Cover Story

Regenerative medicinal products combine devices with biologically active substances to facilitate healing and regenerate damaged tissues. The device often serves as the scaffolding for the growth of the biologic component and the product is often an implant. Examples include Dermagraft (human fibroblast-derived dermal substitute), coated absorbable meshes for bone growth, spinal fusion cages with recombinant human bone morphogenic proteins, and the artificial replacement organs (e.g., bioartificial pancreas). These are the most complex combination products because they have to take into consideration the interaction between the product and the body's response to it. The development process for such products is also the most complicated and integrated because the components under development must be tightly coupled. The primary mode of action varies on a case-by-case basis, as does the lead review and oversight agency.

In order to help in determining the most appropriate regulatory pathway, the FDA developed a categorization scheme for combination products. Under this scheme, a product is placed into one of nine categories:

• Convenience kit or co-package

• Prefilled drug delivery device/system

• Prefilled biologic delivery device/system

• Device coated/impregnated/otherwise combined with drug

• Device coated or otherwise combined with biologic

• Drug/biologic combination

• Separate products requiring mutually conforming labeling

• Possible combination product based on mutually conforming labeling of separate products

• Other type of combination product

World Market Review for Combination Product

There is value in working together versus separately and the advantages are limitless for both the drug and the device. Companies planning to enter this market should establish collaborative relationships with the FDA, physicians and third-party players early in the development process.

The global market for drug-device combinations was valued at $5.4B in 2004. The global market for drug-device combinations is expected to increase at an average annual growth rate of 13.6% and reach $11.5B in 2010.

The US advanced drug delivery market is tipped to grow more than 18% and exceed $76B by 2014. However, only a handful of contract manufacturing organizations exist that can fulfill the task of making such specialized devices on a large scale. In 2004, the US held approximately 65% of the drug-device combination product market. By 2010, the US is projected to hold 57%.

Cardiovascular related combination product revenues will account for approximately 88% of worldwide sales in 2009. A majority of these revenues will be due to drug-eluting stent sales while steroid eluting electrode and waterjet device revenues account for the remainder.

Cardiovascular applications currently dominate with 88% of the market. Other fast-growing segments include coverings, bone growth factors, steroid-eluting electrodes, closed-loop glucose monitoring insulin pumps, inhalation devices and transdermal delivery systems

Challenges to Device Makers

Innovative medical device companies in search of the next big idea are finding ways to combine emerging device technologies with drugs or biologics to address a range of needs. Combination products pose numerous technical, regulatory, and business challenges and the companies that master these challenges are well ahead of the pack.

Device makers are attracted to combination products for a variety of reasons, described as follows:

• By providing multiple and complementary modes of action, these combination products have the potential to offer greater therapeutic benefits than drugs or devices acting alone. For example, in a drug-eluting stent, the wire mesh of the stent opens the clogged artery and is augmented by the drug coating to prevent reclogging.

• The products improve the overall quality of care by enhancing acceptance and functional life of implantable devices. Products such as pacing leads and glucose sensors could benefit from biocompatibility and a lower risk of inflammation and foreign-body responses, which can impede the function of devices.

• They enable healthcare providers to treat diseases with localized drug delivery. In cases such as cancer and diseases of the retina, systemic treatments may be ineffective or potentially harmful. Combination products offer an effective and safe alternative.

Being technologically more complex than device-only development, combination product development requires more discipline and cross-functional coordination. Consider the drug-eluting stent. In the past, manufacturers had to overcome the challenges of designing an implantable mechanical device that was capable of traveling through the vascular system, reaching a blockage in the heart, and propping open a clogged artery for an extended period of time. With the introduction of a drug-coated device, these same manufacturers have had to address a new set of challenges.

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