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TPEs produce soft, colorable film.

New film grades have expanded the Monprene line of compounds, processable in conventional blown- or cast-film extrusion systems. These thermoplastic elastomer (TPE) compounds produce film that has good colorability and processability, and a soft, dry touch like latex. Teknor Apex (Thermoplastic Elastomer Div.; Pawtucket, RI; 401/725-8000) produced the compounds to solve the problem of allergenic reactions caused by latex products. The compounds are presently used for bands and straps in physical therapy and are also suitable for hygiene products. Higher production rates than latex are possible, and the ease of coloring aids in product differentiation or color coding.

Where Have All The Dot-Coms Gone?

Originally Published MDDI July 2001

Editor's Page

Where Have All The Dot-Coms Gone?

Perhaps the Internet is just too good an idea. When something that spectacular, that promising, comes along, it's very difficult not to become irrational.

Looking back a year or so to our last Internet issue, we can only shake our heads in wonder. An entire constellation of companies has vanished, or dimmed so much that few are even aware of them anymore. The Internet was once the Next Big Thing. Is it now the Last Big Flop?

Though we are hedging our bets, we don't think so. True, the facts aren't pretty. As Cliff Henke notes in our lead feature, some of the losses have been staggering. Take, for example, Ventro, the owner of the medical supply marketplace Promedix. Its shares have fallen from a high of $234 to well under a dollar, its staffing has been cut by 80%, it is battling shareholder lawsuits, and it lost some $618 million in 2000. On the bright side, it's still in business, unlike many of its smaller competitors.

What went wrong? Perhaps the Internet is just too good an idea. When something that spectacular, that promising, comes along, it's very difficult not to become irrational. The classic example of this phenomenon is the tulip-bulb craze that afflicted Holland in the early seventeenth century. Not long after being introduced to the country from Turkey, these beautiful flowers were in such demand that people began to speculate in tulip futures. As Burton Malkiel writes in A Random Walk Down Wall Street, "People who said the prices could not possibly go higher watched with chagrin as their friends and relatives made enormous profits. The temptation to join them was hard to resist; few Dutchmen did." Sound familiar?

The market inevitably crashed, of course. But the flowers were not all gone; indeed, tulips became a fixture of Dutch gardens.

Likewise, the Internet will become a fixture in the medical device industry. As described in Henke's article and those that follow it, the possibilities created by on-line technologies remain very exciting. While the business models for e-commerce exchanges may go through bewildering changes, medical device companies will certainly continue to explore the many ways that Web-enabled technologies can improve their business.

The signs suggest that device manufacturers may discard the use of common exchanges or other Internet services, gravitating instead toward solutions individualized for them. In fact, many of the original Internet exchange companies have already morphed into providers of software and developers of private Internet sites for individual clients.

This trend may be even more pronounced in the medical device field than in other, more monolithic industries. One of the comments that we used to hear from developers of on-line marketplaces for the medical device industry was that they saw the fragmented nature of the industry as an opportunity for them to "rationalize" it through their sites. Maybe, though, the industry is fragmented for a good reason. Can an orthopedics manufacturer and an in vitro diagnostics manufacturer really be served effectively by the same one-size-fits-all approach?

It is still very possible that undertakings such as the Global Healthcare Exchange or Ventro's offspring, Broadlane, may succeed where so many others have failed. But even if they do not, the technology will move ahead without them. One way or another, the Internet will still have a profound impact on this industry.

The Editors
[email protected]

Copyright ©2001 Medical Device & Diagnostic Industry

A Winning Bid

Originally Published MX July/August 2001

In developing countries, the World Bank provides a stable source of funding for medtech purchases.

Nicholas H. Ludlow

Over the past two years, Mallinckrodt (Hazelwood, MO), now Tyco Industries, won a $126,040 contract to equip emergency medical centers in Bulgaria; Datex-Ohmeda (Helsinki, Finland), part of the Instrumentarium Group, won a $720,500 contract to install anesthesia apparatuses in Vietnam; Medtechnica (Petach Tikva, Israel) won two contracts amounting to $157,880 for supplying splints and instrument trays to Uzbekistan; and Philips Medical Systems (Amsterdam, The Netherlands) won two medical equipment contracts in Brazil worth $2.21 million.

FDA Reverses Stance on Firm's News Release

Originally Published MDDI July 2001

Washington Wrap-Up

A medical device company's stock was sent reeling after FDA reacted adversely—and publicly—to its press release. How much attention does the agency pay to Wall Street?

James G. Dickinson

How much can a company say about clinical trial results with an investigational medical device? Not as much as Guidant Corp. did in a May 2, 2001, news release about its Contak CD/ Easytrak system, a combination cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillator (ICD) system.

FDA's first reaction to the press release was condemnatory and word of it flew quickly through the Internet to Wall Street, sending the company's stock to the lowest point it has seen in 30 months. Guidant's indignant protest prompted a second reaction by FDA that amounted to a rare public admission of error, sending the stock's price back up.

That embarrassing agency flip-flop may have given a false impression, however, to observers who don't spend a lot of time focusing on the nuances of FDA reversals. Guidant's four-page press release broke the rules—as do many other releases that FDA doesn't see—by overstating the clinical trial's positives and understating (or, actually, not stating) its key negatives. Some enterprising media reporters saw something in its buoyant language that prompted them to ask FDA's press office about it. They got the response they probably expected from veteran FDA press officer Sharon Snider.

According to news reports, Snider told reporters: "It appears from the press release as if Guidant is making claims of safety and effectiveness for an unapproved medical device." Reuters quoted her as adding: "It is a violation of the law to make such claims for a product that is in clinical studies and has not been approved."

In these days of up-to-the-minute Internet news, Snider's comments almost instantly sent Guidant's shares tumbling 12.7%, or $4.80, to a 30-month low of $33.00 on the New York Stock Exchange.

While watching Wall Street has never been part of FDA's mission, these days due note is made of such financial events when they are brought to the agency's attention. When Guidant protested to Snider's "new guard" superiors at the agency, it caused officials to closely examine the company's release. Within hours, associate commissioner for public affairs Larry Bachorik was able to tell reporters that the agency felt there may not be a great deal wrong with it after all.

