The FDA in late October issued a public health notification reporting a variety of adverse events associated with use of the very first drug-eluting stent commercialized in the U.S., the Cypher, made and distributed by the Cordis (Miami Lakes, Florida) subsidiary of Johnson and Johnson (New Brunswick, New Jersey). The adverse events include more than 60 deaths associated with thrombosis following stent placement, according to the FDA. The agency said its Medical Device Reporting (MDR) system began receiving these reports shortly after approval of the stent in April. And it said that as of Oct. 20, it had received more than 290 reports involving sub-acute thrombosis (SAT) associated with use of the Cypher stent. The term "sub-acute" was defined as an occurrence of thrombosis between 24 hours and 30 days post-procedure.

The Cypher stent is coated with a thin polymer containing the drug sirolimus, with the stent releasing the drug over time in order to reduce restenosis. With approval of the first such device in this category in the U.S., Cordis has taken the leadership position over other competitors working toward clearance for their drug-coated and drug-eluting stents. The stent had previously received the CE mark and was being used in Europe before the FDA clearance.

Besides 60 of the 290 SAT reports following stent placement being associated with patient deaths, "the remaining reports were associated with patient injury requiring medical or surgical intervention," the agency said. Additionally, the FDA notice said that it has received more than 50 reports, "including some deaths, that Cordis considers possible hypersensitivity reactions." Those reactions involved symptoms such as "pain, rash, respiratory alterations, hives, itching, fever and blood pressure changes." The agency said that it did not have "sufficient data to establish rates for these events, nor can we determine whether these rates are different from those experienced with bare metal stents."

Overall, Cordis has reported distribution of more than 450,000 units of the Cypher stents, about 260,000 in the U.S. and about 180,000 in international markets. Of the 290 adverse event reports, the FDA said about 260 came from the U.S. and the remainder from outside the U.S. The agency did not similarly break down the numbers of reports of fatalities by region.

The first public red flag concerning problems with the stents came with a letter issued jointly by the FDA and Cordis on July 8, that letter, the FDA said, "reminding physicians to follow the instructions for [stent] use and to report any adverse events to the agency." The letter said that the agency had received 47 reports of "stent thrombosis occurring at the time of implantation or within a few days of implantation." It made no reference to deaths associated with these reports but said that the agency and the company were working together "to determine the exact causes and reduce the incidence of thrombosis." Among the factors cited in the letter that could increase thrombosis risk, according to Cordis, was failure to achieve direct deployment of the stent against the vessel wall.

The FDA and Cordis said they were continuing to gather information to find an explanation for the problems. "As we get new information, we will update the web notification," a spokesperson for the FDA told Cardiovascular Device Update. "We published now what we know which is not too much." In the meantime, she said, an effort continues to find a pattern in the adverse events reported. She said that there has been no indication by either the agency or by the company concerning possible withdrawal of the product or a halt to sales.

Biosensors, Terumo team on DES in Japan

Through its Netherlands-based Occam International affiliate, Biosensors International (Singapore/ Newport Beach, California) has entered into a licensing and supply agreement with Terumo (Tokyo) on a drug-eluting stent (DES) developed for Japan, the second-largest market in the world in monetary terms, according to the companies. The device will be the first of its kind to have the entire course of its clinical trials conducted in Japan, involving Japanese patients and physicians, the companies said. Subject to successful completion of clinical trials, Terumo will distribute the device exclusively in Japan under its name and incorporating its delivery catheter. Terumo also will have non-exclusive distribution rights elsewhere in the world outside of the U.S.

Although specific monetary terms were not disclosed, the agreement calls for Biosensors to receive an up-front payment, additional payments tied to clinical trial milestones and payments based on product sales. Clinical trials of the device in Japan are targeted to begin in 2004. "[Terumo] is the leading cardiology company in Japan," said Scott Olson, chief operating officer of Biosensors. "So their ability to market and distribute interventional technology products is a quite extensive, especially in Japan," he told CDU. He said that given Terumo's size and strength, it is "obviously to their advantage" to introduce a DES to the Japanese market. He noted that while Biosensors does sell in Japan, it doesn't have the sales and marketing experience of Terumo.

Following implantation, this model stent will gradually release into surrounding tissues an anti-proliferative drug called Biolimus A-9. Biolimus A-9, a rapamycin derivative, is formulated to inhibit excessive tissue formation around the stent following implantation, or restenosis, which often threatens to reverse the clinical benefits of the angioplasty and stent implantation procedures. Biolimus A-9 is proprietary to Biosensors and is being evaluated in clinical trials of its Matrix stent platform in Europe, named the STEALTH trial. The structure used in the device for Japan is derived from Biosensors' bare-metal S-Stent, which the company said features a smaller, more flexible configuration than most stents currently on the market or in clinical trials, and which was specially designed for the smaller, more tortuous blood vessels characteristic of Asian physiques. S-Stent is an approved product widely distributed in Asia.

"Basically, the agreement that we've reached with Terumo is that by combining some of the technology specifically related to their delivery systems with some of our technology for the drug-eluting stent, we will as partners address the Japanese market with an exciting product that will be evaluated and clinically trialed in Japan as perhaps one of the first drug-eluting stents to go through a full-blown human study in Japan," John Shulze, the chief technology officer for Biosensors, told CDU. "We felt that by combining our technical resources with their manufacturing strengths and distribution strengths that we would have a winning combination for the Japanese market."

While the companies are targeting their stent designs towards the Asian physique, Shulze said that even more importantly, getting the Japanese and Asian doctors involved in the trials will be crucial to the success of the DES program. He said it would be a "big positive for the Japanese market" if these doctors can "gain early familiarity with this device and with its effectiveness. We think that's a big positive for the Japanese market." He added: "Our goal is to start the trial as quickly as possible. We hope you'll see this coming by the [middle of] next year, or sooner if we can. It depends, of course, on getting approvals from the Japanese authorities and preparing all the appropriate test data."

MdDatacor reports on database

MdDatacor (Philadelphia, Pennsylvania) reported at Barnett International's recent 8th annual Strategies to Maximize Patient Recruitment Conference that it has accumulated longitudinal medical data for more than two million individual cardiology patients. MDdatacor receives medical information from more than 65 cardiology practices representing about 1,200 cardiologists nationwide. It said the database is the largest available set of de-identified, patient-level cardiology data. MDdatacor uses this database to help physicians deliver care to their patients. And it said it is beginning to help pharmaceutical and medical device companies accelerate enrollment for clinical trials and uncover unmet demand for their products.

"A year ago we were at 500,000 patients, and in six months we doubled to one million patients," commented Blake Whitney, chairman, president and chief executive officer. "We've now reached two million patients, and we are still growing fast. Our size and growth allows us to execute large scale projects for our pharmaceutical and medical device customers." He said that the database should be a valuable asset for reducing the time and cost of clinical trials. "Using our solutions, industry can now help the cardiologists in our network treat hundreds of thousands of at-risk patients."

MdDatacor identifies research sites with the highest concentrations of patients and provides a list of eligible candidates for a trial to each site chosen by the sponsor, improving site selection and accelerating patient enrollment. It also identifies cardiology patients medically indicated for a particular therapy or de- vice, but who have not yet received it.

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