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Appendix C
Review of the Reports of the Independent Review Group and the National Science Panel

Two comprehensive reviews relevant to the charge of the Institute of Medicine (IOM) Committee on the Safety of Silicone Breast Implants were released by distinguished groups of scientists and physicians (the Independent Review Group [IRG] and the National Science Panel [NSP]) while this report was being prepared. The reports of the IRG, NSP, and the IOM committee each contain information and analysis not found in the others, and each contains information, analysis, and conclusions which overlap with the others. These reports also differ to some extent in emphasis and in stating conclusions with or without qualifications. Although the reports reviewed somewhat different data from somewhat different perspectives, they are in substantial agreement. Together they form a mutually consistent body of current informed scientific work on the subject of health and silicone breast implants.

The IRG was established in response to concerns expressed by women in relation to silicone gel breast implants. This body was organized in the United Kingdom by the Chief Medical Officer at the request of the Minister of Health, Baroness Jay. The report of the IRG was available to the IOM Committee on the Safety of Silicone Breast Implants in July 1998. The NSP was established to review and critique the scientific literature on the possibility of a causal association between silicone breast implants and connective tissue diseases, related signs and symptoms, and immune system dysfunction. The panel was appointed by the Honorable Sam C. Pointer, Jr., coordinating judge for the federal breast implant multi-district litigation. Its purpose was to provide the court with an independent



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Page 505 Appendix C Review of the Reports of the Independent Review Group and the National Science Panel Two comprehensive reviews relevant to the charge of the Institute of Medicine (IOM) Committee on the Safety of Silicone Breast Implants were released by distinguished groups of scientists and physicians (the Independent Review Group [IRG] and the National Science Panel [NSP]) while this report was being prepared. The reports of the IRG, NSP, and the IOM committee each contain information and analysis not found in the others, and each contains information, analysis, and conclusions which overlap with the others. These reports also differ to some extent in emphasis and in stating conclusions with or without qualifications. Although the reports reviewed somewhat different data from somewhat different perspectives, they are in substantial agreement. Together they form a mutually consistent body of current informed scientific work on the subject of health and silicone breast implants. The IRG was established in response to concerns expressed by women in relation to silicone gel breast implants. This body was organized in the United Kingdom by the Chief Medical Officer at the request of the Minister of Health, Baroness Jay. The report of the IRG was available to the IOM Committee on the Safety of Silicone Breast Implants in July 1998. The NSP was established to review and critique the scientific literature on the possibility of a causal association between silicone breast implants and connective tissue diseases, related signs and symptoms, and immune system dysfunction. The panel was appointed by the Honorable Sam C. Pointer, Jr., coordinating judge for the federal breast implant multi-district litigation. Its purpose was to provide the court with an independent

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Page 506 assessment of the science at issue in litigation brought by women with implants against the U.S. corporations that had made and sold silicone breast implants of all major types. The report of the NSP was available to the IOM committee in December 1998. The committee reviewed the scope, process and conclusions of the IRG and NSP reports and compared them to the same aspects of its own report. The task of the IRG was "to review the evidence relating to the possible health risks associated with silicone gel breast implants, to examine the issues relating to pre-operative patient information, and to report to the Chief Medical Officer on its conclusions. Silicone injections, hydrogel filled implants, or other filling materials such as oil or saline were excluded from the remit given to the IRG." The breadth of this scope of work is similar to that defined by the statement of task for the IOM committee's study (see Chapter 1 of this report). Both projects addressed the full array of associations between breast implants and various diseases or health conditions, including local effects, neurological effects, and effects on children, toxicology, cancer, and autoimmune systemic disease. In addition, the IOM committee considered implant-related effects on screening and diagnostic mammography, reviewed research needs and made specific research recommendations, and included all silicone-shelled implants, not just those with silicone gel fill. The IRG also examined whether patient information was satisfactory and considered how good clinical practice could be ensured. A number of recommendations in these areas were made, as well as several suggestions for research programs. The NSP was asked by the court, "to what extent, if any and with what limitations and caveats do existing studies, research, and reported observations provide a reliable and reasonable scientific basis for one to conclude that silicone-gel breast implants cause or exacerbate...'classic' connective tissue diseases, such as systemic lupus erythematosus, Sjogren's syndrome, etc., 'atypical' presentations of connective tissue diseases or symptoms of immune system dysfunctions, ... and various diseases, symptoms, conditions, or complaints that have sometimes been asserted as possibly associated with silicone-gel implants." Local and perioperative complications were explicitly excluded from this charge. The NSP was also asked to exercise judgment regarding related issues that might require inclusion, the possible scientific basis for any claimed linkages, and whether others generally qualified in the panel's fields of expertise might legitimately disagree with its findings. The panel's work resulted in the examination of silicone toxicology, silicone immunology, and the epidemiology and rheumatology of possible systemic disease in women with silicone gel-filled implants, including silicone elastomer, gel, and fluid compounds that might be present in silicone gel-filled implants,