This difference of opinion derives from a subtle shift in FDA enforcement philosophy, coerced by budget restrictions that many "old guard" FDAers saw as punitive. The old FDA that trained Snider was more likely than the new, post–user fees, post–Modernization Act FDA to take a strict view of its regulations and to fault companies for not being properly familiar with them. A softer, more tolerant attitude seems to have been emerging lately. Another new factor is that the news media are more likely to name their FDA press office informants, ditching an old, unwritten rule that a source be referred to only as "an FDA spokesperson."

CDRH Office of Compliance acting director Larry Spears told Reuters that although he had not yet seen the release, part of it had been read to him over the telephone. Based on that section, he found nothing in the release to be "alarming." He promised to study it more over the weekend.

On the following Monday, Spears stated that after analyzing the release he thought Snider had gone "too far" in her comments to the media and that at the time in question (Friday), "it was an inappropriate suggestion to say that this may have violated the law. We weren't there yet. Yes, we had a few concerns about it, but we were really not in an appropriate position to characterize that as a violation based on just looking at a press release and having no interaction with the company."

In such cases, FDA's new-guard approach is first to engage in dialogue with the company in such cases, rather than simply apply to the offending document what an experienced official sees as the plain language of the regulations. Generally, dialogue with the company is the normal procedure, and by policy it is a necessary first step before issuance of a warning letter. In this case, a warning letter is not a likely result, according to Spears. Snider had told a reporter on Friday that FDA typically issues warning letters in cases like this.

Apparently, that is no longer true. At least in Guidant's case, there was no track record of the company ignoring prior FDA cautions about its language. Spears did acknowledge, however, that FDA did have "concerns" about a buoyant subheading in the release that said the unapproved device "Saves Lives, Improves Quality of Life." In addition, the news release neglected to mention that the reported clinical trial failed to meet its primary end point, but instead quoted Guidant president of cardiac rhythm management Fred McCoy as saying he was "looking forward to making available to patients the first and only heart failure therapy device with the potential both to enhance patients' lives and to protect against sudden cardiac death." FDA's old guard viewed this as an objectionable statement—a public presumption that the product would be approved.

Within just four days, the agency's remedial public statements substantially repaired the damage done to Guidant's stock prices.

To the fleeting glances of those with other things on their minds, it may have seemed that FDA goofed, admitted it, and everything was fine again. But that will be true only if Guidant and other companies have learned from the episode to be more circumspect when describing clinical trial results.

FDA to Be Even Less 'Burdensome'

In its regulatory activities with the device industry, FDA says it will apply a FDAMA provision on the so-called least burdensome concept more broadly than the act originally intended. A newly released guidance document, The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Draft Guidance for FDA and Industry, says the provision "could affect almost all premarket regulatory activities, including presubmission meetings with industry, premarket submissions, and the development of guidance documents and regulations."

In the guidance, FDA defines least burdensome as a "successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA." According to the draft guidance, the concept should be applied consistently to all premarket activities, including the following:

For PMAs where clinical outcome can be predicted from nonclinical data, well-designed bench or animal testing can support approval. "Conditions where nonclinical data may meet the threshold for approval are typically those devices or modifications of approved devices for which information is available in the public domain," the document says. If clinical data are needed, alternatives to randomized, controlled clinical trials should be considered.

The use of scientifically valid surrogate end points and statistical methods, such as Bayesian analyses, should be considered when appropriate. The guidance says FDA and industry should rely on information available from earlier versions of the same device or from marketing experience with similar devices. "The role of postmarketing information should be considered in determining the appropriate type or amount of data that need to be collected in the premarket setting to support PMA approval." FDA feels the use of recognized standards can also streamline PMA submissions.

For 510(k)s, the guidance says information unrelated to the substantial equivalence decision should not be submitted to, or requested by, the agency. It adds that substantial equivalence will normally be determined by comparative device descriptions, including performance characteristics; performance testing should be submitted if there are important descriptive differences between devices of the same type or the descriptive characteristics for the new device are not precise enough to ensure comparability.

In these instances, the most appropriate bench or animal testing—or in the case of IVDs, analytical testing—to address the performance issue should be provided. Summary information about the testing should generally suffice, but the manufacturer should also provide the test protocol and a description of test methods, and cite any standards followed in conducting the testing. The guidance also says that in the rare cases where clinical data may be necessary for 510(k) clearance, the agency should adhere to the least burdensome standards as outlined for PMAs.

The new guidance may be accessed at http://www.fda.gov/cdrh/ode/guidance/1332.pdf.

Nine New PMA Consensus Standards

FDA has added nine new standards to its list of recognized consensus standards. Device manufacturers can now declare conformity to these standards in lieu of including data to satisfy portions of product premarket review submissions or other requirements. The newly recognized standards are as follows:

The standards may be accessed at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm.

Abbott on FDA Comeback Trail

In what may be a signal that Abbott Laboratories (Abbott Park, IL) is making significant progress in correcting GMP deficiencies that resulted in a $100 million consent decree in 1999, FDA says it has agreed to allow the company to again market its HIV test—the Abbott Murex single-use diagnostic system (SUDS) HIV-1 test, the only rapid HIV test currently licensed for the U.S. market.

The test was pulled off the market in October of 2000 because of manufacturing problems related to the company's failure to meet certain specifications. After reviewing lot-release data submitted by Abbott for five consecutive lots of the test kit, FDA has determined that the test may now be released for clinical use.

Two New FDA Guidances Coming

Two industry guidance documents, one on premarket submissions and the other on GMP/quality system regulation inspections, are now under development, according to CDRH Office of Surveillance and Biometrics director Larry Kessler. The transcript of an April 23 presentation by Kessler says that FDA is reevaluating its list of high-risk premarket-exempt products and whether the products should remain exempt.

In addition, Kessler says, the agency is still developing policies on "open but unused devices," on the labeling of reprocessed and OEM products, and requirements for healthcare facilities other than hospitals.

Kessler's presentation may be reviewed on-line, at http://www.fda.gov/cdrh/reuse/L_Kessler_NJ_042301.pdf.

