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Articles from 1997 In March


Submitting a 510(k) for Changes in Device Design

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

HELP DESK

With advances in technology emerging every day, manufacturers are constantly presented with the opportunity to update their devices. While such advances promise to improve health care, modifications may affect the safety and effectiveness of a device. Such changes may also require manufacturers to submit 510(k)s to FDA. This month FDA assists the editors in determining whether design changes warrant such a submission.

A manufacturer produces a finished medical device that can be inserted into the body for aspirating body fluids. The device was introduced into commercial distribution prior to the May 28, 1976, Medical Device Amendments and has not undergone any modifications since that date. The manufacturer would now like to make the following changes to the device: the addition of an O-ring to make it leakproof, the use of transparent plastic instead of the original colored plastic, and the addition of a sounding line to gauge the depth of insertion. These are intended to make the device more accurate and easier to use. Is the manufacturer required to submit a 510(k)?

On January 10, 1997, FDA issued in final form a guidance document entitled Deciding When to Submit a 510(k) for a Change to an Existing Device. The following answer is based on that document.

As written, the question does not contain enough information to make an accurate evaluation because it doesn't explain where the device is to be used in the body or whether it is to be used during surgery or dental procedures. Nevertheless, it appears that the changes made as a whole will require the submission of a 510(k).

Because of the risk of HIV transmission, the transfer of body fluids is not an inconsequential procedure. Under section 510(k) of the Federal Food, Drug, and Cosmetic Act, any change that could significantly affect safety and effectiveness requires a new 510(k) submission. Adding an O-ring to prevent leakage would appear to make the device safer to use. Therefore, a 510(k) must be submitted.

In addition, by adding an O-ring the manufacturer is introducing a new material that may require biocompatibility testing. Changes to device design require some level of design evaluation to ensure that the device continues to perform as intended. Occasionally, changes that are meant to be cosmetic produce unexpected results or adversely affect product performance. In such instances, the safety and effectiveness of a device may be affected, so the manufacturer must submit a 510(k).

The second change involves the use of transparent plastic instead of the original colored plastic. A change in a material that comes in contact with body tissue may require additional biocompatibility testing. If such additional testing is required, a 510(k) is usually necessary. Also, if the device is to be sterilized commercially, the manufacturer needs to consider the effect sterilization will have on the plastic.

Finally, the manufacturer wishes to add a sounding line to gauge the depth of insertion. This type of change will require some level of design evaluation to ensure that the device continues to perform as safely and as effectively as the original.

Deciding When to Submit a 510(k) for a Change to an Existing Device is available from FDA's Facts-On-Demand service by calling 800/899-0381, and requesting shelf number 935, or by visiting FDA's web site at http://www.fda.gov/cdrh/ode/510kmod.html.


"Help Desk" solicits questions about the design, manufacture, regulation, and sale of medical products and refers them to appropriate experts in the field. A list of topics previously covered can be found in our Help Desk Archives. Send questions to Help Desk, MD&DI, 11444 W. Olympic Blvd., Ste. 900, Los Angeles, CA 90064, fax 310/445-4299, e-mail [email protected]. You can also use our on-line query form.

Although every effort is made to ensure the accuracy of this column, neither the experts nor the editors can guarantee the accuracy of the solutions offered. They also cannot ensure that the proposed answers will work in every situation.

Readers are also encouraged to send comments on the published questions and answers.


Copyright © 1997 Medical Device & Diagnostic Industry

Seeking Growth in a Dynamic Market By Embracing Change

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

SNAPSHOT

He laughs as he says it, but Duane Hopper is serious when he compares the medical device marketplace to the game of musical chairs. For the president, COO, and CEO of Graphic Controls Corp. (Buffalo, NY), change and uncertainty represent not threats but opportunities. The goal he sets for his company, Hopper says, "is to make sure we're sitting down when the music stops."

For Graphic Controls, he explains, "it's a matter of trying to identify which way the market is going, and to be ready to respond when that flux, that change, occurs. A lot of people in this business are not happy with the way things have changed in the last five years. But I think it's an opportunity for them to gain market share and faster growth."

For many decades, Graphic Controls was a straightforward industrial printing company, selling charts for recording pressure, temperature, and similar parameters for various process industries. Then, just over 20 years ago, it began to branch into medical applications.

Graphic Controls was still predominantly an industrial business when Hopper joined the company as medical marketing manager in 1988, after more than a decade spent in medical marketing and manufacturing positions at Zimmer, Ohmeda, and other device companies. Within six months, he was named general manager of the medical business.

In 1992, medical sales exceeded industrial sales for the first time. In the same year, Hopper was promoted to his present posts, and medical sales quickly accelerated. Today, he says, following the 1996 purchase of Devon Industries, a Chatsworth, CA, producer of disposable hospital supplies, Graphic Controls "has primarily a medical orientation, with $200 million-plus in medical sales and about $60 million on the industrial side."

Through a combination of in-house development and acquisition, Graphic Controls has built on its medical charts by adding such product lines as diagnostic and monitoring electrodes and catheters and a variety of consumable surgical products.

Given how Graphic Controls has, as Hopper puts it, "evolved rather spectacularly in the last few years into a primarily medical company," a degree of culture shock was inevitable. "The entire cultural background of the company has changed," he acknowledges, "from a slower-growth industrial business to a very fast-paced medical business."

For Hopper, this kind of rapid transition seems to come naturally. It's a fortunate trait in dealing with the current health-care marketplace. To succeed in it, Hopper asserts, companies have to be able to change as quickly as it does. For example, five years ago, Graphic Controls relied largely on a direct sales force and shipped its products directly to the end-user. But as the just-in-time shipment concept began to take hold among customers, they started to ask the company to work through distributors.

"We made a decision that the market is changing, and we have to change with it," Hopper recalls. "The customer wants us to go through distribution, we said, so let's do it. And let's not stop there, but make sure that distributors regard us as a very good partner, and service them so they realize we're embracing the concept." Rapid growth will remain Hopper's imperative for his company for the foreseeable future, to be fueled by both product development and acquisition. Eventually, he hopes, the company will be publicly held to enable it to grow still faster.

Keeping up with steady change can be exhausting, but for Hopper the rewards of setting challenging goals amply repay the effort. "Many times we will have discussions about how fast paced the changes have been and about how tiring it sometimes is," he reflects, "but it is very satisfying to most of us to hit the goals that we have collectively set."

John Bethune is editor of MD&DI.


Copyright © 1997 Medical Device & Diagnostic Industry

Industry Advice to FDA: Put Patients First

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

FIRST PERSON

The chairman of the Health Industry Manufacturers Association and chairman and CEO of Medtronic, Inc. (Minneapolis), offers a prescription for improving FDA's relationship with industry.

If there is one piece of advice I would give to David Kessler's successor at FDA, it would be this: Be a strong advocate for patients. To most people that sounds like a simple prescription, but anyone who is familiar with the development of medical technology in the United States knows that patients are often ill served by a regulatory process that is unpredictable and prone to delay.

In recent months, some gratifying improvements have been made to this process, but much more is needed to ensure that breakthrough medical therapies will reach patients quickly.

Meeting the needs of millions of patients for cutting-edge, as well as safe and effective, medical technology should be the primary goal of our industry, and it should also be a primary goal of FDA. After all, it is the patients, not the medical device companies, who suffer most when the development of an important new technology is stifled or delayed. Putting the interests of these patients first at FDA would be a major step toward revitalizing innovation and smoothing the path of product development.

What are some of the most objectionable characteristics of this obsolete and unwieldy regulatory system? Long product review time is just one element.

Increased FDA enforcement activity of recent years, which has been inconsistent and unpredictable, has also been troubling. The occasionally baffling and contradictory instructions issued by the agency have caused confusion for many companies.

Perhaps most insidious of all, however, has been the agency's impact on product development, prolonging the gestation period for a breakthrough product in ways that are both obvious and subtle. The agency has an impact on the development of a product that is far wider than just the review process.

For example, the prolonged period necessary to negotiate a randomized trial protocol to obtain an investigational device exemption is followed by additional time to conduct trials and complete the review process. To make matters worse, an end date to the process is so unpredictable that adequate organizational, sales, production, or financial planning cannot be done.

Without this planning, the research and development cost of a major new product is three times what it was in 1990. The bulk of funds are being spent not on research and product development, but on clinical trials. Compared with the regulatory systems of other industrialized nations, the U.S. regulatory structure is slow and overly complex, as well as highly unpredictable.

The U.S. regulatory environment is particularly inhospitable to small companies, which are the sources of many of the breakthrough products and much of the innovative thinking in the medical device industry. The smallest, most fragile companies in our industry must negotiate the same labyrinthine FDA requirements that the largest medical device companies do, but without the benefit of the big regulatory affairs staffs that large companies can afford.

Instead of presiding over an agency that regards new technology with doubt and suspicion, a patient advocate in the commissioner's chair would understand that FDA must be in partnership with industry to develop devices that will reach patients as expeditiously as possible. After all, rapid technological advances have been essential for making U.S. health care the most effective in the world. The U.S. medical device industry has been in the forefront in developing products that make faster, less invasive diagnosis and treatment possible, and facilitate delivery of care in the home and other cost-effective settings. Thanks to achievements in fields such as implantology, imaging, biomaterials, electronics, in vitro diagnostics, and biotechnology, medical devices are more sophisticated and effective than ever. Most important, these medical devices have substantially improved health care for patients.

Putting the needs of patients first will also help the new FDA commissioner deal with the complex and changing forces facing the medical device industry. Today, as we approach the millennium, medical technology is advancing faster than ever. Electronic information now moves across continents at the speed of light. Product cycles in many high-technology fields--any that involve computer technology, for example--are measured in months. Some types of medical devices today can become obsolete in the years it can take FDA to review them.

Concurrently, managed health care is transforming the marketplace for medical technology. The focus in the marketplace today is on cost-effectiveness and demonstrable patient outcomes, making it increasingly complicated to market a new technology once it has been approved. In addition, the marketplace for medical technology in this new era is becoming truly global as barriers to international trade continue to fall.

