Category Archives: Testimonies and Statements by NCHR

Testimony of Margaret Dunkle at the FDA on Silicone Gel Implant Studies

Margaret Dunkle, George Washington University, 2011

I am Margaret Dunkle, Senior Research Scientist at the Department of Health Policy of The George Washington University. I also direct the Early Identification and Intervention Collaborative for Los Angeles County. Among other awards, I have received the American Academy of Pediatrics’ Dale Richmond Award for outstanding achievement in the field of child development; and Vice President Al Gore’s “reinventing government” Hammer Award.

I have testified nine times before Congress on issues affecting women, children, and families and have authored more than 100 publications on these subjects.

I am here today solely because of my interest in ensuring that medical products for women be proven to be safe and effective. I am not representing any organization. I am not being paid or otherwise compensated.

The 2006 FDA approval of silicone gel breast implants was controversial because there were so many unanswered questions about the long-term safety of implants, including when they might break and leak inside a woman’s body, and what the consequences of such leakage might be.

“As conditions of approval,” the FDA required that the two implant companies (Allergan and Mentor) each study at least 40,000 women. The FDA also required that these studies be at least 10 years long since some serious adverse outcomes might not become obvious, or even be measurable, in just a few years. And it takes both time and a large sample to identify subpopulations of women who might be at greater risk for problems, such as autoimmune reactions, or reproductive or connective tissue concerns.

It is now five years later, when the studies should be close to half done. But the data for both the Allergan and Mentor studies are not what they need to be for a study of this importance.

Why do I say this? Because of the extraordinarily high “loss” of study participants, as the following table shows.

In just three years, Mentor (now a subsidiary of Johnson & Johnson) has somehow managed to “lose” four out of five of both the silicone-implant patients and the augmentation patients enrolled in its 10-year study. Their paltry overall enrollment rate, with only 21% to 29% of patients still in the study, makes their data virtually useless in terms of assessing either safety or effectiveness.

As you can see, Allergan’s rates are better, but still likely too low to meet the study’s goals. Simply put, when you lose half or more of your sample, you cannot assume that the data for the few left in the study also represent those who were “lost.”

The Mentor rates, especially, would be laughable, were it not for the seriousness of the issues. Let me put it this way. If I can easily find my antediluvian high school classmates with a few “advanced search” clicks on Google, how can it be that these well-resourced medical-device companies cannot keep track of much younger patients that they have already enrolled and consented into their clinical trials? If the will were there, there are many sound methodological ways to ensure high rates of ongoing participation in these studies.

So, what to do about this bad situation?

The FDA’s job is to protect public health by ensuring that such things as medical devices implanted into women are both safe and effective. My five recommendations are aimed at helping the Agency do just that job.

First, rescind approval for the Mentor implants. They did not uphold their part of the bargain for the post-approval study. If they can’t competently do this research to ensure their product’s safety, they should not be putting their product into the bodies of more than a hundred thousand women every year.

Second, do not restore approval of the Mentor implants until they have at least two years of credible data with 80% or more retention of clinical-trial recipients. They could accomplish this by re-enrolling or “finding” the thousands of women they have “lost to follow up.” To ensure credibility, Mentor would need to pay an independent entity to check the validity of their data.

Third, extend the duration of both the Mentor and Allergan studies to 15 years. The FDA’s own “Update” report indicates that 10 years may not be long enough to identify long-term problems from cancer to rarely diagnosed autoimmune diseases, or to detect populations especially susceptible to adverse outcomes.

Fourth, require ongoing transparency and disclosure of the data from these studies by making public meetings such as this, and the June 2011 “Update” report, the rule, rather than the exception.

Fifth, implement a broad FDA policy to put companies on notice that there will be consequences of not doing or incompetently doing FDA-required post-approval research. Consequences could include withdrawing a product from the market, or substantial financial penalties for doing a bad job of the research, and then using that “penalty money” to fund research controlled by AHQR or independent researchers.

In conclusion, with almost 400,000 women getting breast implants each year for augmentation or reconstruction these studies need to be done right. The current situation also provides a window for the FDA to improve the incentive system so that manufacturers do not again ignore post-approval research requirements to the detriment of the public’s health.

Thank you for this opportunity to comment. And I ask that my full written statement be inserted into the meeting record.

Invited Testimony of Diana Zuckerman, PhD, Before the Standing Committee on Health, Canadian Parliament, Ottawa, June 8, 2006

Diana Zuckerman, PhD, National Center for Health Research

I am Dr. Diana Zuckerman, President of the National Center for Health Research. Our independent, nonprofit organization is a think tank that gathers and explains research information and uses it to improve the health and safety of women, children, and families.

I am speaking from the perspective of someone trained in psychology and epidemiology, who was a university faculty member and researcher at Harvard and Yale and taught courses in research methods before moving to Washington, DC to work on health issues in the U.S. Congress, U.S. Department of Health and Human Services, White House, and for nonprofit organizations.

I have read every published epidemiological study on breast implants and will briefly discuss what is known and not known, based on those studies. I will also tell you about a criminal investigation of one of the implant manufacturers, Mentor, and the many calls and emails we have received from women in Canada who are finding it impossible to have their leaking silicone gel breast implants removed in a timely manner.

Who conducts research on breast implants?

Clinical trials are a major source of information on the short-term risks of silicone breast implants. In clinical trials, the goal is to follow women prospectively to determine what complications and health problems occur, and to compare that to a control group. Although silicone implants have been on the market for 40 years, the only well-designed clinical trials have data for only 2-3 years and they do not include a control group. The clinical trials have been conducted by the implant companies as part of their effort to obtain approval to market the implants in Canada and the US.

Epidemiological studies are the major source of information about what actually happens to women who have breast implants for at least five years. Almost every published epidemiological study on breast implants has been paid for by companies that sell or sold breast implants. In fact, one company in the U.S. has received many millions of dollars from Dow Corning to conduct most of these studies, almost all of them in Europe, and every one of those studies has concluded that implants are safe. However, careful scrutiny of the results in the peer-reviewed articles indicates serious health problems among women with those implants. For example, one recent study reported that women with breast implants were significantly more likely to report breast pain and take anti-depressants, but still concluded that breast implants were safe.

