Transformative Technologies Emerge When Worlds Collide

CONVERGENCE

Convergent technologies just may be the key to the future of medicine. Advances in nanotechnology, coatings, and molecular diagnostics have blurred the lines of devices and pharmaceuticals. But the convergence spreads even wider as the drive toward personalized medicine leads to the development of products such as digestible electronics to monitor health. Convergence is also enabling the delivery of lifesaving proteins whose toxicity precludes systemic delivery.

As a market, it's impossible to define. “It's so pervasive, it cuts across everything. When you get down to specific products, then you can measure it. You can measure the growth of drug-eluting stents, for example,” says Charlie Whelan, director of Frost & Sullivan's healthcare and life sciences consulting practice. With the convergence of healthcare IT, diagnostic imaging, clinical diagnostics, medical devices, pharmaceuticals, and biotech, they're all beginning to overlap with each other, says Whelan. “It's moving too fast to define.”
Incorporating pharmaceuticals into devices is certainly not new; these combination products have been around for 20–30 years. But the growth and the reach in recent years has been explosive. FDA formed its Office of Combination Products back in 2001, but the number of submissions continues to increase, and now new GMPs are on the horizon.

Opportunities and Drivers
Some of the opportunities in the world of convergent technologies may be a function of market forces rather than the technology itself. Terry Hisey, vice chairman and U.S. life sciences leader for Deloitte LLP, suggests that there are three promising new opportunities for convergence.
“The first is continued convergence as it relates to targeted therapies or what is most often referred to as personalized medicine,” he says. “This convergence will continue to happen in the increased linking of diagnostics and therapies. With the need to have more novel and targeted therapies, the need to confirm both appropriateness and expected effectiveness will be increasingly important.”
Another area will be the convergence of disease management with the desire to be more mobile and independent in care management, he says. This merger will lead to the introduction of many new products to support the shift from acute to ambulatory to “anywhere” care management. Although many now think of convergence as the combination of a drug and a device, he says that the future will also include the idea of communication and information as part of the convergence formula.
The third key area, he says, is the convergence of multiple components to more effectively support disease management for chronic conditions such as diabetes and cardiovascular problems. In addition to personalized medicine, some other major drivers include unmet medical needs, improving clinical outcomes, and improving access. A movement to more “anytime, anywhere, all-the-time healthcare management and delivery,” will also play a role, says Hisey. He points to continued “consumerism” and healthcare reform as reasons for growth.

Some of the most promising areas for convergence lie in technologies such as the combining of a polymer or similar substrate with a drug or biologic, says Michael Adams, president and CEO of AdvanSource Biomaterials. “Polymers offer a unique platform in that they can easily be impregnated with a therapeutic agent and, based on the polymer, can be released very quickly or very slowly based on the indication. One can easily see a chemotherapeutic agent bound to a polymer and released by a controlled elution.”

Another exciting area of potential opportunity lies in soft tissue regeneration. “As the population ages,” says Adams, “we not only wish to be pain free from injury, but we also want to be active. He suggests that repair of soft tissue injuries by combining a polymer and a drug or biologic is a very exciting possibility that will allow patients a more fulfilling lifestyle.
Adams also points to a number of opportunities that have been created now that stem cell research has been expanded. For example, he says that the possibility of using a polymer scaffold combined with stem cells opens the door for some breakthrough opportunities to treat disease states that up to now have been untreatable, or where current therapies have had marginal benefit.
The primary driving forces behind this convergence are patients, providers, insurers, and industry. Patients want therapies that are less invasive and more effective. Further, they want to maintain an active lifestyle. And with many of the converging orthopedic applications, they will be able to do so.
Some driving forces are not readily apparent. Most agree that providers want access to the latest technology for treating disease states that may not have been previously treatable or have had limited success. Insurers want cost-effective therapies that effectively treat a disease state such that the patient does not require extensive monitoring or follow-up, says Adams. Converging technologies may help to reduce patients' need for long-term follow-up care.
Treatment for each disease has its own delivery problems, notes John Patton, president and CEO of Dance Pharmaceuticals, and new combination devices can work where traditional methods have failed. “In oncology, the old adage that ‘we don't need any new drugs—we just need better ways to deliver them to the tumors' has been around for a hundred years and it's still true,” says Patton. “Topical delivery to the skin is a different issue; you've got to follow the unmet need.”
Combination products will play a key role in all aspects of personalized medicine, says Hisey. In particular, these products will play an increasingly critical role in genetic testing, establishment of risk and predisposition profiles, diagnosis, treatment, and ongoing condition management. The key to developing these products, he says, is to ensure that they meet the necessary profiles for various design goals. These profiles include the quality of the test, usability (for users ranging from trained professionals to home use), ease of understanding, and the right economics. “With changes in reimbursement and the continued emergence of consumerism, the right offering at the right price point is essential for adoption beyond just approval.”

