Dr. Jennifer Yttri, Cancer Prevention and Treatment Fund, February 4, 2013

My name is Dr. Jennifer Yttri and I speak today on behalf of the National Research Center for Women & Families.

Our nonprofit research center includes scientists and medical and public health experts who analyze and review research to provide objective and understandable health information to patients, health care providers, and policy makers.  My PhD is in immunology from Washington University.

My statement today also reflects the written remarks of numerous members of the Patient, Consumer, and Public Health Coalition. The Coalition is comprised of nonprofit organizations united to ensure that medical treatments are safe and effective, and to enhance the scientific and public health focus of the FDA.

Thank you for the chance to speak today.  Like everyone here, we recognize the need for new drugs to reach patients with serious or life-threatening diseases but we have grave concerns about how this vaguely defined pathway will improve development of safe and effective drugs.

The FDA already has 6 pathways to quickly get drugs to patients with unmet needs. Where is the evidence that this new pathway is needed? How will it promote development of drugs that help patients live longer or have a better quality of life? Almost 50% of the drugs approved in 2009 and 2011 were through a priority pathway¹  so there are many ways to get these drugs to patients.

In the President’s Council of Advisors on Science and Technology recommendations, from which the FDA’s proposal was derived, the council said such a pathway would be ineffective without changes in the FDA’s approval and regulatory processes to protect patients.  PCAST said that the FDA would need to establish clear guidelines for clinical trials of drugs to prove benefit given serious and unknown risks. They emphasized the harm that this pathway would cause to ALL patients without a change in the FDA’s authority to regulate distribution after drug approval for one indication. Without first addressing these major changes, designing this new approval pathway is premature.

FDA currently requires adequate and well-controlled trials for drug approval.  As you know, there are inherent dangers when drugs are approved based on smaller and shorter clinical trials. The quality of the research is even more important when the study is done on a narrow population.  Small, short-term studies provide limited information about drug toxicity and safety. Small studies can also overestimate the benefits to patients.

Surrogate endpoints have become common in clinical trials, but they still need to be APPROPRIATE. A surrogate endpoint is valid only if it correlates with the outcomes patients care about which are their health, quality of life, and how long they live. The therapeutic must affect the surrogate endpoint in the same way it affects mortality and morbidity. Clarithromycin was great at killing mycobacterium, with a higher mortality in patients with AIDS. Benlysta helps some patients with lupus get rid of their rash but in exchange will leave them susceptible to severe infection or death.  Avastin slowed breast cancer progression but did not extend or improve patientss’ quality of life – in fact, it did the opposite. These are all cases where surrogate endpoints showed promise but later studies proved the opposite.

The proposed pathway can’t promise improved health, quality of life, or lifespan.  It can try to make a drug available sooner, but shorter trials will have LESS information about whether the drug accomplishes ANY of those 3 patient-centered outcomes.

Waiting for data from post-market studies to identify the safety risks means that patients will meanwhile pay for unproven treatments while serve as unwitting guinea pigs.  Patients may die or be harmed for years before post-market studies are completed.

There is an added complication for approving drugs for very small groups of patients. For many of these serious and life-threatening conditions, specific target populations cannot be readily identified prior to clinical trials. A limited population pathway provides an incentive to create smaller trials but NOT ones that use APPROPRIATE studies with the right PATIENTS.

This brings up the problem of off-label use.  If these drugs are to be used in a limited population, physicians need to prescribe these drugs only in patients who clearly fit the limited population AND have no better options.

This is unlikely to happen.  Currently, 21% of all prescriptions, and 62% of pediatric prescriptions are for unapproved use.  Once a product is approved, it is likely to be taken by many patients who are not in the targeted patient group.  Doctors will be tempted to use these drugs on any patient who might benefit, without evidence of its efficacy or risks in a broader population. In the case of antibiotics, a class of drugs likely to seek approval through this pathway, inappropriate use, even one dose, will add to the problem of antibiotic resistance, the very condition we’re trying to fight.

The goal of the proposed pathway is that, at best, only a small number of patients will be harmed by unknown risks since the approval will be for a limited population. With widespread off-label use, thousands of patients will be exposed to unnecessary harm before we understand under what conditions these drugs work and what the safety risks are.

Since 2004, there have been 28 settlements with companies that promoted drugs for unapproved use, often targeting patient populations in whom these drugs have never been tested.   Just last year, major lawsuits were settled against GlaxoSmithKlein, Johnson & Johnson, and Amgen.  This could change, but not for the better. The FDA has so far done nothing to overturn the recent case of United States versus Caronia, which decided that pharmaceutical representatives can promote off-label use under the First Amendment.

The FDA has not developed effective strategies to stop off-label promotion, and therefore will not be able to restrict the use of drugs to the approved limited populations. A study by Chen et al found that physicians were barely above chance in knowing if their prescription was off-label or for an FDA approved use – even though many of these doctors had prescribed the very same drugs for years.

Worse yet, in another study, only 15% of medical providers stated that they provided safety information to patients if it was indicated on a drug label.  A formal designation and logo will not help much at all. Even with some extended educational plan for clinicians and patients, or medical guide inserts, most patients will not fully understand to what extent the drug is proven safe or effective for their needs.

In conclusion, this poorly defined pathway would promote unproven drugs to high-risk patients. We know that there are desperate patients who are willing to take risks, but with smaller, shorter trials, you won’t be able to tell either the patients or the doctors what the risks are.  If approved based on such limited information, there is no doubt that some of these drugs would harm more patients than they help.  Patients, some of whom would never benefit from these drugs, will die or be irreparably harmed.

There are already 6 expedited pathways used in the approval of almost half of all new drugs.  I share the FDA’s desire to help patients with unmet needs to get access to drugs that could possibly help them.  I wish there were a way to do so without jeopardizing patients who have other treatment alternatives or whom we know are unlikely to benefit.  But, wishing isn’t science.  The FDA is a scientific agency, and it has not provided the science to support this proposal.

Brandel France de Bravo, Cancer Prevention and Treatment Fund, June 21, 2012

I am pleased to have the opportunity to testify on behalf of the Cancer Prevention and Treatment Fund.  We are dedicated to improving the health and safety of adults and children, and we do that by scrutinizing medical and scientific research to determine what is known and not known about specific treatments and prevention strategies.

According to a recent study in JAMA, 1 in 4 women who undergo a lumpectomy will have to have a second surgery because the pathology report found that the margins were not clear. For Ductal Carcinoma In Situ (DCIS), re-surgery rates are even higher, ranging from 21% to 50% -something we heard first hand last year when we conducted in-depth interviews with women treated for DCIS.  Most patients were thoroughly unprepared for the possibility of a second surgery and all that it entailed; and several got fed up with the surgeon not being able to “get all the cancer out,” and opted for a mastectomy that was absolutely not medically necessary. In addition to the high re-lumpectomy rates, prophylactic mastectomies among DCIS patients are on the rise. Not surprisingly, we would welcome a device that reduces the likelihood of re-lumpectomy and makes breast conserving surgery a one-time solution, as mastectomy already is. Our organization has worked on DCIS for a decade so we were very heartened to learn that in a post market study carried out in Germany MarginProbe cut the re-operation rate for women with DCIS by half.  Unfortunately, the re-operation rates in the Pivotal Study were not nearly so impressive: 20.8% in the device arm vs. 25.8% in the control arm.

