Breast implants and anaplastic large cell lymphoma

On 25 September 2019, the Therapeutic Goods Administration (TGA) took regulatory action in relation to un-implanted breast implants sold within Australia. As part of this regulatory action, the TGA made the decision to suspend eight entries from four sponsors (the person or company legally responsible for the product) from the Australian Register of Therapeutic Goods (ARTG), for a period of six months, commencing 25 October 2019.

During this time, the sponsors of the implants had to address the deficiencies identified by the TGA in relation to the safety and performance of the implants. During the suspension, sponsors were not permitted to supply, import, or export the applicable breast implant devices from Australia, without special authorisation. To address the identified deficiencies, sponsors were required to make a submission to the TGA by 24 April 2020. The TGA has not received sufficient evidence to allow us to revoke the suspension for the devices and allow the devices to be supplied.

The TGA decided to extend the suspension period of three ARTG entries, from two sponsors, for a further six months (see the table below for further details). These sponsors provided evidence that they were working towards compliance with the requirements. They were required to provide a submission to the TGA by 24 October 2020 to demonstrate the safety and performance deficiencies of the devices have been addressed. These devices are still unable to be supplied, imported, or exported from Australia, without special authorisation.

Four ARTG entries, from two sponsors, have been cancelled by the sponsor and are therefore not permitted to be supplied, imported, or exported from Australia, without special authorisation.

One ARTG entry was cancelled by the TGA as the sponsor did not provide evidence to support an extension or revocation of the suspension. This device cannot be supplied, imported, or exported from Australia, without special authorisation.

The below tables provide an update on the devices and their current ARTG status.

Next steps

If you have any of the above breast implants, you do not need to do anything except be aware of the symptoms of BIA-ALCL and seek advice from a health professional if you notice any changes.

The sponsors of suspended implants have an opportunity to make submissions at any time during the period of suspension to demonstrate that the safety and performance concerns raised by the TGA have been addressed.

The TGA will take into consideration each sponsor's submission when deciding what, if any, further regulatory action should be taken in relation to particular sponsor's device(s).

TGA review of breast implants

What action has the TGA taken?

The TGA has decided to take regulatory action in relation to all un-implanted breast implants and tissue expanders sold in Australia.

The TGA has reviewed a range of inputs to inform decisions about the quality and performance of breast implant and tissue expander devices, and their compliance with the Essential Principles for Medical Devices that require that the benefits of devices outweigh risks. Evidence considered includes:

• results of extensive laboratory testing on surface texture and analysis of manufacturing processes
• statistical review of BIA-ALCL cases in Australia
• advice from the Breast Implant Expert Working Group
• submissions and information from other stakeholders and patients
• evidence submitted by the sponsors and manufacturers of breast implants and tissue expanders including:
  • clinical evidence reports
  • biocapatibility testing
  • risk management frameworks
  • vigilance data
  • quality management systems for manufacturing processes

Consumers should speak with their medical practitioner if they have any concerns about their breast implants.

Further information can be found in our consumer information or on the breast implant hub.

Affected brands of breast implant devices and the regulatory actions to be imposed are as follows.

Un-implanted stock removed from market

In some cases, the sponsor has chosen to cancel the inclusion of their implant devices in the Australian Register of Therapeutic Goods (ARTG) during the course of this review. The Allergan Biocell macro-textured breast implants and tissue expanders and the Emergo Airxpanders Aeroform tissue expanders are no longer available on the Australian market. This means no new patients will receive these implants.

Suspension of un-implanted devices

Some breast implant devices have been suspended. This means that these implants will not be able to be implanted into patients over the next six months without special authorisation. During this period, the sponsor will have the opportunity to provide additional information to the TGA about the safety and performance of their products. Additional information about the safety and performance of the products is provided to assist health professionals in their decision making. See: Update on safety and performance concerns of suspended breast implants

Suspended implants are those that are "macrotextured" - grade 3 and 4 and some "microtextured" implants associated with higher incidences of BIA-ALCL and other clinical concerns.

To recap:

• The above breast implant devices have been suspended.
• The devices will not be able to be supplied, imported, or exported from Australia for the duration of the suspension (6 months), effective 25 October 2019.
• A suspension can be withdrawn early if the sponsor can address concerns to the TGA's satisfaction.
• If concerns persist, the suspension may be extended or the entries of the devices may be cancelled.
• All un-implanted products will be subject to recall to remove them from the market (i.e. on hospital shelves).
• If a decision is made to recall the above breast implants, this will only apply to un-implanted stock, not devices that have already been implanted.

New conditions for breast implant devices

To ensure the highest level of patient safety possible, the TGA has imposed 'conditions' on all breast implant devices that remain available in Australia. This means that for a sponsor to supply a breast implant device in Australia, they must meet a range of new requirements. If a sponsor fails to comply with any condition of inclusion, the device may be removed from the ARTG.

