FDA Thursday afternoon unveiled questions for its General and Plastic Surgery Devices Panel, covering broad categories including: how to best characterize and address breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) and breast implant illness; how to leverage registries and communicate risks to patients; and the benefits and risks of incorporating mesh for breast reconstruction and MRI screens to catch implant rupture. The panel begins its two-day meeting Monday.
The agency also shed light on methods and findings from data collected by the four approved manufacturers, adding depth to BIA-ALCL medical device report data FDA teased last month and context to the warning letters issued this week to Mentor and Sientra. The FDA repeatedly noted shortcomings of the MDR system and manufacturer study inconsistencies have hindered the ability to draw conclusions. It said that calculating the percentage of breast implant recipients who develop BIA-ALCL would be "impossible" because there is no definitive accounting of breast implant sales worldwide.
Building on its pledge last week to better scrutinize device materials' biocompatibility, FDA presented evidence on delayed onset symptoms that it says may be tied to silicone implants. While FDA has not asserted a clear link between breast implants and reported adverse events, the agency did seem receptive to formally acknowledging and defining breast implant illness, a term it says originated within patient communities, particularly on social media.
As it aims to get a handle on illnesses tied to breast implants, FDA acknowledged the limitations of its own adverse event reporting system.
"MDR is a method of passive surveillance, because it accepts reports, but does not actively interview every patient and manufacturer for information," the agency noted.
Still, the agency indicated mounting evidence of adverse events among breast implant recipients.
"At the present time, there is not sufficient evidence to show an association between breast implants and rheumatologic or connective tissue disease diagnoses," the briefing said. "However, there are numerous breast implant patients convening on social media to discuss a wide variety of symptoms that they are experiencing —symptoms which may or may not meet the diagnostic criteria to be categorized as a disease."
Citing the ASIA theory ("Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants"), wherein substances like aluminum salts, mineral oils and metals can enhance antigen-specific immune responses, FDA also talked about possible complications stemming from the implants' silicone material, for which some patients may be pre-disposed to allergic reaction. The agency added that the average time for these symptoms to present is between four and 10 years after implantation.
"Despite overlap in clinical manifestations, conflicting research outcomes have failed to provide definitive evidence that silicone breast implants are associated with the development of a defined autoimmune or connective tissue disease," FDA wrote, with emphasis on 'defined.'
In its two-day meeting at its Silver Spring, Maryland headquarters March 25-26, FDA is looking for guidance in the following categories:
Best use of registries. FDA wants to make the most of its registries, which include the BIA-ALCL-specific PROFILE registry, as well as the newer National Breast Implant Registry (NBIR), which tracks other adverse outcomes. The agency wants the panel to prioritize the most important types of data to collect, which in turn can guide the types of doctors tapped to enter data. FDA acknowledged critics of the registries, who say that access to data entry for certain physicians, and to data analysis by the public, is too limited. But FDA said it hopes the panel will weigh these concerns against the benefits of consistency and quality that may come from narrowing access. The agency also opened the possibility for mandating stricter registry engagement, asking the panel whether mandatory reporting to registries could be a positive.
Characterizing BIA-ALCL incidence and risk factors. FDA was clear throughout its briefing documents that its MDR data is incomplete and imperfect, making it challenging for the agency to pointedly characterize risk of BIA-ALCL development to patients. MDRs sometimes note implants surface and fill and time from implant to diagnosis, but reports are inconsistent.
To improve in that realm, FDA wants the panel to specify what data manufacturers should be required to report on breast implant placements so it can better track how certain breast implant characteristics impact rate of BIA-ALCL.
Regulators also want the panel of experts to consider whether the benefit/risk profile of breast implants differs by texture. FDA noted that of the 457 unique BIA-ALCL MDRs it reported receiving as of Sept. 30, 2018, 334 noted surface type, with 310 characterized as textured and 24 as smooth.
Addressing breast implant illness. FDA notes that the concept and naming of breast implant illness (BII) originated not from the agency nor from the scientific community, but from patient communities and voluntary reporters. Similar to the communities of women who received Essure or transvaginal mesh, FDA acknowledged that breast implant patients who have experienced adverse outcomes have built networks online, particularly using social media.
Now, the agency is looking to more formally define the term. FDA laid out more than 80 medical outcomes that have been associated with breast implant illness MDRs, with the top five being fatigue, brain fog, rash, joint pain and memory loss.
FDA's more specific questions include how to characterize relative risk of developing BII symptoms compared to the general population, what research questions should be explored, how symptom-presenting patients should be evaluated and how that information should be shared, and what post-operative data should be collected on patients who have implants removed as a result of BII.
FDA also wants to consider how it can use social media, as well as "artificial intelligence, text mining, mobile apps, and digital health," to collect and analyze data on BII symptoms.
Using surgical mesh for breast reconstruction. Among FDA's list of things that women may not know about breast implants, it notes many patients may not be aware that the majority of breast reconstructions involve the use of a surgical mesh device in conjunction with the breast implant itself. The use of hernia mesh or transvaginal mesh for pelvic organ prolapse or stress urinary incontinence has been a separate controversy FDA has addressed this year.
The American Society of Plastic Surgeons reports about 175,000 patients each year undergo reduction mammaplasty and mastopexy each year, otherwise known as breast reduction and breast lift, and that while FDA has not indicated synthetic and biological mesh products for use in these procedures, the agency has noticed "emerging use" of the devices in medical literature.
FDA said that a number of factors can affect the outcomes of mesh in breast reconstruction, like implant type, whether the mastectomy was skin-sparing or nipple-sparing, whether the reconstruction was immediate or delayed, whether a tissue expander is used prior to an implant, and where and how the implant is placed.
"Designing a clinical trial in support of a potential marketing application may require identifying specific patient populations and surgical procedures that demonstrate an appropriate balance of safety and effectiveness," FDA said of future incorporation of mesh in breast procedures.
FDA is asking the panel to help characterize how benefits and risks of mesh ought to be weighed, and whether a registry is needed for breast implant patients who also receive mesh.
Recommendations for MRI screening for implant rupture. FDA said that while mammography, ultrasonography and computed tomography have all been used in attempts to detect silent rupture of silicone gel-filled breast implants, MRI has proved the most effective. A 2006 advisory committee recommended an MRI screen at three years and biennially thereafter for all approved breast implants. FDA said it has tried to track whether that labeling is worthwhile by analyzing rupture detection rates in post-approval study data, but that differences in data collection methods across manufacturers makes meaningful conclusions difficult. FDA also acknowledged it must consider concerns raised surrounding cost and reimbursement of MRI screens.
American College of Radiology guidelines on breast implant imaging, updated in 2018, said that given a lack of consensus on whether ruptured silicone implants require surgery in asymptomatic patients, breast MRI ought not be indicated for implant evaluation in asymptomatic women at any age.
"Due to the differences in the methods in which ruptures were detected and confirmed, the types of data that were collected, length and frequency of patient follow-up, and the methods for analyzing and presenting the data greatly limited the comparisons that can be made between manufacturers," the briefing document said.
Ultimately, FDA wants to know whether it should continue to recommend MRI screening, and if so, what evidence supports its benefit/risk profile. It also wants to know if alternative screening methods can or should be used.
Communicating risks and benefits to patients. FDA acknowledged patients may not know breast implants are not intended to be lifetime devices, and that over time, risk of local complications and adverse events rises, which could lead to implant removal. Rupture rates have been shown to increase four to six years after implant placement, FDA said. Other possible complications to be aware of include capsular contracture, re-operation, removal, and implant rupture, as well as breast pain, wrinkling, asymmetry, scarring and infection.