In addition, we share some of the FDA’s concerns about the device, namely:

• Did the device perform better in Israel due to more extensive training prior to use, or because the design dataset was generated by an Israeli population that is not reflective of the U.S. one? Either way, what are the implications for women in the U.S.?
• Did the device perform better in the Pivotal Study because of design bias giving surgeons an additional opportunity to shave compared to the standard-of-care control arm?
• Also, why was the mastectomy conversion rate higher in the device arm? Was the slightly higher tissue volume causing women faced with re-operation to opt for mastectomy because they were dissatisfied with their appearance following the primary lumpectomy? Any future study would need to include qualitative data from patients after their primary lumpectomy and any subsequent lumpectomies regarding satisfaction with their appearance.

The FDA asks whether the device’s sensitivity is worth its poor specificity. We are somewhat less concerned than the FDA about the false positives and excessive tissue removal because that occurs with or without this device and patients can be informed about this choice.  Patients should be asked: Is it more important to you to avoid repeat surgeries or to preserve as much breast tissue as possible?

Given that routine or complete shaving of the lumpectomy cavity is just as effective at converting to negative final margins, with only slightly more tissue removed, is the device worthwhile? The FDA worries that the extra 5 minutes of intraoperative time in the device arm muddied the results, favoring the device. We believe that this is a positive aspect of the device: it forced surgeons to spend more time assessing the margins.

While many of the FDA’s concerns could be effectively addressed in a post-market study, we know from long experience that post-market studies are rarely implemented with the rigor of pre-market studies, in part because the incentives to retain patients simply are not there: why eat your veggies after you’ve already been given dessert?  Has the FDA ever withdrawn approval of a device because post-market studies weren’t carried out or because of poor results?  I don’t think so, but certainly that is rare if it happens. Given Dune’s track record of responding “too little and too late” to FDA requests, there is no reason to believe that the company will follow FDA requirements better post-market than it did pre-market.

In summary, the benefits of this device are important, and the manufacturers have provided adequate proof of safety, but that is not the only issue here. While the POTENTIAL benefits of the device clearly outweigh the risks-the main risk being the possible removal of noncancerous tissue-the device’s actual benefits have not yet been fully established for the intended use in the U.S.  At the very least, the large number of confusing outcome measures should be reduced and clarified prior to the FDA’s decision, so that patients and physicians can make an informed choice.

June 20, 2012

Statement to an FDA Advisory Committee Concerning the Approval of Semuloparin for the Prophylaxis of DVT in Chemotherapy Patients

Good morning. Thank you for the opportunity to testify on behalf of the Cancer Prevention and Treatment Fund. My name is Sonia Nagda. I am a physician, and I received my training in public health at Harvard University. Our organization is dedicated to improving the health of adults and children, and we do that by scrutinizing scientific research. We do not accept contributions from companies that make medical products, so I have no conflicts of interest.

The data that evaluate the use of semuloparin for thromboprophylaxis in chemotherapy patients is based on 1 study of 1,600 patients on the study drug. However, 36% of these patients did not complete three months on the therapy. Of these, 255 patients discontinued treatment due to adverse side effects.

Semuloparin reduced the absolute risk of DVT and fatal and nonfatal pulmonary embolism by 2.2% compared to placebo, but there are serious side effects.  There were 19 instances of major bleeding in the semuloparin group, and of these 5 were in a critical location, including pericardial, intracranial, splenic, and intraocular events, compared with no critical bleeds in the placebo group. The drug was tested in patients with colon or rectal, stomach, bladder, ovarian, lung, and pancreatic cancer, but was only found to reduce the risk of thromboembolism in patients with lung and pancreatic cancer. Because there were so few patients with each type of cancer, it would be necessary to include more patients to shed light on the impact that semuloparin has on the development of blood clots.

Many of you have already commented on the questionable heterogeneity of the patient population in the study, and it appears that the sponsor has flung a number of arrows with the hope that one of these would hit the target.

Patients in the study were most commonly on fluoururacil, cisplatin, or carboplatin, and some were on a chemotherapy regimen of more than one agent. The sponsor just provided the analysis based on this factor, and found a statistically significant reduction in the risk of thromboembolism in only 1 chemotherapy subgroup.  Further evaluation is necessary to determine which patients, if any, would derive the most benefit from semuloparin.

The secondary outcome of this study was 1-year survival, and there was no difference between the 2 groups, with 40% mortality in semuloparin patients and 41.5% mortality in placebo. This high mortality rate demonstrates the severity of illness facing these patients, and the importance of determining which patients are most likely to benefit without being subjected to additional harm.

With minimal gains in efficacy over the currently accepted treatment regimen, and with risks that should not be overlooked, particularly noting that the number needed to treat is greater than the number needed to harm, we recommend that semuloparin be studied more extensively prior to approval.  Making it available prior to determining whether there are some types of patients who are more likely to benefit could be harmful to many patients, and helpful to few.

May 31, 2012

Division of Dockets Management
Food and Drug Administration
5630 Fishers Lane, Room 1061 (HFA-305)
Rockville, Maryland 20852
Via: http://www.regulations.gov
Fax: (301) 827-6870

May 31, 2012

Comments of Patient and Consumer Coalition on Draft Guidance For Industry
“Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products”
[Docket No. FDA-2012-D-0108]

The members listed below of the Patient, Consumer, and Public Health Coalition appreciates the opportunity to comment on the draft guidance, “Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products,” which recommends that industry avoid the use of dibutyl phthalate (DBP) and  di(2-ethylhexyl) phthalate (DEHP) as excipients in drug and biologic products.

Although limiting the use of these phthalates is a step in the right direction, the draft guidance should ban the use of DBP and DEHP as excipients because these phthalates have been “shown to be developmental and reproductive toxicants in laboratory animals” and “epidemiological studies suggest certain phthalates may affect reproductive and developmental outcomes” in humans.

We are deeply disappointed that the draft guidance would still allow the packaging materials for drugs and biologic products to contain DBP or DEHP, especially since the draft guidance notes that these phthalates can leach from the packaging materials into the drugs, and that “the ubiquitous presence of phthalates in the environment and the potential consequences of human exposure to phthalates have raised concerns, particularly in vulnerable populations such as pregnant women and infants.”  Also, setting safety standards for phthalates individually or for individual products without considering their interactions and cumulative effects could underestimate the real-world risks of phthalates in the health of children and adults.

Serious Adverse Effects

Phthalates are called “endocrine disruptors” because they limit or block the body’s natural levels of estrogen, testosterone, and other hormones.

Researchers have shown that, unlike other chemicals, phthalates appear to have more serious effects at lower levels than at higher levels. It is often assumed that the higher the dose or exposure, the greater the harm, but endocrine disruptors play by different rules.  That is why the director of the National Institute of Environmental Health Sciences, Dr. Linda Birnbaum, says that chemical manufacturers are asking “old questions” when they test for safety even though “science has moved on.”

In animals, DBP and DEHP have been associated with “the disruption of the development of the male reproductive system.”¹ Research indicates that boys exposed to phthalates may be more likely to develop smaller genitals and incomplete descent of the testicles. Boys who are born with undescended testicles are 2-8 times more likely to develop testicular cancer later on than men born with both testicles descended,  Additionally, studies by Harvard researchers have shown phthalates may alter human sperm DNA and semen quality.^{, , ,} Phthalates are believed to also affect girls’ hormones, but the impact on breast cancer and other health outcomes are not yet known.

A number of research studies reveal poor health and behavioral outcomes for children exposed to phthalates.  For example, there is an association between children’s exposure to phthalates and the risk of asthma, allergies and bronchial obstruction.^,,

Mount Sinai School of Medicine researchers in 2011 studied the impact of prenatal exposure to “low molecular weight” phthalates-the kind often found in personal care products and the coatings of some medications-on the social behavior of children ages 7 to 9.  Children who were exposed to higher levels of these phthalates had worse scores for social learning, communication, and awareness.  These children were less able to interpret social cues, use language to communicate, and engage in social interactions.

