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Page 1: Final report for STOA - European Parliament...Final report for STOA Silicone breast implants 3.1.1.6. EU instruments related to harmonisation of legislation, and medical device control
Page 2: Final report for STOA - European Parliament...Final report for STOA Silicone breast implants 3.1.1.6. EU instruments related to harmonisation of legislation, and medical device control
Page 3: Final report for STOA - European Parliament...Final report for STOA Silicone breast implants 3.1.1.6. EU instruments related to harmonisation of legislation, and medical device control

Final report for STOA Silicone breast implants This document does not necessarily represent the views of the European Parliament

Final Report (Study)

�Health risks posed by silicone implants in general, with a special attention to breast implants�

by Dr. J Martin-Moreno, Dr. L Gorgojo, Dr. J Gonzalez and Ms. W Wisbaum

11 May 2000

Table of contents Acknowledgements Abstract 1. Final Options Brief 2. Final Executive Summary 3. Final Study 3.1. Options 3.1.1. Background information for relevant European options

3.1.1.1. Options for implant devices. Foreseeable market forces and social dynamics for silicone implants diffusion and control 3.1.1.2. Summary of European and international efforts and investments in this field 3.1.1.3. Review of European legislation

3.1.1.3.1. Directives related to implants/medical devices 3.1.1.3.2. Directives related to consumer protection 3.1.1.3.3. Other relevant legislative references

3.1.1.4. Consultation with EU Member States, current situation of implants distribution and use, government position, legislative and health policies adopted

3.1.1.5. Review of other relevant references related to international legislation

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Final report for STOA Silicone breast implants

3.1.1.6. EU instruments related to harmonisation of legislation, and medical device control

3.1.2. Operational, potential options, including alternative approaches for new European Directives 3.2. Arguments and evidence 3.2.1. Background information, including arguments for and against the health risks of silicone implants

3.2.1.1. General and specific health risks posed by silicone implants, their effects on the body, the brain and the nerves; possible influences on the genetic make up

3.2.1.2. Life span effects of silicone implants after 4, 8 and 12 years 3.2.1.3. Post-operational effects and follow-up 3.2.1.4. Conclusions 3.2.2. Overview of relevant primary research and reviews. Period 1990-1999 3.2.2.1. Research currently taking place in the EU

3.2.2.2. Current research in other parts of the world 3.2.2.3. Conclusions 3.2.3. Primary information obtained

3.2.3.1. Surgeons 3.2.3.2. Women�s group: European Council on Women�s Health 3.2.3.3. Scientific Societies 3.2.3.4. Patients 3.2.3.5. Manufacturers 3.2.3.6. Researchers 3.2.3.7. European Union Countries 3.2.3.8. Other Countries 3.2.3.9. Self-help groups

3.2.4. Analysis of potential legal precautions to be envisaged 3.2.4.1.Alternative levels of precaution potentially recommended taking into account the current knowledge about health issues.

3.2.4.2. Implications of new legislature. 3.3. Technical File

3.3.1. Basic terminology and concepts 3.3.1.1. Silicon/Silica 3.3.1.2. Silicone and polydimethylsiloxane (PDMS) 3.3.2. General exposure to silicones. The use of silicone in medical devices 3.3.3. Breast implants. Shells and fillings.

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Final report for STOA Silicone breast implants

3.3.3.1. Alternative implants accordingly to the filling material 3.3.3.1.1 Silicone gel filled implants 3.3.3.1.2. Saline filled implants 3.3.3.1.3. Other implants 3.3.4 . Technical summary about silicone implants and their potential effects 3.3.4.1. Potential benefits 3.3.4.2. Potential risks 3.3.4.3. Risks & benefits: The challenging decisionò 4. Cited bibliography

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Final report for STOA Silicone breast implants

ANNEX

Charts with overall response rates Tables 1-5 Table 1: Serious health effects in studies in relation to SBIs Table 2: Summary of surgeons´ responses Table 3: Summary of patients´ responses Table 4: Summary of manufacturers´ responses Table 5: Summary of governments´ responses Annexes A, B, C: original materials (sent in boxes under separate cover)

Annex D: References

Annex D1 (file � BIBLIOGRAPHY): Other available references (sent under separate

cover)

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Final report for STOA Silicone breast implants Acknowledgements: We would like to express special gratitude to the STOA/European Parliament for giving us this opportunity; to the Competent Authorities on Medical Devices in European Union countries for the latest country-specific information; to self-help groups from UK/Scotland, The Netherlands, Germany, Belgium, Switzerland, and Iceland, and individual women with silicone breast implants, for all of the materials and information, and for sharing personal stories; to manufacturers, for all the documents, time and information; to individual researchers/experts on silicone breast implants, who have provided us with their insight and with some of the latest scientific evidence on the subject; to contacted surgeons and individual patients, for completing our questionnaires; to Scientific Societies, for answering our questions and providing us information; to the National Library of Health Sciences of Spain (specifically to Ms. Mercedes Alastruey and Ms. Cristina Gavin), and special mention to specific individuals who provided us with invaluable additional information and insight, including Dr. Jon Samet (Johns Hopkins University), Dr. Peter Boyle (European Institute of Oncology), Dr. Roger Herdman (Institute of Medicine, US), Dr. Louise Brinton (National Cancer Institute, US), Dr. Marita Eisenmann-Klein (European Committee on Quality Assurance and Medical Devices in Plastic Surgery), Dr. Samie Allen (Center for Devices and Radiologic Health, US), Dr. Ulrich Hinderer (International Plastic, Reconstructive and Aesthetic Foundation(IPRAF), Spain), Dr. Julio Villalba (University Hospital of Granada, Spain), Ms. Charo Giner (Department of Epidemiology and Biostatistics, National School of Public Health of Spain), Dr. Julie Kent (University of West of England) and Ms. Peggy McGuire (European Institute of Women´s Health), to whom we are especially grateful. Finally, we are very appreciative to the Spanish authorities on medical devices, including Dr. Carmen Abad and Dr. Teresa Millan (both of the Directorate General for Pharmaceuticals and Medical Devices), and Dr. Rosa Cepeda (National Centre for Pharmaco-biology). This is not an all-inclusive list, and we would like to thank all of you not mentioned here who have contributed to this study. All of these people have helped shed light on this complex area and make this report what it is. It should be noted, however, that only the study team is responsible for any weaknesses, limitations or problems with this report.

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Final report for STOA Silicone breast implants Abstract The main objective of this project is to present well-informed and relevant alternative policy options to the European Parliament on silicone (breast) implants, based on a comprehensive, unbiased analysis of the scientific literature on the subject and of interested actors. With the aim of reflecting all views on this issue (negative and positive), we have interviewed patients, and have contacted and received information from self-help groups, women�s groups, reconstructive surgeons, silicone breast implant manufacturers, countries, and scientific societies. Silicone implants were used for years before there was regulation or surveillance of their use. A great deal of focus has been given to silicone breast implants since the early 90s, leading to many different epidemiological studies that have driven to highly consistent results showing no evidence of a serious risk for major diseases. But because the studies started so recently, most have not been able to look at long-term effects, have mainly focused on certain systemic diseases (cancer and connective tissue diseases�the main two causes of concern�) and have not always controlled for the different types of implants. This must be considered in light of the fact that a significant body of women claim to be experiencing symptoms which they think are associated with their implants. Moreover, local complications are obvious matters of concern. In light of this complex reality, a range of three potential operational policy options could be considered: Option 1: status quo: no ban, keep application of current legal framework: Pros: good legislative basis in place, inconclusive evidence of serious risks, maintain stability; Cons: evidence points to need for proper European harmonisation; self-help groups and others have called for an immediate ban. Option 2: ban on silicone breast implants due to lack of complete information regarding risks and petitions by some groups. Pros: most conservative option based on lack of complete understanding; desired option by some groups. Cons: large demands by women for these implants and available alternatives could even be worse; studies point to inconclusive evidence of risks of serious health concerns, and underline local complications (also present in alternatives) as main health concern; potential for economic damage to industry; non-consistent with the standard precautionary principles. Option 3: no complete ban, but the adoption and implementation of critical specific measures to improve information for patients, tracking and surveillance, quality control and assurance and key research. Pros: studies indicate that local complications (also present in alternatives) are largest cause for concern. Cons: need to make a real investment for co-ordinated efforts and research to happen; self-help groups and others have called for an immediate ban.

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Final report for STOA Silicone breast implants 1. Final Options Brief The main objective of this project is to present well-informed, relevant, and realistic alternative policy options to the European Parliament on silicone (breast) implants. The identification of these options has been based on a comprehensive, thorough, unbiased analysis of the scientific literature on the subject and of interested actors and parties, aiming to help in the European Parliament process so that more informed legislative and policy decisions on silicone can be made. Silicone implants are particularly complex due to the fact that they were used for years before there was regulation, study, or surveillance of their use and there are many different varieties and kinds of implants. Thus, and in spite of the relatively long period of empirical use, most epidemiological studies are fairly recent, beginning in the early 1990s. A great deal of attention and focus has been given to silicone breast implants since the early 90s, leading to many different studies and analyses that have driven to highly consistent results showing no evidence of a serious risk for major diseases. But it is also true that, because the studies started so recently, most have not been able to look at long-term effects, have mainly focused on cancer and well-known connective tissue diseases, were usually based on small sample sizes, and have not always controlled for the different types of implants. Thus, despite the fact that numerous studies have corroborated one another, pointing to inconclusive evidence of an association between silicone breast implants and cancer and connective diseases�the main two causes of concern�there are also some study limitations. This must be considered in light of the fact that a significant body of women claim to be experiencing symptoms which they think are associated with their implants. We have heard from women from self-help groups from the UK/Scotland, The Netherlands, Germany, Belgium, Switzerland, and Iceland (Silicone Support UK (SS/UK); Action Against Silicone Gel (AASG/UK); Silicone Information Network (SIN/UK); Stichting Steunpunt voor Vrouwen met (vragen over en/of problemen door) Siliconene borstprothesen (St. SVS/NL); German Support Group for Victims of Silicone Implants (GHG, DE); Selbsthilfegruppe Silikongeschadigter Frauen e. V. (SHG, BE), Silicone Support Switzerland (SS/Switzerland); Silicone Survivor Group, Iceland (SSG/Iceland), respectively). Without judging the epidemiological and clinical plausibility of the causality claimed in those complaints, we have been able to see that there are some clear areas for improving the guidelines and protocol for silicone breast implantation. In this context, we would like to stress that, in working on this project and, more specifically, in focusing on the project�s core�the development of alternative policy options�we encountered very strong viewpoints, and often conflicting information was received in our quest to be as clear, objective, thorough and unbiased as we possibly can. There are extremely strong interests at stake on either side of this issue, both of which may have valid, legitimate claims. Thus, our aim is to capture the complexity of the issue but try to get to its essence in a way in which the European Parliament can make the most appropriate decision in its regard. Option 1: status quo: no ban, keep application of current legal framework (namely, Directive 93/42/EEC, a general guiding directive which sets the basis without entering in further detail). Pros: good legislative basis in place, inconclusive evidence of serious risks, maintain stability. Cons: evidence points to need for proper European harmonisation aiming for increased and improved measures for further and better protecting women and women�s health in EC; self-help groups and others have called for an immediate ban Option 2: ban on silicone breast implants due to lack of complete information regarding risks and to

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Final report for STOA Silicone breast implants petitions by some groups. Pros: most conservative option�currently exercised, for example, by the US, Canada and France�due to lack of complete understanding and knowledge of risks because of short follow-up period of women and other complicating factors, such as variety of implants used, etc.; desired option by some groups/people (e.g., self-help groups of women suffering from adverse effects of silicone implants). Cons: large demands by women for these implants, especially considering some of problems with main alternative, saline implants�such as a higher risk of rupture, poorer appearance, etc. The available alternatives to silicone implants could even be worse and more studies are needed before promoting these alternatives. Also, studies on silicone-gel filled implants corroborate one another, pointing to inconclusive evidence of risks of serious health concerns, and pointing to local complications as main health concern, also present in alternative implants. Finally, from a social perspective related to health, there would also be the potential for economic damage to industry (e.g., job loss). Option 3: no complete ban, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, quality control and assurance and key research (see seven proposed measures below). Pros: studies do not point to an association between silicone implants and serious health risks, such as cancer and connective tissue diseases. Indicate that local complications�also just as prevalent or more so with other breast implants, such as saline�are the largest cause for concern. Information from self-help groups, surgeons and the literature points to a real need for improved measures, particularly regarding the provision of correct information to patients as to risks. Cons: need to make a real investment for co-ordinated efforts and research investment to happen; self-help groups and others have called for an immediate ban. In view of the evidence, option 3, which proposes additional measures for maximising the benefits of breast implants and limiting the risks in the EU context, perhaps appears to be the most balanced approach. The further measures proposed are described as follows (and are elaborated on more in the full Options section of this report, section 3.1.):

1. To facilitate consensus on a breast implant consent form, including information related to alternatives,

benefits and risks. 2. To guarantee marketing control over breast implants in order to avoid any kind of incorrect and

misleading information. 3. To improve certification, technical standards and regulation. 4. To promote the elaboration of clinical guidelines, standards of care and the development of quality

assurance systems. 5. To facilitate consensus, promotion and support of effective surveillance systems to report adverse

effects and long-term effects. 6. To consider silicone breast implants a research priority and make funds available in the EU research

programmes, specifically focusing on some of the shortcomings of research to date. 7. To foster tolerance and self-esteem and other conceptual alternatives to breast implants, in

collaboration with active groups in this field.

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Final report for STOA Silicone breast implants 2. Executive Summary The main objective of this project is to present well-informed, relevant, and realistic alternative policy options to the European Parliament on silicone (breast) implants. The identification of these options has been based on a comprehensive, thorough, unbiased analysis of the scientific literature on the subject and of interested actors and parties, aiming to help in the European Parliament process so that more informed legislative and policy decisions on silicone can be made. Silicone implants in general Silicone is used in implants located throughout almost every part of the body (for heart valves and other cardiovascular prostheses; for catheters in many parts of the body; in dentistry; in the gastrointestinal tract; in ophthalmology; in the ear, nose, throat, and respiratory tract; in the urogenital tract, including penile prostheses; as a facilitator for nerve regeneration; as a prosthesis or ingredient in prostheses for many parts of the skeletal system; as a tissue expander; and as a cosmetic agent for treatment of scars and wrinkles). In this study, however, we will mainly focus on silicone implants in the breast. There is a large variety of breast implants on the market. Most of these implants have a silicone shell, although there are different kinds of fillings used in these implants (silicone-gel filled, saline, soybean oil, hydrogel). In addition, silicone-gel filled implants have experienced a number of changes since their introduction, and have undergone essentially three stages: a first generation, with a thick silicone shell and smooth consistency; a second one, with a thin silicone shell and smooth consistency, and a third generation, with a thick silicone shell and textured consistency. In this study, it should be noted that, from now on, whenever we refer to �silicone implants� we mean �silicone-gel filled implants,� the main focus of research on breast implants. Historical background Silicone breast implants were widely used in the United States (US) and Europe before there was any requirement for pre-market assessment of toxicity and complications. For many years, there were no requirements to document the composition of implants or the specific type of implant placed in a particular individual. Furthermore, there was no systematic, comprehensive, post-marketing surveillance of the long-term positive and negative consequences of silicone breast implants. Thus, until concerns about the health risks of silicone were raised in the 1980s, mainly in the US, and all breast implants were placed in a class III category (requiring strict standards for safety and effectiveness) by the US Food and Drugs Administration (FDA), the literature on silicone breast implants up until the early 1990s has not been very useful in assessing risk. In the course of the 1980s, increasing health concerns arose regarding breast implants, mainly focusing on silicone implants, due to suspicions that the gel leaks out to surrounding tissue, potentially causing cancer or connective diseases. In April 1991, in response to a number of adverse reaction reports that raised safety concerns about these implants, the FDA published a regulation that required manufacturers to submit pre-market approval applications with data showing the safety of the implants by July 9, 1991. The data submitted at that stage did not fully prove the devices safe, so the agency ordered the devices off the market in April 1992. The health concerns which surfaced in the US during the 1980s and 1990s extended to Europe, even though it is difficult to gauge the number of women with implants, and it appears to be much lower than in the US. In any event, in Europe, various studies were commissioned and conducted on the safety of silicone breast implants. In this context, the issues of safety and regulation of breast implants were discussed on several occasions between the Commission and Member States.

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Final report for STOA Silicone breast implants Current context In the US, since 1992, silicone breast implants are only available for women with special medical needs who need breast reconstruction and who are willing to become part of a clinical trial approved by FDA. In early 1998, the FDA allowed the two existing manufacturers of silicone breast implants in the US (Mentor and McGhan) to conduct studies on women with silicone gel-filled implants who will be followed for 5 years. Saline-filled implants have been allowed to remain on the market for all uses, although beginning in January 1993, the FDA requires manufacturers to submit regular data on safety and effectiveness and conduct clinical trials. It was believed that saline implants have a lower risk than gel-filled implants because leakage would only release salt water into the body. In Europe, different working groups were set up right after concerns were raised in the US. In general, these groups found no reason to ban silicone breast implants, although careful follow-up and studies were recommended within countries. In France, this issue was kept under discussion. Currently, all EU countries with the exception of France have no restrictions regarding availability of silicone breast implants and accept conformity with the Essential Requirements of the European Directive (93/42/EEC) as a basis for their marketing. This Directive requires manufacturers to conform with safety principles and eliminate risks as much as possible, to take adequate protection measures in relation to risks, and to inform users of existing risks. In addition, the device itself cannot put into jeopardy the clinical condition or the safety of patients or users, and any associated risks must be acceptable when weighed against the benefits. The required standards for ¨CE¨ marking of conformity are mainly related to technological standards, materials testing and biocompatibility assessment. In France, tighter restrictions apply, as silicone breast implants have been banned since 1992, and all implants other than saline have been prohibited since 1995. Surgeons must apply for and be granted exceptions in cases of special patient medical needs (e.g., reconstruction after mastectomy). In addition, surgeons are responsible for providing appropriate information to patients, and patients can hold their doctor liable for not fulfilling this right.

