FDA News

FDA weighs breast implant risks, benefits amid links to cancer, other illnesses

Earlier this month, the FDA issued a statement maintaining that textured implants do not meet the agency’s banning standard, despite an association between the implants and anaplastic large cell lymphoma.

The agency announced several steps to protect women considering implants, including improving available information about risks, adding ingredients to labeling and potentially including a boxed warning, educating the medical community, and changing how breast implant manufacturers file medical device reports.

The statement followed a 2-day meeting of the FDA’s General and Plastic Surgery Devices Advisory Panel in March.

The panel discussed long-term risks and benefits of breast implants for breast augmentation and reconstruction. The first day focused on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare type of lymphoma that grows in the scar tissue surrounding the breast, following reports of the disease in 457 women. Also addressed at the meeting were concerns of thousands of women who attributed symptoms such as debilitating joint pain and fatigue to breast implants.

Textured breast implants have been identified as being particularly linked to BIA-ALCL and other illnesses, but panelists clarified that the true number of cases linked to smooth implants is not fully known.

“This meeting occurs against a backdrop of several notable actions taken by international regulators as they continue to consider the benefits and risks of breast implants,” Binita Ashar, MD, general surgeon and member of the FDA’s Center for Devices and Radiological Health, said at the meeting. “Over the past couple of months leading up to this meeting, FDA has been meeting with patient groups to hear their concerns regarding breast implant regulation and the communication around implant complications and risk. We are asking the panel to keep at the forefront the things patients considering breast implants should know, in addition to medical device adverse event reports and patient registries.”

Postapproval studies

Approximately 400,000 women receive breast implants in the U.S. each year, including about 100,000 women who undergo reconstructive surgery following treatment for breast cancer.

Estimates of BIA-ALCL incidence range from one in 3,000 women to one in 30,000. Twelve deaths have been linked to the disease, which is typically slow growing and can be treated by removing the implants.

The FDA temporarily pulled silicone gel implants — the most commonly used implant in the U.S. — off the market in 1992 due to fears they might increase risk for breast cancer, lupus and other illnesses. However, they returned to the market in 2006 after additional studies did not confirm an increased risk.

FDA has relied on postapproval studies to evaluate the long-term safety of the implants.

However, the agency issued warning letters, dated March 18, to two California-based breast implant manufacturers — Mentor Worldwide LLC and Sientra Inc. — for noncompliance to requirements for postapproval studies.

“While we know that the industry-sponsored postapproval studies have issues related to postapproval study compliance, we were working with manufacturers to analyze the available data,” Ashar said.

Representing breast implant manufacturer Allergan was Stephanie Manson Brown, MD, the company’s associate vice president and global head of medical affairs, aesthetics and medical dermatology.

Manson Brown said Allergan’s breast implants are supported by significant clinical evidence, including more than 500,000 patient-years from clinical studies and a body of published literature. She discussed Allergan’s ongoing Breast Implant Follow-up Study, which analyzes a 2,257-patient subgroup from the original large post-approval study cohort of more than 40,000 patients.

“Patients with BIA-ALCL can have an excellent prognosis when identified early and treated appropriately,” Mason Brown said. “Although the range is broad and the etiology is not yet fully understood, literature reports that higher implant surface area may increase the risk [for] BIA-ALCL. The leading hypothesis centers around biofilm and there are three likely factors that contribute to this, including procedure, product and patient.”

She recommended use of an enhanced, 14-point aseptic technique, which includes changing gloves between implant sites, soaking the implant in an antiseptic solution and a minimal touch approach.

Raina Dauria, vice president of worldwide regulatory affairs at Mentor/Johnson & Johnson, discussed Mentor’s implants and the company’s ongoing postapproval studies.

“Mentor gel and saline breast implants are supported by long-term clinical data, including three 10-year prospective clinical trials,” Dauria said. “They’re sold in more than 80 countries and have been chosen by millions of women worldwide for over 30 years.”

She addressed the warning letter Mentor received about the memory shape implants, noting the company’s struggles with study enrollment.

“The memory shape implants are available with a textured surface only over the past several years,” she said. “The use of textured devices in the U.S. has decreased substantially, and Mentor has been challenged in enrolling this study group, despite taking steps to increase enrollment.”