Columbia University researchers in 2011 discovered that 3-year olds with high prenatal exposure to phthalates were more likely to have motor delays. They also reported that phthalates were linked to certain behavior problems in three-year olds, such as social withdrawal.

Closer Regulation of Phthalates

As noted in the draft guidance, Congress prohibits the use of DBP and DEHP in children’s toys; the European Commission prohibits their use as ingredients in cosmetics; the Environmental Protection Agency added them to the list of chemicals of concern; and the Center for Devices and Radiological Health recommends minimizing exposure to PVC devices containing DEHP.  It is past time for FDA to issue guidance on the use of phthalates as excipients.

Conclusions

The draft guidance recommends that industry should avoid the use of DBP and DEHP as excipients in drug and biologic products.  This recommendation is not strong enough.  The FDA should ban the use of DBP and DEHP in excipients especially since “safer alternatives are available.”¹ FDA should also ban the use of these phthalates in packaging materials since DBP and DEHP can leach from the packages into the drug and biologic products.  Banning DBP and DEHP will help to reduce the “widespread exposure of the general population to phthalates,” and reduce the real-world, cumulative negative effects of phthalates in the health of children and adults.¹

American Medical Women’s Association
Annie Appleseed Project
Breast Cancer Action
Cancer Prevention and Treatment Fund
Connecticut Center for Patient Safety
National Women’s Health Network
Our Bodies Ourselves
Public Citizen
Reproductive Health Technologies Project
U.S. PIRG
WoodyMatters

For more information, contact Paul Brown at (202)223-4000 or pb@center4research.org

1 Food and Drug Administration Center for Drug Evaluation and Research (March 2012).  Guidance for Industry Limiting the Use of Certain Phthalates as Excipients in CDER-Regulated Products.

2 Vandenberg et al. (2012). Hormones and Endocrine Disrupting Chemicals: Low-dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews. First published ahead of print March 14, 2012 as doi:10.1210/er.2011-1050

3 Cone, Marla and Environmental Health News. Low Doses of Hormone-Like Chemicals May Have Big Effects. Scientific American. March 15, 2012. http://www.scientificamerican.com/article.cfm?id=low-doses-hormone-like-chemicals-may-have-big-effects

4 Main KM, Skakkebaek NE, Virtanen HE, Toppari J (2010). Genital anomalies in boys and the environment. Best Pract Res Clin Endocrinol Metab.Apr;24(2):279-89.

5 Toppari J, Kaleva M. Maldescendus testis. Horm Res 1999;51:261-9

6 Duty, S. M., M. J. Silva, et al., (2003). Phthalate exposure and human semen parameters. Epidemiology 14(3): 269-77.

7 Duty, S. M., N. P. Singh, et al., (2003). The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 111(9): 1164-9.

8 Duty, S. M., A. M. Calafat, et al., (2004). The relationship between environmental exposure to phthalates and computer-aided sperm analysis motion parameters. J Androl 25(2): 293-302.

9 Duty, S. M., A. M. Calafat, et al., (2005). Phthalate exposure and reproductive hormones in adult men. Hum Reprod 20(3): 604-10.

10 Jaakkola JJ, Knight TL (2008 July). The Role of exposure to phthalates from polyvinyl chloride products in the development of asthma and allergies: a systematic review and meta-analysis. Environ Health Perspect, 116(7): 845-53.

11 Kanazawa A, Kishi R (2009 May). Potential risk of indoor semivolatile organic compounds indoors to human health. Nippon Eiseigaku Zasshi, 64(3): 672-82.

12 Hsu NY, Lee CC, Wang JY, et al. (2011). Predicted risk of childhood allergy, asthma, and reported symptoms using measured phthalate exposure in dust and urine. Indoor Air. Oct 13. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/21995786

13 Miodovnik A, Engel SM, Zhu C, et al. (2011). Endocrine disruptors and childhood social impairment.  Neurotoxicology Mar;32(2):261-7.

14 Whyatt RM, Liu X, Rauh, VA, Calafat AM, Just AC, Hoepner L, Diaz D, et al. (2012). Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor and behavioral development at age three years.  Environmental Health Perspectives 120(2):290-5

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund, May 4, 2012

Thank you for the privilege of testifying at this important hearing. I am president of the National Research Center for Women & Families, a think tank dedicated to improving the health of adults and children.  I am also testifying on behalf of our Cancer Prevention and Treatment Fund.

I was trained in epidemiology at Yale Med School, was a faculty member at Vassar and Yale, and a researcher at Harvard.  I am a fellow at the University of Pennsylvania Center for Bioethics.  My FDA expertise began as a committee staffer in Congress.

Today I will talk about our recently published study in the prestigious Archives of Internal Medicine.

We studied the recalls from 2005 to 2009 that FDA designated as the highest risk to patients because they can kill or permanently harm them.  We found that most of those devices were not approved through the PMA process.  They were cleared through the 510(k) process or exempt from review because they were thought to be such low risk.

GAO explained that FDA is ignoring the law when they clear high-risk devices through the 510(k) process.

I will explain how that harms patients.

There are 3 essential safeguards missing from the 510(k) process – that are in PMAs:

1. There are no clinical trials-testing on human patients.
2. Pre-market inspections are not required to make sure the device is made correctly
3. Post-market clinical trials or epidemiological studies are not required as a condition of approval.

Defenders of the status quo have said that what’s important is that less than 1% of device applications are later subject to a high-risk recall.

That might make sense from a business point of view, but not from the public health or policy points of view.

Americans are dying and being harmed because their devices were not tested in patients or inspected prior to sale.

As a scientist and logical person, I believe that if a device can kill you, it is not low-risk or moderate-risk. I’m not talking about lightning striking out of the blue.  I’m talking about an implant that deteriorates inside the human body.  Or a diagnostic test that is inaccurate. Those predictable life-threatening problems could be reduced.

We don’t celebrate every time we eat a meal that doesn’t poison us.  We expect all our food to be safe, meal after meal, day after day.  That’s why Congress improved food safety even though most foods were already safe.  That will save lives.  Improving how medical devices are tested will also save lives.

Devices are common.  Those of us who wear contact lenses or hearing aids, or have a replacement hip or knee, or had LASIK or Botox, or use test strips for diabetes rely on medical devices every day.

More than 430 million devices were subject to high-risk recalls in just the first 6 months of 2010-more than one device for every man, woman, and child in the U.S.

It doesn’t make sense that standards for even the most innocuous drug-for constipation, for example-are more rigorous than for life-saving medical devices.

Mr. Hall’s analysis would not meet the standards of a peer-reviewed medical journal or even of the research methods course I’ve taught.  I won’t go into details, which are in my written statement, but feel free to ask me about the flaws in his analysis.

There were almost 8,000 moderate risk recalls in the last 5 years – such as Katie’s hip.  If you add those to 113 high-risk recalls, and divide by Mr. Hall’s estimated 20,000 submissions, devices would not have a 99% safety record-it would be 60%.  If we use GAO’s lower number of recalls-almost 3,500-the safety record is still only about 82%. Moderate-risk recalled devices can result in death during surgery, and add billions to Medicare costs.   That’s why we should include those recalls when we evaluate the safety record of the medical device approval and clearance processes.

We don’t know how many people die every year from unsafe medical devices.  Hospitals are required to report deaths that might have resulted from medical devices, but doctors are not required to report them.

Even so, there were almost 5,000 reported deaths from medical devices in 2009, and hundreds of thousands of serious complications.  These are the tip of the iceberg, because most doctors don’t report these adverse reactions to the FDA, even though medical facilities are required to do so.