FDA Cites GE France Facility

In an April 10 warning letter, FDA declared some of GE Medical Systems' responses to agency findings inadequate, and it is requesting more information. The findings were the result of an inspection last December at the company's Senographe 2000D full-field digital mammography system manufacturing facility in Buc Cedex, France. The inspection found the mammography system was adulterated because of the methods used, or because the facilities or controls used for manufacturing, packaging, storage, or installation didn't conform with the quality system regulation.

CDRH rejected GE's responses to four specific failures cited by the center: One, a failure to establish and maintain a procedure to ensure that design requirements are appropriate and address the device's intended use, including the needs of the user and the patient; two, a failure to establish and maintain adequate procedures for identification, documentation, validation or verification, review, and approval of design changes before implementation; three, a failure to establish and maintain adequate procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria; and four, a failure to establish and maintain adequate acceptance procedures to ensure that specified requirements for in-process products are met. In each instance, FDA asked for specific information or documentation so the staff can assess the adequacy of the response.

The company's responses were deemed to be adequate in three other categories: a failure to follow established procedures for implementing corrective and preventive action and failure to document all activities and their results; a failure to assess and determine whether service reports may represent an event that must be reported to FDA; and a failure to ensure that device packaging and shipping containers are adequately designed and constructed to protect the device from adulteration or damage during processing, handling, storage, and distribution.

Device Firms Impressed with QSIT

The majority of medical device firms are pleased with FDA's new quality system inspection technique, according to a just-released survey of 559 firms. Fifty-two percent of the firms said the inspection process was better than that used previously, 40% said it was the same, and 8% said it was worse.

For firms that received an FDA-483 after the inspection, 95% said that all of the inspection observations were "understandable." Eighty-eight percent of firms inspected also said that FDA investigators reviewed observations noted on a daily basis during the inspection.

The surveys showed that domestic medical device firms received 5 days advance notice of an upcoming inspection, compared with 55 days for foreign manufacturers. Eighty-three percent of FDA's in-plant inspection time lasted 5 days or less and 14% lasted 6 days or longer.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

Copyright ©2001 Medical Device & Diagnostic Industry

The Right Mix

Originally Published MX July/August 2001

To bring success to their clients, top medical marketers combine the creative, the scientific, the bleeding edge, and the tried and true.

Geoff Geiger

This May, several hundred marketing professionals gathered in Chicago for the annual national meeting of the Medical Marketing Association (MMA; San Francisco), an event designed to "challenge us to discover methods to do business more effectively, market our brands, and attain enhanced levels of creativity and innovation."

The centerpiece of the event was a ceremony presenting the association's annual International Awards of Excellence (In-Awe). From more than 1000 entries, the association honored 106 winners in this year's competition. A panel of 50 judges reviewed each entry, evaluating its creativity, strategic merit, and measurable results. The winners included 41 gold, 34 silver, and 31 bronze awards.

Enhancing Device Development through Early Supplier Involvement

Originally Published MDDI July 2001

Medical Plastics and Biomaterials

Contract suppliers who get in on the development process early will be the most valuable and reap the largest rewards.

Todd Owens

Today's healthcare industry is a rapidly evolving market in which the requirements demanded of suppliers—including shorter lead times—are projected to become increasingly complex. One of the most dynamic segments of the overall healthcare market is that of medical devices, where it is an ever-more-common practice for manufacturers to outsource part or all of their assembly operations. Many companies offset the risks associated with a new product by relying on experienced partners to design, develop, and manufacture their medical devices. This is especially true with start-up companies that choose not to become manufacturers. Rather than build a staff to handle manufacturing operations, these companies contract with operations experts, thereby freeing themselves to concentrate their time and resources on core product development technologies.

In a poll published in June 1999, 80% of medical device manufacturers who responded indicated that they outsource part of their business, 71% reported that their use of contract services had grown between 6 and 15% in the previous two years, and 35% expected their outsourcing to increase by more than 10% within their companies in the following two years.1 The trend in the medical device market for polymer-based products specifically is clearly toward an increased number of alliances between medical companies, molders, and raw material suppliers.2

REGULATORY COMPLIANCE

For many years, FDA has required medical device manufacturers to validate processes when the quality of their output cannot be fully verified prior to product leaving the manufacturing site. The agency has generally enforced this process validation requirement on medical device manufacturers and not on component suppliers. With the changes to the rule on good manufacturing practices (GMPs) in 1996, FDA put more emphasis on medical device manufacturers (the owners of the device) placing controls on their component suppliers to ensure that those components are safe and effective for the use for which they were designed. As a result, many OEMs are requiring their suppliers to implement GMP-compliant quality systems, including process validation.

In the injection molding arena, for example, manufacturers are demanding that their suppliers provide process validation of plastics molding and component assembly processes. These device firms want evidence to present to FDA that the components in their devices have been verified or manufactured using validated processes.

Figure 1. The elements of product development.

TECHNOLOGY OVERVIEW

As outsourcing increases, the desire to ensure a smooth transition from concept to product means that product design and development is frequently becoming the supplier's responsibility. Design for manufacture and assembly is vital to compressing lead times and enhancing quality. Suppliers are using technologies such as stereolithography, selective laser sintering, and cast urethane models for a variety of applications—from verifying fit and function to creating prototypes for focus groups. Finite element analysis and mold-flow analysis are employed to verify structural and mechanical elements and optimize part design and processing conditions before tool steel is cut. With manufacturers insisting on high-quality, cost-effective components, those suppliers able to provide a range of materials and services—from design through manufacture, including validation, decorating, and turnkey assembly—will be in the greatest demand.

For medical molders, current manufacturing trends include multishot, metal, and magnesium injection molding. In the quest for enhanced ergonomics, aesthetics, and component integrity, multishot molding can be an attractive alternative for medical manufacturers looking for product differentiation, ease of assembly, and reduced component cost. Metal injection molding, used for producing small, complex components at a fraction of the cost of machined parts, is becoming a popular choice for many device manufacturers that require both intricate part detail and cost savings. Magnesium injection molding offers inherent EMI/RFI shielding, exceptional component strength, and part weights comparable to those of engineering-grade plastics.