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Page 507 with some attention also to low molecular weight cyclics, silica, and platinum catalysts. This scope of work excludes most of the items defined by the statement of task for the IOM study. The NSP report did not cover breast implants other than silicone gel-filled implants, although the epidemiological studies reviewed and analyzed often either included other than gel implants or did not specify the type of implant involved. The panel report also did not examine carcinogenesis and cancer (multiple myeloma was discussed, but in the context of monoclonal gammopathy and immunology), effects on children, on mammography, pre operative patient information, or standards for clinical practice. Although local and perioperative complications were excluded from the panel's charge, and no analysis of rupture, contracture, or other local complications was performed, a few comments on infection were made. Likewise, although the NSP did not discuss the associations of silicone gel breast implants with neurologic disease, multiple sclerosis was among the connective tissue diseases examined in the report, neurologic symptoms were among the symptoms and complaints reviewed because they are sometimes asserted to be associated with silicone-gel implants, and results from a few epidemiologic studies of neurologic diseases in women with implants were reported. Finally, although the panel report pointed out problems with existing information and identified areas in which knowledge was lacking, no research recommendations were made. The Independent Review Group and the IOM were constituted differently. The seven-member IRG included expertise in law and pathology. The 13-member IOM committee included expertise in radiology, women's health, neurology, oncology, and silicone chemistry. Both groups included expertise in rheumatology and immunology, epidemiology, internal medicine, and plastic surgery. The committee's plastic surgeon limited her practice to pediatric plastic surgery and did not perform breast implantations; the IRG's plastic surgeon included silicone gel breast implantation in his practice. Efforts were made in both instances to enlist members who did not have previously expressed public views on the issues being considered, financial interests in breast implants, connections to manufacturers, or involvement in any ongoing litigation. One IRG member was, as noted, involved in breast implantation, and another had previously summarized the findings of pertinent epidemiological studies in scientific publications. The IRG was more closely tied to the the national government. It was housed and staffed by the British Medical Devices Agency (MDA), its website has a "gov.uk" address, and some information submitted to it is kept in confidence by the MDA (as noted below). The IOM committee was under the charter of the U.S. National Academy of Sciences (NAS), an independent, private, not-for-profit organization.

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Page 508 The committee met in private venues, was staffed by the IOM, and made information available to the public through its "nas.edu" website and the NAS Public Access Office. The four-member National Science Panel included expertise in toxicology, immunology, epidemiology, rheumatology, and internal medicine. The NSP membership was reviewed for any financial conflicts of interest, involvement with breast implantation or with litigation of implant matters, or previously expressed public views on the issues at hand. The panel was an ad hoc body of the court; its support came from the Federal Judicial Center, its website has a "fjc.gov" address, and its members were questioned before and after the preparation of the NSP report in a process that was videotaped and made available as testimony in breast implant litigation where relevant (Kolata, N.Y. Times, 1998). The IRG reviewed an extensive body of scientific literature. Its website reference list cites 1,026 references. The IRG relied on this body of peer-reviewed scientific reports, although only a limited number of references are actually cited in either the published or Internet version of its report. However, the IRG heard from, reviewed, and discussed publications of both those who support and those who do not support associations between silicone breast implants and the human health conditions considered. The IRG also gathered new evidence and actually commissioned investigations of some of the evidence. Plaintiff and defense submissions were reviewed, and data submitted by manufacturers, which included confidential business information, were used. Some oral evidence from patient groups, physicians, industry, and other parties at interest was heard. The IOM committee relied on its reference list of about 2,200-2,300 published, peer-reviewed scientific reports; used 1,000-1,100 selected industry technical reports, books, letters, opinion pieces, written statements, and abstracts as sources of secondary importance; and heard representations from scientists, women with implants, and other parties at interest. About 1,200 references are cited in the text of the IOM report. The committee carried out no independent scientific research investigations, and was not in a position to accept or keep proprietary information. Informational material submitted to the committee was made public. Presumably all information used by the NSP was from publicly available sources. The panel was provided with more than 3,600 documents by counsel for both parties, of which 2,000 were said to be references (Kolata, N.Y. Times, 1998), and carried out its own searches of the literature, which identified 1,600 articles, some of which were duplicates. The panel also heard multiple presentations from various invited expert scientists and physicians on three occasions over a 13-month period. The panel heard from, reviewed, and discussed the publications of both those who supported and those who did not support associations between silicone gel