More importantly, a small number of studies have been conducted by independent researchers, not using implant company funds or funds from plastic surgeons. These include government-funded researchers in Canada and the U.S. Their findings almost always indicate problems with implants that are in direct contradiction to the findings of the studies funded by implant companies. I will focus on their findings today.

What do we know about the health effects of ruptured silicone gel implants?

The FDA funded, designed, and conducted the best study on the health of women with ruptured silicone implants. FDA scientists concluded that most women with implants for 11 years or more have at least one ruptured implant, even if they don’t realize it. They also found that 21% of women with implants for at least 7 years have at least one implant that is leaking silicone outside the scar tissue, and that women with leaking implants were more likely to report fibromyalgia or several other painful and debilitating autoimmune diseases. The FDA study is superior to other studies because it focused on women who were basically happy with their implants, and who had implants for at least 7 years. That length of time is key. Other studies have included women who had implants for an average of 7 years — but not at least 7 years.

Most women who have had problems with rupture had implants for a long time — usually much longer than seven years.

Cosmetic Problems

More independently funded research is needed on the risks of ruptured silicone gel implants. Meanwhile, let’s look at some of the cosmetic results of silicone gel implant problems.

Here is a 29-year old woman who had her implants removed after 7 years. Her capsular contracture was so painful that she apparently preferred getting her implants out to keeping them in. This photograph is from the FDA’s website.

That is obviously not a good outcome, but here is a woman who wasn’t so lucky — Sharyn Noakes. Her ruptured implant had leaked into her healthy breasts. When the silicone was removed, this is all that was left of her breasts.

And this is Kathy Nye, a breast cancer survivor who suffered from necrosis and her implant extruded through her skin. Inamed reported a 6% necrosis rate among reconstruction patients in their Core study.

Signs and Symptoms

Now that you have seen some of the cosmetic problems, let’s take a look at the women’s symptoms. In data presented to the FDA, Inamed and Mentor both found that women with implants for only two years had a significant increase in auto-immune symptoms such as joint pain and nervous system symptoms. FDA asked a statistician to determine if this was due to aging. It wasn’t. And, these findings are consistent with what we have heard from thousands of women with silicone breast implants. Most were happy with their implants for years and never suspected that their increasing problems with fatigue or aches and pains might be related to their implants. The women’s personal experiences are not conclusive evidence, but they indicate a pattern that needs to be considered — especially since they are consistent with Inamed and Mentor’s own data showing an increase in autoimmune symptoms over a period of only two years on a cohort of young augmentation patients.

What do we know about the health risks of silicone gel implants more generally?

Aleina Tweed, an epidemiologist at the British Columbia Centre of Excellence for Research on Women, conducted a study of breast augmentation patients in Canada, most of whom had implants for 10 years or longer. She found that the women with implants visited doctors and specialists more often, and were four times as likely to be hospitalized, compared to other women the same age from the same communities.

Why has that important Canadian study received so little attention? Probably because no one was paid to do PR on the study. In contrast, studies funded by Dow Corning, the maker of silicone, have received enormous publicity. You may have heard that hundreds of studies, including studies at Harvard and the Mayo Clinic and a report of the U.S. Institute of Medicine, provide clear proof that breast implants are safe. However, the Institute of Medicine report is outdated – completed in 1999 and based on studies conducted before that. And, it was based on the other studies that are so often quoted, such as the Mayo Clinic study and the Harvard study – studies that were all funded by Dow Corning and other implant makers.

Almost all the studies included in the Institute of Medicine report suffered from the same shortcomings: they were too small, and they lacked statistical power because they included women who had implants for too short a period of time. For example, the Mayo Clinic study included only 749 women with breast implants, only 125 of whom were reconstruction patients. To be in the study, women had to have implants for at least one month. The average length of time was about 7.5 years, which means that only about 375 women had implants for more than 8 years. Since diseases like lupus, scleroderma, and rheumatoid arthritis are not very common among women in their 20’s and 30’s, this study doesn’t have the power to detect most of the diseases it measured. The authors themselves acknowledged that major shortcoming.

So, while I agree with the Institute of Medicine that there is not sufficient evidence to conclude that implants cause autoimmune disease, the report can’t be considered conclusive proof that implants don’t cause autoimmune disease.

The U.S. government has also funded some important studies of breast implants, and like the Canadian study, they tend to report serious health problems for women who have implants for a long period of time. The National Cancer Institute study found a doubling of brain cancer, lung cancer, and suicide. It is an exceptionally well-designed study, because all the women in the study had breast implants for at least 12 years. Another major strength of the study is that it compared women with silicone implants to women who underwent other kinds of plastic surgery, such as liposuction. This is important because all plastic surgery patients tend to be above average in health and income, but also tend to smoke more than other women.

How do the many implant studies funded by Dow Corning compare to the government funded studies in Canada and the U.S.? Many of the Dow Corning studies focused on women with implants for a short period of time, and at least one on women with ruptures for a short period of time. Many measured illness in terms of hospitalization rather than diagnosis. Remember that most women getting breast augmentation are in their 20’s or 30s, with many in their teens. Think of how unlikely it is that a 30-year old woman will be hospitalized for rheumatoid arthritis.

Inamed and Mentor Research Quality and Integrity

Inamed and Mentor both started clinical trials to analyze the safety of silicone gel breast implants in 1990. Both companies lost track of almost all of their patients to follow-up within 5 years. If only they had done a good job on those studies, we would have great long-term data today. But they didn’t, and so we don’t.

The companies both were given the opportunity to test their silicone gel implants on thousands of patients in the Adjunct Studies that they conducted. They enrolled thousands of patients and then failed to follow-up on most of them, making those studies useless.