In recent years, OEMs and suppliers have been forming alliances to coordinate resources and build relationships based on a lowest-total-cost approach. This provides the OEM with a leading-edge source for technology, faster time to market, and the highest possible quality. However, forming supplier alliances has been difficult for some organizations to accomplish, and many fail to recognize the benefits afforded by this approach.

Suppliers that embrace an early-involvement philosophy and have broad-based expertise in the design and manufacture of medical components are the most capable of ensuring a quality product. A supplier's strict adherence to FDA's quality system regulation—along with certification to ISO 9000 and European medical standard EN 46000—generally results in efficient transfer of documentation, traceability of parts and components, and the ability to meet specialized requirements of specific medical projects.

Figure 2. The traditional product development cycle includes transition spikes at the start of each phase.

ACCELERATED PRODUCT DEVELOPMENT

Time to market is a key parameter for successfully manufacturing medical products in today's worldwide economy. Accelerating the product development cycle plays an important role in time-to-market improvements.

The product development cycle can be compared to a wheel, as shown in Figure 1. The hub comprises the industrial design and mechanical engineering activities that create and build a database of information and product geometries, and the spokes represent the various activities and resources that provide support throughout the evolution of the database. All products go through this development cycle at some level.

In order to achieve an accelerated development cycle, activities must be completed concurrently. Most products today are created using some amount of concurrent engineering; however, the concurrent activities tend to transpire primarily within each phase of the program. Figure 2 shows the spikes in cost and time that can occur due to reengineering at key hand-off points during the traditional development cycle. At each phase transition, a new group of people assumes direction of the program, and there are typically changes that must take place to make the design fit the requirements of the next phase.

Manufacturers can reduce both overall costs and time to market through early-phase partnerships with suppliers that have the in-house technologies to support all phases of the product development cycle. As Figure 3 indicates, the traditional spikes in cost and timing can be eliminated by involving the entire team in the program from its inception. Because all issues are addressed at the early phases, there is no lost information or obligatory reengineering.

The case studies that follow exemplify some of the benefits that can accrue from early involvement of qualified suppliers in the product development process.

Figure 3. With early supplier involvement, cost increases gradually throughout the product development cycle, and the process advances more quickly.

CASE STUDIES: MOLDED COMPONENTS

DNA Separator. A biochemical reagent supply company developed a magnetic resin used to extract DNA from blood and cell media cultures. The resin bonds with DNA in suspension and is then separated from the liquid media using exceptionally strong magnets. The company needed a hand-held separation device to house the magnets and hold the vials during the separation process, and contacted a contract molder to assist in the design and manufacture of the product.

The separator had an array of functional requirements, yet initially there was no clear-cut idea of what the product would look like. The two companies began with concept sketches to determine the direction in which the program would proceed. After a concept was chosen, foam models were made to verify the look and feel of the device prior to the creation of stereolithography models, which were vital in testing the functionality of the separator's magnets. Design issues related to wall thickness surrounding the magnets—a too-thick wall threatened to impede the magnets' power—were resolved, and the process was verified via mold-flow analysis before tool steel was cut, thus saving time and avoiding costly tool revisions.

Meeting Aggressive Timelines. In line with current outsourcing trends, the injection molder was selected for its expansive list of capabilities, its willingness to manufacture highly engineered components in low volumes, and the speed with which it was able to move the program from design through injection molding.

The program was conducted within an aggressive time frame, with the period from concept to initial parts lasting only 12 weeks, including a 5-week tool build. The manufacturer had a targeted release date for the resin, and needed to produce the separator within a certain work cycle. The injection molder's in-house capabilities—from design and tooling to manufacturing—were critical in keeping the project on track and avoiding the kind of reengineering spikes depicted in Figure 2.

Design and Manufacturability. Of particular importance to the separator project was the molder's in-house industrial design group. According to the manufacturer, the molder's design expertise prevented wasted design-phase iterations by enabling the companies to rule out designs that seemed attractive but cost too much to manufacture or were not manufacturable at all. The project team also designed so as to eliminate complex features in the mold, producing tools that did not require slides, thus saving the company significant tooling costs.

Anesthesia Equipment. A leader in the anesthesia equipment market developed a proprietary patient breathing unit that could be assembled and disassembled for autoclaving without tools using a series of thumbscrews, interlocks, and snap features. These complex, injection-molded components posed unique challenges to the design capabilities of the contract molder selected for the project.

Reducing Tool Costs. The molder used stereolithography, selective laser sintering, and urethane castings to verify fit and function of the various components prior to the costly step of cutting tool steel. In addition, mold-flow software was employed prior to tool build to verify design features and ensure that the difficult-to-process, high-melt-point resins required to withstand autoclaving would perform under the necessary processing conditions. Tools were built in prehardened P20 steel, with hardened tool-steel inserts for shutoff and other critical areas that might need revisions. This method of tool building has long-term benefits because necessary tooling changes can be made with relative ease by revising or replacing an insert rather than rebuilding the entire mold.

CONCLUSION

One of the few constants in the rapidly evolving medical market is the ongoing need of manufacturers for compressed product development time frames and ever-more-sophisticated devices. Those contract suppliers capable of contributing to all stages of a project—from the earliest design and prototyping through manufacturing and assembly—will provide the greatest benefits and reap the largest rewards.


REFERENCES

1. N Sparrow, "Special Report: Outsourcing in the Device Industry," European Medical Device Manufacturer 10, no. 3 (1999): 78–82.

2. NJ Hermanson, "Growth of Plastics Use in Medical Devices is Spurred by Cost-Cutting," Modern Plastics, (November 1998): A-30.

Copyright ©2001 Medical Device & Diagnostic Industry

Navigating the Pathway to Acceptance

Originally Published MX July/August 2001

Advertsing, Distribution & Sales

Third-party validation programs can provide just the support that product managers need to put a dent in the healthcare marketplace.

Sandy Bodner and Jack Curran

In medical product marketing, the rewards of success often come to campaigns that are imbued with such characteristics as verve, luck, and know-how. Verve speaks for itself. Luck may be merely a matter of having great timing. Know-how is a double-edged sword: it implies a critically useful depth of experience while also suggesting a certain tendency toward dullness, toward falling back on the tried-and-true sameness of the past.

