Public Citizen Calls for Criminal Investigation of Breast Implant Manufacturer

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http://www.citizen.org/pressroom/release.cfm?ID=2289

Oct. 12, 2006

Public Citizen Calls for Criminal Investigation of Breast Implant Manufacturer for Withholding Safety Data from FDA

Company Studies Showed Dangers Associated With Silicone Gel Implants

WASHINGTON, D.C. – Public Citizen today called for a criminal investigation into Mentor Corporation’s apparent failure to send the Food and Drug Administration (FDA) data showing safety problems with their silicone gel implants. The consumer advocacy organization also called on the FDA to wait until it has reviewed all available safety data before deciding whether to approve the implants.

On June 22, a former scientist from Mentor – one of the two companies seeking FDA approval of silicone gel breast implants – sent a letter to the FDA accusing the company of withholding from the FDA a variety of important new safety information. Prior to sending the letter, the scientist had raised all of the serious concerns documented in the letter within the company, urging Mentor to submit the data, but it refused and fired the scientist.

An FDA staffer who received the letter told the former Mentor scientist that since the withheld test data were not required in FDA’s request to Mentor for more studies, and since the submitted data from both Mentor and Inamed (another silicone gel breast implant manufacturer) were similar, he had no other comment on the new information, implying that the agency would take no action.

“Unless the FDA opens a criminal investigation into Mentor’s failure to submit the studies, it will only encourage Mentor and other device manufacturers to selectively send the agency only those studies that put their products in the most favorable light,†said Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, who today sent a letter to the FDA calling for an investigation. Public Citizen’s letter and the former Mentor scientist’s letter are available here.

The former Mentor scientist told the FDA that data about the diffusion of chemicals from the implant into the body were invalid and had been fraudulently represented. Other data he referred to understated the magnitude of weakening of the implant shell after implantation, which is relevant to its rupture. Still other data showed that as the distance from the front of the implant to the back increased, the estimated lifetime of the device decreased.

Public Citizen Calls for Criminal Investigation of Breast Implant Manufacturer for Withholding Safety Data from FDA (HRG Publication #1790)

Public Citizen's letter to the FDA written by Sidney M. Wolfe, MD.

Whistleblower's letter to the FDA highlighting dangers associated with silicone gel implants.

Public Citizen's Letter to the FDA

October 12, 2006

von Eschenbach, M.D., Acting CommissionerU.S. Food and Drug AdministrationFood and Drug Administration5600 Fishers Lane Rockville, MD 20857

Dear Dr. von Eschenbach:

I have recently obtained a copy (below) of a June 22, 2006 letter sent to the FDA by a former senior scientist from Mentor—one of the two companies seeking FDA approval of silicone gel breast implants—accusing the company of withholding from the FDA important new safety information concerning dangerous physical and chemical properties of their implants. Prior to sending the letter, the scientist had raised all of the serious concerns mentioned in the letter within the company; he had urged Mentor to submit the withheld data, but they had refused. The scientist sent the information to the FDA only after his employment was terminated after 15 years with the company.

Several weeks ago, the former Mentor scientist was called by the FDA staff member to whom the letter was sent. The scientist was told that because:

(1) the withheld test data demonstrating dangers of the implants referred to in the letter were not required in FDA’s request to Mentor (and Inamed, the other breast implant manufacturer) for more studies (referred to as the “deficiency responseâ€); and (2) since the submitted data from both Mentor and Inamed (the other silicone gel breast implant manufacturer) were similar, that he had no other comment on the new information, implying that the agency would take no action.

This new information is compelling enough to warrant a reassessment of FDA’s position. At the very least it should clearly stop any FDA final approval of either device until the withheld data has been submitted, evaluated by the FDA staff, and made available to the public. This new evidence that information has been illegally withheld from the FDA should prompt a new criminal investigation into the Mentor’s failure to promptly send the agency all new information bearing on the safety of silicone gel implants.

