FDA Finalizes Guidance on "Least Burdensome" Principles

Originally Published MDDI December 2002


Implementation of the concept will help to expedite the availability of new technology, says the agency.

James G. Dickinson

FDA Gives Gliatech a Green Light | FDA to Expand Probability Sampling | Support for Banning Sutured Catheters | FDA Advises Hospitals on Reprocessed Devices

After reviewing recommendations on the draft guidance, FDA has published the final least burdensome guidance. "When conscientiously applied," the agency states in its final least burdensome guidance, "we believe the least burdensome concept will help to expedite the availability of new device technologies without compromising scientific integrity in the decision-making process or FDA's ability to protect the public health."

The guidance, entitled, The Least Burdensome Provisions of the FDA Modernization Act of 1997; Concept and Principles; Final Guidance for FDA and Industry, says FDA has acceded to recommendations from draft guidance comments that it should develop additional in-depth training sessions to ensure that the least burdensome approach is incorporated at CDRH and CBER. The agency has also created tools for evaluating approach implementation, including checklists to be used following the early collaboration meetings called for by FDAMA.

The final guidance defines the term least burdensome as "a successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA." According to the final guidance, general applications for the least burdensome approach include a "systems approach" to device regulation. When requesting additional information to resolve a regulatory issue, the guidance says, FDA should follow four guidelines: one, identify the specific issue or question to be addressed; two, acknowledge the submitted information and explain why it is deficient; three, establish the relevance of the request to the determination that is being made (e.g., substantial equivalence or reasonable assurance of safety and efficacy); and four, remain open-minded to alternate ways to address the issue or question.

When responding to FDA's requests, industry "should make every attempt to respond completely and promptly." Industry should state the agency's issue and provide either the information requested or one of the following: an explanation of why the issue is irrelevant in determining substantial equivalence or a reasonable assurance of safety and efficacy, or alternative information and an explanation as to why this information adequately addresses the issue.

Additional applications of the least burdensome approach include a reliance on postmarket controls to reduce the burden associated with PMAs and 510(k)s, and an effective use of well-designed bench and animal testing. Whenever possible, industry should incorporate by reference other premarket submissions as a means of saving resources. According to the guidance, FDA should also avoid using premarket review to ensure compliance with statutes and regulations unrelated to the regulatory decision.

The guidance can be viewed at http://www.fda.gov/cdrh/ode/guidance/1332.html.

FDA Gives Gliatech a Green Light

FDA told Gliatech Inc. (Cleveland) that it has adequately completed required audits and corrective actions under the agency's Application Integrity Policy (AIP), and that the agency will resume review of the company's submissions. Earlier this year, the troubled device maker entered into a plea agreement, which included a $1.2 million fine, with the U.S. Department of Justice to settle an FDA Office of Criminal Investigations probe into alleged wrongdoings involving its market-withdrawn, scar-inhibiting Adcon-L barrier gel.

The company's FDA problems began three years ago when the agency issued an import alert on the contract-manufactured product following an inspection and the issuance of a warning letter to its Netherlands-based supplier, Medical Contract Manufacturing. Further difficulties arose eight months later, when an FDA inspection questioned company data and the process it used in presenting the data in a supplemental PMA application for Adcon-L. The company subsequently removed the product from the U.S. market and FDA placed the firm on its AIP list.

According to Gliatech, FDA has said that for a period of two years all submissions related to Adcon must be certified by an independent auditor before they are submitted to the agency. Adcon-L has been relaunched outside of the United States. The Adcon product line is up for sale as part of the company's bankruptcy proceedings and if it is sold, the new sponsor will need to resubmit a PMA to the agency to market in the United States.

FDA to Expand Probability Sampling

CDRH is developing a new framework of "probability" sampling of medical device company quality systems to look at areas where there could be an increased risk sufficient to warrant more-frequent or more-targeted inspections.

Center director David Feigal said at a Regulatory Affairs Professionals Society meeting on October 7 that this approach had recently been tested among about 100 companies that manufacture only Class I devices—a sector that for almost six years has been exempt from routine inspections. FDA selected the sampled firms for one-day inspections because of a recent rash of product recalls and because the agency identified the sample as representative of the 5000 companies that make only Class I devices.

