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Articles from 1996 In August


On Product Liability: Stupidity and Waste Abounding

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August 1996

The sky did not fall on June 26, 1996. As noted on page 12 of this issue, the Supreme Court's ruling on that date in the Medtronic, Inc. v. Lohr case was indeed unfavorable to medical device manufacturers. But the concept of preemption of liability claims--the notion that the FD&C Act invalidates not only state regulations and statutes affecting devices but also product liability claims--was a relatively new and untested idea. It was a good try, but I don't think the industry lost much.

With preemption as a strategy to combat product liability abuses pretty much ruled out, perhaps attention will be focused once again where it belongs--on tort reform. Last May, the Common Sense Product Liability Legal Reform Act of 1996 succumbed to a veto, but a key component of that act for device companies--the Biomaterials Access Assurance Act--is very much alive. It would essentially eliminate the danger of suppliers being sued for providing materials used in a device they neither designed nor manufactured. With passage of this law, makers of critical materials would presumably resume supplying them to device companies. Chances seem good that President Clinton would sign this bill.

This law would do much to strengthen the device industry and particularly its relationships with materials suppliers, which have, alas, fallen into counterproductive and sometimes inane practices. Although I would like to think these two parties would be standing together against abuses of the liability laws, at the news of the Lohr ruling the suppliers to the device industry let out a collective "Whew!" As representatives of one suppliers group put it, the Supreme Court decision was good for suppliers. Litigious consumers, they reasoned, won't come after them if device companies are not given immunity through preemption.

The relationship between suppliers and device companies implied by this reaction reminds me of the two hikers who were being chased by an angry bear. Asked by his partner why he was stopping to change into running shoes, since he had no hope of outrunning the bear, the other hiker replied, "I only have to outrun you."

In the past week, I've witnessed a similar instance of counterproductive relationships between suppliers and manufacturers. One of MD&DI's sister publications received notification from a major materials supplier that in a new product report the publication had named one of the supplier's trademarked materials in a banned implantable application. When we inquired further, we were told that the supplier had already contacted the manufacturer of the product in question. The manufacturer denied having sent us the information, and speculated that we had used outdated source material.

This response was nonsense, of course. But then, everything about the situation is ridiculous. The material is perfectly good, the product is perfectly good, the business between the two companies benefits both them and the patient--and yet, all their energies are devoted to either preventing the use of the material or denying that it is actually used.

I understand, of course, the legal necessity for this wasteful behavior--I would no doubt do exactly the same. But how tragically absurd that the U.S. liability system has driven them to this extreme.

It's time for both the device industry and its suppliers to put aside any regret or pleasure about the loss of preemption and focus on fighting for the passage this year of the Biomaterials Access Assurance Act. Failure to pass it will only heighten the waste and stupidity of two great and innovative industries unable to cooperate for their greater good, and that of all consumers.

John Bethune

Industry Embraces UPN

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August 1996

Bar Coding

Just a short 18 months ago, the Department of Defense (DOD) announced that by July 1 its suppliers would have to provide universal product numbers (UPNs) on all health-care products. At press time, Lieutenant Commander Mitchell Cooper, DOD's UPN coordinator, predicted that 98% of its suppliers, which include device companies and distributors, would be in compliance. The success of DOD's compliance campaign has sparked a minor revolution in the health-care industry, with 9 major buying groups following DOD's lead in February and another 10 joining in March, according to the Healthcare EDI Coalition.

By mid-June, more than 77% of DOD's suppliers had already complied. Cooper says that because DOD has well over 1000 suppliers and uses 135,000 products, its requirement for the UPN encoded in a bar code has affected a large portion of the device industry. The few companies not in compliance will be granted a six-month waiver if they have already selected their standard, purchased the license to bar code, and have the needed equipment in place. If they have not met these conditions, they will be dropped from DOD's prime vendor program.

Although the device industry had supported the idea of a unique identification system in general, many companies had resisted the move because they would have had to invest hundreds of thousands of dollars to convert from one data structure -- either UCC/EAN (Uniform Code Council­International Article Numbering) or HIBC-LIC (Health Industry Bar Code­Labeler Identification Code)--to another. A break in the logjam came when UCC/EAN and the European Health Industry Business Communications Council agreed last fall to accept either the UCC/EAN or HIBC-LIC data structures as an open standard. According to Bob Hankin, president of the U.S. Health Industry Business Communications Council (HIBCC), the two European groups and their U.S. counterparts have drafted an agreement of cooperation that they expect to sign in the coming weeks.

A recent informal survey of MD&DI Readers Board members showed that of the companies responding, 25% were already using bar codes. A further 66% of the respondents said they would use bar codes in the coming year. Those manufacturers already placing bar codes on their products use the HIBCC standard.

Cooper says DOD doesn't need to know which data structure its suppliers are using. "Suppliers are using both. The structure they choose doesn't affect DOD or any other buyer because the scanners differentiate between whether the bar code is the UCC's numeric symbology or HIBCC's alphanumeric data structure," he says. Hankin says that for the past 10 years the industry has used autodiscriminating scanners that can read many symbologies.

Because both codes will be recognized internationally, manufacturers and distributors don't have to incur any conversion costs. Cooper says manufacturers became enthusiastic about complying once it became clear that there would be an open standard that would not require them to change systems.

Walt Mosher, president of Precision Dynamics Corp. (San Fernando, CA), predicts that most manufacturers and distributors will see substantial cost savings. One of DOD's distributors predicts substantial savings due to decreased product returns. It now gets 8000 returns monthly because a wrong unit or wrong amount was sent. This costs the company about $70 per unit in administrative costs such as restocking. "Eliminating those returns will result in a $6.6-million savings for one distributor on one part of its business," Cooper says.

The 10 newest buyers to require a UPN as a significant consideration in awarding medical supply contracts are Aurora Healthcare (Milwaukee), Catholic Healthcare West (San Francisco), Catholic Materials Management Alliance (St. Louis), Child Health Corp. of America (Shawnee Mission, KS), Health Partners of Southern Arizona (Tucson, AZ), Health Services Corp. of America (Bridgeton, MO), NJHA Group Purchasing (Princeton, NJ), Samaritan Health System (Phoenix), SSM Diversified Health Services (St. Louis), and West Jersey Health System (Camden, NJ).

Mosher points out that hospitals have claimed they don't use bar codes to order products because the manufacturers haven't put the codes on their packaging. He predicts that even more hospitals and purchasing groups will begin to use them now that so many manufacturers and distributors have begun to label their products with a bar code.--Sherrie Steward

Lohr Ruling Creates Doubt about Future of Preemption

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August 1996

Product Liability

According to device manufacturers, industry innovation may be the primary victim of the Supreme Court's ruling in the Medtronic, Inc. v. Lohr case issued on June 26.

In a 5-4 decision, the Court disallowed Medtronic's claim for federal preemption against the state suit filed by Lora Lohr, clearing the way for the case to be heard in the Florida courts. Lohr's suit, which stems from the failure of her pacemaker lead in 1990, alleges that Medtronic is liable for negligent design, negligent manufacturing, and failure to warn, and seeks to recover $1 million in damages.

Industry associations were quick to voice their disappointment. Alan Magazine, president of the Health Industry Manufacturers Association, commented that the ruling "may present a potential step backwards for medical device innovation." On behalf of the Medical Device Manufacturers Association, Wayne Barlow, the association's vice chairman and president and CEO of Wescor, Inc. (Logan, UT), said the high court's decision "is a setback for medical device innovation, and will likely change some elements of research and development for small, entrepreneurial companies."

Officials at Medtronic echo industry sentiment. "We're concerned about the long-term impact on innovation that any complication in regulatory standards would create," says Medtronic spokesman Dick Reid. "If, as a result of this decision, verdicts and settlements in state liability suits tended to set standards--in other words, if one state said that a characteristic of a medical device was inadequate while another state said it was adequate--industry would have to design its devices to meet a very complicated set of standards. It would become more difficult to design new devices, and more difficult to improve the ones we have."

Meanwhile, industry attorneys are poring over the justices' opinions to determine how they will be applied in future cases. "There will be debate over how broadly the decision is read," says Jeffrey Shapiro, a medical device attorney with the firm of Hogan & Hartson (Washington, DC). "Plaintiffs' attorneys will argue that this decision means there is no more federal preemption, and company attorneys will take the opposite view. Neither position will be completely correct. On the one hand, it is clear that product liability claims against a 510(k) device will no longer be preempted. On the other hand, it looks possible--though not certain--that a majority of the justices would be predisposed to find design, manufacturing, and labeling claims preempted for a PMA device."

The remaining uncertainty stems from the fact that the high court justices offered three separate opinions in the case. Justice Stephen Breyer concurred with the judgment of the Court, but offered a separate opinion that split the difference between the other eight justices. Breyer concluded that the Medical Device Amendments of 1976 "will sometimes preempt a state-law tort suit," but did not specify under what circumstances such preemption could be expected.

"In terms of future cases, Justice Breyer is clearly the swing vote," observes Shapiro. "In the past, the circuit courts were split on the issue of preemption for 510(k) devices. The Court's decision in this case denied preemption of claims related to the design, manufacture, or labeling of a 510(k) device, but Justice Breyer's opinion left the door open to preemption for PMA devices.

"Justice Breyer believes that preemption should be granted if FDA's requirements for a device are specific enough. He did not feel that the agency's substantial equivalence process, GMP regulations, or labeling regulations were specific enough to sustain a preemption claim for a 510(k) device. But his opinion suggests that he might rule differently for PMA requirements, which are much more device-specific."

"The closeness of the vote--a 4-1-4 plurality--makes it apparent that the justices could not agree," says Medtronic's Reid. "But once you include the opinion of Justice Breyer, a majority believes that preemption should be upheld in certain cases. And we interpret that as meaning that devices subject to the premarket approval process would fit the requirements for such a case."

"On the whole," says Shapiro, "manufacturers are in much the same situation after the Lohr decision as they were before, in the sense that they can still litigate such cases on their merits. It would have been more surprising if the Court had gone the other way and found in favor of a sweeping preemption, because that would have outlawed virtually all state legal remedies for plaintiffs in cases involving allegedly defective devices. The current decision is closer to preserving the status quo."

With the apparent uncertainty of the high court's decision over when preemption can be claimed, manufacturers will be turning their attention to the case of Mitchell v. Collagen, which raises the preemption question for a PMA product. That case is now before the Seventh Circuit Court of Appeals (Chicago). "If Mitchell v. Collagen eventually comes to the Supreme Court, and the Court agrees to consider it, that could close the loop," says Reid. "Then we would know exactly where we stood, for both 510(k) and PMA devices. Right now, we still don't know."--Steven Halasey

Leadership and Reform: FDA's Ongoing Duty

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August 1996

Robert L. Sheridan

Vice President for Device Evaluation

C. L. McIntosh & Associates, Washington, DC

Virtually everyone, it seems, is in favor of FDA reform. Such sentiments are not new--even within the agency--but the demands being voiced now are qualitatively different from those of the past. To begin with, they are louder, and they are coming simultaneously from many sectors of society. More important, today's demands are aimed at modifying some of the agency's fundamental operating principles.

