Expanding the boundaries of communication, Apple’s much-ballyhooed iPhone harnesses the functionality and features of a cellular phone, camera, video iPod, and the Internet into one compact device. Integration of such different—and popular—capabilities into this single versatile device gratifies consumer desire for convenience and consolidation of useful communication products.
But this trend toward convergent technologies is not confined to consumer products. The medical device industry is experiencing a similar paradigm shift. Devices are becoming increasingly complex as components and technologies typically found in separate products spanning several industries are being incorporated into one multipurpose product. Owing to this unique composition, combination products are forcing change and innovation in everything from business partnerships to regulatory affairs and manufacturing operations.
A blossoming relationship between the pharmaceutical and medical device industries is producing a growing number of offspring in the form of combination products. Engineered from a mix of drug, device, or biologic components to form a single entity, combination products represent a relatively new business approach for both pharmaceutical and device companies.
Instances of drug and device companies teaming up for a medical application are multiplying in part because of positive feedback about existing combination therapies.
Encouragement for entering into a cross-disciplinary development project lies in the success of such combination products as drug-eluting stents, inhalation systems, drug-delivery pumps, and drug-impregnated films or wound-care products. Approval of the first drug-eluting stent in 2003—engineered not only to hold open arteries, but to reduce the chance of restenosis—was trumpeted as a landmark event in the healthcare industry.
Adding a drug component to a traditional stent enhanced the functionality of the device for the benefit of patients. Likewise, a number of combination products have arisen from the modification of a standard device or simple incorporation of a drug or coating. Antimicrobial-coated catheters and wound-care products, preloaded syringes, orthopedic implants infused with proteins to facilitate bone regeneration, and transdermal patches are just a few of the many products falling under this banner.
As seen with the drug-eluting stent, pioneering combination devices can put drug and device companies on the map. These distinctly different markets are reaching out to one another and joining forces to remain competitive in a technologically evolving marketplace.
“Companies want growth, they want innovation, they want a new way to drive and differentiate rather than just being in a one-upmanship [contest] against their competition, and they see combination products as a way to do this,” observes Chris Cramer, a principal in the Life Sciences Business Group of the consulting firm PRTM (Boston; www.prtm.com). His business is actively involved with combination products and assists companies with everything from determining the right time to enter the market to structuring the development and manufacturing processes, even to finding a suitable partner.
Nurturing these budding drug-device liaisons could prove to be extremely worthwhile: A report by Navigant Consulting Inc. forecasts that the market for combination products will reach an estimated $9.5 billion worldwide by 2009. Driving development will be such factors as competition, opportunities for localized drug delivery, and miniaturization.
“Nanotechnology will lead the way,” predicts Shay Ahmed, CEO of FlexOne (San Jose, CA; www.flexone.com), an electronics manufacturing company. “There are so many things going on, one of which is targeted drug delivery. I think that will be one of the biggest achievements of nantotechnology: diagnostics and the selective delivery of drugs at the same time.”
The development of drug-delivery products especially appeals to both healthcare sectors. In many cases, a single product consisting of both the drug and the delivery mechanism is safer and more effective than either one of the components acting alone. Targeted drug delivery, cost reduction for manufacturers, and convenience for patients and healthcare workers are also potential advantages of this growing market segment.
“Drugs and devices are fundamentally quite different,” says Sharad Rastogi, also a principal in PRTM's Life Sciences Business Group.“But lately, what people are finding out is when you put the two together there are enormous benefits. Companies see the promise of a new technology, yet they have a little fear or skepticism of dipping their toes in the water.”
And it’s no wonder many companies have hesitated in taking the plunge into the development of combination products. Despite the potential profit, an endless stream of challenges arises with the development of these convergent technologies. Bringing together the pharmaceutical and device industries means collaboration must occur between people with very different mind-sets and practices, Cramer says. Furthermore, Cramer points out that manufacturers must reevaluate marketing strategies. Device companies typically target hospitals and healthcare environments, whereas some combination products will be available for consumer use.
Blurring Regulatory Boundaries
Novel concepts inevitably introduce a slew of new questions and concerns. In the case of combination products, FDA approval and regulation have been the sources of many obstacles. Whereas drug, device, and biologic products are typically submitted to one of FDA’s three medical-focused agencies, combination drug-device, device-biologic, and drug-biologic products contain elements that fall under the authority of more than one center.
“The biggest challenge centers on product classification, which is a function of how the combination product is likely to affect the patient,” says Ann Quinlan-Smith, president of Alquest Inc. (Minneapolis; www.alquest.com), a contract research organization specializing in combination products. “Does the product have more of a localized effect, which is common to medical devices, or is it systemic, as in the case of pharmaceuticals? Investors often will push to get combination products classified as a device, which traditionally has a lower regulatory and cost burden.”
Established as a result of the Medical Device User Fee and Modernization Act of 2002, the Office of Combination Products (OCP) oversees the handling of these products that straddle the jurisdictions of the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH). OCP is responsible for determining the submitted product’s primary mode of action and, based on this decision, assigning it to the appropriate FDA agency. In 2006, FDA received 231 original applications for combination products.
And yet, despite the institution of an office dedicated solely to matters associated with the boundary-blurring inventions, ambiguities surrounding development, manufacture, and FDA regulation of combination products persist.
“FDA is putting more focus on combination products—they put together the OCP; it’s good to see they’re making strides in that respect,” Cramer says. “However, that model is still evolving, and for all intents and purposes, they’re coordinating between two different agencies.
