24 octobre, 2006 13:20

March2006CitizensPetition

CITIZEN PETITION 2006P-0151/PSA 1

April 10, 2006

Dockets Management Branch

Food and Drug Administration

5630 Fishers Lane, Room 1061 (HFA-305)

Rockville, MD 20852

FAX 301/827-6870

The undersigned submits this petition under 21 C.F.R 10.35 to request the Commissioner of the Food and Drug Administration (FDA) stay the current approvable letter with conditions of any and all Premarket Applications ("PMA’s") for silicone gel-filled breast implants (SGFBIs) for an indefinite time due to the (2006) peer-reviewed published research finding significant levels of ionized platinum are released after implantation from second and third generation SGFBI’s. The risks of this non-life saving device clearly outweigh any benefits and will cause women and their children born after implantation irreparable injury. We request that in accordance to 21 C.F.R. 14.7, the Commissioner expedite the review of this petition and make a reasonable effort to render a decision before any final action is taken regarding the approval of SGFBIs.

Statement of grounds

* Peer-reviewed published research by Maharaj 2004 "Platinum concentration in silicone breast implant material and capsular tissue by ICP-MS" (Exhibit A) found significant platinum levels in the connective tissue of breast implanted women. In conclusion the author states "Platinum (Pt) concentration in each group of breast implant material (gel, elastomer, double lumen, or foam) varied considerably. All materials contained much higher levels of Pt than has been reported by manufacturers… Platinum most likely occurs in implant material as hexavalent platinum (Pt) compounds, along with other ionized forms of Pt, and organoplatinum or silicon-Pt complexes. Although the concentration of Pt+6 is unknown, given the high toxicity and biological reactivity of ionized forms of Pt, any amount may be too much. A major toxicologic issue is immunogenicity, where absolute amounts have little significance in the development of allergic and immune disorders. As Pt in the form of soluble salts is a potent allergic sensitizer, a "safe" dose is unknown."

* Peer-reviewed published research (2006) by Analytical Chemistry titled "Total Platinum Concentration and Platinum Oxidation States in Body Fluids, Tissue, and Explants From Women Exposed to Silicone and Saline Breast Implants by IC-ICP-MS." (Exhibit B) came to the conclusion "Women exposed to silicone breast implants had higher Pt levels by approximately 60 to >1700 x for urine, 14 x for hair, 3 x for nails, and 100 x for breast milk samples, than individuals with no known Pt exposure. Pt in explanted silicone breast implant gel, whole blood, urine, brain tissue, and breast milk samples from women exposed to silicone breast implants occurred mainly in reactive forms…Silicone breast implants are the most likely source of the elevated total Pt levels, and the reactive forms of Pt in women exposed to these devices."

* The abstract "Total platinum in urine of women exposed to silicone breast implants and in their children conceived after implantation by ICP-MS" was presented to the American Chemical Society Meeting 2005 by S.V.M. Maharaj, Ph.D. The abstract (Exhibit C) states "Inductively coupled plasma-mass spectrometry (ICP-MS) was used to determine the total platinum (pt) concentration in urine samples of women exposed to silicone and saline breast implants. Total Pt concentration was also determined in urine samples of children conceived before and after their mothers were implanted with silicone breast implants. Mean Pt concentration in urine samples of women exposed to silicone breast implants was higher [48.50 ug/L (range n.d. – 219.00); n-41] than in the general population. Mean Pt concentration in urine samples of children conceived after their mothers were implanted with silicone breast implants was higher [88.63 ug/L (range, 15.30 – 382.00); n=7] than in children conceived before their mothers were implanted [12.60 ug/L (range, 0.10 – 23.30); n= 4]." CANDO has now tested over twenty children born prior to and after their mothers were implanted with silicone gel-filled breast implants.