In conclusion, lives could be saved and patients would spend less time in the hospital if FDA implemented the law as required.  Billions of Medicare dollars could be saved.

The 510(k) process may be acceptable for devices that are truly low or moderate risk, but not for implanted devices or those that diagnose or treat potentially deadly diseases.

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund, January 5, 2012

Dr. Jeffrey Shuren, Director
Center for Devices and Radiological Health
Food and Drug Administration
Silver Spring, MD 20993

RE: FDA Needs to Provide Breast Implant Patients and Physicians with Unreported Industry Data about Quality of Life, Connective Tissue Symptoms, Rupture Rates per Patient, and Other Complications

Dear Dr. Shuren:

At the FDA Advisory Panel meetings in 2003 and 2005, FDA provided and presented data from the Breast Implant Core studies regarding connective tissue disorder (CTD) signs and symptoms (S/S) and Quality of Life measures.  The data indicated poorer outcomes for patients after implants.  Neither the previous data nor any follow-up data were presented nor discussed in the FDA’s June 2011 summary nor at the August 2011 meeting of the General and Plastic Surgery Devices Advisory Panel, when those same studies were summarized. Moreover, in direct contradiction to the 2005 FDA scientific summaries of data from the Core Studies, the 2011 FDA summary erroneously stated that there was no evidence of breast implants influencing connective tissue diseases.

We are writing to request that the data reported by FDA in 2005 be included in an updated version of the 2011 summary that is available on the FDA web site, and to ask for an explanation about why these important data were not included in the 8-year and 10-year Core Study data summaries provided to the Advisory Panel or presented in recent summary documents on the FDA web site.

At the August 31, 2011 meeting, Dr. Dana Casciotti asked that question during the public comment period.  Dr. Marinac-Dabic told Dr. Casciotti that FDA would respond later that day (pg. 371 of the transcript), but no response was ever provided at the meeting or subsequently.

At the same FDA Advisory Panel Meeting on August 30, 2011, Dr. Diana Zuckerman pointed out that both Mentor and Allergan had reported higher complication rates at 3- and 4-year follow-up according to the FDA analyses of their data in 2005, compared to their cumulative 8- and 10-year complication rates reported in 2011.  This makes no sense, since cumulative complication rates should be higher in longer-term studies than shorter-term studies.  Dr. Zuckerman also pointed out that rupture rates were mistakenly reported “by implant” rather than by patient in the FDA 2011 summary.  Five months later, that error has not yet been corrected.

In this letter, we provide those previously reported data on Connective Tissue Disease Signs and Symptoms, Quality of Life, rupture rates, and other complications from FDA 2003 and 2005 public documents. Information in quotations and italics are quoted from FDA documents, and all data and summaries are based on FDA documents.  When available, we also provide data from FDA documents presented in 2011, and show how those comparisons indicate inaccurate reporting in 2011.

Connective Tissue Disease Signs and Symptoms

According to the FDA Summary Panel Memorandum from the FDA review team of the Inamed data, dated March 2, 2005, comparing data from before and two years after getting implants, there was an increase in “5 out of 8 of the CTD S/S [connective tissue disease signs and symptoms] categories for augmentation patients, even after adjusting for age.”

The FDA memo pointed out that Inamed claimed that age accounted for these changes, which the memo stated “is incorrect” (see page 57).  That document is on the FDA web site at:  http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4101b1_tab-1_fda-Inamed%20Panel%20Memo.pdf

In the memo summary on page 59, FDA concluded (entire section is directly quoted, with key sections highlighted):

“• In evaluating whether the increases in CTD S/S from baseline were related to age, the increases in the following CTD categories occurred despite age:

o   Augmentation: Other, Skin, General, Muscle, Joint

o   Reconstruction: Other, Skin, General

o   Revision: Other, Muscle, Joint.

• The responses to fatigue questions increased by 3% from baseline; however, the prevalence of FM S/S reporting was within the range reported for the U.S. population.

• No statistical associations were found for CTD S/S reporting and implant rupture or patient satisfaction; however, lack of statistical association could have been due to the sample size rather than the lack of a relationship.

• Patients in the MRI Cohort and patients with unresolved complications tended to report higher frequencies of CTD S/S and FM S/S.

• When compared to the patients having undergone saline-filled breast implants, the increase in CTD S/S were not significantly different for patients having silicone gel-filled breast implants.

• Without a control/comparison group of patients without implants followed for the same duration of follow-up and with similar demographic characteristics, the interpretation of these data is difficult.”

In addition, at the April 2005 meeting, FDA panel member Brent Blumenstein, a statistician, indicated that the Inamed analysis was inadequate to evaluate changes in signs and symptoms when age was controlled.  According to the FDA transcript, Blumenstein stated, “The model was incorrectly fit….The bottom line is that while there exists data addressing this connective tissue disease signs and symptoms there’s no inference possible at this time.  We are still in a state of ignorance with respect to whether there are notable changes in connective tissue disease signs and symptoms following an implant.”

The FDA Summary Panel Memorandum from FDA’s Mentor PMA Review Team, March 2, 2005, is presented in tables and text, as shown below (for original, see http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4101b1_Tab-1_fda-Mentor%20Panel%20Memo.pdf )

On Page 62, the FDA memo states “The tables below summarize the cumulative incidence through 3 years of any individual sign/symptom and the two most commonly reported individual sign/symptoms for each indication.  Joint pain was one of the top two most commonly reported CTD sign/symptoms for all three surgical indications.”

Although the tables do not compare pre and post-tests, on page 63 the FDA team discusses how the incidence increased significantly:

“For augmentation patients, the following CTD signs/symptom increases from baseline were statistically significant and, therefore, were due to reasons other than aging: fatigue, exhaustion, joint swelling, frequent muscle cramps, joint pain, combined fatigue, combined pain, and combined fibromyalgia.Generalized aching was nearly statistically significant at p=0.0641.  For reconstruction patients, the GEE analysis yielded no statistically significant results.  Therefore, for the reconstruction population, it can be concluded that the increases noted in CTD signs/symptoms from baseline were due to aging.  The symptom of joint pain, however, was nearly significant at p=0.0579 for reconstruction patients.  For revision patients, the GEE analysis results indicated statistically significant findings for fatigue, generalized aching, and combined fatigue.  Therefore, for this population, the increases from baseline in fatigue and aching were due to reasons other than aging.”

Although the FDA did not mention it in their 2005 memorandum, the lack of statistical significance for the Mentor reconstruction sample may have been related to the smaller sample size.  According to the table on page 51, only 251 reconstruction patients were included in the study, less than half the number of augmentation patients (551 women).

Statistician Brent Blumenstein presented additional analyses on Mentor augmentation patients for the FDA meeting and concluded that the Mentor data were superior to previous CTD studies on breast implants, saying (from the FDA transcript for April 13, 2005) “What we have here is a well-designed study with subjects serving as their own control.  And that these findings are consistent, that is the specific list of signs and symptoms and classes of signs and symptoms are consistent with our a priori expectations, and we have adjusted for age. And also, it is important to remember that these signs and symptoms changes track well with some of the quality of life changes that we have seen.  So, in my opinion, I find these results disquieting.” Dr. Blumenstein suggested FDA require additional studies, advising “Find patients who have these high symptom scores and study these women, plus a sample of women with low scores, in a supplemental study.  You might even think about assaying tissues if you could get that.  Assess their lifestyles….put them under intense follow-up.  Find out what is going on with these women, because there is something going on here.”

