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Positive Studies Boost Stent Manufacturers as Market Competition Heats Up

Following nearly two years of negative reports and speculation regarding the safety of drug-eluting stents, manufacturers of the devices had to be pleased with the almost universally positive clinical findings presented at the recently held joint meeting of the American College of Cardiology (ACC; Washington, DC) and the Society for Cardiovascular Angiography and Interventions (SCAI; Washington, DC) in Chicago. The most significant outcome of the meeting was the general consensus among researchers and industry analysts that drug-eluting stents, while continuing to demonstrate superior performance in preventing restenosis, do not present a greater risk of late-term thrombosis than their bare-metal counterparts.

Mauri: The antiplatelet caveat.

Commenting on one of the key studies that was widely interpreted as vindicating drug-eluting stents, Laura Mauri, MD, an interventional cardiologist at Brigham and Women's Hospital (Boston), said, “I would feel comfortable considering drug-eluting stents on the basis of these results, with the caveats that treated patients must be able to take antiplatelet therapy and that we definitely want to see even longer-term follow-up.” Mauri was the lead investigator for the study.

Many industry analysts who considered the blood-clot issue to have been blown out of proportion cited the comments of SCAI President Bonnie Weiner, MD, who said that concerns regarding late-term thrombosis “have been largely put to rest now that we have a much larger body of data.”

Weiner: Data wins out.

In addition to the positive findings regarding late-term thrombosis, other studies demonstrated that drug-eluting stents are as effective as coronary bypass surgery for preventing adverse cardiac events, including heart attack and death. However, the researchers noted that patients receiving the angioplasty procedure often required revascularization and repeat stenting.

Over the past two and a half years, widespread concern that drug-eluting stents might be linked to blood clots and potentially fatal cardiac events has resulted in a precipitous decline in their usage. The use of drug-eluting stents peaked at the end of 2005, when it represented 85–90% of all implanted coronary stents. By the end of last year, the utilization rate of drug-eluting stents is estimated to have dropped to 65%. During the same period, the U.S. market for drug-eluting stents declined dramatically from nearly $4 billion in annual sales to a current estimated valuation of around $2 billion.

There is general agreement among analysts that market recovery for drug-eluting stents is already under way. But the eventual size of the recovering drug-eluting stent market—and how soon the market will get there—remain questions of interest.

Jan Wald, managing director and medtech analyst at the Stanford Group Co. (Houston), says the drug-eluting stent market began to show signs of recovery at the end of 2007. “The studies presented at the ACC/SCAI meeting should provide a further boost in physician confidence, and increase adoption rates going forward,” he says. Wald expects the U.S. market for drug-eluting stents to reach $2.15 billion this year—a figure that is generally in line with other market forecasts.

Wald: Increasing adoption.

Venkat Rajan, a medtech analyst with Frost & Sullivan (San Antonio, TX), doubts that drug-eluting stents will ever get back to the near-90% penetration rate they enjoyed in 2005. Nevertheless, Rajan still sees significant recovery ahead. “They could get back to the low 80% range, considering both the largely successful resolution of the safety issue and the introduction of more advanced, next-generation devices,” he says.

A More Competitive Market

As recovery proceeds, stent manufacturers will face a market that is much different and more competitive than it was at the start of the downturn. The drug-eluting stent duopoly enjoyed by Cordis Corp. (Miami Lakes, FL), a Johnson & Johnson company, and Boston Scientific Corp. (Natick, MA) no longer exists. Medtronic Inc. (Minneapolis) received FDA approval for its Endeavor stent last February, and Abbott (Abbott Park, IL) expects to enter the market with its Xience drug-eluting stent before the end of the second quarter.

Medtronic's zotarolimus-eluting Endeavor, which received the CE mark in 2005, is based on the company's Driver bare-metal stent platform. Although some initial studies of the Endeavor stent raised concerns about potential blood clots, Medtronic says the stent is now recognized as having a safety profile similar to that of a bare-metal stent. More important, according to the company, is Endeavor's deliverability, which enables cardiologists to implant the stent successfully in more hard-to-reach and difficult lesions.

Gunderson: Meeting expectations.

Thomas Gunderson, managing director and senior medtech analyst with Piper Jaffray & Co. (Minneapolis), says that “Endeavor should meet or beat expectations due to a history of extensive clinical trials and ease of tracking in the artery. However, the stent still does not offer a true rapid-exchange implanting system, which could stunt sales.”

Stanford Group's Wald agrees: “Endeavor will not do well in the United States until it gets a rapid-exchange system,” he says. “Ultimately, it could tap 10–15% of the market. But lingering concerns about late loss with this particular stent may be cause for some concern. Is there enough here for physicians to switch from what they're currently using?”

Among industry analysts, there is wide variance of views about how much of the market Endeavor can capture. Shortly after the device received FDA approval, Medtronic President and CEO William Hawkins said, “If you look at what we've done outside the United States, we've been able to garner in excess of 20%.” According to Scott Ward, president of the cardiovascular unit at Medtronic, the company distributed about 100,000 Endeavor stents in the United States within the first 30 days of regulatory approval.

Abbott's Xience everolimus-eluting stent seemed to generate the greatest buzz at the ACC/SCAI meeting. In a study comparing its performance to the Taxus drug-eluting stent from Boston Scientific, patients with the Xience stent were found to have a reduced rate of restenosis; less need for target lesion revascularization; and fewer major adverse cardiac events (MACE), including heart attack and death.

Abbott's Simonton: Encouraging data.

“At any given point in time, across both the pivotal SPIRIT II and SPIRIT III clinical trials, Xience V consistently reduces observed MACE rates by 40% or more compared to Taxus,” said Charles Simonton, MD, divisional vice president for medical affairs and chief medical officer at Abbott Vascular. “The single-digit MACE rate seen with Xience V out to two years is encouraging data for interventionalists as they look for ways to improve patient outcomes with next-generation drug eluting stents.”

The Xience stent received a 9-1 favorable recommendation from FDA's circulatory systems panel last November, and is expected to receive full agency approval in June.

Abbott is also developing a completely absorbable drug-eluting coronary stent, which has just recently begun clinical trials. Current projections suggest that the stent could be on the market by 2012.

Game Changers

Is the 2008 market entry of Medtronic's Endeavor and Abbott's Xience a stent-market game changer? It could be, particularly considering the heady forecasts for Xience, which, according to several medtech analysts could capture up to 40% of the U.S. market six months after entry.

While stent stalwarts Cordis and Boston Scientific are not expected to sit idly by and risk losing out to newcomers, the market is recovering at a time when both companies are somewhat flatfooted in terms of having readily available new products.

Cordis's Cypher Select and Cypher Select Plus stents—which the company considers to be its next-generation products—are still not available in the United States. The devices are generally considered to represent incremental improvement over the original Cypher, which was introduced in 2003 as the first FDA-approved drug eluting stent.

Cordis had expected that its $1.4 billion acquisition of Conor Medsystems, in November 2006, would provide the company with a product that was generally hailed as a true next-generation stent with both a novel design and innovative drug-eluting system. In May 2007, however, after the Conor Costar stent failed to meet any of the end-points in a pivotal clinical trial comparing its performance with Taxus, Cordis pulled the stent from the market. Costar was originally designed for use with the drug paclitaxel. But last month, Cordis reinstituted clinical trials with a reformulated version of the stent using sirolimus, the drug coating used in its flagship Cypher series.

Boston Scientific's next-generation Liberté is available in Europe and many other countries, and was just cleared for distribution in Canada. The company says Liberté is the first stent designed to accommodate a drug coating, unlike previous drug-eluting stents in which the coating is basically an enhancement to the bare metal version. The more-flexible design of the Liberté device is expected to permit easier deliverability and stent implantation, while its strut structure is intended to ensure more even distribution of the drug. Boston Scientific expects to receive FDA approval later this year following resolution of a warning letter relating to manufacturing issues within its cardiovascular division.

Boston Scientific will also market Abbott's Xience stent under the Promus brand. This marketing arrangement is related to Boston Scientific's $27 billion acquisition of Guidant in 2006, which required the company to divest itself of Guidant's stent business in order to avoid antitrust concerns. Abbott bought Guidant's stent unit for $4.1 billion. Under the terms of the deal, Boston Scientific will gain distribution rights to Promus immediately following FDA approval. Boston Scientific will reportedly pay Abbott a 40% royalty on sales for an undisclosed period of time.