Findings to date Silicone implants are particularly complex due to the fact that they were used for years before there was regulation, study, or surveillance of their use and because there are many different varieties and kinds of implants. Thus, and in spite of the relatively long period of use, most epidemiological studies are fairly recent, beginning in the early 1990s. A great deal of attention and focus has been given to silicone breast implants since the early 90s, leading to many different studies and analyses that have driven to highly consistent results showing no evidence of a serious risk for major diseases. But it is also true that, because the studies started so recently, most have not been able to look at long-term effects, have mainly focused on cancer and well-known connective tissue diseases, were usually based on small sample sizes, and have not always controlled for the different types of implants. This must be considered in light of the fact that a significant body of women, supported by some clinicians, claim to be experiencing symptoms which they think are associated with their implants. A summary of the literature on health risks follows: Systemic Effects Cancer There appear to be sufficiently consistent and convincing studies to support the conclusion of no association between breast cancer and implants, although research is currently being conducted to rule out the long-term risk. At the same time, the short average follow-up time of completed studies (and the still limited evidence in this field) does not allow us to conclude whether silicone breast implants are or are not

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Final report for STOA Silicone breast implants associated with other malignant neoplasms (other solid tumours, sarcoma, lymphoma, or myeloma), and the ongoing and future studies will hopefully shed light on these/ point. In the meantime, the available evidence does not support an association of silicone breast implants with other non breast cancers. Neurological disease Neurological symptoms or disease have been reported in some case series of women with breast implants. These findings are not consistent with other experimental and observational studies. Overall, it could be stated that the most properly designed and conducted epidemiological studies show no evidence that silicone implants cause neurological signs, symptoms or disease. Well-defined connective tissue diseases (related to autoimmune disorders) Recently published studies have indicated that women with silicone breast implants do not have a greatly increased risk of some well-defined autoimmune diseases (potentially fatal connective diseases), such as schleroderma, lupus erythematosus, rheumatoid arthritis, Sjogren´s syndrome, dermatomyositis or polymyositis, and health disorders such as fibromyalgia and ¨chronic fatigue syndrome.¨ Other systemic effects According to the information provided by self-help groups, some clinicians, and some additional sources, a substantial body of women with silicone implants have experienced these disorders, as well as a variety of symptoms that could be related to the immune system. These symptoms include pain and swelling of joints; tightness, redness or swelling of the skin; swollen glands or lymph nodes; unusual or unexplained fatigue; swelling of the hands and feet; excessive hair loss; memory problems; headaches; and muscle weakness or burning. In some cases, women have reported a reduction in symptoms after the implants were removed; in other cases, there was no change in symptoms after explantation. It is unclear at this time whether the signs and symptoms experienced by these women are related to their implants. In sum, the epidemiological literature has indicated that the evidence for an atypical disease or novel syndrome is insufficient and that there is no robust, convincing support for these disorders. However, the existence of a specific syndrome or syndromes in women with silicone breast implants cannot be completely proven or dismissed at this point in time, and deserves further analysis. ¨Vertical¨ Effects (mother to child) Risks to infants At this time, there does not appear to be evidence of harmful effects to infants breastfed by women with silicone breast implants, although further study is needed in this area to shed further light on this area. Local Effects Local complications Studies points to local complications, including perioperative complications from the surgical procedure itself, as the largest potential health risk from silicone breast implants. The relatively high frequency of these complications is noticeable. While these are normally not life-threatening, they may result in discomfort, inconvenience, explantation, disfigurement, pain and other morbidities, and when further corrective procedures are necessary, an additional potential risk (e.g., additional surgery). Breast implants have a limited lifetime, which is not well-established. In any event, the probability of having a reoperation is high and it increases over time.

Concerns by certain women�s groups In the US, a major class action litigation, brought on behalf of women with silicone breast implants, was

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Final report for STOA Silicone breast implants settled with a substantial award to the plaintiffs. Most importantly, assessment of the case points to the lack of appropriate warnings and information on potential risks by manufacturers. In Europe, in March 1999, two petitions were tabled by self-help groups of women who claim to have suffered adverse effects from implants calling for the European Parliament�s immediate ban on silicone implants. The EP is asking for formal replies and evidence to be submitted to the Petitions Committee, and has asked for counsel from the Committee on Women's Rights, the Committee on Public Health and Consumer Protection and the Committee on Research. Many women with silicone breast implants feel that they were not given sufficient information on the health risks to consent to have these implants. In the US, signing an informed consent form which explains all known and possible risks is now part of the required procedure for all women undergoing breast implant surgery. In Europe, all countries have general legislation or rules establishing the right of patients to be clearly informed of risks and benefits, although a common, fully accepted and standardised form does not yet exist.

Potential benefits of breast implants and available alternatives There is a clear demand for breast implants by women, both from a cosmetic (augmentation) and reconstructive (reconstruction following mastectomy) standpoint. As a result, breast implants need to be considered also in light of their benefits. Reasons such as interest in improving self-confidence through the apparent improvement of self-image, a subjective sense of attractiveness and social relationships are the main apparent reasons for demanding cosmetic surgery. In addition, silicone breast implants must be compared with available alternatives. With the aim of reflecting all views on this issue (negative and positive), we have interviewed patients, and have contacted and received information from self-help groups, women�s groups, reconstructive surgeons, silicone breast implant manufacturers, countries, and scientific societies. We have incorporated this information and these positions into the report as best as we could, and have sent the Parliament original primary information in order to assess these materials firsthand. We would like to stress that, in working on this project, we encountered very strong viewpoints, and often conflicting information was received in our quest to be as clear, objective, thorough and unbiased as we possibly can. There are extremely strong interests at stake on either side of this issue, both of which may have valid, legitimate claims. Thus, our aim is to capture the complexity of the issue but try to get to its essence in a way in which the European Parliament can make the most appropriate decision in its regard. Operational, potential options Option 1: status quo: no ban, keep application of current legal framework (namely, Directive 93/42/EEC, a general guiding directive which sets the basis without entering in further detail). Pros: good legislative basis in place, inconclusive evidence of serious risks, maintain stability. Cons: evidence points to need for proper European harmonisation aiming for increased and improved measures for further and better protecting women and women�s health in EC; self-help groups and others have called for an immediate ban. Option 2: ban on silicone breast implants due to lack of complete information regarding risks and to petitions by some groups.

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Final report for STOA Silicone breast implants Pros: most conservative option�currently exercised, for example, by the US, Canada and France�due to lack of complete understanding and knowledge of risks because of short follow-up period of women and other complicating factors, such as variety of implants used, etc.; desired option by some groups/people (e.g., self-help groups of women suffering from adverse effects of silicone implants). Cons: large demand by women for these implants, especially considering some of problems with main alternative, saline implants�such as a higher risk of rupture, poorer appearance, etc. The available alternatives to silicone implants could even be worse and more studies are needed before promoting these alternatives. Also, studies on silicone-gel filled implants corroborate one another, pointing to inconclusive evidence of risks of serious health concerns, and pointing to local complications as main health concern, also present in alternative implants. Finally, from a social perspective related to health, there would also be the potential for economic damage to industry (e.g., job loss). Option 3: no complete ban, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, quality control and assurance and key research (see seven proposed measures below). Pros: studies do not point to an association between silicone implants and serious health risks, such as cancer and connective tissue diseases. Indicate that local complications�also just as prevalent or more so with other breast implants, such as saline�are the largest cause for concern. Information from self-help groups, surgeons and the literature points to a real need for improved measures, particularly regarding the provision of correct information to patients as to risks. Cons: need to make a real investment for co-ordinated efforts and research investment to happen; self-help groups and others have called for an immediate ban. In view of the evidence, option 3, which proposes additional measures for maximising the benefits of breast implants and limiting the risks in the EU context, perhaps appears to be the most balanced approach. The further measures proposed are described as follows (and are elaborated on more in the full Options section of this report, section 3.1.):

1. To facilitate consensus on a breast implant consent form, including information related to

alternatives, benefits and risks. 2. To guarantee marketing control over breast implants in order to avoid any kind of incorrect

and misleading information. 3. To improve certification, technical standards and regulation. 4. To promote the elaboration of clinical guidelines, standards of care and the development of

quality assurance systems. 5. To facilitate consensus, promotion and support of effective surveillance systems to report

adverse effects and long-term effects. 6. To consider silicone breast implants a research priority and make funds available in the EU

research programmes, specifically focusing on some of the shortcomings of research to date. 7. To foster tolerance and self-esteem and other conceptual alternatives to breast implants, in

collaboration with active groups in this field. In summary, the option consisting of no complete ban, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, clinical guidelines, quality control and assurance and key research could be reasonably consistent with the philosophy underlying the criteria of the European precautionary principles and perhaps is the most balanced alternative after weighing the existing evidence.

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Final report for STOA Silicone breast implants 3. Final Study 3.1. Options 3.1.1. Background information for relevant European options 3.1.1.1. Options for implant devices. Foreseeable market forces and social dynamics for silicone implants diffusion and control

Background and principles The development of innovative technologies and the growing need for harmonising the European political context have drawn increased attention to the regulatory environment of new medical devices. New technologies may offer potential benefits in terms of health gain or the relief of suffering, but there may also be some risks to health, social or economic costs, or ethical issues of concern. It would seem sensible to state that safeguards must exist in order to prevent the adoption of potentially harmful technologies, while permitting innovation and accessibility to new effective medical devices aimed at satisfying the demands and needs of the European population.

Types of implants There is an enormous diversity of breast implants on the market. Hundreds of different types have been marketed and used. Variations affect the shell, filling materials, number of lumens (cavities), size, shape, type of intervention, and other characteristics. A great number of changes in silicone breast implants have been made since they were introduced in 1962. These changes represent additional difficulties when assessing the health effects of breast implants. In addition, modifications were introduced with little or no pre-testing for biological or clinical effects. Varying control of the diffusion of silicone fluid through gel implant shells, shell strength, and therefore durability of both gel- and saline-filled implants, as well as polyurethane coating, were among the changes which affected the clinical performance of silicone breast implants in ways that, in many instances, were not predicted. Modifications have been made aimed to improve implants, as plastic surgeons and manufacturers have learned of problems with existing implant models. Barrier shells, texturing, better valves in saline implants, and stronger shells that are more resistant to rupture or deflation have been some of these changes. For example, polyurethane coating of breast implants, lipid (new soybean oil-filled) or polymer breast implants, expandable prosthesis and other implant types have been developed with this objective. In fact, since the beginning of commercial manufacturing of silicone breast implants in the 1960s, there have been three generations of implants filled with silicone gel. The first generation implants were made with a thick silicone-gel and thick shell (smooth surface). These implants present a low rupture rates, and a high rate of gel bleed and capsular contracture. The second generation, used from mid-1970s to the late 1980s, were made with a thin silicone shell (smooth), and presented a high rate of gel bleed and rupture. The third generation, manufactured since the mid-1980s, have a thick silicone shell (textured) and presumably present a lower rate of gel bleed, rupture and capsular contracture, but a larger, closer follow-up is needed before a definite statement on this can be made. There are other kinds of breast implants. As mentioned, for example, there are polyurethane-coated implants, which have a coating intended to reduce the risk of contracture. Concerns with this material, which surfaced through realisation that it could cause cancer in animals when broken down, led to a recent study in women. Findings from this study indicate that there are no increased risks of cancer in women from polyurethane. Increased risks of cancer in nursing infants have not been completely ruled out, although the lack of increased risk found in women is reassuring. While the majority of breast implants contain a silicone shell, there are also different kinds of fillings used

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Final report for STOA Silicone breast implants in these implants (silicone-gel filled, saline, soybean oil, hydrogel). Both silicone-gel (the main focus of this study) and saline have been mentioned earlier, but a trilucent implant also exists (made with purified soybean oil). In the US, women were enrolled in a clinical study to assess this implant�s safety, and currently, FDA is analysing results. In the UK, this implant was banned in 1999 due to some reported problems and a lack of information regarding its long-term effects. Finally, hydrogel implants exist on the market. Some pros and cons of different types of breast implants can be found below: Silicone: Pros: long experience on use, relatively low rupture rate, better appearance and feel, usually stays in capsule if ruptures; Cons: concerns and potentially negative perception of silicone and its safety, some clinicians and groups of women claiming adverse symptoms associated with silicone. Saline: Pros: physiological, no swelling or shrinking, rupture taken up by body itself; Cons: higher rupture/deflation rate than silicone, increased likelihood of shell folding, prone to weakening�look much worse, associated with noise (can actually sometimes hear saline solution). Trilucent/purified soybean oil: Pros: soybean oil, perceived safer, Cons: reports of some swelling, pain, short experience of use and not enough information on safety, pending data. Hydrogel: Pros: more consistent than saline, natural materials, so �perceived� to be safe; Cons: not isotonic; takes up water and can swell up to point of rupture, safety not established/some toxicity not ruled out, no long-term studies. Autogenous tissue: mainly used in breast reconstruction. Such reconstruction are often combined with implants. Dermis flaps or dermis-fat-fascia grafts, musculocutaneous flat from the abdomen or from other sites, and microsurgical free flats have been used. Pros: safe, generally good results: Cons: use cautiously, problems depending the origin of tissue.

Manufacturers of breast implants Manufacturers of breast implants are mainly US multinational companies, but there is also a clear European component in this business. Silicone and saline implants are produced by big companies such as McGhan and Mentor Corporation. Hutchinson International and Poly Implants Prostheses also produce saline filled implants. Many manufactures import breast implants to the EU countries. Other companies which are or have been manufacturers of breast implants in the EU include: Polytech/Silimed and Novamed located in Germany; Nagor and Jutchinson in the UK; Poly Implant Protheses, Laboratories Eurosilicone, Sebbin, and Arion located in France; and Biomedica Sviluppo and Impax Diffusion in Italy. EUCOMED is an �umbrella� organisation representing the main companies of this sector and their interests in Europe.

Demand for implants As for the social dynamics for silicone implants, it is important to stress the large demand for breast implants, both for cosmetic and reconstructive purposes, in the industrialised world. According to references in the US from 1997, approximately 70% of breast implants were performed for augmentation and 30% for reconstruction. Demand for breast implants has been present since the 1960s, and has continued growing. Recently, demand for implants has been growing for men (i.e., sex change surgery) as well as for women. Relevant and definite benefits in terms of health and quality of life seem to be substantial for many women and men demanding cosmetic breast surgery. Although reasons for obtaining breast implants are not very well studied, interest in improving self-confidence through the apparent improvement of self-

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Final report for STOA Silicone breast implants image, a subjective sense of attractiveness and social relationships are the main apparent reasons for demanding cosmetic surgery. Breast implants appear to be an effective procedure for satisfying these demands.

Satisfaction The majority of reports on satisfaction present very good results, but two things should be kept in mind. First, satisfaction is a very subjective dimension. It is also true that many published reports of satisfaction have obvious limitations. They are frequently carried out without a solid design and often by plastic surgeons, which could lead to incomplete or even biased reports. In addition, they usually report on an unspecified or very short postoperative interval. Other possible biases or distortions of patients� responses are the small number or non representative women who are interviewed, the voluntary nature of the surveys and the use of overall satisfaction in general terms as a main outcome. Women have shown considerable tolerance for contracture, either by not seeking medical attention for serious contracture (class III or IV) or by pronouncing themselves satisfied with their implants when surveyed. A 1990 study reported that 85% of women appeared satisfied with their implants even though 35% had experienced severe contracture (Gylbert LO, et al., 1990). Studies present a range of general satisfaction from 80% to 95%. A survey carried out by plastic surgeons in the U.S. reported that 84% of women with implants for augmentation and 91% for reconstruction were satisfied to very satisfied at least one to ten years from operation (Park AJ,et al., 1996). On the other hand, national U.S. data on satisfaction and adverse effects (from 1984 through 1995) shows notification of 94,120 adverse events, the majority of which were local and perioperative complications (contracture and rupture). The number of adverse experiences peaked in 1992-1994 and decreased markedly in 1995. For the sake of gathering primary data for this report, as requested at the Scoping Meeting (held at the European Parliament for the sake of specifying the objectives of this project), we have interviewed breast implant patients to gauge their views and degree of satisfaction with their implants. We succeeded in identifying women who were willing to talk with us and be interviewed. We would like to underline both that the sampling approach is not, of course, methodologically generalizable (due to the fact that women were selected by word of mouth) and the numbers are small, but, in spite of this, we believe that this anecdotal information is interesting to consider and points to high levels of satisfaction (see Annex A for the patient questionnaire and compilation of results). We were also able to directly experience the complexity and difficulty of this appraisal exercise, due to the inherent personal nature of implants and individuals� sense of privacy. At the same time, a selection bias may occur when only certain women are willing to provide their views on satisfaction. That is why we have directly witnessed some limitations of the direct interviews commonly used as indicators of satisfaction. It seems logical to state that the existence of potential risks associated with the intervention must be weighed against the potential benefits perceived by women. Women�s appreciation of good results have sustained the demand for breast implants. Along with these demands, however, there have been increasing concerns and have been definite problems, made particularly acute through attention to this issue in the US over the course of the last decade. This concerns have spilled over to Europe. This is explained in the next section, 3.1.1.2. 3.1.1.2. Summary of European and international efforts and investments in this field It is difficult to understand the background around European efforts in this field without understanding the corresponding background in the US.

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Final report for STOA Silicone breast implants

The US experience In the US, the Medical Device Amendments were enacted in 1976, giving FDA the authority to regulate medical devices such as breast implants, which had already been on the market since the 1960s. FDA has three regulatory categories for medical devices. Class I and class II are for devices whose safety and effectiveness are well-established. Class I devices are simple devices whose risks can be controlled by the manufacturing process; class II devices require additional measures, called special controls, to control risks. Special controls may include performance standards, post-market surveillance studies, user education or other measures. If there is a lack of information about what makes a device safe and effective, it is put into class III, the highest level of pre-market review is required. Class III devices include innovative, medical breakthrough and new technology devices, as well as devices with poorly established or questionable safety and effectiveness. A short review of regulation by the Food and Drug Administration (FDA) explains why current breast implantation is primarily with saline-filled implants, and describes the effects of government actions on gel-filled, polyurethane-coated, and other implants and on the companies that manufactured them. In 1976, the FDA General and Plastic Surgery Devices Panel (referred to as the Panel) recommended that breast implants be placed in class II, requiring general controls and performance standards. On January 19, 1982, because of some reports of adverse events in the medical literature, the FDA announced a proposal to place breast implants in class III, with the most stringent controls for safety and effectiveness. In 1988, the FDA classified all breast implants into class III. After a prescribed waiting period of 30 months, the FDA could require the submission of pre-market approval applications (PMAs) in which manufacturers present data showing the safety and effectiveness of these devices. In April 1991, in response to a growing number of adverse reaction reports that raised safety concerns about the silicone gel-filled implants, the FDA published a regulation that required manufacturers to submit pre-market approval applications with data showing the safety and effectiveness of the implants by July 9, 1991. The data submitted did not fully prove the devices safe, as required by law, so the agency order the devices off the market in April 1992 and restricted their use to clinical trials studies for reconstruction after mastectomy, correction of congenital deformities, or replacement for ruptured silicone gel-filled implants for augmentation. FDA denied applications for using silicone breast implants for augmentation but planned that the manufacturers would later conduct clinical trials that would include a limited number of augmentation patients (the stage 3 or core studies). On June 5, 1998, FDA approved McGhan�s medical IDE study for silicone gel-filled breast implants for augmentation, reconstruction, and revision for a set number of patients at a limited number of sites. Mentor Corporation�s adjunct study was also approved by FDA. Silicone gel filled breast implants and alternative breast implants also may be available to women who participate in Investigational Device Exemptions (IDE) studies. Regarding saline breast implants, although still on the market in the US, on December 23, 1994, FDA announced that companies marketing these implants are required to enrol patients in clinical trials and conduct laboratory and clinical studies to determine the safety and effectiveness of these implants. Since this time, manufacturers have had to submit data to the FDA under a pre-market approval application (PMA). Currently, FDA is evaluating data submitted by manufacturers on these implants and the law requires that, based on the data, FDA will have to approve the applications in order for companies to continue selling saline implants. A meeting on saline PMAs was held from 1-3 March 2000, and the FDA Advisory Committee recommended approval of Mentor and McGhan saline implants, although the FDA