It is worth noting that of the several men and women on the published list of 2011 Advisory Panel members who had participated in previous FDA Advisory Panel meetings on breast implants, Dr. Blumenstein was the only member who had consistently recommended against approval at the 2005 meeting.  Despite being listed as a Panel member for the 2011 meeting, however, Blumenstein was apparently excluded from that meeting.  His exclusion may help explain why these issues of missing Signs and Symptoms data and Quality of Life data were not raised at the 2011 Panel meeting.  His exclusion also raises questions about bias in the final roster of 2011 panel members.

Quality of Life

Despite claims that breast implants would improve self-esteem and quality of life, most of the data presented in 2005 FDA summaries do not support those claims.

In summary, for Inamed augmentation patients, 12 quality of life scores differed significantly in the pre-test and post-test.  Nine of the 12 (75%) were worse in the post-test.  For Inamed revision patients, 9 of 9 (100%) that differed significantly were worse in the post-test.  For reconstruction patients, only two scores were significantly different in the post-test, and both showed improvement in physical functioning, which probably reflects the fact that many of these women were being treated for breast cancer at the pre-test and their quality of life was better as cancer survivors two years later.

The FDA summary points out that for both Mentor and Inamed, the patients showed higher scores on quality of life than the general population, in the pre-test and post-test.  This indicates that the women who had breast implant surgery are not generally women suffering from low self-esteem or poor quality of life.

Inamed (Allergan)

Here are the details from the FDA Summary Panel Memorandum from FDA’s Inamed PMA Review Team, March 2, 2005 (http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4101b1_tab-1_fda-Inamed%20Panel%20Memo.pdf)

“With respect to the Health Status Questionnaire (SF-36 and MOS-20), the core augmentation cohort….There were small, statistically significant declines in some subscales of these measures in breast implant recipients over time.  However, the 2-year values for the augmentation cohort were generally numerically higher than normative values for the general female population” (page 71).

Although the FDA summary does not mention it, most of the significant differences showed lower scores on quality of life in the post-test.  Nine of 12 were worse for augmentation patients and nine of 9 were worse for revision patients.

Quality of Life measures include the SF-36, which measures 8 health concepts: physical functioning; role-physical; bodily pain; general health; vitality; social functioning; role-emotional; and mental health.  The 8 scales can then be collapsed into two summary scales with the first 4 scales comprising the Physical, and the last 4 scales comprising the Mental Health.

Inamed Augmentation Patients

All Statistically Significant Changes are as follows:

• SF-36 Role Emotional:  Significantly worse in post-test
• SF-36 Role Physical:  Significantly worse in post-test
• SF-36 General Health:  Significantly worse in post-test
• SF-36 Social:  Significantly worse in post-test
• SF-36 Vitality:  Significantly worse in post-test
• SF-36 Mental Health:  Significantly worse in post-test
• MOS-20 Health Perceptions:  Significantly worse in post-test
• MOS-20 Mental Health:  Significantly worse in post-test
• Tennessee Self-Concept Scale: Physical Self:  Significantly better in post-test
• Body Esteem-Total Score:  Significantly better in post-test
• Body Esteem-Sexual Attractiveness:  Significantly better in post-test
• Body Esteem-Physical Condition:  Significantly worse in post-test
• Scores on the Rosenberg Self Esteem Scale were worse in the post-test, but the difference was not statistically significant.

Allergan Reconstruction Patients

• SF-36 Role Physical:  Significantly better in post-test
• MOS-20 Physical Functioning: Significantly better in post-test

Inamed Revision Patients

• SF-36 Role Emotional:  Significantly worse in post-test
• SF-36 General Health:  Significantly worse in post-test
• SF-36 Social:  Significantly worse in post-test
• Mental Health: Significantly worse in post-test
• MOS-20 Health Perceptions: Significantly worse in post-test
• MOS-20 Mental Health: Significantly worse in post-test
• Tennessee Self-Concept Scale Physical Self:  Significantly worse in post-test
• Rosenberg Self-esteem Scale:  Significantly worse in post-test
• Body Esteem-Physical Condition:  Significantly worse in post-test

Mentor

Below are the data from the FDA Summary Panel Memorandum from FDA’s Mentor PMA Review Team, March 2, 2005 (http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4101b1_Tab-1_fda-Mentor%20Panel%20Memo.pdf)

Similar to the Inamed findings, when there were statistically significant changes from pre-test to post-test for Mentor patients, almost all were worse in the post-test compared to the pre-test.  For augmentation patients, scores on physical health and mental health were significantly worse, scores on the Rosenberg self-esteem scale were better, and there was no change on the Tennessee self-concept scores or body esteem scale.  For revision patients, scores on physical health, mental health, body esteem and Tennessee self-concept scale all were worse in the post-test, and there was no change in the Rosenberg self-esteem scale.  No scores were better in the post-test.  For reconstruction patients, there were no significant changes on any of the scales.

The data below are not as detailed as the Inamed data, because the FDA memo did not provide as much specific information.  However, it includes differences in scores that were provided by the FDA.

Mentor Augmentation Patients

• Physical Health: Significantly worse in post-test (1.0)
• Mental Health: Significantly worse in post-test (1.1)
• Tennessee self-concept scores: No significant change
• Body Esteem scale: No significant change
• Rosenberg Self-Esteem Scale: Significantly better in post-test (0.6)

Mentor Reconstruction Patients

• Physical Health: No significant change
• Mental Health: No significant change
• Tennessee Self-Concept Scale: No significant change
• Body Esteem Scale: No significant change
• Rosenberg Self-esteem Scale: No significant change

Mentor Revision Patients

• Physical Health: Significantly worse in post-test (1.8)
• Mental Health: Significantly worse in post-test (2.5)
• Tennessee Self-Concept Scale: significantly worse in post-test (6.6)
• Body Esteem Scale: significantly worse in post-test (5.0)
• Rosenberg Self-esteem scale: no significant change

FDA also noted the following about the literature review on Quality of Life information (provided by Mentor):

• Page 70: “…the literature does not provide strong scientific support that breast implants have measurable psychological and psychosocial benefits for women seeking breast augmentation.”
• Page 73: “Literature that adequately evaluates the short-term or long-term psychological or psychosocial benefits of breast implants as a reconstructive procedure utilizing appropriate control group was not provided by Mentor.”

Cumulative Complication Rates

Allergan Patients at 3 Years and 10 Years

The long-term safety data on breast implants provide data on the cumulative complication rates for a wide range of risks, including health problems and cosmetic complications.  These data provide important information that patients can use to determine if the risks of implants outweigh the benefits.  Either health risks or cosmetic complications can result in additional surgeries to remove and/or replace breast implants.

At the August 2011 FDA Advisory Panel meeting, the FDA presented data on 8-year complication rates for Mentor and 10-year complication rates for Allergan.  Rates at 3 and 4 years had previously been made available at the FDA’s 2005 Advisory Panel meetings, but were not presented in 2011 at the FDA meeting or in the FDA’s summary report.  However, the earlier data are still available on the FDA web site, and when we compared the complication rates, we discovered that numerous reported complication rates decreased over time for both companies’ data. This shows problems with the data, since the complication rates are reported to be cumulative and should therefore stay the same or increase over time.

The 3-year complication rates for Inamed/Allergan were reported in this FDA official memorandum in 2003:http://www.fda.gov/ohrms/dockets/ac/03/briefing/3989b1_clinical-summary-memo.pdf

For Allergan Primary Augmentation Patients, the following complications were reported to be lower at 10 years (N=455) than at 3 years (N=494).  That raises questions about the accuracy of reporting.  The FDA reported that the samples sizes decreased because some patients died and some withdrew from the study.  However, in order to maintain accurate reports of complications, patients who reported problems earlier in the study should not be eliminated from the later sample.  We ask that the FDA explain whether some of the patients with earlier complications were excluded from the 10-year sample, and if so, under what circumstances and how did that affect complication rates? Accuracy problems are more obvious when the reported percentages decreased over time, but even those where the percentages increased may be inaccurate.

