Originally Published EMDM January 2006
Market Watch
Drug-Eluting Stents
J&J and Boston Scientific have profited handsomely from their blockbuster devices, but competition for this lucrative market is ramping up just as questions begin to surface about the cost-effectiveness and overall safety of drug-eluting stents.
The term “blockbuster device” officially entered the lexicon in 2003, when the drug-eluting Cypher stent manufactured by Johnson & Johnson (J&J) subsidiary Cordis was approved by US FDA. The following year, Boston Scientific launched its Taxus stent. The market for bare-metal stents, which was valued at US$2 billion per year in 2002, imploded with the arrival of their drug-coated cousins. Sales of drug-eluting stents (DESs) are expected to surpass US$5 billion in 2005. By 2010, the global market for DES products is expected to reach US$8 billion, according to Business Communications Company, Inc. (Norwalk, CT, USA).
As the first companies out of the gate, J&J and Boston Scientific currently own the DES market. But there are some clouds on the horizon. Medtronic plans to enter the fray with its Endeavor DES. Abbott Laboratories is also developing a DES that will access J&J’s rapid-exchange delivery system. Meanwhile, several papers published in medical journals have called into question the safety of existing DES devices, and, in one case, their necessity in all but a limited number of treatments.
Endeavor and Zomaxx
Medtronic announced the results of a US clinical trial of the Endeavor DES at the Transcatheter Cardiovascular Therapeutics (TCT) meeting in Washington, DC, in October. The trial’s primary end point was the amount of restenosis occurring after eight months of stent implantation. While the Endeavor exhibited a smaller incidence of late lumen loss than the Cypher, the difference was not sufficient to achieve noninferiority status. This may jeopardize approval by US FDA, according to some observers. Medtronic officials remain optimistic, however, citing that real-world clinical outcomes are more important in the long term. The firm also points to Endeavor’s uptake in Europe, where sales have exceeded company projections since the product was introduced in the summer of 2005.
Medtronic is currently enrolling patients in its Endeavor IV study, which has a clinical end point instead of the previous trial’s angiographic surrogate end point. If all goes well, Medtronic hopes to submit a PMA application to US FDA by 2007.
Market prospects for Abbott Laboratories’ Zomaxx DES improved considerably with the announcement in October that its product will access J&J’s rapid-exchange delivery system. Rapid-exchange delivery systems currently enjoy an 80% market share. Abbott’s access to the technology is the result of a condition set forth by the US Federal Trade Commission when it approved J&J’s purchase of Guidant. Currently, three firms—J&J, Guidant, and Boston Scientific—offer rapid-exchange technology in the United States. The FTC-mandated agreement ensures that three companies will continue to offer the technology when the purchase is finalized.
Rapid exchange allows physicians to implant stents without the help of an assistant. Companies offering stents without such a delivery system historically have garnered minimal market share. Indeed, it will get even more difficult to succeed in the marketplace without rapid-exchange technology, as experts predict that it will ultimately control as much as 90% of the market.
Arterial Anomalies
The initial euphoria that greeted the truly remarkable results of DES clinical trials has been tempered more recently with a series of papers questioning their safety. Cases have surfaced of patients experiencing blood clots more than one month after receiving a stent and, in some instances, a year or more after the procedure. Although there are no hard data to prove it, some cardiologists suspect that this may be more common with drug-coated stents. Clot formation, it should be noted, is relatively rare, and associated fatalities are rarer still. However, with an estimated 2.5 million stents implanted in 2005, and that number continuing to soar, even a statistically insignificant failure rate will get the attention of the mainstream media. In the United States, it has also piqued the interest of litigators.
Researchers currently are looking at two possible causes for the occurrence of blood clots. Some theorize that the polymers that hold the drug on the stent may cause a reaction in some patients or possibly flake off. Other scientists hypothesize that the drugs themselves may be to blame. The drugs that prevent cell growth on the inside of a stent work by inhibiting the body’s normal healing process. Once the effect of the drug ceases, the body reverts to its normal process to wall off foreign objects and fix injured vessels, which may include the formation of a blood clot.