So far, however, the agency seems unaware of both the magnitude of the challenges it faces and the potential for adverse results if it does not take an active lead in developing its own new operational methods. If FDA does not take the lead in shaping reform, outside pressures will force the agency into broad swings of policy, and into inadequate, inefficient, and inconsistent regulation--much of which will be detrimental to patients and business alike.

RECENT REFORMS

During the past two years, FDA has responded reasonably well to outside pressures, particularly in its device program. The agency is now reviewing premarket notifications (510(k)s) much more quickly than at any time since 1993; wisely or unwisely, it has exempted many Class I devices from 510(k) requirements; it has obtained Health Care Financing Administration reimbursement for investigational devices; it is more amenable to up-front discussions with applicants about their product submissions; and it has modified the very troubling reference list procedures. Given the difficulties inherent in changing bureaucratic systems, these are not small achievements.

With few exceptions, however, the agency has enhanced its performance by fine-tuning established procedures rather than by adopting new models. Third-party review, for example, is a potential new regulatory model. But considerable political force was required to compel FDA to establish its third-party pilot program, and the agency has shown little enthusiasm for expanding that program to more complex devices.

Without implementing some such new operational models, however, FDA will be unable to meet the demands of the 21st century. Most readers would agree that it is neither feasible nor wise for FDA to embrace within its organization all the scientists, statisticians, quality control specialists, and police forces necessary to keep under its central control all the device innovations and related medical procedures that will be developed over the next 50 years. But, even in light of the obviously compelling need to do so, will FDA change? Unfortunately, the nature of the changes made by FDA to date, coupled with what appears to be the motivation for those changes, suggests two troubling answers to this question. Fundamental changes may not soon occur; and, if they do, they will not be satisfactorily effective. Thus, some new strategies should be considered for ensuring that FDA keeps abreast of the public's needs.

OUTSIDE PRESSURES

It is troubling to conclude that most of the changes that have been effected at FDA--with the exception of those that extend the agency's authority--have resulted primarily from outside pressures. Troubling, because such changes tend to have undesirable features and are not optimally effective.

When FDA designs changes only in response to outside pressures, those changes tend to be merely refinements in existing operational methods. Although they may provide relatively minor opportunities for improvement, they cannot alter the agency's system. Regrettably, such reactivity means that FDA is not using its skills and knowledge to develop other options.

Of course, Congress can force the agency to alter its basic operating principles by amending the Federal Food, Drug, and Cosmetic Act. But without FDA's constructive participation in developing such legislation--and sometimes even with such participation--Congress will often miss the mark. All too often, the burden of creating such legislation falls to congressional staffers who do not have intimate knowledge of FDA's regulations and operations, and the laws they write frequently create unanticipated problems, fail to solve the problems they were intended to solve, or even fail to address the very issues most critical to improving FDA operations. In addition, political and philosophical persuasions on Capitol Hill can change remarkably fast. Congress cannot be relied upon to manage FDA steadily over an extended period, nor is it really supposed to do so.

The relations between FDA and Congress become still more complicated when one factors in the considerable pressures of the executive branch and the media. In the past, whenever the legislative and executive branches have been under the control of different political parties, Congress has endeavored to embarrass the various federal agencies under the control of the administration. This has been a major factor underlying many of the oversight hearings conducted to deal with both real and fabricated FDA failures, and the agency has rarely had the fortitude or skill to withstand such congressional criticism or to win the battle for public opinion. In the face of such intense media scrutiny, it has been easier for FDA to move to a higher level of regulatory control than to explain why a program that tolerates well-calculated regulatory risks is more beneficial than injurious.

ADVANCING REFORM

With elections looming once again, it is not unreasonable for the device industry to be concerned about what might happen in 1996. Should the results of this November's elections be the primary influence on defining FDA's programs for the next several years? Should the next commissioner's personal philosophy, political aspirations, or capacity to face down potential criticism dictate the nature of the agency's programs for the foreseeable future?

Fortunately, FDA need not be at the mercy of such events and personalities. The agency can accomplish true advancements in its device program by effecting its own changes, which should include the following:

* Depoliticize the agency's device regulation program.

* Create a balanced media program to inform the public about the risks inherent in new medical-care systems, even in a regulated environment.

* Offer greater latitude for physicians to practice medicine without FDA intrusion, even when the procedures require liberal discussion, labeling, and use of general- purpose or physician-manipulated devices.

* Make greater use of outside resources to accomplish FDA's mission.

* Recognize that marketing approval should not be the centerpiece of device regulation.

In turn, achieving these goals will require two further accomplishments: a closer, ever-present cooperation among academicians, health professionals, manufacturers, and federal regulators; and an FDA management system designed to ensure the constancy and effectiveness of agency activities and to continually evaluate adjustments to the system.

One way of improving the odds that any of this will happen is to have FDA managed by a commission rather than a commissioner. Such a commission could be designed in any number of ways. For instance, it could be required to include representatives of academia, the health professions, industry, and FDA's civil service. Its members could have tenures that would expire nonconcurrently and overlap presidential terms.

Functionally, such a commission could compel FDA to consider all of society's needs when making policy, and would make the agency more responsive to changes occurring in the environments represented by its members. It would be charged with maintaining stability and order, but also with continuously considering how FDA should adjust its operating programs. Most important, it would eliminate the potential for FDA policies to be dictated by a single person throughout his or her tenure.

CONCLUSION

The idea of instituting a commission at FDA deserves serious consideration. But however compelling the arguments in its favor, it is still only one of many such reform proposals that should be explored. What is more critical is that all such ideas be made the subject of study within the agency. FDA needs to change itself, but it cannot do so without the introduction of some institutionalized method for achieving that end.

WASHINGTON WRAP-UP

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August 1996

James G. Dickinson

Although the Federal Trade Commission (FTC) was assigned by Congress to be the lead agency in regulating the marketing of medical devices, FDA's expansion into this area has proceeded swiftly, and without apparent FTC protest, since agency commissioner David A. Kessler came aboard five years ago.

Until Kessler's arrival, FDA's Center for Devices and Radiological Health (CDRH) had no office dedicated to device marketing practices. In setting one up, Kessler drew from the expertise long established in the agency's Center for Drug Evaluation and Research (CDER)--specifically, its Division of Drug Marketing, Advertising, and Communications (DDMAC). The result of Kessler's efforts, the Promotion and Advertising Policy Staff (PAPS) of CDRH's Office of Compliance, is now firmly established and operating in much the same way as DDMAC--but more controversially.

One reason for the greater controversy is the symbolism of this development. Not only can the setting up of PAPS be interpreted as an encroachment of a more stringent agency on the laxer FTC's turf, but it also magnifies the perception of the "drug-izing" of medical device regulation.

Although there's little in writing to substantiate their argument, critics of FDA's expansion contend that in the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act), Congress intended the agency's role in the regulation of device marketing to be small. The amendments therefore limited FDA's activities to "restricted" devices (which Congress did not define), and then only to the actual advertising of such devices, not their promotional labeling. Congress, these critics say, intended FTC to have exclusive jurisdiction over the marketing of most devices. Since 1976, FDA has exercised its authority over restricted-device marketing only once, to regulate the advertising of hearing aids.

But nature, it is said, abhors a vacuum. And so, apparently, does FDA. With no definition of restricted devices in the FD&C Act, and with Kessler deciding to harmonize his agency's approach to regulation across product lines in order to achieve the greatest possible uniformity, it followed that the weaker and less-defined area (devices) would soon be invaded and filled by the operating policies of the stronger and more explicitly defined area (drugs).

Why FDA did not use the FD&C Act's restricted-device provision as the basis for formally embracing more devices than hearing aids is anybody's guess. Perhaps it was just easier to restrict certain devices informally, through the terms of their approval letters--which is what FDA has been doing for devices that enter the market through the premarket approval (PMA) process. In reality, though, it is probable that FDA did not deliberately set out to acquire restricted-device classifications in this indirect manner during the time between passage of the 1976 amendments and the accession of Kessler, but rather developed the strategy only after he came aboard.

This retroactive harvesting of informally restricted PMA devices did not give FDA a large slice of FTC's turf, however. By far the overwhelming majority of new devices enter the market through the so-called 510(k) process, under which their manufacturers merely have to declare them "substantially equivalent" to predicate devices that were on the market before May 28, 1976.

In the case of PMA devices, FDA's tactic has given it an inventory of hundreds of devices that have been informally restricted through their approval letters. With nothing in the FD&C Act to contradict this approach, nobody in industry has yet sought a reversal in federal court.

In this respect, the medical device industry appears to have much in common with the drug industry, which has been reluctant to sue FDA over such regulatory adventures as appear to infringe on companies' First Amendment rights. Both industries, when encroached on by FDA, shrink from mounting a frontal legal challenge, reasoning that the agency that guards the gateway to their products' markets is not to be irritated unless a company's livelihood depends on it.

Kessler's harmonizing of FDA strategies with respect to drug and device marketing practices was reinforced by the posting of two highly skilled drug advertising experts, Arthur Yellin and Kenneth Feather, from CDER's DDMAC to CDRH's fledgling PAPS. Each served successive short-term assignments, Yellin first, then Feather.

DDMAC and PAPS now operate similarly as a result of this cross-pollination, but Feather observes that there are significant differences caused by the different statutory authorities. Since FDA doesn't have the same statutory authority to preclear new-device launch materials as it has to preclear such materials for new drugs, PAPS has no role in market launches. And, Feather notes, it does not issue as many advisories to marketers as DDMAC does. But it does listen to the same snitching among marketplace competitors as DDMAC does, and it monitors journal advertising as well as professional and trade presentations with the help of FDA field offices around the country.

PAPS director Byron Tart says that his staff, like DDMAC's, regulates "intended use." This means that if a device manufacturer uses an advertisement to change a product's intended use under 21 CFR 801.4 ("Special Requirements for Specific Devices"), then "we don't go after the advertisement itself, but we will comment on the fact that the intended use has been changed and that the manufacturer/ distributor may have misbranded or adulterated the device as a result."

This approach apparently gives PAPS a way of broadening its reach beyond PMA devices. "The intended use of a device," Tart explains, "can be changed by a manufacturer through advertising, statements that are made, including oral statements, and by whom they sell it to. So if a manufacturer changes the intended use, we would go after it because the labeling doesn't cover that intended use and neither does the 510(k) or the PMA application."

Another similarity between PAPS and DDMAC is that both employ letters to industry that contain nonpublic enforcement information. DDMAC's use of such letters is of longer standing and is more aggressive (and controversial) than PAPS's, often bypassing the use of conventional warning letters, which are public and therefore provide useful instruction on specific regulatory actions to nonparticipants.

