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Material Matters

Originally Published MX January/February 2005

COVER STORY

In the world of orthopedic joint replacement research, the big buzz is all about advanced bearing materials. Over the past decade, major players in the orthopedic sector have invested heavily in R&D to develop materials that can withstand the significant stresses exerted on a hip or knee under a normal range of motion. In a joint replacement implant, the bearing material must be tough, with high fatigue strength and the ability to withstand considerable sliding and rotating.

For Smith & Nephew Orthopedics (Memphis), the need for such advanced bearing materials is being amply filled by a form of oxidized zirconium that the company has trademarked as Oxinium. The company's unique manufacturing process enables zirconium to absorb oxygen, turning the surface of the alloy from a metal to a ceramic. The resulting material incorporates the best features of ceramic and cobalt chrome, and is 4900 times more resistant to scratches than cobalt chrome.

Angie Craig

Medtech Product Liability Defense Firms

Originally Published MX January/February 2005

GOVERNMENTAL & LEGAL AFFAIRS

Return to Article:
Liability Defenders


(click to enlarge)

Copyright ©2005 MX

Building a New Model for Spine Care

Originally Published MX January/February 2005

MARKET ANALYSIS

When the dust settles, technologies and procedures for treating spine conditions will look very different.

Marc R. Viscogliosi

Throughout the world, musculoskeletal impairments and conditions are the most frequent causes of disability. Encompassing more than 150 diseases and syndromes, musculoskeletal conditions affect every age and socioeconomic group, and will affect every human being who lives a normal lifespan.

The musculoskeletal business sector as a whole—including all treatment, services, devices, pharmaceuticals, and biologics used to treat the six types of musculoskeletal tissues in the body—represents a market of approximately $350 billion, or roughly 10% of the global healthcare industry.

Figure 1. Composition of the 2004 global market for medical devices in the musculoskeletal sector, by type. Total revenues for 2004 are estimated at $22.4 billion. Source: Viscogliosi Bros. LLC (New York City).
(click to enlarge)

USP : How It Affects Medical Device Manufacturers

Originally Published MDDI January 2005

Sterile Compounding

USP <797>: How It Affects Medical Device Manufacturers

Manufacturers of compounded sterile preparations have been faced with proving the compliance of some of their products with USP's new sterile compounding regulation.


Robert Reich and Hal Patterson

Products like I-Flow's ON-Q PainBuster postoperative pain relief system are subject to USP <797>.

On January 1, 2004, United States Pharmacopeia (USP) Chapter <797> “Pharmaceutical Compounding—Sterile Preparations” became effective.1 The regulation has raised many questions for compounding professionals as well as for medical device suppliers. Compounding centers found themselves required to institute and validate certain practices and procedures that were new to them. They also were faced with the requirement for a defined and documented quality system.

Because of these new requirements, medical device suppliers have had to respond to the compounding centers' questions about the suppliers' products complying with <797> requirements.

This article outlines one program a medical device manufacturer can implement to address such questions.

USP <797>

USP <797> was initially published in USP 27/NF 22. Chapter <797> details procedures and requirements for compounded sterile preparations (CSPs) and sets standards that must be followed in any facility that is compounding sterile preparations. CSPs are defined in <797> as

a.) Preparations prepared according to the manufacturer's labeled instructions and other manipulations when manufacturing sterile products that expose the original contents to potential contamination.
b.) Preparations containing nonsterile ingredients or employing nonsterile components and devices that must be sterilized before administration.
c.) Biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals that possess either of the above (a or b) two characteristics, and which include but are not limited to baths and soaks for live organs and tissues, implants, inhalations, injections, powers for injection, irrigations, metered sprays, and ophthalmic and otic preparations.

These new regulations have significant effects on manufacturers that offer sterile, nonpyrogenic, single-use devices to healthcare facilities for use in sterile compounding operations and other types of devices defined in <797>. When these devices are used in a healthcare setting, they are by definition CSPs. Such devices must therefore comply with the requirements of <797>.

In 1938, Congress passed the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FD&C Act recognized USP/NF as the official compendium of drug standards. FDA is responsible for enforcing the FD&C Act.

Each general chapter of the USP/NF is assigned a number, which appears in brackets along with the chapter name. The general chapters <1> to <999> are considered requirements and official monographs standards. Since <797> is a requirement, healthcare facilities that compound sterile preparations may be subject to inspection against it. The inspections may be performed by boards of pharmacy, FDA, and accreditation organizations like the Joint Commission on Accreditation of Healthcare Organizations.

This new regulation is causing problems for compounding professionals because many had never previously considered implementing many of the practices and controls specified in <797>. Now compounding professionals must be concerned with the design and classification of their filling cleanrooms, environmental monitoring, expiration dating, process validations, media-fill qualifications, sterility testing, and preparing a comprehensive quality manual.

However, these issues have been common practice in the medical device manufacturing industry for many years. In <797>, compounding facilities are instructed several times to refer to “manufacturers' labeled instructions” and to “consult the manufacturer of particular products for advice on assigning beyond-use dates on chemical and physical stability.” It is the responsibility of medical device manufacturers that produce the products to provide the compounding centers with this required information. It is a statutory requirement for any medical device manufacturer that claims its products are compatible with <797> to provide this information.

This situation is analogous to medical devices sold into healthcare facilities labeled as sterile but that allow reuse, or for devices sold as nonsterile but intended for resterilization by the consumer before use. In both situations, the device manufacturer must provide the healthcare facility with validated cleaning and sterilization instructions that the facility is capable of executing.2 Because these requirements are new to compounding centers, they are turning more frequently to medical device manufacturers for answers.

Medical Device Manufacturer Responsibilities

There are several sections of USP <797> about which a medical device manufacturer of CSP-application products should be aware. In addition, manufacturers should have validated data available consistent with the pharmacopeia requirements to support the use of their products. The sections include:

• Microbial risk.
• Expiration dating.
• Packaging—chemical stability.
• Product integrity—microbial barrier.
• Validation—media fills.
• Compounding accuracy.

Microbial Risk

One of the main areas of concern for the compounding professional is the microbial risk assessment required for all CSPs. USP <797> has assigned three potential CSP microbial contamination risk levels (low, medium, and high) that depend upon the compounding environment, contamination risk, and in some cases the nature of production of the CSP (e.g., using automated filling equipment or reservoirs of injection and infusion devices).

An evaluation by the manufacturer is the first step in assisting the compounding center with compliance with <797>. The report should include how the products are used in the compounding center and an assessment of the microbial risk of the device. Medical device manufacturers also should have a documented rationale position that clearly outlines the microbial risk assessment of their devices used in a specific application.

Expiration Dating

Based on the microbial risk classification, a manufacturer can evaluate “prior to use” and “ beyond use” storage. These terms, used in USP <797>, refer to what medical device manufacturers usually refer to as expiration dating. For example, a CSP designated as a medium-risk preparation can be stored, prior to administration, for no longer than 30 hours at room temperature, 7 days at 2° to 8°C, or no more than 45 days at –20°C.

Medical device manufacturers should perform container-closure studies that demonstrate that their devices, when used according to instructions, will maintain sterility. Studies should be performed where the container, filled with growth-supporting media and under medium-risk conditions (ISO Class 5 environment), is demonstrated to be capable of maintaining sterility for at least the periods specified above. Appropriate media controls and bacteriostasis and fungistasis studies should be included in the study design.

