FDA's General & Plastic Surgery Devices Panel will likely consider gel migration and "silent rupture" of silicone breast implants when reviewing Inamed's premarket application.

Last December, Inamed filed a PMA for a silicone implant, based on data from 1,000 patients followed for at least three years. Mentor is developing a similar device and expects to complete a modular PMA filing later this year, based on two-year follow-up data.

Since 1992, silicone implants have been cleared only for use in FDA-approved clinical trials or as part of an ongoing adjunct study of the devices for breast reconstruction. Inamed and Mentor received FDA clearance of saline-filled implants in 2000.

Although Inamed's and Mentor's devices will be considered separately, FDA may ask the panel to review both PMAs at the same panel meeting, depending on the timing of Mentor's submission. Inamed expects to go before the panel by December (¹ Also see "Inamed Performance Enhanced By Tech Assessment: Shares Up 38% In May" - Medtech Insight, 9 June, 2003., p. 28).

"FDA intends to take the data to our advisory panel for their review and recommendation," the agency notes in a July letter to Senate HELP Committee Ranking Member Edward Kennedy (D-Mass.). "Additionally, FDA will consider how to address long-term issues for each of the indications, as recommended by the panel," the letter explains.

In the letter, FDA Associate Commissioner for Legislation Amit Sachdev responds to a March 7 request by Sens. Kennedy, Jeff Bingaman (D-N.M.), Hillary Clinton (D-N.Y.), Barbara Boxer (D-Calif.) and Mary Landrieu (D-La.). The Dems expressed a number of concerns with "significant gaps in our knowledge about the safety of these products."

Given the availability of saline-filled breast implants, the Senate letter asks: "Will silicone breast implants need to show a higher level of safety and effectiveness than if saline breast implants were not available?"

The agency maintains that its threshold of safety and effectiveness "does not change because a similar product previously has been approved," but acknowledges silicone implants present safety issues, such as silent rupture, that saline implants do not.

FDA's February ² guidance on PMAs for all breast implants specifies that patients should be evaluated for at least two years in a premarket study and at least eight years postmarket.

The agency's application of the same premarket data standards for all types of breast implants has drawn criticism from some patient advocates, including the National Organization for Women, Public Citizen and the National Women's Health Network.

At a May 8 meeting convened by NOW, a consensus panel concluded that FDA should require at least seven years of premarket clinical data for approval of silicone gel-filled breast implants. Overall, "seven to 10 years of data would be necessary to begin to properly evaluate the health effects of the devices," NOW claimed in a July 21 release accompanying a ³ consensus document.

The panel was moderated by former FDA Office of Women's Health Director Audrey Sheppard and included ExpertTox Inc.'s Ernest Lykissa, PhD, Duke University Medical Center's Bercedis Peterson, PhD, and Case Western Reserve University School of Medicine's William Katzin, MD/PhD.

With Public Citizen, NOW intends to pressure FDA to insist on patient follow-up of at least seven years. On July 21, representatives of the NOW consensus group and Public Citizen met with Reps. Gene Green (D-Texas) and Louise Slaughter (D-N.Y.) to generate legislative support for the document's conclusions.

NOW cites a retrospective, 10,000-patient study conducted by FDAer S. Lori Brown, PhD, to argue that the median age of silicone gel implants at rupture is approximately 10 years (⁴ Also see "Silicone Gel-Filled Breast Implant 69% Rupture Rate Found In FDA Study" - Medtech Insight, 29 May, 2000., p. 10).

The organization claims that neither Mentor nor Inamed has enough data to demonstrate safety of their devices because "long-term properties are key to several safety issues." The consensus document notes that "silicone gel-filled breast implants are known to have an increasingly high prevalence of rupture over time."

"The issue of long-term safety [of silicone implants] has not been adequately addressed in past research, specifically regarding the integrity of devices over time, [and] the varying physical and chemical properties of the implant materials over time," the panel concludes. "The panel was very concerned that the recognized latency effects of silicone breast implants are not being considered," panelist Paul Wooley, MD, Wayne State University explained.

In response to the panel's claims that their study will not demonstrate the device's safety, Inamed cites an April ⁵ NIH report to Congress on an ongoing National Cancer Institute registry of 13,500 women who received silicone implants prior to 1990.

The retrospective study showed that women receiving implants for breast augmentation had no significant increase in breast cancer incidence/mortality, compared with patients undergoing other types of plastic surgery (⁶ Also see "NCI Silicone Breast Implant Study Will Assess Connective Tissue Disease" - Medtech Insight, 12 May, 2003., p. 38).

The report was mandated by the Medical Device User Fee & Modernization Act. Reps. Green and Roy Blunt (R-Mo.) originally proposed this requirement in 2001 (⁷ Also see "Energy & Commerce Looking To Include Breast Implant Bill In Device Package" - Medtech Insight, 30 September, 2002., p. 19).

FDA will consider the NCI registry, along with any other relevant studies of silicone-gel breast implants, in its review of Inamed's and Mentor's PMA applications, according to the agency.

NOW maintains that the retrospective analysis is not a substitute for a long-term premarket study, because the NCI registry focused on breast cancer and systematic diseases - not local complications often associated with silicone implants, such as inflammation, disfigurement, pain and hardened capsules.

In its assessment, NIH explains that although silicone breast implants were not associated with higher mortality in the study, the implant patients had higher rates of suicide, brain and lung cancer - a trend warranting "further scrutiny."

Furthermore, NIH observes that women undergoing elective surgery are generally healthier then the overall population, which may explain the generally low mortality rate for women with implants. Similarly, NOW notes that the study relies on medical charts of symptomatic patients - as opposed to physical exams - and therefore may have failed to capture many complications associated with silicone implants.

NOW expects that more information on the long-term safety of silicone breast implants will be gained from an ongoing study supported by FDA and the National Institute of Environmental Health Sciences. The 231-patient study on immunologic and immunogenic factors in silicone-associated connective tissue disease is expected to be complete next spring.

Silicone Breast Implant Data Requirements Questioned By Patient Groups

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