Recently, DDMAC decided that its untitled letters may be accessed under the Freedom of Information Act (FOIA), thus releasing to requesters much valuable insight into practical interpretations of agency marketing policy. Then, in May, PAPS also OK'd access to its untitled letters under FOIA, releasing a batch of 22 to this writer.

These letters, like those of DDMAC, show a consistent pattern of FDA concern about off-label uses. For example, a February 5, 1996, letter to Fukuda Denshi America Corp. (Redmond, WA) complained that two information manuals not necessarily authored by the firm but distributed by it contained statements promoting the UF-4500 ultrasound scanner for intended uses not covered by the product's 510(k) application. PAPS consumer safety officer Steven Budabin wrote:

We also note that Fukuda Denshi has distributed promotional materials and has funded seminars and symposia which promote the UF-4500 for off-label uses. Although the agency does not regulate scientific and educational activities, it does regulate promotional activities by manufacturers.

Therefore, manufacturers may not provide equipment or devices for hands-on training purposes either directly or indirectly, to another distributor or supplier with knowledge that those devices will be used in a manner which promotes an off-label use.

Similarly, a manufacturer may not promote a device by distributing literature, publications, brochures, pamphlets, or other written materials which discuss the unapproved use of a device. Fukuda Denshi may, however, distribute reprints of journal articles in response to unsolicited requests from health-care practitioners.

Budabin's letter also objected to the company's use of its initials, FDA, throughout its literature, "since those initials may easily be confused with those of the Food and Drug Administration. You should be aware that reference to FDA in advertisements or other promotional materials for medical devices is prohibited by the [FD&C] Act and represents misbranding under section 502(a)."

In the past, in both DDMAC and PAPS, such regulatory instructions to companies would probably have routinely been handled through public warning letters. The growing use of untitled letters for such purposes spares recipient companies some embarrassment and possibly induces better company cooperation by being less publicly chastening. At the same time, however, such use deprives interested bystanders of the education that comes from watching others' mistakes being made and corrected.

As a matter of fairness, when FDA releases untitled correspondence under FOIA it should also provide the recipient companies' responses. DDMAC has been doing this but PAPS did not, at least in this first instance. This may not be PAPS's fault, however. FOIA requesters should explicitly request not only FDA letters but also the company responses.

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

The Role of Product Testing in CE Marking

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August, 1996

Greg Freiherr

Except for the simplest of medical devices, such as tongue depressors and wheelchairs, there is no direct route to a CE mark--no easy way to win approval to sell that product in the European Union (EU). Many companies on this side of the Atlantic are being advised by consultants to seek certification of their quality manufacturing systems under ISO 9000 or EN 46000, certification that can cost hundreds of thousands of dollars. But quality systems certification in itself does not ensure a CE mark. Obscured by the political shadow cast by certification is a second process that is essential to obtaining the CE mark. When performed correctly--and strategically--this process can shorten the route to obtaining a CE mark and can cut the cost of getting a product to market in Europe. It involves testing products to obtain data that support the application for a CE mark.

Simply put, product testing ensures that a device presents no danger to the patient and end-user from a number of possible hazards--biocompatibility, electromagnetic compatibility, electrical safety, mechanics, functional safety, and performance. "There is a difference between FDA efficacy and the European approach to performance," says Victor C. Clements, vice president of international business development for Technology International, Inc. (Swindon, UK). "Europeans are not concerned about whether a product is beneficial--just that it performs as intended."

The product manufacturer determines which tests should be conducted based on the type of device. Clements explains that the product test plan is really a matter of common sense founded on a clear understanding of the product and its use. For example, an implantable pump would likely require data supporting biocompatibility, electromagnetic compatibility, and sterility, as well as addressing product safety issues. "There is no list or guidance for specific devices," Clements says. "It is up to the manufacturer to figure out."

But the manufacturer is not entirely alone. Notified bodies will review a preliminary test plan put together by a company. They may even recommend various approaches for testing. The best consultants will go even further, developing a complete regimen of tests in the context of a proposed quality system that fits the company's goals. "The first thing we do is try to understand where the company is in terms of its own operations to determine strategically which is the best way to go," says Donald F. Grabarz, managing partner of International Regulatory Consultants (Salt Lake City), a consortium of consulting firms in the United States and United Kingdom.

Use of a consulting firm can prove to be critically important to a company because of the myriad choices that must be made when pursuing a CE mark. Product tests, for example, might be done by the company itself in its own lab or in a nearby lab that specializes in the tests needed. In fact, a responsible company developing high-quality products is likely to have performed many of the tests necessary to gain a CE mark as a natural part of its product development.

But there is a catch. To be valid, test results must meet certain standards established by the EU. One way to establish that validity is for the manufacturer to conduct the testing according to criteria that meet the applicable EU directives--for example, the Medical Devices Directive and the Active Implantable Medical Devices Directive. Another way is for the notified body to send one of its engineers to the manufacturer's facility to do the testing. The German notified body TÜV Essen, for example, offers such on-site testing, with the balance of the investigations and submission of additional documentation done by phone, fax, or mail.

Unfortunately, there is no way for a company to know up front the preferences of any one notified body. "There is no formal structure, no one telephone number that anybody could call to find out," says Clements. "The best advice is to contact the notified body at the outset or get in touch with a medical device consulting company."

It is at this point that the product testing phase can become as daunting and laden with bureaucracy as the process for certifying quality systems. Each of the major players involved in quality systems certification plays a similar role in product testing. A competent authority, which is to a European country what FDA is to the United States, selects notified bodies--nonprofit organizations that issue CE marks for specific products. These notified bodies also audit testing laboratories to ensure compliance with criteria associated with the Medical Devices Directive--which includes by reference both the EMC and Low Voltage directives, for example--or the Active Implantable Medical Devices Directive. Labs anywhere in the world that have been and continue to be audited by a notified body can conduct testing for that notified body to obtain the data needed to support a CE mark application. Or the notified bodies themselves can conduct the tests. TÜV Rheinland, for example, offers two major test laboratories--one at its North American headquarters in Newton, CT, and the other in San Francisco. Smaller labs are located in cities throughout the United States.

When it comes to electromagnetic compatibility (EMC), the vernacular expands further to include competent bodies, which fall somewhere between notified bodies and testing laboratories. These competent bodies are essentially engineering firms that make technical decisions related only to the EMC Directive, explains Walter Poggi, president of Retlif Testing Laboratories (Ronkonkoma, NY). "You need the competent body in EMC because EMC is a generic directive and it can spread over a very broad product spectrum," he says. "It can apply to many types of products and multiple product families."

All these players come together on a global stage, acting out different roles under different circumstances. In product testing, notified bodies often accept data gathered by a company through the efforts of its own laboratory staff. "Our job is to review those data and go on-site and look at the systems that are in place," says Steve Anderson, director of the North American medical division for TÜV Product Service (New Brighton, MN). "We look at the way test equipment is set up and the way the data were procured. On that basis, we decide whether the data are acceptable." If the data were obtained from a laboratory hired to do the testing, the notified body may go on-site to do a quality systems audit to ensure that the laboratory is qualified and competent.

That can all be avoided, however, through a process called self-declaration. This process is the simplest way to obtain a CE mark. As might be expected, however, self-declaration can be applied only to medical devices that pose little or no hazard. These devices are usually placed in Class I, which is dominated by nonactive, unpowered devices that do not penetrate the body (although some low-risk powered devices are included in this classification). A company seeking a CE mark for such a device may choose to self-declare its compliance with the appropriate directives.

Such a declaration does not mean product testing was avoided, but rather that the laboratories doing the testing did not need to go through the process involving the notified body. In fact, self-declaring compliance means the company can skip the notified body entirely. Because Class I devices pose little hazard to patients, an error in the CE marking process carries few consequences. "When you get into a low enough class, they figure even if a company does something wrong, there is not that much risk to the patient," Anderson says. The only exceptions are if the device conducts some kind of measurements or requires sterilization, in which instances it is necessary for the product to be assessed by the notified body--but only according to the directives that apply to measuring devices or sterilization.

But just as self-declaration is the simplest method, so is it the one most prone to error. In rushing to obtain a CE mark, a company may not conduct all the tests necessary to identify hazards. If an incident then occurs with the device, the procedures and test data to support the self-declaration will be requested by government, and the company will be liable if an error was in fact made.

That is not a problem for the manufacturers of more sophisticated devices, such as those residing in either Class IIa or Class IIb (medium risk) or in Class III (high risk). Class IIa devices are generally nonhazardous active devices. If they are surgically invasive, their use does not exceed 30 days. Class IIb is composed of potentially hazardous active devices--for example, those transmitting x-rays, or surgical devices carrying higher risk. Class III devices contact the heart, vascular, or central nervous system, or are invasive for long periods.

When assessing these devices for the CE mark, product testing takes on added significance. It is the means by which critical questions about the safety of the device are answered to the satisfaction of the notified body. And just as there are many ways to test a device, so are there many ways to use product testing to obtain a CE mark.

Typically, data attesting to the safety of the device are submitted to the notified body as part of a design dossier, which is reviewed for completeness and validity. According to TÜV Product Service's Anderson, this dossier is a complete listing of all the test data--animal data, clinical data, and design description--that have to do with a device. If all the required data are not included in the dossier, the company has the option of conducting additional testing itself, having the notified body conduct the additional testing, or hiring an independent testing laboratory approved by the notified body.

But in such a circumstance, testing alone, no matter how rigorous, cannot in itself win a CE mark. Before issuing the mark, the notified body must be confident that the product tested is representative of the product being routinely manufactured by the company. This usually means that the notified body must then certify the quality system associated with the manufacture of that product. For medical devices, this entails certification according to EN 46001, a standard written for the medical device industry that includes a variety of components--including postmarket surveillance as well as design considerations found in the broader ISO 9001 standard.

Alternatives to undergoing a full-blown quality systems assessment exist, however, and may be especially appealing to companies that are trying to get a product onto the European market to test its marketability and that may not want to commit to a long-term investment in that product. In such a case, the company may have several options, depending on the risk presented by the device. If the device falls into Class IIa, the manufacturer can declare conformity to the applicable standards and then have a notified body audit only the manufacturing and inspection processes, says Clements. If it is a Class IIb or Class III device, the company must choose between going the full QA route with a certification of the quality system by the notified body or seeking what is called a type examination. "That usually means you give your device to a notified body, and they do the testing to make sure the device meets the standards that Europe has established," says Anderson.

One form of type examination involves 100% testing of the product as it rolls off the factory line; the other involves batch testing. The first form is most applicable to companies producing a low volume of units, perhaps a dozen or so per year. In that case, the notified body would test each unit to determine whether it meets the appropriate standards. The second route, batch testing, is based on statistical analysis. If, for example, 1000 units were produced, testing a batch of 100 might be enough to ensure that the product meets European requirements for the CE mark. "This provides an almost superimposed quality control system, statistically sampling the product as it comes off the production line," Clements says. It does not, however, free the company from the need for a quality system. It merely has a less-demanding quality standard to meet. Rather than complying with EN 46001, which includes design controls, the company using type examination would only have to meet EN 46002, which is specific to quality manufacturing and does not include design.

