Despite promise, drug-eluting balloons face obstacles in U.S. adoption

Regulatory requirements are just one challenge.

The use of drug-eluting balloons for the recanalization of the peripheral and coronary vasculature presents clinical potential, but also a challenge for device makers and clinicians.

Although useful in some patients, balloon angioplasty has traditionally been associated with problems such as in-stent restenosis, elastic recoil and restenosis from cellular perforation. The adoption of drug-eluting stents minimizes cellular perforation, late negative vessel remodeling and elastic recoil but is still limited by stent thrombosis and fracture.

The use of drug-eluting balloons has recently emerged as a potential alternative for recanalization of coronary arteries and endovascular vessels, but despite results from some early studies suggesting clinical benefit from drug-eluting balloon technologies for certain indications, interventionalists and regulatory authorities are demanding more robust clinical data before urging wider adoption of the technology.

Clinical trials

Most drug-eluting balloon technologies use paclitaxel and a surface coating. Although preclinical trials evaluating drug-eluting balloon technologies that do not use paclitaxel have been conducted in animal models, there have yet to be any randomized clinical trials conducted in humans.

Michael R. Jaff, DO, said the community should be cautiously optimistic about drug-eluting balloons. Source: Bill Truslow

There have been several clinical studies of the paclitaxel-eluting balloon for in-stent restenosis. Pooled results from the PACCOCATH I and II studies suggested a reduction in in-segment late lumen loss in the patients who had their restenosis treated with a paclitaxel-coated balloon vs. a non-coated balloon (P<.001), resulting in a lower restenosis rate in the paclitaxel-balloon group vs. the non-paclitaxel group (P<.001).

Results from the PEPCAD II randomized pilot study, which compared the safety and efficacy of a paclitaxel-eluting balloon with a paclitaxel-eluting stent (Taxus, Boston Scientific) for the treatment of in-stent restenosis in native coronary arteries, were also encouraging. The primary study endpoint of angiographic late loss at six months was reduced in the drug-eluting balloon group vs. the drug-eluting stent group (0.17 ± 0.42 mm vs. 0.38 ± 0.61 mm, P=.03), resulting in a lower rate of binary restenosis (P=.06) and a reduction in the rate of major adverse cardiac events at one year (P=.08).

Studies examining paclitaxel-eluting balloon catheters in the setting of peripheral arterial disease have also been conducted, albeit with the limitation of small sample sizes. Results from the THUNDER trial, a randomized study of 154 patients with stenosis of the femoropopliteal artery treated with either paclitaxel-coated catheters, uncoated catheters with paclitaxel dissolved in the contrast medium or uncoated catheters, suggested a reduction in mean late lumen loss in patients treated with the paclitaxel-coated catheters (P<.001).

Results from the FemPac study, in which uncoated catheters were compared with paclitaxel-coated catheters in patients with femoropopliteal PAD, suggested that patients treated with the paclitaxel-eluting balloon had significant reduction in target lesion revascularization at six months and maintained the benefit out to 24 months.

“Right now, the only application I can see for drug-eluting balloons in the coronaries is for in-stent restenosis,” Ron Waksman, MD, associate director of cardiology at Washington Hospital Center in Washington, D.C., told Cardiology Today. “For the superficial femoral artery, it could also be in-stent restenosis and perhaps for focal de novo lesions. The challenges for diffuse lesions and large vessels in the periphery would be the amount of drug that will be spilled out to the system. Nevertheless, since drug-eluting stents are not doing well in the periphery, there is an unmet need for the use of drug-eluting balloon for this indication. Since the regulatory challenges are similar to drug-eluting stents and the use is for niche indication, I do not foresee any other indications for this technology in the current environment.”

Regulatory considerations

Study results suggest potential for specific indications, but companies that design and manufacture drug-eluting balloon technologies, according to one physician, face a significant regulatory hurdle in the FDA’s approval process.

Michael R. Jaff, DO, an associate professor of medicine at Harvard Medical School and a member of the Cardiology Today Editorial Board, said the regulatory hurdles faced by drug-eluting balloon manufacturers are essentially the same faced by manufacturers of drug-eluting stents.

“There will be a lot of basic science that will have to be shown to the FDA to demonstrate what these companies know,” Jaff told Cardiology Today. “They will have to know how much of the drug actually makes it into the vessel wall, how long it stays there, how much of the drug, if any, embolizes downstream and if that affects the limb locally or systematically over time, as well as if there is something about the top coating that is either advantageous or disadvantageous.”

The technology, considered by the FDA to be a hybrid product consisting of an interventional device and a drug, would be a class III device falling under regulation by the Center for Devices and Radiological Health with consultation from the Center for Drug Evaluation and Research. Other regulatory concerns for manufacturers to contend with include the amount of the drug present on the balloon coating, the effects of multiple balloon inflations, the potential for higher concentrations of the drug to be administered with drug-eluting balloons vs. drug-eluting stents and the potential for the drug to be washed away during application.

Because of the lighter preclinical regulatory burden, most preclinical and clinical studies of drug-eluting balloon technologies are currently being conducted in Europe. Jack Springer, president of Invatec USA, told Cardiology Today that the company is working on bringing several drug-eluting balloon technologies for indications in both the coronary and peripheral arteries. The challenge in the United States, he said, was demonstrating adequate efficacy in addition to safety.

“In the United States, proving effectiveness is more challenging and requires a premarket application for approval,” Springer said. “The FDA has made it clear that they consider this technology a combination of a drug and a device, and the requirements for preclinical testing, bench testing and for a pivotal United States trial are both significant and time-consuming.”

Springer also said the trial designs and trial goals varied according to the indication. Studies comparing drug-eluting balloons with drug-eluting stents will probably be designed as noninferiority trials, whereas other comparisons to treatments will probably require the manufacturers to demonstrate superiority. The FDA may be willing to accept some safety data gathered in Europe to expedite the approval process in the United States.

Potential indications

The rationale for the development and use of drug-eluting balloons, according to one analysis, stems from the limitations of drug-eluting stents. Replacement of drug-eluting stents as the standard of care, according to Waksman, is not likely.

“We have to be realistic in terms of what the expectation of the device is in the armamentarium of interventional cardiologists, as this is not going to replace drug-eluting stents,” Waksman said. “This could be more of a niche application, where drug-eluting stents are not performing as well in the periphery. At this point, the earliest we could likely see a clinical trial would be toward the end of the last quarter of 2010.”

Springer suggested that device designs looking at the superficial femoral artery or lesions below the knee will most likely be the first to be studied.

“The early data look promising, at least for certain indications,” Springer said. “Everyone is excited about the potential of drug-eluting balloons for the treatment of peripheral disease and especially for the superficial femoral artery. We are optimistic that this is going to become a new standard of treatment and an opportunity to give patients a better outcome than we have experienced with previous technologies.”

Jaff said the use of drug-eluting balloon technologies in native vessel superficial femoral arteries has thus far received the greatest amount of attention in the peripheral literature, and there remains enthusiasm for the potential treatment of in-stent restenosis.

“Everybody should approach these technologies in the periphery with cautious optimism, as we have been through this before with a host of different technologies that look like they will change the face of treatment; once you really get into trials, this may start to fade,” Jaff said. “The advantage that drug-eluting balloons have is that there are at least two studies published in good peer-reviewed journals suggesting that there is a clear, measurable advantage of a drug-eluting balloon over an uncoated one.” – by Eric Raible

For more information:

• Scheller B. N Engl J Med. 2006;355:2113-2124.
• Waksman R. Circ Cardiovasc Interv. 2009;2:352-358.