CHANGING REALITIES

The regulatory process at FDA must take these new realities into account. To their credit, some people at the agency do recognize the changed circumstances for industry and are trying to make FDA more responsive. Thanks to the influence of these people, a new approach to the medical device industry seems to be developing at the agency, and it is coming not a moment too soon.

The signs that this new approach is needed are evident. Many U.S. patients have been deprived of newer, more advanced generations of devices to which European patients already have access. The U.S. patients have had to go abroad to take advantage of these technologies. In addition, U.S. device firms are moving production and research facilities to other countries.

Medtronic has been among the companies shifting research and development and manufacturing operations overseas. Between 1993 and 1995, all 15 of its major new products or ventures were developed, tested, and produced in Europe, and all of them were made available to patients overseas long before they were introduced in the United States.

Medtronic is just one company, but its experience is typical of what has been happening across the industry in reaction to a U.S. regulatory system that is outmoded in terms of today's technology. Understandably, a cumbersome, delay-prone system that was created three decades ago has been overwhelmed by the rapid-fire demands of technological progress. Yesterday's regulatory system is simply not conducive to innovation in the United States today. That is a major reason why so many manufacturing operations have moved overseas.

Europeans seem to recognize that evaluating the effectiveness of therapies is an inexact science, and requiring evaluation to be done through a regulatory process can result in very long delays in getting technologies to market. The European system is no less committed to patient safety than the U.S. system is. But Europeans are conscious of the need to carefully balance regulation with the impact of unnecessary delays on patients who can benefit from innovative therapies. They concentrate their resources on the safety and efficacy of the device instead of on the efficacy of the therapy. The European regulatory process is careful not to inject itself into the practice of medicine.

SOLUTIONS

Should FDA simply adopt the European regulatory system wholesale? Some in the industry are saying that FDA should do just that.

A wiser approach, however, would be to combine the best elements of the European regulations with the best of U.S. regulations to create a reasonable, safe, and much more efficient global regulatory system.

A new session of Congress and a new FDA commissioner will offer industry a chance to explore some new ideas. Industry must seize this opportunity and engage Congress and FDA in discussions about creating a healthy, rather than hostile, environment for innovators.

To ensure such a friendly climate for innovation, some industry members and senior officials at FDA are already beginning to look for ways to get safe and effective technologies to patients faster by reviewing the process in its early stages of design and development. Industry must provide information to FDA officials about ways the agency can accelerate the development of a product. The goal should be improvement not just in product review time, but in overall product development time, of which actual product review is but a part.

If Congress and the new FDA commissioner choose to act to speed up product development, here are four steps they can follow.

  • Identify and eliminate unnecessary regulatory requirements that increase the time it takes for a manufacturer to develop a new product.
  • Reduce review times for premarket approval (PMA applications). FDA has already greatly improved the review times for 510(k)s, but an expedited review process for PMA applications still needs to be established.
  • Speed up the product review process with the use of authorized third-party review bodies, starting with 510(k)s.
  • Conditionally approve new medical technologies that have been shown to be safe for patient use, subject to postapproval studies made to demonstrate effectiveness. Approval would be withdrawn whenever these studies show that the risk/benefit ratio of a technology is not acceptable.

If U.S. patients are to receive the latest and best in medical technology, government, industry, and the medical community must work as a team, not as adversaries. The regulatory process must serve the needs of patients and innovators alike. The new FDA commissioner will have a challenging job description.


Copyright © 1997 Medical Device & Diagnostic Industry

Before Design: Thoroughly Evaluate Your Concept

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

DESIGNER'S TOOLBOX

A close look at all angles of a design from concept to completion can enable the design team to meet development goals on time and on budget.

A lot of effort is required to take a medical device from the concept stage through to distribution and sales. This article addresses effective ways to evaluate the viability of a basic concept before expending major company resources. Concept evaluation, refinement, and reevaluation should begin immediately after an idea is conceived and should be an ongoing process throughout the development and market life of the product.

Before beginning an in-depth evaluation, the development team should be in place. A project champion should be assigned to coordinate collection of information from the affected company functions to create a preliminary plan and report. Such a report provides management with sufficient basis to authorize and fund the project. Figure 1 is a checklist for organizing a product development plan. A chart enables the development team to anticipate and track the interaction between the activities and events. The plan should become a living document that creates as a minimum the following criteria.

Product Description. Describe the medical function the product is intended to perform and the benefit it will provide the marketplace. Discuss the potential technological and manufacturing advantages and weaknesses.

Medical Efficacy. Provide qualified medical opinions of the proposed device. This is an ongoing function from initial concept review through to completion of clinical trials, if required, and the evaluation thereof. The medical investigators should be involved from the earliest discussions of the concept.

Patent Protection and Infringement Potential. Include legal opinions. The patent is a critical aspect of any design project, and legal issues should be considered almost simultaneously with the consideration of the concept. It is important to regularly monitor possible infringement. Systematic review of patents for similar devices issued during the life of the project is essential.

Probable Regulatory Requirements. Predict likely regulatory status, such as 510(k), investigational device exemption (IDE), or premarket approval application (PMA). If a predicate device exists upon which to base a 510(k) submission, then proceed toward making the case in the early stages of planning. Determining this information early provides the design team with a critical factor in development: the time it will take to prepare appropriate documentation as well as an indication of how long FDA will need to process it.

Market Potential. Speculate market sensitivity to function, price, and features early. Refine this information on a regular basis as data are collected from surveys, focus groups, discussions with potential users, and buying groups. This provides the development team with information needed to make appropriate decisions regarding configuration, features, and fabrication methods.

Development and Manufacturing Costs. Estimate possible modes of fabrication and probable make or buy decisions. Cover basic manufacturing questions, proposed automation, and tooling. Use cost and sales estimates to provide potential break-even point analysis and the product's likely contribution to margins.

Probable Staff and Support Needs. Provide an estimate of personnel and outside services needed to support the project so that management can plan for appropriate staffing levels and can factor these costs into its funding decision.

If the project is approved and funded, continual review and refinement of the concept becomes a key charter for the development team along with regular reporting of status. The purpose of reviews should be the approval of ongoing activities and budgets based on demonstrable results. The timing of reviews should be based on reaching key events and milestones in the project.

PRODUCT DEVELOPMENT PLAN CHECKLIST

  • Clinical trials plan
  • Design reviews
  • Development schedule
  • Employee training
  • Facilities and maintenance
  • Financial analysis
  • Failure modes and effects analysis (FMEA)
  • Focus group organization
  • Manufacturing plan
  • Market analyses
  • Materials selection
  • Medical efficacy reviews
  • Models and prototypes
  • Packaging and labeling
  • Patent reviews
  • Process validation
  • Product description
  • Quality assurance plan
  • Regulatory requirements
  • Staff and consulting needs
  • Sterilization plan
  • Vendor selection

    (Tasks listed alphabetically)

    Floyd V. Edwards is a consultant to the device industry and a member of MD&DI's editorial advisory board.

A 'New Way of Life' at FDA

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

WASHINGTON WRAP-UP


Center for Devices and Radiological Health director Bruce Burlington reveals new strategies for reforming the agency from within.

It's a whole new way of life at FDA these days. As Washington, DC, gropes for a broader middle ground in the aftermath of both the November elections and David Kessler's resignation, FDA is far along the road toward reinventing itself to reach its own new middle ground with industry.

Conceptually, at least, nothing is off the table--even FDA's statute-driven, regulation-bound approach to its core mission, the assurance of product safety and effectiveness. The end won't change, but the means will.

The agency demonstrated its new attitude at the medical device sessions of FDLI's educational conference last December, an annual megaevent traditionally regarded as the tribal gathering of all who do business with FDA.

Center for Devices and Radiological Health (CDRH) director Bruce Burlington, for instance, publicly called for an industry-FDA "consensus" process to develop "focused" FDA reform legislation in tandem with internal administrative reforms. By focused he means changing only a few areas--which he declined to name--with legislation and correcting all other problems administratively.

FDA's main focus will be on achieving greater device approval efficiency without pressing for user fees. Perhaps the agency considers Kessler's farewell speech at the FDLI meeting, boasting of a stellar drug approval performance made possible by user fees, sufficient inducement to device industry leaders to reevaluate their opposition to device user fees (and there are covert signs that some will do just that).

Representing the enforcement side, CDRH Office of Compliance director Lillian Gill also showed unprecedented openness by announcing that her office will seek public input on a compliance strategy to examine 4 out of the 15 most-recalled, most-complained-about types of devices from 1991 to 1995. She identified those 15 as apnea monitors, cardiac monitors, cardiology catheters, defibrillators, electrosurgical devices, hexokinase-glucose strips, implantable pacemakers, infusion pumps, intraocular lenses, intravenous administration sets, linear accelerators, patient examination gloves, radiation therapy devices, surgical lasers, and ventilators.

Many earned their place on the list because of the agency's medical device reporting (MDR) regulation, Gill indicated, vindicating an expensive CDRH program that has drawn more than a few bitter complaints from industry sources, along with charges that it has been unproductive.

The fact that any FDA enforcement office, whether Gill's or any other, would submit its police work to public scrutiny speaks volumes for the new way of life that is evolving at the agency.

Traditionally, FDA's detective work to find wrongdoers was often conducted in tight secrecy out of fear they would be tipped off and would paper over their misdeeds, thereby foiling FDA investigators. FDA seems to have junked that tradition, concluding that misdeeds really can't be papered over. And if advance information of a raid does impel violators to mend their ways, society benefits even if the investigation never takes place.

By choosing only 4 out of 15 device categories for comprehensive compliance review, Gill was candid in acknowledging that that's all her office can afford to tackle at one time. That, in itself, was an unprecedented confession.

After speaking at the FDLI meeting, CDRH director Burlington elaborated further on his new approach to the review of medical devices. On the topic of product safety, he explained that CDRH is reassessing how it categorizes risk. Devices in Class III, Burlington said, pose two types of risk--the risk inherent in the product itself, and the risk presented by a lack of knowledge about the product. "There are products about which we know precious little because they embody new concepts but for which the inherent risk is not necessarily very high. You can reason some things deductively, and you don't have to base everything on experience. If the inherent risk in a Class III product is small, then we shouldn't be putting the same effort into it that we should put into one that has high inherent risk."