Last year, shortly after Inamed and Mentor silicone implants were considered by advisory committees in Canada and the U.S., I heard from several Mentor employees who expressed concerns about the accuracy of the data that Mentor provided to the FDA, and also informed me that the patch used on Mentor implants leaks silicone and should be fixed. I contacted the FDA and arranged for the Mentor employees to speak to FDA officials. As a result, the FDA started a criminal investigation, interviewing me and several former Mentor employees. I was told several weeks ago that the investigation is still underway. I would be glad to put those former Mentor employees in touch with officials at Health Canada as well.

What does approval matter?

Although there are restrictions on silicone gel breast implants in Canada and the U.S., tens of thousands of women have continued to get them. Many of those women were not breast cancer patients.

Even so, approval matters. If Health Canada approves silicone gel breast implants, it will send a clear message that it believes that the implants are safe, and more teenage girls and women will certainly choose silicone implants as a result.

The study by Aleina Tweed shows that in Canada, women with breast implants have more health problems and their efforts to get well are costly to the Canadian system. Most of the women had at least one surgery to fix an implant problem, and 17% had four or more additional surgeries. Tweed’s findings are especially striking to us because our Center hears from many Canadian women with breast implants who tell us that they can’t get help from most Canadian plastic surgeons. Many have discovered — often after years of symptoms – that their implants are leaking. They need a plastic surgeon to remove them, and often can’t afford to pay for the surgery. But the waiting list is very long. We know a patient who contacted Dr. Mitchell Brown’s office this spring, because she heard he is an excellent surgeon who knows how to remove leaking silicone implants. She was told she would need to wait until December 2006 just to see him for a consultation. She was told that if she needed surgery, that would have to wait until December 2007. My staff found that hard to believe, so we also contacted Dr. Brown’s office more than a week later and we were told the exact same thing. My staff asked if there was a shorter wait if she could pay for the surgery, and we were told that the wait was much shorter.

We know several patients who tried to arrange surgery with other Canadian plastic surgeons. They were told that silicone would likely leak during the surgery and that they could be left looking deformed, They were discouraged from removing their implants, and told that at least they should replace them with new implants.

If Health Canada approves silicone gel breast implants, the number of teenagers and women needing to have leaking silicone implants removed will increase dramatically. To allow that to happen in a country where few plastic surgeons know how to remove leaking silicone gel breast implants, and those that do have very long waiting lists is not ethical or appropriate. And, according to Aleina Tweed’s research, it will cost the Canadian healthcare system dearly.

The full transcript can be viewed here

All articles are reviewed and approved by Diana Zuckerman, PhD, and other senior staff.

Statement of Diana Zuckerman, PhD on FDA Approval of Breast Implants

Diana Zuckerman, PhD, National Center for Health Research, September 21, 2005

Today the Food and Drug Administration (FDA) issued an “approvable letter” to Inamed Corporation for their silicone gel breast implants. Inamed Corp. was granted this first step in the approval process based on a revised application that is missing most of its breast cancer patients. After their application was rejected by the FDA a few months ago, Inamed belatedly decided to eliminate a defective style of breast implant (Style 153) from their application for approval. Unfortunately, two-thirds of the breast cancer patients in their study had this defective style of implant, which had a tendency to break even during the first three years in the body. When the company resubmitted their application, they removed those women from their study, apparently leaving fewer than 30 breast cancer patients who underwent MRIs to determine if their implants had ruptured or were leaking silicone. Yet the agency had asked that at least 250 breast cancer survivors be studied. In August, the Mentor Corporation also received an approvable letter.

STATEMENT –

“It is absolutely unacceptable to approve a breast implant that hasn’t been carefully studied to make sure it is safe for breast cancer patients. Sadly, this isn’t the first time — rival implant maker Mentor’s long-term data included zero breast cancer patients.

“The approvable letter was sent despite FDA scientists’ scathing criticisms of the company’s data and a vote from FDA’s advisory panel recommending that the implants not be approved. This action by the FDA once again raises questions about whether the agency is making decisions based on scientific evidence.

“This sounds familiar. Just a few weeks ago, the FDA ignored their own scientists when they refused to approve the morning-after pill for over-the-counter sales. Once again, the FDA is ignoring the concerns of their own scientists, this time potentially endangering breast cancer survivors.

“Only scientific evidence and solid safety data can protect women. Wishful thinking should not be a basis for approval.”

Statement of Dr. Diana Zuckerman, President of the National Center for Health Research, Regarding the FDA Breast Implant Decision

Diana Zuckerman, PhD, National Center for Health Research: July 28, 2005

WASHINGTON, July 28 /PRNewswire –The Food and Drug Administration (FDA) has issued an “approvable letter” to Mentor regarding their silicone gel breast implants. This does not mean that these implants have been approved, but it is a warning sign that corporate pressure on the FDA has once again put women’s health at risk.

The FDA letter is a stumbling step in the wrong direction, amid mounting questions about FDA decision-making. Approval would be an embarrassment unless the Senate and the FDA give Mentor a “clean bill of health” after thoroughly investigating allegations that Mentor misrepresented the rupture rate of its implants.

A Senate investigation of the Mentor safety data and the FDA approval process is currently underway, and concerns are growing. Just before the FDA announcement today, key women members of the U.S. Senate sent a letter to the FDA Commissioner, expressing their strong concerns about the lack of safety data on silicone gel breast implants. And, as the public learns about defective pacemakers, recalls of defibrillators and the dangers of several other medical devices, questions still remain as to how safe these breast implants are.

Every week we hear from women with leaking breast implants, who can’t afford the surgery to have them removed. FDA needs to make sure that they don’t approve a product that adds to this frightening situation for so many women across the country.

The FDA needs to listen to its scientists and demand more long-term safety data before issuing any kind of decision. They also need to make sure that the data they are given are accurate. The credibility of the FDA is on the line, as is the health of millions of women.

