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  Part 2

FOOD AND DRUG ADMINISTRATION

MEDICAL DEVICES ADVISORY COMMITTEE

GENERAL AND PLASTIC SURGERY

DEVICES PANEL

Next is Dr. Anne Kasper.

DR. KASPER: My name is Anne Kasper, and I've been an advocate social science researcher and public policy expert in women's health for more than 25 years. I'm currently a senior research scientist with the Center for Research on Women and Gender at the University of Illinois at Chicago, which is a national center of excellence in women's health.

I've conducted two studies of women with breast cancer, the most recent study completed in May of '99 and supported by the U.S. Agency for Health Care Research and Quality.

I'm the co-editor of a book on breast cancer forthcoming later this year.

I've not received any travel money nor do I have financial ties with any industry or health society, and I am not associated with any implant lawsuits, nor do I derive income from implants in any way.

I'm pleased to present testimony to you today and thank you for the opportunity to do so. The focus of my testimony will be on women's perceptions of the safety of breast implants following mastectomy and the importance or lack of importance breast implants have in their recovery from breast cancer.

In my testimony I draw on the experiences of 53 women who participated in the two qualitative research studies for which I was the principal investigator.

Most of these women diagnosed with breast cancer had a choice of treatment between lumpectomy with radiation and mastectomy. Although since 1985 we have known that the science has demonstrated equal survival with these two forms of treatment, individual women have their preferences.

Many of the women in my studies chose mastectomy for several reasons. One, they feared that lumpectomy would leave cancer remaining in the breast.

Two, they were afraid of the long term effects of radiation.

Most important, however, their choice of mastectomy was made possible by the availability of breast implants and the assurances given them by their physicians.

The women were assured by their physicians that breast implants are safe and effective. Indeed, if any of the women had known at the time that neither silicone gel implants nor saline breast implants have never been approved by the FDA as safe and effective, they would be astonished.

As these women weighed their choices between lumpectomy and mastectomy, the issue of safety and effectiveness of implants did not enter their equations. Rather, like most Americans, they trusted their doctors, and they assumed that some independent authority had tested and approved the devices their doctors would assert in their chests.

In some, the belief that implants were safe and effective made the choice to undergo a mastectomy possible for most of these women. Without this belief, I contend that few of the women would have had mastectomies, and their treatment choices would have been severely limited.

In a paper published in a peer reviewed journal, I discuss the effects of breast loss and breast reconstruction for the women in the earlier of the two studies. The women in this study stated that their physicians promoted breast reconstruction as important to the women's recovery from breast cancer and to a renewed sense of well-being.

A majority of the women who underwent mastectomy chose implants because they hoped to replace the breast lost to cancer, wanted to erase the memory and reminder of cancer, and believed that reconstruction would make them feel whole and normal again.

However, when the women were able to reflect back on their experiences, the majority of them were not convinced that breast reconstruction had meet their hopes and expectations, nor the assurances of well-being promoted by their physicians. The women found that reconstruction did not erase the reality of cancer, nor did it assure their return to normalcy. Neither did the implant replace the lost breast. Rather, the reconstructed breast was a physical approximation that had none of the sensory, sexual, or maternal capacities of the normal breast.

Many of the women sensed that the sole purpose of the implanted breast was for it to appear to be what it was not. Many of the women had a sense of deception, deceived by their doctors, by their own expectations, and by the implant itself.

Breast reconstruction with implants should remain a choice for all women who have lost a breast to cancer. However, the FDA has an opportunity to end another deception, that breast implants are safe and effective for women who have had breast cancer.

I urge this panel to not approve saline inflatable breast implants until appropriate studies have determined whether or not these implants are safe in the short and the long term for women who have had breast cancer.

Thank you.

(Applause.)

CHAIRMAN WHALEN: Thank you.

Are there any questions?

DR. BURKHARDT: Yes, I have a question. In terms of breast reconstruction not duplicating the real thing, we all know that's the case. Is that the reason for your recommendation that we don't approve --

DR. KASPER: No. I'm just telling you that the women had a lot of faith in their implants. They had great hope as to what the implants would be for them, and that they were not a perfect replacement was a disappointment to them. Even though many of them had been told by their doctors it wouldn't be perfect, it was for them, for many of them, it was far less than perfect.

And the point I think I was trying to make was the risks associated with implants for many of them were not worth it because the satisfaction levels were not high.

DR. BURKHARDT: So is it your recommendation then that until the implants can be made more perfect we not approve them?