CDRH is reassessing all device categories, not just Class III, Burlington explained. The initiative is not a typical, bureaucratic, top-down exercise, either. As Burlington put it, "the people who know where the real problems exist are the people who do the work. They know where work is organized inefficiently, they know where work is misdirected." CDRH is trying to tap such internal expertise and use it creatively to maximize efficiency. It is also talking with industry as it proceeds.

There's no time frame for producing results from this process, Burlington said. "I think it's a new way of life....Learning the lessons that many in industry and large sections of the government have already gone through, you don't change processes once and say, 'OK, we did that, let's get on with our lives.' You have to be engaged in continuous process improvement. Not all processes come up in the first round. You stagger when you start reassessing them, because you can't commit all your resources to process improvement. You review where you have made progress and where you haven't. You pick up new topics where they become timely and as resources become available to do it. If it's done right, you can get your mission accomplished with fewer resources and greater satisfaction among the people you're dealing with."

By empowering lower-level managers to make decisions, thereby improving efficiency, FDA is constrained by an element that rarely hinders industry when it engages in process improvement--the need to maintain consistency in decision making while delegating those decisions, Burlington said.

"The one thing that, to my mind, is most different between working inside the government and working in the private sector is that, being a mission-oriented rather than a profit-oriented organization and working in a regulatory context, we have to set a higher level of consistency of decision making than most people in industry would. If your local long-distance carrier treats different customers differently, they can switch--they don't have to go back. On the other hand, we have to treat similarly situated applicants the same, or else we have to have a distinguishable reason why we're treating them differently. So we have to build in mechanisms to achieve consistency."

One vivid example of CDRH's success in this area is the real-time review of premarket approval (PMA) supplements, Burlington noted. While only about 15 supplements have so far undergone this resource-intensive process, the results have been "strikingly successful," encouraging the center to expand the concept "significantly." He believes that a "high fraction" of CDRH's 400-some PMA supplements can be handled this way, thereby yielding review decisions in about a week, or even the same day.

Candidates for real-time review so far have been supplements of "limited complexity" that don't involve clinical data (such as product improvements and labeling changes). The supplements are presented and reviewed interactively in person or by video- or teleconference.

"We're rolling it out to the rest of the program so all PMAs can take advantage of it," Burlington said. An internal PMA review team is now looking at whether original PMA applications might also be reviewed this way. On the surface, at least, it seems that the agency could afford this procedure only for a limited number of applications, simply because it is resource intensive. But Burlington isn't so sure. "It's not obvious," he said carefully, "that our existing approach is more efficient than real-time reviews." PMA supplements traditionally average about 180 days, each involving about one-and-a-half rounds of questions, plus minor questions. "That has involved a lot of passing the application around, a lot of queue time. In aggregate, the number of hours we spend doing that seems higher than when we ask four people to sit in a room for an afternoon."

How far this concept may be stretched beyond PMAs remains to be seen. For 510(k)s, the sheer volume of applications would seem to preclude real-time reviews, but the appeal of greater efficiency through decreased handling surely exists. Burlington said the center is reassessing the presubmission requirements it presently demands of industry, as well as the time it spends determining whether those requirements have been met in each submission.

FDA could also trim review time by using published data on a sponsor's own device or on a similar product to satisfy clinical data requirements for 510(k)s. There is a caveat, however, Burlington warned. The sponsor must be able to establish a bridge between comparable data and his own device.

"When we look at literature in the public domain, we look for two things that are not necessarily easy to accomplish. One of them is whether there is a redundancy of data. If you have five or six reports, all headed in the same direction, that would be far more compelling than if you had only one. If there isn't a redundancy, the other thing we consider is whether you have the full reports. Are we able to look behind the published article, get the original data listings, and give it an independent, full scrutiny?"

The changes have been discussed with a "number of folks in industry" that Burlington declined to identify, other than Fred Halverson, Medtronic's vice president, corporate regulatory affairs, whom Burlington called "very helpful."

It's up to industry to request grassroots meetings if it wants to provide input on the process, but Burlington is anxious to move quickly without unnecessary delays. "We need to get started now. The management literature on process improvement clearly indicates that it doesn't happen overnight. It takes time to develop a clear vision of what the new process will look like. You have to analyze it, develop standard operating procedures, and then teach people the ways to do the new process. You have to institutionalize it. That takes time."

In every area that CDRH is examining as it reinvents itself, it is assessing the need for new legislation, and its recommendations will be forwarded to the commissioner's office for consideration in the Clinton administration's own FDA reform legislation. But the changes being made now won't wait for that effort. Burlington emphasized that CDRH is proceeding on the assumption that the present law will remain.

On another note, the third-party review pilot program, while disappointing in terms of the number of companies that have submitted products for approval through third parties, has gone "very smoothly," with third-party reviews tak-ing half the time FDA takes, Burlington explained.

He doesn't buy the argument that companies would rather wait for FDA to review a device more slowly for free than pay a third party to review it twice as fast--although he does not claim to understand the commercial implications of such time savings. He believes industry's hesitancy may be more attributable to caution in the face of something new than to the program's failure to include higher-risk devices.

The list of candidate devices for third-party review is, however, being expanded, and more guidances are being written to facilitate submissions to third-party reviewers.

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

The Race to Develop a Painless Blood Glucose Monitor

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

R&D HORIZONS

Hopes are high for alternatives to finger sticks, but so are the technological hurdles.

If blood sugar were better controlled, the complications associated with diabetes might be far less prevalent and far less severe. Yet the average insulin-dependent diabetic exerts relatively poor control, injecting insulin just twice daily, despite conclusive evidence that three to four precisely measured administrations of insulin daily could prevent long-term complications, such as blindness.

The pain and inconvenience of current blood glucose tests, which require finger sticks with lancets to draw blood for analysis on personal glucose monitors, are one reason that the average insulin-dependent diabetic administers the hormone twice a day. But help may be on the way.

Entrepreneurs are racing to develop the ultimate expression of biosensor technology--a fast, painless, and convenient means for testing blood glucose. Ultimately, such a monitor could be tied into an implantable insulin pump that would deliver exact amounts of insulin to the patient. Adequate control could reduce--even eliminate for some patients--complications that impose some $45 billion in health-care costs annually in the United States alone.

In the process, companies making these monitors could reap an impressive financial harvest. Industry sources estimate that the worldwide market for glucose-monitoring products surpassed $1.5 billion in 1994 and continues to grow at a 14% clip annually. Of that market, U.S. sales make up about 59% of total revenues.

About 90% of the total sales today are related to disposable glucose reagent strips for finger stick monitoring. Painless monitors could take away a substantial portion of those sales. "Given the size of the market, anyone who can come up with a viable noninvasive or painless technique is going to make a lot of money," says Gregory Faris, an analyst at SRI International (Menlo Park, CA).

MiniMed's flexible glucose sensor is housed in a tube for subcutaneous placement using a needle introducer.

Faris notes that there has been a virtually endless stream of ideas driving entrepreneurs, including tests using samples of tears, saliva, and urine; an optical technique that scans the eye; and technologies for shining infrared or laser light into and through the body. "It's easy to mislead yourself that you can do it," Faris says. Several companies do, however, appear to be making significant progress.

Cygnus, Inc. (Redwood City, CA), has developed several prototypes of its GlucoWatch, a wrist-worn device that promises to noninvasively monitor glucose levels. The watchlike instrument would use electroosmosis to draw glucose molecules from the patient's skin into a dermal patch, whose contents would be measured and the data interpreted by an integrated circuit.

SpectRx (Norcross, GA) is developing a handheld device that uses a laser to create a micropore about the width of a human hair in the outer, dead layer of skin from which interstitial fluid is collected. This fluid is then measured using off-the-shelf glucose test strip chemistry. Integ (St. Paul, MN) is designing a device that would use a small needle to penetrate the skin and gain a sample of interstitial fluid containing glucose. A handheld battery-operated infrared photometer would then measure the glucose in the sample.

BROKEN PROMISES

But amid the hopes for developing a painless glucose monitor are stories such as that of Futrex Medical Instrumentation, Inc. (Gaithersburg, MD). For years, the firm showcased its DreamBeam, a battery-operated box about the size of a television remote control designed to provide noninvasive glucose measurements with the use of infrared radiation. Last September, the Securities and Exchange Commission (SEC) filed a fraud action alleging that Futrex and its senior officer, Robert D. Rosenthal, made false claims to investors in connection with a $1.85 million private placement of debt securities. The SEC alleges that the company and Rosenthal knowingly deceived investors, presenting false conclusions from clinical studies. During at least one meeting with investors, Rosenthal used the device on himself, and claimed the readings were accurate. But according to the SEC, he allegedly had "directed a Futrex employee to program a DreamBeam to function as if it were giving a glucose reading." Rosenthal was not available to MD&DI for comment.

The Futrex incident has not quelled hopes that a painless glucose monitor can be built. "There's a rich array of technologies supporting biosensor R&D," says Cort Wrotnowski, principal of the consulting firm Amvir Associates (Greenwich, CT), which specializes in the assessment of biosensor technology. "Somewhere there is an answer for what these guys want to do."

Several big names in the medical industry agree. Becton Dickinson (Franklin Lakes, NJ) and Yamanouchi Pharmaceutical (Tokyo, Japan) have signed on to market products under development by Cygnus. Yamanouchi bought marketing and distribution rights for Japan and Korea; Becton Dickinson bought them for the rest of the world. Similarly, Abbott Laboratories (Abbott Park, IL) purchased exclusive worldwide rights to SpectRx technology except in Singapore and the Netherlands, where the company has coexclusive rights.

The leaders in the race to develop a painless glucose monitor are taking either of two tacks. One is the use of infrared--or near infrared -- technology to noninvasively obtain optical signatures indicating the level of glucose. The other collects samples of interstitial fluid for analysis.