But more important than all of these factors combined is the element of thoughtful and thorough advance planning. In the big picture of a medical product marketing campaign, it is planning—or the absence of planning—that is most often responsible for success or failure. The influence of campaign planning is reflected in literally everything that is seen, felt, and heard about a company and its product offerings.

Vibration Method Strengthens Injection-Molded Plastics

Originally Published MDDI July 2001

R&D DIGEST

The color gradient in projected plastic samples reveals internal residual stress.

The increasingly competitive nature of manufacturing is driving the search for technologies that offer OEMs advanced capabilities. The goal is to find ways to create products that are stronger, lighter, more cost-efficient, or less harmful to the environment. Often the key element is to explore new materials or processes. At times, however, researchers examine potential improvements in existing technologies. Work being conducted at Lehigh University (Bethlehem, PA), for example, could lead to development of injection molding processes capable of producing stronger plastic products that are also environmentally beneficial.

According to John Coulter, PhD, associate professor of mechanical engineering and mechanics at Lehigh, only a small amount of recycled plastic is used in traditional injection molding processes. This is because recycled plastic is poor in quality and would reduce the product's strength. The process uses a vibration-assisted injection molding technique to enable manufacturers to recycle previously unusable plastic but still generate products that are stronger than those manufactured with conventional means.

Other researchers have tried to vibrate heated plastic, but doing so requires costly machine or mold changes. Coulter has found that vibrating the feed screw can achieve similar results without the need to vibrate the mold. Simple changes were made to the screw's hydraulic system, and software was designed to direct the device to vibrate at low frequencies after plastic is fed into the mold.

The researcher suggests that plastics are strengthened through vibration because the motion changes their molecular orientation or alignment. Molecules in nonvibrated plastics may stick to the wall of the mold or become folded over. He speculates that vibration of the molecules mixes them more uniformly and allows them to stretch out to their entire length.

Coulter says, "If this process takes off, any company involved in injection molding could duplicate what we are doing inexpensively and probably do it better."

"Viral Angels" Treat Tumors

The concept of gene therapy has received substantial attention by the mainstream media in recent years. The idea of using tiny biological agents to deliver therapeutic substances directly to disease sites has tantalized researchers and the public alike. In June, the University of Arizona College of Medicine (Tucson) was selected as the first U.S. site for a study to investigate the use of viral gene delivery to treat tumors in certain patients.

The research, which will begin in January 2002, will entail use of the therapy to treat patients diagnosed with difficult-to-treat glioblastoma multiform brain tumors. Patients with such tumors must now undergo such treatments as surgery, radiation, and chemotherapy.

According to Allan J. Hamilton, MD, FACS, head of the department of surgery, "One of the biggest roadblocks with current treatments is reaching and killing every last cancer cell."

In the study, trillions of nonreplicating virus cells containing the beta interferon gene will be injected directly into each tumor site. The gene then causes the tumor cells to produce beta interferons, which have been shown to act as anticancer agents because of their ability to stimulate the immune system.

Hamilton notes that the amount of virus injected will be smaller than a teardrop. "You know the phrase, 'How many angels can fit on the head of a pin?' Well, in this case, it's about three trillion," he says.

The gene will cause the tumor cells to produce beta interferons, which act as anticancer agents. Beta interferons act as "antiangiogenic" agents, interfering with the tumor's ability to recruit blood vessels, says Hamilton.


The tiny probe functions similarly to conventional transducers.

Ultrasonic Probe Rapidly Detects Solid Tumors

A miniature probe that incorporates an ultrasonic sensor could reduce the need for surgical biopsies, which can be uncomfortable if not painful for patients. The technology, which is being developed at the University of Illinois (Champaign, IL), could also eliminate delays and stress while patients wait for lab results. "Our system could facilitate the early diagnosis of cancer," says William O'Brien Jr., professor of electrical and computer engineering and the director of the Bioacoustics Research Laboratory at the university's Beckman Institute for Advanced Science and Technology.

"When evaluating a potentially cancerous tumor, a pathologist will look for certain features in cell structure and growth pattern," said James F. Zachary, interim department head of veterinary pathobiology and collaborator on the project. "By examining the size and shape of the cells, and how they interact with surrounding tissue, a determination can be made whether the tumor is malignant or benign."

According to the researchers, the probe functions similarly to conventional transducers used in diagnostic ultrasound imaging. The tiny ultrasound transducer can be fabricated on a needle and operated in vivo at high frequencies. The researchers believe that the device will eventually be capable of resolving individual cells, including those of a solid tumor.

Operating at a frequency of 300 MHz, they say, the probe would have an image resolution comparable to what a pathologist sees when examining tissue under a microscope. The pathologist could thus use the minimally invasive procedure to achieve the same goal as a surgical biopsy. Says Zachary, "By inserting the probe into a tumor and displaying the image on a monitor, we could identify and classify the tumor in real time. We could also send the image over the Internet to specific specialists for help in identification."

To achieve the target frequency of 300 MHz, transducers are being fabricated from a new type of high-strain piezoelectric material that can provide sufficient electromechanical efficiency for the ultrasonic microprobe. The piezocrystals were grown using a modified flux growth method. "This material has the potential for being extremely efficient, but it's also very fragile," O'Brien says. "The thinner the crystal, the higher the frequency response—and that has presented certain mechanical difficulties." A fabrication process has also been developed for the proposed ultrasonic probe.

Ultrasonic transducers can be fabricated on needles for in vivo applications.

The researchers state that progress is being made on three major parts of the project. Miniature probes that work at up to 70 MHz have been created, functional image-formation techniques have been devised, and a database of ultrasound images of both tumors and healthy tissue has been developed. "We still need to push the transducer frequency response up to 300 MHz, and we need to make the probes much smaller," O'Brien explains. "Ultimately, we want to mount the transducer on the end of an acupuncture needle. That way, when the probe is inserted, the patient will feel no pain."

According to Mark A. Haun, who is assisting on the project, "A variety of synthetic-aperture and tomographic imaging techniques are being explored to reconstruct the three-dimensional tissue volume surrounding such a probe." He adds that methods will also be explored to compensate for phase errors caused by tissue inhomogeneities, as required for coherent imaging. Other challenges caused by the nonlinear propagation of sound may also need to be addressed. Haun says, "One imaging concept uses a single focused transducer on the surface of a needle and builds on earlier work with synthetic-aperture image formation with virtual sources."