* A recent 2006 review by Inamed consultant Michael A. Brook titled "Platinum in silicone breast implants" produces no new peer-reviewed research but simply critiques any published research finding significant platinum levels in breast implanted women or their explants and any connection to disease by a treating physician. Brook states "Implanted women are reported to have platinum urine concentrations similar to those of unimplanted women…the half-life of platinum in vivo is relatively short (<3 days), although there is some evidence that workers with these very high exposures take considerably longer to rid the Pt from their system than the average population." It should be noted that these statements are based on a letter to the editor of a journal and not peer-reviewed research. Brook further notes "Non-peer-reviewed data provided by Mentor to the FDA as part of their submission for approval of a new implant design is available. Platinum release profiles into the biological medium porcine serum, a system that may approximate the constitution of the human breast cavity, showed Pt loss over 120 days of 4.1. ug of a total 529 ug in a 125 cm3 implant silicone. The oxidation state of the platinum was shown by X-ray absorption to be Pt(0)." At the April 2005 FDA advisory panel, one of the panel members Stephen Li, PhD, president of Medical Device Testing and Innovations stated "My own experience with X-Ray absorption is that it can’t tell you the valence state." Brook concludes "The experimental evidence supports the conclusion that there are no clinical consequences of the platinum in silicone breast implants, which is to be expected based on the known toxicity of this metal in this oxidation state (zero)." To support this conclusion Brook uses the 1999 IOM Report and the 2002 FDA article. Both reports merely reviewed the published literature on platinum in breast implants and non-peer-reviewed statements by the manufacturer’s of breast implants and their paid consultants. The large studies to date looked only for cancer rates and autoimmune or connective tissue diseases among breast implanted women. No questions were asked regarding neurological disease or known symptoms to toxic and hyper-sensitizing platinum exposure. If no independent research is conducted, then a "review" of the literature finds no "clinical consequences". Ernest Lykissa, Ph.D., forensic toxicologist states the following "Brook has made certain statements that clearly demonstrate his primary interests which are not the advancement of science, and definitely he is not driven for the public welfare. He is a hired consultant by the manufacturers of silicone breast implants. He puts no scientific evidence forth, as to how old aged silicone explants have sickened thousands of women in the USA and the rest of the world, but rather he continues in restating whatever evidence is declassified that applies only to brand new devices never implanted in the human body. He criticizes peer reviewed scientific data that has been published in some of the most important scientific journals in the world, but his challenges are mere opinions propagated by his employers. Our current publication in Analytical Chemistry (2006) finally arrives with ample evidence for the cause of ill health effects from these devices. The platinum catalyst that has been incorporated into the silicone gel component of the implants is being released from the depolymerized silicone gel and in the ionized form it is free to attack the human tissues, including the nervous system. I hope that this new research will alert the women and their physicians in evaluating very carefully their options, and it will shed some light to the dilemma that has been plaguing the women that were left uninformed by the manufacturers of these devices, as to the dangers that were hiding behind these prosthetic devices that were purported to offer aesthetic enhancements of their appearance."

* At the 2005 FDA advisory meeting Inamed stated that their implants did not leak platinum. Their methodology was determined to be irrelevant. Both Inamed and Mentor submitted unpublished data on brand new implants never implanted in the human body. Lykissa and Maharaj (2006) comes to the conclusion "the platinates utilized in the manufacture of the silicone gels of silicone breast implants were neutralized with vinyl binding that detached in the reactive, hot organosilicone oil mixture…all heavily crosslinked organosilicone envelopes (used in silicone- and saline breast implants, and in testicular implants) catalyzed with ionized Pt would be expected to undergo degradation and depolymerization with aging. Depending on the amount of ionized Pt that is liberated by the degradation process, proteins may become vulnerable to denaturation."

* Subject #3 in the Lykissa and Maharaj (2006) research had 1993 Mentor H.S. Siltex, Lot #65789, Catalog #354-4007 low bleed gel-filled third-generation implants which document the release of ionized platinum. Additional subjects who had third generation implants and their children born after implantation have been tested and found to have ionized platinum in their urine or breast secretions. They include the following:

* ExhibitD Subject #47 Still implanted with 1997 Mentor H.S. Siltex Low Bleed gel 450 cc breast implants Cat. No. 354-4507, Style 7000 Round, Lot 147384 Platinum urine results by ICP-MS 6.2 ug/l (speciation zero (0) 57%, +4 = 43%) Subject #47a Son born 7/5/01 after implantation Platinum urine results by ICP-MS 81.2 ug/l (speciation zero (0) 59%, +4 = 41%) Exhibit E

Subject #53

Explanted 2/2/06 of 1990 Third-generation gel-filled breast implants Platinum urine results by ICP-MS <0.01 ug/l Platinum results from right breast secretion by ICP-MS 32.5 ug/l Platinum results from left breast secretions by ICP-MS 7.5 ug/l Platinum ionization by IC-ICP-MS of breast secretions (speciation zero (0) 34.4%, +2 =61.2%, +4 =4.4% Platinum results from breast fat tissue taken at time of explantation 1.7 ug/l

* Michael Harbut, M.D., MPH, FCCP with the Center for Occupational and Environmental Medicine states "I have treated over 1,000 women with breast implants and have regularly seen the diseases caused by platinum salt exposures. As I published in 1999, women with exposure to platinum salts via their implants commonly present with shortness of breath, asthma, itching, rhinitis, memory loss, gastrointestinal disturbances, sometimes pulmonary fibrosis and sometimes COPD, among other, less common presentations."