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Final report for STOA Silicone breast implants has not yet made a decision in this regard (we have been informed that it will be made before the end of May). A major class action litigation brought on behalf of women with silicone breast implants was settled with a substantial award to the plantiffs. Assessment of the case, most importantly, points to the lack of appropriate warnings and information on potential and real risks by manufacturers. This case spurred the court�s request to a panel of experts for a report on specific issues concerning health consequences of silicone breast implants. Thus, a report by the National Science Panel (NSP) (four experts on toxicology, immunology, epidemiology and rheumatology) was presented in 1998 to the Honourable S.C. Pointer, Judge for the Federal Breast Implant Multi-District Litigation. This report reviewed the scientific literature related to silicone breast implants and connective tissue diseases and immunological dysfunction. In 1999, the Institute of Medicine (IOM) of the National Academy of Sciences completed a comprehensive evaluation of the evidence associating silicone breast implants with human health conditions, commissioned by the US Department of Health and Human Services. They objective of the study was to conduct an independent, unbiased review of all past and ongoing scientific research regarding the safety of silicone breast implants. With this aim, a committee of experts in relevant scientific and clinical areas evaluated past and ongoing studies of the relationship, if any, between implants and systemic disease; assessed the biologic and immunologic effects of silicone and other chemical components of breast implant; and assessed the impact of breast implants, if any, on the offspring of women with implants or the accuracy of mammograms. Both the NSP and IOM studies found no evidence of an association between silicone breast implants and increased risks of cancer or connective tissue diseases, the main two original causes of concern. Results of these (and other) studies are discussed in depth in 3.2. Arguments and Evidence. According to the IOM study, an estimate of between 1.5 million to 1.8 million U.S. women have breast implants. About 70% of these implants were performed for augmentation, (i.e. enlarging or changing the appearance of the breast), and 30% for reconstruction, (i.e., restoring the form of the breast after mastectomy for cancer, fibrocystic disease, or other medical needs). In 1998 alone, data provided by the American Society of Plastic Surgeons show a total of 132,378 interventions for breast augmentation (97% saline-filled and 3% gel-filled, 61% in women under 35 years old) and 69,683 interventions for breast reconstruction (75% saline-filled and 15% gel-filled, 94% in women over 35 years old). At the same time, 43,681 breast explantations (implant removals) were made, mainly (93%) due to physical symptoms related to these implants, such as capsular contracture. Breast cosmetic and reconstructive surgery represents more than 10% of total plastic surgery interventions. From 1992 to 1998, a large increase in these interventions was observed: breast augmentation (306%), breast reconstruction (135%), breast explantation (76%). In addition to this, more than 10 million persons in the United States have some type of implant, such as finger joints or pacemakers, and many of these implants are made, at least in part, from silicone. The FDA is currently conducting a study to assess the rupture rate of silicone gel-filled breast implants. This study will include more than 1200 women, and medical records will be sought if their breast implants have not stayed intact. A sub-group of women who still have their implants will receive an MRI to determine if the implants are intact. This study began in early 1998, and is currently underway.

The European experience As a result of the growing concern in the US during the 1980s, focus was drawn to possible health risks posed by breast implants in Europe. A variety of study groups and research initiatives were developed to address these concerns. A comprehensive review of these toxicology studies of silicone and other studies

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Final report for STOA Silicone breast implants does not provide a basis for an association between silicone implants and major health risks. However, the large need for additional surgical corrective procedures and frequent local and perioperative complications are important causes for concern. Risks accumulate over the lifetime of the implant, but quantitative data on this for modern implants are lacking and are deficient historically. Due to health risks, particularly concerning the nature and the relatively high frequency of local complications and additional operations, the need for proper informed consent (with complete, adequate information) has become an essential element of the process for women undergoing breast implantation. It also needs to be kept in mind that, in spite of inconclusive evidence of a clear health risk associated with silicone breast implants, a substantial body of women with these implants who are experiencing similar inexplicable symptoms have formed self-help groups across Europe. We have received information and materials from self-help groups in the UK/Scotland, the Netherlands, Germany, Belgium, Switzerland and Iceland. Two of these groups have requested an immediate ban of these devices (see European Parliament, News Report 22-03-99 and Annex B for original materials and information from self-help groups). This position also deserves proper consideration, and, together with the intrinsic complexity of completely ruling out any hazard associated with these implants, explain why this issue is still a concern. It is extremely difficult to know the exact number of implants in women in the EU, and we have to rely on available data in only some countries, such as the UK, which has developed a breast implant registry. For example, during 1996-1997, breast implants registered (12.829) in the UK correspond to silicone gel (80%), saline (2%) lipid or polymer (12%) and other (6%). Most of the women had breast implants for augmentation or other cosmetic reasons (70-80%). In many countries, however, the absence of a registry and a compulsory system for notification makes it very difficult to know the frequency of local complications. These are just some limitations we have to recognise when examining the background of this issue. At the same time, however, progress has been made by scientific societies and others with regard clinical guidelines, quality standards, and other key elements, such as informed consent, for providing better options to women seeking breast implants. Various research and review efforts have been carried out in Europe, such as the report published in France by ANDEM (1996), and the comprehensive overview carried out by the Independent Review Group in the UK (1998). Other observational research initiatives, including a population-based follow-up study in Denmark (1998) and a retrospective cohort study in Sweden (1998) have also been conducted. Regarding efforts to clarify issues of safety and appropriate certification of breast implants in Europe, this issue has been given careful attention and has led to different interchanges and discussions between the Commission and Member States. This process has driven different options currently adopted by Member States in Europe, with the exception of France, which does not share the existing Essential Requirements of the European Directive. Council Directive 93/42/EEC of 14 June 1993 is the current cornerstone in this field (see 3.1.1.4.). In the UK, the Medical Devices Agency (MDA) set up an Independent Expert Advisory Group and published a review analysis in 1992, updated in 1994. A National Breast Implant Registry was established in 1993. Further details are given in 3.1.1.4. In Spain, a working group of independent experts reviewed the existing evidence and arrived at the conclusion of proposing implant and explant registries. We have been informed that within the next months, the first analyses of data arising from these registries will be available. As for technological investments and efforts, new developments in breast implant technology may change

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Final report for STOA Silicone breast implants the horizon, but they need to be considered and assessed with caution. Cohesive silicone gel represents an innovation. A new hydrogel formulation of polyvinylpirrolidone (PVP) device for breast implants has been tested and used in Europe. Also, new saline-filled implants that are pre-filled rather than being filled at the time of surgery with sterile saltwater solution could eliminate valve leakage and improve sterility. In short, these innovations may provide increased options for women seeking breast enlargement or reconstruction, but they need further review and attention. 3.1.1.3. Review of European legislation 3.1.1.3.1. Directives related to implants/medical devices Breast implants are regulated by Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. As a general rule in Europe, all medical devices are required to carry the "CE" marking denoting a European conformity standard. The "CE" mark permits the product to be marketed in the EC, although it does not guarantee its complete safety. It is important to keep in mind the difficulty of ensuring the complete absence of risk in all circumstances. According to the European �CE� marking Directive, the devices must meet the essential requirements set out in the Annex I of the Directive, taking into account the intended purpose of the device. The device cannot put into undue danger the clinical condition or the safety of patients, or the safety or health of users or, where applicable, other persons. In addition, any risks which may be associated with their use must constitute acceptable risks when weighed against the benefits to the patient. The manufacturers must conform to safety principles and eliminate or reduce risks as much as possible, take adequate protection measures in relation to risks, and inform users of the existing risks. During the lifetime of the device as indicated by the manufacturer, its characteristics and performance must not be adversely affected to such a degree that the clinical conditions and safety of the patients are jeopardised. Regarding design and chemical, physical and biological properties of the device, particular attention must be paid to the choice of materials used (toxicity) and the compatibility between the materials used and biological tissues, cells and body fluids. The required standards for "CE" marking of conformity are mainly related to technological standards, materials testing and biocompatibility assessment. Long-term effects of the implants, including adverse effects, must be assessed through a post- marketing surveillance system, the competence and responsibility of each Member State, which is usually organised as a voluntary system of reporting incidents, unwanted side effects, failures, etc. Conformity with the Essential Requirements for safety and performance may be demonstrated by compliance with authorised standards. Relevant European standards for breast implants include generic standards for risk analysis (EN 1441), non-active implant standards (EN ISO 14630), sterilisation, biological safety and other specific requirements for mammary implants (EN 12180, recently approved). The different safety-related features of breast implants, including biocompatibility, mechanical properties, migration of the filling and shell material, compatibility between shell and filling material, ageing, stability and labelling are currently under examination within the European committee for standardisation (CEN) and within a special working party of certification bodies in charge of these products on the basis of Directive 93/42/EEC. There is systematic classification of the different medical devices. Specifically, breast implants are considered non-active implantable medical devices. Thus, as all other implantable devices and long-term surgically invasive devices, breast implants have been classified according to risk and have been placed into Class IIb. This class constitutes a high risk potential. Inspection by a notified body is required

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Final report for STOA Silicone breast implants regarding the design and manufacturing of the devices. In the case of devices falling within Class IIb, the manufacturers shall, in order to affix the CE marking, either:

a) follow the procedure relating to the EC declaration of conformity (full quality assurance). Manufactures must ensure application of the quality system approved for the design, manufacture and final inspection of the products concerned, and are subject to audit and community surveillance.

b) follow the procedure relating to the EC type-examination, coupled with the procedure relating to the EC verification or to the EC declaration of conformity (production quality assurance) or to the EC declaration of conformity (product quality assurance).

The Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and administrative provisions of the Member States concerning liability for defective products also affects liability of the producers of silicone implants. 3.1.1.3.2. Directives related to consumer protection The necessity to guarantee the safety and to protect the health of consumers is a priority of the European Union and of the Member States. Community action as regards consumers' protection is based on article 129A of the Treaty of the European Union which establishes that the European Union will contribute to a high level of the consumers' protection by means of:

-Measures adopted according to article 100 A. -Support and complementary actions to those developed by the Member States in order to protect the health, safety and economic interests of consumers, and to guarantee the population appropriate information.

The number of directives in this sector is very high. Most of those related with health refer to the safety and control of foods (substances with hormonal effects, additives, labelling, special feeding) and general safety of consumption products. The production, marketing, classification , labelling, promotion, and procedures of authorisation of medications and medical devices have also been subject to European directives. 3.1.1.3.3. Other relevant legislative references The Council Directive of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (90/385/EEC) is the only additional legislative reference related to implants, but�in fact�it is not of direct applicability to breast implants as it only refers to �active medical devices� (those devices which function from a source of electrical energy or any source of power other than that directly generated by the human body or gravity). 3.1.1.4. Consultation with EU Member States, current situation of implants distribution and use, government position, legislative and health policies adopted All EU Member States (except France) have no restrictions on the use of silicone-gel breast implants. Thus, there is no specific legislation on silicone implants and most of these countries have not considered or planned any, apart from conformity with and the application of Medical Device Directive (93/42/EEC). All these countries have general legislation or rules establishing the responsibility for providing

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Final report for STOA Silicone breast implants information and the right of patients to be clearly informed of risks and benefits before undertaking any kind of surgery. Some countries have implemented specific regulations on information regarding breast implants, through guidelines directed to patients and surgeons. In addition, National Scientific and Professionals Societies related to breast and cosmetic surgery and also the European Committee on Quality Assurance and Medical Devices in Plastic Surgery (EQUAM) have proposed specific informed consent forms and provide information on risks and benefits to the patients. In the European context, the issues of safety and of certification of breast implants were discussed on several occasions between the Commission and Member States. Excluding France, all EU countries accept demonstration of conformity with the Essential Requirements of the European Directive (93/42/EEC) as a basis for the marketing of silicone breast implants. In the United Kingdom and France, recent scientific literature on risks related to silicone gel-filled breast implants was reviewed in 1996 and 1994 by independent scientific experts, and different options have been adopted by these Member States. These cases are explained below. In the UK, the Medical Devices Directorate of the Department of Health reviewed the evidence for links between silicone gel breast implants and connective tissue diseases in 1991. Later, the new Medical Devices Agency (MDA) set up an Independent Expert Advisory Group and published a review analysis in 1992, updated in 1994. A National Breast Implant Registry was established in 1993. Since then, the MDA has produced several reports concerning silicone and trilucent (soybean-oil) breast implants. In 1998, an Independent Review Group (IRG) published a new report at the request of the Minister of Health, reviewing all the evidence related to the possible health risks associated with silicone breast implants and issues concerning pre-operative patient information. In March 1999, the MDA and the Department of Health decided to withdraw trilucent and oil-breast implants as a precautionary measure, after receiving reports of local complications (swelling associated with implant rupture) in a small number of women. Silicone-gel filled breast implants are available without any restriction. In France, since 1992, silicone breast implants have been restricted. In 1995, all breast implants except saline-filled implants were banned. Surgeons must apply for exemptions in the case of specific medical needs (reconstruction after mastectomy and other) for silicone implants. The ban has been renewed every year. The ANDEM report (1996) was basically consistent with the conclusions and recommendations made later by IOM (USA) and the UK Independent Review Group, considering the surgical and implant contracture or rupture risks as the main health problems. However, and due to precautionary measures, ANDEM asked for restrictive criteria (toxicology and clinical) to authorise the marketing of breast implants under the European existing Directive (93/42/EEC). In 1996, The French Ministry of Health issued a decree in which breast implants were considered at high risk of rupture and subsequent serious adverse effects. Silicone gel breast implants need to be tested to confirm their conformity with strict standards and safety requirements. The European Commission set up a Project Group to develop uniform guidance for the conformity assessment of breast implants according to the Directive. The technical specifications to confirm their conformity with Essential Requirement for Safety and Performance were reported back to the EC, and a new French report establishing technical recommendations for marketing was also appended. The process is still ongoing at this time. In Spain, a working group, including experts in medical devices, oncology, rheumatology, plastic surgery, immunology and other related fields, concluded that there was no reason for a moratorium on silicone implants from existing evidence. Registries for implants and explants have been developed and periodic health controls are conducted. In addition to having reviewed secondary sources of legislative information about the position of EU Member States on this issue, we have also sent formal letters to the responsible authority on health

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Final report for STOA Silicone breast implants products in each EU country, not only to request information on the latest potential regulation, but also on Member States� views about the need for developing a common European position on silicone implants (see Annex A for letter and responses). 3.1.1.5. Review of other relevant references related to international legislation A review of legislation in the US has been comprehensively covered in section 3.1.1.2. In Canada, a moratorium on the marketing and use of silicone -gel filled breast implants was passed in 1992. Saline-filled breast implants are available. The Canadian Department of National Health and Welfare also set up an Independent Advisory Committee to review the health problems posed by gel-filled breast implants. In 1992, this Committee reported the insufficient evidence of autoimmune disease associated with silicone breast implants and recognised the absence of more accurate data on local complications and the need for additional research. The Canadian Society of Plastic Surgeons made recent recommendations to provide information on breast augmentation to patients well in advance, and to thoroughly discuss the risks (surgery, contracture, rupture, limited lifespan) and benefits associated with this procedure. A doctrine of informed consent is well established in Canada and has been reinforced with the case of Hollis versus Dow Corning decided by the Supreme Court of Canada. In Australia, silicone implants are available by special application from the Therapeutic Goods Administration (TGA) in Canberra, the regulatory authority, although saline filled implants are available without any such authority. The country does not have any approval for other types of implants, such as soybean oil. A detailed Breast Enlargement Guide for Women has been produced by the Australian Society of Plastic Surgeons. (See Annex for sample letter sent to Scientific societies across the world and responses). 3.1.1.6. EU instruments related to harmonisation of legislation, and medical device control In general, there is a good EU legislative basis for future developments in this field. It is important, as it covers many of the regulations adopted by Member States and has been a reference point for the approximation of national laws and regulations. Under current legislation, many new measures could be developed. The main EU directives, and those more specifically related with medical devices, are below: • Council Directive 83/189/EEC of 28 March 1983 laying down a procedure for the provision of

information in the field of technical standards and regulations. • Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and

administrative provisions of the Member States concerning liability for defective products. • Council Directive 89/336/EEC of 3 May 1989 on the approximation of the laws of the Member States

relating to electromagnetic compatibility. • Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member

States relating to active implantable medical devices. • Council Directive 93/42/EEC of 14 June 1993 concerning medical devices, which is the current

cornerstone in this area. 3.1.2. Operational, potential options, including alternative approaches for new European Directives In working on this project and, more specifically, focusing on the project´s core: development of alternative policy options, we would like to stress the difficulties encountered by our team through the

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Final report for STOA Silicone breast implants very strong viewpoints and often conflicting information we received in our quest to be as clear, objective, thorough and unbiased as we possibly can. There are extremely strong interests at stake on both sides of this issue which may have valid, legitimate claims. We aim to capture the complexity of the issue but get to its essence in a way in which the European Parliament can make the most appropriate decision possible in its regard. Option 1: status quo: no ban, keep application of current legal framework (namely, Directive 93/42/EEC, a general guiding directive which sets the basis without entering in further detail). Pros: good legislative basis in place, inconclusive evidence of serious risks, maintain stability. Cons: evidence points to need for proper European harmonisation aiming for increased and improved measures for further and better protecting women and women�s health in EC; self-help groups and others have called for an immediate ban Option 2: ban on silicone breast implants due to lack of complete information regarding risks and to petitions by some groups. Pros: most conservative option�currently exercised, for example, by the US, Canada and France�due to lack of complete understanding and knowledge of risks because of short follow-up period of women and other complicating factors, such as variety of implants used, etc.; desired option by some groups/people (e.g., self-help groups of women suffering from adverse effects of silicone implants). Cons: large demands by women for these implants, especially considering some of problems with main alternative, saline implants�such as a higher risk of rupture, poorer appearance, etc. The available alternatives to silicone implants could even be worse and more studies are needed before promoting these alternatives. Also, studies on silicone-gel filled implants corroborate one another, pointing to inconclusive evidence of risks of serious health concerns, and pointing to local complications as main health concern, also present in alternative implants. Finally, from a social perspective related to health, there would also be the potential for economic damage to industry (e.g., job loss). Option 3: no complete ban, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, quality control and assurance and key research (see seven proposed measures below). Pros: studies do not point to an association between silicone implants and serious health risks, such as cancer and connective tissue diseases. Indicate that local complications�also just as prevalent or more so with other breast implants, such as saline�are the largest cause for concern. Information from self-help groups, surgeons and the literature points to a real need for improved measures, particularly regarding the provision of correct information to patients as to real and potential risks. Cons: need to make a real investment for co-ordinated efforts and research investment to happen; self-help groups and others have called for an immediate ban. Health and other benefits of cosmetic treatments are not easily estimated or measured, and are not usually considered when risks and effectiveness of these interventions are assessed. However, the demand for breast implants and other cosmetic interventions is increasing, and women�s reasons for obtaining breast implants are not very well studied. The existence of risks associated with the intervention must be weighed against the benefits perceived by women. Regulation affects the breast implants market in Europe, and it should be aimed at guaranteeing reasonable safety and assuring that any undesirable side-

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Final report for STOA Silicone breast implants effect constitutes an acceptable risk when weighed against the intended purpose. In view of the evidence, option 3, which proposes additional measures for maximising the benefits of breast implants and limiting the risks in the EU context, perhaps appears to be the most balanced approach. The further measures proposed are described as follows:

1. To facilitate consensus on a breast implant consent form, including information related to alternatives, benefits and risks. The lack of appropriate information on risks and benefits has been underlined as a major problem surrounding the issue of silicone breast implants on all fronts (e.g. this has been cited by the scientific literature, such as the IOM report, by self-help groups, by surgeons, etc.).