DR. KASPER: No. It's really more an issue of safety and effectiveness. I mentioned that because this was what some of the women in my studies had told me about implants, and I think it simply behooves the FDA when dealing with women's lives to have the highest standard regardless of other issues, as well.

DR. BURKHARDT: Thank you.

DR. BANDEEN-ROCHE: I'm sorry. I think I just realized that I didn't quite put together everything that you said. At the end of your presentation, I thought I heard you say that implants should remain an option for women who had had their breast --

DR. KASPER: I breast reconstruction.

DR. BANDEEN-ROCHE: Breast reconstruction. Thank you.

DR. KASPER: Should remain an option, yes.

DR. BANDEEN-ROCHE: Thank you. Thank you.

CHAIRMAN WHALEN: Thank you, Dr. Kasper.

Next we'll hear from Ms. Carol Sherman.

MS. SHERMAN: Hello. Although no less passionate about my statement, this should only take about two minutes.

First, I'd like to thank you for listening to me today. I feel it's important for the panel to hear my very positive experience with the saline breast implant.

A little over a year ago I was diagnosed with early breast cancer. Within two weeks of the diagnosis I had a mastectomy and immediate reconstruction with a saline filled breast implant.

The emotional trauma of going from a totally health and fit person to someone who discovers they have this dreaded disease is overwhelming, to say the least. As you can imagine, there were many very emotional thoughts going through my mind, mostly having to do with am I going to live.

At the same time there was one good thing. I never had to envision myself with a deformity. I never even had to think about myself without a breast, not for one day.

I still remember my doctor's words. "But you can have immediate reconstruction and wake up from surgery with a breast." I took tremendous comfort in those words, and I was informed of both the benefits and the risks at that time.

Most importantly, I was luck enough to be able to take comfort in the good news that my cancer was caught early. I thought to myself, as long as I'm healthy and free of the disease I don't care if one breast will be filled with a saline filled implant instead of breast tissue.

What I did care about was whatever the filler, I still had a breast. I was lucky enough to beat this disease. I didn't want a daily reminder. I didn't want to be ravaged with a missing breast. My self-esteem could not have handled that.

A very important part of surviving this kind of emotional trauma for me was to keep things as normal as possible, to bring normalcy back to my life as quickly as I could.

Within four weeks of my surgery, I put on a sports bra feeling comfortable and looking like I had perfectly normal breasts and went back to my regular and fairly rigorous workout schedule. From day one, I have had absolutely no problems with my implant.

About a month later, I attended a special family event where comfortable and feeling good about my appearance, I was able to wear a favorite formal gown. Maybe four to six weeks after that, wearing another favorite stretch bathing suit to the pool was not even an issue for me. You couldn't tell that three months prior I had had a mastectomy because I had reconstruction with a saline filled implant.

I felt like me, normalcy. I know the most important part of my emotional recovery was returning to all of the theaters of my life in my normal way. Thank God I had this option. I had the option to feel whole, my body intact, with two breasts.

I don't even want to think about where I would be emotionally if I didn't have that option. It's a personal decision. I feel very strongly that all women like me should have the option to choose saline filled breast implants as long as they're fully informed of both the benefits and the risks. It's a matter of emotional health.

Thank you.

CHAIRMAN WHALEN: Thank you, Ms. Sherman.

Are you at all involved with any practice or company that is involved with putting these devices in?

MS. SHERMAN: No, I'm not.

CHAIRMAN WHALEN: Are you involved in any lawsuit that involves breast prosthesis?

MS. SHERMAN: No, I'm not.

CHAIRMAN WHALEN: Thank you.

That being done, we will now proceed with the presentation by Dr. Celia Witten, Director of the Division of General and Restorative Devices, to discuss the regulation of saline filled breast prostheses.

DR. WITTEN: Thank you. Thanks for your patience during my effort to enter the 21st Century.

Good afternoon. I'd like to welcome everyone to this meeting of the General and Plastic Surgical Devices Advisory Panel.

I'm Celia Witten, Division Director of the Division of General and Restorative Devices at the FDA.

Over the next few days, we will be asking you to provide us with your expert recommendations on three pre-market applications for saline filled breast implants.

You are also charged with the very important task of providing us with recommendations regarding the kind of information that is important to provide in patient labeling so that women can be adequately informed.

I'm going to provide some brief background information for today's meeting. I will summarize the regulatory history of saline filled breast implants and the events that bring us here today. I will summarize the types of information provided the sponsors to assist them in planning to collect the preclinical and clinical data needed to support a pre-market approval application.