What are the conditions?

1. Reporting of BIA-ALCL: To support the on-going monitoring of BIA-ALCL, all cases of BIA-ALCL must be reported to the TGA by the sponsors within 10 working days of becoming aware of the adverse event.
2. Six monthly reporting: To support greater vigilance and increased awareness and data collection on this issue, the TGA is requiring reports to be provided every six months from the sponsors. The reports must include supply data and detail all adverse events and complaints received regarding breast implant and tissue expander devices, both in Australia and worldwide, including BIA-ALCL, capsular contracture, or rupture of the implant.
3. Instructions for use: To promote clinicians' awareness, the risk of BIA-ALCL must be included in the Instructions for Use of all breast implant and tissue expander devices.
4. Patient information leaflet: To support informed patient choices, all breast implant and tissue expander devices must have access to a patient information leaflet that includes information about warnings and risks associated with the product. Information relating to the Australian Breast Device Registry must also be included, to support on-going reporting and monitoring.

Next steps

If you have any of the above breast implants, you do not need to do anything except be aware of the symptoms of BIA-ALCL and seek advice from a health professional if you notice any changes.

The sponsors of suspended implants have an opportunity to make submissions at any time during the period of suspension to demonstrate that the safety and performance concerns raised by the TGA have been addressed.

The TGA will take into consideration each sponsor's submission when deciding what, if any, further regulatory action should be taken in relation to particular sponsor's device(s).

Background

The evidence available at present indicates that while causes are likely to be multi-factoral BIA-ALCL is more likely to occur in implants with a greater surface area and roughness of their wall. The degree of texturing in the surface is a result of the materials used in the production of the device or the manufacturing processes.

The TGA is taking a precautionary approach and suspending particular breast implant devices which have a higher degree of texturing, or a higher risk of BIA-ALCL, or deficiencies in evidence to demonstrate the manufacturer has adequate risk detection and mitigation measures in place.

Over the past few years there has been a change in the type of breast implants used in Australia with a decrease in macro-textured implants and an increase in supply of micro-textured and smooth implants. The suspensions imposed by the TGA do not impact on the supply of the smooth implants available and to date there are no known cases of BIA-ALCL in Australia where only smooth devices were implanted.

Allergan has elected to recall all of their un-implanted macro-textured breast implants and tissue expanders, due to the risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in rare cases. Micro-textured and smooth breast implants are not affected by this hazard alert and sponsor initiated recall.

The TGA has been advised that removal or replacement of macro-textured breast implants or tissue expanders in asymptomatic patients is not recommended.

This update reflects the TGA's initial views following recent laboratory testing and statistical analysis. Breast implant sponsors have until 24 July to provide additional information which will be assessed before reaching a final decision.

Information is being made available at this stage as people with implants, and those considering implants have the right to make informed choices about their healthcare.

As part of ongoing work regarding breast implant associated anaplastic large cell lymphoma (BIA-ALCL), the Therapeutic Goods Administration (TGA) has completed its review and laboratory assessment of textured breast implants on the Australian market. The review was announced on 3 May 2019 and involved both laboratory testing and statistical analysis of supply information and the known cases of BIA-ALCL to estimate the risks associated for each type of implant.

What is BIA-ALCL and what should you do if you have concerns?

BIA-ALCL usually involves a swelling of the breast, typically 3 to 14 years after the operation to insert the breast implant. This swelling is due to an accumulation of fluid. Less commonly, BIA-ALCL can take the form of a lump in the breast or a lump in the armpit.

It is a rare condition, with expert opinions estimating the published risk of BIA-ALCL at between 1-in-1,000 and 1-in-10,000.

Although fatalities have been recorded, the vast majority of BIA- ALCL are cured by removal of the implant and the capsule surrounding the implant.

If you notice any of these problems (swelling or a lump), or you have any other concerns with your implants, you should seek medical attention.

Because BIA- ALCL is rare, experts do not recommend removal of breast implants where there are no problems with the implant.

Information for consumers about BIA-ALCL, its symptoms and treatments is available on the TGA's breast implant hub.

TGA's proposed regulatory action - textured implants only

Based on the laboratory and statistical review, the TGA has proposed regulatory action in relation to a number of textured implants only. Those proposed regulatory actions are either a proposal to cancel or a proposal to suspend. The TGA has also imposed new conditions on the inclusion of a number of other textured implants in the Register.

The TGA has notified each of the sponsors of the relevant proposed regulatory action (or imposition of conditions, where conditions have been imposed) on 9 July 2019.

