Dana Casciotti, MPH, PhD, National Center for Health Research, August 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.

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.

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.