A standardised consent form should be developed, including risks inherent in surgery, local complications, the realistic lifetime of implants and need for replacement, the incidence of post-operative and long-term complications, other potential health hazards, etc. Many good models of informed consent on this issue exist which could be used as a basis for a standardised informed consent form for Europe. In addition, it should be stressed in the form that women need to have time to reconsider surgery after reading it. 2. To guarantee marketing control over breast implants in order to avoid any kind of incorrect and misleading information. A great deal of misinformation exists around silicone breast implants in both favourable and unfavourable directions. This measure focuses on facilitating access to reliable information about risks and benefits of breast implants, and on imposing tighter controls on misleading information.

3. To improve certification, technical standards and regulation. Council Directive 93/42/EEC should be applied, along with adoption and ratification of strict technical standards for marketing breast implants in the EU. A harmonised standard is a technical specification (European standard or harmonisation document) adopted, on a mandate from the Commission by the competent bodies (European Committee for Standardisation -CEN, Cenelec) in accordance with the general guidelines on co-operation between the Commission and the bodies(Council Directive 83/189/EEC). Relevant European standards for breast implants include generic standards for risk analysis (EN 1441), non-active implant standard (EN ISO 14630), sterilisation, biological safety and other specific standards for breast implants (EN 12180, recently approved ). The different safety�related features of breast implants, including biocompatibility, mechanical properties, migration of the filling and shell material, compatibility between shell and filling material, ageing, stability and labelling have been examined within the European committee for standardisation (CEN) and within a special working party of certification bodies in charge of these products on the basis of Directive 93/42/EEC. These should be carefully examined and reviewed by the legitimate European officers with the potential assistance of qualified experts.

4. To promote the elaboration of clinical guidelines, standards of care and the development of quality assurance systems. Some problems have stemmed from the lack of explicitly standardised quality standards and clinical guidelines. Specific training and specialised competence should be demonstrated by surgeons to carry out plastic reconstructive and aesthetic surgery in the EU. Harmonisation of standards for units and facilities allowed to offer these implant prosthesis is a goal to be achieved. This measure would seek to improve and harmonise quality standards and procedures throughout Europe. It includes fostering a regulatory framework for promoting transparent professional behaviour of high ethical standards, and liability when appropriate. Appropriate consideration of

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indications and properly carried out surgical procedures are essential steps. The relevant scientific societies could play an active role in this area.

5. To facilitate consensus, promotion and support of effective surveillance systems to report adverse effects and long-term effects. In the absence of breast implant registries in most countries in Europe, little descriptive data is currently available on women who have received implants, types of implants, procedures, problems, etc.

A systematic and prospective registry of European woman with breast implants could help track adverse health effects and provide information on the diffusion and characteristics of this market. Registries are often used for multiple purposes. Thus, discussions should take place around development of a standard prospective registry in place by country which would then be compiled at the central level for Europe.

6. To consider silicone breast implants a research priority and make funds available in the EU research programmes, specifically focusing on some of the shortcomings of research to date. Priority research should concentrate on:

• long-term outcomes �illness and health, systemic health effects at sites distant from the implant (not just autoimmune disorders and cancer), and possible effects on the health of children of women with implants;

• reliable techniques for measuring silicone concentrations in body fluids and tissues, and tissue responses to the presence of silicone;

• local complications, including local effects at the site of the implant. Studies should have large sample sizes, control for variations in implants, and include stratified analyses (of reconstruction and augmentation patients). 7. To foster tolerance and self-esteem and other conceptual alternatives to breast implants, in collaboration with active groups in this field. In light of the potential risk of any surgical procedure, it is important to foster self-esteem and self-tolerance (proper respect to an individual�s own appearance) and sensitise European women about the benefits and risks of, particularly, cosmetic breast implants. At the same time, focus should be placed on seeking good alternatives to satisfy demands for implants. A proposal such as the one put forward by the European Institute of Women�s Health (see Annex A) seems particularly sensible.

3.2. Arguments and evidence 3.2.1. Background information, including arguments for and against the health risks of silicone implants

3.2.1.1. General and specific health risks posed by silicone implants, their effects on the body, the brain and the nerves; possible influences on the genetic make up

One of the difficulties studying breast implants and associated risks has to do with the fact that silicone implants have essentially experienced three different stages: a first generation (1960s to mid-1970s: thick silicone shell, and smooth); which presented a high rate of gel bleed and capsular contracture; a second generation (mid 1970s to late 1980s: thin silicone shell, and smooth), which showed a high rate of gel bleed and rupture; and a third generation (mid-1980s to present: thick silicone shell and textured), which point to lower rates of gel bleed, rupture and capsular contracture. In addition, the tremendous variety of implants on the market, including hundreds of different types, complicates their study.

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Final report for STOA Silicone breast implants Health effects related to silicone breast implants have been recently reviewed extensively. Several studies have been published in the last few years, mainly focused on questions posed by litigation cases. Some methodological shortcomings have underlined the need for new research on the safety issue. For example, the available studies focus on a few well-defined autoimmune diseases or cancer rather than provide a comprehensive evaluation of diseases, symptoms or complications. The sample sizes used are not large enough to precisely detect a risk increase of such rare diseases considered. In addition, the studies include women with implants for varying periods of time, of which some are very short. Implants for reconstruction in women who have had breast cancer have not been sufficiently evaluated (under-represented in studies). Due to the intrinsic heterogeneity of the problem, it is understandable that even a close-to-perfect study design would only answer part of the story. Optimal studies would separately analyse patients with saline and silicone implants, consider different generations of silicone gel implants, focus on long-term implant use, differentiate between patients with implants for augmentation and reconstruction, evaluate any risk of serious illness as an outcome, compare with a appropriate control group and have a sufficient sample size. The available studies on the main possible health effects associated to breast implants have been analysed and reviewed. Overall, most published epidemiological studies found no significant health problems associated with silicone breast implants. Systemic Effects

Cancer Experimental carcinogenicity and human malignant neoplasms of the breast and other cancer sites have been analysed and reviewed with negative findings. Summarising first the experimental evidence, it seems clear that subcutaneous implantation of silicone compounds in rodents may produce local tumours at the implantation site. To learn more about the practical implications of these findings, toxicology studies have examined carcinogenic, mutagenic and teratologic effects (Bryson G, Bischoff F.;1967). The effects of doses of many orders of magnitude higher than could been achieved in women with silicone breast implants have been analysed. Toxic effects that have been found occur at extremely high exposure levels. Thus, this phenomenon is not believed to occur in humans. Even though some cases of cancer occurring in the breasts of women injected with silicone for breast augmentation have been reported, these cases not constitute useful evidence of any carcinogenic effect of silicone in humans. Epidemiological studies have not found elevated relative risks for breast cancer in women with implants. In fact, analyses of large groups of women participating in cohort and case-control studies have shown that there is no association or even a slightly reduced incidence of breast cancer in women with breast implants (Berkel H, et al. 1992; Birdsell D.C:,et al 1993; Brinton L, et al. 1996; Bryant H, and Brasher, 1995; Deapen et al. 1997;.Friis S, et al. 1997; Kern KA, et al. 1997; McLaughlin JK, et al 1998; Park AJ, et al. 1998). In addition, a 1998 report by the Independent Review Group (IRG), Committee on Carcinogenicity in the UK, concluded that there was no evidence of any risks of cancer within human hosts. The available evidence does not support an association of silicone breast implants with other non breast cancers (Herdman R., 2000a). The IOM report concluded that there is no increase in primary or recurrent breast cancer in implanted women. However, as women have not been followed over long periods of time, it is still early to completely rule out increased risks of cancer from silicone breast implants.

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Trying to summarise the current evidence, there appear to be sufficient, consistent and convincing studies to support the conclusion of no association between breast cancer and implants, although more research is needed to rule out long-term risk of cancer. There is still limited evidence that silicone breast implants are not associated with non-breast cancers (other solid tumours, sarcoma, lymphoma, or myeloma), and the ongoing and future studies will hopefully shed light on this point. The available evidence does not support an association of silicone breast implants with other non breast cancers. Mammography and breast cancer A side problem with silicone implants is potential interference with mammography readings, possibly delaying breast cancer detection by "hiding" a suspicious lesion. Breast implants interfere with diagnostic and screening imaging examinations of the breast by compressing and distorting breast tissue, requiring special views, and by interposing (particularly with gel-filled implants) a radiopaque mass that obscures some breast tissue. Also, it may be difficult to distinguish calcium deposits formed in the scar tissue from a tumour when interpreting the mammogram (12 relevant studies summarised by IOM). Subpectoral implants do not interfere with mammography to the same extent as subglandular implants. The technician conducting a mammogram needs to be informed if a woman has implants, so special techniques can be used to obtain the best mammogram and to avoid rupturing the implant, which is a potential risk. It is important to mention that from a very recent study (Deapen et al., 2000), the evidence for no meaningful effect of silicone breast implants on diagnostic delay of, or greater eventual mortality from, breast cancer is stronger, but mammography should be performed routinely and using the Eklund views (Roger Herdman, personal communication, April 2000). There are not studies yet available on differential mortality from breast cancer attributed to differences in detection and diagnostic delays in women with or without breast implants. Neurological disease Some authors have also reported neurological effects and symptoms in women with breast implants (Ostermeyer-Shoaib B,and Patten BM.,1996). These studies are mainly case series and reports and their findings do not seem to be consistent with other experimental and observational studies. Summarising the available evidence, in 1997 the Practice Committee of the American Academy of Neurology reviewed the available scientific literature and unpublished data (Ferguson JH, 1997), concluding that the existing studies came from the weakest category of evidence and did not support any association or causal relationship between silicone gel breast implant and neurological disorders. Two large and recent epidemiological studies, one from Denmark (Winther JF, et al., 1998) and the other from Sweden (Nyrén O, et al. 1998), based on their national hospital discharge registry databases, failed to show evidence of increased diseases such as multiple sclerosis, neuritis, Lou Gehrig�s disease, or Meniere�s disease (a disorder of the inner ear) in women with implants. There was no statistically significant difference in the occurrence of neurological disorders between the study group and the control group (age-matched women who have undergone breast reduction surgery). Furthermore, toxicological and animal studies do not support the idea of silicone gel deposits as a cause of neurological disease. Evidence suggests that such diseases are no more common in

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women with breast implants than in women without them. The IOM report concluded that the evidence for a general neurological disease or syndrome caused by, or associated with, silicone breast implants is insufficient or flawed. The IOM also recognised that, if an implant ruptures, migrates or compresses nerves, it can cause pain and other localised neurological problems. In conclusion, and even though neurological symptoms or diseases have been reported in some case series of women with breast implants, the most properly designed and conducted epidemiological studies show no evidence that silicone breast implants cause neurological signs, symptoms, or disease. Further study is needed in this area before entirely ruling out increased risk. Well-defined connective tissue diseases (related to autoimmune disorders) In addition to results on cancer, recently published studies have shown that women with silicone gel-filled breast implants do not have a greatly increased risk of the other major concern of silicone implants, some well-defined autoimmune diseases (potentially fatal connective diseases), such as scleroderma, lupus erythematosus, rheumatoid arthritis, Sjögren�s syndrome, dermatomyositis or polymyositis, and health disorders such as fibromyalgia and �chronic fatigue syndrome.� A review of 17 epidemiological studies (10 cohort, and 4 case-control and 2 cross-section studies reviewed by IOM) on connective tissue disease and the results of three meta-analyses (Perkins LL, et al. 1995; Hochberg MC and Pelmutter DL 1996; Edworthy SM, et al. 1998) were remarkable for their consistency in finding no elevated risk or odds for an association of implants with disease. One of the larger studies included, the long-term cohort Nurses' Health Study involving 87,505 women, showed no link between implants and defined connective tissue disease or rheumatic conditions (Sanchez-Guerrero J, et al., 1995). The IOM committee concluded that there is no evidence that silicone breast implants contribute to an increase in autoimmune and connective- tissue diseases. The IRG, examining case control and cohort studies conducted between 1970 and 1998, reviews, and meta-analyses focusing on the incidence of established connective tissue diseases, concluded that there is no epidemiological evidence of any link between silicone gel breast implants and any established connective tissue disease. According to the IRG, if there is a risk of connective tissue disease, it seems to be too small to be quantified. The overall biological response to silicone is consistent with conventional forms of response to foreign materials, rather than an unusual toxic reaction.

The US National Science Panel�s (NSP) specific main objective was to review and critique the scientific literature pertaining to the possibility of a causal association between silicone breast implants and connective tissue diseases, related signs and symptoms and immune system dysfunction. The report concluded that no association was evident between breast implants and any of the individual connective tissue diseases, all definite diseases combined or other autoimmune/rheumatic conditions. One meta-analysis included only studies that distinguished silicone gel-filled breast implants from any other type. Results were consistent with those from other meta-analyses where breast implants were more broadly defined. There was no association found between silicone gel-filled implants and any of the definite connective tissue diseases or the other autoimmune/rheumatic conditions.

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A very recently published, comprehensive and consistent meta-analysis of the relation between silicone breast implants and the risks of connective -tissue diseases (Janowsky EC, et al, 2000) reviewed nine cohort studies, nine case-control studies and two cross-sectional studies. The study has been taken in part from the NSP report. This study incorporates eight studies not included in the three earlier meta-analyses. The authors adjusted for confounding factors, and conducted a separate analysis restricted to silicone gel-filled breast implants. There was no evidence that breast implants were associated with a significant increase in the summary adjusted relative risk of individual or combined connective-tissue diseases, or with other autoimmune or rheumatic conditions. No evidence was found of significantly increased risk in the unadjusted analyses or in the analyses restricted to silicone gel-filled implants. Atypical connective tissue or novel systemic disease A substantial number of women experiencing severe systemic illnesses are convinced that they are caused by their silicone breast implants. In most cases, the silicone breast implants do not appear to be causally related to these illnesses since they seem to occur at about the same frequency in women without implants. Some studies have signalled the existence of an undefinable, atypical disease (Patten BM and Ostermeyer-Shoaib B.,1995; Ericsson AD.,1998; Brawer AE.,1996), but these are mainly case reports with no control group and rely on very small sample sizes. Some studies have pointed to a lessening or disappearance of symptoms after extraction (Kaiser W, et al., 1990) and another study found a significantly lower duration of implants in asymptomatic compared to symptomatic women (Zandman-Goddard G, et al, 1999). It should also be noted that there are some clinicians who have treated ill women with silicone breast implants and who claim the existence of a silicone-specific disease, sometimes referred to as siliconosis of silicone breast implant adjuvant syndrome (Shanklin DR and Smalley, 1998) (for additional informationand documents provided by self help group, see also Annex B1 ). The issue is complicated by the fact that the proposed syndromes often involve ill-defined subjective symptoms (49 signs and symptoms listed by Tugwell P, in NSP 1998). Most importantly, and although from a scientifically orthodox standpoint these are these mainly anecdotal studies and reports, they underline the importance of further studies in this area. On the other hand, the IOM report concluded that there is no rigorous, convincing scientific support or significant evidence of a "novel" systemic disease as some researchers have claimed, caused by the presence of silicone implants. Evidence for an atypical disease has been considered insufficient or flawed (case series, few describing a reproducible syndrome),and other controlled studies provided stronger, contrary evidence. The NSP report describes the problems in analysing these studies (non-specific signs and symptoms, self-report not verified, timing in relation to the implant not known, small number of women studied, complaints reported are very common in the general population), and states that no distinctive features relating to silicone breast implants could be identified. The IRG report also points out the difficulties of identifying a specific syndrome associated with silicone gel breast implants with available data. There have been very few studies comparing an unselected group of women with implants with a matched population group to examine the frequency of such symptoms. IRG concluded that good evidence for the existence of atypical connective tissue disease or undefined conditions such as "silicone poisoning" is lacking. It is possible that other conditions such as low grade chronic infection may account for some of the

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non-specific illnesses noted in some women with silicone gel breast implants (fatigue and musculoskeletal pains) and further research on this would be required.

At the same time, however, the studies available do not rule out the possibility that a subset of women with implants may have a small increased risk of these conditions, or that some women might develop other immune-related symptoms that don't fit into "classic" disease descriptions. In sum, the epidemiological literature has indicated that the evidence for an atypical disease or novel syndrome is insufficient and that there is no robust, convincing support for these disorders. However, the existence of a specific syndrome or syndromes in women with silicone breast implants cannot be completely proven or dismissed at this point in time, and deserves further analysis.

�Vertical� Effects (mother to child) Risks to infants The silicon concentration in milk in general has been a matter of concern for some specialists in the field. A major concern about implants has been the possible ill effects of the silicone, a compound of silicon (see 3.3.Technical file), on infants who are breastfed. However, much higher levels of silicon have been measured in cows' milk and commercially available infant formula than are found in the milk of nursing mothers with breast implants for augmentation. The exposure to silicone in many forms is very extensive (diet, environment), so the exposure of children born to women with an implant is no greater than that to which they are exposed from other sources. There is no evidence of elevated silicone levels in breast milk or any other substance that would be harmful to infants, nor are there any differences in the milk and blood silicon levels between nursing mothers with implants and those without. There is no evidence of disease or congenital flaws resulting from silicone or any other harmful factor in breast implants crossing the placenta to the unborn child. There is limited evidence that periareolar incision for prosthesis implantation could interfere with natural lactation. The IOM report concluded that the evidence for an association of maternal silicone breast implants and children�s health effects is insufficient or flawed. The IRG report reviewed the papers on this issue (the majority are individual non comparative case studies), and concluded that the published literature does not substantiate the claims that there are significant, clinically apparent, effects in children of women who have had implants. In summary, studies have concluded that there does not appear to be evidence of harmful effects to infants breast-fed by women with silicone breast implants (connective tissue or autoimmune disease .