Research led by Mitrani is focused on creating "microlivers" to function as temporary organ replacements.

Micro-Organs Used for Artificial Livers

Attempts to create a system capable of temporarily replacing essential liver function have centered around using cells harvested from pigs. The porcine liver cells are suspended in a matrix within a container to filter and detoxify a patient's blood. Now, researchers led by Eduardo Mitrani, PhD, of the Alexander Silberman Institute of Life Sciences at the Hebrew University of Jerusalem, are exploring the application of micro-organ technology in developing a bioartificial liver.

The technique enables the researchers to cultivate micro-organs ex vivo, using animal or human cells, to form an array of "micro-livers" that can function as a temporary normal liver. Mitrani recently received the university's Kaye Prize for his achievements. According to the researchers, micro-organ technology allows virtually any type of normal cell to be grown in the laboratory under conditions similar to those existing within the body.

Ordinarily, cells grown in laboratory dishes, isolated from their normal environment, lose some of their specialized functions. Studies of cells taken from various organs using the new technology, however, have shown that the cells continue to function ex vivo and can express tissue-specific genes for long periods.

One practical application of micro-organ technology is the development of the extracorporeal liver device, which will serve as a bridge to transplant or to restore function until the patient's liver regenerates. The liver device, called aLIVE, has been tested successfully on animals and human studies are now planned.

Other applications of the micro-organ technology are being explored as well. Among these are a bioartificial kidney; a genetically engineered biopump that would be worn under the skin and would supply any recombinant protein, such as growth hormone, to a patient who lacks it; and an implanted, cell-based angiopump that would promote formation of new blood vessels from the patient's own tissues.


MRI Technique Relies on Noble Gases to Detect Lung Disease

Research being conducted at the University of Virginia Health System (Charlottesville, VA) could yield an improved imaging technique for detecting such lung diseases as asthma, emphysema, and cystic fibrosis. By detecting such conditions at an earlier stage, when treatment is more likely to be effective, the technology could help hold down healthcare costs and prevent many of the more than 350,000 lung-related deaths in the United States each year.

The new technique, which entails in vivo magnetic resonance imaging (MRI) using new imaging agents called hyperpolarized noble gases, is being developed by James R. Brookeman, professor of radiology and biomedical engineering, and John P. Mugler III, associate professor of radiology and biomedical engineering. According to Brookeman, the procedure can detect subtle ventilation defects in the lung that are not visible with any other medical imaging procedure. Image acquisition requires only a short breath-holding procedure that uses about a liter of a specially prepared gas such as helium or xenon.

Says Brookeman, "The key difference between helium 3 and xenon 129 is that helium is virtually insoluble in any human tissue or fluid and so does not accumulate and is easily exhaled, whereas xenon is fairly soluble, particularly in blood and lipid tissues; it is easily carried from the lungs to the brain; and at lung concentrations above 30%, is an anesthetic." He explains that the properties displayed by xenon may provide specific diagnostic advantages. "This solubility holds out the possibility of hyperpolarized xenon being used to study brain perfusion," he adds.

More than 200 human lung studies have been completed, says Brookeman. "The current results for asthma are very promising, and could point the way to develop and refine new asthma therapies, particularly for children." He believes that such results with the noble-gas method "will undoubtedly stimulate numerous applications in the medical field and beyond."

Brookeman also predicts that future studies could involve conventional proton MRI with T1-weighted, T2-weighted, and diffusion-weighted images. "We anticipate that hyperpolarized noble-gas MRI will have a series of image types such as a ventilation image, where the gas goes at equilibrium; an apparent diffusion coefficient image, which provides information on the lung microstructure; and a dynamic image, in which an image is acquired every 10 milliseconds, to show how the gas sequentially distributes in the lung."

The potential benefits of the technique are speculative but promising, according to Brookeman. "At the moment there is greater diagnostic accuracy, but at greater cost," he explains. "However, the technology is new and on a steep learning curve," he adds.

Says Brookman, "It could be that cheaper, special low-field MR imagers could be developed that would permit patients to stand up, like in a chest x-ray, and hold their breath for 10 seconds after inhaling the polarized gas, and this would provide a complete functional lung study."

Copyright ©2001 Medical Device & Diagnostic Industry

From Patent to PMA

Originally Published MX July/August 2001

Cover Story

Percardia CEO Nancy Briefs says her company has the technology, talent, and tenacity necessary to be a leader in the cardiovascular marketplace.

Interview by Stacey L. Bell

Since its inception a mere three years ago, Percardia (Merrimack, NH) has raised a total of $32 million in funding—and the company is just getting started. Under the leadership of CEO Nancy Briefs, Percardia has built a solid patent portfolio, recruited an expert scientific advisory board and a top-notch management team, demonstrated proof of concept for its new technology, and reached several key milestones. These accomplishments have not gone unnoticed; Percardia counts among its key investors cardiac giant Medtronic (Minneapolis).

Not a bad beginning for a start-up. In fact, the story of Percardia's development is just as compelling to investors as its core technology. The company was founded by a

Incorporating the New HIPAA Privacy Rules into Medical Device Trials

Originally Published MDDI July 2001

HIPAA

Medical device manufacturers who sponsor clinical trials have reason for concern when it comes to the need for a fast, smooth trial process.

Nancy J. Stark and Erica Heath

Advances in information technology have enabled electronic storage of medical information, resulting in the potential for indiscriminate transfer of and unauthorized access to highly private and sensitive medical information. The new privacy regulations for health information, 45 CFR Part 164—Security and Privacy, will create a significant time delay for companies sponsoring clinical research. The timeline for clinical research may extend as long as 2–4 months as investigators apply to institutional review boards (IRBs) for permission to access medical records. The regulations set forth rules for the protection of individually identifiable health information in the United States, and were passed to protect the privacy of citizens while supporting continued advances in medicine. They stem from HIPAA, the Health Insurance Portability and Accountability Act of 1996.