Rajan: Squeezing margins.

According to Frost's Rajan, “The market entry of new drug-eluting stents will likely result in some downward pressure on price—and it will be more difficult to up-sell unless the manufacturer is offering a next-generation stent with some novel design or deliverability features. I don't see a price war, but some squeezing at the margins will occur.”

Piper Jaffray's Gunderson generally agrees. “These companies have participated in oligopolies before and still have not resorted to price wars. Pricing is not what they lead with; high margins will allow any of the current competitors to match on price, negating the initial move. If pricing does become a stronger marketing weapon, the advantage goes to the low-cost producer, which is Boston Scientific.

Stanford Group's Wald concurs. “It's not in the interest of these companies to play the price game. It didn't happen as more devices entered the bare-metal stent market, and I do not see it happening here either.”

Neither Rajan nor Gunderson foresee any significant resistance to new drug-eluting stents coming on the market, now or in the future.

Rajan says that many physicians and hospitals like to keep a “rotating schedule” of stent usage by brand. “It's partly a defensive measure, in case a stent is recalled or becomes subject to legal action,” he says. “By having used stents from different manufacturers, any adverse events can be somewhat contained.”

Gunderson says, “While I suspect Boston Scientific and Cordis attempt to lock in some accounts, it's the nature of interventional cardiologists to give new products a whirl. But the lasting share of such shifts, if any, is the great unknown.”

Wald adds, “Hospitals are increasingly demanding shorter-term buying contracts and there's no exception here. While that means potentially greater receptivity to new products, the issues of physician preference and brand loyalty cannot be easily dismissed.”

In addition to the four major players, there are numerous other coronary stent manufacturers in the United States and around the world. Many of these companies are focusing on drug-eluting stents for particular kinds of coronary lesions or patient conditions that compromise the safety and efficacy of standard stents. While the market may be receptive to innovative technologies that promise greater safety and improved clinical outcomes, it may also prove to be a hostile launch pad for stent manufacturers that offer no significant advantages over current devices.

“New stents will take so long to emerge from FDA requirements that they will have to offer a compelling advantage,” says Gunderson. “Me-too stent manufacturers should abandon their plans.”

In addition to a more competitive market, stent manufacturers will face greater scrutiny from FDA. Last month the agency issued new draft guidelines “to aid the development, testing, and manufacture of coronary drug-eluting stents”. The agency has indicated that under the proposed guidance, the safety data for drug-eluting stents will need to extend out two years before the agency will consider approval. On the postmarket side, studies will be required to follow patients for at least five years.

“This draft guidance is part of FDA's ongoing effort to provide regulated industry with recommendations on measures that can minimize the risks while preserving for patients the benefits of drug-eluting stents,” said Daniel G. Schultz, MD, director of FDA's Center for Devices and Radiological Health (CDRH).

The new guidelines are not expected to affect the Cypher, Taxus, or Endeavor stents—or the expected near-term approval of Abbott's Xience stent. But Cordis, Boston Scientific, Medtronic, Abbott, and other medtech manufacturers seeking FDA approval of new drug-eluting stents will have to conform to the new regulations. Industry response to FDA's proposed guidance was generally favorable, as manufacturers believe the guidelines will establish a more defined and deliberate process.

FDA's draft guidance document, Draft Guidance for Industry on Developing Coronary Drug Eluting Stents (Rockville, MD: CDRH, FDA, 2008), is available via the CDRH Web site at

© 2008 Canon Communications LLC

Return to MX: Issues Update.

A Jury Panel Seeking Excellence

MDEA 2008

Kouros Azar, MD, is a biomedical engineer and a practicing plastic surgeon with a specialization in complex reconstructive and aesthetic surgical techniques. He holds several patents on new technologies used in the operating room. He is on the executive committee of the Engineering in Medicine and Biology section of the Institute of Electrical and Electronics Engineers. Azar has previously served as head engineer and scientist for all collaborative projects in the departments of otolaryngology and biomedical engineering at the Cleveland Clinic Foundation.
Ogan Gurel, MD, is chairman of Aesis Research Group LLC (Chicago), a firm that provides consulting and research services on investing in and developing next-generation life sciences companies. His work has been published in peer-reviewed scientific literature, including the European Molecular Biology Organization Journal and the Journal of Molecular Biology. He is presently on the faculty at Roosevelt University (Chicago), where he has taught cellular and molecular biology, bioinformatics, and mathematical modeling. Gurel is also experienced in international medical relief work, having served during the NATO military campaign in Kosovo as well as in Turkey after the major 1999 earthquake. Gurel is a frequent conference speaker on emerging technologies and their effect on the future of healthcare. He has focused in particular on convergent medical technologies, including medical nanotechnology.
William Hyman is a professor of biomedical engineering at Texas A&M University (TAMU; College Station). Hyman holds an ScD in engineering mechanics, an MS in engineering mechanics from Columbia University, and a BSME in mechanical engineering from The Cooper Union. He is also senior scientist in the biomaterials research center at the University of Texas, Houston, a faculty member in material science and engineering at TAMU, and a participating faculty member in TAMU's sports medicine institute and the Center for Microencapsulation and Drug Delivery. Hyman has served as a consultant for FDA, the National Science Foundation, the National Institutes of Health, the U.S. Army, the General Accounting Office, and in patent and personal-injury litigation. He serves on the American Society for Testing and Materials committees on surgical implants and medical devices, sports equipment and facilities, and forensic sciences.
Edmond Israelski, PhD, is human factors program manager for Abbott Laboratories (Abbott Park, IL). He has participated in the user interface design and evaluation of a wide variety of medical products, including infusion pumps, drug-delivery systems, and diagnostic testing systems. As part of his post, he created an infrastructure to embed human factors process steps in all aspects of design and evaluation of new products. Israelski is cochair of the AAMI human factors engineering standards committee. He is a member of the ISO-IEC joint working group on usability for medical devices, and he is a member of the National Academy of Science committee on human-system design support. Israelski is a board-certified human factors professional and holds 15 patents.
Craig Jackson, PhD, is founder and president of Hemosaga Diagnostics Corp. (San Diego). He has written more than 75 original papers, has contributed to more than 30 textbooks, and regularly writes for both professional and trade journals. Jackson holds several patents. He is a member of Working Group 1 of the Joint Committee for Traceability in Laboratory Medicine (JCTLM), where he has been responsible for developing its quality system. JCTLM provides the mechanism by which the European Union's In Vitro Devices Directive requirement for traceability can be met. He is a fellow of the National Academy of Clinical Biochemistry and also a fellow of the American Association for the Advancement of Science (both in Washington, DC).
Pascal Malassigné is a professor of industrial design at the Milwaukee Institute of Art and Design, a research industrial designer at the Milwaukee Veterans Affairs Medical Center, and an adjunct assistant professor of rehabilitation at the Medical College of Wisconsin in Milwaukee. For the past 22 years, his research has been funded by the U.S. Department of Veterans Affairs and has led to the design of products such as commode-shower wheelchairs, bathing fixtures, prone carts, and bedrails. He has written more than 70 articles and papers and has made numerous presentations internationally on topics ranging from design education to rehabilitation technology. Malassigné is a member of the Industrial Designers Society of America (IDSA), in which he was made a fellow member in 2001 in honor of his service to the industrial design profession and IDSA. He helped found and was the first president of the Design Foundation, IDSA's nonprofit organization.
Jerry McVicker, PhD, is scientific director of Midland Bioproducts Corp. (Boone, IA), which develops human and veterinary diagnostic assays. The company prepares antigens, polyclonal antisera, specific plasma protein calibrators and controls, and lateral-flow devices, which it sells to immunodiagnostic manufacturers for human and veterinary use. McVicker is also an assistant professor in the animal science department at Iowa State University (Ames, IA). He has published a number of papers on topics including animal fertility diagnostics and bovine immunoglobulin G detection. He holds patents on two antibody testing methods.
Sandra Miller is managing director of the Stanford Biodesign Program at Stanford University (Palo Alto, CA). The program fosters interdisciplinary research and education in medical device design and commercialization. As a liaison to the university's Office of Technology Licensing, she helps assess medical device technology commercial viability and provides strategic input for marketing and licensing. She has developed several new programs, including the biodesign pathway for medical device fellowships at FDA's Center for Devices and Radiological Health. Miller is a founding member of the Stanford Entrepreneurship Network, whose mission is to support entrepreneurship education, research, and collaboration. She holds a BA in broadcast communications from San Jose State University (San Jose), and an MBA from Pepperdine University (Malibu, CA).
Molly Story is president of Human Spectrum Design LLC (Santa Rosa, CA), and codirector of the Rehabilitation Engineering Research Center on Accessible Medical Instrumentation (Milwaukee). Story is an expert in universal design of products and in the accessibility and usability of medical instrumentation. She is coeditor of the recent book, Medical Instrumentation: Accessibility and Usability Considerations (CRC Press, 2007). Story also cowrote The Universal Design File: Designing for People of All Ages and Abilities (North Carolina State University, 1998) with James L. Mueller and the late Ronald L. Mace. Story is a member of AAMI's human factors engineering committee, which is developing the forthcoming AAMI HE75 standard on human factors design guidelines for medical devices. Story is also a PhD candidate at the University of California, Berkeley.
Herbert Voigt, PhD, is president and a fellow of the American Institute for Medical and Biological Engineering (Washington, DC). In 2006, Voigt was elected vice president of the International Federation for Medical and Biological Engineering (IFMBE). He will assume the IFMBE presidency at the organization's 2009 world congress in Munich. Voigt is a professor in the department of biomedical engineering at Boston University and also a research professor in the university's department of otolaryngology. He has received grants for hearing research, for providing research experience for students in biomedical engineering, and for enhancing internship opportunities for biomedical engineering students.
Michael Wiklund is president of Wiklund Research & Design Inc. (Concord, MA). Board certified in his profession, Wiklund is an experienced project manager, principal researcher, and designer. He is an adjunct associate professor in the department of mechanical engineering at Tufts University (Bedford, MA). Wiklund is a frequent contributor to MD&DI and is a member of its Editorial Advisory Board. He has published numerous articles, books, and technical papers and has also presented papers at professional conferences in the medical device, human factors, and scientific instrumentation fields. His latest book, Designing Usable Medical Devices, was published in 2005.