Type examination can be extraordinarily costly and time consuming, given the need for continuing tests. This is especially true in the United States. While many European-based laboratories consolidate a variety of testing under one roof, such laboratories are the exception in the United States. Here, labs tend to perform only certain tests, meaning that a device may have to be tested by more than one of them.

This is a concern not only when conducting type examinations but in all aspects of product testing, because notified bodies tend to accept the results of only those labs that they have accredited. Consequently, an American company could have its product tested at several laboratories to obtain data to cover the different requirements. Each laboratory may be an expert in its field, and each may be accredited by a different notified body, but when the time comes to present the data to support a CE mark for a product, only a portion of the data may be acceptable to the chosen notified body.

This underscores the need for strategic planning early in the process. By law, notified bodies are prevented from consulting with manufacturers. "In general, we will help them define what is required," says Reiner Krumme, division manager for medical devices at TÜV Rheinland of North America, Inc. "We can talk about all possible approaches and how to approach the conformity assessment procedures. That is public information. But we cannot do any kind of consulting."

That has led some companies to seek out consultants, who promise to guide the company through the process of obtaining a CE mark. One consulting firm that appears to be ideally positioned to provide that advice is Technology International, which is affiliated with SIRA Certification Service (South Hill, Chistlehurst), a notified body operating out of the United Kingdom. "We are being trained so we understand what their approach is so that we are almost transparent as far as the customer is concerned," Technology International's Clements says.

Technology International's parent company, Interference Technology International, Ltd. (ITI; Swindon, UK), is a competent body that conducts EMC testing. ITI has a similar affiliation with SIRA, a notified body under the Medical Devices Directive for certification of quality systems to EN 46000 and for product conformity within the biomedical and electromedical fields. In this role, ITI is a testing house that generates data regarding EMC and, as such, does not provide consulting to clients.

Nothing is simple when it comes to getting a CE mark, not even choosing a notified body to review the test data. Notified bodies are not all notified for the directives relevant to medical device companies, a fact that may not be apparent until after the notified body is contacted by the device company. Also, notified bodies may only be notified for some medical devices, such as passive or active devices, or invasive products.

Similarly, not all notified bodies even do testing themselves. The National Standard Authority of Ireland (NSAI; Dublin), for example, decided a long time ago against doing any product testing, and there appears to be no chance that it will reconsider that decision anytime soon. "We have too many other irons in the fire," says Richard Bernier, director of U.S. operations for NSAI. "This is just one scope of registration--we have the automotive requirement, the machinery directive, the low voltage directive, the EMC directive, everything." Bernier notes, however, that NSAI will accept test results from recognized testing laboratories.

Companies seeking permission to market their products in the United States do not have to contend with such concerns. FDA has not spelled out specific requirements for testing laboratories, preferring to focus instead on the methodology used to verify that the data are accurate and valid. FDA's steadfast adherence to that approach may benefit American companies elsewhere in the world, as international efforts aimed at developing mutual recognition agreements (MRAs) among global regulatory agencies would ensure that a product cleared for marketing in one country would be cleared for others that have MRAs in effect. "The goal of mutual recognition is that a European would be able to go to a European laboratory and have a product approved for the U.S. marketplace and vice versa," explains Poggi. If that happens, the confusion currently surrounding product testing might just disappear.

Greg Freiherr is a contributing editor to MD&DI.

INDUSTRY PROFESSIONALS GAIN GROUND AGAINST CHANGING MARKET

Eighth Annual MD&DI Salary Survey

Steven Halasey

Introduction
Salary, Raises, and Compensation
The Employee | The Company
Conclusion | Survey Methodology
Order the Full Report | Salary Estimator

Device industry professionals who have been wondering what will be the effects of such industry megatrends as health-care reform, buyer and supplier consolidation, downsizing, and globalized competition need do so no more. To find the answer, it turns out, they probably do not need to look much farther than their pocketbooks.

According to the results of MD&DI's annual salary survey for 1996, during the past year device industry professionals received salary increases averaging 6.2%, and more than half of such employees also received bonuses averaging $7890. Meanwhile, total compensation in the device industry grew at a rate of 2.5% to an average of $83,400, besting last year's figure by $2000. But according to the same survey, overall salary growth during the year was nearly flat, improving by only 0.5%.

The story of what happened to device industry compensation over the past year is told not only in the data compiled for MD&DI's survey, but also in the answers of respondents to the survey's open-ended questions. Asked what industry trends would affect their personal compensation during the coming year, more than two dozen respondents replied that their chief concern was "consolidation" of either device companies or health-care provider organizations--or both. Another two dozen respondents expressed worry about the effects of "downsizing," and a dozen more answered simply "health-care reform."

While the direct implications of these megatrends for employee compensation during the past year cannot be determined from MD&DI's survey, it is clear that respondents to this year's survey understand well their potential effects. "Consolidation in the industry," wrote one respondent, "will reduce percent of raises and bonuses." And another commented that consolidation will reduce the number of available positions, creating a "higher supply of qualified employees for smaller number of positions, reducing salary growth."

The following article describes some of the general results of MD&DI's salary survey for 1996. But the survey report actually contains much more, including tabular breakdowns for each of the seven job categories surveyed. Copies of the full report are available from Canon Communications.

Next: Salary, Raises, and Compensation

MEETING THE CHALLENGES OF MEDICAL PACKAGING

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August, 1996

MD&DI ROUNDTABLE

For packaging engineers, meeting the demands of an increasingly globalized device industry brings a wide variety of challenges. Faced with conflicting regulatory requirements, device packagers are actively engaged in efforts to create internationally recognized test methods and harmonized standards that will make their packaging acceptable anywhere in the world. At the same time, cost pressures in the medical marketplace are compelling materials suppliers and packaging engineers to explore new materials and package configurations that can reduce the expense of packaging without compromising device safety.

To examine these and other issues, MD&DI invited a panel of experts in the field of medical packaging to participate in a roundtable discussion. Brought together in conjunction with the MD&M East Conference and Exposition in New York City last June, the panel was moderated by MD&DI executive editor Steven Halasey.

The seven participants were Paul Fielding, regulatory affairs manager for Rexam (Bristol, UK); Joyce Hansen, director of the Sterilization Science Center for Baxter Healthcare (Round Lake, IL); Curt Larsen, principal packaging engineer for SIMS Deltec (Minneapolis); Hal Miller, director of packaging technology for Johnson & Johnson (New Brunswick, NJ); Barry Page, consultant and North American representative for mdc Medical Device Certification, a notified body that is headquartered in Memmingen, Germany; Mike Scholla, Tyvek medical packaging segment leader for DuPont Nonwovens (Wilmington, DE); and John Spitzley, associate fellow of packaging for Medtronic, Inc. (Minneapolis).

Questions posed by MD&DI are in bold, with the participants' answers following.

THE SUPPLIER'S ROLE

With the acceptance of international standards such as ISO 11607, compiled by the International Organization for Standardization (ISO), is the device industry on the verge of having harmonized requirements for packaging?

Page: A lot of work is being done in this area by ISO, going beyond what was done by CEN [the European Committee for Standardization] in Europe. When standardization first became a concern for manufacturers, FDA made a move to examine expiration dating of packaged devices on the basis of their ability to maintain sterility. One of the first articles that the HIMA Sterile Packaging Working Group put together raised questions about whether this was a realistic goal.

Larsen: According to early statistics, the number of recalls and problems resulting from packaging problems was horrendous. Industry has come a long way since 1974 or 1975 when people really started implementing good manufacturing practices [GMPs], but gathering the data and doing the testing needed to make dating claims is a laborious process.

I would like to see more of that work done by materials suppliers. Right now, they say they can't do it because they don't know what kind of machinery the material will be run on, how the material is going to match up with other materials that will be added to it, or what kind of processing it'll go through. I agree that that's a huge area of concern, but even data that were limited in scope could be useful in answering technical questions or dealing with regulatory issues.

Miller: It would certainly be a service to the medical device industry if materials suppliers would perform broad-based stability and long-term aging studies on their materials with different sterilization methods. When suppliers want to sell me a particular product, many times my first question is "What's in it for me?" The fact is that I would have to put a lot of resources to work in order to test and evaluate the product, and that's expensive. However, if the supplier has already done some of that testing, it becomes an extremely valuable service to manufacturers.

Fielding: Rexam certainly does some materials testing, but there's not a formal procedure. We target the characteristics that are critical to us and consider a range of sterilization procedures. Some such testing is a lot better than nothing, and it gives some degree of confidence. But it's inhibiting knowing that, if we test for several years, the materials will have changed by the time we're halfway done. The big questions are how the testing is done and for how long. If you're talking about real-time testing for periods as long as five years, then chances are the materials would've changed anyway.

Miller: Well, your material may have changed, but device manufacturers would still be using it. We still conduct the five-year shelf study and the accelerated aging study. If nothing else, suppliers could perform the accelerated aging testing so we can at least get to market. Any testing we can do to shorten the lead time from development to getting that product to market--whether through our suppliers or within our own organization--is a benefit.

Hansen: Part of the problem with real-time versus accelerated aging studies is that there's not a standard industry procedure for aging materials. A technical information report is being compiled by the AAMI [Association for the Advancement of Medical Instrumentation] Radiation Sterilization Working Group, which could potentially be accepted as a standard for accelerating aging procedures. While it's only guidance information, it would be beneficial in that people would use similar methods and could share data and give continued guidance on how to perform these studies.

Miller: From what I've seen of the AAMI document, it will give some credibility and substantial background for using the Q10 theory for accelerated aging, and for using a Q10 value of 2.0 as a very conservative approach to accelerated aging.

Hansen: At the very least, it would be a guidance document that people could refer to. And if materials manufacturers were to follow suit, it would be even easier to compare data.

Spitzley: But if a company were to take an aggressive approach, and later the standard became more conservative, would the materials that were evaluated using a faster accelerated regimen have to be retested?

Miller: That's an individual company judgment. The document will also outline boundary limitations for temperature, and manufacturers must look at their material characteristics and compositions to judge whether they've exceeded those boundaries. If the boundaries haven't been exceeded, then the earlier evaluations should be fine.

Will FDA accept that kind of generic test when a company wants to switch a material? How refined is the agency's demand for a material's characterization?

Scholla: ISO 11607 outlines certain information that must be supplied by a material manufacturer. As a result, our company is developing a manual that shows how its material meets the ISO standards and that includes technical data to support that information. FDA will expect that, if I supply device manufacturers information about the microbial properties of Tyvek, it's not going to change unless there's an interaction between the rest of the packaging materials or the device in the material.

However, we can't test every conceivable combination. So our plan is to generate data on the stability of a select number of package types, using various sterilization methods, in order to provide information that will be useful to the device industry in reducing the amount of work it needs to perform.

But presumably, if someone wanted to shift to a material that wasn't Tyvek, that material's manufacturer would have to be supplying similar information.