Swelling:  23% went down to 9%

Scarring:  8% went down to 4%

Seroma:  3% went down to 2%

Ptosis:  3% went down to 2%

For Allergan Primary Reconstruction Patients, the following complications were reported to be lower at 10 years (N=98) than at 3 years (N=221).  That again raises questions about the accuracy of reporting, and whether patients with complications were excluded from the 10-year sample.

Swelling:  16% went down to 7%

Redness:  6% went down to 2%

Seroma:  5% went down to 2%

Malposition:  5% went down to 2%

Bruising:  4% went down to 1%

Skin Rash:  3% went down to 2%

Ptosis:  1% went down to 0%

Mentor Patients at 3 Years and 8 Years

For Mentor Primary Augmentation Patients, the following complications were not reported at 8 years but had been reported at 3 years, for a sample described as 551 patients in 2005 and in 2011.  Since all complications experienced by 1% or more of the sample were supposed to be reported, the absence of these reported complications at 8 years raises questions about the accuracy of reporting, and whether patients with complications were excluded from the 8-year sample even though the sample sizes reported were identical.

Hypertrophic Scarring: 6% at 3 years, not reported at 8 years

Ptosis:  2% at 3 years and not reported at 8 years

The above 3-year Augmentation Patient data are reported in the 2005 FDA Summary Panel Memorandum on page 52.

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4101b1_Tab-1_fda-Mentor%20Panel%20Memo.pdf .  The below 3-year Reconstruction Patient data are on page 53.

For Mentor Primary Reconstruction Patients, the following complications were not reported at 8 years (N=251) but had been reported at 3 years (N=251).  That again raises questions about the accuracy of reporting, and whether patients with complications were excluded from the 10-year sample even though the reported sample size is identical.

Hematoma extrusion: 2% at 3 years and not reported at 8 years

Necrosis: 1% at 3 years and not reported at 8 years

Asymmetry: 7% at 3 years and not reported at 8 years

Ptosis: 7% at 3 years and not reported at 8 years

Hypertrophic scarring: 6% at 3 years and not reported at 8 years

Redness and skin rash were reported for Allergan but not for Mentor.

In addition to the clear errors, where the cumulative percentage reporting a complication decreased or disappeared from 3 years to 8 years, these problems raise questions about the accuracy of all the 8-year data, even those where the percentages increased.  For example, while all experts agree that asymmetry increases over time, especially for reconstruction patients, Allergan asymmetry increased from 15% at 3 years to only 23% at 10 years.  Other increases in complications were also rather modest compared to patient reports: Mentor reconstruction patient reoperations increased from 26% at 3 years to 39% at 8 years and removal from 13% to 23%.  Would those numbers have been higher if the reporting was more accurate, or if patients who had problems had not been dropped from the final sample?  For example, the Allergan 10-year sample is less than half the size of the 3-year sample.  Are women who had their implants removed being removed from that sample and therefore biasing the results?  These questions are important for the Inamed and Mentor data.

Rupture Rates

FDA Memorandum June 2011

On page 10 of the FDA memorandum dated June 2011 (linked above), the implant rupture rate is reported per implant.  Those same percentages are included in Table 4 (page 53), where all the complication rates, including rupture data seem to be reported per patient, since the sample sizes are listed as the number of patients not the number of implants.  This is incorrect, since the percentage of women with ruptured implants is much higher – approximately twice as high – as the percentage of ruptured implants.

Based on the MRI cohort in the 2011 summary, the Allergan rupture rate per implant is 10% of augmentation implants and 27% of reconstruction implants.  No rupture rates per patient are reported.  At 4 years, the Allergan rupture rate per patient was almost exactly twice the rupture rate per implant, according to the March 2, 2005 FDA summary of Inamed (see link on page 3 of this document, pages 21-22).  Similarly, the Mentor rupture rate at 8 years was 14% per implant for augmentation patients and 14% for reconstruction patients, but no data per patient were reported.  At 3 years, the Mentor rupture rate per patient was approximately twice that per implant, according to the March 2, 2005 FDA summary of Mentor (see link on page 5 of this document, page 77).

The use of per implant rupture rates is misleading for patients.  When a patient’s implant ruptures, surgery is required to remove it, regardless of whether one implant is ruptured or both are ruptured.  The risks of surgery and costs to the patients are very similar whether one or two implants are involved.  Therefore, patients want to know what the chances are of having a ruptured implant, not the percentage of implants that rupture.  It is certainly important for women considering implants to know if the rupture rate is more than half the primary reconstruction patients and 20% of primary augmentation patients at 10 years.

An accurate rupture rate per patient is especially important in light of the FDA panel’s discussion about how often women with silicone implants should be advised toundergo breast MRIs to check for leakage.  It is widely acknowledged that most women do not undergo regular MRIs to check for breast implant leakage, but one would expect that to change if patients (especially reconstruction and revision patients) realized how likely it was for their implants to rupture within 10 years.

The importance of per patient rates is true for all complications.  Patients care whether they will have breast pain more than they care whether the pain will be in one or both breasts.  If complications occur that require surgery, that is an important piece of information, whether or not one or both implants are involved.  We ask FDA to clarify whether each of the complication rates reported is per implant or per patient.

The somewhat lower rupture rates for Mentor may reflect a better product or may reflect the different time frames for the analysis (3 vs. 4 years, 8 vs. 10 years).  Or, given other problems with the Mentor data, the data differences raise questions about the accuracy and generalizability of the data because of the high drop out rate.

Summary

In conclusion, we are concerned about missing information and inaccurate or misleading data that were provided to the FDA Advisory Panel on breast implants and that are included (or missing) in the June 2011 summary on the FDA web and in other recent FDA materials.

• Missing information about signs and symptoms of connective tissue disease from 2005 and the most recent follow-up data, and an inaccurate summary of earlier findings
• Missing information about poor outcome on Quality of Life measures from 2005, and missing follow-up data
• Inaccurate cumulative complication rates for at least some outcomes
• Inaccurate and misleading presentation of rupture data, which should be presented per patient rather than per implant.
• Questions about which complications are presented per implant or per patient and questions about whether women with complications at 3 or 4 years were excluded from the 8- and 10-year follow-up samples.

We expressed concern about these omissions and errors during the FDA Advisory Panel Public Comment Period in August 2011, and are very disappointed that the FDA has not corrected any of these problems in the last 5 months.  We would appreciate a response to this letter in writing, and also ask for a meeting to discuss these issues.

Sincerely,

Diana Zuckerman, Ph.D.
President

Cc:  The Honorable Barbara Boxer

The Honorable Rosa DeLauro

The Honorable Dianne Feinstein

The Honorable Olympia Snowe

Dana Casciotti, Cancer Prevention and Treatment Fund, October 24, 2011

I am the public health research director of the Cancer Prevention and Treatment Fund, a nonprofit center that uses research findings to improve prevention and treatment strategies.  Our nonprofit does not accept money from pharmaceutical or device companies so I have no conflicts of interest.

My perspective today is as someone trained in public health at Johns Hopkins and previously worked at the National Cancer Institute.  I am very familiar with clinical trials and research methodology.

You have already discussed how poor the follow-up was on the implant studies.  I was disappointed that an FDA official implied yesterday that most of the post-market studies were fine, and only a few were not.