Staying in Control of the Extrusion Process

Increasingly smaller medical devices require tighter tolerances that make extrusion process control more difficult. Photos courtesy of TEEL PLASTICS INC.
As medical devices get smaller and tolerances get tighter, it has become more important than ever for tubing manufacturers to maintain good control over the extrusion process. But smaller dimensions and tighter tolerances also make process control more difficult than ever for extruders.

How are manufacturers meeting today's process-control challenge? Strategies include a complex mix of factors involving extrusion equipment, practices, and personnel. Potential solutions can come into play before, during, and after the extrusion process, both on and off the production line. Not surprisingly, however, all of the extras that help ensure tight control can also run up the price of extrusion, so medical device firms should be sure that they're not buying more process control than they really need.

Elements of Process Control

The first thing to consider about process control is the setting in which extrusion is performed. Extruders can't expect to achieve tight and reproducible process control if they don't have control of the extrusion environment, says Keith Andrews, director of business development for Upchurch Scientific (Oak Harbor, WA), which extrudes tubing for medical device companies. Upchurch controls the extrusion environment by performing the process in a Class 100,000 cleanroom. Among other things, the cleanroom setting prevents large variations in temperature and humidity that could be detrimental to the extrusion process, Andrews notes.

When setting up a new process, extruders can often get help by reviewing data from old processes, according to Don Centell, general manager of ExtruMed LLC (Placentia, CA), which provides custom extrusions to the medical device industry. ExtruMed's database contains information about almost 14,000 extrusion runs over the last 10 years. Company personnel tap this database for information that can be applied to a new job, Centell says.

Particularly important is information about the material used to make the tubing. But device companies can't go to their databases for information about the many new resins being introduced. Before using a new resin, Andrews says, manufacturers must test the material to obtain data on its characteristics that will help determine a successful, well controlled process for extruding it.

The material should determine what screw design is chosen for the extrusion process. “If a screw isn't properly designed for a particular material, then you typically won't get consistent output from that screw,” says Mark Saab, president of Advanced Polymers Inc. (Salem, NH), which manufactures plastic tubing and medical balloons for dilation procedures. “This means you'll have a lot of dimensional and temperature fluctuations in your process.”

At Advanced Polymers, the first step in finding the right screw for a particular material is evaluating various in-house screw designs. If none of these provides consistent output, the company sometimes turns to an outside manufacturer to produce a new screw for the material. But this can be a lengthy and expensive process, so it's best only when it can be justified by sufficient product volume.

In addition to the screw and other basic equipment, extruders sometimes add a melt pump to their lines. Melt pumps can provide a more consistent flow of material than the extruder itself, which stabilizes the process and improves control, says Bob Asam. He is a senior process engineer at Teel Plastics Inc. (Baraboo, WI), which specializes in manufacturing close-tolerance plastic tubing.

Process control systems can include screw designs, diameter measurement equipment, and melt pumps, which can be expensive.
In some cases, melt pumps reduce pressure fluctuations that can cause dimensional inconsistencies during the extrusion process. For example, Centell says, pressure on the inlet side of the melt pump might be fluctuating by 20 or 30 psi, but by less than 5 psi on the discharge side.

On the downside, Saab notes, a melt pump is a costly piece of equipment and is expensive to maintain. It also exposes the extruded material to additional heat, which can cause thermal degradation. For these reasons, he says, most extruders either don't use melt pumps at all or only use them when necessary to meet customer requirements.

Beneficial Advances

All up-to-date extrusion lines have benefited from advances in motors and drives, which allow manufacturers to tightly control the speed of screws and other equipment along the line. “When you set the machine to 46 rpm, the speed is exactly 46 rpm,” says Guy Schultz, a process engineer for Filtrona Extrusion (Athol, MA), which manufactures plastic tubing. “There's no variation over time, which allows us to hold tighter tolerances.”

In addition to precise speed regulation, state-of-the-art extrusion lines feature improved temperature control. In the past, Schultz says, the temperature of the extrusion process “could bounce around a little bit.” Now, however, temperature controllers on the machines maintain process temperatures within a range of ±1°F.

According to Saab, most new extruders include high-end proportional integral derivative (PID) temperature controllers. But many older extruders that lack these temperature controllers are still in operation. Such extruders are “something you really want to avoid if you're in the medical industry,” Saab says. “In extrusion, being able to control the temperature in your line is fundamental. But that doesn't mean everybody does it or does it well.”

Besides temperature controllers, Advanced Polymers uses data-acquisition systems to collect temperature and pressure information from different points along the line during an extrusion run. These data help plant personnel pinpoint production problems and determine their cause.

In-Line Measurement

Perhaps the most common and useful process-control tools are devices that perform in-line measurement of critical tubing dimensions. At Filtrona, tubing outer diameter (OD) is checked by a high-speed in-line monitoring system. The system features a dual-axis laser micrometer that measures tubing from two angles 90° apart, to catch any ovality in tube cross sections. Also included is a large LED readout that displays tubing ODs to the fourth decimal place.

Some commercially available laser gauges add a third axis to the measurement process, increasing the likelihood of catching tubes that aren't perfectly round, according to Saab.

On Filtrona's extrusion lines as well as others, laser gauges that measure tube OD are joined by ultrasonic devices that can determine the thickness of tube walls. With a tube's OD and wall thickness known, a system can calculate the inner diameter (ID) to the fourth decimal place, Schultz says.

In-line measuring devices make it possible for tube manufacturers to set up feedback loops that operate during the extrusion process. For example, ExtruMed engages feedback loops based on the tube OD readings taken by a laser micrometer. If the OD readings are moving toward the high end of the allowable range, the system removes a little air from the extrusion process and then takes more readings to see the results of that action, Centell explains. Then, if necessary, the system can remove more air to further adjust the process.

Because feedback loops introduce another variable into the extrusion process, ExtruMed uses them only when absolutely necessary. “One rule of thumb is that if you've got a real slow drift, go ahead and engage the feedback loop. It will help you out,” Centell says. “But if [the process] is running stable on its own, keep it manual.”