Enabling Technologies and Platforms
Advances in many fields are contributing to the development of converged products. Some will play a larger role than others, of course. Hisey notes, for example, that those dealing with molecular diagnostics will be increasingly important for development and bringing targeted therapies to market.
Adams says that the ability to place a drug or therapeutic agent on or in a polymer scaffold is a platform with wide potential for adoption. “What is paramount,” he says, “is that the drug/biologic and biomaterials companies form alliances that bring the two technologies together.” Doing so, he explains, enables each to better understand the special conditions necessary for a successful product and shortens time to market.
One of the most talked about opportunities of the future is development of products at the nano level where combinations of very small amounts of targeted agents can be implanted directly to the site of interest, says Adams.

Advances in coatings technologies have been a primary component in the development of the drug-eluting stent (DES), one of the most well-known combination devices. “We are one of the pioneers in drug-delivery coatings. Our Bravo coating was used on the Cypher stent,” says Robert Hergenrother, PhD, senior director of process development for SurModics.

Hergenrother notes that those DES coatings were durable, but that the company is now also working with biodegradable coatings for stents. Its SynBiosys coating, which is a multiblock polymer, is made up of poly(lactide-coglycolide) (PLGA) and polylactic acids that have polyethylene in them. He says the multiblock structure offers nice properties in terms of its adhesion to metals. The structure also allows the drug to elute out with a bit of a lag on the release and then accelerate several weeks later. In addition, he says, the structure allows it to degrade a little faster.
“That time between when the drug is out and when the polymer is degraded has been shortened, and so once the drug is out, you really don't need the polymer anymore. We've been able to shorten that by a month—sometimes even two—depending on the material.”
Hergenrother says some SurModics customers wanted to move more toward the degradable polymers because for some applications there is a concern about leaving the polymer behind for long periods of time.
But coatings aren't just enabling development in the cardiovascular market. SurModics has used its durable coating in its own I-vation intravitreal implant for ophthalmology applications. “This is one where we have complete control of the whole delivery platform. When we're talking to pharmaceutical companies, we tell them we can marry that platform with their particular drug,” he says.
One coating technology still in the development phase is a polysaccharide-based, naturally occurring polymer that SurModics modifies with fatty acids and other hydrophobic chains to prevent them from being water soluble. It enables the release of the hydrophobic drugs such as paclitaxil to be controlled. “We're working on finding that sweet spot of the drug-delivery aspect and the degradation aspect, as well as the mechanical adhesion properties and expansion properties. It's a very intriguing platform for us because it's made out of more-natural materials, and so that's our next-generation biodegradable coating.”
SurModics has licensed PolyActive, another degradable polymer, from a Dutch company called OctoPlus. This polymer will be used to develop protein-delivery coatings. Proteins, which are larger than conventional drug compounds, tend to be water soluble and fragile. “That has created a unique set of challenges in terms of delivery. They can denature, and they must have a tertiary structure in order for them to work,” says Hergenrother.
The company has been working with the PolyActive as well as other polymers to come up with coatings that not only deliver the proteins, but that deliver them in an active form. “These are designed for site-specific drug delivery, and in those cases, you usually have a considerably lower dosage than a systemic delivery of the compound. Reduced toxicity is one of the advantages of a using a coating for site-specific delivery.”
Hergenrother says that advances in coatings technology have revolutionized and rejuvenated the stent market, and that now other markets are seeing growth. “Certainly in the ophthalmic space we're seeing delivery of site-specific drugs, and the orthopedic space is increasingly integrating coatings in terms of infection control for some implants as well as the bone morphogenetic protein drugs to stimulate bone growth.”
There's another aspect of convergent technologies that doesn't require a drug, says Hergenrother. In this case, coatings are used to induce what SurModics calls a prohealing response, which involves using a coating to encourage the body to heal itself. For example, the company's Finale coatings help promote endothelialization. The extracellular matrix protein-based coating is designed to improve tissue healing for implantable medical devices such as vascular stents and grafts. The coating is put onto a device or stent and placed into the bloodstream to help minimize thrombosis events.

Leading to the Future

Many combination products provide benefits over existing therapies or enable the development of products to address problems that couldn't be solved using traditional methods. “There are limitations as to where you can go with current approaches and components,” notes Hisey. “The problems in the healthcare arena are multifaceted in nature; combination products will impact diagnosis, care, new delivery models, access, and ultimately the new economics of healthcare with increased focus on comparative effectiveness and the role that will play.”

