Originally Published MDDI February 2005

WASHINGTON WRAP-UP

Rumors about who will be nominated to head FDA raise questions about the future of many agency programs.

James G. Dickinson

FDA User-Fee Program in Peril | Symbols OK for IVD Professional Labeling | Why FDA Can't Apply What It Knows | Guidance on Clinical Data Formats | FDA Disputes Are Best Resolved Internallys | Silicone Breast Implants Reconsidered | Guidance on Radio-Frequency Transponder Implants

President Bush's second term brings multiple challenges and uncomfortable prospects to the medical device industry this year. The dollar's steep descent in the wake of the deficit, federal cost cutting, and new leadership at HHS make the tea leaves hard to read.

The weak dollar assists U.S. exports and thus the affordability of U.S.-made medical devices in foreign markets. But the domestic, nonmilitary outlook seems difficult as the government strives to fund rapidly expanding Medicare expenditures.

The first ripple will likely be felt at FDA. There, industry disquiet over device user fee increases threatens the whole program, even as budget cuts affect other areas. The agency's state of drift became acutely embarrassing to the White House last year. Drug safety and field enforcement issues arose from the Vioxx withdrawal, the flu vaccine shortage, and the uproar over antidepressants.

Although none of these issues directly affected medical devices, they combined to seal the fate of acting FDA commissioner Lester Crawford. He had been hospitable to device manufacturers before the November elections as he sought to be nominated as permanent commissioner.

In December, his hopes faded as editorial writers and activists around the country described his agency as “sick.” They said that the agency needed a “cure” to its “coziness” with industry. The White House could not risk presenting him to the Senate, since several members were harshly criticizing FDA. Crawford was rumored to be entertaining at least two private-sector opportunities.

One name reported to be under consideration for FDA commissioner is Zachariah P. Zachariah. The Florida cardiologist has been an active political fund-raiser for the Bush family for many years.

Zachariah emigrated from India to the United States in 1972 and obtained a U.S. medical license in 1976. He currently is director of cardiology at Holy Cross Hospital in Ft. Lauderdale, FL. Zachariah is listed as a member of the Florida Department of Education Board of Governors for the state university system. A biographic statement on that agency's Web site says he is on the board of trustees for Nova Southeastern University. It also says he is a clinical (voluntary) professor of medicine at the University of Miami School of Medicine. However, the medical school's Web site does not show him as a faculty member.

The Alliance for Technology Education lists Zachariah as a member of its medical advisory board. Other members include GOP luminaries Alexander Haig, former HHS secretary Caspar Weinberger, and USP president Jerome Halperin. The alliance says its purpose is to “inform and educate the medical community on the latest technologies, procedures, studies, and business strategies available to them, and how these may be applied in their respective disciplines.”

In 2001, Zachariah was sworn in as a member of the President's Advisory Commission on Asian Americans and Pacific Islanders. The biographic statement distributed at that time said he had served on the National Institutes of Health's National Heart, Lung, and Blood Advisory Council. He was said to be a leading proponent of improving heart health through education, exercise, and financial incentives. He has received awards for his humanitarian work, community service, advocacy on behalf of children, and leadership in public health. Such awards include the American Heart Association's Zachariah P. Zachariah Golden Heart Award, of which he was the first recipient. He has also received the Freedom Foundation at Valley Forge's George Washington Honor Medal, the Ellis Island Medal of Honor, and the Ellis Island American Legends Award.

A Florida political watchdog group reports from media accounts that Zachariah was the only cardiologist to receive an exemption from paying a tax used to fund indigent care. It says he donated $25,000 to the Republican Party of Florida. Since 1996, he also personally contributed more than $100,000 to candidates, most of them Republicans, including $25,000 at a 2002 Orlando fund-raiser.

He also served as Florida campaign finance chairman for the first President Bush in 1992, enjoying rides on Air Force One, invitations to White House dinners, and Barbara Bush as a houseguest, according to the St. Petersburg Times. The newspaper also reported that, from 1999 to 2002, he was exempted from the special state tax on healthcare providers to fund indigent care. It estimated that the exemption saved him thousands of dollars a year. “I really don't know why he's been the only doctor in the state able to get an exemption,” the director of the Florida chapter of the American College of Cardiology told the newspaper. “Probably because of his connections.”