Dr. Diana Zuckerman is the president of the National Center for Health Research, a nonprofit research and education organization that works to improve policies and programs that affect the health and safety of women, children, and families. Dr. Zuckerman is a nationally-recognized health policy expert with post-doctoral training in epidemiology from Yale Medical School. She was on the faculty of Vassar and Yale, and a researcher at Harvard, prior to becoming a Congressional investigator in the U.S. House of Representatives, where she initiated the first Congressional hearing on the lack of safety data on breast implants, held in 1990. She is widely quoted on a wide range of health issues, especially FDA and medical products. For more information about the Center’s work, click here.

All articles are reviewed and approved by Diana Zuckerman, PhD, and other senior staff.

Testimony of Diana Zuckerman, PhD at the FDA on Silicone Gel Breast Implants

Diana Zuckerman, PhD, National Research Center for Women and Families,  April 2005

I’m Diana Zuckerman. I am President of the National Research Center for Women and Families, and I’m very pleased to be here. I have no conflicts. I’m a psychologist and epidemiologist and president of a nonprofit center that scrutinizes research to see what the implications are for health and safety.

We’ve heard that implants are the most studied medical product in the United States, but in 1991 there were about a million women with breast implants. The number of empirical published studies at that time was zero.

And at that time when they submitted their PMA, Inamed had only studied 39 breast cancer patients. Thirty-nine. And in their augmentation sample they had lost 65 percent of their augmentation patients at three to six months, according to the FDA summary.

Now, it brings us to 2003. Things have changed a little. We’re looking at the two to three year data that was available in 2003. It showed very high complication rates, including a lot of reoperations. It showed an increase in auto-immune symptoms, just about all of them that were measured. And it also showed no improvement and some worsening in most self-esteem and self-concept measures.

Now we know that most of the people talking have said this product has improved the quality of their life. But as has been pointed out by Panel members, the data just don’t support it. There is some improvement on body image, but not on quality of life, not on all of these other measures that have been touted as the main advantage of implants.

It’s very worrisome that all the patients in these studies are white, just about all of them. And, yes, I understand that most people getting breast implants for augmentation are white, but that is certainly not true of reconstruction patients. There are many, many thousands of reconstruction patients in this country that are women of color, and yet just a handful — I thought it was six African-American women, and five Asian American women, but according to the data shown this morning, it’s actually even lower. And I don’t understand how it could possibly be acceptable to approve a product with no data.

The reason why it’s important to have racial diversity in these samples is because there are racial differences in scarring and in auto-immune disease. African-American women are more likely, more susceptible to auto-immune disease. So we’d want to know are they more at risk, and we can’t conclude that because not only weren’t they analyzed separately, there weren’t even enough women to analyze separately.

That brings us to 2005. I thought that we’d have additional year of data. I was very interested to see what would the new data show and how would it be different. So I thought there’d be more data on complications compared to last time, but no, there aren’t. And I thought that there’d be another year of data on auto-immune, and no, there aren’t. And I thought there’d be another year of data on self-esteem and quality of life, and no, there aren’t. There is rupture data, and that’s great. But it was really for the three-year MRI data. It’s called four-year data, but since MRIs were done in the third year, it doesn’t take us very far.

When Inamed compared ruptured and intact implants, they did not evaluate connective tissue disease symptoms for most women with ruptures. I say that based on the FDA’s scientific analysis in your package.

They did find a significant increase in muscle pain. They didn’t find too many increases, but they had a very, very small sample to work with, partly because it just wasn’t measured.

The Adjunct Study has, according to Inamed, included 25,000 paients, but they didn’t follow-up on them. This is very upsetting because this was such a great opportunity to provide really good data and longer term data. And let me say that the young woman who testified about her problems not being reported, whether she was in the Adjunct Study or the Core Study, her problems should have been reported. And it says something about the commitment of the sponsor that they seem to think as long as it was the Adjunct Study, it doesn’t matter. I think it does matter. They should be taking care of patients in their studies, and they should be reporting them regardless of which — I don’t know which study she was in, but whichever one it is, she should have been reported.

And also remember that Inamed started their studies in 1990. Had they followed those women, we’d have at least a dozen years of safety data, the data we want. But they didn’t do that.

The literature review that FDA did talked about the Danish registry, but the mean number of years of women, and that was less than four years –not long enough.

It talked about the Danish rupture study. Forty percent of the implants were tested with a faulty MRI, so that study was not helpful.

And basically the data that many of you talked about showing up to ten years of rupture is faulty data. And I hope that Dr. Blumenstein will say something more about that later.

The FDA study did have a 21 percent extracapsular leakage for implants that were seven years old or more, and they also found an increase in fibromyalgia, which has not really been discussed at this meeting.

Thank you.

NCHR Press Release on Inamed High Complication Rates for Breast Implant Patients

Diana Zuckerman, Phd, National Center for Health Research: October 16, 2003

In a split decision, an advisory committee to the FDA recommended approval for Inamed’s silicone gel breast implants on October 15th. “The news is not good for breast implant patients, especially those with breast cancer,” noted Dr. Diana Zuckerman, President of the National Center for Policy Research for Women & Families, a Washington-based think tank. “The company’s own research indicates high complication rates for the first three years, including the need for additional surgery for 46% of breast cancer patients. The long-term risks remain unknown.”

Inamed’s “core” study included 221 breast cancer reconstruction patients, 494 augmentation patients, and 225 revision (replacement) patients. According to the FDA, their complication rates are very high. For example, 46% of reconstruction patients underwent at least one re-operation within 3 years, 25% had removal or replacement, 6% had a diagnosed ruptured implant, 6% had breast pain, and 6% were diagnosed with necrosis, a painful and disfiguring condition where the skin or tissue dies. Complications were lower but still substantial for augmentation patients (for example, 21% with re-operations, and 1% diagnosed rupture) and revision patients (33% with re-operations and 4% diagnosed ruptures). The FDA assumed that the rupture rate was higher than reported, since three out of four ruptures would not be diagnosed unless a woman underwent an MRI.

