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Articles from 1996 In April


Applying Reliability Engineering duringProduct Development

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Lee Heydrick and Kenneth A. Jones

A familiar term from advertisements for products and services, reliability is the probability that an item will perform as intended, under specific conditions, for a specified time. It can be measured in several ways, the most common being probability of success and mean time between failures (MTBF), which is calculated by dividing the total performance time of a group of items by the total number of malfunctions incurred.

In turn, reliability engineering is the discipline of quantifying a product's reliability requirements, ensuring that practices are in place to design in reliability, and verifying that reliability requirements are met through design analysis and testing. It has long been a critical component of the design and production of electronic and electromechanical equipment in the aerospace and defense industries, and it seems logical that its proven techniques also should be routinely applied in the design and development of medical devices, where the consequences of failure may be patient injury or even death.1­3

As the complexity of medical equipment continues to increase, it becomes critical to focus on reliability during product development rather than attempt to test reliability into a product after the design is complete. Designed-in reliability can be accomplished most effectively by integrating reliability engineering activities with other design engineering tasks throughout all phases of product development.4,5 As reasonable as this concept may sound, it has not been uniformly applied by the medical device industry.1

There is a perception that reliability engineering adds significantly to product development costs. In fact, when proven reliability engineering techniques are applied during the design and development phases, the resulting benefits far outweigh the costs. Optimum equipment reliability, and the associated reduction in operating and maintenance costs, can typically be achieved with an increase in development costs of less than 5%. Conversely, the consequences of poor reliability--degraded equipment performance, excessive repair costs, patient safety hazards, and even patient fatalities--are well documented.6,7

The reliability of the various types of equipment used during open-heart surgeries to manage myocardial protection is one area of critical concern. The perfusionist, who is responsible for the setup and operation of the heart-lung machine, must be confident that the system assembled not only can support the preferred protocol and deliver the prescribed cardioplegia solution, but also can respond to changes during the course of surgery as the patient's condition dictates. This article describes the reliability engineering process that was used during the development of a device that provides cardioplegia delivery and real-time management of myocardial protection. The reliability tasks that were implemented are identified; additional detail on how to execute these tasks is available elsewhere.2,8,9

The cardioplegia delivery system provides for multiple combinations of blood, crystalloid, arresting agent, and additive solutions under the programmable control of the perfusionist. These features reduce the probability of human error and contribute to reduced operating costs, an important feature in today's cost-conscious health-care environment.

THE RELIABILITY PROGRAM

As emphasized above, it is important to apply established reliability engineering techniques concurrently with the product design and development phases. In the case study, the underlying theme of the reliability program was to identify potential problem areas and to incorporate effective preventive measures to preclude the occurrence of hardware or software failures. The primary elements of the program were the establishment of quantitative reliability and safety requirements, design analysis, and verification of reliability through analysis and testing.

Reliability Requirements Definition. It is common practice at the beginning of a product development project to define detailed quantitative performance criteria (based on customer needs) in a specification document. Ideally, these specifications should include quantitative reliability requirements. For the cardioplegia delivery system, such quantitative requirements were established, with consideration of several clinical scenarios, for three reliability specifications: the probability of successfully completing an operation without a system performance failure, the probability of a safety-critical failure, and a minimum operating life. These requirements were then reviewed by a panel of cardiovascular surgeons and perfusionists, and changes were incorporated based on their feedback. Once the overall system requirements had been established, a quantitative requirement was assigned for each subelement of the delivery system. For the purpose of these requirements, a typical surgery is assumed to consist of a 2-hour setup, a 90-minute surgery including 30 minutes of cardioplegia solution delivery, and a 2-hour shutdown.

Design Analysis. Parts selection was based on the defined reliability and operating life requirements, as well as other performance parameters. To increase the probability that inherent design reliability will be maintained throughout the life of the system, parts with an established reliability history were used whenever possible. Components also were subjected to additional burn-in (environmental stress screening) when necessary to eliminate marginal parts and early-life failures.

High reliability in electronic equipment is generally achieved by limiting the electrical, mechanical, and environmental stresses (voltage, current, temperature, duty cycle, and so forth) that are applied to each part during normal operation. To ensure that the operating stresses for each design application were well below the various components' maximum rated operating values, derating criteria were defined for each part type used in the cardioplegia delivery system. (Derating is limiting the use of a part to conditions that are less severe than the maximum levels specified by the part manufacturer.) Generally, the ratio of operating stress to rated stress was limited to 50%, which represents a 100% design margin. For example, a maximum voltage of 25 V will be applied to a capacitor that is rated for 50 V. Complex parts such as microcircuits have multiple derating criteria, covering such parameters as output load current, frequency, fanout, and power dissipation, which are typically held to 80­90% of maximum rated levels.

Mechanical and electrical stress analyses were performed by measuring or calculating the stresses to which each part will be exposed, determining the applied stress­to­ rated stress ratios, and verifying that the ratios met the derating criteria. The key parameter that affects reliability was analyzed for each part type--for example, power dissipation for resistors, junction temperature for semiconductors, and applied voltage for capacitors. Parts that did not satisfy the criteria were replaced with similar parts that did, or a design change was incorporated to reduce operating stress.

Because lowering temperatures increases part reliability, a thermal analysis was performed to identify any hot spots, eliminate high temperatures, and improve overall heat dissipation. The internal thermal profile of the delivery system was fully characterized and airflow patterns were evaluated. Improved thermal management techniques, such as additional heat sinks and increased airflow in the power supply, were incorporated to enhance system reliability.

Failure mode, effects, and criticality analysis (FMECA) and fault-tree analysis are commonly used during medical device development to assess potential safety hazards.10 FMECA is the evaluation of potential part failure modes, the effects each failure would have on unit performance, and the criticality of degraded performance relative to safety or system functions; fault-tree analysis is the logical diagramming of single and combined failures that could create a potential hazard. For the cardioplegia delivery system, potential fault conditions that would cause major performance degradation or significant equipment maintenance were identified as part of the FMECA process and their occurrence minimized. In addition, the probability of a safety-critical failure mode occurring was determined for each part, the individual probabilities were combined, and the resultant probability of a safety-critical system failure was compared with the predefined quantitative delivery system requirement.

A software reliability analysis was also a key element in the reliability program for the cardioplegia delivery system. Until recently, hardware safety and reliability received much more attention than did software. However, the application of reliability techniques to software development is critical if satisfactory system reliability is to be realized in automated devices.11 The core elements of the software reliability program that was implemented during development of the operating software for the cardioplegia delivery system were the following:

  • Documented performance requirements.
  • Design and coding standards.
  • Quality practices and standards.
  • Code inspections.
  • Requirement tracing.
  • Simplified design.
  • Reliability modeling to predict operational reliability.
  • Extensive testing beginning at the module level.
  • Periodic audits and audit trails.
  • Documentation and resolution of all defects.
  • Safety hazard analysis.
  • A clearly defined user interface.

Product development programs usually include some type of design review prior to release of a design for manufacture. For the cardioplegia delivery system this process included a review of the reliability requirements that were defined in the final product specification and of the design's ability to meet those requirements. Adherence to design criteria were discussed and any exceptions to guidelines were resolved prior to approval of the design.

Reliability Verification. The cardioplegia delivery system design was subjected to testing and analysis to verify that both the hardware and software met specified reliability requirements and that the system could be produced without degrading its inherent reliability.

A reliability assessment is the use of historical data on part applications and failures to predict the expected inherent reliability of a system. For the cardioplegia delivery system design, this was done by assigning a failure rate to each electrical, electromechan-ical, and mechanical part, with the value of the failure rate dependent on the part's operating stress and duty cycle. (The failure rate of a part operating at 90% of its maximum value can be eight times higher than that of the same part operating at 30% of its rating.) The part failure rates were derived from sources such as MIL-HDBK-217F, the RAC handbook for nonelectronic parts, and the Bell Communications Research Reliability Manual.12­14 These rates were then combined at the assembly, subsystem, and system levels to predict the device's inherent reliability, which is expected to be approximately 20% higher than the specified requirement. In addition, the individual predicted failure rates were compared to the specification document to ensure that each element of the system met its reliability requirement. In some cases, additional design changes or part reliability improvements were incorporated to meet the overall design goals.

Reliability testing was integrated with other development-phase tests to create an overall integrated test plan for the delivery system project. Such early, well-planned testing can provide assurance that system reliability will be achieved in production.15 Testing of the system prototype units included accelerated-life testing to verify the system's ability to perform satisfactorily throughout its expected 10-year operating life and reliability growth testing (RGT) to identify potential failures, determine their causes, and then take corrective action to prevent failure recurrence. (Accelerated-life testing is the evaluation of life expectancy by subjecting an item to combined stresses well in excess of those expected in normal usages, while RGT involves evaluation of the device's performance in extreme specified-usage environments.) Additional RGT was conducted on preproduction systems to verify the effectiveness of the corrective actions as well as to ensure that inherent design reliability is not degraded by manufacturing processes and to identify possible additional reliability enhancements. This integrated "test, analyze, and fix" approach is effective because after malfunctions are documented, analyses are performed to identify the root cause of each failure, corrective action is taken to prevent failure recurrence, and the effectiveness of the corrective action is verified with additional testing.

The reliability of the system's software was verified by combining analysis and auditing with thorough formalized testing. As with the hardware, all delivery system software defects were documented, their causes determined, and changes incorporated to prevent their recurrence. Sufficient regression testing--the repetition of previously completed tests--was performed following each modification to verify the effectiveness of the change and to ensure that no other errors had been introduced.

Once the device enters the marketplace, user feedback will be evaluated and changes incorporated to ensure that all customer expectations are satisfied. This approach will continue the reliability verification process in the actual-use environment, so that system reliability will continue to increase.

CONCLUSION

Applying reliability engineering techniques during the product development process can help ensure the reliability of medical devices. A reliability effort such as that described above, coupled with a comprehensive quality assurance program during production, can result in a device that will perform as expected and meet the stringent reliability requirements of critical health-care applications such as open-heart surgeries.


Lee Heydrick is principal of the Heydrick Consulting Group (Denton, TX), which provides reliability and quality engineering services. Kenneth A. Jones is vice president of research and development for Quest Medical, Inc. (Allen, TX).

REFERENCES

1. Bell DD, "Contrasting the Medical-Device and Aerospace-Industries Approach to Reliability," in Proceedings, Annual Reliability and Maintainability Symposium, Washington, DC, Institute of Electrical and Electronics Engineers, pp 125­127, 1995.

2. "Best Practices: How to Avoid Surprises in the World's Most Complicated Technical Process: The Transition from Development to Production," NAVSO P-6071, Washington, DC, U.S. Department of the Navy, March 1986.

