Medical Device Daily Washington Editor

WASHINGTON The 51st edition of the annual conference sponsored jointly by the Food and Drug Law Institute (Washington) and FDA offered no blockbuster announcements partly because the agency has not yet dried the ink on the upcoming guidance for drug-eluting stent (DES) development (though that guidance was issued on Wednesday [see related story, this page]).

Nonetheless, attendees got a look at the difficult task faced by the agency in its approach to regulation of drugs and devices and especially the growing proliferation of products which combine a drug and device. This translates to increasing regulatory uncertainty and more difficult regulatory decision-making.

In a session dealing with these combinations, Suzanne O'Shea, formerly of FDA's Office of Combination Products and now with the DC law firm of Baker & Daniels, said that a key differentiator is that a device cannot do its work by chemical means. Still, she acknowledged that in the modern world, the question "of what is a chemical action is a difficult one."

Two drugs together do not make a combination product, O'Shea said, but she reminded the audience that the primary mode of action determines which of FDA's centers will review a combo application. FDA typically determines how to approach a combination product by determining "the single mode of action that provides the greatest contribution to the therapeutic effect," with the relevant center at FDA taking responsibility for reviewing that application.

As an example, O'Shea pointed out that a DES is classified as a device because the stent holds the vessel open, and the drug works adjunctively from there. On the other hand, a drug-eluting chemotherapy disk is classified as a drug because the mechanism of action is the drug, the method of delivery secondary.

Discussing a hypothetical scenario, O'Shea described a company that makes an irrigator nozzle usable in conjunction with a bottle of debriding fluid for wound cleansing made by another firm. The two firms would both market the full product separately in this scenario.

Panelist Evan Phelps, an attorney with Olsson Frank and Weeda (Washington) said "I've seen this example [categorized] as both types" of combination applications, and that he knew of a case in which such an application ended up at the Center for Devices and Radiological Health (CDRH) as a 510(k). But "the agency in the past has regulated a pre-filled hypodermic syringe for debridement as a drug."

O'Shea said the definition of the combo product as a drug or a device "depends a lot on what the liquid is doing," even though the nozzle is clearly a device.

Another hypothetical described that same nozzle with a different firm's fluids, separately exerting exert antiseptic, anti-inflammatory and surfactant properties. Which center would the application go to?

One participant said a sponsor "can't do this with one application" because some of the fluids exert pharmaceutical effects, such as the anti-inflammatory, while others that have more of a device effect would require a separate filing as a combination product.

O'Shea responded: "You'd have to look at the identity of each of the components" to determine which center should do application review. Even if one of the solutions was listed in an over-the-counter drug monograph, the combined product would still end up at the CDER because the primary mode of action is that of a pharmaceutical.

In a third scenario, the company making the irrigator nozzle expressed no interest in dealing with the CDER and informed the second firm that the first firm's investors feel the same way. What recourse would the second company have?

One attendee suggested that the maker of the nozzle could license manufacture of the nozzle to the second firm, pushing the need to deal with CDER onto the second company.

Ashley Boam, acting deputy director for science and review policy at the Office of Device Evaluation, said "so long as there is a fluid that is cleared" as a device, there should be no need to deal with CDER.

However, she added: "You see catheters coming through [the regulatory pipeline] for physician-specified fluid" that require no acknowledgement of the substance to be used with it. An audience member seconded that, citing "general delivery systems out there [labeled for] whatever you can deliver.'"

If the maker of the nozzle chooses to sell it separately for use with bottles of soda or pre-mixed saline solution, the product most likely is a device until coupled with a product with a structure/function claim sounding like a drug.

Panelist Marta Villarraga, PhD, principal engineer in the biomechanics division at Exponent (Menlo Park, California), said the nozzle would be a device in such an arrangement because "the system for delivery" is the product in question for the company making it.

"I think it's what the nozzle is labeled for, what it is used with, and for what it is used for," she said. "It's really the indication or the intended use" that determines the regulatory status of the product.

Whether the soda would have to be cleared as a drug or device in such a situation "is something FDA has not sorted out," O'Shea said.

What would the maker of the nozzle be required to do should the nozzle be involved in the death of a user from an infection, assuming the cause of the infection is not clear?

The group quickly came to a consensus that the company that makes the nozzle would be required, at the very least, to file a medical device report and make sure that the company making whatever rinse product that was in use with the nozzle was also aware of this.