Drugs can, and in many cases should, be locally delivered in a controlled way, says Steve Oesterle, MD, senior vice president for medicine and technology at Medtronic. “The issue here is that a lot of the side effects that you see with systemically distributed pharmaceuticals that are taken by mouth is that you basically are trying to get a dose of drug to a specific area to do good.” Oesterle uses the treatment of Parkinson's disease as an example. “People take pharmaceuticals like L-dopa or Sinemet with the hope that they can get enough through the blood-brain barrier to have some good happen.” But, because the L-dopa has to move through the body, it causes systemic side effects.
Medtronic's approach is that controlled, local delivery of the drug is a much more effective way to treat certain problems without the systemic side effects. It has developed products through its neurological pump business to address these issues. “We've been infusing the drug into the central nervous system by putting a catheter in the intrathecal space (the space between the spinal cord and the dura), sneaking around the blood-brain barrier in the back door,” explains Oesterle. “We basically deliver drug to the spinal cord directly using a catheter and a SynchroMed pump to deliver a drug called Baclofen.
Medtronic has spent more than 10 years working on a combination product for the spine. The InFuse product, which is a recombinant human bone morphogenetic protein (BMP), enables local delivery of the protein. “You can't just squirt in BMP. It has to be locally delivered and controlled. We do that through a polymer sponge and a spinal cage (a so-called Michelson cage). That was approved as a combination product.”
Advances in vibrating mesh technology have changed the landscape for liquid inhalation devices. “They're called soft mist inhalers, and basically it's a vibrating mesh that doesn't take a great volume of air,” says Patton. “It's enabling smaller liquid system devices. I think you'll see more electronics in inhalation devices.”
The other explosion of medical drug-delivery devices has been in the injectable area. Patton says advances in the cartridges that contain the drug have revolutionized pen technology. “The pen technology has really taken over the diabetes injectable devices. This has spilled over into biotech where they have injectable proteins. As more of these molecules come off patent, really nice autoinjectors are taking over the market and determining [which companies are] going to be competitive. These include some molecules given by IV infusion. Now they're figuring out ways so that you can give yourself a subcutaneous injection at home.”
An interesting development in the asthma market is that the devices are becoming the blockbuster part of the product. “There are a whole bunch of drugs that are old and they work fairly well, and if you put two of the most common ones together in a combination powder, for some reason the patients do better. “So if you're working in this particular area of asthma, your device could be a blockbuster,” he says, adding that if a company had a great multidose dry-powder inhaler, that company could rise above the rest of the pack. But, he cautions that the uniqueness of each molecule is important.
Intelligent Medicine

One company, Proteus Biomedical, is bringing together electronics and pharmaceuticals to develop pills that monitor health and send the results back to the patient or physician. “There are roughly 4 billion people in the world who can access computer networks. An absolutely huge opportunity is to help health systems access that already-existing network,” says Andrew Thompson, cofounder and CEO of the company. “At Proteus, the drug is the plug. It is how you plug a patient, a family, a health system, and an insurer into that network so that they know what therapy the patient is on, when they take it, how they respond to it, whether they're using tools and applications to live a healthy life. And if you know that, you can reward people—you can pay them—for doing those things.”
The company's ingestible technology turns the pharmaceutical into an intelligent medicine. The microchip-enabled medications and associated personal health companion—a small electronic Band-Aid—monitor medication adherence, heart rate, sleeping, activity, and even heart rate variability. The patient and doctor can use the data to customize therapy.
“We can show you whether you're doing your exercise. We can do a lot of good things to help you understand how to manage your life better,” says Thompson. “We do all of that for the same price that you currently pay just for a drug. One price. Once a day. We're in clinical studies now, but these are products that will [probably] hit the market in 2011 or 2012.”
China, which has a huge emerging urban population, and Europe, which is poorer than the United States, will likely be early adopters of such technology, he says. “They'll have to innovate faster. We are going to do interesting clinical work in Europe. And then Asian countries—China, India—are going to be the places where we see by far the most innovation from a delivery-system perspective.” Thompson says that the company is “trying to be highly relevant in the kinds of technologies we're trying to develop to solve those problems. We're in tuberculosis, where we are replacing directly observed therapy, which is what the World Health Organization currently requires, with electronically observed therapy.”
The company is also focusing on heart failure. The pills can track people's use of their medications. It uses physiologic sensing to track wellness to see when people have disrupted sleep, when they're not able to do their prescribed activity, and how the use of medication affects activity and sleep. “We're using the drugs that people already take, the cell phones they already carry, and the networks that they're already part of.”