3.2.1.2. Life span effects of silicone implants after 4, 8 and 12 years Local Effects

Local complications A large potential health hazard (which recent studies now point to as the main health concern of silicone breast implants) has to do with the local complications that are clearly related to breast

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implants, such as rupture and migration of the silicone gel, capsular contracture (shrinking of scar tissue around the implant, which can cause painful hardening of the breast or distort its appearance), and infection. Some of the risks posed by silicone implants are attributed to the leakage of silicone gel through ruptured shells of silicone implants. Local complications have been considered as the primary safety concerns with silicone breast implants (Herdman R., 2000 b). Regarding rupture alone, for example, published studies show that it is experienced by between 5% and 51% of women with silicone breast implants, which represents a very large range (Reviewed by IOM). The relatively high frequency of local complications that are unique to women with silicone breast implants is quite significant. Although they are not normally life-threatening, these local complications may result in discomfort, inconvenience, explantation, disfigurement, pain, and other morbidities, and when further corrective procedures are necessary, an additional potential risk (e.g. additional surgery) and expense. Although breast surgery has a low risk of death, many complications occur when implants are removed, revised or replaced. The occurrence of local and perioperative complications presented in reports is extremely variable. Differences observed are due to individual biological variability, differences in women's characteristics (age, comorbidities, indication for implant), types of implants, type of study (design, reporting or clinical and basic research), surgery techniques and skills of surgeons. The ANDEM report concluded that local complications are very frequent and they constitute the main health concern. The frequency of fibrous capsular contracture is considered as ranging from 41% to 56% at four years for smooth surface implants and at about 10% for textured. The frequency of rupture ranges from 2% to 14% at 10 years, and it increases overtime. Low bleeding occurs at 10 years in 17% of cases. The incidence of local complications is not known for the new generation of breast implants. The IRG report also gives special attention to local effects (capsular contracture, infection, gel bleed, rupture), and recognises that the precise incidence of these complications is not well known and scientific data are incomplete. The IRG recommends prioritising research around this issue. The IOM report presented three major general conclusions regarding local and perioperative complications: first, they are so frequent that must be considered the primary safety issue with silicone breast implants (includes overall reoperations, ruptures, deflations, contractures, infections, hematomas, and pain); second, risks accumulate over the lifetime of the implant, but quantitative data on this point is lacking for modern implants and are deficient historically (lack of data from representative samples of the population, lack of information on implant characteristics that affect complications and lack of precise and reliable detection of complications); third, information concerning the nature and relatively high frequency of local complications and reoperations is an essential element of adequate informed consent for women undergoing breast implantation. We believe that these are sensible and practical considerations. Additionally, the importance of explicitly standardised clinical and surgical guidelines should be emphasised. Need for reoperation and replacement It has been found that women undergoing reconstructive surgery have greater complication rates than those undergoing cosmetic surgery. The operation for immediate reconstruction is more serious, because it involves a significant surgical procedure (mastectomy or removal of the breast) in addition to the implant. Some studies have suggested that from 30% to 40% of these patients with reconstructive surgery may expect complications. That percentage may rise when an

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expander is used to help generate tissue growth in the breast area, and complications are probably more frequent when the breast has previously undergone radiation therapy. The possibility of more frequent and serious side effects of immediate reconstruction must be weighed against the psychological benefits. Women undergoing augmentation have fewer complications. Still, the frequencies are high. A large prospective study by McGhan Medical Corporation of 2,855 women with modern saline implants showed 18% of augmented women and 36% of those with reconstruction had complications within a year of receiving their implants, in one of four categories: infection, severe contracture, deflation, and implant removal. A 1997 Mayo Clinic Study reported in the New England Journal of Medicine found that 24% of women who receive a breast implant will have a complication requiring an additional surgical procedure within 5 years of initial implantation.

It has also been found that women with silicone implants appear to have a greater chance of capsular contracture than women who have saline implants (Gylbert LO, et al., 1990).

Breast implants have a limited lifetime, which is not yet very well established. The odds of having at least one replacement implant are high, and some women have had many more. The IOM committee found that a large number of women with implants could expect to have an additional procedure within the first 5 years after the original implant. A study of women receiving reconstruction over an average of 6 years showed 16% of those with saline implants required replacements because of deflations and another 8% due to misplacement or severe contracture (Gylbert LO, et al 1990). Another study reported an l8% implant loss in women reconstructed with gel implants or submuscular expanders. A smaller study of women with implant complications showed that, on average over 12 years, there were about three implant procedures performed per woman. The risks of having a replacement operation continue to accumulate over time. This deserves further consideration in ongoing and future studies.

Rupture When the rupture of a silicone gel implant occurs, the gel can sometimes escape or leak into other tissues, (extracapsular). Often, the gel is contained in the space between the fibrous capsule and the implant, and the rupture goes unnoticed (intracapsular). Surgery for extracapsular rupture consists of removal of the implant (explantation) as well as the capsule surrounding the implant (capsulectomy). These operations will require anesthesia, incisions, and stitches. The surgical procedure may include a new implant as well.

The frequency of rupture is reported in most studies based on findings at explantation (standard for diagnosis), detection by mammographic technologies and surveys of results in cohorts of patients. On case series reported from surgeons, the detection of ruptures depends on patient complaint, routine screening mammography or physical examination, none of which is absolutely reliable. The lower rupture rates reported by manufacturers based on returns, complaints, legal proceedings and other sources probably are affected by underreporting and low sensitivity.

Many different studies have reported extremely variable rupture rates of gel implants, ranging from 0,3% to 96%. There is a relationship between implant age and rupture. As an example, some results on rupture reported are 62,5% ruptured for 10 years (Malata CM et al., 1994), 71,2% ruptured at 14 years , and 95,4% ruptured at 20 years (Robinson OC, et al., 1995).

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In fact, the extreme variability of these percentages is due to the type and model of the implants, their length of implantation, the types of groups of women studied and many other factors. It is necessary to consider that ruptures are not always detected, that composition of implants has changed over the years, and that it is difficult to detect later ruptures (due to short time periods of follow-up). According with implant vintage, first generation implants (1963-1972) have very few ruptures, second-generation implants (1972-mid 1980s) experience a 95% rupture rate at 12 years, and third-generation implants (late 1980s to date) had only 3,5% ruptures by 1992 (Peters WJ, et al., 1996). We do not currently have enough information about long-term effects of the third generation implants, so it is not possible to precisely predict current rupture frequencies. Available information suggests that rupture may be more common in current gel-filled implants than in current saline-filled implants and expanders (IOM), although new studies are needed to resolve this issue. Based on recent observations, some authors have estimated that probably less than 10% of modern gel implants will have ruptured by five years and that ruptures will continue to accumulate and prevalence will increase in ensuing years. The safety implications of rupture include the risks of additional surgery and anaesthesia (explantation or replacement).

A fact that needs to be kept in mind is the effect of bias in estimating the rupture rates of gel-filled implants, based mainly on explant series (overestimation or rupture frequency), instead of measuring rupture in more representative women using sensitive diagnostic tools. Dismissed variation and inclusion of implants no longer in use in most explant series do not provide a good basis for an estimate of modern or future rupture frequencies. Rupture rates of modern implants will not be known until long-term, prospective observational studies of sufficient large and random cohorts of women are completed, using reliable detection methods (Magnetic Resonance Image, MRI).

Deflation. Deflation is basically a problem of saline-filled, not silicone gel-filled, implants Early saline implant models had frequent deflations; later ones have shown less chance of this happening, with a 5% to 10% frequency after 10 years (IOM).

The IOM committee concluded that deflation of modern first-year saline implants might range from 1% to 3% and that this percentage would rise steadily with time. The IOM report strongly recommends more studies to answer questions about today's implant rupture and deflation rates.

Capsular Contracture The production of an enclosing capsule of fibrous scar tissue around the implant is an important component of the foreign body reaction. A severe capsular contracture can cause painful and disfiguring squeezing as well as distortion of both the implant and overlying tissue. The ensuing complications can be serious, including additional medical procedures to break down the capsule, or to remove it, or even to replace the implant itself. Additional surgery has its own risks, including infection, possible ruptures, and the hazards of anaesthesia. Some of these medical procedures, particularly �closed capsulotomy,� where strong pressure is applied to the outside of the breast to help break up the fibrous capsule, are performed repeatedly on the same women. Problems with capsular contracture made up 28% of secondary procedures carried out on women with breast augmentation and 14% of those with reconstruction.

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Final report for STOA Silicone breast implants

The severity of contracture is often measured using the Baker Classification (most common standard), which has four categories: Class I. The augmented breast is as soft as an unaugmented one. Class II. The breast is less soft and the implant can be palpated (felt) but is not visible. Class III. The breast is more firm and the implant can be palpated easily and can be seen (or a distortion can be seen). Class IV. The breast is firm, hard, tender, painful, and cold. Distortion is marked. Most surgeons consider the first two classes satisfactory but not the last two.

The reported prevalence of contracture depends on several factors, such as varying degrees of detection, placement of implants, texture and other characteristics of the implant, steroid use, selection bias, length of follow-up. Reports used different units (patients, breasts), Baker classes or other, refer contractures into class II-IV or II-IV.

Women have shown considerable tolerance for contracture, either by not seeking medical attention for class III or IV contractures or by pronouncing themselves satisfied with their implants when surveyed. A 1990 study reported that 85% of women appeared satisfied with their implants even though 35% had experienced severe contracture (Gylbert LO, 1990). A 1997 report on 186 implants showed Class III and IV contractures continuing to occur (100% at 25 years) (Strom SS, et al., 1997). Treatments for contracture other than closed capsulotomy include �open capsulotomy,� in which an incision is made into the body to break up the capsule, and a �capsulectomy,� or surgical removal of the capsule itself. This operation may also involve removal and replacement of the implant as well as loss of breast tissue. Repeated capsulotomy, open or closed, has progressively less chance of success.

Although there are only limited studies, the available evidence suggests that saline-filled implants have a reduced rate of contracture compared to implants filled with silicone (IOM). Fewer cases of severe contracture are also reported in studies of textured surface implants compared to those with smooth surfaces, in women for cosmetic purposes rather than reconstructive, in women undergoing immediate reconstruction compared with women having later reconstruction and in implants placed behind the chest muscles compared with submammary implants. This lower incidence of severe contracture with submuscular implant placement is considered very important.

3.2.1.3. Post-operational effects and follow-up

General surgical risks associated with any operation are possible. These include complications from general anaesthesia, with symptoms and signs such as pain, nausea, vomiting, fever, infection, hematoma, haemorrhage, thrombosis. Skin necrosis is also possible. The chance of skin necrosis may be increased by radiation treatments, cortisone-like drugs, or an implant too large for the available space.

A very brief description of some of the most pertinent of these complications can be found below.

Pain associated with implantation is very common and constitutes one of the significant reasons for implant removal and replacement (present in 15%-20% of requests). Some authors have reported complaints of pain in a majority of women after implant surgery, and this pain may be long-term. Patients also reported more pain with implants after mastectomies compared with 9 mastectomies alone and with implants placed under the chest muscles instead of under the skin and breast glands. One study (Wallace MS, et al., 1996) reported substantial local pain after reconstruction (up to 50%) and up to 38% after augmentation. Pain was also more common after

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submuscular (50%) than submammary implants (21%), and with saline implants (33%) than gel ones (22%). About 20% to 29% of patients with pain required pain control medication. The implant capsule, especially when the implant is under the chest muscles, may cause painful nerve compression requiring additional treatment. Pain with late onset usually represents contracture pain, but it can also be indicative of bacterial infections or rupture.

Infection Skin flora that reside in the lactiferous ducts of the normal breast, often can be cultured from implants, and can cause infections. There is suggestive evidence that the presence of bacteria correlates with contracture. It is not proven that infection is a cause of contracture. A few investigators have reported finding an association between the presence of bacteria around implants and systemic symptoms or breast pain, although this evidence is limited. Significant contractures are reported considerably more frequently than clinically observable hematomas.

Chronic infection may occur with any surgical implant, and then, the implant may have to be removed and replaced. Some authors support that subclinical infections may also contribute to such symptoms as fatigue, muscle or joint pain, weakness, intermittent fever, and diarrhoea.

Hematoma. Hematoma or seroma is variable reported in case series and other observational studies. Hematoma is considered as just a minor or small contributor to contracture. It was the indication for reoperation in 3,5% of the women in the Mayo Clinic series (Gabriel SE, et al., 1997) The frequency of hematoma reported within days after implantation for augmentation and reconstruction with both silicone gel or saline implants varies between 0,5% and 5%. In a small number of cases, reoperations have been necessary to correct the problem. Rarely, hematomas occur many years after the implant operation in association with contracture. The main safety implications of hematoma involve added interventions, associated infection, and potential association with contracture.

3.2.1.4. Conclusions The two main original causes of concern (cancer and well defined autoimmune or connective-tissue diseases) have been the subject of considerable scientific attention and discussion over the last 10 years. Despite the methodological and other shortcomings of the available studies, we can generally assume that no relevant increased risk exists which can be attributed to these two conditions, as they appear at the same frequency in the population with implants as they do in the population without implants. There appear to be sufficient, consistent and convincing studies to support the conclusion of no association between breast cancer and implants, although studies are being conducted to rule out long-term risk and other types of cancer. There is no evidence that silicone breast implants contribute to an increase in autoimmune and connective- tissue diseases, although the studies available do not rule out the possibility that a subset of women with implants may have a small increased risk of these conditions, or that some women might develop other immune-related symptoms that don't fit into "classic" disease descriptions. Nevertheless, the epidemiological literature has indicated that the evidence for an atypical disease or novel syndrome is insufficient and that there is no robust, convincing support for these disorders. However, the existence of a specific syndrome or syndromes in women with silicone breast implants cannot be completely proven or dismissed at this point in time, and deserves further analysis. The evidence provided from epidemiological studies that silicone breast implants cause neurological signs, symptoms, or disease is insufficient. There does not appear to be evidence of harmful effects to infants breast-fed by women with silicone breast implants (connective tissue or autoimmune disease). The potential interference of breast implants with mammography readings by compressing and distorting

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Final report for STOA Silicone breast implants breast tissue requires special techniques to obtain the best mammogram and to avoid rupturing the implant. Surgical, local and perioperative complications are so frequent that we agree with previous reports considering them as the main safety issue with silicone breast implants and any other type of breast implant. Overall reoperations, ruptures, deflations, contractures, infections, hematomas, and pain are very common and the main cause of women's complaints. Breast implants have a limited lifetime, which is not very well established. In any event, the odds of having at least one replacement implant are high. We do not currently have enough information about long-term effects of the third generation implants, making it difficult to predict frequencies of 3rd generation rupture, reoperations, and contractures. Quantitative data on this point is lacking for modern implants and have been deficient historically. Thus, the precise incidence of local and perioperative complications should be considered a research priority and an essential element of adequate informed consent for women undergoing breast implantation. See Table 1 on serious health effects considered in studies in relation to silicone breast implants. 3.2.2. Overview of relevant primary research and reviews. Period 1990-1999 3.2.2.1. Research currently taking place in the EU Various research and review efforts have been carried out in Europe, such as the report published in France by ANDEM (1996), and the comprehensive overview carried out by the Independent Review Group in the UK (1998). Other observational research initiatives have also been conducted. Two large and recent epidemiological studies, one from Denmark , based on national hospital discharge registry databases, and the other from Sweden, based on three large cohorts (Friis et al., 1997; Nyren et al., 1998, respectively). The Danish Cancer Society study included 1135 women with breast implants for cosmetic purposes, 1435 for breast reconstruction and another two groups of non implanted women. The study failed to show evidence of increased systemic diseases such as definite connective-tissue disease, multiple sclerosis, neuritis, Lou Gehrig's disease, or Meniere's disease (a disorder of the inner ear) in women with implants. In Sweden, three large cohorts were studied (Nyrén et al. 1998). Women with cosmetic breast implants (3502), women with implants for reconstruction (3931) and women who had undergone breast reduction surgery (3351) were followed for ten years through cross-linkage within hospital discharge registers. The author concluded that no significant increase in risk of connective tissue disease nor neurological diseases was apparent comparing these cohorts of woman and the general population. Other relevant epidemiological studies have been recently conducted in EU countries, including the cohort studies by Park et al. in Scotland (1998) and by Giltay et al. in The Netherlands (1994). Both studies did not show any relevant association between breast implants and connective-tissue diseases. Regarding efforts to clarify issues of safety and appropriate certification of breast implants in Europe, this issue has been given careful attention and has led to different interchanges and discussions between the Commission and Member States. This process has driven different options currently adopted by Member States in Europe, with the exception of France, which does not share the existing Essential Requirements of the European Directive (see 3.1.1.4.). In the UK, the Medical Devices Agency (MDA) set up an Independent Expert Advisory Group and published a review analysis in 1992, updated in 1994. A National Breast Implant Registry was established in 1993. Further details are given in 3.1.1.4.

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Final report for STOA Silicone breast implants In Spain, a working group of independent experts reviewed the existing evidence and arrived at the conclusion of proposing implant and explant (implant removal) registries. We have been informed that within the next few months, the first analyses of data arising from these registries will be available. A project of systematic review by an expert panel on silicone breast implants is being undertaken by the Council of the Netherlands Gezondheidsraad (GR), a member of the International Network of Agencies of Health Technology Assessment. We have no information about new relevant research being developed on this issue with EU funds. As for technological investments and efforts, new developments in breast implant technology may change the horizon. Cohesive silicone gel represents an innovation. A new hydrogel formulation of polyvinylpirrolidone (PVP) device for breast implants has been tested and used in Europe. Also, new saline-filled implants that are pre-filled rather than being filled at the time of surgery with sterile saltwater solution could eliminate valve leakage and improve sterility. In short, these innovations may provide increased options for women seeking breast enlargement or reconstruction, but they need further review and attention. 3.2.2.2. Current research in other parts of the world Breast implants have been available since the 1960s. In 1976, the US FDA placed breast implants under class II devices whose safety and effectiveness were considered as well established, only requiring performance standards or surveillance studies. In 1982, due to reported problems, breast implants were proposed to be moved into class III, under the strictest controls, requiring studies demonstrating safety and effectiveness, and all implants were placed into this category in 1988. In April 1991, in response to a growing number of adverse reaction reports that raised safety concerns about the silicone gel-filled implants, the FDA published a regulation that required manufacturers to submit pre-market approval applications with data showing the safety and effectiveness of the implants by July 9, 1991. The data submitted did not prove the devices safe, as required by law, so the agency ordered the devices off the market in April 1992 and restricted their use to clinical trials. A report by a National Science Panel (NSP) (four experts on toxicology, immunology, epidemiology and rheumatology) was presented in 1998 to the Honorable S.C. Pointer, Judge for the Federal Breast Implant Multi-District Litigation. This report reviewed the scientific literature related to silicone breast implants and connective tissue diseases and inmunologic dysfuntion. In 1997, the Institute of Medicine (IOM) of the National Academy of Sciences agreed to carry out a comprehensive evaluation of the evidence for the association of silicone breast implants with human health conditions, asked by the U.S. Congress. The final report was presented in 1999. The IOM made a clear distinction between local complications and systemic health concerns. The IOM determined that there was insufficient evidence to establish that breast implants cause systemic health effects such as autoimmune disease. The IOM concluded that there is no definitive evidence linking breast implants to cancer, immunological diseases, neurological problems or other systemic diseases. However, the IOM also concluded that local complications are the primary safety issue with silicone breast implants. In the US, silicone gel-filled implants are only available through an adjunct study (focussed on collecting data while allowing for continued access to the device for reconstruction and revision patients) or a investigational device exemption (IDE) study (focussed on collecting both safety and effectiveness data to support premarket approval). An IDE study also may include augmentation patients.

