BBI Washington Editor

A standard vision-correcting contact lens will be reviewed and regulated by the FDA’s Center for Devices and Radiological Health (CDRH). That’s pretty much a no-brainer. Now what happens if the lens also were designed to elute a drug that treated glaucoma? That’s not – pardon the pun – as clear.

That’s where the FDA’s Office of Combination Products (OCP), founded almost three years ago, steps in. The FDA recently released its final rule to help improve the process by which its own regulators and industry determine the center – CDRH, the Center for Biologics Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER) – is best equipped to review new combination product applications. The release followed an extensive public comment and review period.

The proposed rule originally was published in the Federal Register in May 2004. The FDA held a series of stakeholder meetings prior to last year’s issuance of the rule.

“We are seeing more and more products like this, where they are doing two different things and one is not clearly subordinate to the other,” Mark Kramer, director of the Office of Combination Products, told The BBI Newsletter. “Therefore one is not clearly primary.”

The new rule defines a product’s mode of action (MOA) and primary mode of action (PMOA). The rule also outlines an algorithm the agency will use to assign combination products to a center when the agency “cannot determine with reasonable certainty” the mode of action that provides the most important therapeutic action of the combination product.

“The final rule is intended to promote the public health by codifying the agency’s criteria for the assignment of combination products in transparent, consistent, and predictable terms,” according to the agency.

Kramer explained that a basic definition of primary mode of action has been on the books for about 15 years now since enactment of the Safe Medical Devices Act of 1990.

“But what it didn’t do is – beyond those four words – explain what it really meant or precisely how we would do it,” he said.

Mode of action in the final rule is defined as “the means by which a product achieves its intended therapeutic effect or action,” which means any action of the product intended to diagnose, cure, mitigate, treat or prevent disease, or affect the structure or any function of the body.

As a mix of a biological product, a device or a drug, combination products typically will have more than one mode of action. According to the rule, a product has a device mode of action if it meets it does not have a biological product mode of action, and it “does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and is not dependent upon being metabolized for the achievement of its primary intended purposes.”

Primary mode of action is defined as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product.” The most important therapeutic action is the mode of action that is expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.

In some cases, Kramer said, the FDA and the product sponsor aren’t able to determine which mode of action of a combination product provides the most important therapeutic action. Figuring out the PMOA of a combination product is complicated for products where the product has two completely different modes of action, neither of which is subordinate to the other. This is where the algorithm comes into play.

“What this algorithm does is set out a mechanism we would use to assign those products,” Kramer said. “We’d first look to see if we have other products that raise the same kinds of safety and effectiveness issues as this new product. If the answer is ‘yes,’ we would assign it the way those previous products were assigned in order to be consistent and fair. He said if the product is “different in an important way,” or raises different safety and effectiveness questions, the product would be assigned to the center with the most expertise to review it.

Kramer called the algorithm a “very forward-looking part of the rule. We see that as the wave of the future with new types of products.” He added: “Now we have a mechanism that was laid out so that people will know how we’re making those assignments.”

In the little more than a year since the proposed rule was announced, Kramer said the feedback from industry was overwhelmingly positive, and that ultimately there only were “minor” differences in the final rule. “Most of the comments we got were very supportive of it,” he said. “They asked for three basic things: clarifying the rule for intended use; clarifying the rule for precedent; and providing more examples. In the regulation itself, there were only a few words changes. But in the preamble, we did provide more clarification and background.” Most notably, both the PMO and PMOA definitions now include the word “intended.” The prior definition only defined a “therapeutic effect.”

Kramer told BBI that the final rule should make the process easier for the FDA and for companies submitting new-product applications. “Ultimately it will make [the process] better because people will know what the rules are and ultimately their submissions will be designed with the rule in mind,” he said. “In terms of actual practices, the final rule – particularly with respect to the definition of primary mode of action – really codifies the proactive way we’ve thought about PMOA for a long time. We didn’t have a regulation on it and clearly people wondered how we did it.”

But this doesn’t mean his office will be any less busy. Kramer pointed out that directing product review assignments to the correct center within FDA is only part of the Office of Combination Product’s work. “It’s really only the first part of it,” he said. “We have responsibilities regarding the development of policy for combination products, coordinating the inter-center review process, making sure the review is going smoothly and the issues are clear. While the individual centers have lead responsibility for the actually review, it doesn’t mean we are out of it at all.”

Kramer said OCP also serves as a resource for questions as they come up throughout the life cycle of different combination products. A sponsor can go directly to OCP for an assignment or to the center the company thinks would be responsible for the review, he said. There usually is discussion among the different parties involves prior to an actual submission.

The new rule explains that when a center’s jurisdiction is in dispute, an application must be made to OCP to figure it out. Kramer said his office is busy posting more information on its web site to give people “a better window into where things fit,” which he says should reduce the number of formal requests for designation.

“We hit the ground running when we were formed almost three years ago and things have been consistently busy,” he said. “Besides the actual products that come in, we’re developing policy, guidance and regulation, and ultimately a whole spectrum of regulation will need to be clarified. So I think we’ll be busy for a long time.”

Based on a range of indicators, including questions and feedback received from industry, more companies seem to be developing combination products. “New companies are developing them and even more established companies are adding combination products to get more mileage out of the products they already have,” Kramer said. “I think it is going to be a fairly dynamic issue.”

For fiscal 2004, OCP received 210 inter-center consultation requests among CDRH, CBER and CDER, the agency reported. Also during FY04, the agency categorized 251 original applications under review as combination products. Of that number, CDER received and categorized 114 applications as combination products; CDRH categorized 100 applications; and CBER processed 37.