So far, Feigal said, the inspection data are preliminary, but "there were only a small fraction of firms found to be violative." But he also noted that only nine firms had in place corrective and preventive action systems and other good quality systems. Over the next year as it analyzes the data, the center will report on quality systems issues and common deficiencies for this segment of the industry.

Feigal sees probability sampling fitting into his center's risk-based strategy. He said this tool and others will help the agency move from coverage-based inspections to those that deal with identified issues. Gone are the days when the center measured success by reporting that 40% of Class II devices had been inspected during a specific year. "We'll now be talking about the kinds of risks that we are aware of and how we targeted the inspectional process to reduce those risks, and what are our findings."

The important thing, Feigal said, is to provide industry with information on the common inspectional findings FDA is discovering, so these situations can be addressed and corrected if they potentially can occur in other areas of manufacturing.

Support for Banning Sutured Catheters

According to Venetec International (San Diego), FDA should ban the use of sutures for securing catheters because the needles unnecessarily expose physicians and nurses to viruses such as hepatitis C and HIV. So said the company in recent comments on a two-year-old Public Citizen petition seeking such a ban. The petition asked FDA to ban all intravenous catheters, blood collection devices, blood collection needle sets (also known as butterfly syringes), glass capillary tubes, and intravenous infusion equipment that do not use needleless technology or recessed needles, including intravenous catheters and related infusion equipment.

In its comments, Venetec noted several reasons for an FDA ban on suture securement. Sutures have been used in the past only by default, in the absence of proven alternative technology, the company said, and a proven alternative now exists, in the form of sutureless securement devices (i.e., Venetec's Statlock device). Also, sutureless securement devices comply with the federal Needlestick Safety and Prevention Act, as well as with regulations issued by the Occupational Safety and Health Administration, and sutureless securement devices have been recognized by the congressional authors of the Needlestick Safety and Prevention Act. Furthermore, sutureless securement devices are widely available and used in numerous U.S. healthcare institutions.

In a related move, the National Alliance for the Primary Prevention of Sharps Injuries (NAPPSI), founded by Venetec International, petitioned FDA to post and distribute its Needlestick Safety Device List—an up-to-date compilation of technologies that reduce or eliminate healthcare workers' exposure to needlestick injuries.

FDA is expected to rule in the coming months on Venetec's requests, as well as on the initial petition from Public Citizen.

FDA Advises Hospitals on Reprocessed Devices

Monitoring temporary pacemaker connections, selecting a third-party reprocessor, and hazards in patient-controlled analgesia are among the topics addressed in the latest issue of User Facility Reporting—CDRH's quarterly bulletin to assist hospitals, nursing homes, and other device-user facilities. The issue provides a brief synopsis of each topic with links to the information on-line.

In the article "Monitoring Temporary Pacemaker Connections," Diane Dwyer, a CDRH Office of Surveillance and Biometrics nurse consultant, describes a case in which a patient admitted to an ICU died following the insertion of a temporary invasive cardiac-pacing catheter. Because the catheter pin design was incompatible with the pacer adapter, Dwyer says, it could not be connected to the pulse generator. The patient was instead connected to a transcutaneous pacemaker and died shortly after arrival at another facility.

Another article advised facilities selecting a third-party reprocessor of single-use devices (SUDs) to talk with other hospitals to determine their experiences, and to arrange a visit to the reprocessor's facilities. Questions to consider asking a potential reprocessor include:

  • When did FDA last inspect the facility? What were the inspection results?
  • Does the facility have documentation that the company is approved or cleared for each type of SUD reprocessed?
  • How does the facility monitor manufacturing processes and what records are maintained in compliance with FDA's quality system regulation?
  • What aspects of the overall process have been validated?
  • Has the company set limits on the number of times an SUD can be reprocessed? If yes, how was that number determined and what procedures are in place to make sure that number is not exceeded?

To view the latest issue of User Facility Reporting, visit http://www.fda.gov/cdrh/fusenews/ufb40.html.

Copyright ©2002 Medical Device & Diagnostic Industry

Rheometer measures elongational properties.