In discussions with the scientist, he has explained to me the details and significance of the information. This is summarized below, under five subheadings that correspond to the five points made in the letter to the FDA:

Tests/data concerning gel leakage, composition

Diffusion Testing Validation: The gel bleed (diffusion out of the implant and into the body) chemical test data submitted to the FDA is invalid and has been fraudulently represented. A new procedure to correct this problem was successfully tested but the data from this more valid method was never submitted to the FDA. The importance of this is that the submitted data might understate the amount of low molecular weight siloxanes (the more toxic component of silicone gel) that is seeping out from the implant into the body.

Explant Semivolatile Extractable Testing: In tests of explanted silicone gel implants, the company found that there were very large amounts of the above-mentioned low molecular weight siloxanes compared to the amounts in devices that had not yet been implanted, implying that the larger molecular weight siloxanes were continually being degraded in the body to low molecular weight siloxanes. This suggests that a continual degradation of higher molecular weight gel to lower molecular weight siloxanes and bleeding of this may subject women to a constant source of the more dangerous low molecular weight siloxanes. These data were not submitted to the FDA.

Tests related to mechanical properties of the implant

Explant Mechanical Testing: The company found a significant decrease in some of the mechanical properties of explanted devices in comparison to unimplanted control devices from the same manufacturing lot. In their submission to the FDA, however, these comparisons with unimplanted devices were not explicitly made, thus obscuring as much as a 50% decrease in some of these mechanical properties. This magnitude of weakening of the implant shell is extremely relevant to the issue of implant rupture.

Device Projection Fatigue Testing: Device projection refers to the distance from the front of the implant to the back (the anterior-posterior distance). A Mentor investigation of the relationship between device projection and fatigue lifetime (the time until the implant ruptures) found an inverse relationship, i.e., as the device projection increased, the estimated lifetime of the device decreased. This information was also not sent to the FDA.

More toxic form of platinum in the implant shell

Platinum Valence: As noted in the letter, Mentor studies showed that in the silicone rubber envelope of the implant, Platinum existed in the +2 oxidation state (Pt (II). This previously unknown finding is of potential importance since this oxidation state is thought to be more toxic than the Pt (0) oxidation state of the metal. Again, this information was not sent to the FDA.

In summary, this former Mentor scientist has made the FDA aware of previously undisclosed information based on company files. These include considerable test data showing safety problems with silicone gel breast implants. Although some of these studies were not “required “ to be done in the Guidance among the studies the FDA asked Mentor to do, their results directly address important issues of safety that are of relevance and concern. The fact that they were done and that they found some serious problems with the safety of the implants is reason enough for the FDA to take them into account and demand that Mentor provide the actual data from the studies.

As mentioned above, no approval decision on either the Mentor or Inamed implants can be made until the FDA is in possession of and has evaluated these new studies. Unless the FDA opens a criminal investigation into Mentor’s failure to submit the studies, it will encourage Mentor and other device manufacturers to selectively send the agency only those studies that put their products in the most favorable light. Please note that in his letter to the FDA, the former employee identified the specific Mentor staff files containing the withheld information.

I look forward to a prompt response concerning this serious matter.

Sincerely,Sidney M. Wolfe, MDDirector, Public Citizen’s Health Research Group

Letter to the FDA from a Mentor Employee

June 22, 2006

Food and Drug AdministrationCenter for Devices and Radiologic HealthMr. Carl DeMarco, R.Ph., J.D.Integrity OfficerOffice of Device Evaluation301 594 2022 134

Round Profile Gel Mammary ImplantsPremarket Approval ApplicationPreclinical Chemical and Mechanical TestingMentor Corporation201 Mentor DriveSanta Barbara, CA 93111Research and Development Laboratory Services Document Control Program

