Diana Zuckerman, PhD, Nyedra Booker, PharmD, MPH, and Sonia Nagda, MD, MPH

Published in Reproductive Health Matters, December 2012

Tens of thousands of defective silicone breast implants were recalled in Europe in 2011–12 soon after the FDA’s unrelated announcement that a rare cancer of the immune system was associated with all saline and silicone gel breast implants. These developments raised questions about whether U.S. and European regulations were protecting patients from unsafe medical implants.

In the US, breast implants are regulated as high-risk medical devices that must be proven reasonably safe and effective in clinical trials and subject to government inspection before they can be sold. In contrast, clinical trials and inspections have not been required for breast implants or other implanted devices in Europe. As a result of these differing standards, the PIP breast implants that were recalled across Europe had been removed from the market years earlier in the US. Nevertheless, the FDA track record on breast implants indicates that studies have provided limited information about safety.

The authors conclude that neither the European Union nor the US has used their regulatory authority to ensure the long-term safety of breast implants. However, in 2012 the EU announced regulatory changes that could improve that situation.

To see the official summary: http://www.ncbi.nlm.nih.gov/pubmed/23245415

Diana Zuckerman, PhD, Archives of Surgery: July 2006

Henriksen et al provided useful data on the short-term complications of breast reconstruction with implants.[1] Although the invited critique described the complication rate as “alarmingly high and arguably unacceptable,” the complication rate is even higher in other studies with superior study designs.

For example, a study conducted by implant manufacturer Inamed found that 46% of reconstruction patients needed additional surgery within the first 2 to 3 years after getting silicone gel breast implants 2 – more than twice as high as the 21% reported by Henriksen et al. One explanation is that the women in the Henriksen study had breast implants for an average of only 23 months, compared to 2-3 years in the Inamed study. Henriksen et al reported that 31% developed at least one serious complication and 16% developed at least 2 serious complications. The Inamed study reported that 25% underwent implant removal, 16% experienced Baker III-IV capsular contracture, 6% experienced necrosis, 6% had breast pain, and 6% had scarring, in addition to infections and other complications. [2]

Henriksen et al concluded that “reconstruction failure (loss of implant) is rare.” However, in addition to the short follow-up, Henriksen et al did not use Magnetic Resonance Imaging (MRIs) to detect rupture, thus undercounting the number of ruptures according to the FDA. [3] A study using MRIs found that 20% of reconstruction patients had ruptured implants by the third year;4 very few ruptures were detected without MRIs. Food and Drug Administration scientists concluded that the risk of rupture would likely increase exponentially every year.

Henriksen et al’s lack of MRI use also helps explain the lower rate of additional surgery. If a woman underwent an MRI and learned that her implant was ruptured, she would probably have surgery to remove it.

In his critique, Singh states that “the immunologic and systemic complications ascribed to implants (silicone or saline) have been debunked by the Institute of Medicine’s 1999 definitive report.” However, most research on diseases among implant patients was published after 1999. The IOM report included only 17 studies of autoimmune diseases among implants, almost all of which studied small numbers of women for short periods of time. Many of the studies reported higher levels of disease or symptoms among women with breast implants, which would have reached statistical significance if maintained in larger studies conducted for a longer period of time. For example, the study by Schusterman et al, included only 250 women with implants, all of whom had implants for 2 years.

In 2001, Food and Drug Administration scientists reported a significant increase in fibromyalgia and several other autoimmune diseases among women whose silicone gel breast implants were leaking, compared to women with silicone implants without extracapsular leakage. [3] The National Cancer Institute (NCI) found a doubling of deaths from brain cancer, lung cancer, and suicides among women with breast implants compared to other plastic surgery patients. [5] National Cancer Institute findings regarding autoimmune diseases were not definitive. [6] National Cancer Institute scientists concluded that more research was needed to determine if implants increase the risk of cancer or autoimmune diseases. [5,6]

The unanswered questions about diseases and the high complication rate for breast cancer patients raise important safety issues about breast implants. It is difficult for patients to receive informed consent when definitive long-term data are not yet available.

References:

1. Henriksen TF, Fryzek JP, Holmich LR et al Reconstructive breast implantation after mastectomy for breast cancer: clinical outcomes in a nationwide prospective cohort study. Arch Surg. 2005; 140: 1152-1159.
2. Inamed Corporation’s McGhan Silicone-Filled Breast Implants, October 14-15, 2003, slides presented by the FDA, http://www.fda.gov/ohrms/dockets/ac/03/slides/3989s1_02-update_files/frame.htm
3. Brown SL, Pennello G, Berg WA, et al. Silicone gel breast implant rupture, extracapsular silicone, and health status in a population of women. Journal of Rheumatology. 2001; 28:996-1003.
4. FDA Summary Memorandum, 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
5. Brinton LA, Lubin, JH, Murray MC, et al. Mortality among augmentation mammoplasty patients: an update. Epidemiology. 2006; 17: 162-169.
6. Brinton, LA, Buckley, LM, Dvorkina, O et al. Risks of connective tissue disorders among breast implant patients. American Journal of Epidemiology. 2004, 180: 619-627.