Spitzley: Yes, but it's not only materials. In a lot of cases it's an adhesive, and the same situation applies. If, under a broad range of parameters, an adhesive supplier can demonstrate that he's tested his material and it remains relatively stable over time, then the manufacturer just has to demonstrate that any processing he's doing doesn't interfere with that stability. Such a procedure would make it a lot easier for everybody. Currently, however, users must generate all those data for themselves, and that's time-consuming and expensive.

Larsen: And those data aren't shared between companies--each company performs the same tests. It's certainly a duplication of effort. If testing results were available from materials manufacturers, it would reduce the workload industrywide.

Miller: Often the types of materials used aren't as extensive as manufacturers think. While there are a lot of adhesive coatings on films and papers, there are certain films that are fairly standard. Data on these films would be a great benefit, because companies wouldn't have to continually reinvent the wheel.

Who would put together that sort of packaging materials compendium?

Miller: Device manufacturers aren't really looking for one packaging materials compendium. Instead, they would like suppliers to focus on selecting materials to create the overall package, not just one part of the package. Suppliers are the ones who really control the formulations for their particular product line. Maybe they don't want to share that information with other competitors, but they could still share it with device manufacturers.

Spitzley: It would be helpful if suppliers provided a guideline sheet that outlined their material, testing procedures, equipment it was sealed on, sterilization processes, sealing parameters, and so on. Then, if a manufacturer's packaging fell within those ranges, the company wouldn't have so much testing to do. If it chose to go outside those ranges for a particular application, it could provide that gap in the data without having to repeat the entire testing procedure every time.

Larsen: Believe me, if two companies come through my door and only one has this sort of guideline sheet, the one that makes it available to me will be the primary candidate to get its materials in-house. So such information is certainly a valuable marketing tool for these materials manufacturers. Of course, manufacturers want to be able to compare the data from vendor to vendor to make sure they're comparable.

STANDARDIZED TESTING

In the area of test methods and sterility barriers, what's the next step? Has FDA made some moves to accept physical testing?

Hansen: Medical companies have used many test methods, some of which have not gone through the qualifications and validations necessary to ensure they can detect the maintenance of a sterile barrier. Improving, qualifying, and validating those test methods will be the push for the future. One recently published ASTM [American Society for Testing and Materials] test method allows researchers to rank the ability of materials to maintain sterility, but each company must then determine what level is acceptable for it, and these acceptable levels are likely to vary.

Spitzley: FDA has indicated orally that it's open to accepting physical testing, although it hasn't elaborated on what conditions would apply to such testing. However, I doubt there's ever going to be one method for evaluating the integrity of sterile packages because packaging systems can be complex. What's more important than trying to establish one worldwide standard is ensuring that such testing is documented and validated.

Who would actually be carrying out the testing you're talking about? Is it the manufacturer of the materials, the device manufacturer, or both?

Larsen: Both. People who are manufacturing and shipping the materials have certain requirements they must meet, based on their customers' specifications. When the customers get the material, they then perform tests and evaluations to make sure the requirements were met. So there need to be standardized systems at both ends of the pipeline to evaluate the materials. There's currently an effort at the ASTM F2.6 subcommittee level to standardize such methods.

How refined is the system now for characterizing materials? Can you distinguish between different blends of materials, or is there a need to so?

Miller: There's no real need to distinguish between different blends of materials. Each company has a specific material that it needs to perform a specific function. Depending on the physical or chemical properties of the product or its sterilization process, manufacturers may need to look at tensile, tear, or seal strength, or at puncture or impact resistance, and so on. These factors are more important than whether the material is a certain kind of coextrusion blend.

Hansen: I agree, but with the ASTM test method researchers can rank and compare materials. The method is sensitive enough to determine how well materials perform as barriers. But, as others have said, industry will still be faced with deciding what is acceptable.

Scholla: It will be impossible to agree upon a value, regardless of how many test methods there are, because the devices on the market, their distribution channels, and how long they last in the life cycle vary. Some products have a 3-month shelf life and probably don't need the same microbial barrier that is needed for products that have a 10-year shelf life. If that material will maintain the sterility and package integrity as well as the sterility of the device inside it and it meets the needs of the customer, that's great. However, the difficult part is judging what's acceptable in each instance. It may be impossible to establish a final value that is acceptable unless studies are conducted that demonstrate a correlation between microbial barrier properties and sterility over time, and that's expensive.

Is anyone suggesting that if you had a ranking of materials and a set of devices, and you knew that a device was going to have a shelf life of 5 or 10 years, you should necessarily use a material of a certain rank?

Spitzley: Jack van Asten from the Netherlands is putting together a test to rank materials and evaluate intact packages. He suggests that there will be some materials and systems that won't meet the requirements of that particular test and that would consequently be abolished. That's where there's going to be a lot of contention.

Scholla: It's up to each company to decide what materials it uses. If a company chooses a high-end material with excellent microbial barrier properties, it generally means less risk and greater ease in bringing a product to market. However, if a company is completely cost-driven, it may choose a low-end material that has greater risks associated with it. It doesn't matter what kind of standard you put out there. If a company can prove its system works, it's going to use it.

ISO 11607 and EN [European Norm] 868 have prompted a need for more-standardized test methods, as well. But because of the vast array of devices that are packaged and maintained in a sterile environment, it's difficult to say one material is good and one isn't. What people would really like is to have a checklist they could go through item by item. That may be fine for the device manufacturer who understands his product and can establish the criteria for it, but for an international organization to say, "This will work for every device out there," there's no way.

Miller: Most materials on the market have been around for a long time and have been accepted by use. What comes into play is cost. Companies are increasingly cost-driven and are looking at source reduction to keep materials costs down. My company's going to use the material that's most effective for its product and the package. If that happens to be a 21-lb paper, that's the way we'll go. If it happens to be the high end of a rugged Tyvek material, that will be our choice.

ENVIRONMENTAL STANDARDS

What is the status of European Union environmental standards for medical packaging, and where does the United States stand with regard to them?

Fielding: Regulations are being drawn up in Europe that affect medical packaging as well as packaging in general. While the regulations are expected to be implemented throughout the European Union at the end of June, the problem is that they will be implemented in various ways, according to each member state. Trade associations representing the medical device and packaging industries in Europe, EUCOMED [European Confederation of Medical Devices Associations] and ESPA [European Sterilization Packaging Association], are trying to have medical primary packaging in Europe eliminated from that legislation, but whether this will happen is still unknown.

Miller: In the United States, each of the individual states is trying to implement its own environmental regulations. The federal government has been stalled for years, except for what the Federal Trade Commission has set for guidelines. California and Oregon are probably the leaders in consumer packaging, setting the pace for reducing, reusing, and recycling. Consequently, it's tougher for companies to comply when doing business in those states.

Page: In the United States this is a local issue. Some sort of uniformity would be helpful, but with the shrinking of the federal government it's less likely to happen, and the matter will continue to be addressed at the local level in various states.

Larsen: A good example of the work toward recycling has been the international effort within the plastics industry to design a numeric or alphanumeric system for identifying materials and their constituents. It's been on the docket for years and sure, we've got the chasing arrows symbol, but what we do in the United States is not the same as what is done in Europe and around the world, so we need to work toward an international methodology.

Is there a need for industry to take the lead in this area? Presumably manufacturers are the ones who are most harmed if they need to satisfy 50 different sets of regulations.

Page: The trouble with that is whom you identify as manufacturers. Many manufacturers of other products have bigger packaging problems than the device industry does. The device industry is a relatively small part of all manufacturing and packaging.

Miller: It's also a sheltered industry. As Paul Fielding noted, the European industry is attempting to get exemptions from the European Packaging Waste Directive for regulated products such as pharmaceuticals and medical devices. And so far, whenever the American states have implemented environmental laws, they have exempted FDA-regulated materials because of the restraints that companies have. So from a primary package standpoint, the medical device industry is pretty well sheltered and, as a result, hasn't paid as much attention to the issue as perhaps it should.

OPTIMIZING PACKAGING DESIGN

What are the key challenges facing the designers of medical packaging?

Larsen: One challenge designers face every day involves making conversions to existing packaging systems, evaluating different materials, and gaining confidence that those materials will perform as needed. Making changes to packaging materials and designs has been laborious in the medical device industry, and now our marketplaces are requiring packaging engineers to do it more quickly.

Scholla: The key challenge facing packaging engineers is designing packages that protect the device and meet the needs of the customer--while also keeping in mind the increased pressure to lower costs.

Spitzley: Increasingly, single-barrier packages are being used instead of double barriers because of cost and environmental pressures. Strangely enough, most of the resistance to these changes comes from within a company, not from outside. Internal regulatory people often think they're violating some statute that requires a double barrier, but I am not aware of any requirement stating that a sterile medical device must have a specific number of barriers. Consequently, industry needs to intensify its efforts to educate people about single-barrier packaging and its performance.

Scholla: When switching from a double-package design to a single-package design, do you need to reengineer your primary package?

Spitzley: It doesn't really involve a lot of engineering changes, but manufacturers have to consider how the product is used by the end-user. Obviously, a manufacturer can't just decide to remove the outer barrier and give customers a package that doesn't allow them to be comfortable with the way it's handled.

Miller: Primary packages don't always need to be reengineered. If a company decides to remove the outer pouch of a general-purpose medical device that was formerly packaged in a double pouch, for instance, the primary package doesn't need to be reengineered. However, if a company chooses to eliminate a tear-open outer pouch and instead use a peelable foil, then reengineering is needed because of the design and material changes. In still other instances--as with sutures that have historically been packaged in a foil tear-open pack and peelable outer pouch--reengineering may not be required but may be done to improve the efficiency of internal operations.

Then there's the area of orthopedic implants, in which no company wants to be the first to eliminate the double package for fear that doing so could put it at a competitive disadvantage. In such a case, however, where the inner and outer packages were designed primarily to prevent the product package from opening during handling and distribution, the elimination of the outer package would likely require a major redesign.

When a package is reengineered or its process is reengineered, what's the magnitude of savings that you're looking at?

Spitzley: Most of the advantages a company gains by changing to single-barrier packages are not in materials savings but in manufacturing savings realized by not having two seals to inspect, two pieces of equipment, two separate lines, and so on. Companies may have to switch their materials because they're now using a single-barrier configuration, but that's not where the cost savings commonly occur.

Larsen: Obviously, a portion of the packaging cost is eliminated, but the extent of the savings depends on the materials used. Cost savings are also achieved because auditing and inspection in the processing and quality assurance steps are virtually eliminated. But companies must do their homework in evaluating the closures for the maintenance of sterility, in performing proper testing to ensure that they'll have the barrier they need, and perhaps in reengineering outer shelf containers or multiple containers to keep these devices in usable condition.

Miller: Johnson & Johnson has had an internal source reduction program since 1992. Our overall goal is a worldwide source reduction of 10% by 1997, and that will probably be reached fairly easily. Our goal for the year 2000 is 25%.

Spitzley: Is that by volume?