1) Diffusion Testing Validation

The gel bleed or diffusion testing for low molecular weight siloxanes representing Round Gel Mammary Implants is invalid. I discovered this discrepancy shortly after the submission of the first PMA deficiency response (August 2004) upon thorough review of the raw data and results. Xxxxxxxxx performed the testing and failed to inform me of these difficulties. Consequently this information was concealed from me until I confronted her with the issues. Had I been aware of the problems I would never have submitted the work to the FDA since it could not be defended. The two major issues with the test method were the signal-to-background ratios (~0.1) and now recovery for the duration of the study. This was communicated with upper management Xxxxxxxxxxxxxxxxxxxxxx and also shared with other senior management personnel. I was eliminated from any further participation with FDA to discuss and provide an appropriate interpretation of the results. Subsequently the results were defended by Xxxxxxxxxxxxxxxxxxxx and no acknowledgement of the inability to validate the submission data was communicated. Eventually alternate methodology was developed, reviewed and approved by me (~1 year) however this also was not communicated since it would directly contradict previous submission data. The report for the new method is located in 1 of 2 file cabinets in Document Control labeled Gel Mammary Implants. This report outlines the new and distinct test method that was developed and validated. It describes the manner in which to present data using statistical analysis and includes recovery results for the 90 day duration of the diffusion experiment. The previous method could not be validated for recovery since after approximately 7 days the target analytes disappeared. Accordingly comparison of the old method results to the new method results will reveal the the former yielded erroneous data. Work ultimately returned to my oversight upon the reassignment of Xxxxxxxxxxxx. However no further communication was permitted with FDA during the RPG PMA review..

2) Explant Semivolatile Extractable Testing

Chemical testing of explanted implants was undertaken during the preparation of the deficiency response directed by Xxxxxxxxxxx. Again I was eliminated from participation due to my objection of the preliminary experimental design. Results showed that explanted device gel exhibited exceedingly large quantities of low molecular weight siloxanes compared to devices that had not been implanted. This report is located in 1 of 2 file cabinets in Document Control labeled Gel Mammary Implants. It was added as an addendum to another project conducted at SwRI (Southwest Research Institute) pertaining to total platinum analysis of shell and filler components in gel mammary implants. The immediate interpretation was in vivo biodegradation. Xxxxxxxxxxxxx responsibility for damage control. These results were not submitted to FDA in the deficiency response. No further studies have been undertaken to address the issues. Xxxxxxxxx were reassigned. I have separated from Mentor. Project status unknown.

3) Explant Mechanical Testing

Mechanical testing of explanted implants was undertaken during the preparation of the deficiency response directed by Xxxxxxxxxxxx. Results indicated that a significant reduction of some mechanical properties ha d occurred compared to devices that had not been implanted. These results were misinterpreted in a manner to conceal the relative change compared to control devices such that only absolute changes were reported during implantation. This presentation of the data yielded the apparent result of minimal degradation. No further testing was conducted to determine the origin of the discrepancies between control and explant test results. The original version of the report including control device data from PPQ manufacturing support and presenting percent retention of mechanical properties, in some instances showing a 50 % loss, is an electronic copy retained in Xxxxxxx Mentor directory.

4) Device Projection Fatigue Testing

Mechanical testing of device lifetime from fatigue has been underway since the deficiency submission. The influence of device projection on fatigue lifetime was investigated. Results showed that the device projection and lifetime were inversely proportional. In other words, as the device projection increased the estimated lifetime decreased. Both smooth and textured high profile devices yielded fatigue data statistically unique from moderate profile devices with a corresponding shorter lifetime. This has not been communicated with the FDA. Since I was the only scientist aware of this and I have separated from Mentor I don't know if this will ever be revealed or reported. The raw data for this work in on my desk in a folder label RPG Addendum I or it may also be in Xxxxxxxxxx office area since she was conducting the experiments. Coincidentally the same outcome for CPG was encountered after the PMA submission also indicating the higher profile devices have an apparent shorter lifetime. I'm certain this has also been concealed from FDA.

5) Platinum Valence

Chemical test data exists that indicates platinum is present in the shell with valence Pt (II). This is far more toxic than platinum valence Pt (0) which is the chemical species currently used for potential toxicological exposure. This information has not been communicated with the FDA. The work was conducted by Xxxxxxxxxx who was informed not to publish that information. I believe the results for gel showing Pt(0) were being prepared as a publication at the time of my separation from Mentor. The interim report showing the Pt(II) valence in shelll components is on my desk in a folder labeled Platinum. In addition Xxxxxxxxx has a copy in her office area since was a participant in this project.