I completely disagree.  It was not just the Mentor large study that was so outrageous after only 3 years, and Allergan barely kept half their augmentation patients after only two years.

The Adjunct studies were even worse – only 16-23% of the women were still in the studies after 5 years.  The Core Studies were slightly better, but Mentor had only 58% of their patients at 8 years, and that is not acceptable in any of the places where I have conducted research.

Our nonprofit has talked to many women who have had serious problems with their breast implants, and I am talking about recent patients, not patients from 20 years ago.  But, many of these patients have already missed work because of their illness and couldn’t take the time to be here this week.  Some told us that their kids are going back to school this week, and they need to be there.  Others didn’t even hear about this meeting in advance – it wasn’t exactly highly publicized to the general public.

But history should be our guide.  We know that most new breast implants seemed great at first.  It isn’t until years later that it becomes obvious that the “newer safer breast implants” also break and leak and cause problems.  So, it may take a few years to get a better idea about the safety of the “new cohesive gel implants” but we already know after yesterday’s testimony and from talking to many other patients that these new implants can bleed silicone into the scar capsule even when the implant is intact.  And even the new implants can break.

I also want to correct some misconceptions that were reflected in yesterday’s panel discussion.  The large studies done by Allergan and Mentor are not asking women to come to the plastic surgeon’s office every year.  Most years, they are asking women to fill out a questionnaire, which they can do online at home.  I have seen copies of these questionnaires and they are much too long.  By the time women get to the questions about their symptoms on page 22 of the Allergan questionnaire, for example, they will have already answered questions about 20 connective tissue diseases, many of which they never heard of and can’t pronounce, such as eosinophilic fasciitis.  They will also have answered the same 20 questions about each of their children.  I have to assume that by the time they get to page 22 to answer questions about symptoms they might actually have, they are in no mood to answer the question about “dilated red blood vessels under the skin surface that appear as red marks, especially on the face, hands, and lips.”  Given these questions, I think it is very unfair to blame the low response rate on the patients.

Similarly, Mentor patients have told us that the symptoms listed on their questionnaire were often confusing and difficult to answer.

I have one more thing to add.  The first 2 years of the Allergan and Mentor Core studies showed that self-esteem on the Rosenberg Self-esteem scale went down in most patients with implants, and that symptoms of connective tissue diseases went up.  Those data were reported at previous FDA Advisory Committee meetings.  But, those data are missing from the analyses that the FDA has reported for the 8-year and 10-year Core study follow-ups.  I ask the FDA to explain why.

Thank you for your time.

Diana Zuckerman, PhD, October 6, 2011

Conclusion of Post-Approval Studies: Many of these rates are too low to provide useful data for augmentation patients.

Rupture Rate: The FDA mistakenly reported the rupture rate per implant as if it were per patient. Previous data shows that the price per implant is approximately twice as high as per implant.

Why the Poor Follow-up?

Once company did a much better job than other. There is no excuse for Mentor’s poor performance because their patients and studies are like Allergan’s.

Plastic surgeons tell women that complaints are so safe that the women aren’t concerned about follow-up. Does the contribute to patient’s lack of interest in participating in these studies? Or are incentives poor? In addition, women are being “fired” by their plastic surgeons.

Cumulative Complications

Cumulative complication rates are decreasing in data the FDA has presented now compared to a few years ago! That’s impossible. They should stay the same or increase from 4 years to 10 years. (Allergan: swelling decreased from 23% to 9%)

Since come complication rates are going down there is a problem with the data. Either the company is not reporting complications correctly or the sample is changing in ways that reduce complications.

Cumulative Complications

Mentor seems to have stopped reporting certain complication rates. For example, asymmetry. For example, asymmetry and ptosis, 2 complications for reconstruction patients, are simply not reported at 8 years.

What else might Mentor have decided not to report?

Given these problems, it is difficult to have faith in the integrity of the Mentor data.

Conclusions:

Incentives are lacking for companies or surgeons to do post-market research correctly. Enforcement is needed to provide incentives.

Data are not capturing the problems many implant patients report-especially Mentor.

Literature is funded by silicone and implant companies, and medical foundations with conflicts of interest.

Pam Noonan-Saraceni

I was diagnosed with breast cancer and had a mastectomy at the age of 25.

I waited 5 years before I decided to have reconstructive surgery. I played tennis, jogged, and taught aerobics.  But the prosthesis often shifted or fell out of my bra when I perspired.  So, as a well-educated woman, I did my homework on breast implants prior to choosing the plastic surgeon to perform my reconstructive surgery. However, I was told that they would “last a lifetime” and “complication were rare”.

Within 3 months of the initial reconstruction, I was back on the operating table. My body had formed a capsule around the implant and the implant had shifted up under my collarbone. The searing pain at that time was causing my shoulder to become immobile.

My symptoms began slowly. At first I attributed the fatigue, aches, and pains to just getting older. (I was only 36 years old!) This was 6 years after I had been implanted.

Then I got a severe case of the flu, and 6 weeks later I was still so fatigued that my life was being drastically effected. I had GI problems, sleep disorders, night sweats, chronic fatigue, myalgias, and joint pain.

Before I had the implant removed  (10 years after the initial reconstruction), I was again wearing a partial prosthesis over the implant. Capsular contracture had again become a problem and I was misshapen and lopsided. The explantation was the 5th surgery at my breast site.

I never fully recovered.  I have gone to various doctors and specialists and have been given a list of various possible diagnoses. Atypical Connective Tissue Disease is number one, but that diagnosis was made quite a bit later, not within the first 10 years.

To date, my out of pocket medical expenses exceed $40,000. My husband and I are self-insured. The insurance policy that we took out carried an exclusion. I was not covered for any illness or disability related to the reconstructive surgery. Apparently the insurance companies understood that there are health risks associated with breast implants and they are not willing to bear the financial costs.

There is not a miracle cure for me. But I hope that by telling you what happened to me, you will understand why better research on breast implants is so important.

Kathleen Van Fossen Nye

My name is Kathleen Van Fossen Nye and I am from Reading PA. I am not well enough to travel to this meeting so I thank you for the opportunity to have my words read before this panel.

I first got breast implants after undergoing a bilateral mastectomy at the age of 22 at the U.S. Naval Hospital in Portsmouth, VA.

My experience with implants is like a history book on breast implants, because I started with some of the early implants and those were repeatedly replaced as newer models became available.

I beseach you to make sure that well-designed and implemented long-term studies are conducted on all breast implants that are sold. Then make these studies available to the public on the internet so women can read them for full disclosure.

When I was 22, the doctor claimed I was lucky to live when reconstruction was available with silicone breast implants. He said before the implants I would have walked around with a sunken chest. He also said they would never sag, that I would be the sexist old lady in the nursing home. In addition, they would self-seal if I was stabbed in the breast.

I wasn’t so lucky, after all.  My original breast implants had to be cut off my chest wall, because the mesh backing from the implants grew into the chest wall. The implants had become as hard as rocks.

I was told that the new silicone gel implants were greatly improved and would not get hard. In addition, if for any reason they do get hard, all the doctor had to do was squeeze the breast until they break the scar tissue capsule.

Claims of being able to break the scar capsule were not true. After 5 years of squeezing the hardened breast, I could no longer take the pain. My doctor told me it was my fault because I had no breast tissue. However, he told me that the new Meme implants were covered with polyurethane foam that would stay soft and never get hard, so he was going to use these new and improved implants.

When asked about the safety of the foam, I was told to trust the doctor because he knew what was best for me.

And yet, the new implants also got hard.  The old Meme implants were removed and I had surgery to get a new set of Meme implants.