3. Dhillon BS, "Reliability Technology in Health Care Systems," in Proceedings of the International Association of Science and Technology for Development (IASTED) International Symposium, Computers and Advanced Technology in Medicine, Healthcare and Bioengineering, Anaheim, CA, ACTA Press, pp 84­87, 1990.

4. Greenberg HP, "Achieving Product Reliability," 44th Annual Quality Congress Transactions, Milwaukee, American Society for Quality Control, pp 398­403, 1990.

5. Heydrick L, "Effective Reliability Engineering during Product Development," in Fifth Annual Leesburg Workshop on Reliability and Maintainability Computer-Aided Engineering in Concurrent Engineering, New York, Institute of Electrical and Electronics Engineers, pp 183­188, 1991.

6. Joyce E, "Software Bugs: A Matter of Life and Liability," Datamation, May 15, pp 88­92, 1987.

7. Leveson NG, and Turner CS, "An Investigation of the Therac-25 Accidents," Computer, pp July, 18­41, 1993.

8. RADC Reliability Engineer's Toolkit, Griffiss Air Force Base, NY, Rome Air Development Center, July 1988.

9. Reliability, Maintainability, and Supportability Guidebook, 2nd ed, Warrendale, PA, Society of Automotive Engineers, 1992.

10. Elahi BJ, "Safety and Hazard Analysis for Software-Controlled Medical Devices," in Proceedings of Sixth Annual IEEE Symposium on Computer-Based Medical Systems, New York, Institute of Electrical and Electronics Engineers, pp 10­15, 1993.

11. Leone AM, "Practical Techniques for Ensuring Software Reliability," presented at George Washington University, Washington, DC, August 27­29, 1991.

12. Military Handbook, Reliability Prediction of Electronic Equipment, MIL-HDBK-217F, Washington, DC, U.S. Department of Defense, December 1991.

13. Nonelectronic Parts Reliability Data, NPRD-91, Densen W, Chandler G, Crowell W, et al. (eds), Rome, NY, Reliability Analysis Center, 1995.

14. Reliability Manual, SR-TSY-000385 (Issue 1), Redbank, NJ, Bell Communications Research, June 1986.

15. McLean H, "Exceeding the Limits of Traditional Reliability Tests," Med Dev Diag Indust, 16(4):96­100, 1994.

Burlington to HIMA: A Challenge, or a Threat?

Originally published April 1996

Relationships between FDA and the medical device industry are not supposed to be cozy. Even when the two are cooperating, their interests should never fully align. Indeed, it's a mark of a healthy regulatory relationship when each side regularly challenges the other without rancor or fear of retribution.

Until very recently, I'd have said that industry and FDA were steadily moving toward this ideal state. But after hearing Bruce Burlington's address to the annual meeting of the Health Industry Manufacturers Assocation last month in Palm Beach, FL, I'm not so sure.

At the end of his speech, the head of FDA's device center presented HIMA members with what he called a challenge, but most of the audience interpreted as a threat. "Is HIMA," he asked, "going to be an adversarial organization to the FDA? Are you going to devote your time and energies, essentially exclusively, to lobbying the Hill for a new statute that you think you'll like better?

"We need to be interacting constructively," he continued, "as opposed to strictly in-your-face, adversarial, back-and-forth bickering about the [application review time] numbers and . . . how to position yourself in terms of members of Congress." Would FDA be better served, he wondered out loud, by working with regional industry groups and individual companies rather than with HIMA?

Some in the audience took his remarks as an attack on their First Amendment rights, but I think this is too grand an interpretation. Rather, I believe he meant that, to his mind, it is not possible for HIMA at once to lobby for an overhaul of the device law and to work with FDA to improve the current system.

Undoubtedly there is some logic behind his assertion. From his perspective, it may well appear that the temptation for HIMA to impede or discount internal agency reforms in order to improve chances for statutory reform is irresistible. His concern, as he put it, is to be sure that when FDA develops policies with HIMA, "we are really sitting down at the table" and not posturing for Congress.

I do not know whether Burlington's doubts about HIMA's willingness to support his internal reform efforts are justified. But given that statutory reform is far from a sure thing, it is clearly in HIMA's and industry's interest to support any policy changes that will improve agency operations.

Underlying Burlington's concerns appears to be a conviction that the current device law is basically sound. As he told the audience, "Those who blithely call for the wholesale replacement of our current system, I don't believe, have looked at all the ramifications of that. FDA's current system of regulation . . . is not today nearly so broken as many of you characterize it."

Perhaps it isn't. But it should not be assumed that those who see the 20-year-old law as fundamentally outmoded cannot both work to change that law and simultaneously support attempts to implement its current requirements more efficiently.

In the aftermath of Burlington's address, it appears that each side sees what the other considers to be beneficial challenges as deleterious threats. Nothing good can come of this situation.

As HIMA president Alan Magazine said in his response to Burlington's comments, HIMA and FDA in fact have "a pretty close and pretty positive relationship on the specific issues that affect the industry." In order to preserve this relationship, both sides must ensure that their challenges to each other are not in fact veiled threats. True challenges in this vital relationship will ultimately bene- fit health care in the United States and the world; threats can only damage it.

John Bethune

FPA Awards Medical Packagers for Environmental Achievement

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Packaging

The Flexible Packaging Association (FPA; Washington, DC) recently honored two medical industry packagers with its top environmental award. The 1995 recipients, Rollprint Packaging Products, Inc. (Addison, IL), and Kapak Corp. (Minneapolis), are the first medical packagers to receive the association's Green Globe Award since the award's creation in 1992.

The Green Globe Award, a part of FPA's annual Top Packaging Awards competition, recognizes the converter whose package has achieved the most significant gains in source reduction, pollution prevention, and resource conservation. Of the recipients of the Top Packaging Awards each year, only one is chosen for the Green Globe Award.

The two companies collaborated on the winning package, a stand-up pouch for the Avitene microfibrillar collagen hemostat, produced for MedChem Products, Inc. (Woburn, MA). The previous version of the package, a screw-top glass jar inside a paperboard spiral-wound can, was more complicated to open than the newer version, whose easy-open pouch allows operating room personnel quick access to the sterilized product. The package's latest incarnation is a foil pouch housing a plastic tray with a peelable lid; it weighs 80% less than the previous version.

"Easy access to the package contents in the operating room is a very big issue right now," says Catherine Hyde, assistant director of public relations and marketing at FPA. "The opening instructions for the new package use large type and are easy to find and to read. Although the new package weighs a lot less, it has a lot more surface space for the instructions." Hyde attended the judging sessions and says that the judges "were very impressed by the source reduction from the spiral-wound can to the stand-up pouch. The easy-peel opening was also very impressive because it maintains the integrity of the package throughout the rigors of dry-heat sterilization, during which there is gas expansion and high temperature, and yet opens easily."

A Top Packaging Award was also presented to American National Can (Chicago), the converter for a redesigned sterile operating room package for the Ethicon peelable suture. The product was previously packaged in a two-part system that enclosed the sutures in a foil laminate pouch within a polyolefin film/Tyvek overpouch; it required two passes through an ethylene oxide sterilizer, one to sterilize the foil pouch and one for the overwrap. The four-ply lamination of the new, single-layer package requires only one pass through a sterilizer and reduces package weight by 18% and volume by 25%.

The Ethicon package can now be peeled instead of torn open, an easy access feature that was praised by the judging panel, according to Hyde. "The judges were also very impressed by the change from a two-part to a one-part system using a laminate structure to maintain barrier properties," she says.

The competition was judged by a panel of 7 experts, who selected 14 winning packages from among the 33 entries for all industries. For the first time since the competition began, all converters with U.S. operations were eligible to submit entries. Packages were evaluated on their individual merits instead of by category. Packages were judged on their product protection, convenience, environmental impact, innovation, technical and marketing contributions, and potential breadth of application. Each winning package excelled in at least one of those categories while meeting minimum requirements in the others.

The FPA awards were announced at the association's annual meeting, held last month in Scottsdale, AZ. For more information on the FPA Top Packaging and Green Globe awards, call FPA at 202/842-3880.--Sashi Sabaratnam *

New EtO Association Vies for Device Market

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Sterilization

Gamma sterilizers may be hearing footsteps. After years of experiencing diminishing market share, the makers and users of ethylene oxide (EtO) sterilization technologies have banded together to form a new trade association designed to promote the benefits of using EtO.

"EtO has historically been one of the simplest, safest, and most cost-effective methods of sterilization," says Ron Ahnell, sales manager for sterilants at ARC Chemical (Slate Hill, NY) and president of the new association. "This group intends to reinforce that positive message."

Dubbed the Ethylene Oxide Sterilization Association, Inc. (EOSA), the new association resulted from informal meetings among representatives of about 20 companies with interests connected to EtO sterilization. Founding members include suppliers of EtO and related sterilants, makers of EtO sterilizing equipment, contract EtO sterilizers, and device manufacturers that use EtO sterilization. Election of the association's board of directors took place on January 24.

"Many in the EtO industry have felt that they were not able to have adequate representation through existing trade associations," notes Barry Page, a sterilization specialist and industry consultant based in Garner, NC. "They have needed a forum where they could discuss EtO sterilization issues independently of other considerations, and an organizing body that would enable them to present positive information about EtO--especially to balance some of the negative things that have been said about it."

The new association fits that bill precisely. According to Clark Houghtling, national director of sales and marketing for the Cosmed Group (Queensbury, NY) and EOSA vice president, the organization's objectives include information-sharing, monitoring regulatory activities, advocating policies favorable to the industry, fostering reasonable regulation, and disseminating "truthful communications" about EtO.

The truth about EtO has been a rare commodity in the recent past, says Page. "When they talk about sterilization, those who support and use radiation and newer technologies have tended to slip in negative comments about EtO. Consequently, there has been a lot of misunderstanding about the hazards of EtO."

"The negative impressions are out there," agrees Ahnell, "and in the past the EtO industry hasn't done a very good job of countering them with positive information. That's the mission of EOSA."

Ahnell attributes the need for a sector-specific trade association to the unique circumstances that apply to EtO. "This chemical is regulated by a lot of agencies because it is toxic, carcinogenic, and flammable. So much regulatory activity can be confusing to customers, who then begin to question the safety of EtO. But when it's used properly, the way a sterilizer uses it, EtO is a safe and very effective sterilant. Without it we would all be either very sick or dead."

Members of the organization are uniformly determined that its activities should remain positive in nature, and should not become a means for criticizing other technologies. "When we go to visit clients, the key question is what method best meets their needs," says John Masefield, chairman of Isomedix, Inc. (Whippany, NJ), a contract sterilizer that offers both gamma and EtO services and a founding member of EOSA. "We're very unbiased, but we appreciate the potential for this new society to provide comprehensive, detailed information about EtO and its use. This will enable those in the EtO sterilization industry to develop a uniform response to common problems that can't be handled through existing organizations and committees."