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Page 509 breast implants and the human health conditions the panel was asked to evaluate. The NSP noted in its report that it relied on the peer-reviewed scientific literature, often giving secondary or no importance to abstracts. However, the report also cites, when appropriate (though seldom), textbooks and other scientific books, a presentation from an expert, and industry technical reports. The different chapters of its report cite from approximately 60 to 110 references, each. In addition, the panel did original work and made independent calculations, such as meta-analyses and recombinations of the epidemiological data and studies. The NSP report was at the request of, was prepared for, and was delivered to, the court, but it was also quickly made available to the media and, through the Internet, to interested women, scientists, physicians, and the general public. Although the IRG was funded by government and responded to the requirements of, and delivered reports to, its sponsor, the group intended the report for a wider audience, including women who had or were considering breast implants and their families; plastic surgeons and other clinicians; manufacturers; lawyers; health care policy makers; and scientists. The IOM report was originally ordered by the U.S. House of Representatives Committee on Appropriations. In addition to the National Institutes of Health, specifically the National Institute of Arthritis, Musculoskeletal and Skin Disease, the IOM report was intended to respond to the needs of other agencies of the U.S. Department of Health and Human Services; the U.S. Congress; women who had had implants, had them currently, or were considering them; their loved ones; physicians; scientists; implant manufacturers; and the general public. The preparation of an accompanying short lay version of the IOM report is emblematic of this interest. Legal issues were not addressed by the committee. The IRG and IOM reports cover essentially the same subject matter. Subjects examined included a brief history of gel implants and regulatory actions; a description of gel implants; and a review of local and perioperative effects, including contracture, infection, gel fluid diffusion, and the consequences, frequency, and detection by imaging of implant rupture. In general the IRG report contains less detail and less extensive citation. It is focused and friendly to the lay reader. The two reports are in agreement on many points in the background and descriptions of local effects. However, the IOM committee's review of the available evidence did not support the categorical conclusion of the IRG that the type of filling in an implant has not been shown to have any effect on contracture. The committee also found the evidence for exacerbation of contracture by infection still limited, whereas the IRG concluded that infection might, on occasion, exacerbate contracture. Lastly, the description of rupture, its frequency, and its consequences, by the IRG did not emphasize safety

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Page 510 concerns as did the committee's review of the available data. The committee expressed considerably more concerns about reoperations and local complications. The IRG report also analyzed and discussed systemic effects including immunological and pathological effects, among them inflammation and pathological signs of immune activity such as vasculitis; the presence of substances potentially capable of inciting immune disease such as silica; the prevalence of autoantibodies, antibodies to silicone, and T-cell responses to silica; silicone adjuvant activity; and the correlation of signs and symptoms of health conditions in women with implants with specific HLA (human lymphocyte antigen) types. The IRG report's findings of the lack of evidence or plausibility for the presence of silica in tissues of women with gel breast implants, the lack of credible evidence for specific silicone antibodies or adaptive immune responses to silica, and the failure to discover reliable biomarkers for a particular silicone associated systemic condition are generally consistent with the committee's views. Existing data do not allow the definite exclusion of systemic or local immune responses associated with silicone breast implants, but no valid scientific evidence currently establishes any such association. In fact, the nature of science is such that no scientific data can ever allow the definite and unexceptional exclusion of this possibility. The IRG commissioned an independent investigation that came to different conclusions than a report by one U.S. investigator of silica and the diagnosis of vasculitis in tissue of women with silicone implants. The IRG report reviewed epidemiological studies of defined connective tissue disease or a new systemic silicone-related disease associated with silicone gel-filled breast implants. Neurological disease, effects on children born to women with implants, toxicology, and cancer were also discussed. The IRG did not find evidence to establish an association of these conditions with silicone gel breast implants. The IOM committee also found no convincing, valid scientific evidence of such associations with gel- or saline-filled breast implants. An evaluation of the effects of silicone breast implants on mammography was not part of the IRG report. Coverage of ways of ensuring quality clinical care for women undergoing breast implantation and adequate provision of preoperative information for such women was not part of the IOM committee's charge (except insofar as the committee called for adequate informed consent) and thus was not part of its review. The body of the National Science Panel report consists of four chapters. The first chapter, "Review of Animal Studies Relevant to Silicone Toxicity," focuses on poly(dimethylsiloxane) and related silicones that are present in implants and are known to have similar chemical reactivities. Other silicones were not examined. Minimal effects by minor silicone

