Letter of concern to Dr. von Eschenbach, Acting Commissioner of the FDA
April 24 2006
Andrew C. von Eschenbach, MD, Acting Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. von Eschenbach:
We are writing to urge you to carefully review new research that has important implications for medical devices that the FDA is considering for approval. Two newly published peer-reviewed studies have increased our concerns about the safety of silicone breast implants for all patients, including breast cancer patients. A new study by Dr. Louise Brinton of the National Cancer Institute (NCI), published in Epidemiology1 , found that women with breast implants for augmentation were almost three times as likely to commit suicide compared to other plastic surgery patients. A study published in Analytical Chemistry2 found extremely high levels of a potentially toxic form of platinum in the breast milk and urine of women with silicone gel breast implants.
We are especially concerned about the new platinum research because it raises serious questions about the safety of breast implants for all women who use silicone gel breast implants. Platinum is used as a catalyst in the vulcanization of the shells of silicone gel breast implants, yet implant manufacturers have repeatedly assured the FDA that the form of platinum involved is zero valence, and therefore safe. Unfortunately, the newly published study in Analytical Chemistry indicates that for at least some patients, the platinum in the women’s bodies has positive ions, and is therefore potentially toxic.
Breast cancer patients who undergo chemotherapy may already be exposed to platinum or other potentially toxic substances, so it is essential to ensure that their implants do not expose them to increased levels of dangerous substances. Since most augmentation patients are of reproductive age, the platinum found in breast milk also raises concerns about the possible health effects on breast-fed children of women with implants. We believe it would be unethical for the FDA to approve silicone gel breast implants until the agency conducts its own research on women who have silicone implants in their bodies for many years, including breast cancer patients and augmentation patients whose silicone implants have leaked. Almost all the published studies of breast implants (including the studies in Scandinavia) have been funded by Dow Corning, and are designed to minimize long-term risks. Although some of these studies include women who have had implants for long periods of time, they also include large numbers of women who have had implants for only a few weeks or months, thereby reducing the statistical power of their analyses. As you know from your leadership at NCI, cancer risks and many other kinds of health risks develop over many years and may not be apparent in the first months following exposure.
The other study, recently published by NCI’s Dr. Louise Brinton, compared women with breast implants for augmentation to other plastic surgery patients and found that women with breast implants were nearly three times as likely to commit suicide. This study was published in Epidemiology in March 2006. All the women had implants for at least 12 years, and the average length of time was 20 years. Implant makers have claimed that previously published findings of increased suicide rates were the result of depression that pre-dated the implant surgery. Although it is possible that women who choose breast augmentation have lower self-esteem or are more depressed than women who do not undergo plastic surgery, it is extremely unlikely that they feel worse about themselves than women who decide to undergo liposuction, tummy tucks, and the other types of plastic surgery chosen by women in the NCI comparison sample. For this reason, the NCI study design is superior to previous studies that compared women with implants to women in the general population.
This NCI study is the sixth3 published study to find a statistically significant increase in suicides among women with breast implants. Five of the studies were of breast augmentation patients, and one was of breast cancer reconstruction patients. Only one study, by Jacobsen et al, indicated an increase in psychiatric hospitalizations prior to getting implants, and that was in a country (Denmark) where proof of psychiatric need was required for the national health system to pay for augmentation. Therefore, women in that study may have sought psychiatric help in order to be eligible for free implants.
It is also worth noting that numerous women (and one widower) who testified at the FDA advisory panel meetings in 2003 and 2005 described pain and depression related to implant complications and health problems. In some cases, the removal of leaking silicone gel implants resulted in the loss of most of their breast tissue, so that women who had never had cancer looked like they had a mastectomy. In other cases, the removal of implants decreased their pain and improved their health, so that they no longer felt suicidal.
The NCI study also found an increase in deaths from brain cancer (relative risk of 2.07) and respiratory cancers (relative risk of 1.63). Although these might have occurred by chance, research on a sample of older women is needed to determine cancer risks from implants.
The increase in suicides reported by NCI and other studies raises important questions about the quality of life of breast-implanted women. Implant makers and plastic surgeons have testified that implants improve quality of life, but the data presented by the FDA scientists in April 2005 do not support those claims. On the contrary, on most objective measures of self-esteem and quality of life, women with breast implants rated themselves lower two years after getting breast implants than they did prior to getting implants. Reconstruction patients often reported feeling the same or worse two years later, which is especially shocking since many of those patients were coping with the fear of their cancer diagnosis and mastectomy prior to getting their implants.
In addition to this new research, we will briefly summarize our concerns about several other unanswered health questions on silicone gel breast implants.
The relationship between silicone gel breast implants and connective tissue disease has not been adequately addressed to date. An analysis by FDA advisory panel member Brent Blumenstein, PhD found that women experience a potentially significant increase in the signs and symptoms of connective tissue disease, such as joint pain and central nervous system symptoms, two years after getting silicone gel breast implants compared to before the women had implants. Dr. Blumenstein asked that the FDA conduct additional analyses because of his concerns about these findings. To the best of our knowledge, these analyses have not yet been done. We are sure that Dr. Blumenstein would be willing to discuss these concerns with you.
Neither of the two implant manufacturers with pending PMAs has adequately studied implant ruptures in reconstruction patients. Inamed’s “Core Study” included fewer than 30 breast cancer reconstruction patients who have undergone the necessary magnetic resonance imaging (MRI) testing to detect implant rupture or leakage. MRIs were conducted during the first and third year that the women had implants, which is before most ruptures occur. Mentor Corporation included 250 breast cancer patients in its Core Study but reported MRIs for only the first two years, again years before most implants break. Mentor submitted one longer-term study to the FDA, but that included absolutely no breast cancer patients at all.