An extensional rheometer analyzes the thinning and breakup of a fluid filament, providing valuable information about a material's physical properties. The CaBER 1 from Thermo Material Characterization (Madison, WI; 608/327-6777) can function as either an analytical instrument or a quality control tool. Standard features include computer control, a Class 1 laser micrometer, a linear motor drive with variable speed, automatic repeated testing, and a closed temperature-controlled sample chamber. The rheometer is ideal for applications involving adhesives, industrial resins, surfactants, and associated polymers.

New Law Accelerates FDA's Combination Product Reforms

Originally Published MDDI December 2002


Transparency is one goal of Mark Kramer's program.

John Bethune

For most of 2002, FDA has been quietly working to effect a complete overhaul of the way combination product applications are reviewed within the agency. Now, a section of the recently passed Medical Device User Fee and Modernization Act of 2002 makes the reforms permanent.

Describing the agency's reform efforts on October 8, a few weeks before the passage of the law, Mark Kramer, director of the Combination Products Program, said, "We don't want anything inherent in FDA to bog down the progress of reviewing products." Kramer spoke at the annual meeting of the Regulatory Affairs Professionals Society in Washington, DC.

Section 204 of the law requires the establishment of an office dedicated to combination products within the Office of the Commissioner. Evidently anticipating the idea, FDA set up a similar entity within the Office of the Ombudsman months earlier, in February.

Since being named the director of the new program, Kramer has undertaken a complete review of the agency's approach to combination products. To "separate anecdotes from facts about combination products," Kramer met last spring with 75 FDA employees from various centers who had experience reviewing such products. He found that "reviewers tend to view other centers as a black box," he said.

Citing a recent example of intercenter work on drug-eluting stents, Kramer noted that "in the beginning, CDER [the Center for Drug Evaluation and Research] was not in sync with the CDRH time frame." By the end of the process, however, things had changed. "I personally view the way these two centers are working on this as a model for the way all combination products should be handled," he said.

Much of the program's efforts have been devoted to improving the ability of reviewers in the centers to work with each other. In part, Kramer said, this is being accomplished by placing greater value and importance on the role of the consulting center reviewers. In the past, the center with lead responsibility for reviewing a product has tended to overshadow its consulting partner. The consulting center, in turn, tended to treat its role too lightly. Now, Kramer said, "it needs to be treated as a priority. In a nutshell, consult counts." The work consulting reviewers do, Kramer said, needs to be recognized by the consulting center. "They need to receive credit for their work, so that they are fully on the radar screen for management and personnel review purposes."

In addition, the Combination Products Program is helping to alleviate some pedestrian but persistent intercenter problems. As one example, Kramer cited the problems the centers had experienced in sharing documents. "From the employee point of view," he said, "there is no easy way to get documents from one center to another. In the past, people felt they couldn't sleep at night unless they drove the materials to the other center." Effective October 15, he said, FDA planned to begin a new courier system to solve this problem.

To ensure that the new office is working effectively, the law requires a report after one year detailing the "number and types" of products reviewed. This will apparently pose a challenge to the agency, given the state of its database. While stating that a key role of the program is "to make sure that things are staying on track," Kramer pointed out that "none of [FDA's] existing database systems have a flag to identify combination products." Ultimately, he added, "we would like to be able to post metrics—the number of products reviewed, review times, and so forth—but until the database problems are resolved, we can't."

Again anticipating the new law, which directs FDA to review all of its guidelines and agreements regarding combination products, Kramer emphasized the importance the program places on guidance documents. On July 31, the program released a new standard operating procedure on the consultative and collaborative review process. (Although an internal document, it is available for public review on the FDA Web site.)

More guidances are on the way, Kramer said. "It is time to begin providing a lot more clarity," he said. "Transparency is something that we are working to achieve."

Copyright ©2002 Medical Device & Diagnostic Industry

Atomic Battery Could Power Medical Implants

Originally Published MDDI December 2002


A 2-cm cantilever device may be able to power remote sensors or medical implants.

The trend for some time in the development of medical devices has been to make them smaller, yet more complex and powerful. But development of smaller electronic circuits and nanoscale components has not been matched by similar advances in power supply technologies. Batteries have generally remained huge by comparison, and have been limited by short life spans. Now, a tiny device developed by researchers at Cornell University (Ithaca, NY) may be capable of supplying power to remote sensors or implantable medical devices for decades by drawing energy from a minute amount of a radioisotope.

