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FDA, CMS Make Parallel Review Program Permanent; Will Device and Diagnostic Companies Engage?

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NEW YORK (GenomeWeb) – After five years of piloting an effort under which the US Food and Drug Administration and the Centers for Medicare & Medicaid Services sought to simultaneously review devices for premarket approval and national insurance coverage, the two agencies recently said they've garnered enough experience to make the program permanent.

So far, only one company, Exact Sciences, has been able to simultaneously receive CMS's and FDA's nod for a product — the firm's Cologuard colon cancer screening test — and it remains to be seen if device and diagnostics developers will embrace the pathway. According to an FDA spokesperson and Louis Jacques, a former CMS director who co-created the so-called Parallel Review program, there is at least growing interest among industry players to engage in the process.

The FDA and CMS launched the Parallel Review pilot program in October 2011, aiming to facilitate earlier access to medical technologies by reducing the time it takes to gain premarket approval or a de novo clearance, and a national coverage determination. The agencies decided to continue the pilot in 2013 for another two years, and announced in October that it would make the program permanent.

During the years of the pilot, Exact was the only graduate of the program, although Medtronic attempted to take its Symplicity Renal Denervation Device through the program without success. Recently, Foundation Medicine, announced it was pursuing the parallel pathway for FoundationOne, a next-generation sequencing test that doctors can use to molecularly profile cancer patients' tumors and identify the right treatment strategy. 

An FDA spokesperson said in an interview that the agencies have gotten around two dozen applications for parallel review and 60 inquiries. The spokesperson wouldn't disclose how many applications the agencies had accepted to date.

"My sense is that there is a lot more industry or sponsor interest in being a part of Parallel Review," said Jacques, former director of CMS's coverage and analysis group and currently chief clinical officer of the consulting firm ADVI. He added that industry interest might even outstrip CMS's bandwidth to review products within the program, since parallel review can take several years depending on how early in product development the company engages with FDA. This can make it challenging for CMS to determine its staffing needs over that time.

In the early phases of the pilot, however, it seemed like industry players were suspicious of the parallel review concept. Jacques had quipped in 2011 that perhaps sponsors were hesitant to engage in parallel review because they didn't necessarily want FDA and CMS in the same room talking to each other about the evidence underlying their products. 

After consulting industry players for two years at ADVI, Jacques sees this hesitation dissipating, and companies don't see more FDA and CMS coordination as a bad thing. "I think it's encouraging that people have realized after [several] years that this is not two federal agencies trying to take advantage of a company," he said.

One of the oft-cited barriers to simultaneous FDA and CMS review is that the agencies have divergent congressionally mandated charges. The FDA determines if a device is safe and effective, and CMS determines if it is reasonable and necessary for the Medicare population — requirements that can be satisfied by different types of studies. The Parallel Review pilot was an attempt to test out if it was possible for the two agencies to work together with a device manufacturer to design one study that would meet both agencies' mandates.

In a Federal Register notice announcing that the Parallel Review program would be permanent, the FDA and CMS said manufacturers appreciated getting feedback from both agencies in designing a single pivotal trial for regulatory approval and coverage, and they liked that the program reduced the time it took to launch a test on the market with the FDA's and CMS's blessing. 

According to Exact Sciences CEO Kevin Conroy, the Parallel Review pilot "made all the difference in the world in terms of bringing Cologuard to patients."

After discussions with the two agencies, Exact got the go ahead to conduct a single pivotal trial involving 10,000 patients, called DeeP-C. Based on the results of the study, which cost more than $50 million, the FDA granted Cologuard premarket approval in August 2014, and on the same day CMS initiated a national coverage analysis. Less than two months later, CMS published a favorable national coverage determination for the test — seven months ahead of when the decision was due by statute. 

A study for a screening test, by definition, had to be "exceptionally large," Conroy said in an interview. "And to do it twice would have been nearly impossible for us financially."

When FDA convened an advisory committee meeting in the spring of 2014 to discuss the evidence on Cologuard, CMS officials sat in and heard experts talk about the test's potential role in colon cancer screening. "There was a venue for a scientific exchange in which CMS officials were able to listen and potentially get a deeper understanding of Cologuard," Conroy said, adding that FDA officials likely similarly benefited from CMS's perspectives on Cologuard.

After getting a national coverage determination, Exact didn't have to seek local coverage through Medicare contractors and was able establish test pricing directly through CMS's annual process. Once Cologuard was on the market with FDA approval and coverage, the data from Deep-C further informed bodies, such as the American Cancer Society, the National Comprehensive Cancer Network, and the US Preventive Services Task Force, as they considered how to include the test in screening recommendations.