The largest study, called the Adjunct Study, enrolled 15,465 reconstruction patients and 9,881 “revision” patients (who had replaced their previous breast implants with new Inamed silicone gel implants). The Adjunct Study was the compromise developed by the FDA to enable large numbers of mastectomy patients and women with broken gel implants to use silicone gel implants at a time when the company had not proven that their product was safe. Although women wanting silicone breast implants were required to participate in the Adjunct Study, the company apparently made little effort to comply with this requirement: barely half (54%) of the breast cancer patients who received Inamed implants stayed in the study for one year. Even fewer — 27% — stayed in the study for three years.

Women who wanted silicone gel implants to replace broken gel implants were also required to participate in the Adjunct Study, but they were even less likely to stay in the study than breast cancer patients. Less than half (44%) stayed in the study for one year and only one in five (20%) stayed for three years. “Most women did not stay in these studies for even one year, making the largest study useless in determining whether the implants are safe” explains Dr. Zuckerman. “Inamed was told that they were supposed to study the safety of implants as a condition of sale. The main concern about silicone implants is the health risks when they break, but the company did not study women long enough to find out what those risks are.”

Inamed also gathered data about health symptoms experienced by their patients. In the FDA review of Inamed’s data, FDA scientists noted the following:

  • Muscle pain, joint pain, hair loss, rashes, and fatigue all increased within two years of getting implants.
  • In terms of their quality of life, almost every measure of emotional and physical health, including social interactions and self-esteem, declined within two years of getting implants. The improvements were in self-reported sexual attractiveness.

In its description of the components of the implant shell, the FDA noted the presence of 24 potentially toxic metals, including arsenic, lead, mercury, and platinum. (FDA Review Team Memo, p. 9)

In its review of scientific studies conducted by other researchers, FDA scientists noted:

Cancer — “The finding of excesses in lung (or respiratory), cervical, vulvar, and leukemia have been reported in more than one study. These findings are difficult to interpret, and further research is needed to clarify this issue.” (FDA Review Team Memo, p. 35)

Mammography — “The possibility that implants may delay cancer detection is of concern.” ( p. 38)

Silicone Migration — “Cases of distant migration of gel to breasts, axillary lymph nodes, abdomen, groin, arm, and fingers have been reported, some with serious consequences and deformities…” (FDA Review Team Memo, p. 37)

Inamed also reported results from a 5-year study started in 1990, but it included only 29 reconstruction patients. The study started with 547 augmentation patients, but most were not studied for all five years. Since most of the patients dropped out of the study and most had breast implants that the company is no longer selling, results from this study were not useful.

“The findings show many areas of concerns and unanswered safety questions, and provide worrisome evidence that women with silicone gel implants will face numerous complications directly related to the implants, symptoms such as pain and fatigue, and declines in health and mental health,” concludes Dr. Zuckerman. “Although the rupture rate is low during the first two years, it is expected to increase every year, as it has in other studies.”

The FDA advisory panel held their public meeting on October 14-15 in Gaithersburg, MD to decide whether to recommend Inamed’s silicone gel breast implants for FDA approval. All the plastic surgeons on the panel recommended approval. Most of the other doctors and scientists on the panel voted against approval, including a toxicologist, epidemiologist, statistician, radiologist, dermatologist, and cancer surgeon. The pediatric surgeon who chaired the panel only votes to break a tie, but stated publicly that he would have voted against approval.

Silicone gel breast implants have been available under FDA-imposed restrictions since 1992 because implant makers did not provide adequate research evidence that they were safe. The FDA is expected to make a final decision about whether or not to approve the implants within a few months.

Testimony of Diana Zuckerman, PhD, at the FDA for Silicone Gel-Filled Breast Protheses

Diana Zuckerman, PhD, National Center for Health Research, October 15th, 2003

To the General and Plastic Surgery Devices Panel Center for Devices and Radiological Health Food and Drug Administration Regarding Premarket Approval Application for Silicone Gel-Filled Breast Prostheses:

I am Dr. Diana Zuckerman, President of the National Center for Policy Research for Women & Families. Our independent, nonprofit organization is a think tank that gathers and explains research information and uses it to improve the health and safety of women, children, and families.

It’s very difficult to testify as the last public comment. Since you already discussed the key questions last night, I wonder how I can say anything you haven’t heard and might want to hear or be willing to hear. I will express my sympathy to you for the very difficult work you have put in, and let you know that after I left this meeting very late last night, I had to rewrite this testimony. So, I may have been up even later than you all were.

Let me start by saying I am speaking from the perspective of someone trained in psychology and epidemiology, who was a university faculty member and researcher and taught courses in research methods before moving to Washington to work in the Congress, U.S. Department of Health and Human Services, and for nonprofit organizations.

I have read every published epidemiological study on breast implants and would like to briefly discuss the Inamed studies in the context of those other studies.

What do we know about the health effects of ruptured silicone gel implants?

The FDA’s study, described by Dr. Lori Brown yesterday, is the best designed study ever conducted on the topic. One reason for its superiority is that it focused on women who were basically happy with their implants, and who had implants for at least 7 years. That length of time is key. Other studies have included women who had implants for an average of 7 years — but not at least 7 years.

You know from hearing testimony from women yesterday and today that most women who have had problems with rupture had implants for a long time — usually much longer than seven years.

What do we know about the health risks of silicone gel implants more generally?

I have heard the Institute of Medicine report, the Mayo Clinic Study, the Harvard Nurses study, and the meta analysis all cited as clear proof that breast implants are safe. First of all, its important to note that they are pretty much all the same thing. The Institute of Medicine report was based on the same studies as the meta analysis, and they both included the Mayo Clinic study and the Harvard Nurses study as key components.

Almost all the studies included in the Institute of Medicine report suffered from the same shortcomings that many panel members described for the Inamed safety research: too small, and too short. For example, the Mayo Clinic study included only 749 women with breast implants, only 125 of whom were reconstruction patients. To be in the study, women had to have implants for at least one month. The average length of time was about 7.5 years, which means that only about 375 women had implants for more than 8 years. Since diseases like lupus, scleroderma, and rheumatoid arthritis are not very common among women in their 20’s and 30’s, this study doesn’t have the power to detect most of the diseases it measured. The authors themselves acknowledged that major shortcoming.