The group has already constructed a prototype device that can convert energy from the radioactive material directly into mechanical motion. They speculate that such a power system eventually could directly move the parts of a tiny machine. It could also generate electricity in a form that is more useful for small-scale electronic circuits than is now possible with conventional methods.

According to Amit Lal, PhD, assistant professor of electrical and computer engineering at Cornell, the approach being developed creates a high-impedance source that he believes is better suited to powering many types of circuits. The prototype is the first microelectromechanical version of a larger device that Lal designed and built while a faculty member at the University of Wisconsin, Madison. Lal developed the earlier device with nuclear engineering professors James P. Blanchard, PhD, and Douglas L. Henderson, PhD, and created the prototype in collaboration with Cornell doctoral candidate Hui Li.

The prototype comprises a 1 mm ¥ 2 cm ¥ 60-µm copper strip that is cantilevered above a thin film of radioactive nickel-63. As the isotope decays, it emits beta particles—but not hazardous alpha particles or gamma rays. Lal chose this isotope because beta particles do not penetrate human skin. As the emitted electrons collect on the copper strip, a negative charge builds. At the same time, the isotope film, losing electrons, becomes positively charged. The attraction between positive and negative bends the copper strip down. When the strip gets close enough to the isotope, a current flows, equalizing the charge. The strip then springs up, and the process repeats.

Because the half-life of nickel-63 is more than 100 years, Lal believes that a battery using this isotope could supply usable energy for at least half that time. Other isotopes would offer various combinations of energy level versus battery life span. Unlike chemical batteries, the devices will work in a wide range of temperatures and could be left unattended for long periods. This would make them well suited for use in medical devices implanted inside the body, the researcher says.

Aside from use as a power supply, the design may have other novel applications. The moving cantilever could actuate a linear device directly, or produce rotary motion using a cam or ratcheted wheel. Electricity could also be generated by attaching a magnetized piece of material to the strip and moving it through a tiny coil.

Lal explains that in other versions of the design, the cantilever is made of a piezoelectric material. In these devices, the cantilever generates electricity when deformed and releases a current pulse as it snaps up. This also generates a radio-frequency pulse that could be used to transmit information, says Lal. The electrical pulse could also drive a light-emitting diode to generate an optical signal.

Copyright ©2002 Medical Device & Diagnostic Industry

Research Program May Aid Device Development

Originally Published MDDI December 2002


MCNC (Research Triangle Park, NC), a nonprofit research and advanced computing/networking facility, has initiated a novel life sciences program intended to develop, model, prototype, and test a range of diagnostic and therapeutic biomedical equipment. For example, MCNC's Materials and Electronic Technologies Division (METD) is working on a project that will apply microfabrication tools and techniques to developing such items as glucose monitoring sensors, devices for characterizing biological processes in cells, and neural prostheses.

METD recently began collaborating with Duke University (Durham, NC) to develop miniaturized ultrasound devices. The research project, which is being funded by a five-year National Institutes of Health award, will develop microfabricated high-resolution 2-D ultrasound arrays for integration into existing 3-D imaging systems developed at Duke for real-time cardiac catheter-based imaging.

The research team expects the technology to enable heart surgeons to view real-time ultrasound video of the heart and arteries during catheter-based surgical procedures, such as angioplasty. This capability would aid in catheter navigation and help physicians to assess the presence of plaque. Current 2-D ultrasound arrays are too large to fit inside of a cardiac catheter, according to the researchers. Applying microfabrication technology to the ultrasound transducer will enable the researchers to reduce the size of such components so that they can be used inside a 2-mm-diam catheter that will be small enough to fit within coronary arteries.

Copyright ©2002 Medical Device & Diagnostic Industry

Albany Women Launch Contract Molding Company

Originally Published MDDI December 2002


Two new players have arrived on the injection molding scene. They share the distinction of having started what might be the only women-run molding company in the country. Lynn E. Momrow and Joanne H. Moon are managing partners for Extreme Molding LLC (Watervliet, NY). The new company will manufacture injection molded products for use in biotechnological and other applications.

The injection molding industry, like manufacturing in general, is dominated by men. In a recent Albany Times-Union story, Momrow is quoted as saying that Toshiba Machine Co. (Elk Grove Village, IL) had "never shipped an injection molding machine to a woman" before shipping one to her earlier this year. Indeed, the Center for Women's Business Research reports that of all the manufacturing companies in the country, less than one-fifth of them (18.8%) are owned by women.