ExtruMed's database of information from past extrusion runs can alert operators to situations that might require a feedback loop. For example, Centell says, data from previous runs may show that a pressure feedback loop is usually engaged when extruding a certain material. In a case like this, the feedback loop may not be engaged to begin with, but the operator won't hesitate to do so if run data indicate that it can help solve a control problem.

Though it can be a useful tool in many cases, closed-loop control has significant limitations. “It can only adjust what it's set up to adjust,” Saab notes. “So if you have another problem, it's not going to correct for that.” It can make matters worse by repeatedly making adjustments in an effort to solve a problem that it hasn't been set up to solve.

Saab says a better control system is one that involves a trained operator. In such a system, a drifting process sets off an alarm that alerts the operator, who can then assess the situation and decide on a course of action.

Advantages of SPC

Filtrona's monitoring system prints out quality-control reports during the extrusion process, when they can be used to make any necessary process adjustments. “Once the job is done, it's too late” to get this information, Schultz says. “We [get] real-time quality control information.”

At Teel, computerized statistical process control (SPC) makes it easy for operators and quality control personnel to access process data. “I can just go to my computer and pull up a run to see if we were in control or out of control,” says Rachell Bainbridge, the company's director of quality.

Before SPC was computerized at Teel, operators wrote process information on paper control charts. In addition to plotting data points on the charts, they had to calculate ranges and averages. Now, operators enter measurements into the system and it produces process information at the press of a button, speeding up data analysis and eliminating the possibility of human error in the calculations.

Like the Teel system, ExtruMed's process provides real-time data in chart form that allow plant personnel to spot trends. “It's visual, so you can very quickly see whether you're running stable or experiencing very slow fluctuation,” says Centell.

Most of ExtruMed's customers don't ask the company to provide SPC data, but the company still gathers the information for its own purposes. “We use it to find out whether the current run is similar to the other runs we've done for the customer in recent years, so we know whether we're consistent,” Centell explains.

Other Factors

Another factor affecting process control is the caliber of an extruder's engineering and quality teams. At Teel, an engineer is always present for the initial run of a material in order to optimize the process, according to Chris O'Connor, a senior product development engineer at the company. In addition, Saab says, operators who can't get a process to run within specifications call in an engineer, who looks at factors such as tooling, temperature, and screw design. And if a number of recent extrusion runs have produced tubes that are rejected for the same reason, manufacturing engineers and the quality team at ExtruMed get together to try to pinpoint the cause of the problem.

Then there are the operators. Has the extruder established effective training programs for them? In many cases, operators aren't trained well enough to take full advantage of the latest extrusion equipment, Centell says.

In addition to training their operators, companies concerned about process control should make sure they follow standard work procedures. Examples include the steps established by a company for starting up an extrusion line and calibrating gauges. “We don't want five different operators to be doing five different things,” Andrews says. “We want all the operators to follow a proceduralized process that will help us get consistent results.”

Process control also depends on how well extrusion personnel maintain equipment. “The process can drift over time because of equipment wear,” Saab says. “As a result, what you make this year can be significantly different from what you made two years ago.”

No equipment is more important to the process than the screw and barrel. “As these components wear over time, your process will change,” Andrews says. “So it's crucial to keep track of the wear of the screw and barrel—and to know when you have to repair or replace them.”

In addition to checking for wear, Saab says, extrusion personnel should make sure that their equipment is properly calibrated. Consider, for example, the temperature controller on an extrusion line, which could “very easily” be off by 5°F, Saab says. Although that may seem like a small amount, it can have an effect on the properties of tubing made on that line.

The Importance of Inspection

Inspection personnel use optical comparators that can magnify a cross section of tubing 20 times, making it easier to check critical dimensions.
To ensure that an extrusion process remains in control, no job is more important than inspection. At ExtruMed, technicians constantly check their products and fill out in-process inspection sheets. Depending on what data a customer wants, technicians record measurements of tube OD, ID, and wall thickness. If multilumen tubing is being extruded, inspectors also record all lumen dimensions.

Once every half-hour during the extrusion process, Filtrona personnel cut a cross section out of the tubing and inspect it using an optical comparator. This device magnifies the cross section 20 times, making it easier for inspectors to examine tubing and check critical dimensions.

Vision systems are crucial tools at Molded Rubber and Plastic Corp. (MRPC; Butler, WI), which extrudes silicone tubing for the medical industry. These elastomeric products can't be measured with a touch probe because contact with the measuring device can cause deformation of the soft material, explains Greg Riemer, MRPC's vice president of sales and marketing.

But measurement using a vision system doesn't require any contact with the product. These systems put a magnified color image of a tube cross section on a computer monitor, allowing inspectors to manually take dimensions such as OD, ID, and wall thickness. Because the systems can “see” dark and light, they can also locate the edges of a tube for an inspector, notes Mark Tesch, MRPC's engineering manager.

Plant personnel certainly need help in meeting today's greatest inspection challenges. For example, studies done by Advanced Polymers have found that inspectors simply can't measure tubing with the supertight tolerances now being specified by many medical device firms. So the company is working with Lumetrics Inc. (West Henrietta, NY) to develop a noncontact optical gauging system that will be used offline to measure tubing. An operator will set up the system and load tubing into it, but the system automatically takes measurements without operator involvement, thereby freeing the
measurement process from human error and limitations. In addition to providing greater accuracy, Saab hopes that the system will also be faster than manual measurement.

Customers and Control

How much inspection is necessary? That's ultimately up to the customer. ExtruMed can show customers a year's worth of in-line measurement data to statistically prove that an extrusion process is under tight control—and, therefore, that costly inspections can be reduced. But if a customer still insists on frequent inspections to check critical tube dimensions, “then that's part of the price that the customer is willing to pay,” says Brandon Gosiengfiao, ExtruMed's senior quality engineer.

ExtruMed makes several different tubing products for Spectranetics Corp., a medical device firm in Colorado Springs, CO. These include three sizes of bump tubing made of high-density polyethylene, which is a very difficult material to extrude, according to Jamie Fearing, the company's purchasing supervisor. Adding to the difficulty of the job are the tolerances, which, in one case, are as tight as ±0.0001 in., Fearing notes.

To help ensure that ExtruMed's processes are up to the job, Fearing's firm conducts regular audits at the extruder's facility. During these audits, Spectranetics personnel look for the following:

  • Quality systems that are ISO or FDA certified.
  • Records showing that operators are properly trained.
  • Evidence that processes are in control. This is obtained by watching production runs and reviewing inspection data from past runs.

Of course, the evidence that would satisfy Spectranetics might be different from the evidence that would satisfy another medical device firm. So the quality plan for an extrusion job may be more or less demanding, depending on customer requirements. “Some of our stringent customers want an ID, OD, wall, and concentricity measurement for every 20 pieces we run,” Tesch reports.

The price paid by these customers for their stringent requirements can be very high. According to Saab,
process-control equipment and personnel can easily double or triple the cost of an extrusion run. “There's a huge difference between what we charge a customer who has broader tolerances and specs and a customer with tight tolerances and specs.”

Copyright ©2008 Medical Device & Diagnostic Industry

Ignoring an Inconvenient Truth


In case you were wondering whether FDA was going to learn from its loss in court to Utah Medical, the answer is apparently no.

Just as with three previous agency defeats in federal court, the Utah Medical case has been omitted from The Enforcement Story, the agency's official public report of significant legal decisions, which is published annually by the Office of Regulatory Affairs (ORA).

The Utah Medical case is legally significant because it established that, in quality system regulation or GMP compliance, a medical device company is free to depart from the prescriptive direction of FDA officials—that “many roads lead to Rome.” In other words, government enforcement of penalties requires officials to identify which Code of Federal Regulations requirements are being violated by a device firm, not dictate methods that a company must use to comply with those regulations.

In normal circumstances, such guidance from the federal judiciary could lead to a change in agency practices. The current practice is one of prescribing “how to” advice to industry, through workshops, speeches, informal advice, interpretive guidances, and other means, as opposed to “what to” advice.

However, shortly after the Utah Medical decision was handed down, a senior FDA attorney was reputed to have said, informally among other lawyers, that the decision was delivered by an “aberrant” judge. (Utah Medical judge Bruce S. Jenkins, who was appointed by President Carter in 1978, actually has a long list of home-state accolades and honors to his credit.)