Texans for Public Justice, a group whose Web site can be found at www.WhiteHouseforSale.org, says Zachariah cochaired the first President Bush's Florida fund-raising operation. After that, he raised $4 million for Senator Bob Dole's 1996 presidential campaign, and cochaired the Florida reelection campaign of the current president.

“After the first President Bush headlined a fund-raiser in Zachariah's home for 200 people who gave $10,000 apiece to the Republican Party, Zachariah reportedly raised more money for Bush's 1992 campaign than any other individual,” the group says. “After reportedly considering Zachariah as a possible surgeon general, the second President Bush appointed him to the President's Advisory Commission on Asian Americans and Pacific Islanders. Florida governor Jeb Bush appointed Zachariah to the Florida Board of Medicine, as chair of the Governor's Task Force on the Obesity Epidemic, and to the state university system board of governors.” He also was one of the Florida electors who recently voted in the Electoral College to confirm George Bush's reelection.

Texans for Public Justice says Zachariah helped found the Indian American Policy Institute, a think tank to promote Indian-American interests. He also chairs the Florida Council on Economic Education, which promotes free-market values to schoolchildren.

FDA User-Fee Program in Peril

The very future of FDA's user-fee program for medical devices is at stake. Any reference to “renegotiating” the Medical Device User Fee and Modernization Act (MDUFMA) may be regarded as code for “killing” the program, CDRH director Daniel Schultz told FDA's annual MDUFMA stakeholders meeting.

He appealed to industry representatives for a united front in urging Congress to continue the user-fee program. MDUFMA authorizes the agency to accept payments from industry to partially fund the regulatory process for medical devices. The payments may also help to expedite review of medical devices.

“If this program goes away, you should not believe it will be fixed in some other way,” Schultz said. “Considering all of the other priorities that are now facing Congress, failure to maintain continuity of the user-fee program will mean the user-fee concept, with respect to medical devices, is dead for the foreseeable future.”

Schultz expressed satisfaction with the progress FDA has made under MDUFMA to date. Particularly, he noted the agency's success in meeting all performance goals established for the timeliness of regulatory reviews. He attributed this success mainly to augmentation of the CDRH review staff, made possible by user fees.

Mark Leahey, executive director of the Medical Device Manufacturers Association (MDMA), also expressed general satisfaction with the performance of FDA under MDUFMA. However, he insisted that problems remain with the legislation that must be corrected. He said calling for changes to the user-fee program need not mean that it is in danger of “going away.”
Among complaints cited by Leahey is the fact that user fees have risen more than 55% in the past two years. This is coupled with a $20 million shortfall in promised FY 2004 congressional appropriations for FDA's medical device program.

“We're optimistic that the agency will receive full funding in FY05, but this will not address the more than $30 million appropriations shortfall from FY03 and FY04,” he said.

Leahey argued that any future fee increases should be calculated for inflation only. He also said that so-called “workload” and “compensating adjustments” to fee schedules now authorized by MDUFMA should be abandoned. He said, “Unless steps are taken to stabilize fees, the FDA-industry ‘partnership' is in trouble.”

Moreover, Leahey said that original performance goals established in MDUFMA should be “revisited” and “enhanced where appropriate.” He pointed out that, according to FDA's own statistics, 75% of 510(k)s were already being reviewed within 90 days prior to MDUFMA. In addition, current goals envision an increase to just 80% in the same 90-day time frame by FY 2007.

Frank Claunts, representing FDA's Office of Financial Management, said that “unstable fee revenue” remains a problem for the medical device user-fee program. He also agreed that less-than-envisioned congressional appropriations is a major factor. But, he pointed out, fee revenues have also been less than expected.

Claunts said that he believes revenue targets will be closer to expectations beginning in 2005 through 2007. However, it is imperative that the FY 2005 device appropriations be at the level envisioned by MDUFMA ($217 million). If they are not, he said, performance by the agency will be in jeopardy.