With the new association still in its infancy, gamma sterilizers aren't yet concerned about its long-term impact on the medical sterilization marketplace. "If you have a better mousetrap, you're sure to catch more mice," says Mac Connelly, director of sales and marketing for SteriGenics International (Fremont, CA), a contract gamma sterilizer. "Naturally, we believe that gamma technology is safer and cleaner, and because of its faster turnaround times offers an overall better option for many device manufacturers."

Nevertheless, Connelly admits that EtO is a tough competitor. "Unlike gamma sterilization, the barriers to use of EtO are quite low. Whereas the costs of setting up a gam-ma sterilization facility are affordable only by the largest device companies, the costs of in-house EtO sterilization can easily be borne by medium-size companies. Gamma's advantage comes in contract sterilization use on a regional basis, where faster turnaround times can more than compensate for EtO's lower freight and transportation costs," he says.

According to Ahnell, EtO's key advantage is flexibility. "EtO can be used with 99.9% of medical products, and can even be used when it's necessary to resterilize." Ahnell has conducted an informal survey on EtO use in each of the past three years, and says that EtO is currently edging out gamma radiation in the market for terminal sterilization of medical devices. "The margin is close," he says, "but EtO is still used to sterilize more products annually than is gamma."

Gamma radiation is the largest but far from the only competitor for market share that EOSA will have to face. While the two majors are running neck and neck--each with an estimated 45% of the U.S. market for industrial medical device sterilization--steam, electron-beam, and other technologies account for the remaining 10%. Novel technologies such as gas plasma, which is already eating away at EtO's share in the hospital marketplace, may also become contenders in the industrial market.

Although EOSA intends to serve as a clearinghouse for information about EtO, the organization will not be developing technical guidances or standards. "Those activities are being adequately handled by committees of HIMA [the Health Industry Manufacturers Association] and AAMI [the Association for the Advancement of Medical Instrumentation]," says Ahnell. "Instead, EOSA will be setting up committees to serve as liaisons with those other organizations, so that we can inform our members about what they're doing."

"We'll keep track of relevant activities being conducted by key standards-writing organizations," agrees Houghtling. "If we feel they warrant our input or involvement we'll see that our members know how to follow through."--Steven Halasey

WASHINGTON WRAP-UP

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

James G. Dickinson

A major FDA final rule on medical device manufacturer reporting procedures has become an unintended test of the agency's readiness to reform itself internally in the face of congressional efforts to inflict reform externally.

While most pundits were predicting in January that general FDA reform simply wouldn't make it into law this year, and as the focus shifted to possible reform legislation for devices only, the reporting final rule erupted in an unprecedented blizzard of substantive industry comments seeking to reopen the debate and test the agency's stated policy of being more flexible and responsive to industry input.

That policy, of course, is a key part of FDA's strategy for diverting and even dissipating political pressure for far-reaching legislative reconstruction of the way it regulates devices, but nobody in the agency intended the reporting rule to be a demonstration project of the strategy. If it was meant to demonstrate anything, the reporting rule, published in the December 11 Federal Register, was meant to show the agency doing business as usual, fairly and objectively, unswayed by the tumult of reform politics.

But on the way to the Federal Register, FDA's final rule ran into the Clinton administration's "Reinventing Government" initiative as interpreted by the White House Office of Management and Budget (OMB). Because you're announcing new forms that industry hasn't seen before, OMB said, you should provide an opportunity for comment on those forms. FDA objected that doing so could open a whole new can of worms affecting the broader rule, but OMB insisted. Naturally, OMB got its way.

Thus, despite FDA's apprehensions, there appeared a most unusual final rule that, because of its poor wording, did indeed let the worms out. Instead of confining comments to the format and content of the new forms, the notice proclaimed at its head an address and deadline for unqualified "comments" and deep in its bowels a solicitation of "public comment on the information collection requirements."

To complicate matters, the final rule with its solicitation appeared in the midst of both blizzard and budget shutdowns of the federal government, causing almost everyone to be late in both noticing its publication and meeting its January 10 deadline for comments. As for FDA's eventual embarrassment when no fewer than 26 entities submitted substantive comments on what was supposed to be a concluded, closed, final rule, few in industry had any sympathy.

"How can you ask for comment on 'information collection requirements' without also expecting to get comment on the information's purposes?" scoffed Health Industry Manufacturers Association (HIMA) director and counsel for technology and regulatory affairs Marlene Tandy. She and other commenters, like Medical Device Manufacturers Association (MDMA) executive director Jeff Kimbell, took full advantage of the unintentional opening FDA had created by asking, in effect, that the "final" rule be rendered nonfinal through an extended comment period. Kimbell asked for another 30 days, Tandy for deferment of the rule for 6 months.

The commenters' unstated but barely concealed bottom line, of course, was the fact that the medical device industry doesn't like any type of reporting. However, given that reporting is the law, the comments sought maximum mitigation of its inconvenience--or, depending on your point of view, the economic damage it does to the industry. MDMA's comments, for example, echoed the well-expressed cynicism of medical industry counsel Larry Pilot of the law firm McKenna & Cuneo (Washington, DC): After 11 years of reporting at a rate of over 100,000 reports a year, Pilot has noticed, FDA has yet to demonstrate any benefits to the public. Yet it was able in the final rule to make the facile statement, "Unfortunately, there are insufficient data to quantify the benefits of the rule."

Of particular concern to HIMA was the final rule's display of a common agency habit--introducing in a final rule a substantive policy element that had not been offered for comment in the original proposal. All government agencies do this regularly. Whether they are challenged on it depends on the degree of impact the new element is perceived to have. In this case, HIMA took exception to the final rule's establishment of a new requirement that foreign manufacturers must designate U.S. agents that will maintain their complaint files. Such a requirement, Tandy said, violates the Administrative Procedures Act and could lead the agency into litigation. Instead, FDA should allow either the foreign manufacturer or the U.S. agent to maintain the files.

Informally, Center for Devices and Radiological Health (CDRH) associate director for compliance Chester Reynolds expects that the 26 substantive comments will be factored into guidance documents that will help to implement the final rule. And there will likely be a deferment of the rule's effective date.

What else the agency can do, squeezed between the dictates of a previous Congress's statutory edicts on medical device reporting and the current political climate, is hard to tell. One thing it and OMB can do in the future, one hopes, is to avoid the policy dilemma created by inviting comments on a final rule when there is no legal, formal intention of doing anything with them.

Although the medical device industry--or at least its Washington representation--remains officially insistent that it won't accept FDA user fees, FDA continues to flaunt the gains being made in drug review times as a lure to persuade the industry to change its mind.

For instance, figures released in January show that FDA's Center for Drug Evaluation and Research (CDER) approved 27% more new molecular entities (NMEs) in 1995 than it did in 1994, a performance the agency attributes to three new assets: drug user fees, better-quality industry submissions, and a new attitude of accountability on the part of the center's drug reviewers.

Calendar year 1995 closed with 28 NME approvals, compared with 22 the year before. In addition, CDER achieved improvements in both median and mean review times. Further, the cohort of almost 100 new drug applications (NDAs) received for review during 1995 encountered only 6 refusals-to-file (6%), compared with 30% in 1994. This reflects a major improvement in the quality of industry submissions, according to Murray Lumpkin, CDER's deputy director for review management.

"The industry has done a good job, they really have," Lumpkin enthused. "They've heard the message on refuse-to-file." From FDA's standpoint, the user-fee program put in reviewers' minds the need to be accountable, to manage the review workload, and to meet or beat the statutory time- lines Congress set for the agency. "It really has gotten into people's mentality that this is important, this is real," Lumpkin said.

Based on the cohort of 1994 submissions, FDA is now approving 96% within the one-year time frame, a much better rate than the 55% goal set for that year's submissions in the Prescription Drug User Fee Act. FDA's statutory goal for the 1995 cohort is to approve 70% within one year, for the 1996 cohort 80%, and for 1997 (when the user-fee program sunsets) 90%. Lumpkin hesitated to predict how much better than 70% the agency will do this year, but said everyone is committed to beating that goal.

The device industry's Washington representatives hate to hear this kind of talk. They have worked extremely hard, with some prospect of success, to con- vince congressional staffs that they should disregard the user-fee panacea and instead craft stringent reform measures that would obviate the need for user fees. Meanwhile, device association leaders have also been draw-ing some comfort from the experience of their drug industry association counterparts, who have begun quibbling with FDA over the methodology used to measure and demonstrate great gains from drug user fees.

FDA has been fudging some of its numbers, and has not been factoring in the greater development delays its new requirements force on drug companies, complain officials of the Washington, DC­based association Pharmaceutical Research and Manufacturers of America (PhRMA). It's all very well to boast that FDA is moving faster at its end of the approval chain, says PhRMA, but it should be honest in acknowledging that some of that improvement comes at the cost of greater delays inflicted on drug companies before CDER sees their marketing applications.

That may well be the case, but PhRMA's argument sounds a little like changing the rules in the middle of the game. Although both sides have done a little midgame switching with the numbers, the inescapable bottom line is that drug user fees have worked to shorten review times.

That doesn't mean user fees are the only way to go in the device area. FDA has improved device review times without user fees, and could doubtless do even better. But user fees are still worth looking at, especially if the legislative reform effort peters out, as many expect it may.

In January, FDA was three months late on a promise it made to deliver a final rule for eliminating conflict of interest among clinical investigators. Naturally, House Commerce oversight and investigations subcommittee chairman Joe Barton (R­TX), a tireless agency overseer, demanded to know why. Could it be that FDA commissioner David Kessler (a Republican appointee, after all) was not as energetic as Barton himself in promulgating the ideas of Republican House Speaker Newt Gingrich?

In a January 4 letter to Kessler, the indefatigable Barton picked up on a report of statements Kessler had made on National Public Radio's Diane Rehm Show addressing problems he has with Gingrich's FDA reform ideas. In the letter, Barton quoted the FDA leader as saying, "The real concern I have with [Gingrich's] proposal is that it would turn over the decision making to people who potentially could have certain conflicts of interest. The most important thing that FDA has to offer is that product reviewers are independent."

Barton delved into FDA's April 1994 announcement of the proposed rule on investigator bias to remind Kessler of the importance FDA had then placed on this rule as an answer to a problem that is "significant" and whose solution would "strengthen the FDA review process."

Given that the comment period ended more than a year ago, and given the importance Kessler has personally placed on conflict-of-interest issues, why did the agency miss the initial publication date of October 1995? Barton demanded to know. He acknowledged that a recent FDA regulatory agenda had shown the rule making still to be necessary, and that it is expected by April 1996. Yet that date is 11/2 years after the comment period ended.