Since then, no FDA or Department of Justice attorney associated with the case, or any other federal official, has been willing to discuss the case, either on or off the record. Because most professional legal forums in what is known as the “FDA bar” rely heavily on the fraternal participation of FDA attorneys, that reliance effectively discourages anyone from discussing this case in formal programs. It's as if it has simply vanished.

When I reported on Jenkins's record in January on, it attracted a sneering anonymous comment from someone who seemed to be familiar with the case from FDA's perspective. “These plaudits all come from the judge's alma mater or the Utah [State] Bar. Utah is well known as a rogue state with uber-libertarian sentiments regarding federal regulation of any kind, and that sentiment is even more prevalent in the realm of drug, device, and dietary supplement regulation.”

Two separate requests for an explanation for the omission from ORA's most responsible officer, associate commissioner for regulatory affairs Margaret O'K. Glavin, garnered no response.

Apparently, in FDA's mind, this “aberrant” and inconvenient truth never was.

In an agency over which commissioners may reign but not rule, as reported last month, why should we be surprised if, below these nominal commissioners, subordinates may overrule the orders of judges?

New Guidance Issued on CLIA Waivers

FDA has issued a guidance for industry and FDA staff, titled Recommendations for Clinical Laboratory Improvement Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices. It makes recommendations to manufacturers seeking to submit information through a CLIA waiver application to FDA and modifies recommendations presented in draft guidances released in 2001 and 2005, respectively.

The HHS secretary has authorized FDA to determine whether particular tests are simple and have an insignificant risk of an erroneous result under CLIA regulations. Only diagnostic tests that meet these
criteria are eligible for a waiver.

FDA says the guidance recommends an approach for manufacturers to use in demonstrating that a test meets these criteria. As part of demonstrating an insignificant risk of erroneous result, FDA recommends that studies be conducted to demonstrate a test's accuracy.

FDA says its recommendations are based on interpretation of the law, experience with CLIA complexity determinations, and interactions with stakeholders. Manufacturers may adopt a different approach for their waiver application if it meets the CLIA statutory requirements.

The guidance covers components of a CLIA waiver application, demonstrating “simple,” “insignificant risk of an erroneous result,” “insignificant risk of an erroneous result—accuracy,” labeling for waived tests, and safeguards for waived tests.

The guidance may be accessed at

Changes in Updated Guidance

Changes from previous guidances include the following:

  • Greater emphasis on scientifically based flex studies and validation or verification studies, linked to the risk assess­ment for each device.
  • Recognition that reference methods may not be available for every device type.
  • Additional emphasis on the use of quality control procedures.
  • Greater emphasis on intended users during studies testing a device.
  • Updated study recommendations with emphasis on use of patient specimens, in an intended use environment, over time.

FDA Seeks Tougher Court Sentences

John Fleder is not convinced that the sentencing system is broken, or that FDA's proposed changes to sentencing guidelines are necessary.
FDA is making a pitch to the U.S. Sentencing Commission for more-stringent maximum sentences. The commission is considering new sentencing guidelines.

In February, FDA assistant commissioner for accountability and integrity William McConagha told the Sentencing Commission that it should determine the adequacy of the existing guidelines for the Federal Food, Drug, and Cosmetic Act (FD&C Act), which covers medical devices.

“We at FDA believe that establishing an appropriate penalty framework for violations of…[the FD&C Act] is critical to provide a specific and general deterrent to crimes that threaten…the public health,” McConagha testified. “For that reason, we believe that realistic sentencing guidelines for these offenses are of vital importance to the agency's public health mission.”

He said that the current guidelines are inadequate to address the significant public health consequences of various FD&C Act offenses. Most FD&C Act offenses, he said, involved adulterated or misbranded products.

Products, he said, can be adulterated or misbranded for many reasons set forth in the FD&C Act. The existing sentencing guidelines don't directly address whether misbranded or adulterated FDA-regulated products can be viewed as having value when loss is calculated. So McConagha suggested revising the guidelines to provide that, in those cases, loss would include the amount paid for the product with no credit for a product's purported value.

That proposal drew fire from attorneys at the Washington, DC–based law firm of Hyman, Phelps & McNamara, who said it “raises many questions and concerns. First, creative lawyers in the context of civil litigation may try to employ FDA's proposed finding to seek a monetary recovery based on that

“Second, the change would almost certainly dramatically increase sen-tences to be imposed in cases where loss is at issue, including all felony cases.

“Third, if adopted, it may make it very difficult for companies and individuals to work out guilty pleas with the government because the guidelines will warrant a sentence that the defense will find intolerable.”

The firm's FDA law blog says FDA's position is “breathtaking in its scope.” The attorneys note that every day, many manufacturers distribute products that are not in full compliance with all FD&C Act mandates and thus are technically adulterated and misbranded. Such distribution routinely occurs with FDA's knowledge, the blog says. To say that all adulterated and misbranded products are worthless “raises serious legal and policy issues that the commission should fully explore before adopting FDA's suggestion.”

John Fleder, a director in the law practice, said there is “no evidence that the system is broken or that the proposed changes…are necessary or appropriate based on the FD&C Act statutory scheme, the purposes of the guidelines, or the actual record of FD&C Act criminal enforcement.”

Multiple Violations Alleged at Hill-Rom

An inspection last June at Hill-Rom's Batesville, IN, facility where VersaCare beds are manufactured found quality system and medical device reporting violations, according to a January 15 warning letter from FDA's Detroit district office.

Reporting violations included the following:

  • Failure to report to FDA no later than 30 days after the company became aware of information reasonably suggesting that a marketed device has malfunctioned, and that the device would be likely to cause or contribute to a death or serious injury.
  • Failure to submit a written report to FDA of any correction or removal of a device to reduce a risk to health posed by the device.
  • Failure to submit reports of initiating corrections or removals.

The company's responses to these violations also were inadequate, the warning letter said. Hill-Rom was told to respond within 15 days with specific steps taken to correct the violations, documentation of corrective actions taken, and an explanation of plans to prevent these or similar violations from occurring again.

Other Violations at Hill-Rom

Quality system violations found during the inspection last June included the following:

  • Failure to establish and maintain procedures for implementing corrective and preventive action.
  • Failure to establish and maintain adequate procedures for reviewing and evaluating complaints involving the possible failure of a device, labeling, or packaging to meet any of its specifications.

The warning letter said the company's response to these observations was inadequate because there was no evidence submitted of revised procedures.

Medtronic Infusion Pumps Recalled

FDA has classified as Class 1 (most severe) a recall involving Medtronic's SynchroMed EL Implantable Infusion Pump Models 8626-10, 8626L-10, 8626-18, 8626L-18, 8627-10, 8627L-10, 8627-18, and 8627L-18. There is a potential pump-motor stall problem that affects motors manufactured before September 1999. “If a pump motor stalls, drug delivery will stop suddenly and without warning,” an FDA recall notice says. “This stoppage will result in loss of therapy, return of the patient's symptoms, and/or symptoms of drug underinfusion or withdrawal.”

Stryker Trident Acetabular Cups Recalled

Stryker has recalled all Trident PSL and Hemispherical Acetabular Cups manufactured at its Cork, Ireland, manufacturing facility after the devices failed to meet the company's internal acceptance criteria. The recall follows a corporate-wide “comprehensive review of internal processes” that resulted after FDA sent the firm a warning letter in November about GMP problems found during an inspection at Stryker's Mahwah, NJ, facility. The warning letter said violations and inspectional observations may be symptomatic of serious problems in Stryker's manufacturing and quality assurance systems.

FDA Cites Siemens Molecular Imaging

An inspection last summer at Siemens Medical Solutions's molecular imaging division facility in Knoxville, TN, found quality system problems in the firm's manufacture of molecular imaging diagnostic equipment.

A January 28 warning letter from FDA's New Orleans district office included the following violations:

  • Failure to establish and maintain adequate procedures to control design validation, including software validation and risk analysis, where appropriate.
  • Failure to establish and maintain adequate procedures for implementing corrective and preventive action to ensure that quality data sources are analyzed to identify existing and potential causes of nonconforming product or other quality problems. Also, failure to employ appropriate statistical methodology where necessary to detect recurring quality problems.
  • Failure to establish and maintain adequate procedures to ensure that the cause of nonconformities relating to product, processes, and the quality system is investigated.

