PM360 JUNE 2010

TrendSetters

UpClose with Michael Drues, President, Vascular Sciences
BY BRUCE LACEY

Dr. Michael Drues, President of Vascular Sciences in Grafton, Massachusetts, is an expert on combination products and their impact on the pharmaceutical and medical device industries.  Dr. Drues has worked for and consulted with leading medical device pharmaceutical and biotechnology companies ranging in size from startups to Fortune 100 companies.  He also works on a regular basis with the FDA, and teaches undergraduate and graduate courses and company seminars in tactile physiology, biotechnology, regulatory affairs and clinical trials. 

PM360: Can you give us some examples of combination products?

MICHAEL DRUES: A combination product is not simply a drug or a medical device or a biologic, but a combination of two or three of them.  Probably the best known example at the moment is the drug-eluting stent.  Other examples are bone cements that have antibiotic incorporated into them, transdermal patches for drug delivery, inhaled formulations of drugs or biologics (for example, recumbently-produced insulin that is delivered in an inhaler like Exubera),  glucose monitors that have insulin pumps, and so on.  Actually, it’s a growing list.  
It's equally important to be clear on what a combination product is not.  It is not, for example, a drug/drug or a device/device combination.  For example the polypill, which is five cardiovascular drugs combined in one formulation, is not a combination product because they’re all drugs. 
Finally, some products that are combination products by definition are not regulated as such.  A preloaded syringe is obviously a combination product, but is not regulated by FDA as a combination product or even a medical device. It’s regulated as a drug.  
What are the prospects for growth in the market for combination products? 
I’ve been saying for the last 15 years that combination products are clearly the future of medicine.  I don’t think there’s any doubt about that anymore.   
In terms of actual growth, there are some statistics available on the website of the Office of Combination Products, a section of FDA that acts as sort of a information clearinghouse (www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm110653.htm). They indicate that over the last five years or so, the number of combination product submissions is increasing by a factor of anywhere from 20 to 40 percent per year.  Right now we have several hundred applications for combination products being put into FDA.  That doesn’t necessarily mean that there are several hundred different combination products.  Many of them, in fact, are iterations on the same product, as is common elsewhere in the industry.  But the bottom line is that this is definitely a growth area and the numbers are increasing. 
Much has been said about the promise of combination products to deliver greater profit margins than other forms of product development.  What is your view of this? 
When we start combining products from different categories we get a synergistic effect.  We get a one plus one equals three.  The business implication is that if we can use a combination product as opposed to a single product therapy, and get a bigger clinical benefit with less hospitalization or quicker symptom relief or something like that, obviously we can charge more for it.  Of course, that’s the theory; then we have to consider issues of reimbursement and everything else, which could be the topic of a whole other interview.   
What’s your advice to a company seeking to extend the life of its brands by combining them or packaging them with other components?   
If you have a successful single product,  and you want to extend its life, I don’t think turning it into a combination product for that reason alone, quite frankly, is worth it.  The reason is that you will take on a great many additional challenges in development, regulation, manufacturing, and sales and marketing.   
If, for example, instead of delivering a drug orally, you want to change the route of administration – perhaps to deliver it on a transdermal device or by means of a stent or a pump -- that's quite another matter.  But extending the life or maybe creating some new intellectual property shouldn't be the principal justification.   
Since combination products often cross regulatory boundaries they raise a host of legal and regulatory issues.  What are the most important of these in your view? 
I could go on at some length about this question, but let me just share a couple of things that I think companies need to be aware of.   
One of the first questions a manufacturer has to ask is :   do we follow the device manufacturing regulations or the drug manufacturing regulations?  I don’t think any company wants to follow both of them.  So now you get into the issue of selecting which drug regulations you follow and which device regulations you follow.  And most importantly, who decides?  There are some significant proposed rule changes at FDA right now in the area of combination product GMPs (good manufacturing practices) that address these issues.  
Another thing to keep in mind is that from a regulatory/FDA perspective the area of combination products is still relatively new.  Regulatory folks love to look at precedent, but there isn’t a huge amount of precedent there.  Moreover, when there is precedent trying to get access to that information is not always easy.  Companies are not keen on releasing proprietary information for obvious reasons. 
Finally, most of your audience who know something about medical devices will be familiar with the 510(k), which is one of the two major regulatory pathways that medical device manufacturers can get products onto the market (the PMA, or pre-market approval, is the other one).  The 510(k) is based on the concept of substantial equivalence.  If you can show that your device is substantially equivalent to  a device that’s already on the market, you can get it onto  market much quicker.  