For 3 years I was weak and sick and after visiting three different doctors complaining of pain and lumps on the edge of the implant, two doctors told me it was scar tissue. The third doctor said to give me peace of mind he would remove the lumps. The implants were removed and the 3 lumps were biopsied.

Foreign material was found in two of the masses.  The mass that was sandwiched between the other two was cancer.

After chemo and radiations treatments I had two expanders and I was implanted once again, against my wishes.

Within 3 months, I developed necrosis and the implant pushed itself up and out through my skin.

My physical health has suffered greatly. I have had over 25 breast related surgeries, including 6 sets of implants and 4 single silicone implants, 2 expanders, and 4 individual saline for the left breast.

I now have lupus and many other health problems.

I have given my history to show you that there is always great optimism about the newly designed implants, but as the years go by, the optimism gives way to reality and those old implants are always replaced with new ones, until those new ones become the bad old implants that need to be replaced.

It is 49 years and about 3 generations of women since Drs Cronin and Gerow implanted the first breast implants. If the manufactures’ make safety claims, they should back them up with studies that really provide accurate long-term data, not biased samples where half of the patients are missing and we don’t know if the half that are missing are healthy or terribly sick.

Anne Stansell

My name is Anne Stansell and I live in New Mexico.  I wish I could be there today, but I hope you will listen to my story.

I am a breast cancer survivor. I was diagnosed at the age of 39. The doctor said I needed mastectomies, radiation therapy, and breast implants. Implants were just part of the treatment, no discussion. I trusted the doctors who I felt had just saved my life.

I was fine for the first five years. Then I became very ill. I was diagnosed with Graves Disease and fibromyalgia. My eyes were so dry that my retina tore.

My implants were taken out about two years later. I had to fight with my insurance company to get them to cover the removal.

Half of one of my implants was gone. Where did the silicone go? I don’t know.  Here is a photo of me with my half empty implants.

They couldn’t remove all the silicone from my body, but even so I began to get better almost immediately. My family noticed the difference even before I did.

I’m still recovering, and I can work some now.

When I heard about the new post-market studies, I saw that the complication rate was high, but was surprised that the complication rate wasn’t even higher.  I had many of the same local complications. I can’t even remember how many surgeries I needed. Silicone was found in my side, when it migrated from the broken implant.

At a previous meeting, the data indicated that cancer patients and augmentation patients also had an increase in some autoimmune symptoms during the first two years after getting implants. I think my symptoms started in the third year, so it is likely that those signs and symptoms will increase over time, just like mine did.  But it doesn’t seem that the post-market studies measured symptoms.  It seems that they just measured diagnosed diseases.

When the FDA approved breast implants, they demanded post-market studies to find out how often these debilitating complications occur.  But based on the women I’ve talked to with breast implants, it seems that the women with implant problems tend to stop going to their plastic surgeons and are therefore dropping out – or being intentionally dropped out – of the studies.

I didn’t have informed consent as a cancer patient, and from what I hear from other patients, that is still true today.

This meeting is focused on research but to do the right research, you need to listen to the patients who were harmed by implants.  We illustrate the data. We are the examples of what can – and has – happened to tens of thousands of women across the country.

Carolyn Wolf

My name is Carolyn Wolf; I live in Virginia. I have paid my expenses to be here and I have no conflicts of interest.

At 41, I had subcutaneous mastectomies due to fibrocystic disease.  Reconstruction was with Dow Corning silicone implants (1972).

Seven years later, small burning blisters formed on my neck. I stopped wearing neck jewelry, though allergy tests were negative. I wear no makeup.   I continue to develop these blisters, and other implants report they have similar blisters.

By the 15^th year, my implants had become very hard; after 17 years I was hospitalized for 3 days with all the  symptoms of a heart attack, but tests showed no heart problems. I asked the internist “could the implants have caused this?” and was told “no”. In hindsight, I think this episode was the result of silicone leaking from my left implant.

Three years later, I had developed joint problems on my left side,  my shoulder, elbow, knee, ankle and foot. Gradually my fingers and toes became numb.

I went for checkups every year at Walter Reed. No suggestion was ever made for an MRI until a bubble appeared on top of my right breast, about 26 years after getting implants. Because there was a long wait to get an MRI, a radiologist did an ultrasound. The report was “no cancer, everything okay”.

About a year later, I started feeling burning in my scalp; it felt like a red hot worm crawling along the part line.  I also had three episodes when long strings of silicone came out of my ear.

Twenty-eight years after implantation, the left breast collapsed fully.  I finally had my firstMRI, which showed both implants extensively ruptured. When the implants were  surgically removed in 2000, the total material that came out would not have filled a small sized Styrofoam coffee cup.  Obviously the rest had leaked or deteriorated into my body.

Because of continuing dizziness and brain fog, a brain MRI was performed in 2001.  This showed more than 20 lesions on my brain.  EMG tests showed much damage to my left eye, to my left arm and hand, and extensive neuropathy in the extremities. The neurologist studied a Mayo –he was no charlatan.

Three years ago I was hospitalized with Giant Cell Temporal Arteritis, with the same pain in my scalp.  I have been able to control the inflammation with high doses of Prednisone.

I am diagnosed with connective tissue disease, multi-nodal thyroid chronic fatigue; fibromyalgia, PMR, asthma and COPD; MS-like syndrome with neuropathy; platinum poisoning (my platinum lever is 140, 35 times normal by CDC/OSHA standards), and Irritable Bowel Syndrome.

I am not the only woman with these kids of experiences.  There are still thousands of women who have had leaking silicone breast implants in their bodies for decades.  Many cannot afford surgery to remove them. Others, like me, had doctors who told them that their health problems are unrelated to their implants.  In recent years, many of those doctors are saying “the FDA says they are safe and leaking silicone does not cause problems.”  And many women believe the doctors, and just get sicker and sicker.  Many of them just “give up” and even commit suicide – and it is NOT because they don’t have knobs on their chests.

I ask the Advisory Committee to think about how your recommendations will affect these women.  Why is there no research focused on the women with leaking silicone implants and what happens to them??  The FDA did such a study 10 years ago, but the manufacturers say the newer implants are safer.  But there are not studies to PROVE whether that is true, because the studies required by the FDA follow women for only 10 years.

Is the FDA willing to publicly state that silicone and platinum leaking into women’s bodies, year after year,  is “perfectly safe”?

So far, the FDA keeps requiring the companies to do research, but the research if NOT getting done properly.  Women are being terribly harmed as a result.

Please make sure that these research requirements are enforced.

Conclusions of Pam, Kathleen, and Anne in their Joint Testimony

So far, the post-market studies have all started studying women from the time they got implants for the next 10 years — although many women dropped out of the studies before 10 years had passed.  In our experience, many women with implant problems have told us that they no longer felt welcome in their plastic surgeon’s office, so they sought health care from other doctors.  We are concerned those are the women who dropped out of the post-market studies.  If they are, then the complication rate is much higher than the studies are reporting.

We have heard on the news where plastic surgeons say that breast implants have been studied more than any other medical device.  We don’t know if that is true, but if it is true, that is an indictment of research on other medical devices.  The studies of breast implants aren’t asking the right questions.  You need independent researchers, not the implant companies, to do this research.

We may not be your typical breast cancer reconstruction patients, but we have talked to a lot of women who have stories just like ours.  The FDA needs to interview women like us, and ask questions about our kinds of symptoms.  Then, include those symptoms in the studies that are done.

And why not find the women who were in the implant studies that started 10 years ago, and follow them for the next 10 years?  Complications are much more rare at first and increase over time.  So, starting with women who had implants put in 10 years ago would provide much more useful safety information than starting with women who got implants 2 years ago.