It should be noted that much of this new data was generated after the PMA submission and that Xxxxxxxx would not support further updates since it may influence the decision of FDA to approve the RPG product. Much of Mentor personnel have been terminated after the divestiture of Urology. Only xxxxxxxx are still employed in R & D in Santa Barbara. Xxxxx is now part of Coloplast. Xxxxxx has retired. Accordingly it is unlikely if any of this information will ever be shared with the FDA. It is my understanding the laboratory is slated for complete shutdown in the next 90 days.

Xxxxxxxxxxxxx PhD.(former Mentor Employee)

Jan. 8. 2003

Statement of Sidney M. Wolfe, M.D., Director, Public Citizen’s Health Research Group, Concerning FDA Non-Approvable Letter for Silicone Gel Breast Implants

As the group that petitioned the U.S. Food and Drug Administration in 1988 to ban silicone gel breast implants, we commend the FDA for the non-approvable letter it released today, concerning Inamed silicone gel breast implants. Responding to a review of the data, the strong urging of the chairman of its advisory committee chairman, Dr. Whelan, against approval and other outside pressures against approval, the FDA is wisely asking for more data upon which to judge the safety of the implants. The agency is thereby rejecting its own flawed "guidance," which encouraged companies such as Inamed to think that dangerously inadequate amounts of data could be used as a basis for approval.

The FDA decision to not approve Inamed’s silicone gel breast implants is a rejection of what would have been the most dangerous, defective medical device ever approved by the FDA despite advanced knowledge of its dangers. Although saline implants are also defective in their frequent ruptures, there is an extraordinary difference between rupture and leakage of salt water – which is immediately and safely absorbed by the body – and the spread of highly reactive silicone gel, causing local and regional scar tissue formation as well as gel migration to other parts of the body.

Oct. 14, 2003

Approval of Silicone Gel Breast Implants Based on Only Three Years of Data Would Be Foolhardy, Public Citizen Tells FDA

As Many as Half of Women With Breast Reconstruction Require Implant Removal Within 10 Years

WASHINGTON, D.C. – The U.S. Food and Drug Administration (FDA) should heed a series of red-flag warnings and not permit the return of silicone gel breast implants to the market, Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, told an FDA advisory panel today.

In testimony before an FDA panel convened to address the Inamed application for approval of silicone gel breast implants, Wolfe said that because the company has submitted only three years of data from a study intended to run 10 years, the FDA cannot be reasonably assured of the implants’ safety.

Wolfe pointed out that the three-year data show similar complication rates evident in the three-year data from a previous Inamed study that continued for five years. At five years, the previous study showed that 26 percent of women had breast pain, 15 percent had asymmetrical breasts and 12 percent required implant removal or replacement.

"It is not unreasonable to hypothesize that in the current incomplete study, when the five-year data are collected, the risks will be as high or even higher than those found in the 1990 study," Wolfe said.

Wolfe also presented data from an industry-funded study using National Cancer Institute data that showed that, among women receiving breast implants for reconstruction after cancer surgery, 21 percent had their implants removed within five years and 51 percent had theirs removed within 10 years.

Additionally, Inamed’s application includes a two-and-a-half-year shelf life for the implants. This is ironic, Wolfe said, because many women are led to believe that implants will last at least 10 years, if not a lifetime.

If the FDA proves unwilling to require implant manufacturers to provide longer-term data as a prerequisite for approval, serious questions will be raised about the agency’s enforcement of a 1976 medical device law that was enacted to protect patients, Wolfe said. The law was passed after the Dalkon Shield intrauterine device (IUD) caused the deaths of 17 women and made thousands of others sterile. Like breast implants, the device had not been tested for a long enough time.