Companies that are used to dealing with CDRH, CBER, or CDER are dealing with 2, 3, or 4 agencies. And they’re still getting their feet wet learning how to walk and to get this model to work. But what it means for companies now is that there will be extra effort around the regulatory push,” he continues.
FDA regulation of combination products tends to be one of the most prominent hiccups in the development of combination products. For example, FDA requires that drugs adhere to current good manufacturing practices (CGMP) regulations while devices follow quality system (QS) regulations.
But what about products that combine both? Because of some overlap in the two regulations, the development and manufacture of each separate component only has to meet the standards set forth by the applicable regulation. However, upon copackaging or combining the drug and device into a single product, it must comply with both sets of regulations, according to FDA.
Alquest Inc. witnessed a pharmaceutical client’s struggle with regulatory systems while developing a combination product. “We were surprised at how difficult it was for the drug company to handle nonconformities in the device manufacturing process,” says Quinlan-Smith. “In particular, product variability with medical devices is treated differently than in the pharma sector. In both directions—pharma and device—we learned that you have to be prepared to adapt to disparate manufacturing controls and to develop a single quality system that meets both drug and device good manufacturing practices requirements.”
To assist in doing so, FDA has identified key differences in the two regulations and recommends that manufacturers of combination products take these points into account during and after combining the drug and device components in order to ensure compliance. FDA also suggests that manufacturers discuss regulations and how they apply to their specific combination product during preinvestigational meetings and development stages.
Despite all of the frustration and changes it has caused, compliance is not the only stumbling block. Merging two vastly different technologies into one application also breeds a host of additional development and manufacturing challenges.
“More often than not, when you’re [developing] a combination product, you’re bringing together two on-market approved products, and the fundamental disconnect is that people think if we put these two together, lo and behold we have a product,” Cramer notes. “The type of thinking FDA wants to see, however, is what happens at the boundary between these two. How does the interface change the fundamental characteristics of the product?”
A combination product may consist of an FDA-approved drug and device; however, using the two components together may yield unexpected results. The addition of a drug to an existing device could make the combination therapy more vulnerable to cracking or corrosion than the stand-alone device. Consequently, interaction between the drug and the device should be evaluated for adverse reactions, FDA cautions. Using the combination product for a broader target audience, new route of administration, or different part of the body than that of the already-approved device could generate developmental hurdles, according to the agency.
Despite the incorporation of an approved device into a combination product, manufacturers may also have to conduct additional preclinical safety testing. The device’s functionality within the new environment and role as one part of a combined therapy will likely require this phase.
Similarly, packaging and sterilization of drug-device products may differ from standard operations for individual components. Drugs may not be capable of withstanding processes typically employed for device sterilization. Furthermore, because of dissimilarities in drug and device requirements, manufacturers also are confronted with packaging considerations. Packaging for combination products may demand more and different tests than the single device, to confirm that the package is protecting the device and preserving the drug.
Shelf life is another factor that must be acknowledged when developing a drug-device application since the shelf life of a drug is often much longer than a device. Plus, some drugs do not change significantly over time, while device technology evolves at a much faster pace. The device component of a combination product could theoretically become obsolete long before the drug does.
“You have to be a lot more careful about the manufacturing changes you make on the combination product side because you don’t know how those processing and manufacturing changes will affect things like shelf life and sterility,” warns Cramer. “From a development standpoint, you have to have a greater focus on internal business requirements early in the development process.”
Predicting the Future
Most experts agree that combination products are the next big thing in the medical device industry. Visions vary of this future industry landscape, however.
Because of the therapeutic and financial advantages of making a combination product, there may come a day when drug and device companies secure a permanent partnership, according to Ahmed of FlexOne. He hypothesizes that as soon as five years from now, mergers and acquisitions may unite many drug and device companies under one roof for cost-effective and convenient manufacture of combination products. The notion of a one-stop shop offering complete control over design, development, and manufacture of these enhanced devices is the logical next step, he surmises.
This potential union of industries will not come without significant obstacles, Ahmed admits. “There are hurdles to cross and things to learn before we can get to that point,” he says. “They are different cultures; the drug industry and the device industry are totally different. They have different technologies.”
Significant industry cross training would be necessary to successfully produce combination products via the merger of these disparate companies. Manufacturers that may absorb drug firms will have to be knowledgeable about both the drug and the device. “If you’re going to be designing a product that is going to be delivering something, you have to have a complete understanding of the drug itself,” Ahmed says. “If you don’t understand the drug and its composition, how it acts under certain situations, you won’t be able to deliver it with the device that you’re designing.”
Quinlan-Smith of Alquest is less convinced of a union between drug and device manufacturers. “Pharma and device mind-sets and differences are substantial enough that integration in our view will be very difficult,” she says. “However, we do believe that biologic and device manufacturers represent a more natural fit. The inherent variability of both product types lends itself to more common manufacturing, compliance, and regulatory approaches.”
But a surge of mergers across any of these industries may not be in the cards for combination product manufacturers, according to Cramer and Rastogi. After all, some pharmaceutical companies have had device divisions in the past, but elected to spin them out for economic reasons, Rastogi points out.
“The development model is changing,” Cramer says. “The new trend that we’re seeing is the idea of open innovation.” Rather than contemplating mergers, major device manufacturers are focusing on honing their specific skills and keeping a sharp eye out for ideal partnerships and opportunities in such areas as combination products.
Regardless of what the future holds for combination products, the present is marked by innovation, anticipation, and perhaps a bit of trepidation. Proving two heads are better than one, combination products draw from the expertise of two vastly different cultures to produce one device that holds immeasurable possibilities for the medical industry.