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Final report for STOA Silicone breast implants Mentor Corporation�s and McGhan Medical�s adjunct studies, were approved by FDA in 1992 and 1998, respectively, both limited to reconstruction patients. In June 1998, FDA approved McGhan Medical�s IDE study for augmentation, reconstruction and revision patients. Clinical data of all these studies are being collected and submitted to FDA on an annual basis. To date, no manufacturer has yet provided data to support the safety and effectiveness of their breast implant, so no premarket approval (PMA) or product development protocol (PDP) application has been approved for silicone gel-filled implants. FDA recently required manufacturers of saline-filled breast implants to submit safety and effectiveness data, and several manufacturers submitted PMA applications for their saline implants in 1999. A meeting was held in March 2000 to review the PMA applications and the FDA Advisory Panel recommended their approval, but the FDA has not yet made a decision, which is expected before end-May 2000.

Current studies in the US and Canada Currently, the largest study to date is being conducted on the long-term effects of breast implants, involving 13,500 women who had implant surgery before 1998. Dr. Louise Brinton, Chief of the Environmental Epidemiology Branch at the National Cancer Institute of the National Institutes of Health, is Principal Investigator. The scientists will study whether breast implants are linked to risks of breast cancer, other cancers or connective tissue disorders. The results of the study on breast cancer will be available during 2000; the findings on other cancers and connective tissue disorders will be released during 2001. This study aims to address many of the limitations of other studies, particularly because of its large sample size and its focus on the long-term effects of breast implants. Another study is currently under way in the US to look at rupture rates. This study should be closely followed. In 1992, Canada�s Minister of Health requested all implant manufacturers to withdraw all silicone gel breast implants from the Canadian market and released the Baines report, indicating that existing scientific information was inconclusive and more data was required on safety implants. In 1996, Health Canada announced a plan to fund an Ontario and Quebec Breast Implant Study focused on risk of cancer, and would involve 40.000 women who received implants. The Conseil d�evaluation des technologies de la santé du Québec has now developing a research project titled: Effectiveness of alternative imagery techniques in the diagnosis of leakage of silicone breast implants. 3.2.2.3. Conclusions A relevant effort and investment has been made in several developed countries (mainly in U.S. and Europe) over the last ten years considering the health effects posed by silicone gel-filled breast implants. Governmental agencies and independent groups have extensively reviewed or have carried out epidemiological studies or meta-analyses on this topic. Current studies are developing on long-term effects of breast implants (mainly on cancer or connective -tissue diseases) in the US. Manufacturers are also involved in the U.S. on adjunct studies or on investigational device exemption (IDE) studies focussed on collecting both safety and effectiveness data to support premarket gel-filled implants. Clinical data of all these studies are being collected and submitted to FDA. Most likely, manufacturers of saline-filled breast implants will consider the initiation of new IDE studies. Despite the research carried out, lack of information and insufficient evidence have been recognised and some research areas are considered of priority: -reliable techniques for measuring silicone concentrations in body fluids and tissues, and tissue responses

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Final report for STOA Silicone breast implants to the presence of silicone; -long-term outcomes illness and health, systemic health effects at sites distant from the implant (not just autoimmune disorders and cancer), and possible effects on the health of children of women with implants; -the frequency of local complications, including local effects at the site of the implant. 3.2.3. Primary information obtained The reality of silicone breast implants is enormously complex. From the epidemiological literature, there is inconclusive evidence of an association between silicone breast implants and cancer or connective diseases, the two main original causes of concern. Studies point to local complications as the principal risk. However, without underestimating the importance of local complications or of these studies, communication and materials from key actors uncover other crucial information which needs to be taken into account, demanding further critical research, action and due consideration. We contacted key actors to gauge their views and positions on silicone breast implants: surgeons, women�s groups, scientific societies, patients, manufacturers, researchers, EU countries, other countries, and self-help groups. At the end of this document, we have compiled charts with response rates for these different groups. A summary of these groups� responses can be found below. 3.2.3.1. Surgeons Please see Annex A1 and A1/2 for sample letter and individual responses. In Table 2 there is a summary of responses by surgeons. 3.2.3.2. Women�s group: European Council on Women�s Health Please see Annex A2 for statement on silicone breast implants. 3.2.3.3. Scientific Societies Please see Annex A3 and A3/2 for letter and responses. 3.2.3.4. Patients Please see Annex A4 and A4/2 for sample questionnaires and individual responses. In Table 3, please find a summary of patient responses. 3.2.3.5. Manufacturers Please see Annex A5 for letter and individual responses. In Table 4, please find a summary of manufacturers� responses. 3.2.3.6. Researchers Please see Annex A6 and A6/2 for letter and individual responses. 3.2.3.7. European Union Countries Please see Annex A7 and A7/2 for letter and individual responses. In Table 5, please find a summary of government responses. 3.2.3.8. Other Countries Please see Annex A8 for the United States� official response (we have also received useful country-specific information from scientific societies: please see Annex A3).

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Final report for STOA Silicone breast implants 3.2.3.9. Self-help groups We have heard and received information from self-help groups from the UK/Scotland, The Netherlands, Germany, Belgium, Switzerland, and Iceland (these include: Silicone Support UK (SS/UK); Action Against Silicone Gel (AASG/UK); Silicone Information Network (SIN/UK); Stichting Steunpunt voor Vrouwen met (vragen over en/of problemen door) Siliconene borstprothesen (St. SVS/NL); German Support Group for Victims of Silicone Implants (GHG, DE); Selbsthilfegruppe Silikongeschadigter Frauen e.V. (SHG/BE) Silicone Support Switzerland (SS/Switzerland); Silicone Survivor Group, Iceland (SSG/Iceland), respectively). Contact with self-help groups of women has underlined the importance of the following. 1) Information is critical. Many women complain of not having been informed of the potential risks with breast implants before they had their operation. In fact, we have also been informed by some expert surgeons that information to patients was uncommon before 1992. A significant group of women report that they were not told about risks of the surgical procedure itself, the potential for infection, or the limited lifetime of implants. At the same time, some women who underwent explantation and/or other additional operations as a result of complications did so without having received proper information or without having given their informed consent. Specifically, two critical areas in which information was claimed to have been lacking were as follows:

• Implants are not for life and may need to be replaced or explanted�they do not last forever, which was originally believed and disseminated. Many women, not informed that their implants would need replacing, have experienced problems years after their implantation, long after the time at which their implants should have already been replaced. Women need to be aware of this fact upfront.

• Rupture occurs significantly. Although exact figures are unknown, studies detect rupture rates of between 5%-51%, an enormous range. At the same time, some studies point to a rupture rate of 50% after 7-10 years and up to 95% after 20 years. Inherent with rupture are many problems related to local and distant inflammation, infection caused from the release of gel, other potential unknown problems related to gel migration, not to mention the need for emergency reoperation. Currently, studies in the US are looking at rupture rates and it is important to follow this work. In addition, women need to know about the potential for rupture and many were not appropriately informed.

2) A distinction needs to be made for women considering implants for augmentation or for reconstruction in light of local complications alone (rupture, capsular contracture, and infection) (not taking into account other potential risks, such as risks inherent in surgical procedures). The majority of the women from self-help groups had implants for cosmetic purposes and state that, if they had been given a realistic view of the risks (not taking into account their current health problems), they might not have opted for implants. In addition, due to the lack of registries in Europe, not only are overall numbers of women with implants unknown, but also the breakdown of augmentation versus reconstruction patients. However, for example, numbers from the UK point to a larger demand for implants for cosmetic purposes, which, again, highlights the critical need for proper information and informed consent so that an appropriate, informed assessment of risks and benefits can be made. 3) A significant body of women with silicone gel-filled breast implants are claiming the same inexplicable serious symptoms: chronic fatigue, dizziness, memory loss, forgetfulness, insomnia, abdominal pain, bowel and bladder trouble, aches and pains, flu-like symptoms, redness or swelling of the

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Final report for STOA Silicone breast implants skin, itchy scalp, rashes, tingling, extreme temperature changes, cold extremities, swallowing difficulties, pain in back, armpit, hands and feet, eye dryness and irritation. These women, whose symptoms have begun at varying times and which are experienced to differing degrees, all claim to have been healthy before implantation and to have fallen ill afterwards, as a result of their breast implants. In some cases, women have reported a reduction in symptoms after the implants were removed; in other cases, there was no change in symptoms after the implants were removed. We have been sent information from European women representing themselves and others in their 6 respective countries. Their stories and health problems are remarkably, eerily similar. (see Annex B1 and B1/2 for original materials sent from these women and self-help groups). They have provided us with references from physicians and researchers who have coined these symptoms �siliconosis� and believe that it is an undiagnosed, not yet classified, man-man-made disease directly associated with the presence of silicone gel-filled implants ( Shankin DR, and Smalley DL.,1998). Although there is inconclusive epidemiological research pointing to this association, these women seem convinced of this. While the actual number of women experiencing these same symptoms is unknown, it should be noted that according to the information provided by the lead petititoner, 2000 women in the UK alone signed the petition presented to the European Parliament calling for a ban on silicone breast implants. In Germany alone, according to the Head of the German self-help group, since 1992, 6000 sick women with silicone breast implants have sought advise from the self-help group. The Dutch Silicone Supportgroup has answered 17,500 calls (from 5 minutes to 1 ½ hours or more) and has heard 4000 stories from sick women since it was formed in 1992. 4) The self-help groups point out the shortcomings of available epidemiological studies Silicone breast implants were widely used for years with no regulation, study, control or monitoring of their use whatsoever. The exact number of women who have breast implants is impossible to know. To complicate the issue, a multitude of different kinds of implants exists, as well as three distinct generations of implants. Thus, until 1990, there were actually not very many useful studies and/or the research that were conducted on silicone breast implants was not very useful in assessing risk. A great deal of attention and focus has been placed on silicone breast implants since the early 1990s, leading to many different studies. However, there are some limitations to these studies, which could be summarised as follows (extracted and summarized from Diana Zuckerman (1998) and other sources):

4.1. Small sample sizes. Lack of power may hamper the capacity to detect risk of an atypical disease. 4.2. Studies only focused on classic disease criteria, mainly cancer and classifiable autoimmune diseases, not on other problems and/or symptoms and the potential for new atypical disease. 4.3. Lack of long-term data (e.g., 8-14 years after, when problems are most likely to arise). Studies only really started in the early 1990s; many women in studies were included after 1 to 5 years after having implant--too close after implantation. 4.4. Comparison samples not always good. Weak sampling schemes in many studies (e.g., convenience samples), which could lead to non-generalizable results. 4.5. Mixing of different kinds of implants and patients from different generations often grouped together, which skews results (second generation believed to have greater possibility of rupture, but studied with other generation implants), and augmentation/reconstruction patients considered together, although they have differing degrees of complication.

For the sake of objectivity, we should also point out, however, that the published studies supporting the idea of an underlying link associated with silicone implants have very clear intrinsic limitations, given that their epidemiological designs are not strong, they are mainly case reports with no control group, and they rely on very small sample sizes. 5) There is a need to address these women�s claims. Public health consists not only of epidemiological

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Final report for STOA Silicone breast implants studies, but of information and input from patients. of Overall, women from self-help groups in Europe have informed us that they feel that they have had no �voice� in the silicone breast implant debate. Generally, they feel shunned from the researchers who have been studying silicone breast implants and believe that their position has not been adequately reflected, they feel ignored by surgeons, and do not feel that they have been given adequate attention by their governments as to their very real problems. In Annex B1 to our draft final report, we sent all original materials and information sent to us. They were sent with our draft so that the European Parliament could carefully and fairly consider these in the assessment of the draft report and of this important issue. As an Annex to this final report (Annex B1/2), we send all new original materials and information received since submission of our draft final for direct review by the European Parliament. As a side, we think that a short anecdote highlights the need for further attention to the issue and for stronger, improved measures on silicone implants in light of local complications alone and the underlying risk of any surgical procedure. According to information from certain newspapers (El Pais, April 2000), there is a television game show currently on the air in Austria which consists of the audience�s active participation in the awarding of free breast implants to women contestants. 3.2.4. Analysis of potential legal precautions to be envisaged

3.2.4.1.Alternative levels of precaution potentially recommended taking into account the current knowledge about health issues.

The different perspectives and views on the right way and the right time to impose appropriate levels of precaution have been a matter of a lively debate not only in the European Union, but in most regions of the world. The main objective of the creation of a Single Market in the EU was to guarantee free movement of products, and was based on prevention of new barriers to trade, mutual recognition and technical harmonisation. However, the underlying philosophy is obviously to make this compatible with an acceptable level of risk for the population. The directives based on New Approach and Global Approach on procedures to conformity assessment (Council decision 90/683/EEC, decision 93/465/EEC) have the following principles: The legislative harmonisation is limited to essential requirements that products placed on the Community market must meet. In particular, these requirements deal with the protection of health and safety of users (consumers) and sometimes cover other requirements (property, environment); The technical specifications of products meeting the essential requirements set out in the directives will be laid down in harmonised standards; Application of harmonised or other standards remains voluntary; Products manufactured in compliance with harmonised standards benefit from a presumption of conformity with the corresponding essential requirements. The operation of New Approach requires that the standards offer a guaranteed level of protection with regard to the essential requirements established by the directives, and that the national authorities carry out their responsibilities for the protection of safety or other interests covered by the directive. Directive 98/34/EC defines European standards as technical specifications adopted by European organisations for repeated or continuous application with which compliance is not compulsory. Accordingly to the internal rules of these organisations, European standards must be transposed at national levels. Given that this is a dynamic process, the European Parliament and the legitimate bodies within the European Member States needs to continuously tackle the challenge of finding the right balance between

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Final report for STOA Silicone breast implants freedom of rights of individuals, manufacturing and commercial enterprise on the one hand, and the need to maximise the lessening of risk to human and environmental health on the other. It is self-evident that the EU should have the right to establish the level of health protection that it deems appropriate. In order to face this challenge, a scientifically-based risk assessment is usually considered as the first step, followed by risk management and risk communication. In other words, the scientific evaluation should be the pivotal element to confront this process. At times, the scientific evaluation does not fully clarify (with reasonable degree of certainty) the risk to be determined. Scientific uncertainty is a very common scenario, and �as previously stated�this is a dynamic situation by which the degree of scientific uncertainty may gradually change over time. In the meantime, judging what is an �tolerable� level of risk for society is a matter of political responsibility. The right answer is not always simple, and in could range from a legally binding measure to fostering a research project or publicly stating a recommendation, and all of the factors need to be taken into consideration. The procedure tailored to provide solid basis for the right answer should be transparent and should involve all interested parties. The team responsible for this commissioned work has tried (to the extent reasonably feasible) to fulfil this transparent desire of involving the interested parties in the area of silicone implants in order to summarise the different views, but it may be well the case that the European Parliament finds the need to consider other sources of information to add to this effort. Moreover, issues like the one analysed in this report may need to be revisited periodically (in the light of new scientific data). The Commission of the European Communities has recently (February 2000) prepared a Communication on the �Precautionary Principle� which is a good reference for this purpose. Accordingly to this document, where action is deemed necessary, measures based on the precautionary principle should be proportional to the selected level of protection (taking into account that in most scenarios it is impossible to speak of risk equal to zero), non-discriminatory in their application (which means that comparable situations should be treated in an equitable way), consistent with similar measures already taken, based on a careful examination of the potential benefits and costs of action (or lack of action), subject to review (whenever new evidence arises), and capable of assigning responsibility for producing and demonstrating the scientific data necessary for a reasonably comprehensive risk assessment (that could be articulated within the structured, formalised authorisation procedures). 3.2.4.2. Implications of new legislature In light of the previous considerations, the different alternatives would have pros and cons that we have tried to summarise in the Options section. In short, the �status-quo� is a legitimate option, given that we have a good European legislative basis in place, and there is no evidence of serious risks, but it would perhaps dismiss the perspective of self-help groups and the current areas of scientific uncertainty in the field of local complications and secondary effects. Moreover, the need for an improved harmonisation on clinical guidelines, quality assurance and informed consent is apparent. The option consisting of a complete ban on silicone breast implants could be based on the need to fully complete information regarding risks and petitions by some groups. However we also need to keep in mind the large demands by women for these implants, especially considering some problems with the main alternatives (and incomplete data on many of these alternatives). Also, studies on silicone-gel filled implants tend to be highly consistent in showing inconclusive evidence of risks of serious health concerns, and in pointing to local complications as main health concern, also present in alternative implants.

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Final report for STOA Silicone breast implants Therefore, the non-discriminatory and the consistency principles would go against this option. Finally, there would also be the potential for economic damage to industry, job losses and other social dynamics which have an impact on health (the action�s cost/benefit principle would perhaps be an element to be precisely determined). Lastly, the option consisting of no complete ban, but the adoption and implementation of critical specific measures to increase and improve information for patients, tracking and surveillance, quality control and assurance and key research (see seven proposed measures in the options section) could be reasonably consistent with the philosophy underlying the criteria of the above mentioned European precautionary principles.

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Final report for STOA Silicone breast implants 3.3. Technical File 3.3.1. Basic terminology and concepts It is essential to distinguish relevant terms. In spite of their phonetic similarity, in practical terms, we may be speaking about quite different compounds. 3.3.1.1. Silicon/Silica When we speak about Silicon, we refer to the second most abundant element in the earth's crust. In simple chemical terms this is a non-metallic (or semi-metallic) element having amorphous and crystalline forms. It is not found in its elemental form but occurs mainly as oxides and silicates. Silica is the dioxide form of silicone, also called silicone dioxide, most commonly encountered as sand. Silica is chemically resistant at ordinary temperatures but can undergo a variety of transformations at high temperatures (greater than 500ºC) and pressures. High purity amorphous silica is used as a reinforcing agent to increase the tear resistance of silicone rubbers used in medical devices and implants. 3.3.1.2. Silicone and polydimethylsiloxane (PDMS) Silicone is the name given to a family of man-made polymers (not found naturally) containing alternate silicon and oxygen atoms. Depending on the specific polymers� features, we may be speaking about different materials (fluid, resinous, rubbery, extremely stable in high temperatures, and water-repellent). These are used as adhesives, lubricants, and hydraulic oils and in electrical insulation, cosmetic, and other products. Polydimethylsiloxanes (PDMS) are prominent members of the silicone family of silicon-based organic compounds. PDMS compounds are polymers, and the length and cross-linking of the polymer chain(s) affect the physical properties of these substances. It is important to point out that implant devices have outer shells made from an elastomer, that is, a high molecular weight, cross-linked rubbery substance. In fact, most of breast implants have a silicone shell. Then there are different kinds of fillings (a sort of gel) used in these implants. Silicone gel is a less cross-linked spongy substance permeated with lower molecular weight silicone fluids. 3.3.2. General exposure to silicones. The use of silicone in medical devices There is an extensive presence of, and citizens in developed countries are widely exposed to, silicones in foods, cosmetics, lubricants for machinery, insulators, and a wide array of consumer products. Silicone is used in food processing (for example, in canned goods and ready-made meals); and as putty and sealants. Silicone is also used in domestic and personal products, such as cleaning solvents, hand cream, hair and skin products, and antiperspirants. Furthermore, silicone is incorporated in some medicines and medical devices. For example, silicone oil is commonly used as a lubricant for syringes and blood donor kits, and is utilised during surgery to repair retinal detachment. A systematic list of medical products containing silicone is included below:

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MEDICAL PRODUCTS INDUSTRY Medical-grade tubing and medical-grade elastomers, adhesives, defamers and fluids. PHARMACEUTICAL INDUSTRY Monograph and medical-grade fluids, emulsions, antifoams, adhesives and silicone rubber tubing. OTHER MEDICAL PRODUCTS Temporomandibular Joint ("TMJ") silicone products; Small Joint Orthopedic ("SJO") products; Large Joint Products ("LJO") products; Long term implantable contraceptives; Silicone fluids (injections); and silicone implant products (further details given below).