Statement by Sidney Wolfe, M.D. at FDA Hearing on Silicone Gel Breast Implants (HRG Publication #1678)

Statement by Sidney M. Wolfe, MDDirector, Public Citizen’s Health Research Group

FDA Hearing on Silicone Gel Breast Implants

October 14, 2003

Both the FDA approval standard for medical devices, “reasonable assurance of safetyâ€, and the validity of informed consent/informed choice are legitimate only if studies are long enough in duration and comprehensive enough to answer existing questions about safety. Instead of reasonable assurance of safety, there is more accurately “reasonable assurance of ignorance†and therefore reasonable concern about safety. If the decision is to approve now, women will not get the information they need for truly informed consent before deciding whether to undergo silicone gel breast implant surgery.

It is ironic that the clear evidence of certain dangers such as local and regional complications, often from rupture, and remaining questions about other risks that led to the 11.5 year-old moratorium on silicone gel breast implantation (excluding post-mastectomy) were based on much longer exposures than now exist for the implants being seriously considered for approval today.

Despite these deficiencies in the duration of data being considered by the FDA, (only the first three years of a planned 10-year study) there are many red-flag warning signals within the thousands of pages of documents put up on the internet last week, more than enough to justify a decision to wait at least five more years to collect more information on the thousands of women who already have had implants, rather than precipitously approving these unsafe devices for marketing to hundreds of thousands of women a year who will, once they are told by the government the devices have “reasonable assurance of safetyâ€, opt for the surgery to insert them and thereby participate in a massive experiment.

The chart below shows that the complication rates of the three year data in the 1990 Inamed study and the current “Core†study are quite similar, examining only the data on those implants in the 1990 study for which Inamed is now seeking approval.

The chart below compares the data from three years with that of five years in the 1990 study and shows the striking increases in the risk of various complications occurring between years three and five. For example, the risk of removal/replacement increased from 6.3% to 11.5% in just two years. Similarly, the increases in capsular contracture were from 9.5 to 14.9%. The cumulative risk of breast pain, not provided at three years in these data was 25.8% and loss of nipple sensation was 17.2% at five years. Since the five-year follow-up in the 1990 study was not as great as it could have been, it is not unreasonable to hypothesize that in the current core study, when the five-year data are collected, the risks will be as high or even higher than those found in the 1990 study.

The charts below show the increasing risk of various complications with time:

The following charts are derived from data in the unpublished SEER study, funded by Inamed and Mentor, using NCI surveillance data of breast cancer patients. The most striking finding is that based on 181 implant removals, the Kaplan-Meier risk of removal, 21% at five years after implantation for silicone gel breast implants, had risen to 50.5% by ten years - more than doubling. In other words, by 10 years more than half of these women had their implants removed. This compares with 40.7% for those women getting saline implants. This is the only population-based study, with the advantages of better ascertainment, to examine the problem of implant removal. It is noteworthy that of the 6563 women with breast cancer in the geographic areas covered by the study, only 1159 (17.7%) had breast implants, and in the study there are details for 1012 of these 1159 women (87%).

In addition to the primary deficiency of only having three years of data in the ten- year core study, according to the FDA “In the reconstruction study, only 59% of patients have reached the 3-year follow-up visit.[1] Worse, the follow-up in the adjunct reconstruction group was only 53.8% at one year and 27% at three years.[2]

Other problems noted by FDA reviewers were that in addition to 92 protocol violations in the core study, many involving a lack of informed consent, the adjunct study had even more egregious violations including 211 patients in whom informed consent was not obtained before surgery, 86 patients implanted at a facility without ethical review board approval and 25 patients implanted by a non-authorized investigator.[3]

According to the FDA medical officer reviewing the Inamed application, “Given these limitations in the ascertainment of asymptomatic rupture [most patients did not have an MRI], there is concern regarding the determination of both asymptomatic ruptures and the total rupture rate.â€[4] This concern is greatly heightened by the findings of other FDA scientists, who studied the use of MRI in the U.S. on 344 randomly chosen women (average age 51) who had had silcone gel breast implants. Sixty eight percent of the women had at least one ruptured breast implant, median age of implant at rupture was 10.8 years, and 21% had silicone gel outside of the fibrous capsule in at least one breast.[5]

