of the way the statutes and the regulations are written around colorectal cancer screening, it wouldn't be covered unless CMS affirmatively made a decision to cover it," noted Jacques, who left CMS and joined the consulting firm ADVI in March as its chief clinical officer. "There are other technologies where local coverage is possible without an NCD, but you cannot have local coverage on prevention or screening. A company might engage in parallel review with the expectation that if the evidence is compelling [for a test] then there would be no need for an NCD because the Medicare local coverage contractors would be persuaded by that evidence and [the test] would be covered locally."

Besides, should the test developer want to put in the work to craft and conduct a single study that successfully satisfies the requirements of both CMS and FDA, it definitely has its advantages when it comes time to launch the test, he pointed out. Detractors of parallel review in the past have emphasized that the charges to FDA and CMS are distinct and conducting one study to meet both their demands would be overly burdensome for a company.

However, as Exact's experience in conducting the DeeP-C trial suggests, after FDA review, the firm was much better set up from a reimbursement standpoint for Cologuard, allowing it to move quickly toward test commercialization. Moreover, by answering some critical questions for CMS, the company also curried favor during the FDA review process.

"If Exact had decided not to go through parallel review, and had just gone through the FDA, … their advisory panel meeting may or may not have gone as well as it did," Jacques said. "The payback for them for the investment they put into the clinical trial was that their FDA panel meeting went extraordinarily smoothly."

Indeed, at the March meeting of the FDA Medical Device Advisory Committee's Molecular and Clinical Genetics Panel, upon reviewing and discussing the DeeP-C data, panel member Steven Skates from Massachusetts General Hospital said that Cologuard was "one of the biggest improvements to early [colorectal cancer] detection" he had seen. During public presentations to the advisory committee, speakers representing advocacy organizations, physicians, and patients urged for Cologuard's approval and reimbursement, highlighting its ability to pick up pre-malignant polyps (advanced adenomas) that wouldn't otherwise be gauged by other tests and citing the need for a non-invasive screening test that can reach rural or at-risk populations.

"They had unanimous 'yes' votes on all three questions [on the safety and efficacy of the test], and the panel members were spontaneously saying nice things about Exact," Jacques recounted. "Most FDA advisory panel meetings don't turn out that way."

Around the time that the FDA advisory panel reviewed Cologuard, the committee also looked at safety and efficacy data for EpiGenomics' Epi proColon colorectal cancer screening test. Although less effusive than in their discussion on Cologuard, the committee gave a generally favorable review of Epi proColon, while expressing concerns about the limited long-term data on use of the screening test. Experts at the meeting also questioned Epi proColon's performance compared to FIT and fecal occult blood tests. In June, EpiGenomics received a "not approvable letter" from the FDA, in which the agency said it wanted to see additional data that the test would increase screening compliance compared to colonoscopy or FIT.

Without having conducted the DeeP-C trial, after garnering FDA approval Exact would then have had to – as most other firms separately taking on FDA and CMS do – embark on discussions with CMS and private payors and likely perform additional studies that would have pushed back its timeframe for reimbursement and test pricing. "In terms of going through parallel review, there is a definite upside from them having done this," Jacques observed. "There are products out there where parallel review isn't going to matter. But this is one case where it does matter."

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