So, while I agree with the Institute of Medicine that there is not sufficient evidence to conclude that implants cause autoimmune disease, the report can’t be considered conclusive proof that implants don’t cause autoimmune disease.

The National Cancer Institute study finding a doubling of brain cancer, tripling of lung cancer, and quadrupling of suicide is also an exceptionally well-designed study, because all the women in the study had breast implants for at least 8 years. Again, other studies included women who had implants for an average of 8 years, but not a minimum of 8 years. And again, that means that other studies included women who were not exposed for a long enough time to develop a disease and be diagnosed.

Most of the Scandinavian studies were funded by Dow Corning, and had some shortcomings such as measuring illness in terms of hospitalization rather than diagnosis. Again, think of how unlikely it is that a 30 year old woman will be hospitalized for rheumatoid arthritis.

Signs and Symptoms

Now that you know some of the shortcomings of the research literature on systemic disease, let’s take another look at the signs and symptoms. Think about the testimony you heard from the women, many of whom were happy with their implants and never suspected that their problems with fatigue or aches and pains might be related to their implants. This is not conclusive evidence, but it is a pattern that needs to be considered — especially with data showing an increase in every symptom over a period of only two years on a cohort of young augmentation patients.

Cosmetic Problems

Even if the data on systemic illness and signs and symptoms are not conclusive, let’s look again at some of the photos you have seen of the cosmetic results of silicone gel implant problems.

Here is a 29-year old woman who had her implants removed after 7 years. Her capsular contracture was so painful that she apparently preferred getting her implants out to keeping them in. This photograph is from the FDA’s website.

That is obviously not a good outcome, but here is a woman who wasn’t so lucky — Sharyn Noakes. You saw her photo yesterday. Her ruptured implant had leaked into her healthy breasts. When the silicone was removed, this is all that was left of her breasts.

And this is Kathy Nye, a breast cancer survivor who suffered from necrosis and her implant extruded through her skin. Little attention was given to the 6% necrosis rate among reconstruction patients in the Inamed Core study.

Inamed Research Quality

Like many of you, I applaud Inamed’s excellent response rate in their Core study.

But like Dr. Whelan and Professor Dubler, I share your amazement about the lack of long-term research.

The company started to analyze the safety of silicone gel breast implants in 1990. It was terrible that they included only 29 breast cancer patients. But, they also lost most of their patients to follow-up before ending the study after 5 years.

The company was given the opportunity to test their silicone gel implants on thousands of patients in the Adjunct study. They enrolled thousands of patients and then failed to follow-up on most of them, making that study useless.

And, the core study is almost entirely White women. Women of color get breast cancer, for example, but only 6 African American women and only 5 Asian American women are in the reconstruction sample. And, of course both groups are more likely to have scarring problems, and African Americans are more susceptible to autoimmune diseases.

What does approval mean?

If Inamed silicone gel implants are approved, and the company is required to continue research for 7 or even 10 more years, consider the company’s track record so far.

You need to know that the FDA can’t truly enforce any requirement of post-market research. The FDA has leverage before a product is approved, since the company will comply in order to get their product approved. It has no real leverage after approval.

If Inamed silicone gel implants are approved, the FDA can try to improve informed consent. But again, it can’t enforce that.

If Inamed silicone gel implants are approved, the FDA can specify that it is approved for women ages 18 and older. But physicians will be free to use these implants on 17-year olds or younger girls — just as they do now, with saline implants.

If Inamed silicone gel implants are approved and you try to require women to get MRI’s, that can’t be enforced either. Even in the Inamed study, where the MRI’s were presumably free, many of the women did not comply.

Perhaps most important, approval is the seal of approval. We live in a sound bite world. If you recommend that silicone gel implants be approved, despite all the members who said last night that long-term safety is unknown, the message will be: “silicone gel implants are safe.” That will be your legacy. If you’re not sure that they truly are safe, then you should vote against approval.

A final word about the inadequacy of the 1-year, 2-year, and 3-year data. I agree with those who questioned why in the world the FDA issued a guidance asking for only 2 years of safety data, for a product whose main concerns are long-term safety. It doesn’t seem quite fair to then change their mind. On the other hand, the company has not exactly done everything they could do, in their 1990 study or their Adjunct study, to collect safety data. Is it really unfair to expect that a company would try to improve their product in the last 10 years, or try to evaluate the safety of their product. Better guidance would have been helpful, but the real responsibility is with the sponsor.

Testimony of Jae Hong Lee, MD at FDA on Silicone Breast Implants

Jae Hong Lee, MD, MPH, National Center for Health Research, July 9, 2002

Two years after the FDA’s controversial approval of saline breast implants, the FDA Advisory Committee on breast implants held an unusual meeting to review the latest research on implant complication rates on July 9, 2002.

In 2000, saline breast implants were approved by the FDA despite a 70% rate of serious complications among breast cancer reconstruction patients during the first three years and 40% among augmentation patients. The Advisory Committee expressed strong concerns about the high complication rate but recommended approval on the condition that the manufacturers conduct long-term safety studies.

Meanwhile:

• The number of teens getting saline implants has more than doubled.

• The number of women getting breast augmentation is at an all-time high
(more than 200,000 in 2001).

• Government-sponsored research has shown an increased risk of cancer and
deaths among women who had saline or silicone breast implants for more than
8 years.

A 4-year criminal investigation of one of the manufacturers has attracted Congressional attention.

This following testimony was presented at the public comment period at the Advisory Committee meeting on Tuesday, July 9, 2002. [Dr. Lee’s testimony has been slightly modified after the hearing to reflect additional information he received about the manufacturers’ data that was not available before the statement was given].