HARNESSING INFRARED LIGHT

Infrared analysis is as tantalizing as it is difficult to achieve. "Infrared can penetrate the skin, so measurements are possible at different depths," says biosensor consultant Wrotnowski. "But the feedback can be extremely complex, which means you need very sophisticated mathematical methods to do the analysis." The complexity of the data is a result of the way infrared interacts with aqueous solutions. Water soluble substances absorb infrared radiation very strongly, he explains, returning a "very messy signal." Ironically, nonaqueous substances return a much better signal. "These guys are trying to make something useful out of what constitutes infrared's greatest weakness," he says.

Ominously, the Futrex DreamBeam supposedly was based on infrared technology that could measure blood glucose levels by passing infrared light through a finger. The SEC complaint against Futrex states that studies of an earlier prototype, the Futrex 9000, as well as a version of the DreamBeam were unsuccessful and that a field study conducted in 1995 with the DreamBeam generated useless results, allegedly because of a manufacturing defect.

Another light-based technology, the Diasensor 1000 by Biocontrol Technologies (Pittsburgh) has had its share of problems. The tabletop spectrophotometer is designed to recognize a person's glucose patterns through the use of a light beam that passes through the skin of the forearm into the blood and is then reflected back to a sensor. A microprocessor is intended to interpret the data and calculate the blood glucose level.

Early last year enthusiasm was running high that FDA would soon clear the Diasensor 1000. But an advisory panel in February 1996 recommended against approval. At the meeting, the company produced successful data on only eight patients in its clinical trials, despite enrolling 85. Twenty-two were eliminated due to malfunction of the machine; two were eliminated because glucose levels did not vary sufficiently to calibrate the machine to them. Of the remaining 61 patients, 47 had the machine successfully calibrated to them. The company chose to follow 23 of them for 30 days, and FDA did not object, according to the company. The eight successes were found among those 23 subjects.

In an open letter to stockholders and diabetics, CEO Fred E. Cooper defended the company's position that eight patients provided sufficient data on efficacy and safety: "It was enough because for those eight patients, 263 data points...were submitted to FDA--that's an average of 32 data points per patient. Firms currently using finger stick technology only submit an average of one data point per patient for devices they are attempting to get cleared. That means 100 data points submitted equals 100 patients studied. Therefore, 263 data points submitted for the Diasensor 1000 is equal to having tested 263 patients--a substantial test size."

In the 10 months following the panel meeting, Biocontrol withdrew, revised, resubmitted, and then withdrew again a 510(k) application for the device. The company is continuing to work toward FDA clearance of the Diasensor 1000, says company spokesperson Susan Taylor, "and we are going to keep working at it." Company officials are now trying to finalize the details for a new study to be conducted in the homes of subjects. When completed, Biocontrol expects to submit a newly revised application to FDA.

Descriptions of the Diasensor 1000 published by the company refer only to "optics, electronics, and detection subsystems; software; and algorithms." Details about the device are not released by the company due to the competitive nature of the industry, says Taylor, who will state only that the device uses "a near infrared spectrum."

Cygnus's GlucoWatch uses electroosmosis to draw glucose molecules from the skin into a dermal patch for analysis.

Whereas Biocontrol Technologies is trying to use light radiation to non-invasively probe the patient, Integ's LifeGuide System uses a small needle to sample interstitial fluid in the upper layer of the skin. "We do not puncture the skin; we go into the dermal layer," says Dave Talen, Integ marketing manager. "The dermal layer has very few capillaries and very few nerve endings, so when the needle probes only to that depth, you don't draw blood and you don't feel pain, in the traditional sense." Pushing the device, which is about the size of a large cellular phone, against the skin forces the fluid into a "read" window positioned between an infrared source and a detector. "The glucose molecules absorb a certain amount of the energy and we measure that absorbence," Talen says. Clinical trials are expected to begin in summer.

SAMPLING INTERSTITIAL FLUID

The SpectRx system also samples interstitial fluid but rather than use a needle, the device fires a laser into the skin, creating a micropore approximately 80 µm across and 20 µm deep. The interstitial fluid that flows into the micropore is sampled and then passed to a test strip analyzer now on the market for conventional finger stick blood glucose testing. SpectRx spokesperson Bill Wells refused to provide more details about the device or its stage of development, noting that "we have developed a handheld prototype that successfully creates micropores." In some subjects, Wells says, the interstitial fluid rushes into the micropore quite readily. "In other people, it has to be coaxed out," he says. "There are some enhancements that are part of the development process that allow us to collect the fluid."

The analysis is much more straightforward than the collection process. As a result of its alliance with Abbott, the company is integrating Abbott's MediSense test strip technology into the device. According to SpectRx, preliminary tests have shown a high correlation between glucose in the interstitial fluid and in blood.

MiniMed (Sylmar, CA) is working on a minimally invasive monitor that would use a small flexible probe to sample interstitial fluid from the subcutaneous tissue between the skin and muscle. The probe is inserted using a needle and then the needle is removed. "There is a temporary immediate pain, the same as you would get from an injection," says John Mastrototaro, director of sensor development at MiniMed. The probe would be replaced with a new one after three or four days to prevent undue irritation and the risk of infection, he says. A sensor in the probe analyzes the fluid for glucose content, passing the data via cable to a microprocessor that might be worn on the belt like a pager. Early models might not provide a quantitative readout of glucose levels, but rather be programmed to emit an alarm if glucose levels exceed a certain range. "If it detects that the glucose is low, an alarm would signal the patient to do a finger stick to determine the glucose level," Mastrototaro explains.

Feasibility studies involving 12 to 20 insulin-dependent diabetics are under way. A trial involving up to 50 subjects is scheduled for midyear.

MiniMed is currently a leading manufacturer of external insulin pumps, holding about 75% of the U.S. market for those pumps. The company has also developed an implantable pump being sold in Europe. Ultimately, an automatic glucose sensor capable of delivering precise glucose measurements might be integrated with a version of the pump. "We have the delivery device; the next step is closing the loop by creating a sensor that will automatically tell the pump how much insulin to deliver and when," says Jim Berg, a MiniMed spokesperson. "That is our grand design--to create an artificial pancreas."

Cygnus, Inc., advocates a noninvasive approach that leverages electroosmosis to obtain interstitial fluid. "When exposed to this low-level electrical energy, charged particles in the interstitial fluid pull the fluid out of the skin and the glucose molecules go along for the ride," explains Craig Carlson, Cygnus vice president for corporate marketing and strategic planning. A small disposable pad, constructed from proprietary material, located between the GlucoWatch hardware and patient skin collects the glucose molecules. Those molecules trigger an electrochemical reaction with a reagent in the GlucoPad, thereby generating an electric current. A sensor in the GlucoWatch measures the resultant current and an application-specific integrated circuit (ASIC) calculates the glucose in the patient's blood.

Levels are calculated automatically at set times throughout the day and night. At the push of a button, those calculations are displayed on the watch dial in the context of trends in glucose levels. Alarms would be designed to go off if the levels exceed specific limits. An electronic memory also would allow downloading of the data to a computer for long-term trend analysis, potentially helpful in managing the disease. "We see ourselves not so much as providing glucose measurements as information managers," Carlson says.

CHALLENGES IN DEVELOPMENT

Common to all developers is the challenge of providing accurate blood glucose measurements, regardless of such variables as patient exercise and the digestion of different kinds of foods. The approach that is being taken by most companies, including MiniMed, is to control for these variables by testing subjects under different conditions and then modifying the device to render accurate measurements.

Each of the companies have other specific challenges to overcome. The invasive nature of the MiniMed device, minimal though it is, presents the danger of skewing data. "If the sensor causes a lot of irritation or trauma at the site of insertion, it can cause the local glucose concentration to change," Mastrototaro says. "Another possible problem is that proteins in the body could foul the sensor or impair its performance."

Noninvasive infrared technology presents special challenges because skin and bone absorb and deflect light. There is the added problem of trying to iden-tify optical signatures of glucose levels, signatures that may be as specific to patients as fingerprints. Therefore these devices may have to be calibrated to individual users.

Calibration proved to be a problem for Biocontrol in its clinical study presented to the FDA advisory panel last year. Other companies have been able to avoid that hurdle. SpectRx, for example, uses an off-the-shelf test strip technology provided by Abbott. "It certainly shortens the development time to use existing technology," Wells says.

Cygnus officials believe their technology has no serious technical challenges ahead. But the company must contend with the pitfalls of being a device integrator. "The task we have now is making sure all of the components that have been optimized and tweaked since the early prototype testing operate effectively as a unit," Carlson says.

Cygnus, whose strength is in the design of transdermal patches, most notably the mass-marketed Nicotrol patch, must rely on contract engineering firms to build hardware for doing the analysis and providing the readings. The pitfalls of such an arrangement became obvious in November 1996 when Cygnus announced that a change in the ASIC that serves as the brains of GlucoWatch would delay delivery of the latest prototype and, consequently, clinical trials. The problem, according to Carlson, was a defect in the design of the chip. "Two wires were touching one another," he says. "So when the chip was put in place, there was a short." At press time, it appeared that a reengineered ASIC would soon be delivered and integrated into the latest prototype.

Cygnus executives have shunned media attention, partly because of the highly competitive nature of the industry, Carlson says, but also because hopes have been unduly raised by competitors. Company policy, he explains, is to make a viable product and then seek publicity --not the other way around. MiniMed has a similar policy. "People's lives are involved and we don't want to suggest that this technology is right around the corner," says MiniMed spokesperson Berg. "This is very tricky, difficult work."

Greg Freiherr is a contributing editor to MD&DI.


Copyright © 1997 Medical Device & Diagnostic Industry

Site Selection Criteria for the Medical Device Industry

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Column

BOTTOM LINE

Five essential considerations for device company directors choosing a strategic business location.

In today's rapidly growing medical device marketplace, many expanding companies are searching for better locations. Manufacturing and nonmanufacturing organizations tend to approach location decisions in a similar way, but the factors that are important to each tend to differ. Five essential factors for all OEMs' site selection checklist are: availability of labor force, cost of doing business, regulatory environment, transportation network, and community attitude and assistance.

