Cover Story

For example, one of the biggest design and manufacturing challenges for drug-enhanced devices is ensuring adequate sterility and shelf life of the drug on a device.

Medical device companies face both opportunities and challenges as they develop and commercialize combination products. Companies must be able to formulate a coherent strategy, develop the right capabilities, establish a common development process, and drive the changes needed to sustain their pipeline of combination products. Combination products have the potential to unlock significant value by providing the next level of safe and highly effective treatments for patients. However, getting these products to the market in a timely, compliant, and sustainable manner is not easy. New and challenging technical problems will persist. Interacting with key regulatory authorities, such as FDA, requires a dedicated and collaborative effort as their approaches continue to evolve. Companies that make the leap to combination products will need to take an integrated approach to defining their strategy, development process, and organization.

Regulation Framework

Combination products have the potential to vastly improve medical care-making treatment more effective and safer, as well as improving compliance for patients. But because of the novelty and complexity of such products, companies face unique challenges in navigating them through regulatory channels and bringing them to market. To ensure timely and successful review, companies need to understand the current approaches to combination product regulation and develop strategies for partnering with the FDA during product development and approval.

PMOA Rule

The PMOA - or Primary Mode of Action - regulation is the rule governing assignment of a new combination product to one of the three FDA regulatory centers for review:

the Center for Biologics Evaluation and Research (CBER),

Center for Drug Evaluation and Research (CDER),

or the Center for Devices and Radiological Health (CDRH).

The FDA defines PMOA as "the single mode of action of a combination product that provides the most important therapeutic action of the combination product." Products may have a drug, biologic or device primary mode of action. For example, if the PMOA of a drug-device combination product is attributed to the device, it will be assigned to CDRH for pre-market review. An example of such a product is a drug-eluting stent.

Office of Combination Products (OCP)

The role of OCP, the OCP has overseen combination product regulation since December 2002. Its primary role is to ensure "timely and effective pre-market review," although actual reviews are done at one of the three FDA regulatory centers, based on the product's PMOA. In its capacity as a facilitator, the OCP has taken an active role in reaching out to industry representatives and developing resources to streamline the regulatory process. The OCP also maintains a combination products tracking database, enabling it to monitor how the review process is working and pinpoint any bottlenecks.

A recent study commissioned by the FDA, published in February of this year, found that manufacturers value the work of the OCP and its efforts to bring predictability, transparency, and consistency to the process of combination product review.

Request for Designation (RFD)

In case if the jurisdiction of a combination product is unclear or in dispute, sponsors should submit a formal RFD to the Office of Combination Products. It is not necessary to submit an RFD for every combination product; only sponsors who are uncertain about the proper designation of their product and appropriate regulatory pathway need to file such a request. A Request for Designation (RFD) is the formal document submitted by the sponsors of a combination product providing information the FDA needs to determine the regulatory identity of a product as a drug, device, biologic, or combination product and assign the product to the appropriate center for review and regulation.

Combination Products: Some of the Examples

The current intense interest in drug-coated, coronary-artery stents is an example of a combination product that includes a device-the metallic stent-with a variety of drugs coated on its surface. The drugs are intended to enhance the physical effect of the device by preventing closure of the vessel after treatment. Another example is the recently approved tapered-metallic spinal-fusion cage. This is used in combination with recombinant human bone morphogenic protein, which is placed on a resorbable collagen sponge. The recombinant protein induces formation of new bone.

Catheter intended to deliver an angiogenesis gene to heart muscle are also considered combination products, as their clinical utility depends on their use with the biological product. In addition, several photoactivated drugs have been approved by FDA. These drugs, which are regulated by CDER, require a specially designed light source to activate the drug. The photoactivationlight sources are cross labeled with the drug and regulated by CDRH via the PMA path.

The I-vation TA drug-delivery system releases drugs to the back of the eye to treat ocular diseases is an example of combination product. The screw-like device is a non-ferrous metallic scaffold coated with a polymer from SurModics Inc., Eden Prairie, Minn., which is then coated with triamcinolone acetonide. The helical design maximizes surface area for drug delivery and ensures secure anchoring of the implant against the sclera.