Originally Published MDDI February 2003

WASHINGTON WRAP-UP

The new FDA commissioner is demonstrating an impressive decisiveness and understanding of agency bureaucracy. A top priority is reduction of medical errors.

James G. Dickinson

Who Reviews Combination Products? | Bard Avoids Liability for Labeling | Uterine Fibroids Device Cleared | Stair-Climbing Wheelchair | Carbon Dioxide Monitor Guidance | More Answers on Reprocessed Devices

By mid-December, after one month in office, FDA Commissioner Mark B. McClellan was making a mark as a leader who had hit the ground running. He impressed employees and outside observers alike as an extraordinarily quick study of the arcane labyrinth that is FDA.

In his first broadcast to all employees on December 3, McClellan hailed third-party inspections of medical device manufacturing facilities. Provided for in the new Medical Device User Fee and Modernization Act, the inspections are “a promising area for us,” he said, “to augment [our] limited regulatory resources.”

Responding to a question, he speculated that his background as an economist might bear fruit at FDA in a future initiative to apply cost-benefit analysis to the way the agency reviews product risks. He also identified reduction of medical errors as a top priority. 

Asked how FDA's postmarket surveillance responsibilities could be strengthened, he cited pilot programs in CDRH and sister centers that collect real-time information on the use of new products to identify problems more quickly. “By getting more information like that,” he said, “we can learn a lot more about why problems are occurring postmarket.” With such information, he added, FDA can, through updates to drug labels and to device guidances, “help people use the treatments in a way that will prevent errors.”

A few days later, McClellan's energy showed itself when a key FDA officer resigned. Kathryn Zoon, director of FDA's Center for Biologics Evaluation and Research (CBER), abruptly announced her resignation on December 13. Three days later, McClellan appointed Zoon's deputy director for medicine, virologist Jesse Goodman, MD, as her replacement. This unprecedented speed was made possible by McClellan's decision not to formally advertise the vacancy, as is usually done.

The last time a program center director of Zoon's rank left the agency was in January 1999, when CDRH director Bruce Burlington quit to join Wyeth-Ayerst. Then-commissioner Jane Henney took more than three months to name David Feigal as Burlington's successor.

Goodman joined FDA in 1998 as part of the Office of the Commissioner, where he led an interagency task force on antimicrobial resistance. “He later moved to CBER, where he has been active in a wide variety of clinical and public health issues including bioterrorism preparedness and response, product development, human subject protection, and blood and vaccine safety,” McClellan said in an e-mail to employees.

Who Reviews Combination Products?

When deciding which of its centers should be responsible for review of a combination product, should FDA change the way it decides that product's primary mode of action? Certainly not, Becton Dickinson regulatory affairs vice president Pat Shrader told an FDA hearing in November. 

The hearing was conducted to gather public input on the agency's formal establishment of an Office of Combination Products. Speaking on AdvaMed's behalf, Shrader said FDA's jurisdiction decisions over the past decade have produced a wealth of “interpretive instructions” on determining the primary mode of action. 

More than 300 designation requests have been processed for potential combination products since FDA began looking at them in 1991, added David Fox, another speaker. Fox is a Hogan & Hartson attorney and former FDA Office of Chief Counsel senior drugs attorney. Many precedents were set in evaluating these requests, Fox said. They should be used to establish “limiting features,” he continued, to help decide combination product jurisdictional issues in the future. Without such limiting features, Fox warned, FDA could apply the principles that were unsuccessfully used when it attempted to regulate cigarettes as combination products.

Based on mode of action, many apparent combination products have successfully been classified as single-entity devices, Shrader pointed out. These types of decisions, such as those on drug-eluting stents and wound dressings containing antimicrobial agents, have served both industry and FDA well. She cautioned the agency not to alter the factors it now uses to interpret the mode of action. These factors include evaluation of the combined product instead of the relative contribution of each component, and the primary intended function of the combination product.