FDA does everything much more slowly than even it expects, and the more Barton and his Republican colleagues rein in the agency's budget, the more likely it is that that slowing process will continue. Which, to many who philosophically fear governmental efficiency, may not be an entirely bad thing.

A specialized panel of practitioner experts could be assembled by the American Medical Association (AMA) to provide clinical guidance for FDA device reviewers, AMA vice president Roy Schwarz said after a January meeting with top FDA officials. CDRH director Bruce Burlington was among those who seemed interested in the AMA suggestion, Schwarz said.

Schwarz gave the recent pedicle screw controversy as an example of how such a panel could help FDA. The agency acted against manufacturers' demonstrations of unapproved uses of this device without making any effort to gather input from qualified medical practitioners who had successfully used the screws in off-label ways.

"Let FDA lay the issue on the table and we could discuss as a house of medicine how we might work with them to solve the problem," Schwarz said. FDA said it is willing to discuss the concept further.

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

INTERNATIONAL TRADE

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Ames Gross and Pat Dyson

Asian countries represent the fastest developing area for medical technology in the world, with an expected 15­20% annual growth rate in that area in the near future. As per capita incomes have begun to rise above $5000 per year in many Asian countries (excluding Japan, which has a greater per capita income than the United States), there has been a striking increase in health-care and medical technology spending.

The Republic of Korea presents one of the best opportunities for businesses seeking to benefit from the phenomenal growth of the Asian market. From 1965 to 1990, the Korean economic growth rate was the second highest in the world. With per capita incomes exceeding $6000, the purchasing power of over 40 million Koreans has been and continues to be very strong.

The Korean market will expand for U.S. medical exporters in the future. Statistics from the Korean Hospital Association show 650 hospitals with 125,100 beds and 51,425 physicians in 1994. In 1993, $730 million was spent on medical devices in South Korea. Surgical and medical instruments accounted for $205 million, surgical appliances and supplies for $214 million, and x-ray apparatus and tubes for $112 million.

U.S. manufacturers have attained a strong market position in the Republic of Korea, supplying 40% of total imports in 1993. Among the U.S. companies that have enjoyed success in the Korean market are Abbott Laboratories (Chicago); Beckman Instruments, Inc. (Fullerton, CA); DuPont Co. (Wilmington, DE); Nova Medical, Inc. (St. Paul, MN); Immucor, Inc. (Norcross, GA); and Ciba Corning Diagnostic Corp. (Medfield, MA). Several European and Japanese manufacturers, such as Coulter of the United Kingdom and Fujirebio and Iatron of Japan, are also competitive in the Korean health-care product market.

One of the most successful market sectors for U.S. manufacturers has been laser equipment. Since medical laser technology was first introduced to South Korea in the 1980s, this sector has experienced unprecedented growth, particularly in the specialties of ophthalmology, dermatology, and orthopedics. Imported equipment accounts for 98% of the Korean laser market. The United States has held a strong position in this market, with a market share of approximately 70%. However, German and Japanese manufacturers are expected to increase their shares.

MEDICAL FACILITY EXPANSION

Recently, the Korean government extended comprehensive medical insurance to the nation's entire population, a plan that includes upgrading hospitals and building new ones. In addition, the government plans to construct new residential areas--and a number of new medical facilities--in Seoul and other satellite cities. Under this plan, market sectors that historically have had low growth rates in South Korea, such as patient monitoring systems, may offer increased export growth opportunities.

Although the plan to increase the number of medical facilities is encouraging, medical device manufacturers should be aware of the Korean government's policy of restricting the purchase of high-cost medical devices to be installed in Korean facilities. Hospitals that wish to install equipment such as computed tomography scanners and magnetic resonance imaging devices are required to obtain approval from the High Cost Medical Equipment Council of the Ministry of Health and Social Affairs. This policy, adopted in 1991, led to a decrease in imports of these devices. However, the Health Industry Manufacturers Association (HIMA) reports that, since 1994, the ministry has eased its standards for these approvals.

NEW REGULATIONS

In the past, the Korean medical device market suffered from excessive testing requirements and regulations that lacked a sound scientific basis. Today, several new regulatory developments promise an improved export environment for U.S. manufacturers.

In December 1995, the Korean government released a draft of revised regulations that are a major improvement over those issued on July 1, 1993. The new regulations introduce a risk-based classification system for devices, improve testing and quality control systems, and establish a postmarket surveillance system.

Further regulatory modifications are in the works, to be finalized this May and translated by July. The Korean Academy of Industrial Technology (KAITECH) is preparing a draft of a globalized regulatory system. As a part of this new system, the government is considering the use of the family of quality systems standards, commonly known as ISO 9000, developed by the International Organization for Standardiza-tion, as well as International Electrotechnical Commission standards. Additional reduction or elimination of testing requirements and the removal of Korean Medical Instruments Industrial Cooperative (KMIIC) involvement are under consideration as well. The government may also establish an agency similar to FDA. HIMA has submitted comments to the Korean government regarding the proposed new regulations.

The number of product categories subject to testing has been reduced from 36 in 1987 to 11 in 1995, and KMIIC no longer requires the quantity and unit price for import notification. However, some medical devices, such as anesthetic equipment, electrosurgery equipment, incubation equipment, and high-pressure sterilization equipment, are still subject to piece-by-piece mandatory testing.

Further reduction of mandatory testing and a move toward adoption of ISO 9000 standards will streamline and speed up the import process for medical devices. U.S. medical device manufacturers need to stay on top of the swiftly changing regulatory scene to be successful in Korea.

MEDICAL DEVICE CLASSIFICATION

The Republic of Korea's new regulatory system divides medical devices into three classes according to the risk associated with the equipment. Class I medical devices are those that do not come into direct contact with, or do not pose any hazards to, the human body. Typical products falling into this category include knives, scissors, drills, beds, and wheelchairs for medical use. A manufacturer or importer has a single requirement for Class I devices--notification to KMIIC of general information on the medical device, such as the name and address of the manufacturer, product name, and product type.

Class II medical devices are those whose safety and effectiveness can be guaranteed if they are designed and manufactured according to relevant standards relating to their raw materials, components, structure, and performance. Such devices include transcutaneous electrical nerve stimulators, ultrasound scanners, defibrillators, and electro-encephalographs. The government requires approval of these devices before they can be sold and distributed. The approval application must be in Korean and must contain the name and number and date of issuance of applicable technical specifications.

Class III medical devices are defined as those that have a serious effect on the human body, such as life-supporting devices or permanent implants. Products in this class include such devices as pacemakers, prosthetic heart valves, vascular graft prostheses, and artificial tissue. The application process for approval of these devices is similar to that for Class II devices; however, information pertaining to the device's safety and effectiveness must also be submitted for Class III medical devices.

PRODUCT TESTING

Imported medical devices must be tested by an agency in South Korea designated by the Ministry of Health and Welfare (MOHW). Testing results from a foreign agency may also be acceptable if they meet Korean standards. Testing is generally done on the first shipment of a particular device, except for those Class I devices exempt from quality control; subsequent shipments of these exempt devices are tested.

Different Korean testing agencies are designated according to the type of medical device involved. General medical devices such as catheters are tested by the Korea Testing and Research Institute for Chemical Industry and the Korean Merchandise Testing and Research Institute. For other types of devices, KAITECH is the testing agency. Implants and devices based on new technologies are tested by the Korean National Institute of Safety Research. Certification from any of these agencies is good for five years.

PERMISSIONS TO EXPORT

Products sold in South Korea prior to January 1, 1995, are grandfathered under the new regulations, and additional testing is not required. This is a significant change because prior grandfathering protection extended only to July 1, 1992. Exporters of these devices must submit the following documentation to an MOHW-authorized testing agency:

* A certificate of free sale or a certification of products of export.

* A certification that the product has been sold in Korea for three or more years.

* Evidence that at least 50 pieces have previously been imported to South Korea.

For implants, the exporter must present shipping records and certify that no problems have occurred.

In order to export new products into South Korea after January 1, 1995, applications should be submitted in Korean to an MOHW-authorized testing agency. A single application may be submitted for multiple products. The agency has 15 working days to complete reviews.

For medical implants and newly invented devices, an applicant will also have to include data concerning the safety and efficacy of the product. Applications for implants and new devices are sent to the National Institute of Safety Research for a review, which takes about 90 days. Local governments handle follow-up monitoring and report nontested devices to MOHW.

After a device is certified, the manufacturer must submit an import notification to KMIIC, including an import license and a certificate of free sale. Three days before going through customs, a report of the customs clearance plan must be sent to the testing agency. After customs clearance, stock is held in quarantine until it has passed testing.

CONCLUSION

Foreign medical device exporters receive substantial product exposure at the annual Korean Medical Equipment Show, organized by one of South Korea's major daily newspapers, Hankook Ilbo. In addition, foreign manufacturers now hold their own presentations for physicians or hospital purchasing officers.

U.S. manufacturers cannot ignore political factors when appraising the Korean medical market. Korean politicians often support protectionist policies, particularly in election years. Thus, restrictions on imports into the Republic of Korea could continue through a maze of nontariff barriers.

The relationship between South Korea and the United States, however, has remained healthy, and South Korea is one of the United States' most important commercial partners. Given Korea's receptiveness to new medical technology and its plans to reduce regulation, U.S. manufacturers will have the opportunity to hold on to and even increase their share of this growing market.

Ames Gross is president and Pat Dyson is an associate of Pacific Bridge, Inc. (Washington, DC), a consulting firm specializing in Asian business.

POSITIVE SIGNS: REGULATORY CHANGES FOR THE IVD INDUSTRY

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

A number of FDA actions and proposals over the last several months appear to indicate a more flexible and, hopefully, more practical approach to the regulation of in vitro diagnostic (IVD) devices. Communication has improved noticeably between industry and the Division of Clinical Laboratory Devices (DCLD), the division within FDA's Office of Device Evaluation that clears or approves IVDs prior to marketing. In this improved atmosphere, companies can more easily discuss proposed clinical studies and premarket submissions with the agency. The agency encourages both conference calls and face-to-face meetings. DCLD has even suggested meetings with companies to examine questions and concerns about proposed products or studies and to exchange scientific information with company scientists and clinicians. Although DCLD has always met with regulated companies to discuss submissions, recently the agency appears to have a more open attitude and is making a greater effort to cooperate with industry.

At the same time, FDA has raised the bar for attaining regulatory clearance of a number of IVDs, particularly regarding the kinds and amount of clinical data required. In fact, DCLD has indicated that some Class II devices will be sent to a device advisory panel for review and possibly to a formal panel meeting. These are similar to those for premarket approval applications, and requirements for clinical trial data and panel review seem to reflect the concerns DCLD has raised repeatedly regarding the effects of IVDs on health and safety.