Some categories of CSPs, such as infusion devices, contain drugs that may be administered to the patient for several days at room temperature. With these types of devices, the stability of the container poststorage and during administration should also be evaluated and documented. Medical manufacturers should conduct or contract protocol-controlled studies and create comprehensive final reports that clearly support their position and recommendations for expiration data. This information should be available for distribution to the compounding centers as requested or required. If the manufacturer includes a <797> compliance statement on the product label, this information must be available.

Packaging, Chemical Stability, and Product Integrity

The regulation specifically requires that manufacturers ensure that the “packaging selected for CSPs is appropriate to preserve the sterility and strength until the beyond-use date.” The final packaging for a CSP, such as empty evacuated containers, plastic infusion bags, or elastomeric pumps, must maintain the sterility and strength of the CSP. Sterility refers to microbial barrier properties, while strength refers to the CSP's potency. Although it is impossible to assess every chemical entity that may be placed into a package, manufacturers can use bracketing studies to identify basic chemical stability parameters like pH, oxygen transmission, etc.

A series of microbial stability studies and microbial ingress studies should be performed to evaluate the container. The studies should be done for each of the USP <797> microbial risk categories that are appropriate for a particular device. Microbial ingress studies with Brevundimonas diminuta and containers filled with microbial growth media, under the appropriate risk conditions for the device, should also be conducted. Since most compounding centers will not have the technical expertise or facilities to perform these studies, medical device manufacturers should perform these studies under defined protocols. The manufacturers can then generate final reports that document and defend their positions. These reports and protocols also should be made available to the compounding centers.

Validations and Media Fills

USP <797> requires that compounding centers have written and approved procedures for filling a CSP under certain conditions of microbial risk. The sterility assurance of an aseptically filled product is based upon process validations, environmental monitoring, and acceptable media fills. USP <797> outlines different media-fill procedures that compounding professionals can perform at their facilities, depending on the risk category of the CSP. Manufacturers should prepare device-filling instructions for the compounding professionals based on media-fill studies performed under the appropriate risk-condition environment. Such studies can be performed either by the device manufacturer, if the laboratory facilities are available, or at a contract laboratory. Typical studies involve filling multiple containers with a growth-supporting medium under the appropriate risk conditions (e.g., ISO Class 5 environment).

Multiple interventions should be designed into the study to represent the worst-case conditions under which the CSP would be filled. Examples of interventions include multiple transfers of a medium from one container to another before final filling. The device manufacturer should prepare comprehensive instructions from these media-fill studies and provide them to the compounding centers.

USP <797> has borrowed much of its content from the aseptic fill industry. It also has established media-fill qualification procedures to train the individual compounding professionals to perform aseptic transfers. These employee qualifications must be performed on an annual or biannual basis. Medical device manufacturers should prepare specific media-fill protocols for their medical devices. These procedures should be independently validated and made available to the compounding centers. This information can also be used by the manufacturers' sales force to structure in-service training programs to reinforce their device's <797> compliance.

Compounding Accuracy

The regulation also has set requirements for compounding accuracies. Automated-filling equipment manufacturers should carefully consider their instructions for use. Clear and concise recommendations for calibrating the instrument and verifying fill volumes should be included. Several filling-equipment manufacturers perform this service and offer good examples of filling and calibration procedures on company Web sites and in published literature. Although not a requirement, some medical device manufacturers offer recommendations on specific filling equipment that has been demonstrated to successfully work for filling their devices. Supporting data should be available in these cases to supply to CSP personnel if requested.

Conclusion

The publication of USP/NF 22 <797> “Pharmaceutical Compounding—Sterile Preparations” in the beginning of 2004 raised many questions for compounding professionals as well as for medical device suppliers. Medical device manufacturers have found that they must be able to answer questions from compounding centers about compatibility with USP <797>. Therefore, medical device manufacturers that supply components to be used in filling, packaging, or storing CSPs must be familiar with the regulation and have information to support the compliance of their devices. This information should include a rationale for the risk classification for their device that is consistent with their directions for use, technical reports, and protocols and procedures to support storage. The information should also include expiration dating and validated recommendations for media fill procedures for personnel qualifications. Although it is the responsibility of the medical manufacturer to generate this information for the <797>-compliant use of a product, beyond that, it is also sound business practice.

References

1. United States Pharmacopeia 27/National Formulary 22, Chapter <797> “Pharmaceutical Compounding—Sterile Preparations,” The U.S. Pharmacopeial Convention (Rockville, MD, 2003).
2. Association for the Advancement of Medical Instrumentation (AAMI), “Designing, Testing, and Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: A Guide for Device Manufacturers,” AAMI TIR, no. 12, (Arlington, VA, 1994).

Copyright ©2005 Medical Device & Diagnostic Industry

FDA's Third-Party Programs

Originally Published MDDI January 2005

Regulatory Outlook

FDA's Third-Party Programs

Harvey Rudolph and John Stigi
Underwriters Laboratories Inc. and CDRH

The first pilot program included all Class I devices and selected Class II devices. Class II devices were allowed if the number of submissions per year was significant and if FDA guidance existed for the review. In 1997, this pilot program was written into law through the FDA Modernization Act (FDAMA). FDA accredited 14 third parties to review 510(k)s under the new Accredited Persons 510(k) Review (APR) program. Under the program, manufacturers could choose to pay a third party to review their submission. Manufacturers could still opt to have FDA do the review at no cost. One might wonder why manufacturers would willingly pay for something that was available at no charge, but the theory was that the free market would introduce efficiencies that would make the reviews occur more quickly. The law required FDA to make a determination on a third party's recommendation within 30 days to create a faster road to clearance that might be more attractive to manufacturers.

FDAMA's legislative history makes it clear that Congress expected FDA to expand the scope of devices eligible for third-party review. FDAMA excluded only Class III devices and the following Class II devices: permanently implantable, life sustaining or life supporting, and those that require clinical data in a 510(k).

FDA ultimately expanded the list of eligible devices to the full scope permitted by FDAMA, first by adding all allowable Class II devices for which FDA review guidance existed. In 2001, FDA added devices that do not have FDA review guidance. The sunset date for the APR program was extended to October 1, 2007, with the passage of the Medical Device User Fee and Modernization Act (MDUFMA) in 2002. More importantly, MDUFMA also established FDA user fees for 510(k)s that are submitted to FDA with no third-party review.

MDUFMA also introduced another third-party program, the Accredited Persons Inspection (API) program. Industry lobbied for the API program. Many manufacturers experience multiple visits from various regulatory authorities or conformity assessment bodies to inspect or audit their quality management systems. Ideally, combining these audits into a single regulatory audit would save the manufacturers and the regulatory bodies both time and money.
As an initial step in that direction, FDA has accredited and trained the first 14 accredited persons to perform regulatory device inspections. The agency is in the process of qualifying, via joint audits, these third parties. As in the APR program, manufacturers can choose to pay an accredited person to perform the inspection or wait for an FDA inspection.