Where Exact reaped the benefits of parallel review, however, Medtronic's experience wasn't as advantageous. In March 2013, the FDA and CMS accepted Medtronic's Symplicity renal denervation system for parallel review, agreeing to evaluate it based on the results of a 530-patient randomized-controlled trial. However, a year later the device — a catheter-based system designed to deliver low-level radio frequency energy through the renal artery wall and reduce blood pressure in patients with uncontrolled hypertension — failed to meet the efficacy endpoints in that study.  

Medtronic declined to discuss its lessons learned from the Parallel Review program. Back in 2014, some industry observers wondered whether Medtronic's experience and the lack of a successfully reviewed product meant the end of the pilot.

The program later that year would get a success story with Exact's Cologuard. Conroy advised companies to only pursue parallel review if they are "willing to go get strong evidence, run the right clinical trial, and do things the right way so both agencies can fully evaluate" the diagnostic.

More and more companies are interested in exploring the pathway it seems. "There is a recognition that FDA approval didn't historically speak persuasively on the value proposition of a technology in real-world use," Jacques said.

The challenge is more pronounced now that the FDA has a number of pathways for approving and clearing medical devices at an accelerated clip, which means that products are entering the market with even less evidence to inform payors' determinations. "Companies are realizing that they need to find some way of getting payor input, whether it's CMS or a commercial payor, or a health technology assessment organization," Jacques said. "They [realize they] need to get that voice and reflect it in their pivotal trials."

Foundation Medicine's decision to take FoundationOne through parallel review, for instance, is part of its overarching plan to improve the reimbursement prospects of its tests. The company is pursuing parallel review while continuing to work with government and third-party payors at the local, regional, and national levels. The strategy is wise given the difficult reimbursement environment for molecular diagnostics.

Certainly, in Exact's case, a national coverage determination from CMS didn't shield it from difficulties with private payors. Earlier this year, the company sued Humana and Blue Cross Blue Shield of North Carolina in state district courts for refusing to pay for Cologuard. Exact argued that these insurers were violating state laws that require them to pay for colorectal cancer screening tests recommended by the American Cancer Society or in line with medical practice guidelines. The testing firm claimed in its lawsuits that Humana owes it at least $800,000 and BCBS-NC owes $410,000 in test payments.

Exact recently settled its lawsuit with Humana, which has also agreed to cover Cologuard as an in-network service for its members beginning next year. The firm is still in discussions with BCBS-NC. 

These types of reimbursement related challenges are precisely why manufacturers increasingly want payor input on the clinical trials they're conducting for regulatory approval. Recognizing this, the FDA has formed a communications task force within its device division that facilitates discussions between manufacturers and payors. Manufacturers not eligible or interested in Parallel Review can also ask CMS to participate in a pre-submission meeting and provide input on clinical trial design. 

In February, the FDA also issued an open request to private coverage organizations interested in providing feedback to device sponsors during pre-submission meetings. So far, a number of groups have responded to the request, including BlueCross BlueShield Association, Humana, Kaiser Permanente, and SelectHealth/Intermountain Health.

These efforts to bring together regulatory and payor coverage processes for the benefit device and test makers comes as the FDA recently decided to hold off on finalizing draft guidelines for regulating lab-developed tests. The lab testing industry and pathologists groups didn't favor the agency's proposal, and has wanted to keep oversight of lab-developed tests under the Clinical Laboratory Improvement Amendments administered by CMS. 

Jeffrey Gibbs, an expert on regulatory law at Hyman, Phelps & McNamara said previously that industry players will likely have a range of reactions to this. "I'm sure there will be companies that were thinking of going through FDA as a hedge against LDT regulation that will say they won't embark on that process because it's too costly, too unsure, too long, and too demanding," he said. "There might also be companies that continue to pursue it because they think there might be other advantages of FDA clearance or approval, perhaps relating to reimbursement or the way they're viewed by doctors and patients. 

It's unclear if FDA's decision to delay broad LDT oversight will impact industry interest and participation specifically in parallel review. Foundation Medicine for one is not changing its plans to pursue the pathway, according to a spokesperson.

Given the positive experience with Cologuard, Conroy said he is considering taking another test in Exact's pipeline through the parallel review, but declined to provide details. As for Cologuard,the company conducted more than 100,000 Cologuard tests last year and expects to perform more than 240,000 this year.