Many cities have organized site selection/business development agencies to establish relationships with companies looking to relocate. The cities that have organized their public and private sectors to plan for future growth and development have a distinct advantage in the high-stakes competition of luring new business to their community. OEMs should identify the communities that are willing to help them through the relocation period.

As Dan Fitzgerald, a senior business development representative at the Colorado Office of Business Development in Denver, explains, "Many companies begin their search by developing a matrix of their needs, weighing each according to its importance. Industries and companies within industries are often distinguished by their needs. Over the years, economic development organizations have developed in-depth and detailed answers to all of the frequently asked questions." The following discussion focuses on five site selection criteria that apply to medical device companies seeking to relocate or start a business in a new territory, and on the questions companies should ask as they map out a site selection strategy.

LABOR FORCE AVAILABILITY

A highly skilled, well-educated, and growing workforce is an essential consideration for a new business location. Commonly asked questions are: What is the skill level of the region's labor pool? What is the average wage rate? Statistics are available to provide firms with accurate state rankings for percentage of residents with college degrees and the number of adults who have completed high school. Specific statistics on biotechnology, medicine, and other industry-related educational backgrounds are usually available from state agencies.

Certain states recognize that specific job training for a new or existing workforce is crucial to the success of a company's relocation or expansion. Specific, quality job training that meets industry standards reduces the need for additional training once new employees are on the job, which saves the company time and money. When selecting a site, firms should look for states that will assist in training new or current workers in long-term, permanent technical jobs, or that provide short-term, job-specific training designed to fit the company's needs. Quality training programs provide a trained workforce that matches specific job skill requirements so that workers are ready to work as soon as the business opens its doors.

States will frequently have requirements and restrictions on their training programs. It is common for states to require companies to hire the trainees, pay them specific wages, and provide them with specific benefits packages. By researching a prospective region's job training programs a company can find answers to many of its specific work force questions.

COST OF DOING BUSINESS

Each medical device company has to assess how much it will cost to operate its business on a daily basis. An important area to research is utility costs, especially electricity. Such issues usually focus on the following: availability of electricity to the site, availability of temporary power during construction, regional generating sources, hookup fees, and cost per kilowatt hour.

"For the medical device industry, it is essential to compare power costs of potential sites. When there is a large and continuous demand for electricity, regions that charge $0.03 per kilowatt are obviously better than regions that charge $0.13 per kilowatt," says Bob Cooper, president of the Spokane Area Economic Development Council.

An area's central location, proximity to natural resources, moderate climate, and generating capacities can allow local utilities to provide an ample and reliable supply of electricity, natural gas, and water at competitive prices. Certain areas are served by municipally owned electric generators, or their own water and sewer operation, which can significantly lower utility costs and make an area a more desirable site.

Additionally, labor costs and productivity can vary from state to state and may significantly influence day-to-day expenses. Site selection agencies encourage businesses to research the specifics of a targeted state's workers' compensation laws. Sometimes workers' compensation laws and rates can change dramatically from year to year. In 1995, Colorado experienced an average rate decrease of 9.6% that saved businesses over $70 million.

Other important issues are the cost and availability of buildings. Are buildings available for immediate occupancy? What are the lease rates?

REGULATORY AND TAX ENVIRONMENT

The tax environment can vary significantly from state to state and region to region. Device companies need to investigate the state, county, and city tax structures, because some areas provide more competitive business tax structures than others. When selecting a site, businesses should seek those areas that have tax structures designed to reward investment and innovation.

Corporate income tax, unitary taxation, sales and use taxes, unemployment tax, workers' compensation, property taxes, and inventory taxes are factors that should be researched. For medical device companies whose annual gross income exceeds $11 million, severance taxes may apply. Another variable companies should consider when comparing potential sites is tax credit incentives. Some states offer investment and enterprise zone tax credits, as well as sales tax exemptions.

For device companies that clean parts and assemblies, or use chemicals or gases in quantity, it is necessary to be aware of local environmental regulations. A coordinated permitting process can help new companies address environmental laws. In Colorado, for example, the Department of Public Health and Environment administers the environmental protection programs, emphasizing pollution prevention in partnership with the business community. The department is responsible for coordinating permitting functions among the major programs--wastewater and storm water, air quality, and hazardous waste and solid waste. Other states have similar departments that assist companies by serving as the key point of contact, providing accurate and timely information regarding permitting and regulatory requirements.

TRANSPORTATION NETWORK

As the medical device industry becomes more global, it is increasingly important for firms to be part of a transportation system that can move people and materials both locally and throughout the world. Companies should investigate the accessibility of the region's interstate highway system, railroad networks, and airport. A convenient and continually developing transportation infrastructure in proximity to major trade corridors, and offering access to major markets as well as to product suppliers, is critical to companies attempting to streamline their supply chain.

The kind of product a company manufactures is an important factor when exploring a region's transportation network. According to Cooper, "Due to the light weight of most medical products, medical device companies have few transportation restrictions." In the medical device industry, proximity to a major international airport is often the most important transportation consideration, allowing next-day delivery of products around the globe.

COMMUNITY ATTITUDE

Fierce competition exists among states to attract businesses and economic growth within their borders, resulting in better business environments for relocating companies. A key component of thorough and successful site selection is the ability to research and recognize which regions offer the best relocation package. Regions that help navigate the permitting and regulatory process; have a highly skilled, flexible workforce; provide workforce training; find buildings or building sites and arrange for loan financing; and identify potential customers, vendors, suppliers, and distributors are the regions that should make a company's site selection short list.

In Minnesota, for example, the Department of Trade and Economic Development works to stimulate growth in the state's health-care and medical product industries through a Health-Care Industry Development Program and a Site Location Program. These programs assist businesses that are interested in expanding or relocating to Minnesota by helping to identify potential sites and acting as liaisons between businesses and local and state government.

Economic development and site selection agencies are reaching out to businesses that are seeking a new location by developing unique incentive packages. Locating these regions is a good starting point for companies involved in site selection.

The availability of a productive, well-trained labor force tops the site selection priority list and is followed by a region's cost of doing business, its regulatory and tax environment, transportation network, and willingness to provide assistance to facilitate a move. Although each company is unique and will have other considerations on its list, these five criteria provide a solid foundation for companies in the medical device industry.

Once these basic criteria are established, companies can focus on case-specific issues and quality of life considerations before making a final site selection decision.

Chris Dray is assistant editor for MD&DI.


Copyright © 1997 Medical Device & Diagnostic Industry

Mapping Human Anatomy from MRI Data for Improved Product Development

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Feature

PRODUCT DESIGN

Magnetic resonance imaging is not just for diagnostics. Converted into CAD models, MRI data can also create virtual anatomies upon which to build medical devices that are sure to fit patients.

For more than a decade, physicians have used magnetic resonance imaging (MRI) to produce accurate representations of internal and external anatomical structures. With these images, abnormalities such as tumors can be easily detected.

MRI scans converted into vector CAD files can be used to create 3-D anatomical models for product development.

Today, MRI data are being used not only by physicians, but also by medical device manufacturers. Through the use of 3-D computer-aided design (CAD) models derived from MRI data, devices can be designed to accurately conform to the shape of the human body. In particular, medical devices that are inserted or implanted into the body, such as hearing aids, surgical tools, and diagnostic imaging probes, can benefit from the use of anatomical models in product development. By seeing how the device will fit the body early in the design process, product engineers can dramatically improve the ergonomics of these types of products and prevent redesigns.

Anatomical models produced from MRI data can also be used to design prostheses. An abnormal structure, such as an amputated limb, for example, can be scanned by an MRI machine and modeled in a CAD program. By comparing the amputation model to a model of a whole limb, a designer can determine the shape of the needed prosthesis.

To use MRI data to build medical devices, designers need to become familiar not only with what the MRI data actually represent, but also with how to convert them to CAD format and then how to manipulate the CAD files to create 3-D anatomical models. Becoming familiar with these aspects of the process will require an understanding of some technical graphics concepts, such as voxels and vectors.

To produce an MRI representation, magnetic fields and radio waves stimulate atoms in the body, which emit radio signals in response. The durations of these response signals vary among tissue or other organic material types. Cancerous tissue, for example, emits a much longer response than healthy tissue does. A microprocessor uses these variations in response lengths to produce an image of a cross section of an anatomical structure. The cross sections comprise rows and columns of 3-D volume elements known as voxels.1 The depth of the voxels is, of course, set by the thickness of the slice of anatomy that is being modeled. The width and height are determined by the area that is within the scope or boundaries of the MRI scan (the field of view), the overall size of the image, and the number of columns and rows of voxels that are used to generate the image (the imaging matrix). Each voxel is either white, black, or a shade of gray. The shade, or intensity, of the voxel is determined by the duration of the radio-frequency response that is emitted from the corresponding area of the patient's anatomy.

One of the first technical challenges of creating CAD models from MRI data is converting the information generated by the MRI scanner--the location, size, and intensity of every voxel--into a vector format that a CAD program can use.

VOXELS TO VECTORS

To create the MRI representation, the coordinates of the voxels, their size, and their intensity are displayed, or painted, as a series of unrelated dots that form a cohesive picture only because they are very close together. Graphics used by CAD programs, however, are composed of continuous lines, or vectors, that represent equations based on beginning points, ending points, and direction.

There are several techniques for converting voxel data sets into vector graphics. Of course, before a conversion technique can be chosen, the MRI images must be clear enough that the structure of interest can be identified. If the images are sufficiently sharp, then practical factors--such as the availability of computer hardware and software resources; the complexity, clarity, and number of MRI images; and the frequency at which anatomical models need to be built--will determine which conversion technique is most appropriate.

Voxel to Triangulated Mesh. The most direct, automated, and expensive method is to use a set of conversion algorithms that generate vector triangulated mesh surfaces directly from the MRI data set.2,3 Typically, such algorithms evaluate neighboring voxels to determine whether the differences in their intensities are within a specified threshold value. Adjacent voxels that have nearly the same intensity can then be linked to form a vector. Using this method, the computer generates vertices and triangular surfaces from the voxel data sets.