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Page 511 species that are seen in animals only at high levels of exposure also were not considered, nor were studies involving silicones that were administered orally or injected in relatively large doses into tissues not accessible to breast implant silicone. The panel did not find credible evidence that silicone could be degraded to silicon or silica in the body, so studies that require this result were not reviewed (e.g., studies on the toxicology of silica). The NSP examined historical studies of silicone toxicity, studies of silicones as adjuvants; a number of studies of silicones in animal models of autoimmune diseases (in great detail); and the immunotoxicology, inflammatory, and macrophage-activating effects of silicone. There was a brief examination of low molecular weight cyclic silicones, silanols, and platinum, which concluded that they have no toxicological implications for women with implants. In summary, the panel concluded that silicone is of low toxicity and that the local reaction to silicone is similar to other foreign-body reactions. Evidence of phagocytosis and transport of silicone by macrophages has not included evidence of systemic effects or adaptive T-cell activation. Adjuvant effects were not deemed by the NSP to have been shown to have biological significance, and the only immune effect was a suppression of natural killer (NK) cell activity insufficient to affect disease models. In 17 animal models of autoimmune disease, only 2 showed any effects of silicone, and these provided weak, preliminary evidence of a promotional effect. The panel concluded that the preponderance of the evidence indicated little probability that silicone induces or exacerbates systemic disease in humans. The second chapter of the NSP report, "Clinical Immunology," summarizes the clinical evidence for silicone induced immune alterations in women with silicone gel breast implants. The panel introduced the discussion in this chapter by examining again what it believed to be the weak adjuvant effect, the NK-cell effects, and the effects in animal autoimmune models of some silicones noting that in general, these effects are of uncertain biological significance. The panel then reviewed relevant studies on cytokines, NK-cell function, superantigen activity, HLA types, and T-cell activation in women with silicone breast implants; antinuclear antibodies, specific autoantibodies—including anti-collagen, antimicrosomal, anti-silicone, and antipolymer antibodies; and monoclonal gammopathy and multiple myeloma. The NSP concluded that, overall, the data do not demonstrate adaptive antigenicity of silicone, immune system activation in women with silicone breast implants, or the presence of autoreactivity in women with breast implants. Absent immune system activation, it seems unlikely that there is sufficient local inflammation to account for reported symptoms in women with silicone gel breast implants. In summary, the panel concluded that there were a number of design flaws in studies of

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Page 512 the immune system of women with breast implants and that, at the time its report was published, there were no consistent data supporting the hypothesis that silicone gel breast implants cause an alteration in systemic immune responses in women. In the third chapter of the NSP report, "Epidemiological Analysis of Silicone Breast Implants and Connective Tissue Disease," the panel discussed descriptive epidemiology and diagnostic criteria for specific connective tissue diseases; it also carried out and discussed meta-analyses of 20 epidemiological studies of silicone breast implants, including unadjusted and adjusted effect estimates and studies of "all breast implants" and "gel-only" implants. The panel calculated the power of these analyses under various circumstances and the population attributable fractions for five connective tissue diseases. Even though this was slightly inconsistent with the approach in the rest of its report, the panel concluded that analyses using all breast implants were preferable, given the problems of identification of implant type by self-reporting and the likelihood that, in the periods of time covered by currently published epidemiological studies, more than 90% of implants were gel filled (including polyurethane-coated, double-lumen, and single-lumen gel implants). The NSP's analyses were complex, and a substantial amount of data with various studies from the literature included or excluded and with various adjustments was presented. The summary relative risk estimates varied among the meta-analyses that were adjusted or unadjusted for confounding variables, those that included or did not include various studies (e.g., Hennekens et al., 1996), and those that involved all breast implants or were limited to gel implants. The panel found that these relative risk estimates demonstrated, and the most likely conclusion from these several analyses was, that there is no meaningful or consistent association between breast implants or silicone gel-filled breast implants and connective tissue diseases or other autoimmune or rheumatic conditions. The power of the analyses was adequate to detect a small increase in relative risk, on the order of 1.2-1.8 for different conditions. The fourth and concluding chapter of the NSP report, "Rheumatology: Clinical Case Definitions/Diagnoses and Clinical Associations," reviews studies of women with silicone gel breast implants that met clinical case definitions or classic, accepted diagnoses of connective tissue diseases or of atypical presentations of connective tissue disease, along with symptoms and signs for the strength of an association with silicone gel breast implants. The panel included 24 classic, accepted connective tissue diseases, as defined by explicit criteria or described in a reasonably consistent fashion in standard textbooks, in its review of the strength of association with breast implants. With one or two exceptions, the studies reviewed were the same as those used for the meta-analyses in the third