A real-world registry

To provide more comprehensive, real-world data on outcomes following breast implantation, researchers developed the PROFILE registry.

“In 2011, when concerns were initially being raised about a new type of lymphoma associated with breast implants, the Plastic Surgery Foundation recognized the need to develop a national registry to gain a greater understanding of the etiology, national history, causation and optimal treatment,” Andrea Pusic, MD, president of the Plastic Surgery Foundation, said.

Between August 2012 and March 2018, PROFILE received reports of 186 distinct cases of BIA-ALCL in the United States. However, complete and detailed case report forms have been received for only 89 (49%) of these cases.

Of the 89 cases with complete data, saline was the filler used in 39 women (44%), silicone was used in 46 (52%) and one woman had a combined silicone/saline implant. Three women had unreported filler type. At the time of diagnosis, 69 women (78%) had an implant with a textured shell, whereas five women (6%) had a smooth implant type.

“The Plastic Surgery Foundation believes clinical registries are powerful means of understanding real-world registries and monitoring safety signals,” Pusic said.

The MD Anderson experience

Mark W. Clemens, MD, a member of the plastic surgery faculty at The University of Texas MD Anderson Cancer, reported on his institution’s experience with BIA-ALCL.

“We’ve treated 64 cases of BIA-ALCL at MD Anderson, with an average of 8 to 10 years to development of the disease from implantation,” Clemens said. “We recognized 152 unique and confirmed cases in the U.S., and the shortest time interval to development has been 2.2 years after implant.”

Clemens noted that the most commonly reported symptom has been delayed seroma, although capsular contracture of mass and overlying rash also have been reported. He noted that there is currently no testing or screening method for asymptomatic cases.

“If you take one thing from my presentation, let it be that although the FDA has reported cases of BIA-ALCL with smooth implants, there have been no cases that were with smooth implants only in any case report or case series,” Clemens said.

MD Anderson has treated an even mix of women with implants for cosmesis and augmentation, as well similar numbers of silicone vs. saline and augmentation vs. reconstruction.

Clemens said MD Anderson has formed a global network of physicians who are tracking confirmed and unique cases in 35 countries.

“We feel very comfortable that the pathology was known and that these were unique cases,” he said.

He said although all implant manufacturers were represented in documented cases, Allergan was overrepresented.

“Compared to all other manufacturers combined, Allergan Biocell had 7.1 to 8.3 times more,” he said. “Pertinent to the U.S. market, which is Allergan to Mentor, it is 9 to 32 times greater.”

Additional steps

In the statement issued this month — by FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD, and Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health — the agency maintained that textured breast implants do not meet the banning standard of the Federal Food, Drug and Cosmetic Act. But, they outlined measures the agency will take to improve patient and provider education about the risks of implants and to strengthen warnings on the product labeling.

The FDA plans to take steps to:

  • improve information available to women and health care professionals about the risks associated with breast implants, including addressing the risk for BIA-ALCL, the greater risk for BIA-ALCL with textured implants, and the risk for systemic symptoms;
  • incorporate product ingredient information into the labeling in a way that is easy for patients to understand;
  • educate the medical community about BIA-ALCL and other risks associated with breast implants and to educate pathologists about testing for this lymphoma specific to breast implants;
  • update the public about any new information related to breast implant risks, as well as update and improve the communication tools for women on the FDA’s website; and
  • change how breast implant manufacturers file medical device reports with the FDA, ending all summary reporting of breast implant medical device reports. Breast implant manufacturers will be required to file individual medical device reports that will be publicly available in the Manufacturer and User Facility Device Experience, or MAUDE, database.

Ultimately, the statement did not include a ban on textured implants.

“The FDA believes regulatory action must be based on scientific data,” Abernethy and Shuren wrote. “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants and many reports do not include the surface texture of the implant at the time of diagnosis. ... We are still investigating the cause of the association and we will continue to monitor, assess and report our findings as we continue to strengthen our evidence collected so that women and providers can be better informed about BIA-ALCL as they consider breast implants.” – by Jennifer Byrne

Earlier this month, the FDA issued a statement maintaining that textured implants do not meet the agency’s banning standard, despite an association between the implants and anaplastic large cell lymphoma.