This information is described in the draft breast implant guidance document. This document was originally provided in 1994 and most recently updated in 1999. The recent updated version incorporated the clinical study design elements that were highlighted in the points to consider letter issued to industry in June of 1996, which I will also summarize briefly.

I will speak also about what we have learned from the literature since the time that these products were classified.

As has already been noted here today, saline breast implants have been on the market since before 1976. FDA classified these products as Class III products in 1988. Because these products were grandfathered as pre-amendments products, they were allowed to remain as marketed products until such time as FDA issued a rule calling for safety and effectiveness information. New products could enter the market via the 510(k) pathway during this time. Products could also be made available during investigational study.

When FDA issued a rule calling for safety and effectiveness information in a pre-market approval application, termed PMA, this regulatory status changed. FDA issued the call for submission of pre-market applications for the saline filled breast prosthesis on August 19th, 1999. The sponsors had 90 days from the time of that call to submit a PMA and have it filed.

All products need to have an approval of the pre-market application within 180 days of that call that was issued on August 19th in order to remain on the market. Thus, the review process for these pre-amendments products, which are already on the market at the time that safety and effectiveness data is called for, is different with respect to timing from the review of PMAs for novel products that are not yet on the market.

For pre-amendments products, there is limited time for interaction with sponsors during the review process prior to the panel meeting because of the 180-day time frame until products are either approved or off the market.

In addition to working interactively with sponsors prior to the call for PMAs, we continue to work with sponsors during the review process.

FDA has provided guidance both in written form and in discussions with sponsors to assist sponsors to develop the data needed to support a pre-market application. The guidance document for these products that is available provides manufacturers with information regarding data to submit in several important areas.

In particular, the chemistry section describes -- suggests how to describe and characterize the device, and the toxicology section includes a description of the types of biocompatibility information that is necessary.

Mechanical testing as described in the type of clinical data need is also covered.

As I mentioned before, the current guidance document is a revision of an older version. The clinical portion has been incorporated -- has been updated to incorporate other information the FDA provided to sponsors. In particular, I want to note in 1996 the letter that FDA issued to sponsors and to industry that outlined essential elements of a clinical study of these products. It is worth highlighting some key points.

The FDA suggested a sample size adequate to determine the adverse event rate with reasonable precision and suggested 500 women be followed to the end of the study. The suggested worst case precision within which to be able to describe the incidence of adverse events, such as deflation, was plus or minus four percent.

Separate augmentation and reconstruction cohorts were suggested because of the potentially different performance in those groups.

A two year minimum follow-up pre-market was suggested in that letter. It was also suggested that sponsors plan ten years' total follow-up, some of the follow-up to be performed post market. The letter suggested follow-up intervals, and in addition to the primary study endpoints, quality of life, and connective tissue disease screening were suggested.

Since 1988, when these products were originally classified, there have been a substantial number of public contributions to the scientific literature that have added to our knowledge of these products. Although there are a number of possible and actual types of complications described in the literature, I would like to touch briefly on two types of complications, in particular: connective tissue disease and local complications and re-operations.

I would like to discuss what we have learned since 1988 these two subjects. There have been a number of epidemiologic studies investigating the potential contribution of these products to the development of connective tissue disease. It appears from the literature that there is no or at most a small increased risk of connective tissue disease from these products.

There are some limitations to the studies performed, however, and these include the heterogeneity of the products in most of the studies and the fact that some of these studies looked at classical connective tissue disease, but were not designed to assess a typical connective tissue disease.

We have also learned from the literature that the risk of local complications and re-operations for these products as a whole is not insignificant. Local complications can include deflation, contracture, infections, breast pain, and hematoma.

These complication rates are reported in the literature very widely. The FDA and DHHS commissioned a report by the Institute of Medicine on the safety of silicone breast implants based on information in published literature. The Institute of Medicine review included saline breast implants which have silicone elastomer shells. The Institute of Medicine report concluded that local and perioperative complications are the primary safety issue with silicone breast implants. This group in their report also noted a deficiency in the literature with respect to product specific information.

Over the next day and a half, you will be reviewing the product specific information that sponsors have provided in their PMAs. You will be asked to evaluate the information in each pre-market approval application and advise us as to whether there is sufficient information in each application to provide a reasonable assurance of safety and effectiveness.

You will be asked to make your recommendations based on data contained within the PMAs and based on your scientific knowledge. You will be provided a list of questions for each PMA to consider as you review the data. Each application will be considered separately on its own merits.