A 3-D model of a medical device is drawn onto a wireframe anatomical model.

Complex computer code can be written to perform this type of conversion. There is also diagnostic imaging software available, although it is costly and requires a significant investment in sophisticated hardware.

Because it is automated, the voxel-to-triangulated-mesh technique is best for manufacturers who plan to convert a large amount of MRI data. One limitation of the method, however, is that CAD files generated by it are made up of collections of flat triangulated planes with no actual curves. The triangles, especially if they are very small, can closely approximate curves, but using very tiny triangles will cause large file sizes and slow processing times, which can have a negative impact on CAD system performance.

Voxel to Vector Polygon. A less expensive and less automated technique uses the raster-to-vector conversion functions that are available in vector-based graphics packages, scanner conversion packages, or mapping and geographical information system software.

Specialized applications, or utilities, are available to save each voxel-based image in a graphic format that is compatible with the vector conversion software to be used. Common formats for saving these raster graphics are bitmap (.BMP) and graphics interchange format (.GIF) for the PC, or picture (.PICT) and tagged image file format (.TIFF) for the Macintosh.

Each graphic file is then imported into the conversion software, which draws a polyline along the edge of the anatomical structure of interest. To help the software select the anatomy of interest, the user can convert the graphic to a negative or monochrome image before conversion to vector format. The vector outlines are exported in a CAD-compatible format, typically the design exchange format (.DXF).4 A batch utility program can then be used to put the .DXF files into the CAD drawing application that will be used.

This conversion technique is not fully automated, because some user intervention and setup is required to enable the software to correctly outline the structure of interest for each image. Therefore, this method is best used when only a moderate number of images are to be converted.

Manual Vectorization. The least expensive way to convert MRI data to vectors is to import a raster graphic file directly into the CAD system and then simply draw a polyline spline, or series of lines and arcs directly over the anatomical structure of interest.

To prevent the creation of excessively large files when using this method, it is best to insert one image at a time into the drawing, trace the image, and then save the drawing to a separate file. Then the designer can delete the raster image and repeat the process for the other images in the data set. This technique should be used when only a few images are being converted.

CAD MODEL BUILDING

After the MRI graphics have been converted to a CAD-compatible format, the next step for a device designer is to create a 3-D surface model of the anatomy. If the voxel-to-triangulated-mesh conversion process was used, then this step will be unnecessary, since the model is already rendered in 3-D. But if either of the two less-expensive methods, the voxel-to-vector-polygon or manual vectorization techniques, was used, then the designer will be left with a collection of 2-D drawing files that must be combined to form a 3-D model.

To create a 3-D surface model, a designer must first build a wireframe model of the anatomy by individually inserting each drawing file into the CAD environment, positioning them relative to each other based on the center point of their fields of view.5 As each graphic is inserted into the CAD system, it must be scaled to ensure that the size of its field of view corresponds to the size of the MRI field of view. As MRI graphics are converted to a graphic file format they are often reduced, so when they are inserted into the CAD application, they much be expanded again. There are now programs, such as AutoLISP, that can automate placing the graphics in the CAD program, expanding them, and orienting them to a center point.5

A surface mesh developed from a wireframe model does not have the smooth transitions of a complex surface model.

When this process is complete, the outlines of the fields of view are deleted and a 3-D wireframe model of the anatomy remains. The components of this wireframe model can then be used to generate the 3-D surface of the anatomy and thus create a nonuniform rational B-spline (NURBS) surface model.

Surface Model Development. One way to generate the 3-D surface is to use the CAD program to create a ruled surface mesh between each of the adjacent entities of the wireframe model. This method is somewhat time-consuming, because separate surfaces must be created between each of the adjacent polyline entities of the wireframe model. Also, smooth transitions cannot be made between the adjacent surfaces.

Complex Surface Model Development. Some CAD systems are capable of generating complex surface models from the wireframe model. This type of 3-D model differs from typical surface model development in the number of entities that can be used to generate a surface and in the type of surface created. The advantages of complex surface modeling are that surfaces can be created quickly and that the surfaces are smooth. This complex modeling method produces the shape and contours of the anatomical structures more accurately than simple surface rendering does.

Solid Model Development. The wireframe model can also be used to generate a 3-D solid model. Because the anatomical drawings that make up the wireframe model can be extremely complex and nearly impossible to parametrically define, it is best to avoid solid modeling software packages that do not allow unconstrained sketches to be used to generate solid features.

To create the solid model, each drawing is simply extruded to a depth equal to the anatomical slice thickness. The disadvantage of this technique is that it generates a model with abrupt steps in its surface where two extruded sections come together. Another limitation is that the sections generated by this technique are extruded along a straight plane, which is not characteristic of most anatomical structures. However, the advantage of producing a solid model is that it can be analyzed to determine mass, volume, centroid, and other physical properties of the structure.

PRODUCT DESIGN

There are several ways MRI representations can be used in product design.

General Reference 2-D. The simplest way to use MRI data is to import the graphic file of the image into a 2-D CAD environment, scale it to the appropriate size, and use it as a reference to develop orthogonal views of the medical product. But this method is not helpful for developing a medical device that has complex shapes that must match those of anatomical structures.

General Reference 3-D. A better way to use MRI data for device design is to use a 3-D wireframe model as a reference. This method offers flexibility, because it allows the design engineer to use almost any type of CAD tool to generate the product design. However, it is not appropriate for a design in which the surfaces of the product and of the anatomy must match one another very closely.

Base Surfaces. A more sophisticated technique is to use portions of the NURBS surface model generated from the wireframe as the base surface of the product. After the product is designed onto the surface model, the anatomical model is simply trimmed away to leave only the product. One limitation of this type of surface modeling is that it may require a sophisticated modeling package or application. Also, although it efficiently combines the product with the anatomical model and maintains the complex surfaces that accurately model the anatomy, this type of model cannot be revised later as easily as can parametric solid models.

Boolean Solid Operations. Using a solid 3-D anatomical model, several Boolean operations can be used to build solid models of devices. Most CAD systems can perform a Boolean subtraction of the shape of the anatomical model from the device. Features of a medical product can also be added to the solid anatomical model by performing Boolean unions between the models. Using Boolean operations would be ideal for product modeling, except that the abrupt steps in the solid anatomical model, which are a result of the model-building technique, are transferred to the product model by the Boolean operations.

Integrated Surfaces and Solids. The most sophisticated and most accurate method of transferring anatomical model contours and shapes to a product model is to use a CAD system capable of integrating complex surface modeling with parametric solid modeling. Using a CAD system with these capabilities, the design engineer, taking advantage of advanced modeling capabilities and parametric relationships, can develop a solid product model and then integrate the shape of the anatomy into the product by performing a cutting operation on the solid to remove the complex surface anatomical model from the product. Changes to the product model can be made quickly because the solid model is parametric, with the complex surfaces providing the most accurate representation possible of the anatomical structures.

LIMITATIONS

The biggest limitation to the use of MRI data in medical device design is inaccuracy of the anatomical images, which is caused by MRI scanning itself as well as by the processing of the images. Slight motions of the subject during scanning can cause the image to be inaccurate. Therefore, modeling rapidly moving structures, such as the heart, is difficult, although new technologies for this are under development. Certain other factors, such as chemical shift, can also affect MRI scans. More inaccuracy is also introduced during processing because raster-to-vector conversion software is not exact.

CONCLUSION

Data from MRI systems can be used not only for diagnostics, but also to help create medical devices that closely match patient anatomy. There are limitations to the accuracy of the MRI data and the CAD modeling of them, but as the technologies improve, this kind of processing can only continue to become faster and more precise.

MRI technology can be an especially valuable tool for designers of devices that are meant to conform to the shape of the human body. Use of CAD modeling of MRI data in device design can significantly reduce the product development cycle by taking ergonomic and human factor requirements into account up front and by reducing trial-and-error iterations necessary to fit the product to patient anatomy.

REFERENCES

1. Kaut C, MRI Workbook for Technologists, New York, Raven Press, 1992.

2. Cline HE, Lorensen WE, Ludke S, et al., "Two Algorithms for the Three-Dimensional Reconstruction of Tomograms," Med Phys, 5(3):320-327, 1988.

3. Wallin A, "Constructing Isosurfaces from CT Data," IEEE Computer Graphics and Applications, 11(6):28-33, 1991.

4. Byrnes D, "From Raster to Vector: A Road Map," CADalyst, 11(7):40-50, 1994.

5. Kristoff J, "Converting MRI Scans to CAD Models for Device Engineering," in MD&M West Conference Proceedings, Santa Monica, CA, Canon Communications, pp 103-109, 1996.

James W. Kristoff now leads product development for Arthur W. Andersen, LLP (Cleveland). This article was written when he was at Picker International (Highland Heights, OH).


Copyright © 1997 Medical Device & Diagnostic Industry

New IDE Manual Clarifies FDA Policy on Clinical Studies

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Feature

CLINICAL TRIALS

Sponsors of clinical trials need to become familiar with the new IDE manual to interact better with FDA and to speed product development.



The new guard at FDA's Center for Devices and Radiological Health (CDRH) in Rockville, MD, has brought new life to an old classic: the investigational device exemption (IDE) manual.

Since the manual was last issued, in 1992, the center has undergone a nearly complete change in the personnel responsible for shaping the policies on clinical studies of investigational devices and evaluating IDE applications. This revision of the manual reflects the efforts of the center, under its new leadership, to clarify its expectations of clinical trials sponsors.

According to FDA, the purpose of the IDE regulation is to encourage the discovery and development of medical devices while also protecting the public health. But to many sponsors, the regulation is an obstacle--a governmentally mandated rite of passage that manufacturers of new medical devices must endure to gain regulatory approval.

Despite their different viewpoints, regulators and industry must communicate. Ideally, increased interaction between manufacturers and FDA will shorten the regulatory process and minimize delays in the development of new devices. Understanding the new IDE manual is a good way to start developing better interaction with FDA. The new manual offers a comprehensive explanation of the IDE regulation, and any manufacturer who plans to conduct clinical trials should become thoroughly familiar with it.