There’s a huge debate going on right now on Capitol Hill, in the White House, and across the country as far as the whole utility of the 510(k).  One open question is :  Will it be possible to 510(k) a combination product?  If we use an existing drug and we combine that with an existing device, it’s certainly possible to frame a pretty strong argument that this should be 510(k)-able.  From a regulatory perspective, it’s a fascinating question because there's no precedent; in essence, nobody has tried it yet.   
My personal opinion is that, while it should be allowable, I don’t think that it should be done. We need to be cautious about going down that path.  
How can companies best minimize the regulatory risks?   
The way, quite simply, that you can minimize risk, especially regulatory risk, is essentially to follow in somebody else’s path; that is, follow the precedent and don't do anything new.   However, if you have an idea for a product that’s not the same,  you're blazing a new trail, and that’s going to be inherently more risky.   
Let me publicly give some credit to Cordis, a division of Johnson & Johnson, who was the first manufacturer to get the first drug-eluting stent on the market in the U.S. They made some mistakes but opened up a new path.   
What are some new pathways in combination products to watch out for?  
The quintessential example of combination products today is what we’re now starting to do in the area of tissue engineering, which combines a variety of mechanical and biological techniques to improve or replace bone, cartilage, blood vessels, bladder, etc., as well as other applications. 
Another trend to watch for is what might be called non-traditional combination products.  For example, putting a nutraceutical  – something like St. John’s Wort and Gingko Biloba and Echinacea and so on – onto a medical device like a stent.  Interestingly enough, this is not hypothetical; intellectual property rights have been established.  From a regulatory perspective, I think it’s going to be a huge challenge.  Food therapeutics are another possibility. 
What we’re doing right now in combination products is so primitive, so simple, compared to what we could be doing in the future, that we can expect a number of such challenges.  
How will the emergence of combination products impact marketing and sales?  
There are number of challenges.  One is that in order to communicate with experts and explain these products to customers, sales and marketing people will need to draw on knowledge from drug, biotech, and medical device domains.   
Another is that off-label use, for better or for worse, is rampant in our society today, and especially so among combination products. Approximately 60 percent of drug-eluting stents used today are being used off label – that is, they are being used  in a way that it was not necessarily intended or designed or tested for by the manufacturer.   While off-label use is not necessarily bad,  I see it as an ongoing challenge, especially for combination products. 
Another topic being discussed at FDA right now that relates directly to marketing is  post-market surveillance and reporting for combination products.  There is a fairly robust post-marketing system in the world of drugs, but very little for medical devices.  So if a manufacturer wants to market a combination product that involves a device and a drug, which post-market surveillance requirements does it have to follow?  
The knowledge and resources required to develop combination products are seldom found in a single company, since they span medical device, pharmaceutical and biologic domains.  What are the consequences of this for the future development of these industries? 
What you’re essentially getting at is the concept that many now are calling convergence.  In the future  we’re not going to have simply medical device companies or drug companies or biotech companies.  We’re going to have medical technology companies that have components of all three of these.  And by the way, when I talk about the future I’m talking about right now, even as we speak.
For example, one of the companies that I’ve been working with for several years was started by three people.  It was started by a molecular biologist, a pharmacologist and a mechanical engineer.  Clearly, that’s the future. 
What is the most important issue faced by developers of combination products? 
The single biggest thing that’s slowing our progress in  combination products is not the regulatory or manufacturing or marketing challenges, nor even the clinical challenges.  It is the huge gaps in  knowledge that we find, especially between medical device experts, on the one hand, and pharma or biotech experts on the other.  When we start combining disciplines like that,  one of the biggest challenges is how to get these folks to work together effectively.  How do you get a molecular biologist and a mechanical engineer to sit down and talk to one another?   
Many years ago I was asked to chair a session at a cardiology conference where the question posed was :  where will the ideas for future products in cardiology come from?  In the past most new product ideas came from physicians.  An interventional cardiologist  would say to the marketing person from the manufacturer, “Okay.  This is a pretty good balloon catheter.” “This is a pretty good stent.” But if you make it a little longer, a little shorter, a little fatter, a little thinner, I can turn it around to do something else.   
This will continue in the future but to a lesser degree.  What is needed is someone with the knowledge to say to the marketing person, “Well, this is a pretty good stent, but if you can take a gene that turns on angiogenesis, put it into a virus, and put that on the surface of this stent to deliver gene therapy to turn on angiogenesis or form new blood vessels when I put the stent in, that’s a whole different ballgame”.  This bears on how we train the workforce of the future, especially in the area of biomedical engineering. 
At the beginning of our conversation I mentioned that combination products are clearly the future, and these are some of the reasons why.  But the mindset, the thinking, and the way we educate students our existing force in the future is the key to success.