AdvaMed executive vice president Janet Trunzo also voiced industry's concerns over continued fee increases and lack of “predictability” in user-fee schedules. She said that, two years ago, industry urged FDA to perform a cost analysis study to devise a more-equitable basis for setting user fees. She again urged the agency to act on this suggestion. Trunzo said it is reasonable to expect that fee increases can be held to “single digits,” including allowance for inflation.

Several FDA presenters testified to their experience-to-date with the enhanced agency resources made possible by MDUFMA and user fees. Donna-Bea Tillman, CDRH Office of Device Evaluation acting director, said the original goal was for 80% of PMAs to receive completed reviews within 320 days of receipt. That goal, she said, has been fully met for FY 2004, and was 95% met during FY 2003.

She expressed confidence that even-more-stringent goals can be achieved in the future. She expects this to happen as FDA improves its information technology infrastructure for electronic submissions and document processing.

Symbols OK for IVD Professional Labeling

FDA says manufacturers of in vitro diagnostic (IVD) devices intended only for professional use may use some approved symbols in place of labeling text. In a new guidance, Use of Symbols on Labels and in Labeling of In Vitro Diagnostic Devices Intended for Professional Use, FDA notes that the market for in vitro diagnostic devices is international. The agency also notes that European Union (EU) member countries have attempted to harmonize their national legislation governing IVDs through a directive that took effect on December 8, 2003.

The EU IVD directive and FDA regulations require substantial information to appear on an IVD or its labeling. The directive also enables each member country to require that information appear in the national language. So, a single IVD could be required to have labeling in multiple languages. As an alternative, the EU encourages use of symbols from harmonized standards in place of text.

“Use of symbols helps IVD manufacturers to create uniform labels and labeling for the United States and European Union (and any other countries that may permit use of symbols from these international standards) instead of needing designated labels for each marketplace,” the guidance says. “Because symbols take up less space than the text for which they may substitute, the use of symbols promotes less- crowded and more-legible IVD labels. An additional advantage is that there are likely to be fewer labeling errors when using a single label, rather than having one set of labels for use in the United States and another set for use in the European Union.”

The guidance's recommendations don't apply to over-the-counter or prescription home-use IVDs. It includes a chart of acceptable harmonized symbols.

To view the guidance on-line, visit www.fda.gov/ohrms/dockets/98fr/2004d-0484-gdl0001.pdf.

Why FDA Can't Apply What It Knows

Once FDA has accepted the safety and effectiveness of materials used in one device, why can't it apply that institutional knowledge in reviewing the same materials in another device? That question was raised recently by Steve Ferguson, chairman of medical device maker Cook Group, during an HHS-sponsored Washington meeting. The purpose of the meeting was to find ways of introducing new biomedical technologies more efficiently.

“FDA should be a source of information and should be able to guide manufacturers to essential questions that need to be answered about materials and the functions of specific products,” Ferguson said. “Utilizing information efficiently will eliminate the waste of resources that occurs when known principles must be proven over and over again by each applicant.”

FDA has come up with several answers to this question, all of which add up to: “It's the law.”

CDRH director Daniel Schultz points to section 515 of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under that section, each device must show a reasonable assurance that the device is safe and effective under the conditions of use recommended in the labeling. Specifically, section 515(d) of the FD&C Act says that FDA must deny approval of a PMA unless specific showings are made.

CDRH Office of Device Evaluation director of program operations Bob Gatling says there is a more-specific prohibition on use of information contained in a PMA. This prohibition is in section 520(h) of the act, titled Release of Information Respecting Safety and Effectiveness. The act can be found on-line at www.fda.gov/opacom/laws/ fdcact/fdcact5a.htm.
Paragraph (3) of that section is explicit, Gatling says. It states that except for provisions in Paragraph (4), information about a device may not be used to establish the safety or effectiveness of another device.

Gatling says the Paragraph (4) exception is known as the “six-year rule” and was established by FDAMA in 1997. It says that any information contained in a PMA application shall be available six years after the Secretary has approved the application. This includes information from clinical and preclinical tests or studies that demonstrate the safety and effectiveness of a device. It excludes descriptions of methods of manufacture and product composition and other trade secrets. The Secretary may use this information in

• Approving another device.
• Determining whether a product development protocol has been completed under section 515 for another device.
• Establishing a performance standard or special control under this act.
• Classifying or reclassifying another device under section 513 and subsection (1)(2).