FDA also administers another third-party program related to inspections and 510(k) reviews. This program is derived from the mutual recognition agreement (MRA) signed by the United States and the European Union (EU) in 1998. Under the MRA, the EU designates EU conformity assessment bodies (CABs) to perform FDA inspections for device manufacturers based in Europe that are marketing devices in the United States. The CABs are also trained and accredited to review 510(k)s for devices (which are listed in the MRA) that are produced in Europe for marketing in the United States. On the U.S. side, FDA designates U.S. CABs to audit firms that produce devices in the United States for marketing in Europe. These CABs are accredited to perform Annex II (complete quality assurance system) audits or Annex III (type examinations) audits that are acceptable to notified bodies in Europe.

Copyright ©2005 Medical Device & Diagnostic Industry

Material Matters

Originally Published MX January/February 2005

COVER STORY

In the world of orthopedic joint replacement research, the big buzz is all about advanced bearing materials. Over the past decade, major players in the orthopedic sector have invested heavily in R&D to develop materials that can withstand the significant stresses exerted on a hip or knee under a normal range of motion. In a joint replacement implant, the bearing material must be tough, with high fatigue strength and the ability to withstand considerable sliding and rotating.

For Smith & Nephew Orthopedics (Memphis), the need for such advanced bearing materials is being amply filled by a form of oxidized zirconium that the company has trademarked as Oxinium. The company's unique manufacturing process enables zirconium to absorb oxygen, turning the surface of the alloy from a metal to a ceramic. The resulting material incorporates the best features of ceramic and cobalt chrome, and is 4900 times more resistant to scratches than cobalt chrome.

Angie Craig

Medtech Product Liability Defense Firms

Originally Published MX January/February 2005

GOVERNMENTAL & LEGAL AFFAIRS

Return to Article:
Liability Defenders


(click to enlarge)

Copyright ©2005 MX

Addressing the Problem of Medical Device Misuse

Originally Published MDDI January 2005

Device Misuse

Addressing the Problem of Medical Device Misuse

Medical device misuse is unavoidable. But how much responsibility should device manufacturers bear for creating safer products?


Michael E. Wiklund

Manufacturers must consider many factors during a product's
development to ensure proper end-use of the device.

For ethical, legal, and economic reasons, medical device manufacturers need to pay close attention to the many ways their products can be misused. Misuse sometimes exposes people to serious hazards that can lead to injury, death, or property damage. Such adverse outcomes can jeopardize a manufacturer's reputation and provoke lawsuits.

Of course, not all misuses are necessarily dangerous, and they may even be desirable. As used in this article, the word misuse is a product development term of art that has sparked considerable semantic debate. To many design professionals, it encompasses not just operating a device in an erroneous, and even malevolent, manner, but also beneficial and widely accepted but off-label uses.

Understanding the full range of possible misuses will allow manufacturers to make fully informed choices about how to prepare for these misuses. They may even be prompted to reassess whether they have correctly identified all the appropriate uses of their products.

Some manufacturers will take great care to prevent or mitigate foreseeable misuses. Others will take a more-limited approach that focuses only on uses described in the product's labeling, even when they may be directly or indirectly promoting the product's off-label uses. Logically, most will seek ways to limit their responsibility for egregious misuses.

Whether a given approach is regarded as reasonable or not depends in part on the work of a joint IEC-ISO standards committee, called IEC-ISO JWG4, which is currently addressing the issue of misuse. It also depends on how particular manufacturers manage their risks and on their assumed responsibility to protect people from design-induced and self-inflicted harm.

Preventing Misuse

Prudent manufacturers engineer their products to reduce the chance of misuse or abuse. For example, a manufacturer may choose to permanently seal a device's case rather than screw it together. That way, people cannot dismantle it easily. Such a solution may complicate repairs or even make them impossible. Still, it reduces the chance that someone will open the device and possibly receive an electrical shock. It also reduces the chance of tampering. As another example, a monitor manufacturer may customize its sensor leads to prevent users from inserting the leads into the wrong ports or outlets.

Other protective strategies in lieu of eliminating a hazard altogether include adding safety features, training people to use products properly, and placing warnings on the products. The last option is especially popular with manufacturers because it represents a simple, low-cost fix that also offers an essential measure of legal protection, since liability lawsuits often focus on a manufacturer's failure to warn users about hazards.

Persistent Forms of Misuse

Still, despite measures to encourage proper use, the misuse of seemingly well-designed products is a relatively common event. In fact, some misuses, often called off-label uses, have actually emerged over time as accepted practice.

For example, it has become routine to send patients home with intravenous (IV) infusion pumps. These pumps were originally designed for use in hospitals by trained medical professionals. IV pump manufacturers may not have anticipated such use or formally sanction it, despite the fact that it may be good for their business. Still, it is happening, and the situation raises concerns about laypeople using the product incorrectly. Matthew Weinger, MD, professor of anesthesiology at the University of California, San Diego, director of the San Diego Center for Patient Safety at the San Diego VA Healthcare, and cochair of AAMI's Human Factors Committee, says such misuses are common. “You have situations where patients and their family members are operating infusion pumps at home,” Weinger says. “For instance, a mother may be caring for a sick child. Should the manufacturer be held responsible if the mom turns off the alarms and there is a problem?”

Another form of common off-label use occurs with single-use syringes. Even though these syringes should be thrown away after just one injection, people may use them repeatedly. Is it enough for the manufacturer to label the syringes as single use? Or should manufacturers be held responsible for somehow disabling the syringe after its first use—a measure that can increase product cost? Some companies have already engineered single-use syringes that become inoperable after one use. Does this place companies that have not taken this step at risk? These questions do not have clear answers at this time.

Ventilators and warmers are also often misused, in the sense of the term of art. Although originally designed for use in operating rooms and ICUs only, Weinger says, “they have migrated into emergency rooms, step-down units, and even people's homes.” He adds, “These devices were intended to be used by individuals with special training but are now being used in less-acute domains by people who may have less skill. This misuse can lead to problems. For example, forced-air warmers can cause burns if you do not use them properly.”

Some manufacturers have treated common off-label uses as an opportunity to develop new products to meet those needs, properly accounting for the intended users' knowledge and abilities. However, this by itself has not eliminated the persistent problem of mismatched devices and users, a problem that must be addressed by both manufacturers and healthcare institutions.

Drawing the Line

As one might imagine, manufacturers want to take a number of steps to protect themselves. Such steps include:

• Drawing a clear line between misuses that are reasonably likely and those that are not.
• Differentiating misuses that are well intentioned from those that are not.
• Limiting their risk-management efforts to misuses associated with the product's intended purposes, which one might define as use error, rather than misuse, which seems to suggest flaws in the user's intent.

Manufacturers wonder how they can protect themselves against somebody using their device for an unintended purpose or to deliberately cause harm. They reason that a deranged individual could always find a bizarre way to hurt someone with a medical device. They suggest that designing a device to prevent such criminal acts while also maintaining the device's effectiveness and usability might be impossible.

Meanwhile, regulators and human factors specialists have been encouraging manufacturers to take a closer look at misuses before dismissing them as unlikely, unrelated to the product's established purposes, or outright aberrant. The proponents of a more-expansive analysis believe that some manufacturers ignore a large number of likely misuses, including the aforementioned off-label uses. Instead, those manufacturers take the logical stance that no one should use a medical device without having the proper qualifications and training to use the device in accordance with the instructions for use.

Weinger is a proponent of intensive human factors analysis of potential misuses. “If you are going to design a device with a certain set of intended uses, doesn't it make sense to ask the customer if those uses are reasonable or not?” he asks. Weinger's proposition assumes that manufacturers will discover differences between their intentions and the users' expectations.

