A Perfect Combination?
Global cost pressures and mounting competition is prompting the medical device and pharmaceutical industries to bury their long-standing rivalry and work together to foster innovation.
There’s a doctor in Clifford Simak’s 1961 science-fiction classic “Time is the Simplest Thing” who touts the miraculous healing powers of an alien drug called Gobathian. Found on a planet thousands of light-years from Earth, the cure-all pharmaceutical was developed by hostile extraterrestrials to repair their broken bodies.
“What do you know about Gobathian?” the doctor asks the novel’s hero, Shepherd Blaine.
“I’ve heard of it,” Blaine replies.
“An alien drug,” the doctor tells Blaine. “Used by an insect race. A warring insect race. And it’s done miracles. It can patch up a smashed and broken body. It can repair bones and organs. It can grow new tissue.”
Wonder drugs that can grow new tissue or fix broken bones no longer are relegated to the pages of pulp science fiction. In the last half century since Simak’s novel was published, life increasingly is imitating art as researchers turn to cutting-edge techniques to help the body heal itself.
One technique being developed at the University of California, Davis, seems as if it belongs in Blaine’s world of telepathic space travel and instantaneous bone fixes. Indeed, the material could have originated in Simak’s imagination (the substance sounds strangely similar to Gobathian, though it was harvested right here on Earth—by humans, no less!).
Kent Leach, a biomedical engineer at University of California Davis, received a grant last year from the U.S. Army to explore the use of stem cells to help heal bone. Leach is experimenting with stem cells taken from fat tissue to stimulate the formation of microvascular networks within developing bone. The regeneration of bone depends on the formation of these networks to deliver oxygen and other nutrients necessary for healing.
Leach embedded the stem cells in a special gel to implant them directly into the injured site, according to the university. This “composite hydrogel” contained a mixture of various polymers that controlled the rate at which the gel degraded. Materials that degrade too slowly impede tissue formation, while gels that degrade too quickly cannot hold stem cells in place. Scientists mixed stem cells and other chemicals into the gel and injected it in liquid form into a bone fracture or defect. The gel congeals, trapping stem cells at the defect site and promoting bone repair. The university claims Leach’s team already has developed a composite hydrogel and used it to deliver stem cells derived from bone marrow to injured horses.
Leach believes his approach to bone healing has several advantages over other approaches.
First, and perhaps most importantly, stem cells from a patient’s own body have a better chance of succeeding and forming bone than donor cells, he said. In addition, the process of extracting bone marrow to obtain stem cells can be excruciating and usually requires several days of recovery time, he noted. Such a procedure is not feasible for severely injured or weak patients. Doctors, however, can extract stem cells from fat with relative ease and minimal invasiveness.
By using a composite hydrogel to affix stem cells to injured bone, Leach is hoping to increase the amount of stem cells that remain at the damaged site. More stem cells theoretically should lead to increased neovascularization and faster bone regeneration. In addition to mixing stem cells into the hydrogel, the team mixes chemicals that attract bone-building substances already present in the patient’s tissues. Those substances stimulate the growth of blood vessels and enable the stem cells to become bone cells.
“Stem cell research is a tremendously exciting area,” said Joseph M. Lane, M.D., a professor of orthopedic surgery at the Hospital for Special Surgery in New York, N.Y. “A study by a group [of researchers] at Cornell [University] concluded that stem cells can lead to the regeneration of cartilage. And, there is evidence to show that stem cells used in higher concentrations at the site of an injury or fracture can lead to a much quicker healing process. There are some new techniques out there for using stem cells in higher concentrations in non-union fractures and achieving union.
One of the newer concepts that has been developed over the last year is osteopromoters, which go to the area of a fracture, strip away the blood supply and add an ingredient to help with [bone] growth. Growth factors are also being added to stem cells to help promote healing.”
One such growth factor that has gained traction in the orthopedic industry in recent years is bone morphogenetic proteins (BMP), which help stimulate bone growth naturally in the human body. Used primarily as a substitute for iliac crest bone graft during spinal fusion and tibial fractures, BMP use more than quadrupled between 2003 and 2007, going from 23,900 procedures in 2003 to 103,194 in 2007, according to statistics from the American Academy of Orthopaedic Surgeons. There currently are two types of recombinant human BMPs approved for use in the United States—rhBMP-7, originally marketed as OP-1 by Stryker Corp. (the implant manufacturing giant recently sold its OP-1 product line to Japanese medical equipment maker Olympus Corporation for $60 million) and rhBMP-2, sold by Medtronic Inc.’s Spinal and Biologics Division under the Infuse brand name.
