BBI Washington Editor

WASHINGTON — With clinical data apparently proving that drug-eluting stents are the golden child device of the new millennium, the next hurdle will be to establish a balance between pre- and post-market data. Jumping from the premarket approval (PMA) process to the post-market surveillance phase will be a challenging race for any device manufacturer to win, however. That's because neither the FDA nor the device industry has a benchmark on how to ensure the drug-coated devices are safe and effective well beyond their intended use.

Despite the efforts of the FDA in establishing an office for combination products, the challenge for device manufacturers lies in the fact that no manufacturer has yet garnered the coveted prize of approval for U.S. marketing. As one conference attendee put it during a surprisingly sparsely attended session at the late-September Transcatheter Cardiovascular Therapeutics 2002 (TCT) conference at the Washington Convention Center, "The industry is in need of a carrot, and the absence of a stick is no carrot."

"Based on the results of the SIRIUS trial ... the drug-eluting stent arena will go haywire. The competition will be intense," Roxana Mehran, MD, director of clinical research and data analysis and management research at the Lenox Hill Heart and Vascular Institute (New York), told TCT attendees. Mehran has clinical credibility behind her statement. She is one of the co-investigators behind the Cordis (Miami Lakes, Florida)-sponsored SIRIUS trial and benefits from the company's existing approved status in Europe, which gives U.S. investigators access to a database gold mine.

Gathering more comprehensive post-market data will only benefit the manufacturer and the FDA, Mehran said. "There will be huge changes taking place. Doctors will put stents in places you'd never think of, and the FDA should allow for such changes [in the indicated] use of the device if it is favorable," she said. The study at Lenox Hill is benefiting from the deep pockets of Cordis, and it can therefore collect more high-quality data during the post-market phase, one attendee countered during a question-and-answer period. Lenox Hill benefits from the e-Cypher registry, which is a patient database of all European recipients and the corresponding clinical trial data. Mehran admitted her facility was indeed lucky in terms of trials it can administer. "The patients who enroll meet the three requirements we established for an e-registry: protection of patient privacy; ensuring the informed consent document had been signed; and ensuring the unit is HIPAA-compliant," she said.

The post-market surveillance database Cordis chose can help regulators in the U.S. make a decision to approve the device faster, Mehran said. "If the FDA can have a 'wish' during this presentation, then my wish is that the emphasis can be shifted to the post-market phase to get faster approval for these devices that patients need, but we need the commitment from the FDA," she added.

But the key in establishing the pre- and post-market challenge, Mehran said, lies in validating what data are entered into an online database. "What's not being done, either from the manufacturers or the providers, is making sure that the data entered are valid and accurate. Right now, there's no one to verify the accuracy of an entry," she said.

In a closing remark, however, an FDA official stated that the agency is in need of some changes to meet the desired response times for the drug-eluting stent challenge. "We are supportive of the statements you've presented, but within the FDA itself there needs to be a shift in some resources from the PMA side to the post-market side in order for your changes to take effect," Susan Gardner warned.

"We can't make any shifts in the pre- and post-market balance without a commitment from the industry," she said.

The contrasting views, presented during a mid-conference plenary point/counterpoint presentation that drew an audience of thousands, said the stent-frenzy era likely to ensue in catheterization labs across the U.S. is either a revolutionary step in medicine or a case of misguided hysteria.

For his part, TCT impressario Martin Leon, MD, of the sponsoring Cardiovascular Research Foundation (New York) and Lenox Hill, said, "The stent frenzy we're in the midst of is the greatest advance in cardiology since the introduction of the balloon." In fact, he said he was so confident in his prediction that he jokingly forecast that cardiac surgeons would have to get a new day job with the advent of the drug-eluting stent.

But more long-term data are needed to prove the effectiveness of the devices, Renu Virmani, MD, a member of the Armed Forces Institute of Pathology (Washington), cautioned the TCT audience. "You cardiologists don't have the necessary tools to prove the benefits of these products. Nine months of data is not a sufficient period to make determinations. We need five years' and 10 years' worth of data," she said.