So, the medical device industry is caught in a debate on misuse and the manufacturer's level of responsibility. It seems headed toward a compromise solution in which manufacturers perform more-intensive analyses of potential misuses. This compromise also may establish a cutoff point for misuses falling outside the manufacturer's responsibility.

Categorizing Misuse

During its 2004 meetings in Vancouver and London, the IEC-ISO JWG4 committee addressed the issue of medical device misuse. Specifically, they discussed how device misuse (alternately described as use error) factors into the overall risk-management process, as defined in IEC/CD Standard 62366, Medical Devices—General Requirements for Safety and Essential Performance—Usability.

One issue facing the committee as well as others concerned with incidence of medical device–related injuries is how to reliably differentiate reasonably foreseeable misuses from those that are not reasonably foreseeable. Another issue is where to draw the line in terms of the manufacturer's responsibility to protect against such misuse. To complicate matters, two analysts could independently evaluate the same potential misuses and draw different conclusions about the reasonableness of a particular user action, never mind the limits of manufacturer responsibility. The second issue introduces all kinds of economic and political issues that are beyond this article's scope.

Currently, failure modes and effects analyses (FMEAs) and fault tree analyses (FTAs) can focus on reasonably foreseeable misuses, but one has to depend on professional judgment supported by available historical data to determine the likelihood of a particular event.

Meanwhile, there is the matter of off-label uses. Although such uses are technically considered misuses, off-label uses may be so common that they become standard operational procedure—the established standard of care. This poses challenges to manufacturers that may have focused their design efforts on the needs of a particular user population, only to see the device serve broader needs. It is these kinds of complexities that have motivated ISO-IEC to take up the issue and work toward a common framework for dealing with misuses.

Most product developers would agree that some misuses (what some developers would term use errors) could be predicted by applying human factors engineering principles. For instance, it is well-known that people often bump into medical devices in corridors and procedure rooms. Such collisions might inadvertently change a critical control setting if the control were not guarded. Product designers can use this knowledge to develop devices that can withstand casual impact.

Also consider the case of a digital thermometer with a pointed tip. One could predict that someone might someday stick the thermometer's tip in an ac power outlet and receive an electrical shock. Such an outcome could be extrapolated from documented cases of people sticking a medical device's leads into an ac outlet and causing burns and electrocution.1 Therefore, some manufacturers may address these kinds of predictable misuses in their risk management efforts. At the same time, some manufacturers might feel this goes beyond their risk-management responsibilities.

There seems to be a strong consensus among manufacturers, regulators, and patient safety advocates that manufacturers should not be held responsible for malevolent acts, such as using a surgical instrument deliberately as a weapon. Gerald Panitz, an anesthesia equipment developer with Draeger Medical (Lubeck, Germany) and an IEC committee member, concurs. “Some theoretical possibilities, such as throwing a device at somebody, should be dismissed,” he says. He thinks that reasonable people would agree that such acts qualify as abuse and should be outside the manufacturer's responsibility.

One possible scheme for characterizing product uses as proper or improper included the following categories:

• Normal use: Using the device as the manufacturer intended, as described in the device's user manual.
• Common use: Using the device in ways that the manufacturer did not intend but that fall within the established standards of care.
• Misuse subject to mitigation: Using the device in ways that could be predicted by a thorough human factors analysis that considers the user population, the task, and the use environment.
• Misuse not subject to mitigation: Using the device in ways that could not be predicted by a thorough human factors analysis.
• Abuse: Using a device in ways intended to cause damage and personal harm.

However, this approach could be viewed as expanding the manufacturer's risk management responsibilities beyond reason, particularly because of the complexities of predicting human behavior.

Another possible scheme for characterizing product uses includes the following categories:

• Correct use: Using the device as intended by the manufacturer and as described in the device's instructions for use.
• Use error: Using the device in a well-intentioned but
incorrect manner.
• Abnormal use: A deliberate act of omission or commission intended to produce adverse results.

Notably, the latest scheme reduces manufacturers' burden to manage the risks associated with off-label uses, even if those uses are indirectly encouraged—or at least not discouraged—due to medical and economic benefits. It instead leaves the responsibility to explore other kinds of predictable misuses unresolved. However, the very existence of a common classification scheme should prove to be a benefit to industry and risk management efforts as a whole. It would provide an industry-consistent method for dealing with a very challenging problem for manufacturers.

Identifying Potential Misuses

While a classification scheme for product uses ranging from normal to malevolent evolves through the work of the ISO-IEC committee and others, manufacturers still face the daunting task of identifying unintended product uses to go along with the intended ones.

Of course, some manufacturers may want to limit themselves to addressing intended uses. But, as Weinger suggests, this could create a false picture of how their products will actually be used. He believes that “if manufacturers approached the task of identifying and mitigating potential product misuses in a manner consistent with the human factors guidance provided by AAMI and FDA, the rate of use error could be reduced by 50%.”

The simplest strategy for identifying unintended product uses is for subject-matter experts and representative users to imagine them. Consider the case of a metered-dose inhaler. What are some of the unusual things that people might do with a metered dose inhaler? A few minutes of creative and mischievous thought might yield to the following list.

• Toss a partially filled canister into a campfire.
• Aim the puff of gas into a flame to see if it works like a torch.
• Direct a puff into someone's ear or eye.
• Try to replace the medicinal gas canister with the kind of butane canister used in lighters.
• Trip and fall with the inhaler's mouthpiece in one's mouth.
• Crush the canister with a pair of pliers to see what will happen.

One could expand this list dramatically with more time and imagination. But the exercise is not just about envisioning absurd and risky behaviors. Rather, it should consider a wide range of scenarios involving not only careless users but also people who err while trying to do their best. Use errors involving an inhaler might include:

• Insert the wrong pressurized canister into the inhaler.
• Drop the device on the ground.
• Forget to shake the inhaler before using it.
• Lose count and administer too many puffs.
• Bite down forcefully on the mouthpiece.
• Fail to remove cap before use.
• Clean mouthpiece with a damaging, toxic cleanser, leaving a residue.

Shifting focus to other medical devices, one could also envision circumstances in which someone might remove a valve from a rebreathing system but fail to replace it before use, or fill an analyzer with the wrong or expired fluid, despite existing protections against this outcome. According to the latest category list, these actions would be use errors.

However, despite its usefulness in identifying potential misuses, individual imagination has its limits. Human factors and ethnographic research methods listed below can make a significant contribution to identifying the range of possible product uses, misuses, and abuses.

Observations. One productive method for identifying common misuses is to observe the device in question or comparable devices in use. Ethnographic research techniques, such as job shadowing, should reveal common misuses and perhaps some rare ones. This technique presumes that the researchers have a sufficient understanding of the associated medical procedures to detect problems. Field researchers can also identify potential misuses by imagining how things might go awry based on their observations.

Conducting Interviews. Another means of identifying potential misuses is to interview the people likely to come into contact with the product. This group can include physicians, nurses, technicians, therapists, patients, the patient's family members and friends, technicians, and maintenance workers. During individual interviews or group interviews, relevant scenarios can be presented and people can imagine how things might go wrong. Interviews may also include brainstorming exercises to identify common uses, misuses (including those due to use error), and abuses.