In spinal surgery, BMPs generally are used in combination with titanium cages that can withstand the enormous forces the body exerts on the spine. Collagen-mediated applications of BMP usually are sponge-like in texture and inserted into the cage; the entire device then is implanted between degenerated vertebrae to keep them properly spaced and aligned during the fusion process.
Though bone growth proteins were identified as far back as 1965 (even further if the 1889 discovery of the therapeutic benefits of decalcified ox bone is taken into consideration), the road to market for BMPs was a long and arduous one for manufacturers due to the flexibility of applications inside the body. For example, BMPs are used with intramedullary nails in shin fractures, titanium cages during spinal fusions and dental implants. Such product marriages made the regulatory process for BMPs a difficult one because they did not fit neatly into the “biologic,” “drug” or “device” categories that existed within the U.S. Food and Drug Administration (FDA) at the time.
A growing number of products have fallen outside the FDA’s categorical boxes over the last decade as device manufacturers and pharmaceutical giants mixed and matched drugs with medical implants to help lower their growing cost margins, find new sources of growth and fend off competition from outside industries as well as each other. These product hybrids prompted the FDA to establish the Office of Combination Products (OCP) in late December 2002.
“Combination products evolved as manufacturers sought improvement and differentiation of their products. This ranged from such basic ideas as improved delivery to innovative secondary mechanisms of action to improve patient health,” explained Lisa Olson, vice president, testing and service development for Wuxi AppTec, a pharmaceutical, biopharmaceutical and medical device/combination product outsourcing company with operations in both the United States and China.
“Additionally, manufacturers wanted to be able to extend the life of their products and hold on to marketplaces without having to completely start at the beginning of the discovery phase. The use of new materials such as processed tissue as device biomaterials evolved was a natural extension of trying to make devices as biocompatible as possible while also engaging the body’s natural healing mechanisms.”
The Combination Conundrum
The medical device and pharmaceutical industries are more dependent upon each other than either is willing to admit. As one drug delivery specialist claimed: “All issues cannot be solved with mechanically performing devices, and most devices are designed as a structural replacement in the body. The medical device function can be enhanced by including a drug on the device.”
Mixing drugs and devices has its obvious advantages, not the least of which are improved treatment options, quicker recovery times and cost effectiveness. Some combination products feature the controlled release of an active pharmaceutical ingredient (API), which allows the drug consistently to be maintained within an optimal therapeutic range. Implanted drug-eluting devices take that controlled release benefit a step further by enabling the medicine to target a specific area of the body, thereby allowing physicians to deliver higher therapeutic doses to diseased or damaged cells while minimizing adverse side effects.
Besides controlling the amount and length of time a pharmaceutical is released into the bloodstream, combination products also help improve patient compliance. Such an advantage is bound to become more important in the next few decades as the nation’s baby boomers mark their retirements and strive to maintain their active lifestyles into their 70s and 80s.
Combining different product types, however, has generated a panoply of challenges for the FDA, pharmaceutical, biologics and medical device manufacturers, and other stakeholders.
One of the most vexing is the fundamental cultural differences, mindsets and business strategies that exist between medical device and pharmaceutical companies. The two industries also target different markets, with medical device firms focusing on hospitals and surgeons and drug makers zeroing in on consumers and medical specialists (cardiologists, for instance, are the prime customers of drug-coated and drug-eluting stents).
“One of the more interesting challenges comes from the differences in the technical disciplines required to successfully execute a development program,” noted Peter D. Noymer, Ph.D., vice president of product research and development for Alexza Pharmaceuticals, a Mountain View, Calif.-based company developing a small, handheld device that can deliver medications for rapid treatment of agitation in patients with schizophrenia or bipolar disease. “Looking at just individual product types by themselves, drugs are typically developed by chemists and medical devices are typically developed by engineers. Those two disciplines have different approaches to development and problem-solving. One isn’t better than the other, they’re just different, and to be successful with a combination product, an organization needs to make sure those groups are focused on the success of the overall product.”
That can be difficult, though, considering the medical device and pharmaceutical industries have entirely different priorities. The medical device industry, for example, develops new products by improving upon existing ones: titanium lumbar fusion cages, intramedullary nails, Paclitaxel eluting coronary stents and steroid eluting pacemaker leads are prime examples of devices that were significantly improved by incorporating a medicinal product or biologic.
