Combo Product Primary Mode Of Action, Dispute Resolution Detailed By FDA

Combination products without regulatory precedent will be assigned to the FDA center with the most expertise in evaluating the products' primary safety and efficacy concerns under a proposed rule.

The reg will facilitate more timely approval of combination products by identifying the proper center for review assignment, FDA says.

The ¹ proposed rule defines "primary mode of action," which determines whether a product is assigned to FDA's device, drug or biologics center, as "the single mode of action of a combination product that provides the most important therapeutic action of the combination product."

Should a combo product be too early in its development to identify a primary mode, or should its actions be independent of each other, FDA recommends assignment to the center that regulates comparable products, unless there is no precedent. The rule is accompanied by a three-step ² flowchart outlining the decision process.

As an example, the rule describes a contact lens combined with a drug to treat glaucoma. Because the lens' function is vision correction and the drug's function is the treatment of glaucoma, they are independent of each other. Since no combination product has been submitted for these functions, there is no precedent to follow in assignment of review center.

However, the drug's safety and effectiveness issues are more significant than those of the contact lens, which are "considered routine." Therefore, the glaucoma-treating lens would be regulated by CDER, the proposed rule explains.

Conversely, drug-eluting stents will still be regulated by Center for Devices & Radiological Health because the function of the drug is secondary and supportive to the artery-opening function of the stent.

The rule employs algorithms based on assignment decisions for roughly 300 combination products that had been reviewed in the last 13 years.

Review assignment can be changed during product development if data show that a product is incorrectly assigned, creating a public health concern.

FDA issued the proposed rule against industry appeals. In February, the device trade association AdvaMed urged the agency to "not move hastily to codification" of primary mode of action, and first draft a guidance defining the concept.

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FDA also addresses review speed in a separate draft guidance on formal dispute resolution for combo products. Requests for dispute resolution should be filed after applicable performance goal timelines have passed, the guidance said.

Exceptions may apply if a sponsor receives advance notice that a center will not meet a pertinent deadline. In those cases, a resolution request to the Office of Combination Products would be acceptable, as it would "further the goal of obtaining review as quickly as possible," the ⁴ guidance explains.

Dispute resolution requests are inappropriate either before the review segment has been initiated or after it has been completed, the agency notes. Requests made after the portion of the review in question has been completed "would do nothing to further the goal" of expediting the review. However, the Office of Combination Products noted it is open to receiving comments related to slow reviews.

"Prospective concerns about [a] reviewing agency's ability to meet performance goals in the future" should be addressed through "informal procedures outside the scope of this guidance," the document states.

Combination product submissions reviewed under a single premarket application are subject only to the performance goals associated with that application. For products requiring two application types, performance goals for both applications would apply.

The 2002 law creating the device user fee system assigned responsibility for resolution of premarket timeliness disputes to the Office of Combination Products. However, the office has yet to receive a complaint that would fall into that category, staffers say.