With this technology, Thompson says that eventually every pill in the supply chain could contain such electronics, and says that is where the company is headed. “If you do that, you've created probably the most secure pill-level supply-chain integrity platform ever conceived,” he says. He also says that it would be a very inexpensive means of addressing the issue of counterfeiting of medications.
Thompson says this technology could have significant implications for the global pharmaceutical industry, noting that there is roughly a trillion dollars worth of discovered—now generic—molecules. “No one will invest in new applications for those molecules because anyone can make them. But, if we put a chip in it, we can put a patent on it. And more importantly,” he says, “we can build applications layers on top of it, build relationships with our customers, and create new competitive barriers.
“It's really important that we don't look to our political class to define the way we innovate. It's much more important that our industry, understanding the scope and scale of resources that are available, figure out what the future might look like,” says Thompson.
The Regulatory Environment

New GMPs for combination products will likely be issued this year. Proposed rules for combination products are moving through FDA for clearance now. Industry can also expect a number of new guidance documents, focusing mainly on policy, but also on specific product areas as needed.

“The proposed GMPs have been in-house for a while, but they are going through the process now. I'm hoping they will get out at some point this year, but I can't predict the date,” says Thinh Nguyen, director of the Office of Combination Products at FDA. “I am excited about transparency, and when those rules are out we will get to talk about them a bit more. Everybody's been waiting for those rules to come out for a while but it has to go through its proper channels.”
Once the proposed rules are published, he says the agency has planned presentations and public forums to discuss the rules. “Internally, we have created a working group to walk through some of the examples on the CGMP for combination products. Once you have a rule, then you need to see how it is applied to the actual products you see,” says Nguyen. The internal working group, which has staff from the different review centers, will go through the GMPs to see what the requirements would be if the rules were applied to a certain type of product.
Nguyen says that the biggest challenge for both FDA and manufacturers is that there is not enough regulation or guidance for combination products. “There are a variety of different combination products, and I think our challenge is to try to get more guidance out to help industry and to help our own staff as to how they should review certain products,” he says. As an example, he points to the recently published draft guidance document on autoinjectors. He says he hopes to provide more guidance “to give the industry an idea as to the kind of technical information we look for in the premarket application.” He is currently working on developing policy and regulatory pathway guidance documents. Other guidances might focus on a specific product type if the office receives a lot of applications or questions in a particular area.
“I don't want to write a guidance document that's not helpful to industry. I'm always engaged with industry organizations to make sure we are doing the right thing,” says Nguyen. For example, he says, companies wanted to know FDA's expectations to ensure that their manufacturing plants for combination products were in compliance. “They told us, ‘We don't want to spend millions of dollars and then have FDA tell us it's not the right one and have to go back and do it over.' We got that message loud and clear and that's what we're trying to work on.”
The Combination Products Coalition. The Combination Products Coalition (CPC) is made up of a group of companies in the drug, device, and biologics industries. It works to improve the regulatory environment for combination products by developing and advocating policy positions on regulatory issues affecting combination products.
“A lot of what I do in my role with the coalition is to urge companies to get active in advocacy,” says Bradley Thompson of Epstein Becker & Green. “A longer-term strategy is trying to make sure that the environment is a sensible one for achieving compliance with GMPs. The GMPs have the potential to affect the industry in profound ways. Factors like design controls will have to be applied to the earliest development on a drug if it's going to ultimately find its way into a convergent product,” he says. “That really affects how you partner with other companies and at what stage you need to work with your partner companies.”