We have heard this morning a number of comments from the public, and one of the themes that emerged is the important question about adequate informed consent from patients and how to make sure that patient consent is truly informed.

On Friday, we will seek your guidance on the important task of assessing what information we can provide to women to best assist them to make informed decision regarding breast implant surgery.

The FDA very much appreciates your giving of your time and expertise to accomplish this important task. And now I'm going to turn it back over to you, Dr. Whalen.

CHAIRMAN WHALEN: Thank you, Dr. Witten.

Does the panel have any questions for Dr. Witten?

(No response.)

CHAIRMAN WHALEN: Thank you very much.

DR. WITTEN: Thank you.

CHAIRMAN WHALEN: Next, Dr. Wendie Berg will discuss considerations of imaging patients with breast implants.

Dr. Berg.

DR. BERG: Thank you, Mr. Chairman, members of the panel.

If I can have the lights down a little bit, as a radiologist.

(Laughter.)

DR. BERG: Can I have the next slide, please?

I'm going to be presenting imaging considerations largely focusing on breast cancer diagnosis in women with breast implants. Rupture, particularly with saline implants, is really a clinical diagnosis.

Periprosthetic fluid is a common finding on imaging, but we dismissed this. It's not thought to represent leakage on the whole, and again, I'm going to focus my comments on detection of breast cancer.

Could I have the next slide, please?

We can argue about the specific number of women who have undergone breast implantation, but approximately two million women in the United States are affected by it, and again, most of my comments are going to be directed to women with augmentation rather than reconstruction since we do not generally image the breast after mastectomy.

If one considers the rate of breast cancer to be approximately one in nine over a course of a lifetime, we can estimate that roughly 200,000 women with breast implants will develop breast cancer.

Next slide, please.

Mammography remains the standard for early detection of breast cancer. The goal, of course, is to detect breast cancer before it becomes palpable at an earlier, more curable stage. We know from the literature that 90 to 95 percent cure rates are achievable when breast cancer is detected at Stage 0 or Stage 1, and this is nonpalpable disease, largely found by mammographic screening.

Survival rates and disease free survival, in particular, drops to 60 to 70 percent when lymph nodes are involved by the tumor. That number further drops to approximately 40 percent when the lymph nodes are involved and the primary tumor is palpable at presentation.

Next slide, please.

There have been several studies looking at the risk of breast cancer in women with implants, and they have rather conclusively demonstrated to date that there is no increased risk of breast cancer as a result of the presence of the implant, and in fact, in several smaller studies there has been actually a slightly decreased rate of breast cancer compared to that expected.

May I have the next slide, please?

Some general considerations first, and then I'll get into specific data that is available.

The American College of Radiology Standards require the performance of routine views, as well as implant displaced views in order to adequately evaluate the breast tissue in patients with implants. As a result, we can expect at least double the radiation dose to the breast tissue per mammogram obtained in such patients.

Further, the presence of implants in and of themselves is an indication for diagnostic mammography, which would allow the mammograms to be reviewed by the radiologist when the patient is there in the suite. The reason for this is that many times the technologist is unable to obtain an optimal mammogram at the first pass, and additional views would be needed to adequately compress or evaluate the breast tissue.

As a result, we again anticipate at least more than double the cost of annual surveillance mammography.

Next slide, please.

These are rather difficult to project, but just to illustrate, this is a mammography with routine views first in a patient with silicone implants, and the next slide, please. The corresponding images are obtained when the implant is pushed back out of the field of view, allowing better compression of the implant -- of the parenchyma itself.

Next slide, please.

Even with such techniques, there is a reduction in the visualized breast tissue in patients who have breast implants. It's difficult to answer absolutely how much that reduction would be in any given patient. There is some data from a series where patients' mammograms were measured both prior to and after implantation, and overall it was found that 30 percent reduction in the visualized breast parenchyma in the absence of any contracture.

If contracture is present, it's more difficult to compress the breast. As a result, greater reduction, on the order of 50 percent, was observed in the amount of visualized parenchyma. Even with implant displacement techniques, the amount of breast tissue that we see is still decreased compared to a patient without implants, and in fact, on average that was 25 percent still obscured with implant displacement; greater, on the order of 35 percent, if the implants are subglandular compare to subpectoral locations.

Next slide, please.

To illustrate, this is a woman who had silicone implant placed behind the muscle and there's very little breast tissue visible on the routine views.

Next slide please.