Notwithstanding these somewhat mixed signals, a number of developments in the IVD regulatory arena warrant close attention. A new compliance policy guide (CPG) addressing the commercialization of unapproved IVDs labeled for research or investigational use will likely be made public for comment in 1996. This will coincide with FDA's proposal for regulating analyte-specific reagents (ASRs). The ASR initiative, designed to address the difficult issue of home brew products, was recently endorsed by an FDA advisory panel. The agency is now working on a Federal Register notice that will formally present its proposal for regulating home brew ASRs.

Industry may also benefit from DCLD's willingness to take a second look at applying FDA's triage initiative to IVD submission reviews.1 DCLD's initial assessment of the initiative was that most IVDs requiring only a tier 1 review had already been classified as Class I premarket notification­exempt devices. It is now, however, working with industry to develop new models for assessing the risk posed by a diagnostic device.

Another promising development is FDA's proposed policy for simplifying submission requirements for primary and secondary reagents on automated analyzers. FDA has sent the proposal to manufacturers for comment and expects to finalize it in 1996.

These initiatives and their implications for the device industry are the focus of this article.

RUO AND IUO COMMERCIALIZATION

The commercialization of IVDs labeled for research use only (RUO) or investigational use only (IUO) has been a particularly thorny issue for FDA and IVD companies. An appropriately labeled diagnostic device can be shipped to investigators without an approved investigational device exemption (IDE) application if the testing "(i) is noninvasive, (ii) does not require an invasive sampling procedure that presents significant risk, (iii) does not by design or intention introduce energy into a subject, and (iv) is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure."2,3

By the early 1990s, when FDA issued a draft CPG on the commercialization of IVDs, a few IVDs distributed under this exemption had become widely used standard tests for diagnosing or monitoring some conditions or diseases. Recognizing that the abrupt removal of these devices from the market would be disruptive to the practice of medicine, FDA proposed that these IVDs be placed on an accommodation list. Listed devices would be allowed to remain on the market for a specified period while safety and effectiveness studies were conducted to prepare premarket submissions. FDA abandoned this approach, however, after its general counsel advised that an accommodation list might be illegal.

FDA's draft CPG, released in August 1992 under the title "Commercialization of Unapproved In Vitro Diagnostic Devices Labeled for Research and Investigation," described a certification program under which these diagnostic devices could be distributed.4 The certification program was to provide an audit trail from the manufacturer or importer through the distributor and laboratory to the end-user, confirming that these devices were not sold or diverted for unapproved uses.

In the draft CPG, FDA indicated that home brew products would be subject to the same regulatory requirements as unapproved medical devices. Such products are brewed in the laboratory by combining components or reagents. These components and reagents are often sold in bulk for further manufacturing, and in some cases are modified for in-house clinical assays. If they are modified, they must be validated according to the laboratory quality regulations of the Clinical Laboratory Improvement Amendments of 1988 (CLIA).5

Because laboratories were not shipping finished devices across state lines, FDA had not previously regulated home brew IVDs. Although its authority to do so has been questioned, FDA has asserted its jurisdiction over IVD components, including reagents intended for use as finished medical devices, whether they are labeled for stand-alone use or not.

In the years since FDA issued the draft CPG, industry has wrestled with whether and how to comply with it. Some companies distributing RUO and IUO devices have chosen not to establish a certification program, and many of these companies have played a waiting game to see whether they would escape FDA's notice. Some struggled with the fairly significant logistical issues of instituting such a program. These issues include:

* Obtaining written certification of compliance from laboratories and individuals.

* Procuring copies of clinical protocols from independent investigators.

* Determining whether distribution to a site should cease because of noncompliance, which can create customer relations issues.

* Maintaining what can be a massive paper trail, depending upon the number of products distributed under certification programs.

Rumors that a revised CPG would be released created a dilemma. Companies had to decide whether to proceed with a certification program or wait to see what a new guidance might entail. In the meantime, FDA did not issue any new guidances on home brew products and therefore seemed to be backing off its original stance that these products would be regulated as unapproved medical devices.

In October 1995, the IVD industry got an indication of FDA's current position regarding commercialization of unapproved IVDs. At a meeting of the Association of Medical Diagnostics Manufacturers, Betty Collins, deputy chief of the IVD branch of the Office of Compliance (OC) of FDA's Center for Devices and Radiological Health, presented an overview of a revised CPG proposal. Collins stressed that FDA considers commercialized IUOs in violation of the Federal Food, Drug, and Cosmetic Act if they are labeled or promoted as safe and effective prior to agency clearance or approval, or if they are distributed to persons other than those conducting a clinical investigation to collect safety and effectiveness data.

Under the proposed CPG, as described by Collins, FDA will provide a period of "enforcement discretion" for most companies distributing IUO IVDs. A company would have 30 months from the effective date of the CPG to gather safety and effectiveness data to support a 510(k) notice, a premarket approval (PMA) application, or an IDE application, and to obtain clearance or approval for the device or IDE application. If, at the end of the 30-month period, FDA has not cleared a product or approved an IDE application, it would remove the product from the market.

The proposal includes conditions for receiving the 30-month grace period. If a company has not already begun a clinical study for a device once the CPG becomes effective, it must do so within 6 months. This means that a company must make a good faith effort to obtain institutional review board (IRB) approval for the study, initiate the clinical study with a reasonable protocol, and demonstrate that it intends to monitor the study to ensure compliance with the protocol and IRB requirements. Furthermore, a company cannot label or promote the product in any way that indicates it is safe and effective. If the company makes any claim through labeling, advertising, conference booth displays, or even a salesperson's oral comments regarding performance characteristics such as sensitivity or specificity, the device could be considered misbranded and adulterated and therefore subject to regulatory action.

The proposed CPG's 30-month grace period, however, would not automatically be available to all IVDs. Devices not receiving it would include the following:

* IVDs that may lead to a significant medical decision without confirmation by another medically established procedure or diagnostic product, and for which adequate safety and effectiveness data are not available.

* IVDs for which data to support a human diagnostic use either do not exist or are only anecdotal.

* IVDs sold by companies that fail to abide by FDA's conditions for receiving the 30-month grace period.

It is likely that OC would consult with DCLD as to what constitutes a significant medical decision, and entirely possible that DCLD's assessment of a product's effect on medical decision making will differ from that of the manufacturer. DCLD's position has generally been conservative, and top division personnel have alluded to FDA's experience with a wide range of devices that can affect health and safety, compared to a single company's more limited perspective.

The proposed CPG has not been finalized and could undergo further modifications before it is released, particularly because it relates to FDA's initiative on ASRs. A final version that incorporates most of what has been described would offer a reasonable approach to companies seeking clearance for their IUO devices. Assuming that companies comply with FDA's conditions, they would have time to collect data for 510(k) submissions and to obtain clearance. Gathering data and obtaining approval for a PMA application within 30 months is clearly more challenging, but not impossible. Nevertheless,while studies are under way, FDA is unlikely to remove products from the market that have become important adjuncts to diagnostic armamentaria unless they pose a health and safety risk. Conducting studies and preparing premarket submissions for IUO IVDs requires resources, but addressing compliance issues also exhausts valuable resources. For its part, FDA will be under pressure from industry to review and act on these submissions to avoid unnecessarily removing products from the market.

HOME BREWS

After the 1992 draft CPG was released, little was heard from FDA regarding its intentions to become more actively involved in regulating home brews. In January 1995, however, the agency conducted a video teleconference on IVDs. During the teleconference, Steven Gutman, DCLD's director, indicated that although the agency might have some role to play in regulating home brews, laboratories are already regulated by the Health Care Financing Administration under CLIA.

For their part, laboratories have faced a different dilemma. Products that have already been validated, manufactured, and labeled in compliance with government regulations may be unavailable because the potential income may not justify the manufacturer's cost to obtain FDA approval. On the other hand, creating home brew tests is risky and resource intensive. Under the CLIA regulations, laboratories are required to validate the performance of a home brew or modified manufacturers' assay, a task that can entail significant work for more-complex diagnostic tests. Most laboratories prefer to use FDA-approved assays without modifying them.

Fortunately, several solutions have been proposed to streamline the device approval process, including reclassifying certain cancer diagnostic tests from Class III to Class II, down-classifying many transitional and preamendment Class III devices to Class II, and automatically placing new IVDs into Class II rather than into Class III. In December 1995, the Immunology Devices Advisory Panel met on a manufacturer-sponsored petition and recommended to FDA that it reclassify tumor markers for patient monitoring from Class III to Class II. DCLD appears to be actively looking for ways to use the 510(k) clearance path for devices that heretofore were likely to require a PMA application. Clearance of these products would decrease the need for laboratories to brew many tests on their own.

CLASSIFYING ASRs

FDA has also pursued alternative regulatory approaches for handling home brew products. In 1995, industry worked closely with FDA on a proposal to create a subcategory for special-purpose reagents (SPRs) within the general-purpose reagent category. SPRs, which could have included polyclonal and monoclonal antibodies, antigens, and genetic probes, would not have been stand-alone products and would not have been labeled for specific medical uses. Under the proposal, SPRs would have been regulated as Class I devices that are exempt from 510(k) notification requirements but subject to general controls, including registration, listing, and compliance with good manufacturing practice (GMP) requirements as well as labeling restrictions.

FDA subsequently chose not to create a subcategory within the general-purpose reagent category but to proceed with a proposal to classify these products as IVDs. At an advisory panel meeting on January 22, 1996, the agency presented its proposal to classify analyte-specific reagents as Class I devices that are exempt from premarket notification requirements but subject to general controls. In addition, FDA proposed placing certain labeling restrictions on ASRs.

After reviewing definitions of analyte-specific reagents proposed by both FDA and the American Association of Clinical Chemistry, the panel agreed on the following definition: "Antibodies (both monoclonal and polyclonal), specific receptor proteins, nonhuman nucleic acids and fragments of nonhuman nucleic acids, and similar biological reagents which, through specific chemical binding or reaction, are intended for identification or quantitation of specific analytes in a biological specimen."6 The panel voted in favor of the classification proposal, concurring with FDA that ASRs used in blood banking and in certain infectious disease tests should be excluded from the Class I, premarket notification­exempt category. The panel also recommended expanding the exclusions to cover ASRs used in genetic disease tests and tests to screen for predisposition to disease. These products would thus be subject to all FDA device and diagnostics regulations.