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund

Executive Summary

The U.S. Food and Drug Administration (FDA) has the responsibility to determine if newly developed medical products are safe and effective. Whether it is a prescription medication, a medication sold over the counter, a medical device, a vaccine, or another type of biologic, the product can be marketed for general sale in the United States only if it has FDA approval.

FDA advisory committees are the most visible part of the FDA approval process. They meet in public to review the most controversial and cutting-edge medical products, examining applications for FDA approval. Committee members discuss the strengths and weaknesses of the studies and their enthusiasm or concerns about the medical product under review. At recent FDA advisory committee meetings on controversial drugs and medical devices such as Vioxx®, silicone implants, and antidepressants, the media have provided the Congress and the general public with a glimpse of the approval process.

Questions have arisen about committee members’ financial ties to the companies submitting applications, their commitment to scientific scrutiny, the independence and objectivity of the deliberative process, and inconsistencies between the panel members’ expressed concerns and their approval recommendations.

This report describes the results of a study conducted by the National Research Center (NRC) for Women & Families, providing the first objective analysis of the key role of FDA advisory committees as part of the FDA approval process. The purpose of this report is to better understand the strengths and weaknesses of the FDA’s advisory committee process for FDA’s two largest centers, the Center for Drug Evaluation and Research (CDER) and the Center for Devices and Radiological Health (CDRH).

The study analyzes the voting patterns and committee discussions of a random sample of 6 of 16 drug advisory committees and 5 of 18 medical device advisory panels:

Drug Committees
Antiviral Drugs
Arthritis Drugs
Dermatologic and Ophthalmic Drugs
Gastrointestinal Drugs
Pulmonary and Allergy Drugs
Reproductive Health Drugs

Medical Device Panels
Immunology Devices
Microbiology Devices
Obstetrics and Gynecology Devices
Ophthalmic Devices
Radiological Devices

Data for these advisory committees were collected from the FDA Web site, based on transcripts of advisory committee meetings from January 1998 through December 2005. In that time, the 11 randomly selected advisory committees considered 89 prescription drugs and medical devices, including arthritis medications, LASIK devices, erectile dysfunction drugs, and devices to improve the accuracy of mammograms. There were 866 committee member votes.

Findings

As described by FDA officials, its advisory committees meet only to discuss the most controversial or innovative products, or products whose data are not clear-cut. The public might expect, therefore, that many of the drugs and devices reviewed by advisory committees would not be recommended for approval. The data indicate that this is true for some advisory committees, but not others. Overall, the 11 randomly selected advisory committees recommended approval for 79% of the 89 products reviewed between 1998 and 2005. The device advisory panels were even more likely to vote for approval than the drug advisory committees, recommending approval 82% of the time compared to 76% for drugs.

Despite the controversies surrounding many of these products, the votes for or against approval were rarely close. On the contrary, committee members agreed unanimously for 66% of the drugs and 75% of the medical devices that they recommended for approval.

Drug and Device Approval Recommendations

A review of the meeting transcripts indicates that advisory committee members frequently expressed strong concerns about the safety or the efficacy of the drug or device under review. However, those concerns were not necessarily reflected in their recommendations for approval.

There were many examples of committee members who strongly criticized the studies or the medical products under review, and then recommended approval anyway. FDA officials at the meetings almost never expressed concerns about the disconnect between the committee members’ explicitly expressed doubts about safety and effectiveness and their votes in favor of approval.

Of the 50 drug committee voting sessions in the study, 38 (76%) recommended approval of the drug. Most of the votes were unanimous, and almost all (93%) of those unanimous votes recommended approval.

Some of the committees were much more likely to recommend approval than others. The percentage of drugs they recommended for approval ranged from 50% for reproductive health drugs to 100% for arthritis drugs. The percentage of individual votes cast to recommend approval ranged from 50% for reproductive drugs to 98% for arthritis drugs.

What happens after the meetings are over? Of the 38 drugs recommended for approval by the drug advisory committees, all were subsequently approved by the FDA except one drug whose application was withdrawn before FDA made its decision. The FDA also approved four (36%) of the 11 drugs that the drug advisory committees voted against, including products that were opposed by almost all the committee members.

Of the 39 device panel voting sessions studied, 32 (82%) recommended approval of the device. Most of the votes were unanimous, with almost all (92%) of those unanimous votes recommending approval.