3.3.3. Breast implants. Shells and fillings. There is no such thing as a "standard" breast implant. Implants may come in a wide range of sizes, generally from 80 to 800 cubic centimeters (cc) or milliliters in volume, although 1,000-cc implants or expanders have been used on occasion. The diameter, or largest dimension, of breast implants ranges from 7.5 to 16.8 cm and the projection, or profile, from 1.5 to 7.5 cm. It should be kept in mind that these dimensions make breast implants significant foreign bodies in both surface area and volume, larger than most other alloplastic (foreign substance other than human tissue) implants, especially when placed bilaterally. Various shapes, such as round, oval, teardrop, or contoured, have been available. Implant devices have outer shells made from an elastomer, that is, a high molecular weight, cross-linked rubbery substance. In fact, most breast implants have a silicone shell. Polyurethane foam-covered implants offered an alternative regarding the outer shell, but the foam-coated type was taken off the market in 1991 because of concerns that the coating might increase the risk of cancer (due to the release of small quantities of the chemical called TDA, which has been shown to cause cancer in animals). Independent from the above shell, it is possible to find single-lumen and double-lumen implants. Some of these implants may be inflatable, so their volume can be changed during implantation using expanders specifically designed to be incrementally inflated. As for the inner materials, there are different kinds of fillings (a sort of gel) used in these implants. Silicone gel is a less cross-linked spongy substance permeated with lower molecular weight silicone fluids. Other fillers are possible and include primarily saline, but also hydrogel, trilucent and other gels. 3.3.3.1. Alternative implants accordingly to the filling material 3.3.3.1.1. Silicone gel filled implants Silicone gel breast implants are made of an outer shell of silicone elastomer filled with silicone gel. There have been three generations of implant since 1962 when they became available.

First generation implants were made with a thick silicone shell, smooth surfaced and they are filled with silicone gel (mixture of silicone solid and fluid). These implants were manufactured from the 1962 and were superseded during the mid-1970s. The principal problems associated with this implant were: gel bleed from the implant and capsular contracture.

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Second generation implants were made with a thin silicone shell, smooth surfaced and they are filled with silicone gel (high rate of gel bleed). With these implants the amount of capsular contracture was reduced, but not the gel bleed and the risk of rupture was higher. This type of implants was manufactured from the 1970s to the late 1980s.

Third generation implants were made with a thicker silicone shell, a textured surface and they are filled with silicone gel. (high rate of gel bleed). These implants presumably reduce the amount of capsular contracture, rupture and gel bleed. This type of implants was manufactured from the late 1980s to the present. 3.3.3.1.2. Saline filled implants Saline used as a filler for implants was considered a long time ago (since 1965). As for the advantages of saline filled implants, they have been perceived as more physiological, with no swelling or shrinking, while the rupture is taken up by the body itself. However they also have some clear disadvantages, including a higher deflation rate, an increased likelihood of shell folding, a greater weight, a fluid wave (�slosh effect�) with sounds that can be heard by the patient, and worse appearance than silicone gel-filled implants (thin consistency and wrinkling that is visible through the skin and/or palpable). Within the month of May, the US FDA will either approve or not approve Mentor and McGhan saline implants, based on the analysis of results from manufacturers� required reports and studies. The FDA Advisory Committee recommended their approval at a meeting held in March 2000. 3.3.3.1.3. Other implants Another option has been the so-called �Trilucent filled implants� (made with purified soybean oil), hoped safer than other implants due to biodegradable oil and transparency to x-rays. In the US, women were enrolled in a clinical study to assess this implant�s safety, and currently, FDA is analysing results. In the UK, this implant was banned in 1999 due to some reported problems and a lack of information regarding its long-term effects. This product is pending further data. Hydrogel filled implants offer new possibilities. They seem to be more consistent than saline, have natural materials, and are still �perceived� to be safe. Nevertheless, it should be kept in mind that the hydrogel is not isotonic, it takes up water and can swell up to point of rupture, and its safety not well established. Long-term studies are needed, and the risk of some toxicity is not yet ruled out. Autogenous tissue is mainly used in breast reconstruction. Such reconstruction are often combined with implants. Dermis flaps or dermis-fat-fascia grafts, musculocutaneous flat from the abdomen or from other sites, and microsurgical free flats have been used. 3.3.4 .Technical summary about silicone implants and their potential effects 3.3.4.1. Potential benefits Relevant and definite benefits in terms of health and quality of life seem to be substantial for many women demanding cosmetic breast surgery. Although women�s reasons for obtaining breast implants are not very well studied, self-confidence and comfort, increased self-esteem and self-image, a positive sense of attractiveness and social relationships are the main apparent reasons for demanding cosmetic surgery. Breast implants appear to be an effective procedure for satisfying these demands.

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Final report for STOA Silicone breast implants 3.3.4.2. Potential risks Systemic effects Cancer There are sufficiently consistent and convincing studies to support the conclusion of no association between breast cancer and implants. On the other hand, the short average follow-up time of completed studies (and the still limited evidence on this field) does not allow us to conclude whether silicone breast implants are or are not associated with other malignant neoplasms (other solid tumours, sarcoma, lymphoma, or myeloma), and the ongoing and future studies will hopefully shed light on this point. Some concern exists about potential difficulties posed by breast implants when screening mammography is taken. Radiopaque mass could obscure some breast abnormality and represent a delay in breast cancer detection. Available data do not allow definite conclusions, but increases in cancer mortality in women with implants because of diagnostic delays have not been shown. Additional mammographic views and specific care could be used to overcome these problems. Neurological diseases Neurological symptoms or disease have been reported in some case series of women with breast implants. These findings are not consistent with other experimental and observational studies. The evidence provided from epidemiological studies that silicone breast implants cause neurological signs, symptoms, or disease is insufficient. Defined connective tissue disorders These disorders of the body's immune, or defense system are mainly related to the connective tissues of the body (connective tissues include mucous, fibrous, fat, cartilage and bone tissues which support body structures and bind body parts together). There have been some concerns related to diseases such as:

�� autoimmune disorders such as lupus �� scleroderma �� rheumatoid arthritis �� fibromyalgia �� �chronic fatigue syndrome�

In summary, recently published studies have indicated that women with silicone breast implants do not have a greatly increased risk of some well-defined autoimmune diseases and/or potentially fatal connective diseases. Other systemic disorders A substantial body of women have experienced a variety of symptoms not easily definable. These symptoms include pain and swelling of joints; tightness, redness or swelling of the skin; swollen glands or lymph nodes; unusual or unexplained fatigue; swelling of the hands and feet; excessive hair loss; memory problems; headaches; and muscle weakness or burning. However, symptoms such as these may be present in persons without connective tissue disease, or without breast implants. So it is unclear at this time whether the signs and symptoms experienced by these women are related to their implants. ¨Vertical¨ Effects (mother to child) �� There is currently no evidence of elevated silicone levels in breast milk or any other substance that

would be harmful to infants, nor are there any differences in the milk and blood silicon levels between

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nursing mothers with implants and those without. There is no evidence of disease or congenital flaws resulting from silicone or any other harmful factor in breast implants crossing the placenta to the unborn child. In sum, current epidemiological studies have concluded that there does not appear to be evidence of harmful effects to infants breast-fed by women with silicone breast implants (connective tissue or related to autoimmune disorders), although more research is needed to completely rule out this risk.

Local Effects Effect derived from surgical procedures • possible complications of general anaesthesia (nausea, vomiting and fever) • Infection • Hematoma (collection of blood that may cause swelling, pain and bruising, perhaps requiring surgical

draining) • Haemorrhage (abnormal bleeding) • Thrombosis (abnormal clotting) • Skin necrosis (skin tissue death resulting from insufficient blood flow to the skin). Local effect derived from the implant device • Capsular contracture (hardening of the breast due to scar tissue) • Leak or rupture: silicone implants may leak or rupture slowly, releasing silicone gel into surrounding

tissue; saline implants may rupture suddenly and deflate, usually requiring immediate removal or replacement

• Temporary or permanent change or loss of sensation in the nipple or breast tissue formation of calcium deposits in surrounding tissue, possibly causing pain and hardening

• Shifting from the original placement, giving the breast an unnatural look • Interference with mammography readings, possibly delaying breast cancer detection by "hiding" a

suspicious lesion.

3.3.4.3. Risks & benefits: The challenging decision It seems sensible to state that the existence of potential risks associated with the intervention (silicone implants) must be weighed against the potential benefits perceived by women, so that the best legislative and policy decisions can be made. As previously stated (see 3.2.4.1.), the Commission of the European Communities has recently prepared a �Communication � on the �Precautionary Principle� (signed in February 2000) which is a good reference for this purpose. Accordingly to this document, where action is deemed necessary, measures based on the precautionary principle should be:

• Proportional to the selected level of protection (keeping in mind that risk can rarely be reduced to zero)

• Non-discriminatory in their application (which means that comparable situations should be treated differently, and that different situations should not be treated in the same way, unless there are objective reasons for doing so)

• Consistent with similar measures already taken (measures should be of comparable scope and nature to equivalent, previous situations in which scientific data are available)

• Based on a careful examination of the potential benefits and costs of action or lack of action (this understood not simply as an economic exercise, but also including non-economic considerations,

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such as the efficacy of possible options and acceptability to the public) • Subject to periodic review (whenever new evidence arises, with action plan amended when

necessary) • Capable of assigning responsibility for producing and demonstrating the scientific data necessary

for a reasonably comprehensive risk assessment (that could be articulated within the structured, formalised authorisation procedures)

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Final report for STOA Silicone breast implants 4. CITED REFERENCES 1. Berkel H, Birdsell DC, Jenkins H. Breast augmentation: a risk factor for breast cancer? N Engl J Med 1992;326(25):1649-53. 2. Birdsell DC, Jenkins H, Berkel H. Breast cancer diagnosis and survival in women with and without breast implants. Plast Reconstr Surg 1993;92(5):795-800. 3. Brawer AE. Clinical features of local breast phenomena in 300 symptomatic recipients of silicone gel-filled breast implants. J Clean Technol Environ Toxicol & Occup Med 1996;5(3):235-47. 4. Brinton LA, Malone KE, Coates RJ. Breast enlargment and reduction: results from a breast cancer case-control study. Plast Reconstr Surg 1996;2:269-75. 5. Bryant H, Brasher PH. Breast implants and breast cancer-reanalysis of a linkage study. N Eng J Med 1995;332(23):1535-9. 6. Committee on the Safety of Silicone Breast Implants of the Institute of Medicine. Safety of silicone breast implants (IoM report). Bondurant S, Ernster V, Herdman R, editors. Washington: National Academic Press; 1999. 7. Deapen DM, Bestein L, Brodi GS. Are breast-implants anticarcinogenic? A 14-year follow-up of the Los Angeles Study. Plast Reconstr Surg 1997;5:1346-53. 8. Deapen D, Hamilton A, Bernstein L, Brody GS. Breast cancer stage at diagnosis and survival among patients with prior breast implants. Plast Reconstr Surg. 2000 Feb;105(2):535-40. 9. Diamond, B.A., Hulka, B.S., Kerkvliet, N.I. et al. Silicone breast implants in relation to connective tissue diseases and immunologic dysfunction (NSP report). Independent National Science Panel, editor. USA. Federal District Judge Sam C. Pointer, Coordinating Judge for the Breast Implant Multi-District Litigation. 1998. 10. Edworthy SM, Martin L, Barr SG, Birdsell DC, Brant RF, Fritzler MJ. A clinical study of the relationship between silicone breast implants and connective tissue disease. J Rheumatol 1998;25(2):254-60. 11. Ericsson AD. Syndromes associated with silicone breast implants: a clinical study and review. J Nutr Envionm Med 1998;8:35-51. 12. Ferguson JH. Silicone breast implants and neurologic disorders: Report of the Practice Committee of the American Academy of Neurology. Neurology 1997;48:1504-7. 13. Friis S, McLaughlin JK, Mellenmkjaer L, Kjoller KH, Blot WJ, Boice Jr Jd, Fraumeni Jr JF, Olsen JH. Breast implants and cancer risk in Denmark. Int J Cancer 1997;71:956-8. 14. Gabriel SE, Woods JE, O'Fallon M, Beard CM, Kurland LT, Melton JM. Complications leading to surgery after breast implantation. N Eng J Med 1997;336(10):677-82. 15. Giltay EJ, Bernelot MH, Riley AH, Tan RG. Silicone breast prostheses and rheumatic symptoms: a retrospective follow up study. Ann Rheum Dis 1994;53(3):194-6.

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Final report for STOA Silicone breast implants 16. Gylber LO, Asplund O, Jurell G. Capsular contracture after breast reconstruction with silicone-gel and saline-filled implants: a 6 year follow-up. Plast Reconstr Surg 1990;3:373-7. 17. Herdman R and Fahey JrT. Silicone implant on cancer. Cancer Invest (submited). 2000a. 18. Herdman, R.. Personal Comunication. April, 2000b. 19. Hochberg MC, Pelmutter DL. The association of augmentation mammoplasty with connective tissue disease, including systematic sclerosis (scleroderma): a meta-analysis. Curr Top Microbiol Immunol 1996;210:411-7. 20. Independent Research Group (IRG report). Silicone Gel Breast Implants. Minister of Health in the UK, B.J., editor. England: Minister of Health in the UK. 1998. 21. Janowsky EC, Kupper LL, Hulka BS. Meta-analyses of the relation between silicone breast implants and the risk of connective-tissue disease. N Engl J Med 2000;342(11):781-90. 22. Kaiser W, Biesenbach G, Zazgornik J. Human adjuvant disease:remission of silicone induced autoinmune disease after explanation of breast augmentation. Ann Rheum Dis 1990;49(11):937-8. 23. Kern KA, Flannery JT, Kuehn PG. Carcinogenic potential of silicone breast implants: a Connecticut statewide study. Plast Reconstr Surg 1997;100(3):737-47. 24. Malata CM, Varma S, Scott M, Liston JC, Sharpe DT. Silicone breast implant rupture: common/serious complication? Med Prog.Technol. 1994;20(3-4):251-60. 25. McLaughlin JK, Nyren O, Blot WJ, Yin L, Josefsson S, Fraumeni Jr JF, Adami HO. Cancer risk among women with cosmetic breast implants: a population-based cohort study in Sweden. J Natl Cancer Inst 1998;2:156-8. 26. Nguyen, J.M., Lairy, G., and Fleurette, F.A.r. Les implants mammaires remplis de gel de silicone. Agence Nationale pour le Développement de l'Évaluation Médicale (ANDEM), editor. Paris: Service des Études. 1996. 27. Nyrén O, McLaughlin JK, Yin L, Josefsson S, Engqvist M, Hakelius L, Blot WJ, Adami HO. Breast implants and risk of neurologic disease: a population- based cohort study in Sweden . Neurology 1998;50(4):956-61. 28. Ostermeyer-Shoaib B, Patten BM. Human adjuvant disease: presentation as a multiple sclerosis-like syndrome. South Med J 1996;89(2):179-88. 29. Park AJ, Chetty U, Watson AC. Patient satisfaction following insertion of silicone breast implants. Br J Plast Surg 1996;49(8):515-8. 30. Park AJ, Black RJ, Sarhadi NS, Chetty U, Watson AC. Silicone gel-filled breast implants and connective tissue diseases. Plast Reconstr Surg 1998;101(2):261-8. 31. Patten BM, Ostenmeyer-Shoaib B. Disquisition on human adjuvant disease. Perspect Biol Med

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Final report for STOA Silicone breast implants 1995;38(2):274-90. 32. Perkins LL, Clark BD, Klein PJ, Cook RR. A meta-analysis of breast implants and connective tissue disease. Ann Plast Surg 1995;35(6):561-70. 33. Peters W, Smith D, Lugowsky S. Failure properties of 352 explanted silicone-gel breast implants. Canadian J Plast Surg 1996;4(1):55-8. 34. Robinson OG, Bradley EL, Wilson DS. Analyses of explanted silicone implants: A report of 300 patients. Ann Plast Surg 1995;34:1-7. 35. Sanchez-Guerrero GJ, Colditz GA, Karlson EW, Hunter DJ, Speizer FE, Liang MH. Silicone breast implants and the risk of connective-tissue diseases and symptoms. N Engl J Med 1995;332(25):1666-70. 36. Shanklin DR, Smalley DL. The immunopathology of siliconosis. History, clinical presentation, and relation to silicosis and the chemistry of silicon and silicone. Inmunol Res 1998;18(3):125-73. 37. Strom SS, Baldwin BJ, Sigurdson AJ, Schusterman MA. Cosmetic saline breast implants: A survey of satisfaction, breast-feeding experience, cancer screening and health. Plast Reconstr Surg 1997;100(6):1553-7. 38. Wallace MS, Wallace AM, Lee J, Dobke MK. Pain after breast surgery: a survey of 282 women. Pain 1996;66:195-205. 39. Winther JF, Bach FW, Friis S, Blot WJ, Mellemkjaer L, Kjoller K, Hogsted C, McLaughlin JK, Olsen JH. Neurologic disease among women with breast implants. Neurology 1998;50(4):951-5. 40. Zandman-Goddard G, Blank M, Ehrenfeld M, Gilburd B, Peter J, Shoenfeld Y. A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants. J Rheumatol 1999;26(1):73-7.

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OVERALL RESPONSE RATES As of 11 May 2000

Surgeons 9/11 (% response: 82%)

Sent questionnaire 21/12/99 Resent 8/3/00

Responded Didn´t respond

Kroll X Clough X Audretsch X Delay X Barreau-Pouhaer X Nava X (still missing some

information: have followed up)

Deraemaeker X Demey X Goes X Wickmann X Hinderer X Scientific Societies (Group e-mail message sent out to the below group) Sent questionnaire Responded Didn´t respond Swizerland X Portugal X Norway X New Zealand X Luxembourg X Japan X Italy X Ireland X Greece X Germany X Finland X Denmark X Belgium X Austria X IPRAS confederation X Sofcpre X Canadian Society X SECPRE X

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Final report for STOA Silicone breast implants EURAPS X NVPC X Australian Society X ISAPS (European Association of aesthetic surgery)

X

INFO X British X American Society of Plastic Surgeons/American Society for Aesthetic Plastic Surgery

From the internet

American College of Rheumatology

From the internet

National Multiple Sclerosis Society

From the internet

Mexico X Manufacturers 6/9 ( % response: 66,7%) Sent questionnaire 18/1/00, later to Dow Corning/Eucomed

Responded Didn´t respond

McGhan X Mentor X Arion X Dow Corning X EUCOMED* X Polytech X PIP X Sebbin X Nagor X * Sent information, but did not reply to structured questionnaire.