In these cases, the publicly available detailed summaries of the safety and effectiveness of devices may be used by the Secretary as the evidentiary basis for the agency actions.

Gatling adds that CDRH does allow use of conformance to consensus standards in PMAs. “If the material is one that meets or conforms to one of the consensus standards that CDRH has recognized, then we can use that conformance to the standard to lessen the data requirements in a PMA.” Information on the CDRH standards program can be found at FDA's Web site, www.fda.gov/cdrh/stdsprog.html.

Guidance on Clinical Data Formats

In a new guidance, CDRH provides its latest recommendations on general clinical data presentation formats for PMA, 510(k), and IDE applications for orthopedic devices. The document, Clinical Data Presentations for Orthopedic Device Applications, is intended to ensure consistency and understanding between FDA and sponsors when discussing and presenting clinical data.

The guidance recommends that for all data presentations, sponsors should clearly identify the number of patients evaluated at a given time in any data presentation, in addition to the rate of improvement—“for example, ‘64/75 patients at 3 months' rather than ‘85% at the 3-month time point.'” It also says that for each table presented, “a clear description of the population on which it is based” should be provided. For example, “if the result is 64/75, but the population was 100 patients, you should account for the remaining 25 patients.”

To view the guidance on-line, visit www.fda.gov/cdrh/ode/guidance/1542.html.

FDA Disputes Are Best Resolved Internally

A request for internal review through the supervisory chain is usually the best way to resolve disputes over payment or refund of medical device user fees under MDUFMA, FDA believes. In a November 17, 2004, guidance for industry and FDA staff, CDRH and CBER say that such a review is an informal process that is usually far more timely than any other review option.

Most disputes concerning actions that affect MDUFMA fee payment or refunds involve a specific application or submission, the guidance says. The remaining disputes usually involve whether an applicant qualifies as a small business or government entity. FDA does not expect such disputes to involve scientific issues, and the guidance is written with that in mind.
Alternative processes that could be considered include a citizen petition, administrative reconsideration of an action, formal evidentiary public hearing, public hearing before a board of inquiry, public hearing before a public advisory committee, public hearing before the FDA commissioner, and a regulatory hearing before FDA.

The guidance is in question-and-answer format and deals with the amount of a fee or refund, an applicant's status, the status of an application, review mechanisms, intended use, and refunds. The guidance, Resolution of Disputes Concerning Payment or Refund of Medical Device User Fees Under MDUFMA, may be viewed on-line at www.fda.gov/cdrh/mdufma/guidance/1303.pdf.

Silicone Breast Implants Reconsidered

FDA's General and Plastic Surgery Devices Advisory Panel plans to review two separate premarket approval applications in April for silicone gel–filled breast implants. If approved, they would break a controversial 12-year FDA moratorium on such approvals, based on safety concerns with previously marketed silicone implants.

One PMA application, from Inamed Corp., was reviewed and recommended for approval by the same panel in October 2003. However, FDA later ruled it was “not approvable” and issued a new guidance providing recommendations on what type of data should be in such applications. The second application came from Mentor Corp. It was submitted in December 2003 and amended last August in response to the guidance's new recommendations.

Guidance on Radio-Frequency Transponder Implants

FDA has issued a guidance for industry and FDA staff, titled Class II Special Controls Guidance Document: Implantable Radiofrequency Transponder System for Patient Identification and Health Information. It supports classifying implantable radiofrequency transponder systems for patient identification and health information into Class II. The guidance says such devices are intended to enable access to secure patient identification and corresponding health information in humans.
Designating the guidance as a special control has certain implications, FDA says. Manufacturers of such systems that follow the recommendations in the guidance can market the devices without following 510(k) requirements.

In the guidance, FDA identifies risks to health generally associated with use of the device. The risks include adverse tissue reaction; migration of an implanted transponder; compromised information security; and failure of an implanted transponder, inserter, or electronic scanner. Other risks are electromagnetic interference, electrical hazards, magnetic resonance imaging incompatibility, and needle stick. The agency provides recommended mitigation measures for each.

To view the guidance, visit www.fda. gov/cdrh/ode/guidance/1541.pdf.

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