When physicians are asked about the safety of breast implants, many — perhaps most — will focus their thoughts on the reported systemic illnesses that spurred significant controversy and not a small amount of litigation about a decade ago. An Institute of Medicine (IOM) report — Safety of Silicone Breast Implants — was commissioned by Congress to examine the issue and concluded that insufficient evidence existed to implicate silicone breast implants as a cause of these systemic illnesses. Many physicians and surgeons now misleadingly and inappropriately cite the study as definitive proof that breast implants are “safe.”

A more careful reading of the IOM report reveals something quite different. Rather than a comprehensive declaration that silicone breast implants were safe, the report noted that the “frequency of local and perioperative complications has been substantial in both augmentation and reconstruction of the breast” and that reoperations and local complications were “the primary safety issue with silicone breast implants.”

This issue remains important for several reasons. First, more and more women are receiving breast implants. According to statistics from the American Society of Plastic Surgeons (ASPS), more than 219,000 breast augmentation procedures were performed in 2001 in the United States alone. In the last two years, over 6,000 girls 18 years old or younger have undergone breast augmentation. There may now be over 2 million American women with silicone breast implants.

Second, breast augmentation is not a life-saving or life-sustaining procedure. In order to justify a completely elective cosmetic procedure, the risks to the patient must be clearly outweighed by the benefits.

Third, the cost of reoperations and local complications associated with breast implants can be significant for both the patient and society. Many health plans do not cover the medical costs associated with cosmetic breast implant complications — forcing many patients to cover these costs out-of-pocket. For example, Aetna — one of the nation’s largest health insurers — does not cover the cost of removing ruptured saline implants in patients who have previously undergone cosmetic breast augmentation. It should be noted that in 2001, more than 62,000 breast implant removal procedures were performed in the U.S.

The Inamed and Mentor Post-approval Studies
In light of the serious concern regarding reoperations and local complications, the post-approval studies recently released by Inamed and Mentor are extremely disappointing. Both studies are poorly designed and executed, and most likely underestimate the cumulative incidence of complications. I will discuss just a few of the more glaring weaknesses of the studies.

A major problem shared by both the Inamed and Mentor studies is the failure to follow-up on patients who have had all their breast implants removed prior to the 3 or 5-year study interval. One can argue that these patients — among the earliest to have all their implants removed — are the most important group of patients to study. Excluding follow-up data from these patients introduces an unacceptable post-entry exclusion bias into both studies. Since it seems likely that these patients were experiencing complication rates higher than those who did not have all their implants removed, the overall effect of this exclusion bias may be to seriously underestimate the cumulative incidence of certain complications — e.g. additional operations performed to improve the frequently unsatisfactory aesthetic result after complete breast implant removal.

It is also legitimate to question the use of Kaplan-Meier risk estimates in both studies. One essential condition for using the Kaplan-Meier method is the assumption of independence between censoring and outcome.1 In other words, one must assume that the rate of local complications and reoperations in the excluded patients was similar to those who remained in the study. Since the excluded patients had all of their initial implants removed early — presumably due to complications in nearly all cases — this is not a reasonable assumption to make. Using the Kaplan-Meier method in this situation clearly results in an underestimation of the cumulative complication rate, especially as time progresses and the more complication-prone patients and implants are removed from the study cohort — a fundamental flaw in both studies. It will be essential to compare the characteristics of the patients and implants who remain in the studies beyond 5 years to those who had all their implants removed at earlier time intervals.

When Inamed conveniently excludes the breast implant-removal patients from further follow-up, they inflate their follow-up rate for patients. For example, they calculated an “expected follow-up” reconstruction cohort of 175 by excluding 11 patients who had died and 51 patients who had all their initial implants removed. As a result, their follow-up rate for reconstruction patients was reported as 80% (or 140 out of 175). As mentioned earlier, it is highly inappropriate to completely exclude those implant-removal patients from the study cohort. If those patients are left in, the expected follow-up cohort consists of 226 patients — not 175 — and the actual follow-up rate for reconstruction patients is a clearly inadequate 62%.

There are also signs that the Inamed study is statistically underpowered. For example, Inamed suggests that because most of the confidence intervals between 5-year and 3-year risk rates overlap, the true rates may not be higher at 5 years. They imply that it may not be necessary to follow complications with overlapping 3 and 5-year confidence intervals in subsequent years. A more reasonable interpretation of this data is that the study is too small and underpowered. Since even a small difference of 3% represents over 6,000 breast augmentation patients, the post-approval studies must be large enough to detect even small differences in risk rates.

As bad as the Inamed study is, the Mentor study is even worse. The Mentor report acknowledges that “low response rate and the differences between the responders and the non-responders is a major limitation” of their study. I would go further and state that most of the data presented in the Mentor study is scientifically worthless due to the disturbingly low follow-up rates.

Perhaps the only compelling result in the Mentor study is their Focus Group data. They reported that breast “augmentation women expressed a degree of cynicism regarding the extensive list of complications” found in the patient brochure and “concluded that the occurrence of complications was exaggerated and not to be taken at face value.” This finding strongly suggests that informed consent is not an adequate solution for the unacceptably high complication rates reported for saline breast implants.

Unjustifiable Complication Rates
Setting aside for the moment the very serious methodological problems of both studies, we find little comfort in the reported data. Even taken at face value, the complication rates are unacceptably high. For instance, Inamed reports 5-year reoperation rates of 26% for augmentation patients and nearly 45% for reconstruction patients. As a physician with surgical training, I find these complication rates to be completely unjustifiable for a purely elective cosmetic procedure.

What Should Be Done?
The poor quality of the studies clearly indicate that both Inamed and Mentor have failed to fulfill all the conditions of their premarket approval agreement. Furthermore, the reported complication rates in both studies reinforce the IOM’s concern about local complications and reoperations. These companies seemingly lack the motivation to perform adequate and appropriate safety studies as long as they can market and sell their products as “FDA approved.”

So what should be done?

At the very least, the FDA should require a black box warning on all advertisements noting that the manufacturer has not adequately completed required 5-year safety studies. The panel should also recommend that patient consent forms include a statement noting the lack of reliable long-term safety data. Another option would be to temporarily suspend general distribution of these implants until better safety data become available.