When instances arise where the primary mode of action is obscure, Shrader told FDA it should first look to see if a similar device has been approved or cleared but with a different intended use. If so, then the product should be reviewed by the same center. Doing so would help reduce instances in which multiple premarket review systems would be employed for a similar product, which could hinder future product development. 
Additionally, Shrader urged FDA to let individual companies decide whether to make dual submissions to different centers. And the fact that one center may have jurisdiction on the review side and another on the postmarket regulatory side should not influence any decision by the agency to require two separate application submissions, she added.

Bard Avoids Liability for Labeling

FDA's decision not to require patient-directed product labeling for an ambulatory, patient-controlled analgesia infusion pump (PCA pump) has allowed C. R. Bard to sidestep liability claims. Bard's pump was set up to deliver morphine when activated by a patient. The company was sued because one of its pumps delivered an overdose; a family member continued to activate the device while the patient was sleeping in the hospital following knee surgery. 

Bard's counsels successfully invoked Georgia's learned intermediary rule against a recent product liability claim in state court, affirmed by the Eleventh Circuit Court of Appeals. The learned intermediary defense has its roots in prescription drug liability cases. Many courts, including those in Georgia, recognize it in prescription medical device cases as well. 

The learned intermediary doctrine applies where drugs or medical devices are available to the public only by prescription from an authorized health professional. In such cases a manufacturer fulfills its duty to warn by advising the professional of the dangers of the product, and has no duty to warn the patient.

In this case, Ellis v. Bard, the plaintiff sought to assert an exception to the learned intermediary defense. As written by the Oklahoma Supreme Court (Edwards v. Basel Pharmaceuticals), it provided that “when the FDA requires warnings be given directly to the patient with a prescribed drug, an exception to the learned intermediary doctrine has occurred, and the manufacturer is not automatically shielded from liability by properly warning the prescribing physician.” 

However, in that case—unlike the Bard case in Georgia—FDA had required a patient package insert warning about risks associated with the product. Noting the difference, the Georgia appeals court ruled: “Without a specific FDA mandate in this case requiring a certain warning on a PCA pump, and in light of Georgia's well-established learned intermediary rule, we need not address whether an exception to Georgia's learned intermediary rule is warranted.” 

Uterine Fibroids Device Cleared 

Saying it could save many women from surgery, FDA in November gave BioSphere Medical 510(k) clearance to market its Embosphere Microspheres, which treat symptomatic uterine fibroids. Typically, women must have myomectomies (surgery that removes fibroids but leaves the uterus intact) or hysterectomies (surgery to remove the uterus) to treat the problem. The microspheres, however, shrink fibroids, and thus avoid the need for surgery.

According to the company, the miniature beads block the growth of fibroids by cutting off their blood supply. BioSphere Medical believes that Embosphere is “the first and only device to receive clearance from FDA for this indication.” 

In U.S. clinical trials involving 182 women, the company said, Embosphere Microspheres were shown to provide substantial improvement in major symptom categories, including pain, excessive bleeding, and bulk uterine. These improvements were similar to those experienced by hysterectomy-treated patients; however, significant adverse events were rare in the UFE group. Overall adverse events were fewer, in number and in severity, than in the hysterectomy group. Additionally, BioSphere said, at six months follow-up, the size of the fibroids and uteri decreased substantially among the UFE-treated group. 

In April 2000, FDA cleared Embosphere Microspheres for treating hypervascularized tumors and arteriovenous malformations.

Stair-Climbing Wheelchair 

The mass media had a field day in November with the stair-climbing wheelchair. The new device was developed by Independence Technology. The iBOT 3000 Mobility System came before FDA's Orthopedic and Rehabilitation Devices Panel on November 20. Network television and wire services quickly issued stories describing the device's climbing capability and focusing on the news that the panel voted unanimously for its approval. FDA's concurrence would mark the first approval of such a device anywhere in the world, the company claimed.