The warning letter says a response from the company last August to the FDA-483 observations was inadequate. The firm was told to correct the violations and to respond within 15 days listing the specific steps taken to ensure that the violations do not occur again.

Copyright ©2008 Medical Device & Diagnostic Industry

Relying on a Breath of Detection


University of Colorado physics professor Jun Ye is developing a very sensitive patient breath analyzer that could detect both heart and kidney disease.
A sensitive laser system that analyzes human breath isn't just a bunch of hot air. Upon exhaling into the device, a patient could quickly be informed of potential health problems, from asthma to lung cancer. The low-cost and non­invasive technology could be a valuable preventive medicine tool.

The device is giving researchers the power to identify certain disease biomarkers from billions of other types of molecules. It is being developed by a team of researchers at the Joint Institute for Laboratory Astrophysics (JILA) of the National Institute of Standards and Technology (NIST) and the University of Colorado (Boulder).

The technology can be applied anywhere that trace amounts of gas must be monitored. In the medical field, it could identify diseases associated with the lungs. This includes kidney disease and heart disease. Heart disease sometimes results in a change in breath patterns, according to Jun Ye, a joint physics professor at the University of Colorado.

The technology has three components—the laser, the cavity (where the laser interacts with the material), and final analysis instrumentation. Although the complete package measures 4 × 3 × 2 in., it could also be engineered smaller.

The device uses a technique called cavity-enhanced direct optical frequency comb spectroscopy. A laser emits a train of short optical pulses, which creates a rainbow of colors with sharp spectral resolutions underneath. Upon zooming, the researchers can see individual components of optical frequency.

The laser is placed into an optical cavity, which allows the light to bounce back and forth so that it interacts with the material.

The laser emits many different colors, so there are hundreds of thousands of channels working at the same time. Researchers can sort through the colors by wavelength while maintaining very high resolution. “We can use individual components of these frequencies underneath the color as an individual detection channel,” says Ye.

Researchers can identify species in real time using the technology's high-spectral resolution. Its large spectral coverage and sensitivity helps them see many different types of molecules all at once. Having the ability to simultaneously detect many breath molecules could help them gather reliable, disease-
specific information.

The researchers are currently trying to improve the device's sensitivity. “We're working on [increasing] sensitivity by a factor of a hundred or maybe even a thousand, so we can detect molecules out of a trillion others,” says Ye. “We want to start analyzing the correlation between the breath and the real disease from real patients.”

Current testing has only involved healthy people. Ye hopes to apply it to clinical trials within a year. He says that companies and doctors have already expressed interest in both developing and commercializing the technology.

The research findings were published in a recent issue of the journal Optics Express. Funding was provided by the Air Force Office of Scientific Research, Agilent Technologies Foundation, the Defense Advanced Research Projects Agency, NIST, the National Science Foundation, and a University of Colorado grant.

Copyright ©2008 Medical Device & Diagnostic Industry

Variety Could Be the Key to Neurostimulation


Researcher Basim Uthman says that pattern recognition could be keeping the brain from responding to neurostimulation.
Researchers from the University of Florida (UF; Gainesville) are hoping that variety is the component that keeps neurostimulation alive. They have developed a technology called variational neurostimulation, which may prevent the body from adapting to and resisting stimulation therapy.

“We think that the brain and the seizure focus are smart and find ways around stimulation,” says Basim Uthman, MD, associate professor of neurology at UF. “Although it may sound counterintuitive, the [brain's] normal activity is chaotic and random. Seizure activity is more of a synchronous activity—it's very organized.”

The researchers compare the body's resistance to stimulation with patients who take antibiotics in the hospital. “When you use certain antibiotics, after a while, they're not effective,” says Uthman. “The bacteria change and because of the environment, they make adjustments so that they won't be killed by the

In order to fool the brain, the researchers have designed a scheme in which no particular stimulus is the same as the previous one. By altering the electrical stimulation, the brain doesn't have a chance to learn the pattern.

“We want to program [the scheme] in a variational way that won't allow the central nervous system and its disorders to habituate to the therapeutic effect of the stimulation,” Uthman says.

Uthman and Panos Pardalos, PhD, are working on how to deliver combinations of different stimulation parameters at various frequencies. Pardalos is a professor of industrial and systems engineering at the university.

The technology also uses data mining and analysis to find certain patterns that could help identify disorders in the brain.

Panos Pardalos, PhD, works with Uthman to define the stimulation parameters and develop combinations at various frequencies.
Uthman hopes that in addition to regulating seizure activities, the technology can be used to treat disorders such as Parkinson's and Alzheimer's diseases. It is currently designed for integration into existing stimulation devices, and it can be used in both the central and peripheral nervous systems.

Uthman is open to working with people who want to apply the technology to different conditions. At UF, the researchers are using the technology to address movement disorders.

“A lot [of disorders] have to do with rhythmic episode phenomenon,” says Uthman. “Maybe with time, this technology may work with deep brain stimulation and not just with vagus nerve stimulation.” It might have use in spinal chord stimulation to treat pain disorders as well.

Uthman says that the technology's program is complex. Manufacturers may need to revise a neurostimulation device so that it has the capacity to run the program. However, he emphasizes that the technology is in its early developmental stages, and the team needs to prove the concept.

The UF researchers plan to introduce the program to rats that have stopped responding to traditional stimulation. If the researchers receive approval to conduct human studies, they hope to find out if the technique works better than current methods of neurostimulation.

“Although vagus nerve stimulation has been used for a long time, nobody knows why it works the way it works. Only lately have we tried to see what we changed in the brain.”

UF's Office of Technology Licensing is currently looking for companies interested in the patent-pending technology.

Copyright ©2008 Medical Device & Diagnostic Industry

Shedding Light on Alzheimer’s Disease


Near-infrared light is being harnessed to detect signs of Alzheimer's disease. Microscopic changes to the optical properties of the brain are hallmarks of the disease. These alterations often occur far in advance of clinical symptoms. The technique measures light as it passes through the brain.

Near-infrared light can safely penetrate the skull and pass harmlessly through the brain. Analysis of how the infrared light scatters provides data on the condition of the brain.

Researchers from Harvard Medical School, Beth Israel Deaconess Medical Center, and Boston University are testing the method to diagnose Alzheimer's disease in living people.

Copyright ©2008 Medical Device & Diagnostic Industry

Industry Welcomes Guidance on Off-Label Use


According to Pamela Furman, the FDA-issued guidance legitimizes the communication between manufacturers and health practitioners regarding truthful and nonmisleading off-label uses.
A draft guidance outlining how companies can distribute journal articles that discuss unapproved uses of FDA-approved devices is being greeted with open arms. It marks the first time that the agency has considered allowing manufacturers to mention off-label uses to physicians in any way.

FDA's Good Reprint Practices document suggests how device firms should disseminate scientific or medical journal articles and reference materials that talk about off-label device use.

“It's significant because it shows that FDA recognizes there's a legitimate zone of communication between manufacturers and the healthcare industry regarding truthful and nonmisleading materials on off-label uses,” says Pamela Furman, partner at King & Spalding LLP (Washington, DC).

Overall, the proposed guidance has been praised within industry, but opponents have criticized FDA for letting companies promote potentially unsafe, unapproved uses of devices.

In a November 30, 2007, letter to FDA commissioner Andrew von Eschenbach, Congressman Henry Waxman (D–CA) wrote that the “ill-advised” guidance would create a “large loophole in the law and create a pathway by which drug and device manufacturers can promote unapproved uses of their products without first obtaining FDA approval.” (The document was not made public until this February, but Waxman saw an internal version of it last October.)

Although there may be potential for abuse, the draft offers guidelines for the types of acceptable articles and how they should be distributed.

“This is not really a loophole,” says Jonathan Kahan, partner at Hogan & Hartson LLP (Washington, DC). “If you look at FDA's criteria for disclosing here, it has to be a peer-reviewed journal article or textbook, and there has to be full disclosure that it includes off-label information. Therefore, I think as long as it's not false and misleading and there is full disclosure, it can actually significantly benefit the patient.”

According to FDA spokeswoman Rita Chappelle, the agency proposed the guidance to clarify its current thinking on what constitutes a good reprint. The guidance on reprints was contained within section 401 of the FDA Modernization Act of 1997, which expired in September 2006.