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Page 513 chapter of its report. The panel also reviewed the association between undifferentiated connective tissue disease and silicone breast implants. The one applicable study had a confidence interval with a lower limit less than one (described in the report as greater than one, but the actual result reported was less than one). The panel examined the information and reports available on novel disease associated with silicone implants as an example of the atypical presentation of connective tissue disease and decided that evidence for such a condition was insufficient. Available studies were examined for information on an association between breast implants and 48 symptoms and signs attributed to women who had had silicone breast implants. For 25 of these symptoms or signs there were no studies that contained data to review, for 17 there were no studies reporting a relative risk point estimate with a lower confidence limit greater than one, and for 6 there were discordant results (at least one, but not all studies reporting a lower limit less than one). The panel concluded that there was no appreciable association of silicone breast implants with any of the classic or accepted diagnoses, with undifferentiated connective tissue disease, or with the signs and symptoms asserted to be associated with silicone breast implants. In the case of an atypical presentation, inclusion of the exposure (silicone breast implant) in the case definition precluded evaluation since there was no possibility of comparing women with and without implants to arrive at an estimate of frequency. Furthermore, many of the signs and symptoms of the proposed condition are common and shared with a number of other conditions. No data were found and no conclusions could be reached from the literature available on the course of connective tissue disease in women with implants compared to women without implants. The IRG also reached summary conclusions that there was no conclusive evidence for an abnormal immune response to silicone from breast implants; that there was no epidemiological evidence for any link between silicone gel breast implants and any established connective tissue disease; and that there was no good evidence for the existence of atypical connective tissue disease or undefined conditions such as ''silicone poisoning." The IRG also concluded that there was no evidence that children of women with silicone gel-filled breast implants are at increased risk of connective tissue disease and that the overall biological response to silicone is consistent with conventional forms of response to foreign materials, rather that an unusual toxic reaction. In the section on toxicology, it might have been preferable to have relied on information that is available to and reviewable by others, rather than citing data that are confidential. The IRG also recommended research into the incidence of rupture and research into the nature of the symptoms of women with implants to

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Page 514 elucidate the possible role of subclinical infection. Research to validate (or not) the work of certain other investigators was suggested. The IOM committee found the IRG and NSP reports useful documents and is in general agreement with their findings. The NSP's thorough compilation and detailed descriptions and analyses of the epidemiological and immunological studies, and the insights from the careful meta-analyses, are particularly useful. The conclusions of each chapter of the NSP report were well supported by data and analysis and were conservatively stated. Although the report was focused, this was by design, and it had the advantage, as noted earlier, of allowing an in-depth approach. The IOM committee agrees with the NSP's general conclusions regarding the formation of silica from silicone in the tissue of women with implants, although a discussion of the availability and biological significance, or lack thereof, of amorphous silica from implant silicone elastomer shells would have been interesting. Also, the panel cites a "fairly high estimate" of the frequency of U.S. women with breast implants (1%) and uses this value in calculating population attributable fractions. The IOM committee's estimate is approximately 1.5% of U.S. women with silicone breast implants of all kinds (1.5 million to 1.8 million U.S. women in 1997), so the source of the NSP's estimate would be of interest. The effect of this difference on the numbers of cases of connective tissue disease theoretically attributable to implants would not be significant, however. The committee's recommendations for research differed from those of the IRG. This difference may reflect the committee's and the IRG's responses to the situation and needs in their respective countries.