Leon, during his pro-stent presentation, equated the refined drug-eluting stents to the sleek sports cars of stents vs. earlier versions that he described as akin to Model Ts. "Just because we started with the Model Ts doesn't mean we should give up and push the Porsche off the cliff," he said. Animal studies are needed to ensure patient safety, Leon noted, but the data shouldn't be used in comparison to humans, he said. "We can't base our results in patients, based on barnyard animals, because we are humans."

The evolution of the stent is moving toward a kinder, gentler device, Leon said. "Studies are under way to develop stents with more effective elution techniques by dripping the drugs on the carrier agent. The EASTER trials are now under way to determine if estrogen-coated stents are superior," he added.

But Virmani countered with the argument that too many histological questions remain surrounding the effectiveness of the drug-eluting stents. "The oral, systemic or intravenous modes of delivering the drugs at the time of stent placement might be a better choice. Polymers are not biodegradable," she warned. The misguided problem with cardiologists, Virmani said, lies in the tools used to determine the effectiveness of the drug-eluting stents. "You have your angiograms and IVUS [intravascular ultrasound] readings, but these tools aren't good enough," she warned. "You need better tools to determine the toxic effects of the drugs."

Virmani referred to current animal studies at the National Institutes of Health (Bethesda, Maryland) whereby the subject is implanted with a bare stent and then receives a particular dosage of a drug intravenously. "What they are finding is that a small amount of the drug administered intravenously is just as effective 28 days later," she said."Drugs don't last forever, and once they are gone from the stent, inflammation will no doubt return," Virmani said.

A 'new ballgame'

The impressive SIRIUS clinical trial data reported by Cordis will no doubt spur a bevy of device manufacturers to mimic the home run, but designing a winning clinical trial could leave many still on the bench. "If you're designing a new stent with a new drug, it becomes a whole new ballgame," Jonette Foy of the FDA's Center for Devices and Radiological Health told attendees at another TCT session.

Stents with an already approved drug from [the FDA] will get approval faster than those that use a new medical entity, or drug, Foy told the standing-room-only crowd. "The worst-case scenario is if both the device and the drug are unapproved," she warned.

The important bench elements in a trial are the in vitro pharmacokinetics and the chemical, manufacturing, and control principles of good clinical practice, Foy said. "That seems to be a big hurdle for manufacturers that have been contacting us," she added. Other items FDA staff will look at include the coating integrity, the durability, fatigue and corrosion, and particulate analysis of the carrier. "For the drug chemistry data, we would collaborate with CDER on that, if the drug has been approved," Foy said.

Another important component to the clinical trial is to establish a correlation between animal and human study data. "The in vivo data should demonstrate a correlation to the in vitro data," she noted.

But Bram Zuckerman, MD, deputy director of the Cardiovascular and Respiratory Devices division of the CDRH, gave stent manufacturers credit for paving the road in the industry. "We should be able to handle the glut of stent PMAs, thanks to the groundwork that the manufacturers helped establish. But the clinical trial issue is still an unanswered question," he said.

Additionally, according to Foy, FDA staff will wants to see an evaluation of the following: the uncoated stent; the uncoated stent vs. the stent and carrier; the uncoated stent vs. the stent, carrier, and drug; and the clinical dose vs. overdose amounts. "It's also important to include data for the intended clinical uses. If you intend for the stent to be longer, then data to support the length should be included," she advised.

Clinical trials also should contain an executive summary, a comparison of local and systemic pharmacokinetics and an animal study report with local, regional and systemic information.

Establishing clinical considerations in the early stages is important as well, CDRH's John Hyde, MD, told the attendees. "You should demonstrate the contribution of the drug to the stent as well as its superiority over a bare metal stent," he advised.

The data should be clinically meaningful, Hyde said. "We'd like to see an assessment of the stent at nine months, even though some of the earlier stents have only shown assessment at six months." Postmarket follow-up also should be extended, he noted. "When developing a PMA, you should expect to offer surveillance up to five years as well as have a reliable data safety monitoring board. I'd recommend one that is online, one that can make decisions quickly to alert you to any problems."