The privacy rules are intended to protect the medical records, health insurance claims, billing records, and related medical information (e.g., case report forms) that are generated and processed by health plans, healthcare clearinghouses, and healthcare providers (e.g., clinical trial investigators). The responsibility of enforcement lies with the U.S. Department of Health and Human Services (HHS) Office for Civil Rights. Violators are subject to civil and criminal penalties. Several states have extensive rules on patient privacy. The federal rules do not preempt state privacy laws if those are more protective.

The rules provide an important benefit to sponsors wishing to bring European data into the United States. The European Union Directive on Data Protection prohibits EU countries from permitting the transfer of personal data to another country without ensuring that an "adequate level of protection" exists in the other country. Compliance with the new privacy rules allows a sponsor to "fairly and correctly" self-certify that it complies with the directive's principles.1

Three important features of the new rules are that healthcare providers must seek authorization from patients—or waivers of authorization from IRBs—in order to examine medical records (Section 164.508), de-identified medical information is not protected (Section 164.514[a]), and patients have the right to access and copy their medical records at any time (Section 164.524). While device manufacturers are not directly regulated, this article examines how these three features will affect medical device clinical trials.

ACCESSING MEDICAL RECORDS

While investigators will continue to have access to the medical records of patients under their direct care, they are now required to obtain written authorization from patients not under their direct care in order to access their medical information. Alternatively, investigators may apply to an IRB or privacy board for a waiver of authorization. The need for authorization or a waiver will present challenges to certain areas of clinical research.

Protocol Design. Many device manufacturers consult with investigators during the protocol development stage. The new rules will affect an investigator's ability to review medical records for hypotheses development, study design, subject selection criteria, protocol preparation, or other activities conducted in preparation for research.

Estimation of Enrollment Capabilities. Many sponsors ask investigators to estimate enrollment capabilities in order to plan study timelines and determine the number of investigative sites needed. Investigators commonly review the medical records of patients within their practice groups, or ask a laboratory for a list of patients whose laboratory values are above a certain range, then use the information to estimate enrollment capabilities.

Subject Recruitment. Investigators commonly review the medical records of patients previously treated by their practice groups. In large hospital settings, study coordinators may frequent the clinic areas, observing patients who come in for treatment. Those who appear to meet recruitment criteria (e.g., all patients who share common characteristics or who are receiving a particular procedure) are approached for study enrollment and have their medical records reviewed.

Authorization and Informed Consent. Authorization under Section 164.508(a) includes elements above and beyond those required by the informed consent regulations (21 CFR Part 50). The authorization, which grants access to the subject's existing medical records, is distinct from the informed consent form, which signifies that a subject has volunteered to participate in research. How-ever, an authorization may be incorporated into an informed consent form by the simple addition of the following elements within the document or as a separate section:

  • Description of medical information involved.
  • Statement of when the authorization expires (e.g., date of the end of the study or date when the possibility of sponsor audit ends).
  • Statement that treatment, payment, or enrollment in a health plan or eligibility for benefits is not conditioned upon signing.
  • Description of information that will not be disclosed to legal or public health authorities other than FDA (e.g., if the study included a test for sexually transmitted disease, the presence of disease would have to be disclosed to local health authorities).

EXCEPTIONS TO REQUIREMENT FOR AUTHORIZATION

Under Section 164.512(i)(1)(ii), an IRB or privacy board may waive the requirement for patient authorization under certain conditions. If an investigator establishes that the use or disclosure of protected health information is solely to prepare a research protocol or other work preparatory to research, that no information will be removed from the premises (unless the information has been de-identified), and that access to the information is necessary to conduct the research, authorization may be waived by an IRB or privacy board. Eight requirements must be met in order for this to occur (Section 164.512[i][2][ii]):

  • Use or disclosure is of minimal risk to patients.
  • Privacy rights and welfare of patients are not adversely affected.
  • The research cannot be done without the waiver.
  • The research cannot be done without access to the health information.
  • Privacy risks are reasonable in relation to benefits.
  • There is an adequate plan to protect identifiers.
  • There is an adequate plan to destroy identifiers at the earliest opportunity.
  • There are written assurances that information will not be used or disclosed for other purposes.

These are, of course, subjective conditions. The right to privacy will always be adversely affected when a third party is allowed to review an individual's medical records, and the reviewing board may have a different opinion from the investigator concerning the ability to accomplish the goal without the waiver.

Permit to Disclose Medical History Use. Once a subject is enrolled in a clinical study, investigators and sponsors will want access to his or her medical history for inclusion in the study database. This use and disclosure goes beyond the scope of a waiver. The waiver only gives the investigator access to medical records for the purposes of preparing for research, not for actually doing the research or transcribing information. In this situation an investigator must obtain authorization from the subject even if the subject is under the investigator's direct care.

WHO REGULATES CLINICAL RESEARCH?

Clinical research is a $4.5-billion-per-year industry in the United States, with medical devices taking only 8.8% of the pie.1 It should be no surprise that investigators and IRBs are more familiar with the rules for drugs and biologica than for medical devices, or that the Common Rule gets applied to device research. Who regulates clinical research? It depends on who's paying the bills.

Pharmaceutical and Biologics Sponsors (in interstate commerce)

  • $3.4 billion per year.
  • Regulated by FDA under 21 CFR Parts 50, 56, and 312.
NIH and Other Non-FDA Government Agencies
  • $750 million per year.
  • Regulated by the HHS Office for Human Research Protections (OHRP) under the Common Rule, 45 CFR Part 46.
Medical Device Sponsors (in interstate commerce)
  • $400 million per year.
  • Regulated by FDA under 21 CFR Parts 50, 56, and 812.
Privately Funded Research (no interstate commerce)
  • Examples include Easter Seals and March of Dimes.
  • Market size unknown.
  • Regulated by individual states.

REFERENCES

1. "Grant Market to Exceed $4 Billion in 2000," CenterWatch 7, no. 11 (November 2000): 1.

DE-IDENTIFIED INFORMATION

Diagnostics research commonly takes advantage of de-identified medical information; for example, to establish the prevalence of a disease or condition. Medical information that is de-identified is not protected (Section 164.502[d]). The use or disclosure of de-identified information does not require authorization or a waiver of authorization.

