Combination products are the confluence mostly of the device and pharmaceutical industries. Examples include drug-eluting stents and implantable chips that can be signaled to release drugs. There are many others and more to come. In the FDA's fiscal year 2006, for example, 235 were submitted for review and 333 in 2007, a 42% increase.

Former FDA regulator and now Chief Regulatory Stratagist for GE Healthcare Mark Kramer led FDA's Office of Combination Products from its inception in 2002 until March 2007. After the recent Informa Life Sciences 3rd Annual Drug-Device Combination Products Conference in London, Kramer shared a few thoughts on best practices for working with the FDA to streamline a combination product review and approval.

First of all, says Kramer, consider how the FDA defines combination products. In a nutshell, such a product is a combines a drug and a device, a drug and a biological product, or a device and a biological product where the different parts are:

• Physically, chemically or otherwise combined,

• Packaged together, or

• Separate products but labeled for use together.

The FDA's regulatory challenge is to define a timely, consistent and appropriate way to evaluate combination products that don't easily conform to what is already approved. “The definition helps you appreciate the diversity in the type of combination products and the challenge in creating a ‘one size fits all’ approach to their regulation,” says Kramer. Hence, approval for combination products can be earned by several routes. For example, combination products can be regulated as devices (by PMA or 510(k)), drugs (by NDA) or biological products (by BLA).

The FDA's Office of Combination Products (OCP) (fda.gov/oc/combination/), established by the Medical Device User Fee Act of 2002, has a variety of functions. One is to make jurisdictional determinations. That is, OCP decides how to classify a new combination product and which of the three medical product Centers (CBER, CDER or CDRH) will have lead responsibility for the product's review and regulation.

“The Office is also responsible for overseeing and coordinating premarket reviews, and ensuring consistent and appropriate postmarket regulation. As you'd expect, the Office develops policy, guidance, and regulations. It also serves as a resource for industry and FDA review staff, resolves disputes, and reports to Congress annually on its activities and progress,” he adds.

The FDA assigns combination products to a Center based on their primary mode of action (PMOA). Until a few years ago, PMOA was not defined by regulations. “Even now, a product's PMOA can be difficult to identify because a company may be early in product development and so may not yet fully understand the product's PMOA. Another possibility is that a product has two or more completely different modes of action, neither of which is clearly subordinate to the other.” Today, a product's primary mode of action is defined by 21 CFR 3, which also describes how a product achieves its drug, device, or biological product mode of action. When the Agency can't determine the most important therapeutic action with reasonable certainty, it considers safety and effectiveness issues (as described in 21 CFR 3.4) with what it calls an assignment algorithm in directing the most appropriate assignment. “The agency first considers consistency. That is, OCP will assign the product to one of the FDA Centers that regulates other combination products that presented similar questions of safety and effectiveness. When no other product has presented similar questions, the Agency looks at the Center with the most expertise related to the product's most significant safety and effectiveness questions,” says Kramer.

One way to help the FDA determine which Center gets regulation duties is to submit a Request for Designation (RFD). In 21 CFR 3.7, the FDA suggests submitting an RFD when jurisdiction is unclear or in dispute. However, says Kramer, don't ignore informal mechanisms that are available, such as a phone call or email to OCP or the Center jurisdictional officers to see whether an RFD is really necessary.

The CFR specifies the RFD, such as write no more than a 15 pages. So be comprehensive but brief. The RFD is actually intended in determining the jurisdiction for any FDA medical product submitted for approval, be it a combination or noncombination product. What's more, a 60-day review clock starts the day you send the RFD to combination@fda.gov.

Kramer suggests that RFD authors focus on describing the product, why and how it would be used, and how the product works (identify all modes of action). “In addition, pay particular attention to describing the product's most important therapeutic action. It is often helpful to include data and literature to support your PMOA recommendation. Explain where you think the product should be assigned and why, using the assignment algorithm when appropriate,” says Kramer.

To get an idea of which Center handles what type of combination products, check out what the FDA calls its jurisdictional determinations website. It holds about 250 such decisions, brief synopses of prior products and how they were classified and assigned. For instance, a dental floss with an antimicrobial agent was assigned to the CDRH.

The Office processes an RFD by first reviewing the filing for completeness and its ability to make a decision on it, usually within a day or two of receipt. “Occasionally, a critical piece of information will be missing. This might be a clear intended use or a comprehensive description of how the product works, such as whether chemical action is involved. The Office occasionally determines that an RFD is not necessary, so a phone call or email before submitting is usually a good idea,” he adds.

Assuming the Request is complete and necessary, the Office assigns a lead reviewer and sends an acknowledgement letter to the company. “The letter identifies the lead reviewer along with filing and due dates. Furthermore, the Office will distribute the RFD to Center jurisdictional officers.” says Kramer. The OCP and the Centers conduct scientific and precedent reviews, and the Centers forward their recommendations to the Office within 21 days of the RFD filing date.

When information is available and clear, the office makes a decision. “And when it isn't, more discussion and consultation may involve the Office, Center jurisdictional experts, product experts, agency management, and the Office of General Counsel,” he says.