This lack of data is particularly egregious in light of the fact that there are tens of thousands of reconstruction and augmentation patients available for retrospective safety studies of women with silicone gel breast implants, focused on rupture, platinum, suicide, or other health issues. There is no reason for the very small samples and limited safety information that implant manufacturers have provided to the FDA regarding reconstruction patients.
FDA scientists have repeatedly expressed concerns about the lack of long-term safety data on these products, and we share those concerns. Women will not be able to make an informed health decision because there is not enough research to determine the safety of the product. If silicone gel breast implants were to be approved, plastic surgeons estimate that most of the 400,000 women getting breast implants every year would chose silicone rather than saline, since patients would assume that the implants are safe. Given this expected surge in use, the FDA should be especially cautious before giving the “seal of approval” to a product lacking long-term safety data.
Post-market safety studies will not make up for a lack of safety research; both Mentor and Inamed have dismal track records for post-market implant studies. In 2000, FDA approved each company’s saline breast implants, based on three years of data, under the condition that Mentor and Inamed conduct an additional seven years of research on the same women. Two years after approval, when Mentor reported on its post-market studies in 2002, it had lost track of 95% of the augmentation patients and nearly half the breast cancer patients at the 5-year point in the study,5 resulting in no useful safety information. The loss to follow-up was actually even higher, because the statistics excluded 97 women (3% of reconstruction patients and 15% of augmentation patients) who had their implants removed and not replaced.
Inamed’s patient post-market follow-up rate appears stronger, but their data are also fundamentally flawed. At the 5-year point (2 years after approval) for saline implants, Inamed reported that it had no follow-up data for about 20% of both augmentation and reconstruction patients. However, the total percentage of patients lacking follow-up data was actually much higher because Inamed (like Mentor) excluded patients from the study who had their implants removed and not replaced, and did not count these patients as “missing data.” Women whose implants had been removed but not replaced accounted for 23% of their reconstruction patients and 6% of their augmentation patients.6
The Mentor and Inamed post-market studies are unacceptable because there is no information about significant numbers of patients that were originally in the study, including those who had their implants removed and not replaced. There is no justification for failing to provide information about the women who removed their implants, since those are the women most likely to have had serious complications. Inamed should have been required to collect information about the women whose implants had been removed and not replaced, and to then re-analyze their data. Mentor’s data could not be salvaged because of the very high loss to follow-up.
The lack of adequate safety research is further complicated by questions that have been raised about the integrity of the data that has been reported to the FDA. The FDA Office of Criminal Investigations is currently reviewing allegations that Mentor failed to provide the FDA with information that it was required to submit to the agency. According to these allegations, the unreported data includes a higher than reported rupture rate and records indicating a large number of missing implants that may have been inappropriately used for young augmentation patients who were not eligible to receive the products under the restrictions imposed by the FDA. The FDA should have full assurance that the company under investigation has not misrepresented data submitted to the agency and information about the company’s monitoring of the use of their silicone implants before granting that product FDA approval based on those safety data.
There is no need for the FDA to act on these applications before it has resolved these outstanding health concerns. Silicone gel breast implants are already widely available to women with breast cancer. Most breast cancer patients can choose lumpectomy or autologous tissue transfer instead of breast implants. And, although the use of silicone gel implants by augmentation patients is restricted, the American Society for Aesthetic Plastic Surgery estimates that under the current FDA compassionate use provisions, more than 58,000 augmentation patients received them in 2005. In addition, saline breast implants are approved by the FDA and are widely available.
We appreciate your commitment to patients and hope that we can count on you to ensure that the FDA proceeds very cautiously, answering these essential questions before taking any final action on silicone gel breast implants. If women’s long-term health considerations are uppermost in your mind, you will defer approval of silicone gel breast implants until such time as sufficient long-term safety data are provided by the manufacturers.
Command Trust Network
National Organization for Women
National Women’s Health Network
Our Bodies Ourselves
1 Brinton LA, Lubin JH, Murray MC, et al. Mortality Rates Among Augmentation Mammoplasty Patients: An Update. Epidemiology. 2006; Volume 17, Number 2, March 2006
2 Lykiss 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-ICPMS. Analytical Chemistry. Published on web 4/01/2006 http://pubs.acs.org/doi/full/10.1021/ac0514016.
3 At least five published studies have found a statistically significant increase in suicides among women with breast implants: Brinton LA, Lubin, JH, Burich MC, et al. Mortality among augmentation mammoplasty patients. Epidemiology. 2001; 12: 321-326. Koot VCM, Peeters PHM, Granath F, et al. Total and cause specific mortality among Swedish women with cosmetic breast implants: prospective study. British Medical Journal. 2003; 326: 527-528. Pukkala E, Kulmala I, Sirpa-Liis H, et al. Causes of death among Finnish women with cosmetic breast implants. Annals of Plastic Surgery. 2003; 51: 339-42. Jacobsen PH, Holmich LR, McLaughlin JK Mortality and suicide among Danish women with cosmetic breast implants. Archives of Internal Medicine. 2004; 164: 2450. Le GM, O'Malley CD, Glaser SL et al. Breast implants following mastectomy in women with early-stage breast cancer: prevalence and impact on survival. Breast Cancer Research. 2005.
5 Panel memorandum, Mentor Corporation Saline-Filled and Spectrum Mammary Prostheses Status of PMA Conditions of Approval. June 11, 2002. pg 3. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3876b2.htm.
6 Panel Memorandum: Inamed (former McGhan Medical) McGhan Saline-Filled Breast Implants Status of PMA Conditions of Approval June 5, 2002. pg 2, 7. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3876b2.htm.
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