The percentage of devices that were recommended for approval ranged from 67% for microbiology devices to 88% for ophthalmic devices. The number of panel member votes cast to recommend approval ranged from 57% for microbiology devices to 91% for radiological devices. Three of the five randomly selected devices panels – the Radiological Devices Panel, the Immunology Devices Panel, and the Microbiology Devices Panel – had unanimous support for approval whenever they recommended approval during the eight years of the study.

Almost all (94%) the devices recommended for approval were subsequently approved by the FDA, and close to half (43%) of the devices that were not recommended for approval obtained FDA approval anyway.

Overall, the study found:

• Many advisory committees recommend approval for almost every product they review, usually unanimously;
• Individual committee members can have a disproportionate influence on approval recommendations;
• Voting patterns differ for drugs and devices, but not when we compare committee members with clinical, scientific, and consumer perspectives;
• Committee members describe pressure to conform and to recommend approval, and they candidly admit that their votes for approval may not be consistent with their concerns about safety and effectiveness;
• FDA officials passively acquiesce when they do not respond to committee members’ statements indicating that votes recommending approval are not necessarily based on scientific evidence of safety and effectiveness; and
• The FDA almost always approves products recommended for approval but also often approves products that advisory committees reject.

Implications and Conclusions

The findings suggest that when the FDA schedules meetings for several of its advisory committees, the outcome is almost certainly going to be FDA approval for the products under review. In most cases the advisory committee will recommend approval, but even products that are not recommended for approval are frequently approved by the FDA. Even lopsided votes against approval apparently do not have much weight, since the FDA subsequently approved many of those products.

Although FDA officials describe the advisory committees as providing diverse perspectives and expertise, the large number of unanimous or nearly unanimous votes suggests that either the data are exceptionally convincing or that the committee members are reluctant to disagree with their colleagues or believe that the FDA wants the advisory committee members to come to consensus.

By combining information from the NRC study with studies of conflicts of interest on FDA advisory committees, it is possible to understand how a few committee members with conflicts of interest can have a disproportionate impact on approval recommendations. NRC’s analysis of meeting transcripts indicates that many committee members’ votes seem inconsistent with their concerns about the safety or efficacy of the drug or medical device under review. These transcripts clearly illustrate the pressures that committee members describe to conform to their colleagues or to be able to vote ‘yes’ even if it means changing the wording of the question so that they can do so in good conscience. The report includes examples of committee members directly trying to influence the views or votes of other committee members.

If the FDA is relying on advisory committees to help determine the conditions of approval, one would expect that FDA officials would provide explicit oral instructions about the types of conditions that the FDA is willing to impose, and that the FDA would impose most of the conditions and then enforce them. That is not the case, however.

Committee members frequently recommended unenforceable or vaguely worded conditions of approval and expressed their intention to recommend approval for products that they did not believe were proven safe or effective. Their candor suggests that they would welcome guidance from the FDA officials present, to make sure their recommendations were appropriate. Nevertheless, during committee discussions FDA officials showed remarkably little interest in providing oral guidance regarding the criteria for approval, or the realities of approval conditions to advisory committee members during the eight years of the study. Conditions of approval imposed by the FDA often did not reflect the conditions recommended by the advisory committees. Conditions that were imposed were rarely enforced.

Overall, the findings indicate that committee members, intentionally or unintentionally, move toward a consensus that often seems inconsistent with their differing views or perspectives in making decisions that may have life-or-death consequences for millions of Americans. Voting for approval contingent upon conditions is a popular compromise, but the FDA does not impose most of the specified conditions on the companies when it grants approval. The Committees’ tendency toward approval seems to reflect the FDA’s goals; in fact, the FDA appears to be even more geared toward approval than the advisory committees. The FDA approved almost all the prescription drugs and devices recommended by the advisory committee, and also frequently approved products that were opposed by the committee members.

Whatever the reasons, many of today’s FDA drug and device advisory committees are rubber stamps for approval almost every time they meet. Moreover, even when an overwhelming majority recommend “nonapproval,” there is a good chance that FDA officials will approve the product anyway. Approval is even more likely for medical devices than it is for drugs.

Recommendations

If the FDA wants to restore confidence in the FDA, and restore the independence that FDA advisory committees were intended to provide, it is essential that the FDA make changes in the policies and process governing its advisory committees. The following recommendations are based on the assumption that the Congress and the FDA are committed to that end:

1. The FDA should stop granting conflict-of-interest waivers for committee members, except under very restricted conditions.

2. The FDA should provide explicit and specific oral guidance whenever needed during advisory committee meetings regarding appropriate criteria for safety and effectiveness, and appropriate criteria for conditions of approval.

3. The FDA should demand more from advisory committee members, and then be more responsive to their concerns.
For a PDF copy of the 50-page report, click here.