It is important to understand that the proposed cancellations and suspensions set out below are proposed. No decision has been made to suspend or cancel the relevant products at this time.

The next steps are for the sponsors to respond to the TGA's notification and invitation to comment by 24 July 2019. The TGA will, as a matter of priority, consider the sponsor's submissions before reaching any decision on whether to proceed to the proposed regulatory action.

More information will follow after the TGA has had an opportunity to finalise its deliberations.

The TGA is providing breast implant recipients, the wider public and medical practitioners, this information identifying the breast implants, mammary implants or tissue expanders affected by the identified proposed regulatory action in the interests of public health and safety. This publication also communicates the preliminary outcomes from the extensive body of laboratory testing and statistical analysis carried out by TGA over the last 2 months.

If you have concerns, please speak with your medical practitioner. The proposed regulatory actions for particular products and the affected brand(s) of implants are as follows:

If the entries of the above products are cancelled, the products would no longer be able to be imported, manufactured or exported from Australia by the sponsor. The TGA is also proposing to require the sponsor to recall the products to remove all remaining products from the market. The recall would only apply to product that is waiting to be implanted. There is not a recommendation to surgeons to remove implants in the absence of a BIA-ALCL diagnosis.

If the entries of the above products are suspended, the products would no longer be able to be imported, manufactured or exported from Australia by the sponsor for the duration of the suspension. A suspension can be revoked if concerns about the products are addressed to the TGA's satisfaction. Alternatively, where concerns persist the duration of the suspension may be extended or the entries of the products may be cancelled. If any of the products are suspended, it is proposed to recall all remaining product to remove it from the market. The recall would only apply to product that is waiting to be implanted surgically. There is not a recommendation to surgeons to remove implants in the absence of a BIA-ALCL diagnosis.

Imposition of conditions - patient information leaflet

To support informed patient choices, the TGA has imposed a condition on the ARTG entries of the products in the table below that the sponsors are to make available to patients a patient information leaflet that includes information about the therapeutic good including warnings and risks associated with the product.

Reminder: next steps

The TGA is required by law to provide the sponsors of affected implants with an opportunity to make submissions in response to proposed regulatory action. The TGA will then take into consideration each sponsor's submission when deciding what, if any, regulatory action should be taken in relation to particular sponsor's device(s).

Sponsors were notified of the TGA's preliminary view on 9 July 2019 and have been given until 24 July to respond. The TGA will then evaluate the submissions as a priority, and more information on regulatory actions will follow.

At this time relevant products will continue to be included on the ARTG (i.e. approved by TGA) and available for use in Australia

BIA-ALCL is more likely to occur in rougher surfaced implants, and the TGA is proposing to either cancel or suspend particular products. There are alternative smooth implants available and these have not been associated with known cases of ALCL in Australia.

Because the risk to women who already have these implants is very low, experts do not recommend that women who already have them need to have them removed unless there is a confirmed diagnosis of ALCL.

The proposed action by the TGA does not change this advice. If you have concerns you should speak to your surgeon.

Consumers with concerns about their breast implants can access information about BIA-ALCL, its symptoms and treatments through the TGA's breast implant hub.

The TGA has commenced its review and laboratory assessment of the surface topography of samples received from the sponsors of breast implants in Australia. A team of engineers and scientists will undertake over 2,000 sets of measurements of more than 150 samples as part of the assessment.

In addition, statistical analysis of information regarding the supply of breast implants in Australia and the known cases of BIA-ALCL will occur in parallel to better estimate the risks associated for each type of implant. This includes working with the Australian Breast Device Registry (ABDR) to ensure that we are aware of as many cases of BIA-ALCL as possible.

Based on the outcomes of the testing and statistical analysis, we anticipate that a decision on whether regulatory action will be undertaken relating to specific implants will be made in mid-June.

Discussions and information sharing with other international regulatory agencies including those from the United States of America, Canada, the United Kingdom, Ireland, Japan, France and New Zealand are ongoing.

To support Australian women, information on signs and symptoms of BIA-ALCL, and a range of questions that women considering a breast implant procedure should ask their surgeon is available on our web site. In addition, we are seeking further guidance from consumer representatives on how to improve the dissemination of this information.

Consumers and health professionals are advised that since the statement on 11 January 2019, the TGA has received more confirmed cases of BIA-ALCL in Australian patients, with a total of 78 cases reported to us to date, which includes four deaths.

Consumers and health professionals are strongly encouraged to report problems with medical devices to the TGA and for breast implants also to the ABDR. Your report will contribute to the monitoring and evaluation of these products.

The TGA convened its breast implant expert working group on 8 April. This followed decisions taken by regulators in France and Canada to remove selected textured implants from their market.