BioMimetic Therapeutics Inc. is hoping a similar improvement will enable the firm to introduce the first new recombinant bone and tissue growth product in the orthopedic sector in nearly 10 years. The Franklin, Tenn.-based biotechnology firm has developed a product called Augment Bone Graft for the treatment of foot and ankle fusions that is based upon recombinant human platelet-derived growth factor (rhPDGF-BB) platform technology. Not yet approved by the FDA, the rhPDGF-BB technology is modeled after one of the body’s principal agents to stimulate and direct tissue healing and regeneration.
The drive to improve existing products also may one day produce a hip or knee implant that is considered a combination product. Researchers at the Georgia Institute of Technology in Atlanta have discovered a way to strengthen the bond between titanium joint implants and bone by using modified high density polymer strands (similar to bristles on a toothbrush).
Chemists modified the polymer to create three or five self-assembled tethered clusters of a substance called fibronectin.
Using rats as test subjects, the researchers found stronger bonds between implants coated with three- or five-strand tethered clusters compared to those coated with single strands.
The experiments also revealed a 75 percent increase in the contact of the three- and five-strand clusters compared with the current clinical standard joint replacement implants of uncoated titanium.
Such painstaking work to improve existing products is not a top priority in the pharmaceutical world. Companies in this sector generally throw their research dollars into projects that examine new ways of introducing and administering drugs to the body. Unlike the medical device industry, the pharmaceutical sector has little, if any, incentives to develop a new product or improve upon an existing one: Not only is the cost of discovering and launching a new drug astronomical (roughly more than $800 million), relatively few new medicines reach the clinical study stage. Historically, only five out of 10,000 possible new drugs have made it to clinical trials; of those five, only one usually is approved for human use, according to industry estimates.
The cost of developing new administration methods, on the other hand, are significantly lower than new drug discovery. In many cases existing products are more effective and avaricious when they are delivered as a combination product. Transdermal versus oral administration is a prime example: The National Institutes of Health lists about 20 different APIs found in approved transdermal patches, with indications for use ranging from hypertension,dementia and Parkinson’s disease to chronic pain and motion sickness.
More often than not, APIs boost the efficacy of combination products. But that potency depends largely upon the kinds of materials used and the ways in which those substances interact with the drug, experts told Medical Product Outsourcing. Materials that do not mix well with drugs can be more of a hinderance than a help. A polymer that does not react well with certain pharmaceuticals, for instance, possibly could block the release of an API.
Leaching and off-gassing from device or packaging materials pose other potential hazards to combination products. Leaching and off-gassing (the release of chemicals through evaporation)—particularly for devices with long shelf lives—can seep into the drug dose of a combination product and affect its healing ability. While medical-grade materials can help reduce the potential for leaching and off-gassing, experts warn that such dangers are dependent upon the specific combination of materials and their configurations. “There doesn’t appear to be a one-size-fits-all solution,” Noymer pointed out.
There is seldom a one-size-fits-all solution in material selection, though the options generally are more plentiful in the orthopedic sector, where a myriad of metals, ceramics, plastics and biologic substances are available for implantation into a patient population that’s as varied as the human body’s chemical elements. Changing patient demographics not only has prompted implant manufacturers to develop longer-lasting substances for artificial joints, it also is dictating the mix of materials they use in combination products.
Unlike their older counterparts, younger implant recipients prefer to have several options available to them when they are considering undergoing a partial or total joint replacement procedure, experts claim. As a result, life sciences companies increasingly are turning to solutions such as polypropylene-bioabsorbable blends to give patients what some experts deem “good, better, best” options.
“By combining polymers such as polypropylene and an absorbable, you’re putting in an incredibly strong product to begin with, but over time you’re reducing the amount of material or mass that’s left inside the body as the wound heals,” explained Todd Blair, national sales manager at Biomedical Structures, a Warwick, R.I.-based designer, developer and manufacturer of biomedical textiles for the orthopedic, cardiovascular, general surgery and tissue engineering and regenerative medicine markets. “Younger people are now going in for procedures and what medical device companies are requesting is good, better, best options depending upon the patient. If the patient is 85 years old with a hernia, for example, a surgeon might consider putting in a permanent material like polypropylene and not worry about the degradation. But in younger patients, say 55 years old or thereabouts, a surgeon might use something that will absorb or degrade over the lifetime of the repair so it won’t leave so much material behind, thus reducing scar tissue and improving patient comfort and surgical outcome. They’re looking for a few options and there are lots of factors at play.”