“By issuing this guidance, FDA hopes to clear up any confusion about our thoughts on this and also hopes to provide guidance on what would constitute a safe harbor from current laws,” says Chappelle. Further, she explains, it enables FDA to begin enforcement action against firms that operate outside of the principles laid out in the guidance. Chappelle adds that the agency retains the legal authority to decide whether the distribution of material promotes an unapproved new use or whether such actions cause a product to be considered misbranded or adulterated.

“The guidance is not an open season to spread off-label information. It's very specific to truthful, educational information,” says Robert Klepinski, an attorney at Fredrikson & Byron P.A. (Minneapolis). He explains that in releasing the guidance, FDA has acted pragmatically and recognized the state of the law.

In addition to being peer reviewed, articles must reveal any conflicts of interest and must be published by an organization that has an editorial board. The draft recommends against distributing materials that have been funded by manufacturers of the product in the article.

Doctors and other users now have instant access to articles via Internet. Kahan says that it's valid for companies to provide truthful and correct documents about off-label device uses when approached by doctors. “Not only should the company be able to do that, they probably [also] have an obligation, so that the doctor fully understands from the journal article what's being done and how the device is being used.”

To adhere to the guidance, companies should employ a standard operating procedure (SOP) to help train employees, Klepinski advises. “People are going to need an SOP to control how they train the sales force in how to follow this guidance and the in-house employees in executing it.”

Klepinski's only criticism of the draft is the labeling recommendations, which are supposed to accompany the journal reprint or reference material. He says the labeling section is either too vague or too detailed, depending on the recommendation.

Furman also feels that more clarification is needed. For example, she says, FDA requires a disclaimer or disclosure attached to any materials for which there is a risk or safety concern posed by any unapproved use that is significant and known to the manufacturer. “I think that's a subjective notion and can sometimes be a tough call,” Furman says.

Klepinski agrees, adding that it puts a big burden on manufacturers. “The purpose of these articles is to tell one doctor what another doctor is doing. The manufacturer isn't going to know, by definition, all of the risks—they haven't done this research.”

Furman and Klepinski expect other stakeholders in industry to express concern over the labeling issues as well. FDA is accepting public comments on the draft guidance until April 21. A copy of the document is available on FDA's Web site.

Copyright ©2008 Medical Device & Diagnostic Industry

The Case for the Use of Polycarbonate-Urethane in Orthopedic Implants

The use of polyurethane in medical applications has been well-documented.1 But there is one member of the polyurethane family — the polycarbonate-urethane subset ­— that has great potential for use in orthopaedics. In this article, we will explain why.

One example of the potential use in orthopaedics is in the hip joint, where a need for new materials exists. Statistics indicate that today’s commonly used materials simply aren’t performing well enough. More than 190,000 total hip arthroplasties were performed in 2002 in the United States alone.2 But it is estimated that by 2012, as many as 21% of all hip arthroplasty procedures will be surgical revisions of the implant.3,4 Such a high revision rate means better implant materials are needed. Traditionally an artificial hip consists of a metallic femoral head and an acetabular cup usually made of ultrahigh molecular weight polyethylene (UHMWPE), a material that has been used clinically for over 40 years. Several studies have concluded that a primary cause of implant loosening is osteolysis (or bone resorption) caused by wear debris generated at the articulating surface of the polyethylene acetabular cup. The goal, therefore, is to develop an alternate material for use in orthopaedics that does not generate wear debris of a type that induces osteolysis.5,6 This article makes the case for using the polymer polycarbonate-urethane (PCU) as a replacement for UHMWPE in orthopaedic applications.

Improving Upon UHMWPE

Figure 1. Stress-Strain Curve showing UHMWPE compared to polycarbonate-urethane (Bionate 80A, Polymer Technology Group). UHMWPE data is courtesy of S.M. Kurtz, and PCU data is courtesy of Polymer Technology Group.
Alternative materials to UHMWPE were studied and ranked according to their biocompatibility and mechanical properties, for use as an acetabular bearing surface in an artificial hip prosthesis, by a team led by F.P. Quigley in 2002. Quigley and his colleagues determined that, based on these factors, the polyurethane elastomers appear the most promising.7 The evolution of segmented polyurethane elastomers has been studied extensively in biomedical applications because of the combination of excellent biocompatibility and mechanical properties of polyurethanes.8 Poly(ester urethanes) (PEUs) were the first generation of polyurethanes used in medical devices, but were found unsuitable for long-term implants because of significant hydrolytic degradation of the polyester soft segment in vivo.8 After replacing the ester linkage of PEUs with an ether bond, PEUs have been used successfully for the past 20 years.8 However, in several long-term studies it has been shown that the polyether soft segment of PEUs is susceptible to oxidation in vivo.8 Any time the human body recognizes a material that is not itself, the normal self-preservation response is to have cells try to encapsulate it. Because they are relatively large, these cells are often called giant cells, and the reaction is called a “foreign body giant cell” response. Foreign body giant cells have been determined to initiate oxidative biodegradation of PEU via oxygen radicals abstracting a proton from the alpha-methylene position of the polyether, resulting in chain scission and/or crosslinking of the polyurethane.8 In vitro studies performed by Khan et al. conclude that PCU displays the best overall resistance to hydrolytic degradation, in vivo stress cracking, metal ion oxidation, and calcification as compared to other medical grade polyurethanes.

PCUs have more oxidatively stable polycarbonate soft segment. Several in vitro and in vivo studies have demonstrated that PCUs are significantly more biostable than PEU.8 PCU is synthesized from a methylene di (-phenyl isocyanate) hard segment chain extended with butane diol and a poly(1,6 hexyl 1,2 ethyl carbonate) soft segment. PCUs are currently being used in vascular grafts, artificial heart valves, and pacemaker leads.5,6

For potential orthopaedic applications, a series of tests indicate that the PCU material developed for biostable cardiovascular applications also has properties that are equal to or better than the UHMWPE currently used as an articulating material in artificial joints. The first test, using a friction measurement, assessed four potential load-bearing plastic materials for use in artificial joints. From this data, PCU was found to have the lowest friction properties of the four materials in the study.9 Compared to UHMWPE, PCU was found in two studies to have lower friction properties.10,11 PCU also will be an easier material to lubricate than UHMWPE, because PCU is a hydrophilic material, while UHMWPE is hydrophobic.12 Most importantly, as a potential biomaterial for orthopaedic wear applications, PCU has been found to have equal to or better wear properties than UHMWPE.2,10,13 And finally, the modulus of elasticity of PCU is similar to cartilage, unlike UHMWPE, which is about 70 times stiffer.14,15 Based on all this information, PCU has already been selected for several orthopaedic applications.

Similarities to Natural Cartilage

It is the case for the use of PCU material as an articulating surface that is the most intriguing. For a material to be selected for this use, it must match the properties of the natural tissue at the surfaces of articulation joints, which are both elastomeric and hydrophilic. The tissue provides both an articulating surface that protects the bone and a source of lubrication to improve motion within the joint.5,6 Future designs of artificial joints should strive not only to replace but to imitate the natural joint. The natural joint is lined with a layer of synovial fluid that completely lubricates and separates the articulating surfaces of the femoral head and the acetabular cup.8 Two engineering concepts referred to as “elastohydrodynamic lubrication” (EHL) and “squeeze-film action” are the main mechanisms of action in the natural joint.8 During the stance phase, EHL predominates when pressure is generated in the lubricant by an entraining motion between the two joint surfaces. Squeeze-film action predominates at heel strike in the walking phase; the two surfaces move towards each other, squeezing the fluid out of the joint space. Both mechanisms are enhanced by elastic deformation in the joint surfaces.8 The natural joint operates under a full fluid-film lubrication regime, where the load is carried by the synovial fluid, resulting in minimal contact between the articulating surfaces.