Thompson says it's essential that manufacturers of combination products comment on the proposals when they are published by FDA. Because the products being developed vary so widely, he says the agency can't be expected to know how these rules will impact this very diverse industry. “FDA is not a business and is not as knowledgeable as a company would be in terms of the business process issues that arise from complying with the GMPs. During the comment period, it will be incumbent on the companies to identify those things that aren't practical and to raise constructive solutions,” says Thompson.
“The new GMPs will be key going forward,” says Hisey who notes that the regulations will provide new and modified regulatory pathways, transparency, guidance on required information, and also a clear understanding of the global needs (assuming products are for more than the U.S. market). He stresses that the future will require an active dialogue with all players. With the advent of comparative effectiveness research and other market factors, he says, “approval does not equal adoption” in the market of new products.
Bridging Different Worlds
Most of the time, converging technologies means the bringing together of two or more companies with differing capabilities. Among the characteristics necessary to move forward are a number of key capabilities related to product development, integration, alliance formation and management, and strong regulatory capabilities, notes Hisey. He says that as most of the convergence efforts involve capabilities that extend beyond a company's four walls, “the alliance skills are a critical component of success with a meaningful technology contribution being expected.”
Thompson says that one of the things that helps companies is to talk with other companies that are in similar businesses to see how they handle regulatory issues. In a call every other week, CPC member companies compare notes about the draft GMPs and discuss how they interpret and apply the requirements. “The most cost-effective technique for ensuring compliance and ensuring that products are safe and effective is to share best practices,” says Thompson.
He says that companies heading into collaborations often fail to map out a strategy for the regulatory and quality requirements. “At the very end, they're looking at what they've each developed separately and they're saying, ‘how are we going to meld this and release this as a combination product when we, the device company, are obliged to apply Part 820 to the whole product but the drug component was not developed with traditional design controls in mind. It is very expensive to go back and recreate that strategy,” he says.
As companies structure these partnerships, they should examine the quality and regulatory issues as soon as they can to ensure that they can meld the products under appropriate quality standards at the time they want to go to market.
One problem that Patton has noticed is that many device companies make a technology first and then they'll approach a pharmaceutical company. “It's very important to make the device with the drug, because there are so many drug-device interactions. You cannot develop these devices in a vacuum.” He says it is equally critical to “put an important molecule” in the device. “Do all of your work with it because particular molecules have different behavior in these devices. One may stick in the corners and one may crystallize and clog up the device. Due to the variety of chemistries involved in any drug, you have to be aware and build your device around that,” says Patton.
Conducting Clinical Trials
Conducting clinical trials for these converged products is another hurdle that manufacturers must address. “The first thing that we have to assume is that folks who are designing the trials really understand how the product will be regulated,” says Barry Sall, principal consultant with Parexel Consulting. The product may be regulated in different ways in different jurisdictions. FDA could classify a product in one manner, and it could be classified differently in Europe.
Sall recommends communication with members of the ethics committees and institutional review boards who may not be familiar with that particular kind of a product or with combination products in general. “This is something that sponsors need to keep in mind and maybe provide them with extra information packages that might smooth the path of ethical review of the study,” he says.
Because combination products are often more complicated than conventional products, sponsors must consider the implications. First of all, if the sponsor is a pharmaceutical company that now has a computer-controlled drug-delivery device, he says that training becomes more of an issue. “You have to train the personnel at the sites; perhaps qualify operators to make sure they understand how the product is supposed to be used. And, you have to train your own personnel who are dealing with the sites, whether it's clinical research associates or others; make sure they understand periodic maintenance, supplies, and consumables.”
In some cases, similar products exist and so the regulatory pathway is clear. Other times, because of the innovative nature of combination products, there are no precedents. Basic fundamental protocol design issues—selecting primary and secondary endpoints for treating some types of diseases—are key. From a device perspective, some endpoints may be more commonly used than from a drug perspective, explains Sall. Drug companies may value endpoints different from the ones of interest to device companies. “You're generating these data in order to support the regulatory application and for a particular indication for use. You have business concerns that are driving you to define a particular market and particular indication for use,” he says. Those factors affect your choice of endpoints as well as the preferences of regulators.
It's also important to address the length of follow-up. “With drug-eluting stents we've seen that the data are refined as the follow-up period increases,” noting that follow-up times for devices are generally shorter than for drugs.
One critical challenge in clinical research for combination products, Sall says, is dealing with adverse events. “There is no universal approach,” he says. “Construct a system that's sensible to you and then go to the regulators and explain your proposals and achieve some common understanding,” he says. FDA's new GMPs are expected to provide more guidance in this area.
“One of the advantages we have on the device side is that risk analysis is ingrained in device development. Doing a risk analysis is going to help identify some of the issues that have to be worked out for a particular technology.”
It is essential to contact the Office of Combination Products and request either a pre-IDE or pre-IND meeting with the center that has primary jurisdiction. Request that members from the other center be present at that meeting. Sponsors can help ensure that those introductions are made at FDA to facilitate communication.
On the Horizon
“It is very difficult to generalize about combination products,” says Sall. “Sometimes you can find precedents, and others because of the innovative nature of the technology, you have to blaze your own trail.”
The widespread convergence of so many technologies holds great promise for improved disease management, the advent of personalized medicine, and the development of intelligent medicine.
Sherrie Conroy is editor-in-chief of MD&DI.
Copyright ©2009 Medical Device & Diagnostic Industry