Conduct Usability Tests. Usability testing reveals how people may use a device based on their intuition rather than the manufacturer's instructions. It also reveals how design complexities can lead people astray as they perform a task, even when the people have received proper training. As such, usability tests reveal misuses that could be hazardous in a real-life setting in a safe environment. Simulating device use in a more controlled setting can protect caregivers and patients while exploring the more troublesome scenarios.

Analyze Incidents. The public record of adverse events is another place to look for potential misuses. The record is particularly useful if a new product has predicates, or devices already on the market that function similarly. Take, for example, a manufacturer of an automated external defibrillator (AED). The manufacturer might look at adverse events involving previous-generation AEDs or defibrillators in current use to inform a new development effort.

FDA's medical device reporting database is another useful resource for identifying potential misuses. However, many of the reports may lack the detail necessary to inform a proper hazard analysis. Panitz often works on the design of anesthesia delivery systems. He suggests also looking over customer complaints to identify possible misuses.

Conduct a Task Analysis. Another step toward identifying potential misuses is to conduct a task analysis. Decomposing an overall task into its myriad components enables manufacturers to develop a sense for the normal, safe way to perform a task. Such an analysis includes data input and output, decisions, and actions. A task analysis is a good way to examine the various and creative ways that the flow of tasks can go astray. For example, protective shields used during shipping might inadvertently be left on a product and produce an electrical or fire hazard.

Conduct a Fault Tree Analysis. Fault tree analysis, a staple among risk managers, can help to identify unintended uses. This analytical method traces negative outcomes back to their root causes. As such, one might start with the terminal event of electrocution and then assess the full range of events that could lead up to it. Then one could move along to other negative outcomes, such as poisoning, blunt trauma, misdiagnosis, etc.

Limitations of Quantification

Numbers can be comforting to those who seek to manage risk. A manufacturer would probably act quickly to protect users from a severe hazard that had a 1 in 10 probability of occurrence. The need for mitigation becomes questionable when the risk and severity of consequences decline. But analyses based on the probability of occurrence and severity of consequences is complicated by the unpredictability of certain human behaviors.

Unfortunately, it is difficult to predict how people will behave in specific circumstances, and not much data exist on the subject. As such, it is hard to predict the probability that someone will inadvertently misuse a device. The probability of misuse depends heavily on factors including the type of user, the design of the device, and environmental conditions.

Human factors resources can offer estimates of the chance of omitting a procedural step (3 ¥ 10–3) or making an arithmetic error despite self-checking (3 ¥ 10–2), for example.2 But the legitimacy of using these values is questionable.

Accordingly, manufacturers may institute a simpler, less-precise risk estimation scheme to prioritize risks of product misuse and determine the need for mitigation. For example, manufacturers could draw on the judgment of an advisory panel that includes human factors specialists, other kinds of experts, and representative users. The panel could rate misuses on a 10-point scale, ranging from low to high probability. At the same time, they could rate the severity of consequences on a 10-point scale, ranging from low to high severity. The final step would be to choose cutoff points for the level of probability and severity that warrants manufacturer action.

However, taking the product of the probability and severity scores might downplay the value of mitigating a potential misuse that could lead to severe consequences but could be easily remedied. For example, one's analysis might identify a misuse with a high severity (e.g., 9) but low probability of occurrence (e.g., 2), yielding a score of 18. This score might make remediation a low priority. However, the remedy might be quite simple and inexpensive. Therefore, one may want to consider each score, rather than the product of the scores, in the course of risk analysis and mitigation.

Along with regulatory compliance, liability exposure will be an important consideration in choosing the appropriate cutoff point. Therefore, manufacturers have a lot of ethical, regulatory, and economic reasons to analyze misuses and implement protections.

Conclusion

There is an increasing concern among manufacturers about their responsibility for device misuse. This may be attributed to the large financial settlements that have gone to people who have sued companies for injuries that could have easily been avoided.

Manufacturers are aware that caregivers are sending patients home with devices that were not designed for use by laypersons. This knowledge leads them to ponder how far they need to go with their risk management efforts. To some, committing to a rigorous analysis of potential misuses feels like opening a Pandora's box, placing them in more legal jeopardy than less. Yet there is also the debate about taking corporate responsibility even if it causes economic consequences.

Weinger is sympathetic to the manufacturers' plight. He says, “Manufacturers want to produce safe and effective devices. But because they are fundamentally economically driven, they are averse to losses, strive to limit their financial risk, and want to ensure they are in regulatory compliance. But, for their long-term success, they have to provide products that enable the best possible patient care, one patient at a time. If they can conceive of a possible device misuse, or even a criminal use for the device, they should examine economically viable ways to mitigate the potential problem. It's in their best interest to do so.”

But Weinger also notes: “A manufacturer may look at a potential problem and legitimately decide not to do anything about it. In our society, this may enable lawyers to attack the manufacturer in the future, saying in retrospect that it didn't do enough to prevent the injury from a recognized problem.”

In other words, manufacturers face the tough reality that once they identify a potential problem, they will be at risk unless they try to mitigate it.

Presently, manufacturers have to make educated guesses about their liability in the absence of any industry conventions or standards on the subject. Therefore, the IEC-ISO's initiative to develop guidance for manufacturers on device misuse promises to clarify the boundaries in ways that could increase the breadth and depth of safety analyses. At the same time, it is likely to cut down on the manufacturer's need to mitigate against malevolent actions. Ultimately, manufacturers may still have to decide for themselves how to address misuses that are likely to occur over the life of a product. Expanded safety analyses may be driven as much by product liability and commercial considerations as risk management policies.

According to Panitz, such analyses fit well with the commercial interests of medical device companies. Taking a commercial viewpoint, “If a device is error-prone, customers will not accept it and will buy from somebody else.” However, Panitz would leave the decision on the depth of analysis up to the manufacturer.

Taking an even broader view of product safety, Panitz makes an important point. He says, “Using a device outside its intended use, even with the best of intentions, has to be considered abuse. What really makes trouble is poor [device] usability leading to risks during normal use.…If a device is ideally safe—optimally designed to prevent use errors—most uses just outside the intended use would create no problem.” Panitz adds that the medical industry has a long way to go to address all of the problems associated with normal product uses. So rather than obsess over the few special cases of misuse, the industry should deal with them in the normal course of designing the safest possible product.

Reference

1. PL Clemens, Fault Tree Analysis, [on-line] (2004); available from Internet: www.sverdrup.com/safety/fta.pdf.
2. U.S. FDA: Medical Devices; Establishment of a Performance Standard for Electrode Lead Wires and Patient Cables, [on-line] (Rockville, MD: FDA, CDRH, 1997); available from Internet: www.fda.gov/cdrh/comp/fr0509af.html.

Michael E. Wiklund, PE, is a certified human factors professional who consults with medical device developers on the design and evaluation of safe, effective, usable, and appealing medical devices. He serves on the AAMI and IEC Human Factors Committees. He can be reached via e-mail at mwiklund@comcast.net.

Copyright ©2005 Medical Device & Diagnostic Industry

MDUFMA: How Far Has It Come?

Originally Published MDDI January 2005

Q&A

MDUFMA: How Far Has It Come?

Experts look at the benefits of MDUFMA and issues that need to be resolved.