The FDA panel, however, supported placing limitations on the device. First, it may be sold only with a doctor's prescription. Second, users must receive strict training to ensure proper device operation. Clinicians must undergo certification to train patients on the iBOT and, according to the panel, the company should update such certifications annually and as changes occur to the device.

Requiring the patient to have the use of at least one upper extremity for chair operation, the iBOT “operates on a system of electronic sensors, gyroscopes, and software,” the company said. Capable of providing mobility in confined spaces and at elevated heights, the device can also ascend and descend stairs, climb curbs, and traverse rough terrain.

A 20-subject pivotal trial proved the four-wheel-drive device to be relatively safe and effective. Adverse events in the trial included two bruises, five falls (two patients fell with their own mobility devices, and three fell with the iBOT), and four adverse events unrelated to use of the iBOT device.
Independence Technology (Warren, NJ) is a subsidiary of Johnson & Johnson. The iBOT was invented by Dean Kamen, better known in recent times for his nonmedical invention, the Segway Human Transporter.

Carbon Dioxide Monitor Guidance

CDRH has posted to its Web site a special controls guidance to describe a means by which cutaneous carbon dioxide (PcCO2) and oxygen (PcO2) monitor devices may comply with the requirement of special controls for Class II devices. Issued on December 13, the guidance is entitled Class II Special Controls Guidance Document: Cutaneous Carbon Dioxide (PcCO2) and Oxygen (PcO2) Monitors; Guidance for Industry and FDA. 

The new guidance supersedes a draft issued on February 12, 2002. The new guidance discusses the testing required to support either a traditional or abbreviated 510(k) for a cutaneous carbon dioxide or oxygen monitor. Such testing should be performed under the following conditions: 

• Ambient temperature between 15º and 35°C. 
• Barometric pressure between 68 and 106 kPa. 
• Ambient humidity between 30 and 90%. 
• Line voltage for line-powered devices between 110 and 125 V rms.

Each 510(k), the guidance says, should identify the risk analysis methods used to assess the risk profile in general, as well as the device's design and the analysis results. The submission should also explain how the device addresses the risks identified in the guidance, as well as any additional risks identified in the risk analysis. 

According to the document, health risks generally associated with these monitors are improper patient management, electrical shock or burns, and electromagnetic interference. Electromagnetic compatibility (EMC) is defined in the guidance as “the ability of a device to operate properly in its intended environment of use without introducing excessive electromagnetic disturbances into that environment.” A complete description of the monitor's EMC characteristics, it says, should be included in the 510(k), as well as information to verify those characteristics. 

“All devices should be tested,” the document says, “with the third wire ground connected at the plug end of the power cord.” An exception is devices intended for home use. Such devices should be tested “with the third wire ground disconnected at the plug end of the power cord.” 

The guidance can be accessed on FDA's Web site at www.fda.gov/cdrh/ ode/guidance/1335.html.

More Answers on Reprocessed Devices 

In its third addition to a July 2001 guidance, CDRH has released a revised final guidance on its single-use device reprocessing policy. The document is entitled Frequently-Asked-Questions about the Reprocessing and Reuse of Single-Use Devices by Third-Party and Hospital Reprocessors; Final Guidance for Industry and FDA Staff. The revision provides two new questions and answers, quoted below, concerning registration and device listing.

Q: My establishment is registered as a manufacturer of medical devices, some of which are labeled for single use. We also reprocess for reuse some of the single-use devices that we manufacture. Do we have to add the establishment operation type of “Reprocessor of Single-Use Devices” to our existing registration information?

A: Yes, your establishment needs to be registered for all of the operations that are being performed at the same location.

Q: My establishment is registered as a manufacturer of medical devices, some of which are labeled for single use. We also reprocess for reuse some of the single-use devices that we manufacture. Do we have to update our existing device listing information?

A: Yes, your establishment needs to have all of the operations that are being performed on a particular device listed with FDA.

The guidance may be accessed on FDA's Web site at www.fda.gov/cdrh/ ohip/guidance/1427.html.

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