The expert working group discussed the current data on breast implant associated anaplastic large cell lymphoma (BIA-ALCL) rates and correlation with type of implant. The group identified gaps in the data currently available to inform an assessment of the true rate of BIA-ALCL in Australia particularly with different grades of texture of the implants.

The TGA takes the potential risk to women's health seriously. We have today written to all Australian suppliers of textured breast implants with a formal request for information under section 42 of the Therapeutic Goods Act 1989.

This includes the provision of data on the date when particular implants were first supplied to the Australian market and how many have been supplied so as to develop a clearer understanding of the rates of BIA-ALCL in specific types of implant. Samples of particular products have also been requested by the TGA.

Suppliers have 10 working days to responds to the request for information. After receiving information from suppliers TGA will consider whether to suspend or cancel particular products from the Australian Register of Therapeutic Goods.

Other regulators, including the US FDA and several European regulators, have also deferred making a decision until more data is available.

The expert group confirmed that the breast implant associated cancer is rare. As of 8 April 2019 the TGA has received 76 reports for BIA-ALCL in Australian women, noting that between 13,000-17,000 breast implant procedures are performed in Australia each year.

The group also discussed the benefits of textured implants, particularly for reconstructive breast surgery and the need to:

• update the TGA website with accurate information about the benefits and risks of different types of implants
• strongly encourage the use of the Australian Breast Device Registry, including for recording details of removal of implants and of BIA-ALCL cases
• continue to support patients and surgeons to report all adverse events to the TGA.

Today, the TGA will also update its website with further information including information on signs and symptoms of BIA-ALCL and a range of questions that women considering a breast implant procedure should ask their surgeon.

Women with any concerns about their implants should contact their surgeon.

Consumers and health professionals are advised that since the statement below was published, the Therapeutic Goods Administration (TGA) has confirmed more cases of anaplastic large cell lymphoma (ALCL) in Australian patients, with a total of 76 cases reported to date.

The previous advice outlined in the 'Information for consumers' and 'Information for health professionals' sections below remains current, and will be updated as new information becomes available.

Information relating to the withdrawal of Allergan textured implants from Europe is contained in the 'TGA statement' and will also be updated as new information becomes available.

Consumers and health professionals are advised that since the statement below was published, the Therapeutic Goods Administration (TGA) has confirmed more cases of anaplastic large cell lymphoma (ALCL) in Australian patients, with a total of 72 cases reported to date.

The previous advice outlined in the 'Information for consumers' and 'Information for health professionals' sections below remains current, and will be updated as new information becomes available.

Consumers and health professionals are advised that since the statement below was published, the TGA has confirmed more cases of anaplastic large cell lymphoma (ALCL) in Australian patients, with a total of 56 cases reported to date.

The Medical Journal of Australia last month published an article discussing anaplastic large cell lymphoma (ALCL) in the context of the Australian Breast Device Registry and advocating strategies to strengthen the registry.

The Plastic and Reconstructive Surgery Journal in May published an epidemiological study of patients in Australia and New Zealand.

The US Food and Drug Administration also published an update regarding this issue on 23 March 2017.

Accordingly in the 'How can the risk be reduced?' section of 'Information for health professionals' contained within our original statement below, our advice regarding pocket irrigation has been updated slightly.

As part of the TGA's ongoing monitoring of the association between breast implants and anaplastic large cell lymphoma (ALCL), consumers and health professionals are advised that an expert advisory panel was convened to discuss the issue on 16 November 2016 and has been providing ongoing advice.

The expert advisory panel included representation from plastic surgeons, cosmetic surgeons, breast-cancer surgeons, cancer epidemiologists, data analysts and public-health practitioners. The panel's advice is outlined in the 'Information for consumers' and 'Information for health professionals' sections below.

Breast implant-associated ALCL is a rare type of lymphoma that develops near breast implants. The TGA published safety communications regarding this issue on 27 January 2011 and 27 September 2016.

Since our last safety communication, the TGA has been provided with additional data and is advising that 46 cases of breast implant-associated ALCL have now been confirmed in Australia, including three that resulted in death. These cases have all occurred since 2007. Most cases of breast implant-associated ALCL are cured by removal of the implant and the capsule surrounding the implant, however a small number are more aggressive.

The TGA is also aware of a small number of unconfirmed cases. These are being investigated. Consumers and health professionals are asked to report any suspected cases to the TGA.

Future TGA actions

• The TGA will work with research groups to obtain better estimates of the risk of breast implant-associated ALCL.^[1]
• The TGA will work with manufacturers, Australian experts on breast implant-associated ALCL, and Australian experts on breast augmentation and reconstructive surgery to evaluate the benefit-risk balance of the various types of breast implants.
• The TGA will continue to liaise with its major overseas regulatory partners and collaborate in international working groups.