Erik Swain

Trunzo
Leahey
Garvey

The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) reshaped certain aspects of medical device regulation. Most significantly, it created a new funding structure for review of new product applications by introducing a user-fee program. For the first time in history, the device industry contributed to FDA's budget to pay for the staff and infrastructure to review applications in a timely manner. As part of the deal, Congress was supposed to increase its appropriation for the CDRH budget as well, but that has not yet occurred at the level that was promised. The legislation also introduced other major changes such as a third-party inspection program and more regulation over the reprocessing of single-use devices (SUDs).

Now that MDUFMA has been in place for more than two years, it is an appropriate time to assess what parts of the regulation have worked, what parts of it haven't worked, and what improvements might need to be made.

MD&DI asked four experts on medical device regulation for their assessment of MDUFMA's successes and the challenges that remain. Executive vice president of technology and regulatory affairs for AdvaMed, Janet Trunzo represents the industry trade associations along with Mark Leahey, executive director of the Medical Device Manufacturers Association. Patricia Garvey is the corporate vice president of regulatory, quality, and clinical affairs at Edwards Lifesciences (Irvine, CA). And Linda Kahan is deputy director of CDRH.

What has been MDUFMA's greatest success?

Janet Trunzo: It is difficult to single out MDUFMA's greatest success since the legislation contains many provisions that positively affect FDA's medical device program and, by extension, industry as well.

Providing CDRH with an adequate and predictable revenue stream via increases in appropriations and user fees is certainly one of the most important consequences of MDUFMA. Without these funds, CDRH would continue to experience shrinking budgets and dwindling resources, leading to a significant slowdown in product approval times. This, in turn, would have a stifling effect on medical technology innovation.

MDUFMA also builds more consistency and accountability into FDA's device review program. The agency is committed to meeting strict premarket review performance goals beginning this year.

Another important provision of MDUFMA resulted in the creation of an Office of Combination Products within FDA. While still in the beginning stages, the office is making significant progress in defining policies and procedures for pre- and postmarket oversight of device, drug, and biologics combinations.

These initial steps are crucial to ensure that, as innovative combination products make their way through the developmental pipeline, patients will have access to them as soon as possible.

Mark Leahey: MDUFMA's greatest success was establishing the framework for protecting patients from multiple use of devices that FDA cleared for
single use only.

Patricia Garvey: The increased funding has allowed FDA to hire many new reviewers, which we hope will ultimately accelerate review times and increase the quality of the review. The funding has also allowed the agency to bring in some external consultants who will fill the gaps in expertise where needed.

Linda Kahan: One major benefit is that it has raised the profile of device review. It has given us more attention within the agency and within the whole government. The Office of Management and Budget (OMB) wrote to Congress requesting it to fund the FY 2005 CDRH budget promised in MDUFMA. Something like that had never happened before. It gives us a sense that what we want counts, and we now have a seat at the table.

Our processes are now better coordinated and integrated across all offices involved in premarket review. MDUFMA has forced us to consider the total product life cycle. And there are methods in place to ensure that we use all the experts that we can, whether they are on our review teams, from other centers, or consultants from the outside.

What has been MDUFMA's greatest shortcoming?

Trunzo: Certainly industry has been dismayed by the significant increases in user-fee rates—more than 50%—that have occurred in just the first two years of the program. AdvaMed was particularly disappointed in the 16% increase in user-fee rates for FY 2005 that FDA announced in August. The association proposed a methodology for calculating the fees based on our projection of a robust number of premarket submissions. This calculation would have capped the fee increase at 9%. However, FDA chose to use a far more conservative submission estimate in its calculations, which led to the higher fee increase.

Leahey: The user fee imposed by Article I of MDUFMA has been the act's greatest shortcoming. Industry supported the idea of a user fee in anticipation of faster FDA review times and additional congressional funding. However, after just two years, the industry's fees skyrocketed more than 60%, and Congress has appropriated only approximately $5 million out of the $60 million committed. And the performance goals laid out in MDUFMA do not represent, based on FDA's own data, the 25% improvement that the industry was promised.

Garvey: The large influx of new reviewers in some divisions of CDRH seems to have actually slowed down the review process. This may be because the new reviewers are not yet fully trained and can be extremely cautious and conservative in terms of decision making. Another reason for the lack of acceleration in review times may be that there are a lot of changes in personnel and positions, which requires informal coordinating that doesn't really further the review process.

Kahan: There are two issues that stand out, though I would call them frustrations rather than shortcomings. One is that we have not been able to benefit from a stable funding base. For the agency, that means we can't predict how much revenue we will receive, nor can we ramp up the programs as effectively as we would like. And we understand that causes concern from industry about not knowing what the fees will be.

The second is that we don't have the resources to upgrade our IT system, which remains fragmented and outdated when it needs to be state-of-the-art. An updated system would enable us to get our work done as efficiently as possible. It would enable tracking and reporting to the extent we need it.

Has there been sufficient interaction between industry, FDA, and Congress regarding how MDUFMA should be implemented?

Trunzo: Industry meets with FDA on a fairly consistent basis to discuss all aspects of MDUFMA implementation. For example, FDA meets with key industry groups quarterly to discuss user-fee metrics. The key topics include submission numbers, amount of fees collected, resource allocation, and progress in meeting performance goals.

Industry shares its comments and concerns regarding MDUFMA implementation with key members of Congress on a regular basis as well.

Leahey: Yes. The interaction between FDA, Capitol Hill, and the industry has been very good. MDMA continues to participate in the quarterly updates with FDA. In addition, we continue to keep Congress abreast of our concerns with the skyrocketing fees and the need for legislative modifications to address this issue.

Garvey: With regard to FDA and industry, there is a great deal of interaction. Agency representatives frequently attend our industry association meetings, proactively solicit input, and are transparent in communicating their intentions. But while the top management at FDA is engaged with industry, the communication does not always translate to the rank-and-file.

Kahan: We have put a priority on communication and are working to have as transparent a process as possible. Quarterly reports on MDUFMA's implementation process are posted on our Web site, and we host quarterly meetings with industry stakeholders to discuss MDUFMA issues. All of us, including other affected branches of FDA, interact with industry at as many educational events as possible. And we participate in conferences that have a strong industry presence. We have used the Internet to get information out quicker. We continue to meet with individual applicants regarding individual applications. We have been listening to industry's comments and responding to them, and some suggestions have been incorporated.

Has the user-fee provision of MDUFMA worked as expected? If not, what changes would you suggest?

Trunzo: We are still gathering data on the user-fee provision and will probably propose changes as part of re-
authorization in FY 2007.

Leahey: Unfortunately, the user-fee program is playing out as we feared. MDMA was concerned about the fact that the industry was held accountable for funding the program from day one, while Congress was given three years to appropriate the additional funding. In addition, the structure of MDUFMA did not provide for predictable user fees from year to year.

Structural changes should be made to stabilize the fees and ensure that all parties are held accountable. Compensating and workload adjustments should be eliminated to prevent the severe fee increases from continuing. Moreover, industry agreed to pay a reasonable fee in exchange for faster FDA reviews of premarket submissions. However, based on FDA's own performance statistics, the current MDUFMA decision goals do not represent faster reviews in more than 90% of the submissions. FDA should revisit the performance goals to see where they can be enhanced. Finally, the lack of congressional appropriations is extremely troubling. MDUFMA was established to provide additional funds to FDA to enhance performance. Yet, in the first two years, the industry user fees have been used to supplement government shortfalls in their budget. If this program is to continue, full congressional appropriations must occur.