Other panel recommendations included restricting the sale of ASRs to laboratories with high-complexity-testing certificates under CLIA. It also recommended restrictions on labeling. Proposed language for ASR labeling is expected to be included in the Federal Register notice regarding the proposed classification of ASRs. FDA plans to publish the notice after reviewing the panel meeting proceedings.

Although the ASR proposal appears to be a positive step toward alleviating the regulatory uncertainties associated with home brew products, it raises new concerns for some product manufacturers. Under the proposal, companies that are not manufacturing finished IVDs, but are making components that qualify as ASRs, would be subject to GMP requirements. Their counterparts in the device industry that manufacture other components are not subject to the GMP requirements. This issue, as well as the exclusions from the ASR classification and the labeling restrictions, will likely generate considerable discussion during the upcoming notice-and-comment rule making process.

TRIAGE MODELS

Along with proposals relating to reclassification and ASRs, FDA and industry have jointly discussed the use of the agency's triage initiative introduced in 1993. Under this initiative, FDA reviewers categorize devices into one of three tiers, based on the agency's assessment of the risk posed by the device, and subject the premarket submission to a level of review commensurate with that risk. Tier 1 devices represent the lowest level of risk, and submissions generally undergo a labeling review. Tier 2 devices undergo both a labeling and a scientific review, and tier 3 devices undergo a more intensive labeling and scientific review. Currently, submissions for most IVDs are subjected to tier 2 reviews; a few IVDs receive tier 1 reviews.

FDA and the Health Industry Manufacturers Association (HIMA) have proposed decision trees for determining review levels. These decision trees were discussed at an October 1995 workshop at which FDA convened a panel of advisory committee members, government agency personnel, and representatives from professional associations. Because the workshop was announced in the Federal Register only the day before it was held, industry attendance was minimal. FDA's purpose in holding the workshop was to solicit opinions from workshop participants rather than to achieve consensus or gather recommendations.

During the workshop, HIMA representatives took the position that a test using a new methodology for detecting a previously cleared analyte in the same matrix in which it was cleared could be sufficiently reviewed as a tier 2 device. They also voiced concerns that FDA's model fails to adequately address whether an IVD is used as a primary determinant of diagnosis or treatment or as an adjunct to other diagnostic information. In addition, FDA's model does not allow for products not used in professional settings to be reviewed as tier 1 devices. Some panel members presented a more conservative position, indicating that FDA should not place point-of-care and physician-office laboratory IVDs in tier 1. They expressed concern that a tier 1 review could mislead users into thinking the device had received a more thorough review than a tier 1 review entails. FDA is expected to form an agency-industry task force to formulate proposals for simplifying IVD review processes or to develop a pilot initiative.

The IVD industry has generally believed that FDA has subjected its devices to more-stringent premarket reviews than other devices that pose potentially greater risk. FDA's willingness to engage in dialogue on this issue is encouraging. In addition, FDA has maintained that it is looking for ways to focus its resources on newer and more complex submissions. Allowing a tier 3, Class II 510(k) submission for an IVD that might otherwise require a PMA application would ease the burden on companies with newer technologies and "first of a kind" devices. The required clinical data would still undoubtedly be significant. Additionally, having 510(k) notices reviewed by an advisory panel would be more complicated than the submission process for most 510(k)-cleared devices. The alternative of submitting a PMA application, nevertheless, is much more daunting. If DCLD assigns the tier 3 designation injudiciously, however, industry would still face ever-increasing delays in product clearances.

REAGENTS USED IN AUTOMATED ANALYZERS

One of the more exciting developments in the IVD regulatory arena has been FDA's proposal to simplify submission requirements for reagents used in automated analyzers. The proposal's introduction, in the version dated October 3, 1995, described the draft guidance as an effort to "clarify, standardize, and streamline" data requirements for reagent and analyzer system applications.7 Such an effort would be welcome to the IVD industry, which has faced requirements that seemed to differ from branch to branch within DCLD. Existing submission requirements, outlined in the proposal, likely came as a surprise to some secondary reagent manufacturers who may have been unaware that they should have been submitting 510(k) notices for use of their reagents on each analyzer for which they distributed reagent application sheets.

Under the proposal, entitled "Data Required for Commercialization of Primary, Secondary and Generic Reagents for Automated Analyzers," submission requirements would become simpler for both primary and secondary reagent manufacturers and for manufacturers of "open" analyzers who wish to distribute reagent application sheets. Primary reagents are defined in the proposal as reagents produced or obtained by an analyzer manufacturer specifically for use on that analyzer. Secondary reagents are those produced for use on specified analyzers that are open systems.

Requirements remain the same for both generic reagent manufacturers and manufacturers of analyzers for which no specific claims are made and for which no reagent application sheets are distributed. These manufacturers must still submit a 510(k) notification showing compliance with labeling regulations and demonstrating the performance characteristics of reagents for a given analyte on one analyzer.

The proposal requires that primary reagent manufacturers continue to submit 510(k) notifications when introducing a new reagent and instrument system employing a new operating principle, technology, or intended use. The manufacturer would include a protocol by which subsequent models of the same system would be tested. FDA must approve the protocol and, if changes are made, the manufacturer must submit a new one. Once a new model has been tested according to the approved protocol and prior to its marketing, the manufacturer would send a letter to FDA that references the initial 510(k) submission, describes the new model, and provides a 510(k) summary or statement. FDA would file this letter with the original 510(k) and send an acknowledgment letter to the manufacturer. The manufacturer must maintain a complete record of the testing performed to qualify the new model.

Under the proposal, secondary reagent manufacturers (or manufacturers of analyzers on which secondary reagents can be used) would submit an initial 510(k) notification for an analyte on an analyzer, and would include a protocol for qualifying the reagents on additional analyzers (or for qualifying additional reagents for the same analyte on the same analyzer). Once testing is completed using the FDA-approved protocol and prior to making specific claims or distributing reagent application sheets, the manufacturer would send a letter to FDA that references the initial 510(k) submission, lists the new qualified analyzers (or new reagents for the same analyte), summarizes the performance testing, and includes the new reagent application sheets. FDA would add this letter to the original 510(k) file and send an acknowledgment letter to the manufacturer. Again, the manufacturer must maintain a complete record of the testing done to qualify the new analyzers or reagents.

Given the permutations of reagents and analyzers that exist, a number of questions arise regarding how FDA would implement the policy for existing reagents and analyzers, how long FDA would take to approve protocols, what protocol changes would require resubmission, and how long FDA would take to provide an acknowledgment letter. Moreover, the policy does not address assay reagents cleared for manual use but not for use on automated analyzers. Some manufacturers have maintained that if no assay parameters are changed when the assay is automated, then no submission should be required. FDA's position has appeared to vary, depending upon the DCLD branch.

Notwithstanding the issues still to be addressed, the proposal appears to demonstrate a willingness by DCLD to simplify the submission process. The proposal has undergone three revisions in an effort to address questions raised by industry, indicating FDA's commitment to putting this policy into effect.

CONCLUSION

Recent proposals in IVD regulation are encouraging in light of the chasms that existed between FDA and industry not long ago. Nevertheless, lengthy approval times still exist and clinical data requirements are increasing significantly for many IVDs. For its part, the IVD industry must take an active role in examining proposals that affect its products and in drafting proposals to address emerging issues on which FDA has not yet focused. Device companies should not assume that other manufacturers will provide feedback to FDA that reflects their own positions. They should also not assume that when FDA or professional associations solicit comments, the comments will be ignored. The time for offering constructive input to proposals on the table for discussion, or for offering alternative solutions, is now. FDA seems to be listening.

REFERENCES

1. "PMA/510(k) Triage Review Procedures," General Program Memorandum G94-1, Rockville, MD, FDA, Center for Devices and Radiological Health (CDRH), May 20, 1994.

2. Code of Federal Regulations, 21 CFR 809.10(c).

3. 21 CFR 812.2(c)(3).

4. "Commercialization of Unapproved In Vitro Diagnostic Devices Labeled for Research and Investigation," Draft Compliance Policy Guide, Rockville, MD, FDA, CDRH, August 1992.

5. Clinical Laboratory Improvement Amendments of 1988, 42 USC 201, October 1988.

6. "Analyte Specific Reagents' Class I, 510(k)-Exempt Status Endorsed by Panel; Few GMP Inspections of ASR Manufacturers Foreseen by FDA," MDDI Reports--The Gray Sheet, pp 3­5, January 29, 1996.

7. "Data Required for Commercialization of Primary, Secondary and Generic Reagents for Automated Analyzers," draft, Rockville, MD, FDA, CDRH, October 3, 1995.

Constance Finch is a regulatory specialist for the law firm of Hogan & Hartson (Washington, DC). She was formerly with Baxter Diagnostics and with Abbott Diagnostics Div. of Abbott Laboratories.

CURRENT AND FUTURE FDA INITIATIVES IN CLINICAL TRIALS

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Susan Alpert

The primary mission of the Office of Device Evaluation (ODE) of FDA's Center for Devices and Radiological Health (CDRH) is to ensure timely delivery of safe and effective medical products to patients. One aspect of this process involves ensuring that each device does what its manufacturer claims it will do and that manufacturers support such claims with valid scientific evidence. Approximately 10% of all submissions ODE receives for marketing authorization include clinical data as part of this scientific evidence.

BACKGROUND

Since the initiation of the medical device program in the United States in 1976, valid scientific evidence of safety and effectiveness from clinical trials has been required to support premarket approval (PMA) applications. However, the Safe Medical Devices Act of 1990 (SMDA) mandated that clinical trials also be conducted to support a claim of substantial equivalence for some Class II premarket notification (510(k)) submissions.1

To understand the need for supplying clinical data, it is necessary to consider the definitions of safety and effectiveness in FDA's statute and implementing regulations.2Safety is defined as "evidence that the risks presented to an individual from the use of a product are not unreasonable as supported by information from preclinical and clinical evaluation of the product." Effectiveness is defined in terms of "benefit derived to a significant portion of the affected population through use of the product." In essence, FDA defines safety and effectiveness in terms of a benefit-to-risk assessment of the use of a product based on valid scientific evidence submitted to support a marketing application. This includes the results of clinical trials conducted with the new product.

Products can reach the marketplace through the 510(k) process if a legally marketed predicate Class I or Class II product exists or if the predicate is a preamendment Class III device. FDA determines product classification by evaluating available evidence that establishes whether a given product type is safe and effective. In turn, a device's classification determines the kinds of controls (general for Class I versus special for Class II) that are needed to provide reasonable assurance of its safety and effectiveness. For a given 510(k), demonstrating substantial equivalence is intended to determine whether the new and predicate devices are sufficiently comparable that an independent classification procedure--establishing new safety and effectiveness and controls--is therefore not necessary for the new product.