* Claudia S. Miller, M.D., M.S., a board certified internist, allergist, and immunologist published research (1999) using a validated screening questionnaire for Toxicant-induced Loss of Tolerance (TILT) called the Quick Environmental Exposure and Sensitivity Inventory (QEESI) to study 87 people with surgical implants, three-quarters of whom had received breast implants. Miller found that compared to controls, implant recipients reported many more, and more severe, adverse responses to everyday chemical exposures. Further, implant recipients reported far more severe reactions to a wide variety of foods, medications, and other common exposures than did controls (Exhibit F). For more than a decade, Dr. Miller research has focused on people who report developing chronic, multi-system symptoms – headaches, memory and concentration difficulties, depression, fatigue, fibromyalgia, gastrointestinal problems, etc. – following an identifiable environmental exposure.

2. Conclusion

In light of new peer-reviewed published research discussed above and the known association between Pt salt exposure with positive skin patch tests, contact dermatitis, asthma, immunogenicity, inhibitory effects on brain enzymes, neurotoxicty, mutagenicity, carcinogenicity, and anaphylactic reactions as well as the high failure and gel bleed factor of silicone breast implants, it would be in the public interest for the Commissioner to stay the current approvable letter with conditions of all PMA’s for SGFBIs using platinum as a catalyst.

3. Environmental Impact

This petition qualifies for categorical exemption under 21 C.F.R. 25, 15, 25.30-32

from the preparation of an environmental assessment.

4. Economic Impact

A statement of the economic effect of the petition will be submitted if deemed necessary by the Commissioner.

5. Certification

The undersigned certifies that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner that are unfavorable to the petition.

Marlene Keeling, President

Chemically Associated Neurological Disorders

P.O. Box 682633

Houston, Tx. 77268-2633

281/444-0662 (281/444-5468 FAX) e-mail keeling.m@worldnet.att.net

Exhibits

Exhibit A:

Maharaj, SVM. Platinum concentration in silicone breast implant material and capsular tissue by IVP-MS. Anal Bioanal Chem (2004) 380: 84-89

Exhibit B:

Lykissa, ED, Maharaj, SVM. Total Platinum Concentration and Platinum Oxidation States in Body Fluids, Tissue, and Explants from Women Exposed to Silicone and Saline Breast Implants by IC-ICP-MS. Analytical Chemistry (published on-line April 1, 2006)

Exhibit C:

Maharaj, SVM, Lykissa, ED. Total platinum in urine of women exposed to silicone breast implants and in their children conceived after implantation by ICP-MS. Abstract presented to the American Chemical Society Meeting 2005

Exhibit D:

Lab reports for Subject #47 and 47a (son born 7/5/01 – four years after Mother’s implantation and tested for urine platinum on 5/4/05)

Exhibit E:

Lab reports for Subject #53

Exhibit F:

Miller, CS, Prihoda, TJ. A controlled comparison of symptoms and chemical intolerances reported by Gulf War veterans, implant recipients and persons with multiple chemical sensitivity. Toxicology and Industrial Health (1999) 15, 386-397

___________________________________________________________________________

Food and Drug Administration

Department of Health and Human Services, Rm 1061

5630 Fishers Lane

Rockvillle, MD 20852

FAX 301/827-6870

The undersigned submits this addendum to citizen petition 2006P-015/PSA 1 filed 4/10/2006 to request that the Commissioner of the Food and Drug Administration (FDA) stay the current approvable letters with conditions of any and all Premarket Applications (PMAs) for silicone gel-filled breast implants (SGFBIs) for an indefinite time. This addendum will address the FDA’s recently released backgrounder on platinum in silicone breast implants and letters to the editor of Analytical Chemistry by Lane and Brook. This addendum also provides a manuscript by Lykissa and Maharaj in response to the Lane and Brook letters.