Garvey: It is premature to make a call now. Initially, the intention of the legislation—to increase the speed of agency review—has not been accomplished uniformly across reviewing divisions. There are a few possible reasons for this, including lack of adequate funds to train new personnel due to insufficient funding from Congress, and a potential FDA miscalculation on the volume of original PMAs designed to bring in revenues, which resulted in a more than 60% increase in user fees in two years.

Kahan: What's working well is that the fee collection process is in place; collection has been kept apart from review so reviewers don't have to be concerned with it. DSMICA is doing a great job with timely decisions about who qualifies as a small business. Fees are set in a timely manner and they are being used for device review work. The program has created visibility and respect for device review. Without MDUFMA in 2004, the review program would have contracted and review performance would have deteriorated.

What's not working well is that revenues are not stable and predictable. Fee revenues and appropriations are less than envisioned. Therefore, staffing has increased more slowly and there is an urgent need to add staff to meet MDUFMA goals. To fix fee shortfalls, we revised our estimated number of fee-paying applications when fees were set for FY 2005, but the fix may have been too modest. Still, we expect collections to be closer to revenue targets in 2005–2007 than they were in 2003 and 2004. The bigger issue now is appropriations shortfalls.

In your opinion, are CDRH review times now sufficient?

Trunzo:
Review times have, in general, shown a gradual improvement in recent years. However, we continue to receive reports from our members that certain review activities are not under the clock. Scheduling early collaboration meetings, for example, has been difficult to achieve. In addition, we hear anecdotally that some 510(k) submissions that previously were typically reviewed in 60 to 70 days are now taking the full 90 days. So review times are far from optimal and more efficiency and consistency could be achieved.

Leahey: Although CDRH has steadily been improving performance since 1999, the time it takes to get a medical device cleared or approved still often exceeds the statutory time frames. So long as the statutory time frames are not met, review times are not sufficient. Furthermore, the goals under MDUFMA do not necessarily represent faster reviews from FDA. For MDUFMA to achieve the goal of faster reviews, the goals should be modified to ensure enhanced performance.

Garvey: No, approval times are inadequately slow and need to be improved.

Kahan: MDUFMA goals are receipt-cohort-based. Because PMAs take a very long time to review, the final data for this coming year are not in yet. But based on the statistics available, we have done very well. For example, in FY 2003 we received 47 original PMAs and panel-track supplements, of which we know decisions for 43. Of those with decisions, 95% produced a decision within 320 days, and our goal was 80% decisions within 320 days. Even if the other six miss the deadline, 83% will have met the goal. For 510(k) applications in FY 2003, we met our goal on decision times but not on cycle times. Preliminary data from FY 2004 suggest improvement in performance on cycle goals.

What is left to do? We look at MDUFMA goals not as a ceiling but as a floor from which to measure both cycle and decision times. We want to continue to improve productivity, but there are challenges ahead. Applications are getting more complex, and our existing staff is working at their limits.

How have the application formats codified under MDUFMA improved the review process?

Trunzo: Both expedited and modular review formats were in place before MDUFMA. However, while the FDA Modernization Act of 1997 authorized expedited reviews, MDUFMA set the performance goals for these types of reviews. The modular review program was a result of CDRH's reengineering initiative, though the program was codified under MDUFMA.

Leahey: The new avenues for approval have given industry additional mechanisms to determine the most appropriate and expeditious pathway to market. These new mechanisms are a significant achievement of the act.

Garvey: It is too early for us to say if the modular PMA application format has improved the process, as we have yet to take one to its conclusion. It is our observation that expedited applications are actually slower, so based on that measure, there needs to be
improvement.

Kahan: Before MDUFMA, we did not have clear definitions for panel-track, 180-day, and real-time supplements. It was sometimes confusing as changes in device design, manufacturing, and even indications for use were submitted without much attention paid to the type of supplement they actually were.

In addition, the guidance on modular PMAs has helped some firms better organize their applications. We have made some improvements to that program. For example, we now allow panel-track supplements to be submitted as modular PMAs. We also allow modules to be submitted at the same time if that is acceptable to the review division. Now that PMA review teams are bigger, we can handle that better.

We are working with industry to establish goals for the modular submission program. The number of modules is decreasing, as per our guidance document. But that means each module is more complex, which makes for unpredictable review times.

There are two options proposed to standardize review times. One would require a high percentage of modules received to have an action taken within 120 days for each review cycle. That means review times would be more predictable, but also more likely to take longer. The other option would involve having a lower percentage of modules received to have an action taken within 90 days for each review cycle. In that case, the average review time would be shorter, but less predictable. We expect input from stakeholders on these and other options.

Has the third-party inspection program worked as expected? If not, what changes would you suggest?

Trunzo: It is too soon to comment on this program because FDA is still in the final phases of training and certifying the third parties that will perform the inspections.

Leahey: The third-party inspection program has taken longer than expected to implement. FDA recently published revised accreditation criteria to incorporate changes to MDUFMA made by a technical corrections bill enacted in April 2004. FDA issued a guidance document on implementation of the program last month. However, this program cannot be evaluated until a number of manufacturers have been through the process.

Garvey: We have no experience with this provision.

Kahan: It's still too early to judge. Four firms designated as accredited persons have two auditors each who have completed all training and joint audits, and can conduct independent inspections. So far, 59 auditors have completed the required training and exam, and approximately half of them have conducted at least their first joint audit. But we have had some difficulty in scheduling joint audits. Qualified manufacturers are encouraged to participate and consider hosting a joint audit.

Has MDUFMA adequately addressed concerns about the reprocessing of single-use devices?

Trunzo: With MDUFMA, Congress sent a clear message that increased regulation was needed over the practice of reprocessing of single-use devices, so that, in essence, reprocessors are held to the same standards as OEMs. MDUFMA gives FDA some good tools to achieve more-stringent oversight of reprocessors, but it is up to the agency to effectively implement those provisions.

Industry was disappointed that FDA gave reprocessors two 90-day extensions to provide the agency with the supplemental validation data as required under MDUFMA. Since reprocessors have been required to maintain these data under FDA's quality system regulation since 1997, I don't understand why so much extra time was necessary.

The results of FDA's review of these validation data raise additional questions about the agency's oversight of reprocessors. FDA deemed that nearly 50% of the more than 1900 device models for which validation data was required could no longer be legally marketed. What assurances can FDA give the public that validation data exist to support continued marketing of the vast majority (nearly 80%) of reprocessed single-use devices that did not require data submissions to the agency? And how will FDA ensure that hospitals and other end-users are properly notified that a large number of reprocessed devices cannot be legally marketed?

In addition, industry continues to urge FDA to reconsider exempting some critical reprocessed single-use devices from the requirement to submit supplemental validation data for agency review, such as heart stabilizers and positioners. AdvaMed recently sent a letter to FDA highlighting known adverse events involving reprocessed heart stabilizers.

Leahey: While MDUFMA has addressed some concerns related to the reprocessing of single-use devices, we look forward to working with FDA to ensure that patients are protected from potentially harmful medical devices. Specifically, we continue to urge FDA to take enforcement action against reprocessors who have not complied with the January 2004 deadline for submitting enhanced 510(k)s including required validation data. FDA has stated that it has received only 5% of the enhanced 510(k)s that are required. Reprocessors who have not submitted the required validation data are currently in violation of federal law and their products are misbranded if they are still being sold to customers.