Moon believes that there is "still a view that women are better suited in corporate environments in more administrative roles, such as human resources, marketing, and sales," and that women are "not actively recruited and promoted into technical roles."

Momrow and Moon's combined experience includes time spent at such major firms as General Electric Co. and C.R. Bard Inc. They also teach a class together at Rensselaer Polytechnic Institute; Moon happily reports that they have several female students interested in manufacturing. "When we talk to them," Moon says, "we say, 'Don't lose the spark. Don't give up.'"

Copyright ©2002 Medical Device & Diagnostic Industry

FDA Okays Heart Pump as Permanent Implant; Reimbursement Decision Looms

Originally Published MDDI December 2002


Maureen Kingsley

In a landmark decision made last month, FDA approved the HeartMate SNAP-VE left ventricular-assist system (VAS) for use in destination therapy for end-stage heart failure patients. HeartMate, manufactured by Thoratec Corp. (Pleasanton, CA), in addition to other VAS devices, had previously been approved by the agency only as so-called bridge-to-transplant devices for Class IV heart failure patients awaiting transplants. This November, however, Thoratec got the green light from FDA to market HeartMate as a permanent, lifesaving alternative to a heart transplant.

D. Keith Grossman, Thoratec's CEO, said he is generally satisfied with the amount of time FDA took to process the destination-therapy PMA supplement Thoratec filed in October of last year. "Our review time of 13 months was probably in-line with—or very close to—FDA averages," Grossman said. FDA had ordered an expedited review for this particular PMA supplement, and Thoratec had originally hoped for approval "around the middle of this year, no later than August or so," according to Grossman. "We were certainly a little bit disappointed in the delay beyond that point," he added. "But I think, in the big picture, [the timing is] in line with what you'd expect."

Thoratec estimates that of the roughly 500,000 heart failure patients who are designated Class IV each year, only about 2000 are matched with donor organs. That would leave hundreds of thousands of patients who could potentially benefit from VAS destination therapy. "If you look at those patients," Grossman said, "the question is, are they all candidates for destination therapy? And the answer is probably not today— but eventually, they will be."

With the FDA-approval hurdle negotiated, Thoratec eagerly awaits a reimbursement decision from CMS. Grossman doesn't seem too nervous. "We're very optimistic," he said. The REMATCH trial was "a blue-ribbon [clinical] trial run by the National Institutes of Health— extremely well run and controlled." He pointed out that the patient population positioned to benefit most from destination therapy currently has no alternative. It's a matter of survival, not quality of life, he said. "These patients die without it and live with it."

Furthermore, CMS does currently reimburse for HeartMate and other VAS devices as bridge-to-transplant systems. "There are no guarantees in this field," Grossman said, "but we came into this process with a high degree of confidence that we'll have reimbursement."

Copyright ©2002 Medical Device & Diagnostic Industry

Institute of Packaging Professionals Revives Committee

Originally Published MDDI December 2002


Erik Swain

After several years of dormancy, the Medical Device Packaging Committee has been revived by The Institute of Packaging Professionals (IoPP; Naper-ville, IL). It plans to begin work on at least four initiatives.

The first meeting of the revived committee took place at the Pack Expo trade show in Chicago on November 5. It drew a large crowd of medical device manufacturers, packaging material suppliers, packaging machinery suppliers, testing laboratory representatives, academic institutions, and consulting firms. Participation of FDA representatives will be sought in the future.

Organizers said they would like the committee to provide a forum for packaging professionals in the medical device industry. This would enable them to exchange, discuss, develop, and disseminate information on technical, regulatory, organizational, and other important packaging-related issues.

"We may be in a position to actually develop information," said John Spitzley, associate fellow, packaging, for Medtronic Inc. (Minneapolis) and one of the committee's co-chairs. "No other trade organization does. We may even decide to fund research or studies."

The meeting produced the formation of four subcommittees, each of which will tackle an issue that participants believe has been underaddressed in recent years.