The document has four major sections: an overview of the IDE regulation; an outline of how to submit an IDE; a compilation, which accounts for half of the manual, of the guidances and policies relevant to the IDE process; and a description of the bioresearch monitoring program.

OVERVIEW

The overview section of the manual summarizes the IDE regulation, which is given in 21 CFR 812. It repeats some parts of the regulation verbatim, but also often modifies the language or organization of the document to make concepts more accessible. The topics covered by this overview are the abbreviated requirements for a non-significant-risk device study, exempted investigations, contents of an application for an original IDE and for supplemental applications, and an explanation of FDA's decisions on applications, including the grounds FDA uses for approval or withdrawal. The responsibilities of sponsors in organizing and conducting an investigational study, responsibilities of investigators in conducting the study, and reporting and recordkeeping requirements are also outlined.

HOW TO SUBMIT AN IDE APPLICATION

The intent of this section is to communicate specifically the items that CDRH's Office of Device Evaluation (ODE) prefers in an IDE application, both in substance and in form, to ensure that applications will be substantively and administratively complete and review cycles will be minimized.

The section includes a suggested original IDE application checklist, which sponsors can use as a screening tool to determine whether their applications are administratively complete.

Typical problems that ODE has encountered with original IDE applications are listed. These problems range from premature IDE submissions to inadequate reports of prior investigations and inadequate investigational plans. The suggested format for IDE submissions is given in great detail; even the size of the margins and thickness of the binders are recommended. Suggested formats for IDE progress reports and final reports are also supplied.

An underlying theme of this section is that no detail, however trivial, should be omitted if a manufacturer wishes to increase the likelihood of timely FDA approval of an IDE.

NEW AND REVISED GUIDANCES

The heart of the new IDE manual is its compilation of numerous guidance documents and policies that ODE has developed to clarify specific requirements of the IDE regulations, and to assist manufacturers in wading through the IDE process. More than half of the guidances are new to the IDE manual, having been initially issued or updated since the 1992 edition. These new guidances, which are summarized below, provide fresh insight into ODE's current thinking about the design, conduct, and analysis of investigational studies of medical devices.

· "Goals and Initiatives for the IDE Program," July 1995. Perhaps one of the most important recent ODE policy statements concerning the IDE process is found in this memorandum. In fiscal years 1993 and 1994, ODE approved only one out of four original IDE applications in the first 30-day review cycle. Under the direction of Susan Alpert, ODE has since sought to reverse the trend of few approvals in the initial review period and, therefore, in part, to fend off congressionally mandated FDA reform.

This memorandum sets forth the ODE goals of substantially increasing the approval rate in the first 30-day review cycle and decreasing the average number of review cycles. Initiatives that have been implemented to foster an interactive review process, and thereby help ODE meet these goals, are described.

The essence of these initiatives is pre-IDE submissions and pre-IDE meetings, in which sponsors are encouraged to submit preliminary information for ODE review and to meet with ODE staff before making a formal IDE application. Procedures for such communications are described in this memorandum. The current IDE fax policy, which permits FDA to consider additional information faxed by sponsors concerning an IDE application that has already been submitted, is also described.

· "Statistical Guidance for Clinical Trials of Nondiagnostic Medical Devices," January 1996. The Temple Report, released by FDA in March 1993, concluded that there were significant deficiencies in the design and, therefore, the conduct of clinical studies performed by sponsors in support of their device marketing applications.

This report led to CDRH's current preference for randomized, controlled clinical trials to support virtually all original premarket approval (PMA) applications and many hybrid 510(k)s. Issued in the wake of these developments, this guidance, prepared by CDRH's Office of Surveillance and Biometrics, provides a comprehensive treatment of the clinical trial process from a statistical perspective. Running the gamut from clinical trial design to conduct and analysis of the clinical investigation, the document provides an explanation of each trial element, and discusses why it should be incorporated and what problems will arise if it is omitted. A useful appendix on sample size is also included.

· "Biological Evaluation of Medical Devices: The Use of ISO-10933," May 1995. Before a new device is studied in humans under an IDE, FDA requires that it be systematically tested to ensure that any risks from device materials will be well understood. Beginning in 1987, FDA relied on the "Tripartite Biocompatibility Guidance for Medical Devices," 1986, to determine the appropriate tests to evaluate the biocompatibility of investigational devices. The International Organization for Standardization (ISO), in an effort to harmonize biocompatibility testing, subsequently developed a standard for biological evaluation of medical devices (ISO 10993). To harmonize biological response testing with the requirements of other countries, FDA adopted part 1 of the ISO standard in July 1995. The guidance document includes matrices laying out initial and supplementary evaluation tests for consideration by manufacturers and a flowchart for the selection of toxicity tests.

· "Significant and Nonsignificant Risk Medical Device Studies," October 1995. The IDE regulations describe both significant-risk (SR) and non-significant-risk (NSR) studies. Distinguishing between SR and NSR studies is of critical importance to IDE sponsors and investigators, because NSR device studies have fewer regulatory controls than SR studies do and are governed by abbreviated IDE requirements.

This FDA information sheet guides sponsors through the decision between SR and NSR, and lays out the institutional review board (IRB) and sponsor responsibilities following the determination. The guidance replaces a July 1986 blue book memorandum of the same title, but contains updated and expanded examples of SR and NSR devices to help sponsors decide to which category their own devices belong. Because the consequences of an incorrect choice of SR or NSR can have significant consequences, sponsors should carefully review this memorandum before initiating an IDE study.

· "PMA/510(k) Expedited Review Process," May 1994. Sponsors are always eager to advance new devices to the marketplace as rapidly as technological development and the regulatory process will allow. In the interest of public health, FDA has determined that it should review 510(k)s and PMA applications for certain devices in an expedited manner. These include revolutionary or breakthrough devices, devices that treat life-threatening or irreversibly debilitating conditions, or those that provide a demonstrable public health benefit.

This memorandum describes FDA's criteria for determining whether expedited review should be granted, and the procedures that sponsors must follow to seek expedited review. It replaces the 1986 memorandum "510(k) Expedited Review" and the 1989 memorandum "IDE/PMA Expedited Review Process."

· "IDE Refuse to Accept Procedures," May 1994. According to ODE, many IDE applications are incomplete or substantially inadequate, lacking information clearly required by the IDE regulation and all components necessary to permit substantive review. The IDE refuse-to-accept procedures establish guidelines by which an IDE that does not meet a minimum threshold of acceptability will not be accepted by ODE for substantive review and approval.

The most significant part of this memorandum is a lengthy checklist for administrative review of all original IDEs. To ensure that an IDE application is sufficiently complete for FDA review, sponsors should make certain that all listed filing review elements described in this document are contained in their submissions. This IDE refuse-to-accept policy complements ODE's PMA refuse-to-file and 510(k) refuse-to-accept policies.

· "Implementation of FDA/HCFA Interagency Agreement Regarding Reimbursement Categorization of Investigational Devices," September 1995. The Health Care Financing Administration (HCFA; Baltimore) is permitted, under the statute governing Medicare, to reimburse for medical products that are deemed "reasonable and necessary" for diagnosis or treatment. Because of Medicare's historical interpretation of "reasonable and necessary," Medicare coverage was traditionally denied for investigational devices.

In September 1995, however, FDA and HCFA entered into an interagency agreement to expand Medicare coverage to include investigational devices, and this new coverage should facilitate patient enrollment in clinical trials. This memorandum describes the criteria FDA uses for deciding whether investigational devices should or should not receive Medicare coverage. The interagency agreement is also included.

· "FDA Information Sheets for IRBs and Clinical Investigators," reissued October 1995. The FDA Office of Health Affairs, with assistance from ODE, developed a series of information sheets, which were originally issued in 1989, to help IRBs protect human research subjects. Also of considerable interest to sponsors who are preparing for a clinical study of an investigational device, these sheets include information on advertising for study subjects, charging for investigational devices, and paying research subjects. A guide to informed consent documents, which describes the consent process, required elements of an informed consent form, and common problems with the consent document, is an important aid to sponsors preparing informed consent materials.

PREVIOUSLY ISSUED GUIDANCES

In addition to the above guidances and policies issued or updated since the release of the 1992 IDE manual, the new manual includes several previously issued documents.

· "Feasibility Studies," May 1989. Although this memorandum is somewhat outdated, given ODE's recent greater flexibility regarding use of pilot or feasibility device clinical studies, it does provide an essential overview of feasibility studies, including the concept of and the IDE requirements for such studies. Feasibility studies are also discussed in the "Statistical Guidance for Clinical Trials," which was described above.

· "Monitoring of Clinical Investigations," February 1988. No matter how well designed a clinical trial is, the failure to monitor a study can lead to the collection of inadequate or inaccurate data, diminishing or destroying the value of the clinical trial. This guidance provides sponsors with directions on proper selection of a study monitor, written monitoring procedures, and essential elements of monitoring site visits.

· "Sponsor and Investigator Responsibilities for Significant Risk Device Investigations." This document is designed to assist sponsors and investigators to understand and comply with the IDE regulations when conducting clinical investigations of SR devices. The general duties of sponsors are described, as well as the selection of investigators, study monitoring obligations, investigational device promotion, and study recordkeeping and reporting requirements. Specific responsibilities of investigators are also described.

· "Emergency Use of Unapproved Medical Devices," October 1985. FDA recognizes that during the development and testing of an investigational device, emergencies may arise in which an unapproved device offers the only alternative for saving a dying patient, and an IDE has not been approved or the patient's physician is not an investigator in the study. This guidance describes the circumstances that, according to FDA, constitute an emergency and the actions that a physician should take in such an emergency.

· "Notice of Availability of Investigational Medical Devices," April 1986. While IDE regulation prohibits the promotion or test marketing of investigational medical devices, this document lays out certain precautions that a manufacturer should take to make known the availability of an investigational device within the confines of a clinical study.