Miller: That's by weight. And in 1995 we had an annual worldwide source reduction of about 12%, which is a fair amount when you consider that's on roughly 400 million pounds worth of packaging at savings of probably a dollar per pound.

THE CHANGING GLOBAL MARKET

To what degree is globalization changing the way companies approach their packaging?

Spitzley: Companies must be prepared to manufacture at sites around the world as they become larger, and those changes frequently need to be made rapidly. They also need to take into account not only the regulations of the various countries, but the various cultures of those who will be working on their products. Manufacturing abroad may be more difficult and lengthen the time of implementation, but in the end a company has a manufacturing line that can move around the world fairly rapidly.

Miller: A lot depends on the type and size of the company. Larger companies may have multiple manufacturing facilities around the world and may have the luxury of assigning a specific site for a designated country or region. Then those specific sites can adapt to the regulations of that area.

Smaller companies have to supply the world from only one area, and for them, the challenge lies not just in adhering to regulations, but also in distribution and ensuring that customers receive what they're used to. For instance, we may typically sell a device in threes, sixes, or twelves in the United States. In many countries, however, customers want singles because that's what they're used to. In such a case, a company then needs to look at redesigning to unit packaging to meet the demands of a specific market--and this redesign may be only for that market.

Hansen: Awareness of the standards outside the United States has increased. In the past, manufacturers looked only at U.S. standards and operated with the idea that if products were manufactured in accordance with U.S. standards, others would accept them. Now manufacturers wanting to sell to the international market must examine the requirements of various countries and then manufacture in accordance with those requirements. If that means doing something extra, companies will often do it because they want to sell there. Consequently, device manufacturers are looking for standards that can be applied globally to any packaging line or manufacturing operation.

FDA'S ENFORCEMENT OPTIONS IN CLINICAL TRIALS

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August, 1996

Halyna Breslawec and Nancy Teague

FDA regulates all aspects of clinical trials for medical devices through enforcement of a variety of regulations. The investigational device exemption (IDE) regulation imposes responsibilities on all those involved in clinical investigations, including sponsors, monitors, clinical investigators, and institutional review boards (IRBs).1 Additional IRB responsibilities are outlined in the agency's institutional review board and informed consent regulations.2,3

In addition to the regulations themselves, a variety of FDA guidances also contain essential information about the agency's requirements and expectations with regard to clinical trials.4,5 Many of these requirements--particularly those related to designing, conducting, and monitoring a good clinical trial--have already been discussed in this series.6,7 The specific responsibilities of sponsors, investigators, and study monitors have also been spelled out previously.8 This article addresses how FDA enforces adherence to these requirements and responsibilities and how study sponsors can avoid becoming the subjects of agency enforcement actions.

COMPLYING WITH REQUIREMENTS

The need to comply with the study requirements should factor in to every study decision a sponsor makes. For example, when selecting a clinical investigator, the sponsor should consider a potential investigator's capabilities in the areas of recordkeeping and reporting. Furthermore, a sponsor should be prepared to dismiss an investigator when he or she is not fulfilling the responsibilities previously agreed upon.

Correspondence and Communications. Obtaining and maintaining FDA approval of a clinical trial under an IDE is an interactive process. The sponsor of the study interacts with reviewers in the Center for Devices and Radiological Health's (CDRH) Office of Device Evaluation (ODE), which is responsible for prompt review and action on IDE applications. Although FDA may communicate orally with study sponsors about an IDE, serious questions or concerns will always be documented in FDA correspondence to the sponsor. Such correspondence may include questions about supplemental applications proposing to change aspects of the study, comments and questions about progress or adverse reaction reports, or questions about other aspects of the study. Often, FDA asks a series of rather specific questions but does not candidly state its underlying concern. Care needs to be taken to read between the lines of such letters. FDA provides sponsors with a time frame for response and a description of what actions it may take if an acceptable response is not forthcoming.

Sponsors should respond promptly to such correspondence. In general, the less response time provided by FDA, the more serious its concern. The intensity of proposed action if no response is forthcoming is also a barometer of the agency's concern. Responses should address each item outlined by FDA, even if some appear duplicative. When a sponsor detects an underlying but unexpressed concern, it should be dealt with directly in addition to responding to the specific concerns expressed in the letter. Sponsors should not hesitate to call for clarification, particularly when they truly do not understand the nature of the agency's concerns.

Reporting Requirements. The IRB and IDE regulations impose reporting requirements on sponsors, investigators, and IRBs involved in clinical trials.9 Some reports, such as progress reports, are routine; others are required as a result of an event, such as an unanticipated adverse device effect, or a deviation from the investigational plan. Complying with reporting requirements forms the basis of good records, which FDA will review during an inspection.

Documenting Compliance. The IDE regulation outlines recordkeeping requirements for all those involved in clinical trials.10 Records must be maintained for at least two years following the end of the study or the date the study data are no longer needed for preparing a premarket notification (510(k)) or premarket approval (PMA) application. During inspections, FDA will compare records maintained by sponsors, monitors, investigators, and IRBs to evaluate their accuracy and authenticity. Maintaining complete and accurate records is the best preventive measure to avoid FDA enforcement action.

Prohibitions. In addition to outlining clinical trial responsibilities, the IDE regulation prohibits participants in clinical trials from performing certain actions. Commonly referred to as prohibitions, these actions are described below.11

Promotion or Test Marketing. Sponsors and clinical investigators may not promote the use of or test-market investigational devices during their investigations. The prohibition does not preclude advertising the availability of the investigational device for the purpose of obtaining clinical investigators or subjects for participation in the study, provided that certain conditions are met. FDA's rather dated guidance describes the appropriate content of such notices or presentations, and discusses certain acceptable and unacceptable activities.12

FDA permits sponsors to announce the availability of a device for testing only in publications or arenas that reach individuals who would possess the qualifications necessary to be an investigator, and the agency considers undirected mass mailings inappropriate. Advertising is permitted only until an appropriate number of investigators or subjects are enrolled. Any notice of availability must clearly state its purpose, with its content limited essentially to the name and address of the sponsor, how to apply to be an investigator, and a list of the investigator's responsibilities. Comparative or subjective comments about the device or its performance may not be included, and no claims of safety or effectiveness may be made. Furthermore, an investigational device statement that reads as follows must be prominently included: "Caution--Investigational device, limited by federal law to investigational use." Inclusion of pricing information is also considered inappropriate.

Commercialization. FDA considers commercialization to be the charging of a price for the device that is greater than necessary to recover costs of manufacture, research, development, and handling. The agency has not defined these recoverable costs.

The initial objective of this provision was to recognize that cost recovery for investigational medical devices was permissible and even necessary to encourage development of new devices. When the IDE regulation was issued, the idea of cost recovery for investigational products, especially drugs, was novel. This is no longer the case.

FDA enforces this provision by requiring sponsors to reveal the amount they intend to charge for the device. If the amount appears excessive, FDA will ask for a justification. This is usually the extent of the agency's enforcement in this area because FDA acknowledges that it has little interest and even less expertise in performing economic analyses of manufacturers' costs. However, it will take enforcement action when it becomes aware of blatant violations of this provision, such as the sale of regional distributorships to clinical
investigators.

Perhaps the most confounding aspect of this provision is that to actually recover the costs of manufacture, research, development, and handling during the course of clinical trials (and not during presumed postmarketing sales), a manufacturer would need to charge an amount for the device that would greatly exceed the price of a comparable approved device. If a sponsor proposed a price that represented a true recovery cost, FDA would likely challenge that amount and ask for its justification.

The recent Medicare decision to cover the costs of certain investigational devices further illustrates the difficulty of setting prices for them.13,14 Medicare reimbursement for investigational devices designated as "nonexperimental, Category B" is based on and may not exceed the cost of comparable approved devices. While the price of an approved device is likely to include a profit, the total amount
is still likely to be less than an actual recovery cost.

FDA and Health Care Financing Administration (HCFA) cost decisions are made independently. The amount reimbursed by Medicare is established by HCFA without routine input from FDA and is intended to be the amount necessary for cost recovery but no more than the cost of approved devices. FDA evaluation of the price charged for an investigational device is done as part of the IDE review and does not include any consideration of reimbursement cost. As a result, the cost of an investigational device to a patient may be different than the amount reimbursed by Medicare, as well as from the true recovery cost. These factors contribute to the difficulty in justifying--and evaluating--a price to charge for such devices. Sponsors who select an amount within the general range of the cost of a comparable marketed device will probably not be challenged.

Unduly Prolonging an Investigation. Manufacturers may not prolong an investigation to avoid making a premarket submission (i.e., a 510(k) or PMA application) or to delay marketing approval for a product. A sponsor can be tempted to do this when studies have shown that the device is ineffective, when the device has been superseded by a new technology or has become obsolete, or when the cost of preparing an FDA submission would not be recovered through postapproval sales.

This provision has occasionally been interpreted as prohibiting continuation of an investigation once the data needed for product approval have been collected. However, FDA often finds itself in a position of wishing to permit, or even encourage, continued patient access to devices during the review period. This is especially the case when there has been public criticism or pressure to approve a product more rapidly. FDA has been creative in developing reasons that permit firms to continue investigations even when all necessary data have long been collected. The agency will take enforcement action, however, when a premarket application or responses to questions about the application are not forthcoming.

Representations of Safety or Effectiveness. FDA prohibits manufacturers from representing an investigational device as safe or effective for the purposes for which it is being tested, and prominent labeling of the investigational status of a device is required whenever the device is displayed. FDA has frequently enforced this requirement; fortunately, compliance is simple. More difficult to interpret and enforce is the applicability of this prohibition to discussions or published materials dealing with the safety or effectiveness of an investigational product. FDA recently developed new guidance regarding the dissemination of information about unapproved uses of approved products.15 While the guidance reinforces the agency's unwillingness to sanction the distribution of information about unapproved or investigational uses of a device, actual enforcement remains difficult except in blatant violative cases.

ENFORCEMENT OPTIONS

True enforcement of the requirements of a clinical trial necessitates the integration of all aspects of the study, the interaction of those involved in it, and their acknowledgment and acceptance of their
responsibilities. FDA's role, in effect, is to verify that study requirements were enforced during the course of the study. The agency's enforcement options are broad and include administrative actions such as withdrawal of IDE approval, as well as traditional enforcement
actions such as issuance of warning letters and legal action. Most of the agency's enforcement activities related to clinical trials occur after trial completion.

Withdrawal of IDE Approval. One of FDA's most effective enforcement tools is its ability to withdraw approval for an ongoing study. While such an action rarely occurs, the proposal to do so is invoked more frequently, particularly when a sponsor fails to respond to FDA correspondence or when the agency becomes concerned about safety aspects of a study. In correspondence, sponsors are asked to respond to concerns about ongoing trials by a certain date; if no response is made, the agency states that it may take action to withdraw approval of the IDE application. Grounds for withdrawing IDE approval include:

* The sponsor has not complied with the requirements of the IDE regulation, or any other applicable requirements.