Boston Scientific and J&J are devoting five years to follow 5000 patients who have had a bare-metal or drug-eluting stent implanted during clinical trials. Because the incidence of late clot formation is rare, a definitive explanation will probably not be found. In the meantime, both companies are investigating ways to further lower the risk of clotting, including the development of biodegradable stents. And research continues among smaller firms to refine drug formulations. One example is X-Cell Medical, a hybrid biotechnology and medical device firm based in Princeton, NJ, USA.
X-Cell Medical announced in mid-November the start of enrollment for a multinational clinical trial to determine the safety and effectiveness of its Ethos I coronary stent system. The stents are coated with slow- and moderate-release formulations of 17b-estradiol, which is commonly used in hormone replacement therapy. The company presented an overview of the potential cardioprotective and safety benefits of the estrogen-based compound in the reduction of restenosis at the TCT 2005 meeting. Ongoing concerns regarding the safety of existing DES products were cited by CEO Oded Ben-Joseph as one of the main issues driving development of the product. “Estradiol’s healing properties are likely to provide patients with a safer alternative to current treatments,” he explained. Estrogens inhibit smooth muscle cell proliferation and accelerate endothelial regeneration. For these reasons, the firm believes that estrogen-coated stents may lead to a reduction in restenosis. Results from the study are expected to be available in mid-2006.
Researchers in Switzerland have taken an entirely different tack when it comes to DES products. A cost-effectiveness study made public in September suggests that the benefits of DES products may have been oversold.
The so-called BASKET study led by Matthias Pfisterer and colleagues at Basel University assessed the six-month outcomes of patients implanted with Cypher, Taxus, or Guidant’s bare-metal cobalt-chromium stents. The study found that the more expensive DES products were not cost-effective compared with bare-metal stents except in high-risk patients. In addition to the higher initial purchase price, the DES products did not substantially reduce the cost of follow-up care, according to the study.
J&J and other manufacturers contested the findings, noting that the follow-up period was too short to provide a picture of the true costs involved. Brian Firth, vice president of medical affairs and health at Cordis, was quoted in the September 17 issue of Clinica as saying that “cost-effectiveness in coronary stenting studies are conventionally not done until at least one year postprocedure.” The additional costs of the DES products were borne up front in the study, but the benefits and reduced follow-up costs that accrue from reduced revascularization with DESs were minimized, thereby disadvantaging the DES group, he explained.
Gaining a Manufacturing Edge
The cost-effectiveness debate may rage for some time, but the undeniable fact that DES products offer superior outcomes to bare-metal stents will continue to propel growth. That momentum has led forward-thinking contract manufacturers and equipment makers to develop machines and services adapted to this new demand.
Machine Solutions Inc. (Flagstaff, AZ, USA) has established a solid niche developing equipment that automates stent production. Its stent-crimping machines, for example, precisely and repeatably perform a task that was traditionally done manually. It has devoted a great deal of its resources into next-generation equipment that will automate the production of drug-eluting products.
“Operator sheathing of the DES prior to crimping is one of the most laborious parts of the production process,” explains global marketing director James Kasprzyk. “We have integrated a thin-walled film into our patented crimp head,” he explains. “The film replaces the sheath and eliminates a costly operator step.” The cost savings can approach US$20 million per quarter in high-volume operations, according to Kasprzyk.
Process automation is also a focus at Fortimedix (Nuth, Netherlands). The firm’s overarching goal is to provide a complete outsourcing service to DES OEMs. “Right now, most of our customers are still doing a lot of their production in-house,” says Marc van de Graaf, general manager. “We want to make it easy for them to outsource that work to us and, thus, reduce investment costs, so that they can devote all of their resources to the development of drug-eluting technologies.”
Van de Graaf foresees OEMs sending their products to Fortimedix, which will perform the coating, drug loading, crimping, packaging, labelling, and so forth. “Our aim is to create a technology platform for stent development and manufacturing. Instead of making the stent and sending it back to our customer, we will provide a complete outsourcing service.”
The company is building a new facility that measures up to its ambitions. It is scheduled to be completed by mid-2007. Pilot projects are currently being run in the existing plant.
For more information about Machine Solutions and Fortimedix, as well as a host of other companies supplying products and services related to the production of drug-eluting and bare-metal stents, turn to the company profiles in the following pages of this section.
Copyright ©2006 European Medical Device Manufacturer