One subcommittee will look into conducting an industry-sponsored research project to determine the appropriate level of sensitivity needed to test medical device package integrity, and perhaps to pinpoint the size at which holes begin to compromise integrity. Debate has raged for years within the industry as to how sensitive an integrity test should be; those that are not sensitive enough may fail to detect leaks and jeopardize the sterility of a package, but those that are too sensitive may produce false positives and result in the waste of good packages. If a project were to get off the ground, it might be conducted at the Michigan State University School of Packaging.

"Previous work on this issue was done with too little information," said Hugh Lockhart, PhD, a packaging professor at Michigan State. "But with the level of expertise we now have, I think it is doable. However, FDA involvement would be critical, because of the differences between what we'd like and what we think they want."

Another subcommittee will examine the sharing of information about materials commonly used for primary packaging of sterile medical devices, with the hope of being able to justify reduced testing of the most frequently used materials.

"Most of us use similar materials and similar processes," said Curtis Larsen, packaging consultant for DuPont Medical Packaging (Wilmington, DE) and the committee's other co-chair. "How many companies have done shelf-life tests on uncoated Tyvek 1073B with a polyesterpolyethylene clear film? Probably everyone. Can we collect all the data, give it to FDA, and say, 'Why do we have to do this over and over again? Why not accept this as a certified packaging system?'"

The catch, Spitzley said, will be getting industry members to share such information, and that might be more likely to happen under the auspices of the IoPP than it would otherwise. "There are a lot of potential hurdles out there," he said. "This is not going to happen overnight."

A third subcommittee will address the issue of standardizing the format of technical data sheets for medical device packaging materials.

Finally, the fourth is charged with providing education and guidance for those new to medical device packaging. "We'd like to get rid of the concept that says, 'I got stuck with packaging,'" Larsen said. "We would like to be a resource for those who have come into the field without any prior experience."

The next meeting of the committee is scheduled during the HealthPack 2003 conference, March 27, 2003, in Scottsdale, AZ. Those interested in joining the committee may contact Spitzley at John.Spitzley@medtronic.com or Larsen at Curtis.L.Larsen@usa.dupont.com.

Copyright ©2002 Medical Device & Diagnostic Industry

Test Methods Become New ASTM Standards

Originally Published MDDI December 2002


Two test methods were approved by the ASTM F2 Flexible Packaging Committee on October 17, 2002. The "Standard Test Method for Nondestructive Detection of Leaks in Nonsealed & Empty Medical Packaging Trays by CO2 Tracer Gas Method" and the "Standard Test Method for Nondestructive Detection of Leaks in Medical Packaging Which Incorporates Porous Barrier Material by CO2Tracer Gas Method" were developed using PacGuard 500 test equipment marketed by Mocon (Minneapolis). Numerical designation and publication is expected to take place in December.

In a recent press release, Ron Pilchik, business manager for Mocon Inc., said the two test methods "represent the first and presently the only instrumental nondestructive methods for testing for integrity breaches in medical packaging trays and . . . packages."

Copyright ©2002 Medical Device & Diagnostic Industry

AdvaMed Argues against Switch to CBER

Originally Published MDDI December 2002


James G. Dickinson

AdvaMed is opposing FDA's proposed jurisdictional change from CDRH to the Center for Biologics Evaluation and Research (CBER) for combination wound-repair products that contain live cellular components. In a letter to FDA general counsel Daniel Troy, AdvaMed cited FDA's newly articulated proposal stating that the basis for making jurisdictional changes is a product's "primary mode of action." This interpretation, AdvaMed wrote, "departs fundamentally from past policy pronouncements and practices; imposes profound costs and other adverse consequences on affected entities; and, consequently, requires notice-and-comment rulemaking. . . ."

AdvaMed argues that the jurisdictional shift is inappropriate for this class of products under the statutory definition of biological product. To justify the change, the group says, FDA must demonstrate a "strong public health or other compelling basis for the change."

FDA first proposed the jurisdictional shift in a May 15 Federal Register notice. Most of these products have been characterized so far as "cultured skin," FDA said, and have been filed and reviewed by CDRH as PMA applications. The agency is now questioning whether the devices should not be transferred to CBER for premarket review.

The letter can be viewed in an on-line Adobe file at http://www.advamed.org/publicdocs/81502troyltr.pdf.

Copyright ©2002 Medical Device & Diagnostic Industry