New generation of products transforms medical treatment

Products composed of both a medical device and a medication have been in limited use for decades. Developing new ways to use such products is a rapidly growing R&D area, particularly with start-up biotech companies.

Currently, dozens of innovative companies are developing revolutionary ways to combine medical devices, medications, and biologic agents (see sidebar). By using these elements together, scientists are discovering unique treatments for diseases such as cancer, diabetes, and heart conditions. One widely used type of combination product is a drug-eluting stent, from which drugs slowly dissolve out of a pipe-shaped device.

This new generation of products typically involves one of the following combinations: device/drug; device/biologic agent; drug/biologic agent or device/drug/biologic agent. The design may involve physically or chemically integrating the elements to create a single product. Alternatively, the elements, provided separately, may have labeling for use together to achieve the desired medical outcome. Design of products may also be as a kit with two or more medical elements packaged together.

Developing these products draws on the traditional knowledge of biologists and chemists, while also capitalizing on the expertise of engineers. These non-medical professionals bring pioneering perspectives on how engineering techniques and devices can integrate with medications/biologics to create novel treatments.

MicroCHIPS implantable wireless chip to control drug delivery compared to a standard USB thumb drive.

Current Research Trends
Although the current avenues of research into this new generation of products encompass a range of creative approaches, they can generally be categorized as follows:

Tiny Materials with Amazing Properties
Nanoparticles are microscopic elements with one or more dimension of less than 100 nanometers. A nanometer is one-billionth of a meter (approximately one-billionth of 39 inches). The unique qualities of nanoparticles offer the potential for effective new methods of treating diseases, particularly when used along with medications and biologics.

Specifically, when medications, biologics, or delivery agents find use at a nanoscale, their physical, biological, and chemical properties change. For example, using a material at a nanoscale may allow it to conduct heat or electricity more effectively than larger particles of the same material. Some materials may reflect light better when used at a nanoscale. Additionally, nanoscale material has a greater surface area than larger-scale material. As a result, it is able to interact more fully with surrounding material, thereby increasing chemical reactivity.

High-Tech Drug Delivery
Traditional drug-delivery products include implantable devices such as coated pacemaker leads and stents; inhalation devices that deliver bronchodilators or antibiotics; and transdermal patches that release medications such as fentanyl and lidocaine. In the past, the properties of many medications precluded their use with traditional drug delivery systems. New avenues of research are expanding the range of medications/biologics for use with these delivery systems. This research often focuses on applying intricate biochemical changes to either the agents or the delivery systems. For example, Delcath Systems (http://www.delcath.com) has developed Chemosaturation Therapy. With this minimally invasive procedure, delivery of ultra-high doses of intra-arterial chemotherapy goes directly into the isolated liver, saturating both the liver and the tumor cells. Other research is investigating “smart” technology, such as microchips and programmable devices to deliver medications.

Groundbreaking Devices
The inclusion of engineers in medical research has resulted in significant advances in medical technology and treatment. One key trend involves the use of devices that apply laser, heat, electrical charges, or other properties to either the treatment material or the patient. These properties may alter a medication’s effect on the targeted disease. Such devices are finding use in conjunction with nanoparticles.

Engineer checking magnetic field strength effectiveness of Actium Biosystems medical device prior to in-vivo experiment for bladder cancer.

The new generation of research includes the development of orthobiologic products. This area of orthopedics incorporates biology and chemistry, resulting in the development of bone and soft tissue replacement materials for skeletal and tissue healing. These materials increase the strength and ability of repair, particularly following surgery. Other innovative research includes unique approaches to treating individuals with cancer (as with Delcath Systems, cited above), heart conditions, spinal cord injuries, and kidney disease. A further method involves the use of a topical patch to deliver very potent anti-cancer drugs directly to a specific location, for example, on the face or inside the mouth.

Benefits of Combination Products
Many of the combination products currently under development offer significant therapeutic advantages. Perhaps most significantly, several of these products cause medications/biologics to interact differently in the body. As a result, these elements may be more biocompatible than they are under traditional treatment methods, thereby reducing the risk of rejection.

Top to bottom shows the use of Medtronic short-term drug-eluting balloon catheter for prevention of clotting; QLT Inc.’s punctal plug ocular drug delivery system; and the Actium ACT System, which is a thermally-enhanced chemotherapy treatment of cancer via combination of quantum particles and chemotherapy agent; ferrofluidic therapy.

The use of new delivery systems and devices allow for more localized drug delivery, reducing systemic side effects, and potentially increasing efficacy in targeting specific diseases. Moreover, the capability to deliver medications in a localized manner has the potential to expand the range of medical conditions targeted with such treatments. Some of the new technology enables controlled release of single or multiple medications/biologics into the bloodstream. In contrast to bolus-type delivery, controlled delivery can result in a targeted release of the active pharmaceutical ingredient as well as enhanced control of dosage. This new method of drug delivery has resurrected the use of older cancer compounds previously abandoned due to toxicity when administered systemically, but that have proven effectiveness when administered locally. Furthermore, since many drug-eluting devices are either implanted or applied as transdermal patches, patient compliance is increased, thus improving disease control.

In addition to their therapeutic advantages, this new generation of products offers economic benefits. Specifically, given the enormous cost associated with developing and launching drugs, combination products provide a less expensive avenue of research. As noted above, thousands of medications once abandoned as ineffective or highly toxic in the past may be safe and effective when delivered using a different method.

A final advantage of this line of research is that if a combination product finds use with a medication/biologic that has prior FDA-approval, obtaining approval for the new application may require only one clinical trial.

Challenges of Combination Products
One of the greatest challenges in bringing combination products to the market is obtaining FDA approval. In 2003, the FDA established the Office of Combination Products (OCP), which assigns a new product to the appropriate review center for evaluation. Generally, the appropriate review center is selected based on the action of the product that has the most significant therapeutic effect (referred to as primary mode of action). When a specific product includes more than one medical element, any one of these elements may be identified as providing the primary mode of action.

The approval process may be simpler for medical device products in which the elements are provided separately, but are designed to be used together. Submission of these products would be to the Centers for Devices and Radiological Health (CDRH), with involvement by other FDA centers required on a case-by-case basis.

Conclusion
The growth rate of the combination product market is surpassing the growth rate of both the pharmaceutical and medical device markets. Although these combination products will not replace traditional products, they hold great promise for the future evolution of disease management and treatment.