There also are lots of factors at play in the sterilization and packaging of combination products. Experts claim current sterilization techniques must be modified to better protect the pharmaceuticals incorporated in the device, while packaging systems must be protective, have a high performance rate and have almost no defects to guarantee efficacy. The most challenging aspect of packaging a combination product, industry leaders claim, is providing the high level of quality these items require while maintaining reliability, ease of use and solid protection from oxygen, moisture and a longer shelf life. Such requirements could command the use of high-barrier-foil laminates coupled with ethylene-oxide sterilizable Tyvek in a sterile-barrier package, for example. Some specialists predict that future incantations of combination product packaging will contain a built-in compartment for dessicant (a substance that induces or sustains a state of dryness) for added protection from moisture.
Resolving the Regulatory Riddles
Medical device and pharmaceutical companies take vastly different approaches to combination product development, but they share the same goal: Gaining FDA approval for their blended items and getting the product to market. And while federal regulations for both medical devices and pharmaceuticals have been in place for decades and generally are well understood by most healthcare executives, the advent of combination products has thrown a proverbial wrench into the FDA’s regulatory approval process, sparking confusion among companies that seek to market drug/device combinations.
Perhaps the most challenging aspect of the approval process is determining a product’s intended use, industry experts told MPO. To make such a determination, however, design engineers and biomaterials specialists must have a solid understanding of the product as well as the technology and materials being incorporated into the item.
Still, an understanding of intended use will only take companies so far. Contradictory guidance documents and unclear definitions of combination products can complicate matters for medical device and pharmaceutical firms, experts claim.
“With the advent of combination products and biomaterials comprised of biologically based materials, not all of the guidelines and standard practices apply,” noted Olson. “In some cases, guidances and the test programs that are currently outlined require significant modification before they can be used to evaluate combination products. Additionally, some regulators may have expertise with single types of products. For example, an expert in biomechanical engineering is going to have more trouble with interpreting the safety issues surrounding a drug product than those issues around a device. With most combination devices, a blending of the diverse regulatory guidances is needed. This can be particularly challenging because these guidances can become contradictory in their instructions.”
Such contradictions has made it difficult to develop broad principles on regulating drug/device combinations. Even the FDA’s formal definition of a combination product is foggy, as its official description of such items include:
1. A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
4. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
The FDA’s definition of combination products is designed to help companies determine whether their drug/device blends should be regulated by the agency’s Center for Drug Evaluation and Research or the Center for Devices and Radiological Health. Firms that need help making such a determination can ask the FDA to step in and make the final call.
Such a request, however, does not guarantee a simplistic, trouble-free path toproduct approval.
Quite the contrary. The FDA can apply any resource it deems necessary to regulate a combination product, according to its own regulations. That means the agency can apply drug directives, device regulations or a combination of both in an effort to assure the safety and effectiveness of a drug/device product. And while most companies consider combination products to be a blend of two different medical product types, it also is possible to mix three (or even more) types in a medical item.
Mary Beth Henderson, a principal advisor at the Regulatory and Clinical Research Institute, a Minneapolis, Minn.-based medical device consulting firm, suggests that companies ask questions of both themselves and the FDA at the start of the product development process to help them navigate the often tricky (and frustrating) regulatory landscape for combination devices.
“The more planning and the more questions you can ask up front, the better off you will be,” she said. “You have to define your product. Ask what is my indication for use? From a regulatory perspective, that sets the stage. The most difficult part of this process is defining the product and figuring out the indication for use. Everything else will fall from that.”
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Engineered from a mix of drug, device or biologic components to form a single product, combination devices represent a relatively new therapeutic and treatment approach. While the market for these products has existed for decades, the device and pharmaceutical industries have only just scratched the surface of the significant earnings potential for this sector. Industry pundits estimate the drug/device combination product market was worth $8.4 billion in 2009 and has the potential to expand at a compound annual growth rate of 12.6 percent through 2016.
That CAG could soar even higher as device firms and pharmaceutical giants put aside their rivalries and work together to ensure their future growth and remain competitive in the global market. As Wuxi AppTec’s Olson noted, “Aging populations, along with the numbers of pharmaceutical products coming off patent and the slowed pharmaceutical approval rate, the opportunities for biomaterials and combination products are vast. There is no indication that any of these factors are likely to change in the near future. Therefore, both device and pharmaceutical manufacturers will want to take advantage of the synergistic effect of combination products.”