The Inamed and Mentor studies leave many questions unanswered but do make clear one important fact: right now, there are no adequate data demonstrating the safety of saline breast implants.

1 Szklo M and Nieto FJ. Epidemiology: Beyond the Basics. Aspen Publishers, Inc. Gaithersburg, MD. 2000

Jae Hong Lee, MD, MPH, is the Senior Medical Policy Analyst of the National Center for Health Research. Dr. Lee has professional experience in basic science research, clinical patient care, clinical research, and public health, and works on a variety of health issues for women and families.

Dr. Lee’s work in research began in college, where he performed studies in psychology and electron microscopy. During medical school, he pursued two years of full-time basic science research in neurology and pathology under fellowships from the American Heart Association and the NIMH/Measey Foundation. After completing a surgical internship at Yale, Dr. Lee performed clinical research for five years at UCLA, focusing his studies on traumatic brain injury and cerebrovascular disease. His work has been published in respected peer-reviewed journals and presented at national and international meetings.

Dr. Lee received his Bachelor of Arts degree with a major in biophysics from The Johns Hopkins University. His medical degree is from the University of Pennsylvania School of Medicine. Most recently, he completed a Master of Public Health degree with a concentration in quantitative methods at the Harvard University School of Public Health.

Testimony of Diana Zuckerman, PhD at the FDA on Saline Breast Implants

Diana Zuckerman, PhD, National Center for Health Research, July 9, 2002

My name is Dr. Diana Zuckerman and I am President of the National Center for Policy Research (CPR) for Women and Families, a nonprofit research-based organization that explains medical and scientific information so that it can be used to improve the health and well-being of women, children, and families.

Our research center works on a wide range of health issues, with particular attention to the safety of medical products. Unfortunately, as the new research on hormone replacement therapy has reminded us, manufacturers’ claims about medical products are not always supported by research. Our goal is to balance the hype by scrutinizing the research and determining the facts — whatever they may be.

In the case of breast implants, the more than 150,000 adverse reactions reported to the FDA is inconsistent with the manufacturers’ claims that implants are very safe and that implant patients are so satisfied that even when their implants break or cause hardness or pain their only desire is to replace a problematic implant with an even larger one. So, we have used our expertise in epidemiology, biostatistics, and public health to carefully scrutinize the research.

I was at the FDA Advisory Committee meeting when saline implants were approved in 2000. For those of you who weren’t here, I want you to know that the Advisory Committee expressed a great deal of concern about the extremely poor quality of the data and the exceedingly high complication rates. I heard the shocked gasps in the audience when the Advisory Committee voted to recommend approval despite their very strongly expressed concerns.

The Advisory Committee recommended approval with the caveat that long-term safety data, and better studies, be required of the manufacturers, Mentor and McGhan. I am sorry that many of those members are not here today. I think they would be very disappointed that the manufacturers made many of the same “mistakes” or misrepresentations now that they were criticized for two years ago.

For example, Dr. Brent Blumenstein, the statistician on the Advisory Committee, clearly stated that the McGhan presentations did not meet the standards of “good, peer-reviewed articles” and specifically stated that “accuracy is not manifest in the presentation of the data.” The FDA statistician, Telba Irony, specifically criticized using Kaplan-Meier analysis when many women are lost to follow-up and the researchers don’t know if those who dropped out are like those who are in the study. Both statisticians criticized the large number of patients who were lost to follow-up. Of course, in the new data presented today, even more women are lost to follow-up.

In the Mentor study, Dr. Blumenstein criticized the company for taking patients out of the analysis if they had their implants removed. He said “This is an extreme limitation and misrepresents the data.” He concluded by saying “I cannot accept the accuracy of any of the data here because of the limitations I’m pointing out…. I cannot feel good about any of the data presented with respect to accuracy and giving that information to an individual patient and having that patient understand what the real risks are.”

Phyllis Silverman, the FDA statistician stated “because of the approximately 50% loss to follow-up with the large, simple trial, the ability to draw meaningful conclusions from this trial is limited.” I agree — and obviously it’s even worse for the new Mentor data, which has a 95% loss to follow-up at 5 years or a 76% loss at six years.

A response rate under 50 percent can not provide useful safety data, because we know nothing about the women who are no longer in the study. If we don’t know if they are alive or dead, or healthy or sick, we don’t really know if these implants are safe.

Are these manufacturers unable to afford good researchers to do this research? They have spent millions of dollars to advertise in every major women’s magazine, including those read by millions of teenage girls.

Perhaps lack of research skills is not the problem here. Two members of Congress wrote to the FDA last month and again yesterday to ask about a criminal investigation of Mentor and to ask to see inspection reports for both Mentor and McGhan. I have a copy of their letters, which specifically asked that this Advisory Committee be informed of the criminal investigation, since it might have implications for the integrity of the research data. The Congressmen also asked that you be provided information about studies published by the National Cancer Institute last year. One showed an increased risk of cancer for women with saline or silicone implants compared to other women. The other showed an increase risk of deaths from brain cancer, lung cancer, and several other diseases among women with saline or silicone breast implants, compared to other plastic surgery patients.

I agree with these Congressmen that in order for you to make wise recommendations to the FDA, you need all relevant information. That would include any information that raises questions about the long-term safety of breast implants, as well as inspections and investigations that apparently raise questions about the research conducted by these companies and the manufacturing quality control practices of the companies.

On behalf of our research center, I am respectfully asking each of you to carefully scrutinize these studies and express your views about their quality — or lack thereof — in the strongest and clearest possible terms. I also ask you to request information about the NCI studies — which were co-authored by an FDA scientist, who also analyzed the adverse reaction reports for breast implants several years ago. If you don’t insist on better long-term research and on accurate reporting of that research and of adverse reactions, teenage girls and women will continue to assume that breast implants are proven safe, despite the lack of long-term safety research.