The agency announced several steps to protect women considering implants, including improving available information about risks, adding ingredients to labeling and potentially including a boxed warning, educating the medical community, and changing how breast implant manufacturers file medical device reports.

The statement followed a 2-day meeting of the FDA’s General and Plastic Surgery Devices Advisory Panel in March.

The panel discussed long-term risks and benefits of breast implants for breast augmentation and reconstruction. The first day focused on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a rare type of lymphoma that grows in the scar tissue surrounding the breast, following reports of the disease in 457 women. Also addressed at the meeting were concerns of thousands of women who attributed symptoms such as debilitating joint pain and fatigue to breast implants.

Textured breast implants have been identified as being particularly linked to BIA-ALCL and other illnesses, but panelists clarified that the true number of cases linked to smooth implants is not fully known.

“This meeting occurs against a backdrop of several notable actions taken by international regulators as they continue to consider the benefits and risks of breast implants,” Binita Ashar, MD, general surgeon and member of the FDA’s Center for Devices and Radiological Health, said at the meeting. “Over the past couple of months leading up to this meeting, FDA has been meeting with patient groups to hear their concerns regarding breast implant regulation and the communication around implant complications and risk. We are asking the panel to keep at the forefront the things patients considering breast implants should know, in addition to medical device adverse event reports and patient registries.”

Postapproval studies

Approximately 400,000 women receive breast implants in the U.S. each year, including about 100,000 women who undergo reconstructive surgery following treatment for breast cancer.

Estimates of BIA-ALCL incidence range from one in 3,000 women to one in 30,000. Twelve deaths have been linked to the disease, which is typically slow growing and can be treated by removing the implants.

The FDA temporarily pulled silicone gel implants — the most commonly used implant in the U.S. — off the market in 1992 due to fears they might increase risk for breast cancer, lupus and other illnesses. However, they returned to the market in 2006 after additional studies did not confirm an increased risk.

PAGE BREAK

FDA has relied on postapproval studies to evaluate the long-term safety of the implants.

However, the agency issued warning letters, dated March 18, to two California-based breast implant manufacturers — Mentor Worldwide LLC and Sientra Inc. — for noncompliance to requirements for postapproval studies.

“While we know that the industry-sponsored postapproval studies have issues related to postapproval study compliance, we were working with manufacturers to analyze the available data,” Ashar said.

Representing breast implant manufacturer Allergan was Stephanie Manson Brown, MD, the company’s associate vice president and global head of medical affairs, aesthetics and medical dermatology.

Manson Brown said Allergan’s breast implants are supported by significant clinical evidence, including more than 500,000 patient-years from clinical studies and a body of published literature. She discussed Allergan’s ongoing Breast Implant Follow-up Study, which analyzes a 2,257-patient subgroup from the original large post-approval study cohort of more than 40,000 patients.

“Patients with BIA-ALCL can have an excellent prognosis when identified early and treated appropriately,” Mason Brown said. “Although the range is broad and the etiology is not yet fully understood, literature reports that higher implant surface area may increase the risk [for] BIA-ALCL. The leading hypothesis centers around biofilm and there are three likely factors that contribute to this, including procedure, product and patient.”

She recommended use of an enhanced, 14-point aseptic technique, which includes changing gloves between implant sites, soaking the implant in an antiseptic solution and a minimal touch approach.

Raina Dauria, vice president of worldwide regulatory affairs at Mentor/Johnson & Johnson, discussed Mentor’s implants and the company’s ongoing postapproval studies.

“Mentor gel and saline breast implants are supported by long-term clinical data, including three 10-year prospective clinical trials,” Dauria said. “They’re sold in more than 80 countries and have been chosen by millions of women worldwide for over 30 years.”

She addressed the warning letter Mentor received about the memory shape implants, noting the company’s struggles with study enrollment.

“The memory shape implants are available with a textured surface only over the past several years,” she said. “The use of textured devices in the U.S. has decreased substantially, and Mentor has been challenged in enrolling this study group, despite taking steps to increase enrollment.”