· "Waiver for Additional Investigational Sites." An excerpt from the IDE form letter to a sponsor, this brief document describes circumstances under which FDA will waive its requirements for submission of supporting information or prior FDA approval for the addition of certain investigational sites.

BIORESEARCH MONITORING

The bioresearch monitoring program at CDRH was expanded in 1992, after then-FDA commissioner David Kessler called for increased scrutiny of clinical trial data, and became the Division of Bioresearch Monitoring within the Office of Compliance in May 1993. The division monitors and inspects sponsors, clinical investigators, IRBs, and nonclinical laboratories involved in the testing of investigational devices. In the current FDA environment, bioresearch monitoring inspections are conducted not only while clinical trials are in progress, but also after almost every original PMA application is filed.

The objectives of FDA's bioresearch monitoring program--to ensure the quality and integrity of data submitted in product applications and the safety of human subjects in clinical trials--as well as the program's related functions and inspections are described in the IDE manual. All IDE sponsors should become familiar with the bioresearch monitoring program functions and inspectional programs to ensure that their clinical trials are conducted in compliance with the IDE regulation and to ensure that adequate and accurate data have been collected to support a PMA or 510(k) application.

CONCLUSION

In the post-Temple Report era of new medical device clinical trials, it is increasingly important for sponsors of investigational studies to be aware of all IDE requirements and ODE guidelines, policies, and preferences concerning IDE studies, and to be willing to engage in an interactive review process with the agency. The updated IDE manual provides a wealth of information in these areas. Thorough review and implementation of the manual by sponsors should enable FDA to accelerate review of an IDE application. Review and use of the manual will also benefit sponsors of clinical trials and the public by shortening the approval process for critical new medical devices.

Gerard J. Prud'homme is a partner with the law firm of Hogan & Hartson (Washington, DC). He concentrates his practice on medical device and drug law.

ILLUSTRATION BY JOHN BERRY.


Copyright © 1997 Medical Device & Diagnostic Industry

Medtronic v. Lohr Decision Underscores Importance of Regulatory Compliance

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

An MD&DI March 1997 Feature

PRODUCT LIABILITY

To protect themselves against product liability, medical device manufacturers should understand the implications of the Supreme Court's decision.

The Supreme Court's recent and highly publicized decision in Medtronic, Inc. v. Lohr has attracted the attention of the medical device industry because the Court clarified the defenses that medical device companies may use when battling product liability suits.1 The Court's ruling restricted the federal preemption defense--the argument that federal regulatory requirements bar product liability claims. Although the full scope of these restrictions is debatable, the Supreme Court did indicate that the federal preemption defense typically will not protect manufacturers against product liability claims involving allegations that a manufacturer violated FDA regulations. As a result, manufacturers can expect that increasing numbers of product

liability plaintiffs will allege such violations as a basis for their lawsuits. This shift in focus for product liability exposure makes it more critical than ever for manufacturers to ensure and document regulatory compliance.

PRODUCT LIABILITY AND REGULATORY COMPLIANCE BEFORE LOHR

Before the early 1990s, most medical device product liability cases proceeded somewhat independently of FDA compliance issues. Although regulatory compliance may have been relevant in certain cases, it did not necessarily determine liability. Thus, compliance with FDA regulations was not a defense to a product liability suit, and violation of agency regulations frequently did not establish liability conclusively, although violations were taken into account as evidence of liability.

In the early 1990s, manufacturers increasingly asserted the federal preemption defense to product liability claims involving allegations of FDA regulatory violations. The basis for the federal preemption defense is the U.S. Constitution, which provides that "the Laws of the United States . . . shall be the supreme Law of the Land."2 Under this supremacy clause, the U.S. Congress has the power to pass legislation that invalidates, or preempts, state law in a particular area. Congress included a preemption provision in section 521 of the Food, Drug, and Cosmetic Act (FD&C Act). This provision invalidates state law requirements that are "different from, or in addition to" federal requirements applicable to a medical device.

The premise of the preemption defense is that section 521 invalidates product liability claims. The Supreme Court made clear more than 50 years ago that the types of claims asserted in product liability suits involve the application of state law.3 Because product liability claims impose state law requirements, they are as vulnerable to preemption under section 521 as state statutes and regulations.

Before the Supreme Court's Lohr decision last June, many lower courts decided that the federal preemption defense bars product liability claims, including those asserting violations of FDA regulations. One classic example is the decision of the U.S. Court of Appeals for the First Circuit in Talbott v. C.R. Bard, Inc., in which the court held that federal preemption bars product liability claims alleging regulatory violations, even when the manufacturer has admitted committing those violations.4 Courts like the First Circuit, which affirmed preemption of claims alleging regulatory violations, concluded that the federal government has the unique authority to enforce FDA's regulations, and that private plaintiffs simply are not authorized to police regulatory compliance.

According to these courts, one major reason for exclusive federal control of compliance is that it maintains uniform court interpretations of FDA regulatory requirements; in contrast, allowing private plaintiffs to bring lawsuits interpreting FDA regulations would inevitably lead to differing, and perhaps contradictory, interpretations by courts across the country. Because the purpose of the federal preemption provision is to maintain a uniform rule of law at the federal level, these courts concluded that claims asserting regulatory violations are preempted.

PREEMPTION IN THE WAKE OF LOHR

In Lohr, the Supreme Court sharply limited the broad protections that many lower courts had extended against claims asserting FDA regulatory violations. The Court concluded that nothing in the FD&C Act preemption provision denies "a traditional damages remedy for violations of common-law [product liability] duties when those duties parallel federal requirements."5 The Court emphasized that this conclusion was at "an early stage in the litigation," leaving open the possibility that such claims could be preempted under other facts in other cases.6 But the thrust of the opinion significantly restricted federal preemption of claims asserting regulatory violations.

Manufacturers can expect that the Supreme Court's decision may well lead to more claims asserting regulatory violations. With the preemption doctrine often unavailable as a defense to these claims, plaintiffs will be freer to assert them successfully. In addition, plaintiffs will likely find these claims attractive, because other types of claims are still barred by the preemption defense. Justice Breyer stated in Lohr that he did not expect that "future incidents of [FD&C Act] preemption of common-law [product liability] claims will be 'few' or 'rare,'" and four other justices agreed that the FD&C Act "clearly preempts any state common-law [product liability] action" to the same extent that it preempts an equivalent state statute or regulation.7 With federal preemption available as a defense against many other types of claims, plaintiffs may be encouraged by the Lohr decision to couch their claims as alleged violations of FDA requirements.

PROTECTING YOUR COMPANY

Manufacturers can help protect themselves against such claims by ensuring regulatory compliance through use of effective standard operating procedures and appropriately trained personnel and by gaining a thorough understanding of relevant FDA requirements. However, companies can implement additional procedures that will offer still more protection.

Document Objections to FDA Allegations of Noncompliance. Every time FDA issues an FDA-483, warning letter, or any other document alleging possible regulatory violations, there is an opportunity for plaintiffs' attorneys to assert

a claim for regulatory noncompliance. When manufacturers have legitimate disagreements with FDA over regulatory requirements, they should make that clear in correspondence with the agency. Even if the agency's position is supportable, manufacturers should address FDA's concerns without admitting violations; such admissions could have significant ramifications in later product liability litigation.

Use Attorney Oversight for Regulatory Compliance Audits. Although FDA has not typically requested access to manufacturers' regulatory compliance audit reports, the same is not true for plaintiffs' attorneys. Under court rules authorizing broad discovery, plaintiffs' attorneys will be allowed access to relevant audit reports unless they are legally privileged. Depending on their contents, these audit reports could dramatically increase product liability exposure. The manufacturer's best protection is to generate the audit report in a manner that is privileged and therefore protected from disclosure. The most significant protections are provided by the attorney-client privilege, which precludes discovery of communications between attorneys and clients for the purpose of obtaining legal advice. With attorney involvement in the audit plan, most audit reports can be generated as privileged documents.

Document FDA Opinions on Regulatory Compliance. Manufacturers should make contemporaneous records of favorable comments from the agency regarding regulatory compliance. Whether made in management conferences at the close of an inspection or in meetings at district offices or at one of the centers, favorable FDA comments can add credibility to a manufacturer's claims of regulatory compliance. It may also be worth documenting circumstances in which the agency does not object to company practices (even if FDA does not make favorable comments). Examples include extensive inspections that end without the issuance of an FDA-483, or important meetings with the agency in which no corrective actions are requested.

Obtain Agency Inspection Documents under the Freedom of Information Act (FOIA). Establishment inspection reports and other agency inspection documents are available under FOIA. Manufacturers should routinely file FOIA requests for these documents following an inspection. If the documents support the company's regulatory compliance, they will be helpful in protecting against product liability claims alleging noncompliance. If the documents contain errors that could entice plaintiffs to make allegations of regulatory noncompliance, manufacturers should correct the record promptly through correspondence with the agency.

CONCLUSION

Although manufacturers always have needed to emphasize regulatory compliance, potential product liability exposure following the Lohr decision makes compliance even more critical. The remedies imposed by FDA for regulatory violations are substantial, but they typically do not involve monetary payments. Although the FD&C Act's medical device provisions were amended in 1990 to provide for payment of civil penalties, for example, the agency has not emphasized this enforcement tool to date. In contrast, product liability claims asserting regulatory noncompliance can impose financial burdens that in some cases are large enough to threaten the manufacturer's very existence. The manufacturer's best protection against these claims is scrupulous adherence to regulatory requirements.

REFERENCES

1. Medtronic, Inc. v. Lohr, 116 SCt 2240 (1996).

2. U.S. Constitution, art. VI, cl. 2.

3. Erie Railroad Co. v. Tompkins, 304 US 64 (1938).

4. 63 F3d 25 (1st Cir 1995), cert. dismissed, 116 SCt 1892 (1996).

5. 116 SCt 2255.

6. 116 SCt 2256.

7. 116 SCt 2262-63.

Daniel G. Jarcho is a partner at the law firm of McKenna & Cuneo llp (Washington, DC), and was counsel of record for Medtronic in Medtronic, Inc. v. Lohr.


Copyright © 1997 Medical Device & Diagnostic Industry