Despite the concern about implant rupture and spread of silicone around the body, FDA stated that “Inamed provided no discussion of the significance of implant rupture…..Cases of distant migration of gel to breast, axillary lymph nodes, abdomen, groin…have been reported…[in the published literature].†[6]

Although the 1999 Institute of Medicine Study review on breast implants focused mainly on questions of systemic disease—and there is considerable new information since the conclusion of that review---it did conclude that local and regional complications were the main safety issues and that they had not been well studied. Like the FDA then, they further concluded that information on these complications is crucial for women deciding whether or not they want silicone gel breast implant surgery.

In a review of 35 different studies that encompass more than 8000 explanted silicone gel breast implants, failure was found to be 30% at 5 years, 50% at 10 years, and 70% at 17 years. The only studies that were used were ones that reported implant duration, the total number of silicone gel breast implants explanted, and the number of silicone implants for which shell rupture or failure ("not intact") was confirmed upon surgical removal.[7]

This year marks Sybil Goldrich's 20th anniversary since her battle with breast cancer. But that was only the beginning of her fight on behalf of women. After undergoing a bilateral mastectomy in 1983, Sybil received silicone gel breast implants. Within 2 years, she underwent 7 operations, 2 mastectomies, for a total of 4 sets of implants. During this time she experienced excessive pain, capsular contracture, migration of gel to her uterus, ovary and liver, extrusion, necrosis and rupture. Finally, she chose to have a tram flap procedure. In 1998, Sybil co-founded Command Trust Network, a national clearinghouse dedicated to providing thorough and unbiased information about breast implants. Since then, she has worked tirelessly to ensure government and corporate accountability with regard to breast implants. Her goal is to ensure a safe implant is available to all women. She does not think that the short-term data submitted for FDA approval begins to approach such a goal.

A final irony can be found in the section entitled “Preclinical-Shelf life in one of the FDA documents. The document states:

“Based on all shelf life data provided, Inamed supported a 2.5-year expiration date on their package label.†(tests included gel cohesion, shell ultimate break force, shell tensile set and shell elongation).[8] Even though many women are led to believe that these implants will last at least ten years if not a lifetime, this 2.5 years “expiration date†is a further insult.

The apparent unwillingness of the FDA to require silicone breast implant manufacturers to provide longer-term data as a prerequisite to approval of such devices raises serious questions about whether the agency is enforcing the 1976 Medical Device law to protect patients. The major precipitating event leading to passage of that law was the disaster concerning the Dalkon Shield intrauterine device (IUD). Seventeen women died and thousands of women were rendered sterile because of the increased uterine infections caused by this device. Requiring adequate pre-approval testing for permanently implantable devices such as breast implants was a major principle underlying the passage of the 1976 law but the agency appears poised to negate this principle as they consider the approval of silicone gel breast implants

[1] FDA Summary Panel Memorandum, Sept. 12, 2003, page 33.

[2] FDA Clinical Summary Memorandum, Sahar MK. Dawisha, MD., page 64.

[3] FDA Clinical Summary Memorandum, Sahar MK. Dawisha, MD., pages 9-10

[4] FDA Clinical Summary Memorandum, Sahar MK. Dawisha, MD., page 75.

[5] Brown SL et al. Prevalence of rupture of silicone gel breast implants revealed on MR imaging in a population of women in Birmingham, Alabama. Am J Roentgenol. 2000;175:1057-64.

[6] FDA Summary Panel Memorandum, Sept. 12, 2003, page 37.

[7] Marotta et al. Silicone gel breast implant failure and frequency of additional surgeries: analysis of 35 studies reporting examination of more than 8,000 explants. J Biomed Mater Res. 1999;48(3):354-64.

[8] FDA Summary Panel Memorandum, Sept. 12, 2003, page 29.

And this one below:

http://www.fda.gov/OHRMS/DOCKETS/ac/05/briefing/2005-4101B1-01-02-Appendix-01-Mentor.pdf ,

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