FDA says final rules on good manufacturing practices and adverse event reporting for combination products could be out as early as this fall.

The agency published a proposed rule in September 2009 laying out a framework for satisfying the manufacturing quality requirements for all the different components of a combination product, whether device, drug or biologic. (See " Also see "Company Questions Remain Unanswered In FDA's Combo Products GMP Rule" - Medtech Insight, 25 January, 2010. " – "The Gray Sheet" Jan. 25, 2010.)

"Every week that passes, more companies are building plants and making financial investments in their production systems that may be out of date once that rule comes out," said Bradley Merrill Thompson, head of the Combination Products Coalition and a health care attorney in the Washington, D.C., office of Epstein Becker Green. "We'd like to see that sooner rather than later."

FDA is also finalizing a rule on adverse event reporting for combo products. (See " Also see "Combo Product Firms Want Simpler Adverse Event Reporting Structure" - Medtech Insight, 1 February, 2010. " – "The Gray Sheet" Feb. 1, 2010.)

"We established work groups to review all the comments for those," said John Weiner, associate director for policy in FDA's Office of Combination Products. "Those groups have been working through the comments and preparing the actual final rules."

"We're shooting for late summer, early fall," he said.

FDA also intends to issue guidance to help firms implement the rules.

Thompson said his group is gathering "nitty gritty implementation questions" from its members to send to FDA.

"The [GMP] regulation is pretty generally written and it leaves a whole lot of specific questions open," he noted. "That's left for guidance."

Guidances In The Works

The Office of Combination Products is also developing guidance on how to determine whether a medical product is a device, drug or biologic.

"The agency thought that since this office is already tasked with classifying products as combination products, it would make sense for this office to be delegated the authority to classify products as drugs, devices and biologics," Weiner said.

FDA is preparing guidance on how to make post-market changes to approved combination products.

The classifications guidance is under review and should be out "fairly soon," he said.

FDA is also preparing guidance on how manufacturers go about getting approval for post-market changes to approved combination products.

This is a key issue for manufacturers because "a lot of companies are on third, fourth, fifth-generation products," Thompson said. "There's a lot of complexity around what the submission obligations are when you modify, for example, just the device component of a drug-device combination."

"People would find it helpful just to understand what the pathway is to even make the request you want to make," Weiner acknowledged.

In addition, on April 18 the office released revised guidance on how to prepare a request for designation. The requests are written by product manufacturers and used by FDA to determine the product classification (device, drug, biologic or combination product) and which FDA center should oversee the product review.

According to Weiner, FDA is often unable to make a determination on a request for designation on the first go-round because the sponsor has failed to include all the necessary information.

"We've been sending them back more," he said. "One important issue is to explain how the product works. It may seem obvious, but very often an important question in deciding how to classify a product is, 'How does it achieve its effect, physically, chemically, mechanically?'"

Combo Product Applications On The Rise

The number of combination product applications is gradually increasing, agency data shows.

According to the agency's recently posted fiscal 2009 report to Congress, FDA received 377 original applications for combination products that year, up 24% from 304 original applications in fiscal 2008. This represented a five-year high, FDA noted in its report.

"We hear that combination products is the fastest growing segment of medical products," Weiner said. "Over the last two years, there's been a pretty consistent upward trend."

Manufacturers Want More Transparency

Meanwhile, manufacturers say they want easier access to FDA information on prior combination product reviews and decisions.

"There is a lot of information which, if it were put on the website, would be a fairly modest hassle for the agency but would really help companies operate in this space," Thompson said.

In the absence of abundant guidance on combination products, he noted, when companies can at least see how decisions are being made, "they can infer what the rules are."

At a recent meeting with the agency, the Combination Products Coalition urged FDA to modify its existing approvals database to create a field indicating which products are combination products so firms can better select 510(k) predicates, he said.

By Jessica Bylander

Combination Products Office Finalizing Manufacturing, Adverse Event Rules

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