As the medical device program has matured, the use of the 510(k) route to market has expanded to encompass significant technological developments. This results in differences between a given device and its legally marketed predicate that require additional clinical data to demonstrate equivalence. Through clinical trials, technological differences that could affect safety and effectiveness, and that might otherwise render a device not substantially equivalent, can be evaluated and demonstrated to have no significant effect. Clinical trials can also be used as a special control to allow a device type to be down-classified when it requires only specific clinical data to demonstrate equivalence.

CLINICAL TRIALS SCIENCE

Clinical trials science is an established discipline that provides consistent guidelines for all product types. Scientific principles direct how a study should be designed and evaluated, the basic requirements to include in a clinical study, and the appropriate and valid mechanisms for evaluating the trial data.

Clinical trials should contain well-defined hypotheses that address the intended use of the test product in the population for which it has been developed. Trials should also identify appropriate controls (historical or concurrent) and use a sample size based on the expected effect of the test device compared to that of the control product or procedure. Clinical trials should include a plan for data analysis that takes into account the amount and types of data to be collected. There are instances, however, where all of these elements may not be applicable. It is the responsibility of the trial sponsor to justify why a specific element is inappropriate or unethical.

As has been described in this series, no single valid clinical trial design is appropriate for all circumstances. The scientific evidence needed from a clinical trial should be the driver of the trial's design and evaluation. The claim a sponsor wants to make for a given product and the patient population in which it will be used define the design and scope of a clinical trial. The disease to be diagnosed or treated, the risks associated with the disease and with the product, and other products available to treat this condition also affect design and scope. In addition, the type of data a trial generates will affect the data assessments that can and should be made at the trial's conclusion. Sharply focused questions for a given trial strengthen trial design and analysis.

Because clinical trials are experiments that involve humans, they must be conducted ethically and appropriately to protect the subjects. To be ethical, a trial must develop useful data. It is unethical to conduct human research for its own sake, without a goal for the result of the study. Goals can be to advance knowledge about the natural history of a disease or to assess the diagnosis of or intervention in the given disease state. When conducting research on a new product, a trial's goal is most often to develop valid scientific evidence that demonstrates safe and effective use to support entry of the product into the marketplace. This is true for all health-care products: drugs, biologicals, and medical devices.

ROLE OF ODE

Within ODE the understanding and use of clinical trials in support of marketing applications have evolved. Early on, observational trials conducted on small numbers of patients were the accepted norm for clinical trials. Currently, trials are more frequently concurrently controlled and designed for statistical evaluation. As the industry has evolved and its products have become more sophisticated, the complexity and importance of medical device clinical trials have also evolved.

This increasing complexity has also led, unfortunately, to delays in the initiation of clinical trials. A recent informal evaluation of the causes of such delays revealed several common problems related to getting trials under way. Common problems include

  • Lack of a clear hypothesis.
  • Lack of a mature, well-thought-out trial design that includes how patients will be identified and assessed.
  • Insufficient sample size to support sponsor claims.
  • Weak plans for statistically evaluating trial results.

Trials that cannot produce the data needed to bring the product to market waste time and money and, most importantly, raise questions about ethical patient enrollment.

FDA's medical device program assists sponsors in identifying the questions to address before ODE will grant a new product marketing access. These questions may form the basis on which a manufacturer designs a clinical trial and determines the direction of data development. To obtain data to support safety and effectiveness, sponsors should design clinical trials that incorporate these regulatory questions as well as other issues to be examined. However, FDA does not dictate the details of clinical trial design because the development of each product is unique.

IDE PROGRAM CHANGES

During the past year, the administration of FDA's investigational device exemption (IDE) program has changed significantly. Changes include encouraging pre­IDE submission contact between ODE staff and sponsors and increased use of pilot trials to gather human data with new devices.3

Encouraging earlier interaction between a device sponsor and the reviewing division enables ODE to provide better guidance to the submitter and more background on new products to the review staff. An important issue to discuss during pre-IDE meetings is the timing of an IDE submission. The product design should be sufficiently mature so that only minimal changes take place prior to the submission of the marketing application. Any changes should not significantly affect patient outcomes. If substantive changes are made during a clinical trial that result in significantly different operating characteristics or expected patient outcomes, additional clinical data may be required before ODE will grant market entry. Clinical trials need to address a device's promotional claims and also FDA's need for sufficient safety and efficacy data. Early contact not only serves to identify these needs and the most efficient means of clinical testing but also reduces the time to initiation of a clinical trial.

Increased use of feasibility trials is being implemented in order to eliminate delays in the initiation of clinical investigations caused by poor clinical trial design. To address IDEs for which no significant safety issues exist that should preclude patient exposure to the device, ODE has allowed sponsors to begin trials in a limited number of patients while developing the definitive trial design. Early feasibility trials can answer device design questions about user interfaces or instructions for use. Sponsors can also use feasibility trials to assess data collection forms or identify problems not anticipated during bench assessments or in animal studies.

These and other changes to the program have increased the IDE approval rate from less than 30% in fiscal year (FY) 94 to more than 60% in FY95 (see Figure 1).4 Clinical trials of new devices now start earlier and because of improved communication are better designed. It will take several years, however, to determine whether these changes result in shorter development times for new products, which is the overall goal behind ODE's increased attention to the IDE process.

STAFF EDUCATION

One focus for course development in the CDRH staff college is training in the design and assessment of clinical trials. In order to evaluate a clinical trial, reviewers must understand the theory of clinical trial design, the logistical elements of conducting a trial, and its proper assessment. To this end, reviewers can attend a basic course in clinical trials, a course in basic statistical methods, and a refresher course on the review process.

The basic clinical trials course is team-taught by staff from throughout the agency. Lectures address clinical trial theory; regulatory requirements of IDEs, 510(k)s, and PMAs; practical issues of trial design and conduct; statistical considerations in trial design and assessment; and the appropriate role of the reviewer in these activities. The course acquaints new reviewers with the FDA resources available to assist in evaluation of trial design and assessment.

Among the most challenging topics in the basic course are those that address appropriate trial controls, the amount of data required to support a safety and effectiveness claim, the variety of valid trial designs, and the trial design flexibility available to sponsors. The course discusses actual IDE trials and uses practical exercises to help reviewers learn how to evaluate design approaches. This course was offered twice in FY95 with a focus on enrolling experienced reviewers. In FY96 ODE plans to offer this module several times and to encourage newer reviewers to attend.

The course in basic statistics is also team-taught by senior staff within the agency. Members of the staff college, senior ODE reviewers, and ODE program operations staff will teach a review process course, which includes modules on IDE, 510(k), and PMA review; documentation of the review process; and writing the summary of safety and effectiveness data.

CLINICAL TRIALS GUIDANCE

ODE's outreach to the industry regarding clinical trials requirements for medical devices is also a focus of current and future CDRH initiatives.

Guidances. Guidance documents are one way ODE consistently communicates regulatory requirements. Product-specific guidances (see box) address clinical trial needs for given product types and outline preclinical requirements as well as the format of marketing submissions. CDRH and ODE plan to make the process of guidance development more accessible as well as to develop guidance documents in more areas of device evaluation.

In September 1993, CDRH sponsored a workshop on clinical trials. One aspect of the center's work at that time involved developing a general clinical trials guidance document for industry use. Following the workshop, the center received numerous comments regarding that document. In FY96, the center plans to issue a revised draft of the guidance that focuses on the statistical aspects of trial design. In addition, CDRH will issue companion documents addressing the clinical considerations of general device trials and a special document on trial design for in vitro diagnostics. CDRH is also currently planning a second clinical trials workshop.

Industry Access. During the past several years, ODE has used public panel meetings and open workshops to involve a wide group of individuals with varying expertise in the review process. These meetings have served as a forum for discussion of the specific FDA requirements for safety and effectiveness for a given type of medical device and the extent of data needed to develop appropriate instructions for the health-care community. Such discussions have included appropriate technical information development and labeling for the reuse of hemodialysis filters, the reclassification of immunohistochemical stains, and the testing and labeling of devices containing natural latex.

Clinical Community. ODE has also increased outreach efforts to practice societies and associations in order to involve the clinical community in the development and evaluation of new technologies. Using FDA's Office of Health Affairs and its own resources, ODE has increased the participation of health-care practitioners in both the pre- and postmarket assessment of devices. As a result, the number of individuals cleared to act as special government employees and to participate in panel meetings as consultants and voting members has also increased. These individuals can be called upon to respond directly to ODE review questions that involve products before they reach the final PMA review stage. ODE has greatly benefited from this valuable clinical expertise.

CONCLUSION

CDRH and particularly ODE have focused much effort on device clinical trials design and assessment. The program is intended to facilitate better, more appropriate assessment of new technologies so that safe and effective products reach consumers within reasonable time frames.

Specifically, ODE has developed new guidances for industry, increased the training of CDRH review staff, and stepped up its involvement and communication with the health-care community, the ultimate users of medical device technologies.

REFERENCES

1. Food, Drug, and Cosmetic Act 515(c) and 515(d).

2. Code of Federal Regulations, CFR 21 860.7.

3. "Goals and Initiatives for the IDE Program," Bluebook memo D95-1, Rockville, MD, FDA, Center for Devices and Radiological Health, Office of Device Evaluation, July 12, 1995.

4. Annual Report, Rockville, MD, FDA, CDRH, ODE, 1995.

Susan Alpert is director of the Office of Device Evaluation at FDA's Center for Devices and Radiological Health (Rockville, MD).

ODE GUIDANCES FOR CLINICAL TRIALS

The Office of Device Evaluation (ODE) has more than 200 guidance documents available that provide information relevant to clinical trials. The following list represents a sampling that have been published in the past two years.

Office of Device Evaluation

"Goals and Initiatives for the IDE Program" (July 1995)

"Availability of Investigational Devices" (May 1995)

"IDE Refuse to Accept Procedure" (May 1994)

Division of Cardiovascular, Respiratory, and Neurological Devices

"Coronary and Cerebrovascular Guidewire" (January 1995)

"Cranial Electrotherapy Stimulators" (August 1994)

"Interventional Cardiology Devices" (May 1994)

"Coronary and Cerebrovascular Guidewire" (March 1994)

"Replacement Heart Valves" (December 1993)

Division of General and Restorative Devices

"Spinal Fixation Device Systems" (July 1995)

"Saline-Filled Silicone Breast Implants" (December 1993)

Division of Ophthalmic Devices

"PRK Laser IDEs/PMAs" (July 1995)

Division of Reproductive, Abdominal, Ear, Nose and Throat, and Radiological Devices

"Benign Prostatic Hyperplasia" (November 1994)

"Vasovasotomy" (November 1993)

All ODE guidance documents are available from the Division of Small Manufacturers Assistance (DSMA). To obtain copies, contact DSMA via electronic docket: 800/252-1366 or 301/594-2741; Facts on Demand (telefax): 800/899-0381 or 301/827-0111; phone 800/638-2041 or 301/443-6597; or by mail at 1350 Piccard Drive, Rockville, MD 20850-4307.