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Final report for STOA Silicone breast implants Researchers: 4/4 (100%) Individual responses sent to STOA Sent questionnaire Responded Didn´t respond Herdsman X Brinton X Eisenmann-Klein X Kees Groeneveld X Governments 12/15 ( % response: 80%) Sent questionnaire 2/2/00 Resent 8/3/00

Responded Didn´t respond

US 11/1/00 X Germany X Austria X Belgium X Denmark X Finland X France X Greece X The Netherlands X Ireland X Italy X Luxembourg X Portugal X Sweden X United Kingdom X Spain X

Self-help groups: Wrote contact petitioner Cosima Meyer 4/2/00

Responses and materials (all originals sent to STOA), organised by Self-help groups (SHG) and initials of sender

Silicone Support UK (CW) (Scotland/UK, 3 packets) Action Against Silicone Gel (RU) (UK) (6 packets) Silicone Information Network (CK), (UK, 2 packets)

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Final report for STOA Silicone breast implants Stichting Steunpunt voor Vrouwen met Siliconene borstprothesen (MB) (The Netherlands, 10 packets) German Support Group for Victims of Silicone Implants (KH) (Germany, 2 packets) Selbsthilfegruppe Silikongeschadigter Frauen e. V, Belgium (1 packet) Silicone Support Switzerland (CM) (Switzerland, 3 packets) Silicone Survivor Group, Iceland (SS) (Iceland, 1 packet) MD´S (personal account) SAG (USA, packet with information from Diana Zuckerman) IW (personal account) LM (personal account) JWE (personal account) HB (personal account) SH (personal account) EH (personal account)

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TABLES 1-5

(ORIGINAL MATERIAL FROM WHICH SUMMARY TABLES 2-5 WERE

DEVELOPED CAN BE FOUND IN ANNEXES A-C OF THIS REPORT)

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TABLE 1: Serious health effects considered in studies in relation to silicone breast implants

Health effects IRG (1998) NSP (1998) ANDEM (1996)

Breast cancer

Sufficient evidence No association

Other tumours

Limited evidence No association

Mammography and breast cancer detection

Interference No studies available on mortality differences

Defined connective tissue diseases

Sufficient evidence No relevant risk increase

Sufficient evidence No association

Inconsistency between studies Small risk increase, if exists

Atypical or novel systemic disease

Lack of good evidence Novel syndrome difficult to identify

Novel syndrome can not be identified

Difficult to define

Neurological diseases

Insufficient evidence

Risk to infants

Insufficient evidence

Local complications

Sufficient evidence Lack of precise incidence. Great variability

Sufficient evidence Very important issue Not well quantified

IRG: Independent Research Group. NSP: National Science Panel. IOM: Institute of Medicine. ANDEM: Agence National pour le Développement de l´Évaluation Médicale.

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TABLE 2: Summary of surgeons� responses

PLEASE NOTE: The surgeons who we contacted are considered to be top reconstructive surgeons and were provided to us by the Director of the Division of Epidemiology and Biostatistics at the European Institute of Oncology in Milan.

Questions Surgeon 1 (Delay: France) Surgeon 2 (Demey: Belgium) Surgeon 3 (Wickman:

Sweden) Surgeon 4 (Kroll: US)

1-Purpose silicone implants -Patients informed

-After mastectomy

-no, not much info, before crisis (1992)

-50/year aesthetic, 10/year reconstructive

-patients informed

-Every week, breast reconstruction and breast augmentation (50-70/year)

-informed, also may have to exchange

-Only saline-filled (US) for mastectomy, 2-3 times year

-Risks of leakage, capsular contract breast asymmetry

2 Major health risks

Siliconomas, but rare with good follow-up

None (minor risk: capsular contracture in 5.6% of submuscular textured implants)

Main problem (not major health risk): capsular contracture

A more important health risk: patient anxiety; use of mammogram for detecting cancer

Capsular contracture (local effect only), leading to hard or asymmetrical breast

3 Major benefits Reconstruction w/o autologous tissues & augmentation

Long-standing excellent results

Excellent �feel�

Moves and feels like ordinary breast, leakage rare

Ability to reconstruct/augment a breast with no donor site morbidity

4 View of what EP´s position on issue should be

Authorised use in Europe and France

Accept use Every country, national register, fed into European register, include complications

Only available if risks (highlighted above) are clearly disclosed

5 Alternatives to silicone

Saline (but own problems, such as deflating)

Inflatable saline (folds, deflates)

Soyabean (deflates, transform of oil)

Hydrogel (change of volume)

Saline, but harder, not as natural�saline expanders have problem of rupture and leakage

Saline (less capsular contracture) and preferred

Autologous tissue are best choice for reconstruction for most patients

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Autologous tissue

6 Other info --- Clinical trial�30% inflatable saline deflated (of 120)

After 15 years as plastic surgeon, only 2 patients with problems (autoimmune diseases)

Quality best for reconstruction with autologous tissue, provided that done correctly

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TABLE 2 (continued): Summary of surgeons� responses

Questions Surgeon 5 (Audretsch: Germany)

Surgeon 6 (Clough: France) Surgeon 7 (Hinderer: Spain)

Surgeon 8 (Nava: Italy)

1-Purpose silicone implants -Patients informed

-Regularly using implants, experience with silicone and saline since 1972, focus on implant exchange, deformity reconstruction and small breast augmentation; decrease from >100 devices/yr. 80s to <50/yr 90s

-Breast reconstruction and augmentation, about 300 cases

-Patients informed about rupture risk, capsule formation, necessity of lifetime follow-up

-Silicone: approximately 800/in 30yr

-informed about capsular contracture, surgical risks, given EQUAM consensus

-Aesthetic (200 implants/year) and reconstructive surgery (550/year)

-Patients receive information form from company (McGhan) and brochure about silicone

2 Major health risks

Capsular fibrosis, frequent repair surgery

-Rupture

-Capsule formation

Capsular contracture (only 1 of 20 at 10 years)

-Capsule (periprosthesis fibrosis reaction)

3 Major benefits

Only benefits in cosmetic surgery

-Suppleness

-Natural aspect

-Anatomic implants

Psychosocial benefits, self-esteem

Silicone gel-filled long experience and accumulated data on safety

-Patients with mastectomy: possibility of having normal social life with minimal surgery and without adding scars or using muscles; for aesthetic reasons, possibility of offering many options of shapes

4 View of what EP´s position on issue should be

Allow all implants from main manufacturers, as there is no difference regarding health influences; support and audit main registries (running one of largest in Europe for 10 years); enforce registration of all implant applications

Authorisation to market silicone implants throughout Europe

Harmonised EU standards

Need of European consensus

INCOMPLETE

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5 Alternatives to silicone

Breast conserving surgery with simple local tissue reconstruction and with coupled partial mastectomy reconstruction; autogenous reconstruction after total mastectomy or skin sparing mastectomy

-Saline implants. Unique possibility in France since ban of silicone

-Non-gel, non-saline filled implants (no experience here)

Autologous tissue (but large complications), other materials (but with less experience)

INCOMPLETE

6 Other info Forwarded questionnaire to implant registry

--- Silicone gel: better aesthetic results and safety

INCOMPLETE

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TABLE 2 (continued): Summary of surgeons� responses

Questions Surgeon 9 (Barreau-Pouhaer, France)

1-Purpose silicone implants -Patients informed

With special permission from the French Health Ministry; about 20/year gel-filled implants

---

2 Major health risks

Rupture, capsular contracture, leakage

3 Major benefits

Consistency of the breast

4 View of what EP´s position on issue should be

Silicone breast implants should be permitted.

5 Alternatives to silicone

Autologous breast reconstruction

6 Other info ---

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TABLE 3: Summary of patients� responses (n= 30)

CURRENT AGE (mean ± std. deviation) 31,2 yrs. ± 7,8 yr.

Single 66,7% CURRENT MARITAL STATUS (percent)

Married 33,3%

More than eighth grade, but not high school

13,3%

High school/Technical training 46,7%

LEVEL OF EDUCATION (percent)

University 40,0%

Breast reconstruction 13,3% TYPE OF SURGERY(percent)

Aesthetic reason 86,7%

Small breasts 76,7%

Asymmetric breasts 6,7% REASON FOR THIS SURGERY (percent)

Sagging breast, post-childbirth 16,7%

Very satisfied 73,4% LEVEL OF SATISFACTION WITH BREAST IMPLANTS (percent) Somewhat satisfied 20,0%

Indifferent (neither satisfied or dissatisfied) 3,3

Somewhat dissatisfied 3,3

No 90,0% PROBLEMS AFTER BREAST IMPLANTS

Yes (*) 10,0%

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(*) 3 cases reported problems, approximately 1 year after surgical intervention (1 capsular contracture Grade I; 1 reintervention for giving bigger size of implants; and 1 reintervention for corrective position of implant)

TABLE 4: Summary of manufacturers� responses

Questions MENTOR MCGHAN ARION

1 Position on silicone breast implants in light of current debate on safety

Safe and effective (product data sheet)�extensive database to demonstrate safety

Always inherent risks with any implant, as well as implant procedures

Independent reviews comprehensive (NSP, IOM, IRG studies), McGhan includes reference to such studies in product information.

McGhan´s position is that silicone breast implants as medical device have a proven safety record.

Long term local complications, breast granulomas from leakage of silicone gel, frequent re-operations and partial mastectomy.

Arion stopped manufacturing silicone gel-filled implants and looked for alternatives (saline serum and hydrogel cellulosique)

2 Any document on stand -Adjunct study for gel-filled mammary prostheses

-IOM report, Summary report Natl. Science Panel (NSP), IRG report, European Committee on Quality Assurance and Medical Devices in Plastic Surgery report.

-2 documents for surgeons for informing and counselling patients

-Document which sets out reasons why McGhan believes ban is unnecessary and undesirable and would deprive patients of real and especially sensitive need.

Adjunct original studies describing 35 years of experience, data on complications found (breast granulomas, and test for new materials to fill implants (carboxy methil cellulose hydrogels)

3 View of European Parliament´s position on issue

Any medical device which complies with Medical Device Directive (93/42/EEC) and bears CE marking should be available for sale

Should not be banned because of their clinical need and because they are safe.

Complete ban of production and distribution of silicone gel-filled breast implants in the EU.

Use of alternative products (saline, hydrogel).

4 Information on use or sale of implants in EU in last 5 years

Total European market last 5 years,

-1999 (100,000 implants/80,000 silicone)

80% silicone/20% saline

McGhan has 50% of total European market: (growing from 96-99) -1999: total sales of 48,777 implants,

41,161 silicone; 7,616 saline

Arion has 40% of the French market and 5-10% of European market. (approx. 22,000 breast implants).

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70%augment./30% reconstruction

5 Other information Option for women to restore breasts or have better appearance, improving self-image

---

There is excessive pressure from US manufactures in the EU market. The EU must make their own decisions. Breast granulomas are the main reason for litigation and why USA has decided to ban.

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TABLE 4 (continued): Summary of manufacturers� responses

Questions NAGOR POLYTECH SILIMED DOW CORNING

1 Position on silicone breast implants in light of current debate on safety

-Confident to say silicone breast implants are safe. Controversy was from lack of knowledge and understanding, which has now been addressed by independent studies, whose findings are consistent with Nagor´s belief that silicone implants are safe.

-Some risk inherent with any implant and risks associated with silicone implants are no greater than for other implants.

-Considers silicone implants at strongest point, due to studies which do not point to association between silicone and cancer or immune/neurological diseases

-Considers silicone breast implants safe: findings commensurate with conclusions of other scientific reviews (IRG, IOM, NSP)

2 Any document on stand

-IRG and IOM Reports, NSP Report -IRG report conclusive and summarised evidence, as well as IOM report;

-Local complications important, but also present with other implants

-Implant Information Booklet, containing extensive overview of safety of silicone breast implants

3 View of European Parliament´s position on issue

Focus of regulation: 1) improved informed consent, with info on risks & benefits/sufficient time to reconsider procedure. 2) The speeding up of updating/making improvements to existing European breast implant standard pr EN 12180 3) European Breast Implant Registry, collating information from National Registries 4) Monitoring/regulation of surgeons/standardised methods of patient follow-up

-All European countries should accept ruling on CE mark given by notified body; do not believe that product with CE mark should not be allowed to be distributed in certain countries.

---

4 Information on use or sale of implants in EU in last 5 years

-Have sold implants for 20 years in Europe (not ever including France): Majority of sales are gel-filled implants; past five years estimate 500,000 units (100,000/year)

-Mammary implants sales are between 12,000-17,000/year

-Has not manufactured silicone breast implants since 92, out of medical device business since mid-93, committed to helping answer questions about silicone

5 Other information

-Assessment of individual´s suitability and surgical technique of paramount importance (not just manufacturer controls)

-France has had lax manufacturing controls, which led to many problems with quality control; French are now penalising industry when they were

-One of first companies to receive CE mark, many controls practiced long before required, product information for surgeons in

---

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with quality control; French are now penalising industry when they were main defaulters

national language taken very seriously

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TABLE 5: Summary of governments� responses

Governmen 1 Have a specific legislation on silicone breast implants and/or other implants

2 Breast implants regulated? Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

Belgium No Yes, by Royal Decree of the 18/03/1999 transposing the Directive

No The legal basis exist (MDD 93/42). Need of a scientific opinion approved by expert of all countries and is necessary guidelines including criteria to verify during the procedure of conformity assessment

No

Sweden No CE-marked silicone breast implants, since 1 January 1995, are regulated in accordance with EU directive 93/42.

No We refrain from taking a position.

__

*The original, completed answers to the questionnaires from countries can be found in Annex 7.

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TABLE 5 (continued): Summary of governments� responses

Governmen 1 Have a specific legislation on silicone breast implants and/or other implants

2 Breast implants regulated? Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

Portugal Medical devices and accesories are regulated by the Decree Law no. 273/95 (Oct 23) and the Governmental Decree no. 136/96 (May 3)

Yes, transposing the EU Directive

At the present time, the registration of persons responsible for placing devices on the market is not mandatory, except the person(s) responsible for marketing medical devices falling within class 1 or custom made

--- ---

UK Not for silicone breast implants

Yes, by the Medical Device Regulations (1994 SI 3017) which implements the EU Directive (93/42/EC)

Yes. National Breast Implant Registry since 1993.

The Medical Device Agency believes that conformity with the Essential Requirements for safety and performance in the Medical Device Directive provides a sufficient framework for

See annex enclosed

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control

Spain Protocol about use of breast prothesis (Dirección Gral. de Farmacia y productos sanitarios; Nov 9, 1992)

Yes, Royal Decree 414/96 (March 1) transposing the Directive 93/42/EEC

No The legal basis exists, but a European registry for implants and more information for consumers are necessary

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TABLE 5 (continued): Summary of governments� responses Governments 1 Have a specific

legislation on silicone breast implants and/or other implants

2 Breast implants regulated? Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

Denmark No Yes, transposing the Directive 93/42/EEC

No, but they have register for orthopaedic implants and pacemakers

It is important to regulate these products in order to prevent risky products being introduced in the absence of surveillance, based on legislation

The standard for product safety should be very strict, particularly for �new products.� The documentation of product safety should be substantial and elaborated according to acknowledged scientific standards

Greece No, except animal and human tissue which are regulated by the Transplantation Committee at the Health Ministry

Yes Not yet. They are planning to proceed for to register high risk implants, used by the Hospitals

They believe that the EP should issue an Alert Report stating the risk and requiring physicians to inform patients �

They suggest that in addition to silicone breast implants attention should be paid also to other implants made from silicone

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The Netherlands No Yes Not yet Implant registry, information exchange

See annex: Health Council of the Netherlands: Committee on Silicone Implants. Health Risk of Silicone Breast Implants. The Hague: Health Council of the Netherlands, 1999, publication no. 1999/16

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TABLE 5 (continued): Summary of governments� responses

Governments 1 Have a specific legislation on silicone breast implants and/or other implants

2 Breast implants regulated? Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

Germany No Yes (EU Directive 93/42/EEC transposed into national legislation); also, use ¨Ordinance on the Installation, Operation and Use of Medical Devices;¨ ¨Guidelines for conformity assessment of breast implants according to Directive 93/42/EEC are expected to be taken into account.

No, but there is one established by one of the medical societies (Study group for reconstructive surgical procedures in gynaecology), which operates on a voluntary basis (does not include all implants in Germany).

General ban not necessary. Certain indications and patients´ right to self-determination justify use despite residual risks. Risks may be directly associated with implant or surgical procedure; they can also be influenced by patient-specific parameters.

Strict indications important for certain risk groups. Preoperative comprehensive information about associated problems/risks, and postoperative care are necessary (breast implants patient information and consent form). Patients should have opportunities for intensive talks with physician, access to written patient info, and a period of days of thought for making an informed decision.

Luxembourg No 93/42/EEC directive has been transposed according to regulations

Our country does not have an implant registry

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Governments 1 Have a specific legislation on silicone breast implants and/or other implants

2 Breast implants regulated? Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

Finland No (yes for some other imNot regulated, but EU directive 93/42/CEE is transposed

No, but there is a Law on Medical Devices (1505/94 and act 1506/94) which requires every health care professional who implants this kind of device to have a registry in his/her clinic to identify implant recipients in case of problems.

There is a current study on cohort of breast implant recipients, from 1960s-1998.

EU should take active role in regulating silicone breast implants in Europe. Long-term effects unknown (on women and offspring). Rupture increases with length of implant, and can happen silently (without knowledge by women), and local complications are problems. Good choice for reconstruction, too risky for augmentation. Difficult to obtain information about

Without knowledge of long-term effects, breast implant registries should be established to find out 1) possible diseases and long-term effects in women and offspring; 2) real rupture rate of breast implants; 3) rate of encapsulation

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implants before operation (Hovi 1999)1. Problems with soya bean oil filled implants example of possible consequences without experience (rupture, chemical reactions, etc.).

TABLE 5 (continued): Summary of governments� responses

1 Hovi Sirpa-Liisa, Hemminki Elina, Swan Shanna H., Cosmetis and postmastectomy breast implants: Finnish women�s experiences. Journal of women�s health and gender-based medicine, 8(7) 1999, 933-939.

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Governments 1 Have a specific legislation on silicone breast implants and/or other implants

2 Breast implants regulated?

Is EU Directive 93/42/CEE transposed?

3 Have a breast implant registry

4 View of what EP´s position on issue should be

5 Other info

France Yes (since May 1995, Yes (16/03/1995) But CE-marked prostheses only approved in France if a specific evaluation is demonstrated in each case. This is felt to be missing. Only salinfilled prostheses currently fulfil this requirement. MEDDEV document (from an ad hoc working group) makes operational recommendations for specific evaluation of breast prostheses.

No It seems necessary to ensure the existence of a reference procedure for evaluating breast prostheses, in order to ensure the essential health and safety requirements.

The MEEDV document could be used as the ground basis for discussion.

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STOA PROGRAMME European Parliament Directorate-General for Research Directorate A

Room SCH 04 A034 RoomASP 6D46 Schuman Building Altiero Spinelli Building Kirchberg 60, rue Wiertz L-2929 Luxembourg, B-1047 Brussels, Tel (352) 4300.22511; or Tel (32-2) 284.3812 Fax (352) 4300.22418 or 24167 Fax (32-2) 284.49.80 or 9059

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