In the end, OCP issues its RFD Decision letter, which classifies the product based on statutory definitions. In addition, the letter assigns the combination product to a Center based on its PMOA. (Of the 333 premarket submissions for combination products submitted in fiscal year 2007, 43 were handled by CBER, 142 by CDER, and 148 by CDRH). “Generally, the letter provides good insight into the Agency's decision-making process, and it usually identifies the regulatory pathway as well as a contact person in the assigned Center. Once a Center is identified, the company may contact the assigned Center to discuss next steps, such as holding a pre-IDE or pre-IND meeting. OCP does not itself review combination products, but it does help establish and clarify regulatory pathways, facilitate intercenter working groups and MOUs (memoranda of understanding or internal agreements worked out on review processes for specific types of products) and facilitate meetings with sponsors (your company representatives). OCP also monitors and facilitates intercenter consultations, monitors the timeliness of combination product reviews, provides training and reviewer tools, and provides guidance throughout the regulatory lifecycle.”

To speed their work, and essentially yours, the FDA suggests several early-development considerations for innovative combination products. “The guidance recommends, for example, that sponsors consider what kinds of new issues are raised when combining the parts. Also consider significant interactions, such as the leachables or extractables from the device into the drug product, or the adhesion or adsorption of a drug onto a device or polymer,” says Kramer.

A combination product sometimes has more than one premarket application or approval route, such as both a PMA or NDA. Just one application, however, is sufficient for most.

Two applications may be necessary and preferred by companies in some circumstances. For example, two applications may be appropriate when the constituents of the combination product are separate and each is a complex product, or when the constituents have uses beyond the combination, or when labeling changes for the approved product are necessary to maintain regulatory consistency.

Cross labeling

Cross labeling presents another wrinkle. This issue occasionally arises when two companies separately develop products intended to be used together, such as a drug and a needle-free-injector pen. Cross labeling is a consequence of one of the types of combination products defined in 21 CFR 3.2(e)(3), and it can get complicated if two separately developed products are considered a combination product and must be labeled for use together. If one of the companies is not interested in pursuing approval for the labeling change, the other product may not have a regulatory pathway for approval.

FDA often must consider when the labeling of an approved product must be changed to reflect its use with another product. Issues the Agency may consider include: When is inconsistency in the labeling acceptable, and to what degree? Would end-users be confused by differences in the product labeling? What would happen if the approved product is reformulated or redesigned without notice to the other company?

Consider again the drug and injector pen. Suppose the drug company alters its formulation. Then the studies conducted by the device company may no longer be valid.

Companies wanting to learn more about this issue may read a transcript posted on the Office's website that refers to a cross-labeling workshop held in 2005. Kramer reports that OCP has indicated that further guidance is in development. Such situations are generally resolved on a case-by-case basis, and Kramer encourages firms to consult OCP if they think they are in this situation.

Postmarket regulation

The Agency strives for consistency and appropriateness. FDA has described its goals for proposed rulemaking on good manufacturing practices (GMP) and adverse event reporting, says Kramer, to ensure consistency by making like combination products subject to similar vigilance reporting and GMP requirements. The Agency also wants to ensure appropriateness by maintaining requirements that reflect the composition and characteristics of the product. “FDA is expected to publish proposed rules for handling GMPs and adverse event reporting by the end of 2008.

OCP first published draft guidance for good manufacturing practices in 2004. It explained that the drug cGMP and device Quality System regulations were similar, but tailored to types of products for which the regulations were originally designed. The draft guidance identifies key provisions to ensure compliance with both regulations. It may be necessary to consider additional aspects of the cGMP or Quality System regulations depending on the product. “For example, if a company uses drug cGMP as its GMP operating system, then design controls, purchasing controls, and corrective and preventative action may also be applicable. But if a company uses the device Quality System regulation as its operating system, then calculations for yield, expiration dating, stability testing, testing and approval or rejection of components, and other requirements may be applicable,” according to the guidance.

Adverse events

Like the case with GMPs, the separate adverse event reporting regulations applicable to devices and drugs were each designed for the individual types of products, i.e., devices or drugs. FDA is also considering how these regulations should apply for combination products. When might it be necessary to supplement the drug or device provisions to ensure consistent and appropriate postmarket regulation for a combination product? The key differences FDA has previously described include Device Malfunction Reporting, 5-Day MDR Reporting, Drug and Biological Product 15-Day “Alert” Reporting, and Blood Related Death Reporting. FDA is expected to publish a proposed regulation on adverse-event reporting in late 2008.

A few recommendations

These recommendations, suggest Kramer, may speed the development and approval of a combination product:

• Don't assume the classification, assignment, or regulatory pathway of a combination product unless it has a clear precedent or PMOA.

• Think strategically. Seemingly small differences in product configuration or co-packaging can make a difference in a product's classification, or PMOA, or both.

• Devices differ from drugs and require different expertise. Have the right people on your team.

• Plan ahead for the proposed GMP and adverse event reporting requirements.

• Contact the Office of Combination Products for advice on getting started.