Combo Products: Infection Busters

By Michael Drues, President, Vascular Sciences (Grafton, MA)

While combination products are being developed for a host of different medical device applications, their use in infection prevention applications is still in its infancy. But looking to the future, combo products may one day be assembled not on the manufacturing floor but at the patient's bedside.

Infection is a big problem on many levels, not the least of which is an economic one. Ironically, I can't help but point out the fact that this problem has been around for a very long time--probably a century or more--and people are still trying to figure out how to deal with it.

Combination products in particular are emerging in many areas, including in infection prevention and control. Moving forward, their role will become progressively more important for several reasons, not the least of which is that from a straight-up medical device perspective, mechanical- or electrical-type devices are limited as to how they can handle a problem such as infection. But once the device has been coupled with an active pharmaceutical ingredient (API), another active agent such as ionic silver, or something more complex such as an antibiotic, the possibilities grow immeasurably.

Part of the problem is that when one talks about infection, there are many different types. One category of infections includes viral or bacterial antigens that cause such illnesses as the common cold, influenza, or tuberculosis. For these applications, combination products can play a role. But they can also play role in treating infections related to or caused by such implantable medical devices as catheters and stents.

Expanding the horizons for the future, I foresee combination products being used for other kinds of infections as well. With a little imagination, it is possible to conceive of using combination products for treating airborne and contact-type infections. A different spin on such potential applications is that in the post-9/11 era, we now have to think about developing medical devices and drugs for the prevention, diagnosis, and treatment of conditions stemming from the use of radiological, chemical, and nuclear weapons. In this field, we're starting to see some work being performed. Suffice it to say that 9/11 has changed our lives in many ways, beyond the inconveniences that travelers endure at airports. Before 9/11, we never had to think about designing medical devices to be terrorist-proof. Now, however, regulations exist instructing us how to do that.

In developing combination products to treat infections, designers and manufacturers face challenges associated both with incorporating APIs and with the physical, mechanical, and electronic aspects of the device. On the drug side, we face the age-old question of antibiotic resistance--something we have been struggling with for a very long time. This should come as no surprise to anyone who is familiar with biology because the little bugs that cause infections do exactly what we should expect them to do. The most resistant bugs are commonly found in hospitals because in the hospital environment, microbes are constantly exposed to nasty medical conditions. The ones that can survive, mutate, and adapt are those that achieve resistance.

The reason why this is important on the medical device side is that if we deliver a drug by means of a device, the device can become a very elegant, very robust delivery system. But if the drug that we're delivering is not effective because the microbes have become resistant to it, the device's efficacy is undermined, rendering it useless. Indeed, in the area of combination products, there is a precedent for this. In the field of drug-eluting stents, clinical trials in which a drug has not been particularly effective have led to naught. In such cases, not only the drug, but the delivery system as well, must be scrapped. This has in fact occurred numerous times, and unfortunately, it probably will continue to happen. Thus, we have to be careful that we don't throw the baby out with the bathwater. If we load a catheter or other implantable medical device with a drug or a biologic and that active agent is not effective, should we throw the delivery system away with it?

While it's challenging to manufacture combination products of any type, manufacturing combination products for use in infection-prevention applications is particularly challenging, especially when they incorporate biologics. One of the interesting differences between drugs and biologics is that drugs are pretty stable. In other words, we have to hit them pretty hard to get them to change. Biologics, on the other hand, are inherently unstable. Thus, when we talk about loading a stent or a catheter with therapeutic proteins, monoclonal antibodies, or nucleic acids--for example, a gene inside of a virus, or a type of stem cell called an endothelial progenitor cell--such applications are orders of magnitude more challenging to manufacture than drug-device combination products. They are more challenging not just from a technological or clinical perspective but also from a regulatory and a manufacturing perspective.

This challenge conjures up all kinds of issues that many in the traditional medical device world have never had to think about before--issues such as sterility, stability, shelf life, and more. For example, how do you sterilize a plain-old medical device such as a bare-metal stent? You can pretty much hit it with whatever you want--ethylene oxide (EtO), heat, gamma--it doesn't matter because you're not going to change the stent. But once you put a drug on it or, especially, once you put a biologic on it, all bets are off. The whole idea of sterilizing a biologic in any conventional sense is ludicrous.

The same thing holds for shelf life. What's the shelf life of a plain-old bare-metal stent--packaging issues aside? A million years perhaps? But once you put a drug or a biologic on it, all bets are off. The whole notion of incorporating a medical device with a monoclonal antibody or a gene contained inside a virus, putting it in a package, and setting it on a shelf for days, weeks, or months is nuts. And never mind incorporating it with a cell!

Consequently, a future trend--one we are just now beginning to see--is to load the device with an active agent at the point of use. Why should a manufacturer, be it a device or drug company, put the product together in a manufacturing facility somewhere, package it, and ship it across the country or around the world and then have it sit on the shelf? Although we have been practicing medicine like this for eons, it makes absolutely no sense.

In the future, we are going to be putting more and more products together at the patient's bedside moments, or perhaps even seconds, before they go inside the patient. There is a litany of ways in which this task can be accomplished. For example, let's say that we want to put monoclonal antibodies on a stent. Instead of a manufacturer putting the antibodies on in advance, the stent will be designed similar to how syringes are made today. Syringes are not designed to deliver a particular drug; rather, they are designed to be loaded with anything you want.

This means that we should start thinking about all medical devices not as devices but more like syringes--like delivery systems. How do you do this using monoclonal antibodies, for example? It's fairly simple: Before inserting a stent into a patient, the physician dunks it in a vial of a monoclonal antibody solution, whereby the antibodies stick to the stent. But how is the physician to know whether the device is sufficiently coated with antibodies? There are solutions to these problems if you use a little imagination.

For example, imagine that you design your stent to be white and you design your monoclonal antibody solution to be red. When you dip the stent into the solution, it comes out pink. This concept resembles the idea behind old-fashioned litmus paper. When you dip litmus paper in an acidic or alkaline solution, it changes color. By comparing this color to a color scale, you determine the pH of the solution.

Analogously, you can do the same thing with a stent. After dipping the stent in the monoclonal antibody solution, the physician compares the color to a color scale and decides whether the device needs to be coated again. This is what I call personalized medicine, or pharmacogenomics, as applied to medical devices. Many people think that pharmacogenomics is limited to pharma products. Absolutely not. Many pharmacogenomic applications involve combination products.

The bottom line is that all of these applications are doable, but the first thing that has to happen is that we have to get people to think.