• The FDA quotes the Institute of Medicine (IOM) 1999 report on platinum in silicone breast implants.
• Some of the biases in the oft quoted IOM 1999 report include the following:

1. The conclusion of the IOM report regarding platinum related health problems in women with silicone breast implants misleads the non-scientific reader, as it suggests that appropriate studies have been conducted and were reviewed, when in fact, if evidence is lacking for an association between platinum and health problems in women with silicone breast implants as the report states, it is because no such studies have been performed.
2. With respect to the amount of platinum in breast implants, the ‘data’ cited in the IOM report consists almost entirely of manufacturer’s non-peer-reviewed company documents, or personal communications by individuals employed by breast implant manufacturers. The one scientific publication (El-Jammal and Templeton 1995) that it did review was deemed questionable by the IOM because it showed a much higher amount of platinum in silicone gel than the ‘data’ reported by the manufacturers and state "the higher measured value is confusing". Why? Because it differed from the ‘data’ in the internal company documents, and personal communications by individuals employed by manufacturers.
3. The bias of the IOM report is evident in the outright error it makes on page 82 where it refers to Appendix B stating that allergies and asthma are not prominent in lists of problems with breast implant patients. Table B-1 in Appendix B lists symptoms reported by individual women or consumer groups (not in order of prevalence or severity). Included in this table are breathing difficulties, allergic reactions, asthma, chemical and environmental sensitivities (among many other symptoms). Many of the symptoms listed in Appendix B are common to those side effects reported in patients treated with Cisplatin.

• The IOM report is now out of date with the publication of independent peer-reviewed published research by Flassbeck, et.al. (2003), Maharaj (2004), and Lykissa and Maharaj (2006). It is no longer scientifically valid to continue citing this document with respect to the amount of platinum in implant gels or shells.
• The FDA scientists (Arepalli, et.al. 2002) simply reviewed the available studies from the medical literature on platinum and breast implants and reported they did not find evidence that platinum in silicone gel breast implants causes illness. The FDA’s bias in quoting this study to imply safety is obvious when one considers that if no studies looking for platinum hypersensitivity or toxicity are conducted or published, then a review of the literature finds no evidence of a link to disease.
• The FDA’s bias is evident when they do not require the manufacturers of implants to follow the health of women who have their implants removed perhaps because of health concerns and do not require the manufacturers to test for platinum levels in breast milk or follow the health of any children born to women with implants while enrolled in a clinical study.
• All women who received silicone gel-filled implants after 1992 had to enroll in a clinical study. It has been reported by a hospital ethics board to the FDA that it appeared these poorly designed clinical studies were simply a "political means" to keep gel-filled implants on the market. Consumers should have 14 years of data on "third-generation" implants at this point. Why does the FDA allow the manufacturers to present only one, two, and three years of data to determine safety?
• In a review of the Flassbeck, et.al. research, the FDA notes that a larger study is needed to establish the significance of these results. Since the year 2003 when this research was published, why has the FDA taken no action to require the manufacturers of breast implants to conduct this larger study on platinum levels in the fat tissue of women who have their implants removed?
• In a review of the Maharaj (2004) research, FDA declares the study seriously flawed. We strongly object to the term "seriously flawed" in reference to peer-reviewed papers published by scientists not associated with manufacturers and published in high quality analytical chemistry journals. For example, Maharaj (2004) is the most comprehensive peer-reviewed scientific publication to date regarding the amount of platinum in silicone breast implants. Also, for the first time in a peer-reviewed journal publication, Maharaj (2004) provided platinum values for some of the shell types. However, the FDA suggested the entire study was "seriously flawed", when in fact, it had limitations (like all studies), and in this case it was regarding the use of control tissue samples. The use of such language by the FDA is another example of bias and intentionally misleads the consumer. This statement should be removed. Since this research was published in 2004, why has the FDA not required studies by the manufacturers of removed silicone gel-filled breast implants or the surrounding breast/scar tissue for platinum content?
• Limited funding did not provide for a large number of control samples from women without implants in the Lykissa and Maharaj (2006) peer-reviewed published research. Of the five control samples that were provided, the FDA has apparently dismissed the significance that the platinum was in the zero (0) oxidation state while all nine silicone gel-filled implanted women’s samples reported had up to a +4 oxidation state. The editorial in Analytical Chemistry on 8/1/06 state, "Perhaps the speciation results of this paper are correct – even though the data are startling." The data are "startling" because oxidized platinum is capable of crossing the placental and brain barrier and carry second-generation risks.
• Raymond E. Biagini, a research toxicologist with CDC/NIOSH who has done a lot of research on platinum salts and allergy in the work place stated in 2001 "In discussion with Dow and other companies which made silicone implants, I’m relatively satisfied that they used chloroplatinic acid as a catalyst. Recent discussions with them lead to much double talk regarding the species of platinum that was used. By definition, catalysts are not changed during chemical reactions, so there is some basic problem in the chemical explanation of silicone catalysis."
• In 1995 a protective "gag" order regarding platinum discovery on breast implants was granted to Bristol-Myers Squibb Company (BMS) by Judge Sam C. Pointer. This order covered discovery related to platinum-containing substances and BMS’s testing of platinum-containing substances. All women with leaking or ruptured implants but especially women with BMS implants and their children born after implantation need to know if they might be sensitized to platinum should they develop cancer and consider treatment with a platinum containing chemotherapy drug.
• The FDA further shows their bias by quoting Brook (2006), a paid breast implant manufacturer consultant, whose published review contains no new scientific data and grossly deviates from the scientifically accepted norm. The paper cites as evidence: information from web sites, internal company documents from litigation and patents, non-peer-reviewed book chapters, and many other such substandard materials, even a book review. The FDA appears to be using this paper by Brook to dismiss the peer-reviewed published data on oxidized platinum being released from breast implants, and to perpetuate non-peer-reviewed data in the field, under the disguise of a peer-reviewed work.
• Brook in his 2006 review states that previous studies have analyzed silicone for the various species. However, no such peer-reviewed study ever analyzed an actual explant for the various forms of platinum after it came out of the human body. Lykissa and Maharaj 2006 was the first (and only) study to do so. It is suspected that the platinum used in the manufacture of the gel and shell of silicone breast implants which is reported to be neutralized with a vinyl binding, over time in the human body detaches from the binding and is leaked to all parts of the body via the lymphatic and blood systems in an oxidized state.
• Peer-reviewed papers with new scientific evidence in scholarly journals have long been the cornerstone of acceptable standards for excellence in science. The research by Flassbeck, et.al., Maharaj, and Lykissa and Maharaj, satisfy this requirement yet the FDA chooses to dismiss or ignore this important research. Lykissa and Maharaj welcome the opportunity to respond to the letters sent to Analytical Chemistry by the Dow employee Lane and the breast implant consultant Brook. Enclosed in this addendum is the Lykissa and Maharaj response titled "Response to Comments on Total Platinum Concentration and Platinum Oxidation States in Body Fluids, Tissue, and Explants from Women Exposed to Silicone and Saline Breast Implants by IC-ICPMS" which provides further clarification on experimental details that will permit the work to be reproduced. Additional work on a large number of exposed women, their children born after implantation, and an equal number of control subjects is needed to corroborate and extend the results of this important study.
• By posting the FDA Backgrounder on Platinum in Silicone Breast Implants on their website, the FDA has committed a great disservice to the public, to consumers, and to women who trust the FDA for unbiased information regarding the safety of medical devices.
• The FDA seems to choose to ignore or dismiss the following:

1. Dow notified the EPA on 12/27/96 of substantial risk to their platinum catalyst used in making breast implants. Manufacturing proprietary documents list chloroplatinic acid as an ingredient in mammary implant material formulation.
2. Oxidized platinum is one of the most allergenic substances and potent sensitizers known to man.
3. Given the hypersensitivity, toxicity, and biological reactivity of oxidized forms of platinum, any amount may be too much.
4. With oxidized platinum a major toxicologic issue is immunogenicity, where absolute amounts have little significance in the development of allergic and immune disorders.
5. A "safe" dose of oxidized platinum is unknown.
6. Both Mentor and Inamed (now Allergan) submitted unpublished data regarding platinum at the 2005 FDA advisory meeting on brand new implants never implanted in the human body.
7. Significant amounts of platinum are now being found in the urine of children born to women with silicone gel-filled breast implants (abstract submitted to the American Chemical Society Meeting, 2005). Platinum was found in the breast milk of six samples from breast implanted women. Cisplatin research has found platinum in breast milk from chemotherapy patients and it is known to cross the blood brain barrier.

In conclusion, the FDA should stay the approvable letters for silicone gel-filled breast implants, for the above reasons, until a well controlled scientific study measuring platinum levels in implants removed from the human body, fluids (including breast milk), and tissues is completed by the manufacturers of implants or by government agencies. FDA admits that implants contain platinum and before approval is given, the toxicological significance of this platinum must be determined to the developing fetus.

Women can never make an informed decision on the amount of risk they are willing to take to their health and that of their unborn children, unless the research is done. Why is the FDA considering approving a non life-saving device that has the potential to leak significant amounts of a heavy metal into their bodies, brain, and fluids without adequate research? Could the influence of this billion dollar breast implant industry be more important than the health of women and children?

The undersigned certifies that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner that are unfavorable to the petition.

Marlene Keeling, President

Chemically Associated Neurological Disorders

P. O. Box 682633

Houston, Texas 77268-2633

281/444-0662

281/444-5468 FAX

United States District Court Northern District of Alabama "Protective Order Regarding Platinum Discovery" Silicone Gel Breast Implant Products Liability. February 1995.