INJECTION MOLDING

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Thomas L. Miller

Development Chemist, Technical Service and Development
Dow Plastics, Midland, MI

Injection molding is commonly used to manufacture medical parts in large quantities with reliable consistency. Understanding all the variables of injection molding and their impact on successful processing is particularly important for medical device manufacturers, who require tight tolerances and unique performance requirements. Equipment design, material performance, process variables, and part design specifics all contribute to the performance quality of any injection-molded medical part.

In brief, the injection molding cycle can be broken down into four phases: fill, pack, hold, and cooling/plastication. The process begins with the mixing and melting of resin pellets. Molten polymer moves through the barrel of the machine and is forced (injected) into a steel mold. As the plastic fills and packs the mold, the part takes shape and begins to cool. The molded part is then ejected from the mold, ready for finishing steps and assembly.

Equipment. Several types of injection molding machines are available with different methods for blending, melting, and injecting the polymer into the mold. These are available in a range of sizes, offering choices in clamp tonnage, machine capacity, and screw design, depending on the needs of a particular application. Figure 1 shows a typical injection molding machine.

Materials. Depending on the end-use requirements for a device, manufacturers may select from a broad range of engineering plastics. Since processing parameters vary for each material family and resin formulation, the best results are usually achieved by following the handling and processing procedures recommended by the resin manufacturer.

Processing Parameters. While machine selection, material properties, and part design all affect the outcome of injection molding, five processing variables specific to injection molding can have as much or more impact on the success of this process. These variables are: injection velocity, plastic temperature, plastic pressure, and cooling temperature and time. Control of these variables during each of the four phases of the injection molding process can help improve part quality, reduce part variations, and increase overall productivity.

In Phase 1--fill--the screw advances and plastic flows into the mold. Flow characteristics are determined by melt temperature, pressure, and shear rate. Injection velocity--the rate at which the ram (screw) moves--is the most critical variable during fill. A polymer flows more easily as injection velocity is increased. However, injection velocity that is too high can create excessive shear and result in problems such as splay and jetting. More importantly, heat from a higher shear rate can degrade the plastic, which adversely affects the properties of the molded part.

The way in which plastics flow during fill is also affected by their viscosity, or resistance to flow. Polymers with high viscosity are thick and taffylike; those with low viscosity are thinner and flow more easily. Melt temperature affects viscosity and to achieve the best results should be maintained within the temperature range recommended by the supplier.

Plastic pressure, another variable, increases sharply during fill. The molten plastic can, in fact, be under much greater pressure than is indicated by hydraulic pressure (see Figure 2). It is important to understand the flow characteristics during fill of the material being used and to operate the process consistently.

Phase 2--pack--is when the plastic melt is compressed and more material is added to compensate for any shrinkage during cooling. Approximately 95% of the total resin is added during fill, with the remaining 5% added during the pack phase.

Plastic pressure is the primary variable of concern during the pack phase. The screw maintains pressure in the melt, compensating for shrinkage, which can cause sinks and voids. Variations in cavity pressure are a primary cause of deviations in plastic parts.

It is important to completely fill the mold--avoiding overpacking or underpacking--since packing pressure determines part weight and part dimensions. Overpacking can cause dimensional problems and difficulty in ejecting the part, while underpacking can result in short shots, sinks, part-weight variations, and warpage.

Phase 3--hold--is affected by all five of the process variables described earlier: injection velocity, plastic temperature, plastic pressure, and cooling temperature and time. After the mold is packed, the plastic is held in the mold until it is partially solidified and the gate freezes. The drop in plastic pressure reflects the amount of shrinkage that occurs from cooling (see Figure 2). One way to optimize this phase is to decrease the hold time until the part weight changes. At that point, the gate is no longer sealed and resin backflows out of the mold. If hold continues after the gate seals, cycle time increases, using more time and energy to produce the part. The key is to maintain pressure on the plastic until the gate freezes.

Phase 4--cooling and plastication--is generally the longest part of the molding cycle--up to 80% of the cycle time. Optimizing cooling time can yield substantial gains in productivity. Because the gates are sealed during this phase, cooling temperature and time are the only variables at work. The key to optimizing the cooling phase is to balance the desire to cool quickly against the amount of molded-in stress the final part can withstand.

Design Considerations. While designed for functionality, parts should also be designed to maximize overall strength and simplify the manufacturing process. Significant problems in both processing and performance can occur when the basic principles of good design are overlooked. Following basic design guidelines for nominal wall, corner radii, holes, projections, draft, and gating increases the likelihood that the part will process and perform successfully.

Since end-use factors (e.g., sterilization) can also affect material performance, design elements can be used to compensate for certain shifts in material properties. Design factors that increase localized stress should be reviewed with knowledge of the selected material and end-use requirements.

A simple list of design basics (see box, p. 51) can be reviewed at any time during the product development cycle to focus on fundamentals. While good design doesn't always guarantee molding success, it does contribute to processing and assembly ease, part performance, and overall productivity. *

DESIGN GUIDELINES FOR INJECTION-MOLDED PARTS

The following list offers some basic guidelines for part design. While not all-inclusive, it covers design elements common to almost all injection-molded plastic parts.

Nominal Wall. The overall thickness of the part.

* Maintain a uniform nominal wall.

* Avoid overly thick or thin sections.

Corner Radii. The intersection of any two walls. Necessary for part functionality, corner radii act as inherent stress concentrators.

* Avoid sharp corners.

* Design rounded inside and outside edges.

* Maintain a uniform wall even at corners.

Holes. Openings for attaching components or fasteners, or for providing ventilation or light.

* Avoid sharp corners, which can localize stress concentrators, cause weld lines and shear the material during fill, and induce polymer orientation.

Projections. Any features that stand up off the nominal wall: ribs, bosses, gussets, tabs, and standoffs.

* Avoid projections that are too thick or too thin; they can create problems during processing and impede part performance.

Draft. The degree to which the side walls are tapered or angled. The objective of draft is to make part removal as easy as possible.

* Ensure adequate draft for any aspect of a part that is oriented perpendicular to the mold so that it can be freed from the mold.

Gating. The opening through which the polymer melt enters the mold. There are several types of gates--sprue, edge, flash, pin-point, diaphragm, ring, submarine, and tunnel.

* Consider the several factors that will determine the type of gate used: the number of cavities in the mold, the need for symmetrical filling, the size and shape of the part, and how tight the tolerances are for the part.

EXTRUSION

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published April 1996

Paul Hendess

Senior Process Engineer; Pipe, Profile, and Tubing Systems
Davis-Standard Corp., Pawcatuck, CT

Plastic extrusion is a steady-state process for converting a thermoplastic raw material to a finished or near-finished product. The raw material is usually in the form of plastic pellets or powder. The conversion takes place by forming a homogeneous molten mass in the extruder and forcing it through a die orifice that defines the shape of the product's cross section. The formed material, or extrudate, is cooled and drawn away from the die exit. The extrudate can then be wound on a spool or cut to a specified length.

By contrast with injection molding, which is a cyclic process, extrusion is a steady-state process. Extruded products are long and continuous, and have a cross section that is usually constant with respect to the axis or direction of production. Injection-molded products are discrete items with varying cross sections in each axis.

Equipment. The major components of an extruding system are the drive, hopper, feed screw, die system, and heating and cooling elements. The drive consists of a motor or belt drive, which should be linked to the extruder through a double reduction gearbox; such an arrangement helps to transform the high speed of the motor into the lower speed and high torque required for the extruder. The hopper should hold enough resin pellets or granules to last at least two to three hours; when medical products are being extruded, the hopper's flow restrictors should be left fully open for "flood feeding," which ensures adequate flow of material to the screw.

The feed screw delivers a homogeneous flow of material to the die assembly at a constant melt pressure and temperature. Screw speed is the strongest contributor to raised melt process temperatures, which can result in a weakened extrudate. To ensure good material performance, screw speed should be monitored to keep temperatures as low as possible.

Several types of dies are used in medical product manufacturing, including sheet dies, profile dies, tubing dies, and coating dies. In-line dies (parallel to the extruder path) are commonly used for sheets, profiles, and tubing; cross-head dies (90° to the extruder path) are used for tubing and coating; angle dies (any setting other than 90°) are used when more than one extruder is being employed to make a single product (such as striped or multilayer tubing).

Cooling of the extrudate is most often accomplished through the use of an open cooling trough or a vacuum sizer. Other equipment options include the use of an extrudate puller, which can help the manufacturer control the tolerances of completed products; this can be an important factor in medical device manufacturing.

Materials. Extrusion techniques can be used to process most thermoplastics and some thermoset plastics. The resins most commonly extruded for medical applications include polyethylene, polypropylene, polyurethane, polystyrene, fluoropolymers, polyamide, polyester, and flexible polyvinyl chloride. A characteristic that often differentiates extruded from injection-molded plastics is the viscosity of the plastic at normal processing temperatures. Extruded plastics often have a higher melt viscosity, which allows the extrudate to retain the shape imparted to it by the die while the extrudate is in the quenching stages.

Combinations of various resins can be used to gain special physical, biological, or chemical properties. Many additives can be used during the extrusion process to enhance processing characteristics of the polymer or to alter product properties. Such additives include lubricants, thermal stabilizers, antioxidants, radiopacifying agents, and colorants.

Processing Parameters. The parameters important to extrusion processing are similar to those of injection molding processes. Resin temperature, resin pressure, resin moisture content, screw speed, and screw motor amperage are usually controlled or monitored to provide a homogeneous melt at a controlled volumetric rate. Quenching temperature and the rate at which the extrudate is drawn are controlled or monitored to provide a controlled product size. Dimension measurements, using a variety of gauging methods, can be taken of the extrudate as it is produced. In contrast to injection molding, extrusion can vary the size of the final product without changing the die tooling. Common extrusion production tolerances are within 1% of the nominal measured value.

Design Considerations. Extruded medical products fall readily into two categories: those having just one resin in the product cross section, and those having more than one. The first category includes tubing with single- or multilumen profiles, films for product packaging, and sheets that can be postformed into fluid containers. The second category includes catheter tubing with encapsulated striping, and multilayer tubing, films, and sheets.

Various materials can also be encapsulated within the extrudate to provide additional properties. Fibers can be braided in to increase burst strength. Stainless-steel wires can be added to improve kink resistance or to provide electrical conductivity. Fiber-optic bundles can carry images or illumination. Each of these techniques has potential for use in medical device manufacturing.