Medical information is considered de-identified if it meets the requirements of Section 164.514(a). The rules provide for two mechanisms of de-identifying information: a statistician (or other person familiar with methods for rendering information not individually identifiable) may determine that the risk of an individual being identified is small, or the following elements may be stripped from the data:

  • Names.
  • Zip codes.
  • Dates.
  • Telephone numbers.
  • Fax numbers.
  • Electronic mail addresses.
  • Social security numbers.
  • Medical record numbers.
  • Health plan beneficiary numbers.
  • Account numbers.
  • Certificate/license numbers.
  • Vehicle identifiers and serial numbers, including license plate numbers.
  • Device identifiers and serial numbers.
  • Internet universal resource locators (URLs).
  • Internet protocol (IP) address numbers.
  • Biometric identifiers, including finger-prints and voiceprints.
  • Full-face photographic images and any comparable images.
  • Any other unique identifying number, characteristic, or code.

Leftover Tissue Samples. Information moving from investigator to sponsor is not the only thing that must be de-identified. Information moving from laboratory to laboratory must also undergo this process. For example, if leftover blood, urine, or other tissue samples are shipped to a central laboratory for use in a study, patient identifiers should be stripped from the specimen tubes and the tubes identified by a code number. The code should not be derived from information about the individual or be translatable, and the investigator may not use or disclose the code (Section 164.514[c]). (Under the Common Rule—the clinical research regulations that are followed by federal agencies other than FDA— de-identified information is called de-linked information. For details see 45 CFR Part 46.101[b][2],[4].)

Access to Tissue Banks. If samples in tissue banks are de-identified, investigators may have unlimited access for use and disclosure of the samples and related information. Again, samples and information should be identified by a code number that should not be derived from information about the individual or be translatable, and the investigator may not use or disclose the code. (Section 164.514[c]). Many institutions have a separate consent form that is boilerplate and allows access to coded tissue for research purposes. Increasingly, IRBs agree that if there is identifiable data there needs to be consent; if the identity link is severed, no consent is required.2

Creating Patient Registries. Many device manufacturers request assistance from investigators in the creation of patient registries. Registry information is used for various purposes, such as tracking complications that occur in patients who have received treatment with a particular device. Unless the device is a tracked device under 21 CFR Part 821, either registry information must be de-identified at the time of creation or patient authorization must be obtained prior to use and disclosure of the data.

PATIENT ACCESS TO STUDY RESULTS

Because patients have the right to view their medical records at any time, a subject could request to see the source documents or case report forms even before a clinical study is concluded. Medical records may include reports of tests, procedures, diagnoses, progress notes, and other source records related to the diagnosis and treatment of a patient. Premature disclosure of data to individual subjects might bias the study's outcome. For example, bias might occur if the study was blinded and access to case report forms would unblind the patient, or if knowledge of laboratory or test results could influence a subject's future responses.

Sponsors may wish to add one more element to an informed consent form, stating when a subject may have access to individual study results. A sponsor does not have the right to permanently withhold medical information from a subject. The privacy rules do not specifically discuss research records, which consist of records from research in which the patient has participated.

RESEARCH ON DECEASED INDIVIDUALS

Access to medical records of deceased individuals is an important component of some medical device research. An example is in vitro diagnostics research, where tissue samples may be collected from individuals who are deceased. Disclosure of research data for a deceased person might allow for identification of living relatives, especially in this era of genetic research. Until now, regulations governing clinical research did not consider deceased individuals to be "human subjects," and informed consent from living relatives or a personal representative was not required.3

The new privacy rules consider medical records of deceased individuals to be protected. Under Section 164.512(i)(1)(iii), investigators may apply to an IRB or privacy board for a waiver or may obtain authorization to access medical records of a deceased person from their personal representative. It is worth noting that the National Bioethics Advisory Committee (Rockville, MD) may recommend a revision to the definition of human subjects with regard to research on biological of the deceased, but no report has yet been issued.

SPECIAL CIRCUMSTANCES

Permitted Disclosure. Disclosure of protected medical information is permitted in certain situations required by FDA, without prior authorization from the individual under Section 164.512(b)(1)(iii). Thus, the new privacy rules do not prevent a sponsor of clinical research from reporting adverse events to FDA. Manufacturers may track products as required under 21 CFR Part 821, or locate and notify individuals to enable product recalls, repairs, or replacement without prior patient authorization. They may also conduct postmarketing surveillance without authorization from subjects, as long as the study is conducted to comply with FDA rules or at the direction of FDA.

Identification of Case Report Forms. Many investigators identify case report forms by both an identification number and the subject's initials. This practice can continue under the privacy rules, as long as the elements of authorization are included in the consent form. The authorization elements are intended to make it clear to the subject that identified medical records may be used by or disclosed to a sponsor.

CONCLUSION

The new privacy rules are about 80 pages in length and the preamble is another 700 pages—not an insignificant amount of information to learn and incorporate into practice. Sponsors should be prepared for a period of confusion on the part of investigators and IRBs during the transition period before the rules require absolute compliance on April 13, 2003.


REFERENCES

1. Preamble to 45 CFR Part 164—Security and Privacy, Federal Register 65 FR:82487– 82488.

2. Research Involving Human Biological Materials: Ethical Issues and Policy Guidance (Rockville MD: National Bioethics Advisory Commission, August 1999).

3. Office for Protection from Research Risks, "Human Subject Regulations Decision Charts." Chart 1: Definition of Human Subject at 45 CFR Part 46.102(f); available from Internet: http://ohrp.osophs.dhhs.gov/humansubjects/guidance/decisioncharts.htm.

BIBLIOGRAPHY

European Parliament, Protection of Individual with Regard to the Processing of Personal Data and on the Free Movement of Such Data, Directive 95/46/EC, in Official Journal L 281 (November 23, 1995): 31–50.

"Standards for Privacy of Individually Identifiable Health Information"; information available from Internet: http://aspe.hhs.gov/admnsimp/final/PvcFR01.txt through http://aspe.hhs.gov/admnsimp/final/PvcFR08.txt.

Copyright ©2001 Medical Device & Diagnostic Industry