Because of the severity of risks associated with the reprocessing of SUDs, we believe that FDA should take immediate action to protect the public from such misbranded devices. The risk posed by these devices is illustrated by the results of the agency's review of supplemental validation data that have been submitted to date by reprocessors of SUDs. As announced [in November, 2004], of the 44 supplemental validation submissions reviewed, FDA found that 11 were not substantially equivalent, and an additional 12 were substantially equivalent for only some models of the device. FDA enforcement is essential to ensure that all data are submitted for reprocessed SUDs as required by MDUFMA and that reprocessors comply with the determinations resulting from FDA's review.

Garvey: No. Reprocessors still appear to be held to different, less-stringent standards.

Kahan: FDA has met the requirements of Section 302 of MDUFMA. The agency published lists detailing which reprocessed SUDs are no longer exempt from 510(k) requirements, and which require submission of validation data. The agency anticipated 53 supplemental validation submissions (SVSs), accounting for 1800 device models. Nine of those were not submitted by the statutory deadline, and thus are declared not substantially equivalent and must be pulled from the market. Of the 44 SVSs received, the agency declared 19 substantially equivalent for all models, 12 substantially equivalent for some models, and 11 not substantially equivalent, some of the latter having been withdrawn by the sponsor. Two are still under review. Of the 1800 device models accounted for, 52% were found substantially equivalent and may continue to be legally marketed, 33% were found not substantially equivalent, and 15% were withdrawn by the reprocessor. Those withdrawn or found not substantially equivalent can no longer be legally marketed. However, the reprocessor can submit a new 510(k) with validation data to FDA, if desired. Reviewing these submissions was a careful, thorough, and resource-intensive process, and we are confident that the decisions were scientifically grounded. We also spent a lot of time defining cleaning validation protocols, for which there were no standards.

Has MDUFMA adequately addressed concerns about labeling?

Trunzo: MDUFMA allows manufacturers to provide labeling in electronic formats to healthcare providers. Unfortunately, electronic labeling has not yet been accepted by other countries. We are pleased that the United States has led the way in this area, but for it to be completely successful, electronic labeling needs to be accepted worldwide.

Leahey: Section 301 established new labeling requirements for both OEMs and reprocessors of SUDs. It addresses underreporting of patient injuries and product malfunctions attributed to reprocessed SUDs. It also ensures that users know the SUDs they use have been reprocessed and by whom. However, by applying the device labeling requirements to both OEMs and reprocessors of SUDs, Section 301 has created an unnecessary administrative burden that threatens to undercut this provision entirely. There has generally been little difficulty in identifying the OEM of a particular SUD. Therefore, it is not necessary to identify the OEM on a label attached directly to the device. In contrast, once a device has been removed from its packaging it is difficult to know whether a particular device has been reprocessed and by which reprocessing company. Without a label, a reprocessed device is likely to be associated with the OEM, rather than the reprocessor.

Reporting patient injuries and product malfunctions is a cornerstone of FDA's postmarketing surveillance system. If the user cannot identify that a product was reprocessed and by what company, the user cannot accurately report malfunctions to FDA. In order to track and account for injuries associated with reprocessed devices, Section 301's labeling requirement should be limited to reprocessors of used SUDs to address significant problems of identifying whether, how many times, and by whom the device was reprocessed.

Garvey: While FDA should be recognized for leading the world in allowing electronic labeling, we have not yet been able to implement it on a global basis due to a lack of international standards.

Kahan: The agency is trying to find the best way to implement Section 301, which requires the name of the manufacturer or reprocessor to appear on all devices. We realize it has raised concerns for industry and the agency, in terms of what it means and how to implement it. We have requested that people give us their ideas and thoughts about how to do this. We have also assured industry that we are exercising enforcement discretion. Enforcement will not begin until 18 months after the final guidance is issued.

Is further legislation required to meet the goals MDUFMA set out to address?

Trunzo: To ensure that the user-fee program continues after FY 2005, it will be necessary to amend MDUFMA so that a premature sunset clause will not be triggered as a result of Congress' failure to provide the amount of CDRH appropriations specified in the legislation during the first two years of the user-fee program.

Leahey: Many of the goals were being met before MDUFMA's implementation. However, legislation is required to amend MDUFMA's labeling provision to better identify reprocessed versions of SUDs. The user-fee program must be modified to eliminate compensating and workload adjustments in order to cap fee increases that accompany inflation. Full congressional funding will help establish meaningful performance goals for FDA.

Garvey: Something needs to be done to address the shortcomings of MDUFMA, although it is not immediately clear that legislation is the answer. In addition to solutions to the problems that have already been mentioned, there need to be some technical fixes on the trigger mechanism that kills the program if FDA fails to meet performance goals or if Congress fails to provide appropriations. It is hard to expect the agency to meet its performance goals if it doesn't have continued funding, and if Congress continually fails to fund the program under its original commitment, then there can be little hope for improvement in performance.

Kahan: As written, MDUFMA will end on October 1, 2005, if Congress does not provide the full appropriation for the first three fiscal years of the program by then. Full funding is not possible, so we need to have legislation passed that waives the requirement for the shortfall and allows the program to continue through 2007.

OMB sent draft legislation to the Hill in May 2004 to fix the trigger. This is a ‘clean bill' that has no other provisions. Its purpose is to keep the program going for the five years that Congress, industry, and FDA expect. We want to get it fixed as soon as possible so we can hire new staff with confidence that we won't have to let them go once FY 2005 ends.

Renegotiations about any other aspects of MDUFMA should be part of discussions about reauthorization of the program after 2007, when the five-year program is scheduled to end. While we share industry's concerns that the fees are unpredictable and that we need a stable funding base, this is not the right time to be addressing those issues or issues about changing the agreed-upon goals. Realistically, if the program stays in place because the trigger has been fixed, negotiations about a second MDUFMA authorization would probably begin early in 2006. That would be the right time to discuss concerns that any stakeholders have about substantive goals, new mechanisms for achieving stable funding, or assigning resources to postmarket safety.

We look forward to putting these and other issues that stakeholders have on the table for “MDUFMA II.” But our focus for the moment is getting a clean fix to the trigger provision so that we can continue to hire, train, and improve performance without worrying about the program grinding to a halt at the end of this fiscal year.

Copyright ©2005 Medical Device & Diagnostic Industry

Three Businesses, Two Continents, One Focus

Originally Published MX January/February 2005

COVER STORY

Interview by Steve Halasey

Generally speaking, institutions are like people: they become less limber with age. But don't tell that to Sir Christopher O'Donnell, CEO of Smith & Nephew plc (London), one of the world's oldest manufacturers of medical products. He's in the business of restoring people to activity—a talent that he has also brought to bear in keeping his 149-year-old company among the industry leaders in the fields of orthopedics, endoscopy, and wound management.

Sir Christopher O'Donnell, CEO of Smith & Nephew plc, on developing technology to improve life for patients and physicians alike.
Photo by BILL ROBINSON

O'Donnell joined Smith & Nephew in 1988 as managing director of the company's medical division and was appointed to the board of directors in 1992. Since becoming CEO, in 1997, he has successfully restructured and revitalized the company, which is expected to report revenues of more than $2.4 billion for 2004.