* The application or any IDE report contains untrue statements or omits required material or information.

* The sponsor does not respond to a request for additional information within the time frame prescribed by FDA (this includes progress reports).

* There is reason to believe that the risks to subjects are not outweighed by benefits, that informed consent is inadequate, that the study is not scientifically sound, that the device used is ineffective, or that any part of the IDE or its conduct is inadequate.16

Although the grounds to withdraw approval are broad, FDA must follow certain procedures that offer the sponsor an opportunity to correct what the agency identifies as problems.

FDA must notify a sponsor in writing that it is proposing to withdraw approval of a study and must include a complete statement of the reasons for withdrawal. The agency must tell the sponsor that it has a right to request an informal hearing with FDA. If granted, the meeting--chaired by a hearing officer (an FDA employee)--gives the sponsor a chance to respond to the agency's concerns. The hearing officer then decides whether the IDE should be withdrawn. This decision constitutes final administrative action. The study can continue until this final action is taken.

If FDA determines that the continuation of testing under the IDE would result in an unreasonable risk to public health, however, it may immediately order withdrawal of IDE approval before any hearing. FDA rarely does this. When it does, it offers the sponsor the opportunity for a hearing on the reasons the IDE approval was withdrawn. The hearing occurs, however, after approval for the IDE has been withdrawn, after the sponsor has had to stop the study, and after IRBs have been notified of the study cessation.

FDA is usually willing to enter discussions with the sponsor regarding problems with the IDE outside of the hearing process, particularly when it believes the sponsor is motivated to take corrective action. The hearing process is time and resource intensive for FDA, and the agency's objective is usually to correct the problems with the IDE. In such a case, it is usually in the sponsor's interest to address the problems outside of the hearing process.

Nonsignificant-Risk (NSR) Studies. One area in which FDA enforcement tends to overstep its bounds is NSR device studies. Such studies are subject to abbreviated IDE requirements that include lesser recordkeeping and reporting requirements and approval procedures.17 An NSR study is considered to have an approved IDE when an IRB determines that the study presents no significant risk and then approves it. FDA approval for such an IDE is not required; in fact, the agency does not need to be notified of the approved IDE. FDA has published lists of device studies it considers to be significant-risk (SR) and NSR.18

Ways in which FDA may become aware of an ongoing NSR study include notification through a competitor, an IRB inspection, or an IRB report of an unanticipated adverse event or study noncompliance. FDA may have concerns about the study, may disagree with the IRB's determination of NSR, or may simply wish to know more about the study. In such cases, FDA sometimes oversteps its bounds by writing to the sponsor of the NSR study to demand that it be stopped and that an IDE application be submitted for review. FDA may not summarily demand that an NSR study be stopped unless it believes that continuation would result in an unreasonable risk to public health. If this is the case, the agency may immediately withdraw IDE approval. If it isn't, FDA must follow the same procedures as necessary to withdraw approval of an IDE for an SR device study; that is, it must propose withdrawal of IDE approval and offer the sponsor an opportunity for a hearing. When this occurs, the sponsor of the NSR study should remember that it has an approved IDE for the study, assuming that the NSR IDE approval was appropriately obtained and that FDA has not previously designated the study as an SR.

FDA may require an application for an NSR study, even while it is ongoing.19 FDA will, of course, review the submitted IDE application and may approve the study, with or without conditions. Although the regulations do not address this issue explicitly, disapproval of such an IDE is not an option for FDA, since such a disapproval would have practically the same effect as withdrawing approval of an approved IDE. Sponsors may, of course, voluntarily offer to suspend enrollment or otherwise curtail the study until FDA's concerns have been resolved.

Bioresearch Monitoring. FDA not only has various enforcement tools available to it, it has the discretion to apply them selectively. The agency bases its enforcement decisions on information obtained from inspections of sponsors, investigators, monitors, IRBs, and testing laboratories, and from review of information submitted to FDA as part of the IDE.

Inspections. Inspections related to clinical trials are conducted as part of FDA's bioresearch monitoring program. Although FDA has the authority to conduct unannounced inspections of anyone involved in a clinical trial, inspections are usually scheduled as a courtesy and in recognition of the impact caused by an unannounced inspection. This courtesy should not be misinterpreted as FDA's lack of interest in conducting thorough, sometimes lengthy, inspections and in inspecting all necessary records.

Unlike GMP and other routine FDA inspections, those related to clinical trials are almost always done for a specific reason. Most inspections are directed inspections, conducted to ensure that data submitted in PMA applications or 510(k)s are accurate and authentic. If the inspection shows that the study was conducted in compliance with the IDE, IRB, and informed consent regulations and that the data submitted to FDA are accurate and authentic, review of the application is permitted to continue. If violations of the IDE regulations or data integrity issues are raised, however, application review may be delayed. And in addition to having an impact on the review of the pending submission, enforcement actions may be forthcoming.

Bioresearch monitoring inspections may be assigned to FDA district offices by the Division of Bioresearch Monitoring (BiMo), a component of CDRH's Office of Compliance. This group assigns most inspections in order to verify data submitted in pending PMA applications under review by ODE. In fact, all original PMA applications must pass a BiMo inspection prior to their approval. Bioresearch monitoring inspections are conducted in the same way as other FDA inspections, with most inspections conducted by investigators from district offices. During inspections, FDA investigators review records to determine compliance with IDE, IRB, and informed consent regulations and to determine whether violations have occurred. Investigators also collect copies of documents to support observed compliance or noncompliance with the IDE regulations.

Upon leaving the inspection site, investigators may issue a form FDA-483--a list of inspectional observations. This form will include observations of activities the investigator believes deviate from FDA regulations. Generally, if no FDA-483 is issued at the completion of an inspection, no violations were observed.

Following the inspection, an establishment inspection report (EIR) is prepared by the investigator. This report contains the FDA-483, any records obtained during the inspection, and a recommendation for action. The EIR is sent to BiMo for review. BiMo staff investigates alleged IDE, IRB, and informed consent violations by reviewing inspection reports of the sponsor, monitor, investigators, and IRBs affiliated with a study. The BiMo group also coordinates involvement of ODE staff in supporting enforcement action. Enforcement decisions resulting from BiMo inspections are made by BiMo, often in consultation with ODE.

A few bioresearch monitoring inspections are "for cause" inspections to examine a specific concern or complaint about the study. Sponsors of clinical studies without pending PMAs should be concerned if anyone affiliated with the study is targeted for inspection.

In 1995, 315 bioresearch monitoring inspections involving medical device clinical investigations were conducted. Most of these inspections were directed data audit inspections of clinical investigators (62%), IRBs (25%), sponsors or monitors (10%), or laboratories (3%) involved in studies of products subject to pending PMAs. The rest of the inspections were "for cause" inspections resulting from FDA concerns regarding ongoing investigations or submitted data. In 1995, these inspections resulted in 40 warning letters issued by FDA.

FDA Enforcement Actions. For the clinical trial itself, the consequences of failing a bioresearch monitoring inspection are limited simply by virtue of timing; the trial is usually completed long before the inspection occurs. The consequences of inspection failure on those involved in the clinical trial are quite significant and can affect much more than their involvement in it.

Delay in Product Approval. If the inspection shows that the study was conducted in compliance with IDE, IRB, and informed consent regulations and that the data submitted to FDA are valid, application review will continue. If violations of these regulations are found or data integrity issues are raised, application review may be delayed.

Warning Letters (and Other Correspondence). Warning letters are sent by FDA to the inspected party to notify it of observations or conditions the agency believes violate any of the requirements of agency laws or regulations. Warning letters to those involved in clinical trials are always issued by CDRH rather than by local district offices. Warning letters identify the violation and request a prompt written response describing the planned corrective action. If no response to such a letter is forthcoming, further enforcement action can be expected. Warning letters, and company responses, are publicly available and can generate considerable adverse publicity.

As previously noted, FDA issued 40 warning letters based on BiMo inspections in 1995, compared to 48 in 1994 and 12 in 1993. The types of violations noted in the letters included failure to conduct the study according to the approved protocol, failure to maintain complete study records (such as records of protocol deviations), lack of IRB approval for protocol and informed consent changes, and informed consent problems.

FDA also issues what it calls "untitled" letters outlining observations the agency believes need corrections. While a lack of responsiveness to these letters will probably not generate immediate enforcement actions, corrective action should be taken to avoid future problems.

Investigator Disqualifications. FDA has proposed regulations on the disqualification of clinical investigators of medical devices.Similar rules for clinical investigators involved in drugs, biologics, and intraocular lens studies exist; their absence from the IDE regulation was a regulatory quirk. Disqualifying an investigator would prevent that investigator from participating in investigations of any FDA-regulated products and would permit the exclusion of tainted data from FDA consideration.

FDA is now reviewing comments on its proposed regulations and is revising them to be more consistent with the disqualification provisions for clinical investigators involved in FDA-regulated drug studies.21 Under the drug regulation, proceedings to disqualify a clinical investigator may be taken when FDA believes an investigator has repeatedly or deliberately failed to comply with the investigational new drug (IND), IRB, or informed consent regulations.21 The regulation also outlines the procedures for disqualification.

The impact of disqualification on an investigator would be significant: FDA will not permit him or her to participate in any FDA-regulated clinical trial. The impact of disqualification on the sponsor will be equally significant. Data from any study in which the disqualified investigator participated could be rejected for consideration in a PMA application or 510(k). Furthermore, if the investigator is participating in other trials at the time of the disqualification, those studies could be terminated, suspended, or otherwise constrained. Finally, the status of an already-cleared 510(k) or approved PMA based on studies conducted by the disqualified investigator could be affected.

IRB Impact. FDA considers IRBs to be its surrogates in patient protection. As a result, FDA usually deals with problems identified during an IRB inspection in an educational rather than an enforcement manner. While warning letters to IRBs have been issued in cases of serious violations, a letter outlining problems and suggesting solutions is usually sent.

When FDA finds egregious violations in the operations of an IRB, it may apply administrative enforcement actions against the IRB, including disqualifying it from reviewing any FDA-regulated research and preventing the approval of any application involving the violative IRB.22 FDA may also restrict, suspend, or terminate an IRB's use of certain expedited review procedures when necessary to protect the safety of study subjects.23

In 1995, at least two IRBs were suspended from approving new studies until corrective actions were in place.

Applications Integrity Policy. FDA's applications integrity policy permits it to defer review of an application when it suspects that data submitted in a pending application are fraudulent or unreliable.24 The review of any other pending application submitted by the company may also be delayed, pending resolution of FDA's concerns. Resolution of agency concerns is an elaborate process, involving subsequent investigations and audits of data and individuals involved in the study, and intensive FDA involvement. The sponsor has no administrative mechanisms to challenge being subjected to the policy. A number of sponsors have withdrawn their pending applications following their involvement with the applications integrity policy.

FDA has invoked this policy against a substantial number of firms that have had BiMo inspections. In 1995, four were subjected to it, and only one resolved FDA's concerns and consequently was no longer subject to the policy.