This favorable situation leads to a great reduction or elimination in wear at the articulating surface because the natural compliant layers allow a fluid film to generate between the two opposing articular cartilage surfaces. PCU appears to mimic this natural process and does not appear to develop the same type of damage as UHMWPE, as shown in in vitro and in vivo studies.5,6 Preclinical data show that friction levels are low and sufficiently thick levels of lubrication exist to prevent contact between the surfaces. These results suggest that the low modulus of the PCU can simulate the function of articular cartilage in the natural joint and allow a layer of synovial fluid to form between the surfaces of the articulating prostheses. Also, as with the natural joint, should third-body wear particles be introduced between the interface of the articulating surfaces, either the particle will roll out off the surface because the surface is so compliant, or the third-body will embed in the polymer surface. Lack of third-body wear was observed in a four-year sheep study of PCU acetabular cups.16 All of this information and discussion is compelling evidence that PCU can recreate an effective fluid-film lubricating layer within the joint and is a potential material for use in joint replacement.5,6


Table 1. Comparison of Typical UHMWPE and Polycarbonate-urethanes (Bionate, Polymer Technology Group).
In three studies PCU was reported to have less wear than UHMWPE.2,10,13 One theory is that PCU has the ability to allow the formation of a fluid film to separate the two surfaces, which reduces the contact pressure and decreases the friction.2 An acetabular cup with PCU as the bearing surface showed great promise in in vivo experiments.6 The PCU cup showed no evidence of significant wear at four years post implantation. This data provides compelling evidence for the use of PCU in orthopaedic load bearing/wear applications. The articulating surfaces were in excellent condition, suggesting that there was good joint function over the implant period. Environmental scanning electron microscopy and surface profilometry showed minimal normal wear. Supporting animal study findings revealed no significant soft tissue damage, wear particle generation, or inflammatory response. The absence of significant physical or chemical degradation suggests that the prototype PCU acetabular cup functioned well in a sheep total hip arthroplasty model during a four-year period of study. The PCU material showed excellent biostability in regard to maintenance of molecular weight. The absence of wear debris confirms the histological findings, which show no soft tissue damage or inflammatory response. The lack of third-body wear damage on most of the retrieved cups and the absence of third-body particles in the articular surface confirm laboratory studies suggesting that PCU acetabular cups can perform a similar function as the natural joint by allowing synovial fluid-film lubrication.5,6


The case for the use of polycarbonate-urethane in orthopaedic applications is compelling. PCU has good wear properties, good compatibility with natural tissues, and is easy to lubricate. For those reasons and others, it appears to be a viable alternative to the traditional UHMWPE weight-bearing material that has been used for more than 40 years in orthopaedic joint replacement prostheses.

Richard W. Treharne, PhD, is vice president of orthopaedic research with Active Implants Corp. (Memphis). Alex H. Greene is an assistant research engineer with Active Implants.

Learn more about material selection for orthopaedic implants and other related subject matter at the Orthotec orthopedic conference and expo in Warsaw, Indiana.


1. James Wright, “Using Polyurethanes in Medical Applications,” Medical Device & Diagnostic Industry, 28, no. 3 (2006): 98-109.

2. Christian J Schwartz and Shyam Bahadur, “Development and Testing of a Novel Joint Wear Simulator and Investigation of the Viability of an Elastomeric Polyurethane for Total-Joint Arthroplasty Devices,” Wear, 262, 3-4 (2007): 331-339.

3. American Academy of Orthopaedic Surgeons (AAOS), “Primary Total Hip and Total Knee Arthroplasty Projections to 2030,” American Academy of Orthopaedic Surgeons; Rosemont, IL: 1998.

4. National Center for Health Statistics (NCHS), “National Hospital Discharge Survey,” Hyatsville, MD: 2002.

5. Imran Khan et al, “Analysis and Evaluation of a Biomedical Polycarbonate Urethane Tested in and in vitro Study and an Ovine Arthroplasty Model. Part I: Materials Selection and Evaluation,” Biomaterials, 26, (2005): 621-631.

6. Imran Khan et al, “Analysis and Evaluation of a Biomedical Polycarbonate Urethane Tested in and in vitro Study and an Ovine Arthroplasty Model. Part II: In Vivo Investigation,” Biomaterials, 26, (2005): 633-643.

7. F P Quigley et al, “Selection of Elastomeric Materials for Complaint-Layered Total Hip Arthroplasty,” Proc.Inst. Mech. Eng, 216, no. 1 (2002): 77-83.

8. Elizabeth M Christenson et al, “Poly(carbonate urethane) and Poly(ether urethane) Biodegradation: In Vivo Studies,” Journal of Biomaterials Research Part A, 69A, no. 3 (2004): 407-416.

9. S C Scholes et al, “Compliant Layer Acetabular Cups: Friction Testing of a Range of Materials and Designs for a New Generation of Prosthesis that Mimics the Natural Joint,” Proc. Inst. Mech Eng, 220, no. 5 (2006): 583-596.

10. S L Smith et al, “A Tribological Study of UHMWPE Acetabular Cups and Polyurethane Compliant Layer Acetabular Cups,” J Biomater Res Part A, 53, no. 6 (2000): 710-716.

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Studies Counter Recent Medtech Pricing Claims


Medtech Pricing by the Numbers

Annual percentage increase in medical device prices

Percentage of total NHE spent on medical devices and in vitro diagnostics

The amount, in billions, spent on medical devices and in vitro diagnostics in 2004

A study has found that there has been a slow rate of growth in overall medical technology prices over the past 15 years. This is in contrast to the views of some who cite the costs of new technology as a major driver of escalating healthcare costs.

Medical technology is a relatively small and constant share of total national health expenditures, the study found. The AdvaMed-sponsored study was coauthored by Roland Guy King, a former chief actuary for Medicare and Medicaid, and Gerald Donahoe, a retired economist.

“The report's findings are significant in light of recent comments by some suggesting policies to limit the diffusion of and access to advanced medical technology in response to cost pressures,” said Edward Ludwig, chairman, president, and CEO of Becton, Dickinson and Co. (Franklin Lakes, NJ). He is also board chairman of AdvaMed.

“Simply put, medical technology is part of the solution to managing healthcare expenses. Limiting patient access to lifesaving, life-enhancing technologies compromises patient health and may actually increase costs,” he said.

Many in the medical device sector believe that the innovative and competitive nature of medical technology, which has economic benefits, also helps patients by providing continual improvements in care.

“This study shows that there is also an economic benefit of competition due to the relatively slow rate of growth in overall industry prices,” said Michael Mussallem, chairman and CEO of Edwards Lifesciences. He is AdvaMed's board chairman-elect and chair of AdvaMed's board committee on payment and healthcare delivery.

Spending on medical devices and in vitro diagnostics totaled $112 billion in 2004, which was the latest year studied. This figure represents 6% of total national health expenditures. Over the 15-year period studied, the percentage has stayed relatively constant, the study found.

During the same period, overall medical device prices grew at a slower rate than either the Consumer Price Index (CPI) for medical services or the overall CPI. The study found that medical device prices have increased about 1.2% annually from 1989 through 2004, compared with 5% for the Medical Consumer Price Index and 2.8% for the CPI.

“Medical device prices, on average, have grown at less than half the rate of overall CPI and less than one-quarter the rate of other medical goods and services,” said Stephen Ubl, AdvaMed's president and CEO.

A copy of the study can be accessed at

Another study on medical technology pricing has found that mandatory price disclosure for the medical technology sector would likely increase prices. The study examines the potential economic effects of the Transparency in Medical Device Pricing Act of 2007, which was recently introduced in the U.S. Senate.

“We found that mandatory price disclosure, as proposed in S.2221, is unlikely to benefit patients or hospitals,” said Robert Hahn, who co-wrote the study with Criterion Economics president Hal Singer. “Worse, [it] will likely increase costs.” Hahn is executive director of American Enterprise Institute's Center for Regulatory and Market Studies.

The authors used evidence from case studies and other sources to isolate conditions that, if satisfied, would imply that mandatory price disclosure would offer substantial benefits to consumers or other purchasers.

The study determined that for price disclosure to have a favorable effect, large search costs must be substantially reduced, and pricing information disclosed must be current.

The report also found that the industry-specific market conditions necessary for lower prices would require savings to be passed on to end-users, at the expense of purchasers. Currently there is a large variation in the price paid by purchasers and consumers.

“Applying these conditions to the medical device industry, we conclude that mandatory price disclosure would likely increase prices hospitals pay for [medical technology] and provide no tangible benefit to patients,” the authors said.

For more information, including access to the full report, visit

Reports on other compliance-alliance surveys can be viewed on MD &DI's blog.

Copyright ©2008 Medical Device & Diagnostic Industry