A real-world registry

To provide more comprehensive, real-world data on outcomes following breast implantation, researchers developed the PROFILE registry.

“In 2011, when concerns were initially being raised about a new type of lymphoma associated with breast implants, the Plastic Surgery Foundation recognized the need to develop a national registry to gain a greater understanding of the etiology, national history, causation and optimal treatment,” Andrea Pusic, MD, president of the Plastic Surgery Foundation, said.

PAGE BREAK

Between August 2012 and March 2018, PROFILE received reports of 186 distinct cases of BIA-ALCL in the United States. However, complete and detailed case report forms have been received for only 89 (49%) of these cases.

Of the 89 cases with complete data, saline was the filler used in 39 women (44%), silicone was used in 46 (52%) and one woman had a combined silicone/saline implant. Three women had unreported filler type. At the time of diagnosis, 69 women (78%) had an implant with a textured shell, whereas five women (6%) had a smooth implant type.

“The Plastic Surgery Foundation believes clinical registries are powerful means of understanding real-world registries and monitoring safety signals,” Pusic said.

The MD Anderson experience

Mark W. Clemens, MD, a member of the plastic surgery faculty at The University of Texas MD Anderson Cancer, reported on his institution’s experience with BIA-ALCL.

“We’ve treated 64 cases of BIA-ALCL at MD Anderson, with an average of 8 to 10 years to development of the disease from implantation,” Clemens said. “We recognized 152 unique and confirmed cases in the U.S., and the shortest time interval to development has been 2.2 years after implant.”

Clemens noted that the most commonly reported symptom has been delayed seroma, although capsular contracture of mass and overlying rash also have been reported. He noted that there is currently no testing or screening method for asymptomatic cases.

“If you take one thing from my presentation, let it be that although the FDA has reported cases of BIA-ALCL with smooth implants, there have been no cases that were with smooth implants only in any case report or case series,” Clemens said.

MD Anderson has treated an even mix of women with implants for cosmesis and augmentation, as well similar numbers of silicone vs. saline and augmentation vs. reconstruction.

Clemens said MD Anderson has formed a global network of physicians who are tracking confirmed and unique cases in 35 countries.

“We feel very comfortable that the pathology was known and that these were unique cases,” he said.

He said although all implant manufacturers were represented in documented cases, Allergan was overrepresented.

“Compared to all other manufacturers combined, Allergan Biocell had 7.1 to 8.3 times more,” he said. “Pertinent to the U.S. market, which is Allergan to Mentor, it is 9 to 32 times greater.”

Additional steps

In the statement issued this month — by FDA Principal Deputy Commissioner Amy Abernethy, MD, PhD, and Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health — the agency maintained that textured breast implants do not meet the banning standard of the Federal Food, Drug and Cosmetic Act. But, they outlined measures the agency will take to improve patient and provider education about the risks of implants and to strengthen warnings on the product labeling.

PAGE BREAK

The FDA plans to take steps to:

  • improve information available to women and health care professionals about the risks associated with breast implants, including addressing the risk for BIA-ALCL, the greater risk for BIA-ALCL with textured implants, and the risk for systemic symptoms;
  • incorporate product ingredient information into the labeling in a way that is easy for patients to understand;
  • educate the medical community about BIA-ALCL and other risks associated with breast implants and to educate pathologists about testing for this lymphoma specific to breast implants;
  • update the public about any new information related to breast implant risks, as well as update and improve the communication tools for women on the FDA’s website; and
  • change how breast implant manufacturers file medical device reports with the FDA, ending all summary reporting of breast implant medical device reports. Breast implant manufacturers will be required to file individual medical device reports that will be publicly available in the Manufacturer and User Facility Device Experience, or MAUDE, database.

Ultimately, the statement did not include a ban on textured implants.

“The FDA believes regulatory action must be based on scientific data,” Abernethy and Shuren wrote. “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants and many reports do not include the surface texture of the implant at the time of diagnosis. ... We are still investigating the cause of the association and we will continue to monitor, assess and report our findings as we continue to strengthen our evidence collected so that women and providers can be better informed about BIA-ALCL as they consider breast implants.” – by Jennifer Byrne