The impact of the policy on ongoing investigations is not as significant as on premarket applications. FDA will generally allow continued patient accrual in studies, although no new IDE applications will be reviewed.

Other FDA Action. Sponsors, monitors, clinical investigators, and IRBs are also subject to judicial actions, such as criminal prosecution and imposition of civil money penalties. Such FDA action is rare; however, FDA will move swiftly when egregious IRB violations are found. As always, FDA enforcement action can result in adverse publicity.

Using Grounding to Control EMI

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published August, 1996

William D. Kimmel and Daryl D. Gerke

Electromagnetic compatibility is an important consideration in the design and operation of today's sophisticated medical electronic equipment, particularly as portable systems proliferate. Electronic devices can both emit and be damaged by electromagnetic interference (EMI) and must be protected from its harmful effects. Issues of patient and operator safety must also be addressed. Previous articles have covered such means of achieving EMI control as filtering, cable shields, and enclosure shielding (MD&DI, February, July, and November 1995, respectively). This article focuses on grounding.

Perhaps no topic in electronics is as misunderstood as grounding, which usually evokes an image of a long braid snaking off to a ground post set into a concrete floor. As the following discussion makes clear, an earth ground is not essential to EMI control and is almost never needed. In the overwhelming majority of medical electronic applications, good grounding involves achieving a sufficiently low-impedance return path for the highest interference frequency of interest. If it were possible to achieve zero impedance, all other grounding issues would become meaningless. Since it isn't, device designers need to seek ways of maximizing the effectiveness of the grounds that can be implemented.

WHAT IS A GROUND?

Succinctly put, a ground is a return path for current. Its purpose is to close the current loop, not to lead it into the earth. If an interference current is diverted successfully into earth ground, it will simply come out elsewhere in order to return to its source. The only time earth ground is necessary is for lightning.

Confusion arises because the term ground is used for a variety of applications and means different things to different people. Facility engineers, for example, look at a ground as a return for lightning strikes. In this application, the ground needs to be able to handle currents up to 100,000 A for a few milliseconds. Because the approximately 1-microsecond rise time produces significant Fourier frequency components up to about 300 kHz, inductance can become an important concern. In contrast, electricians look at a ground as being a return path for fault currents, which may involve tens or hundreds of amperes at 50 or 60 Hz. At this frequency level, inductance is not important, so a length of 4/0 wire connected to the nearest building steel works just fine--an earth ground may be present, but is not needed for electrical safety.

These two cases are the most commonly known uses of grounding, but the grounding requirements for EMI control in medical device applications are vastly different. EMI can cover a very wide range: currents from microamperes to amperes and frequencies from direct current to daylight. The duration of an event can range from nanoseconds, in the case of a transient, to years, in the case of a continuous wave. For the specific case of electrostatic discharge (ESD), transients are measured in nanoseconds (giving Fourier frequency components up to 300 MHz), and currents range to 10 A or even higher. The edge rates and current magnitudes are such that significant voltage bounce will occur across even the smallest length of wire or circuit-board trace. Whatever the condition, however, device designers must provide a way for the interfering current to return to its source, and that rarely involves earth ground.

GROUND LOOPS AND SINGLE-POINT GROUNDS

Whenever grounding is an issue, design engineers inevitably turn to ground loops and single-point grounds. What do these terms mean and when are the techniques appropriate?

A ground loop exists whenever there is more than one conductive path between two points. This condition allows interference currents to mix with signal currents, which may lead to ground interference. Figure 1(a) shows the effects of a ground loop when stray interference currents divide and flow through signal ground. This problem can be eliminated by having a zero-impedance ground. Lacking such a ground, separate ground paths can be provided. As shown in Figure 1(b), by breaking the ground loop, the device designer has created a single-point ground. The need for a single-point ground originated in telephony, where it was almost impossible to get impedances low enough to prevent power line frequencies from intruding as a hum, and the technique is still useful in a number of low-level, low-frequency analog applications.

However, a single-point ground is not suitable for handling the higher frequencies encountered in modern computing devices. Figure 2 shows the effect of a standing wave on a cable shield that has been grounded to its enclosure at a single point. If the shield were exposed to an incident interference of 150 MHz (a popular land mobile radio frequency) with a wavelength of 2 m, the cable, which is represented here as being a 1/4 wavelength of the interfering frequency, or 0.5 m, would act as an efficient antenna, with standing wave voltage on the shield as indicated in the figure. In the immediate proximity of the ground connection, the shield voltage is near zero, but at the unterminated end, the voltage is at a maximum, and with stray capacitance, there is ample coupling to the signal lines.

The fundamental assumption behind the principle of single-point grounding is that the velocity of light is infinite. Any time designers need to consider the velocity of light, notably at computer speeds, the single-point ground technique doesn't work. A useful rule of thumb is that a single-point ground is appropriate if the longest dimension of interest is less than a 1/20 wavelength of the highest-frequency threat. Thus, single-point grounds are appropriate for handling EMI with audio frequencies in most cases but inappropriate and unachievable for radio frequencies used in digital electronics.

Consider, for example, the case of a designer who wanted to use a single-point ground for two freestanding cabinets located about 10 ft apart. Based on the common assumption that the inductance of a wire is 20 nH/in., the minimum inductance for the single-point ground path would be about 2.5 µH. Using the formula for impedance

Z = 2¼fL

where f is frequency in megahertz, L is inductance in microhenries, and Z is in ohms, the impedance at 100 MHz would be 1600 ‡, which is hardly a short circuit. Using the rule of thumb that capacitance between freestanding equipment and ground is ~100 pF and the formula

where C is capacitance in microfarads, the impedance with two 100-pF capacitors in series with a ground plane is 30 ‡. This is not a short circuit either, but is certainly a lot lower than that of the intended single-point ground path.

ACHIEVING GOOD GROUNDS

Achieving a low-impedance ground for a medical electronic device is easy in concept-- use a ground plane. At 50/60 Hz, the impedance of a grounding wire will be primarily resistive, but above audio frequencies inductance begins to dominate and at radio frequencies the inductive impedance of even a short wire or circuit-board trace is enough to cause problems. To determine the requirements of a particular application, the designer needs to know what voltage the device can tolerate, the magnitude and frequency of the anticipated interference current, and the impedance of the path. Given these data, Ohm's law can be applied to find out when problems will occur.

A lightning strike, for example, might result in 10,000 A flowing in an I-beam with 10-V transients across even short lengths. Two interconnected devices grounded to that I-beam at different points may easily experience upset. Or suppose a 1-in. length of wire or circuit-board trace were subjected to a 10-A ESD event. Assuming an inductance of about 20 nH, the voltage drop across the wire or trace could be calculated using the equation

where E is voltage drop across wire, L is inductance in nanohenries, di is magnitude of current transient (assumed to be 10 A), and dt is rise time (assumed to be 1 nanosecond). For these typical conditions, E = 200 V. Thus, it can be seen that a length of wire as short as 1 in. makes a poor ground for ESD purposes.

Because ordinary wire is not a satisfactory ground in many circumstances, the common wisdom is to use a flat strap instead. This approach is indeed appropriate, but the rationale behind it is widely misunderstood. To achieve low inductance, the key factor is not the strap's flatness but its length-to-width ratio. To ensure that the inductance of a ground strap is sufficiently low, its width must be at least one-fifth or, better yet, one-third of its length. If a designer cannot achieve this ratio, there will not be a satisfactory high-frequency current return path.

Circuit-Board Grounds. It is almost impossible to get good low-impedance grounds on two-sided circuit boards, so it is critical to keep ESD currents and high-level radio-frequency interference off such boards. On the other hand, it is easy to achieve low impedances with the ground plane underneath the traces on multilayer boards. Circuits built immediately above the ground plane are well protected, regardless of the threat. Our observation is that EMI control is always problematic with double-sided boards, while electronic devices with multilayer boards are rarely harmed. If a manufacturer is adamant about using double-sided boards, the product development budget should include additional funds and three months should be added to the schedule for test and redesign. Even then, there will be a high probability that EMI control will not be achieved.

Probably nowhere in electronics do designers face such a difficult challenge as that posed by sensitive analog input circuits. The circuits can be fairly well protected on an isolated ground plane; the problem involves interconnections to an unisolated ground or to the wires and cables that connect the sensor to other equipment. For an isolated ground, it is important to minimize the amount of external EMI currents that reach the ground plane. Once the sensitive input signal has been captured and amplified, or perhaps digitized, crossing the boundary to unisolated circuits is the remaining design problem. Any interference currents that are diverted to the isolated ground become common-mode interference and must be handled by an isolator component, of whatever type. Although some fairly effective isolators are available, they have their limits, so it pays to minimize the common-mode currents in the first place.

Interconnect Grounding. Once the designer has coped with the circuit-board ground, the next consideration is the interconnects within the equipment, such as the connections between the mother and daughter boards and the ribbon cables between modules. EMI problems are frequently the result of high-impedance interconnects. Again, designers need to keep the ground impedance low, either by connecting the circuit boards or modules to a common ground plane or by providing a very-low-impedance ground interconnect via the cable, usually by allocating as many connector pins to grounds as possible. Although the connector space is an important concern, so is functionality. For high-speed (100-MHz) interconnects, there should be one ground line for each signal line. For lower speeds (~10 MHz), one ground line for each five signal lines may be sufficient. Anything less is inviting trouble.

External Grounding. Finally, designers need to consider the interconnections between various pieces of equipment. If a low- impedance ground plane can be implemented between enclosures, and multipoint grounds are used for cable shields, problems should be minimal. However, if cables run long distances or if sensitive low-frequency analog signals are being transmitted, audio-frequency interference may be a concern. In such cases a single-point ground may be needed as well as the multipoint ground required to control high-frequency interference. A hybrid ground with a capacitor termination at one end, typically 0.01­0.1 µF, and a hard termination at the other end can provide an open circuit at audio frequencies and a short circuit at radio frequencies, thus combining the best of both worlds.

CONCLUSION

Medical electronics designers can base their decisions on how to implement grounding for EMI control on three principles:

* An earth ground is not necessary for EMI control (although it may be needed for safety). What is needed is a low-impedance current return path, usually a conductive plane or a shield.

* Single-point grounds are usually appropriate only for handling audio-frequency interference and are not achievable at radio frequencies. The 1/20-wavelength criterion can be applied to determine if a single-point ground is acceptable.

* Ground impedance must be kept acceptably low at the current frequency of the anticipated interference event. At high frequencies, inductance gives rise to high impedances, so use of ground wires is generally not acceptable. A wide ground strap or plane can be used to reduce impedances.

William D. Kimmel and Daryl D. Gerke are principals in the EMI consulting firm Kimmel Gerke Associates, Ltd., based in St. Paul, MN.

Figure 1. Schematics showing ground loop currents: (a) unbroken and (b) broken (thereby providing a single-point ground).

Figure 2. Effects of a standing wave on a single-point-grounded cable shield.