And this is difficult to project, but on the implant displaced views, a subtle cluster of calcifications was noted, and it's actually right here in the middle of a spot magnification view. This patient had a very small focus of ductile carcinoma in situ that was detected despite the presence of the implants.

Next slide, please.

However, it's not always so easy to displace the implant. This woman has a saline implant, and you can see that it's still quite dense, although you can see a little bit of the internal structure and the folds of the edge of the implant.

And despite every attempt at implant displacement, this is the best mammogram that could be obtained. She had very little breast tissue.

Next slide, please.

She underwent an ultrasound. I don't know if we can have the lights down any further -- underwent an ultrasound that showed the implant itself, and there was a very subtle mass anterior to the implant that was an early infiltrating ductile carcinoma, completely invisible on mammography as a result of the implant.

Next slide, please.

In general, as I've mentioned, the implant can hide the breast tissue directly and, as a result, can hide lesions as well in the breast tissue. Adequate compression is sometimes difficult to achieve due to contracture, pain, and the mass effect of the implant itself. It can displace the tissue and cause overlap in the normal parenchyma.

It can be difficult to visualize lesions in both projections. You might see that lesion inferiorally in the breast, and yet it's hidden by the implant in the craniocaudal projection, despite implant displacement techniques, and this can confound interpretation as well as limit the biopsy options and make it more difficult to biopsy any lesions that are seen.

And finally, in the woman who had undergone removal of an implant, there can be extensive scarring, not always, but there can be. That can confound interpretation. There can be residual calcifications, particularly if the capsule is left behind after removal of the implant, and both of these can mimic cancer.

Next slide, please.

To illustrate, again, this is a patient who has a silicone implant behind the breast tissue, and this was the best mammogram that could be obtained. Very poor compression was achieved in the tissue itself, and you can see there's a rather large density. This is approximately four centimeter invasive ductile carcinoma was visible, but if there were any other lesions in this breast, it would be very difficult to assess that.

Next slide, please.

And, again, this doesn't project well in this lighting, but this was a patient who was found to have a subtle cluster of calcifications in the inferior breast.

Next slide, please.

But she had ruptured saline implants bilaterally, and we were unable to localize the calcifications in the other plane because they really proved to be on the inferior breast directly underneath the implant. We were able to biopsy these with stereotactic technique and found fibrocystic change in this case.

Next slide, please.

After implant removal we can see a variety of changes that are very suspicious. This particular patient had explantation of an intact saline implant, but remained with a spiculated density at the chest wall which, if you didn't know the history, would be considered highly suspicious.

She then underwent ultrasound -- next slide, please -- and was found to have a seroma.

Next slide, please.

Another patient who had undergone explantation, again, had a spiculated density of the chest wall, and there were actually calcifications evident within this, a lot of deformity in the breast tissue, difficult to get an adequate mammogram, especially in the inferior breast.

This proved to be an infective collection. We're having fund. I think you need a few more microphones.

Next slide, please.

I mentioned that the capsule itself can cause some problems with interpretation, and the main reason for that is the presence of calcifications in the capsule itself, a rather common finding. Judy Distouet and colleagues found about a quarter of the patients have some degree of calcification in the capsule. Usually it's relatively easy to identify because it's relatively coarse and typically benign, but when it's first starting it can, again, mimic early cancer.

Next slide, please.

Just an illustration of these calcified capsules. You can see it really can get quite extensive. This patient had severe contracture, as well.

Next slide, please.

And the calcification in that capsule can be visible, easily distinguished from ligament calcification or not. If it's left behind, this capsule itself can form the pocket for collecting fluid, and as I mentioned that one case, infection.

Next slide, please.

I think the overwhelming question which I was asked to address is really will the diagnosis of breast cancer be delayed in women with implants as a result of suboptimal mammography. Unfortunately I'm not sure I can answer this question. There are only several small, retrospective studies that have been performed which are really inadequate to answer this question at this time.

Next slide, please.

I'm going to present a literature review, but there is, again, minimal data and keep in mind most serious report results from silicone implants, not saline.

Next slide.

I think there is some evidence to suggest, however, that the results may be generalizable between silicone and saline implants. A study again from Washington University in 1989, using the American College of Radiology and Mammography Phantom, which includes a variety of artifacts, including dense specks, which mimic calcifications, and densities which mimic early cancerous manifests as masses, was used with a variety of types of implants positioned on top of the Phantom and a normal mammography exposure performed.

In their study, they found the shell alone minimally altered the ability to detect the various artifacts, but the shell filled with either silicone or saline completely obscured all artifacts.

Next slide, please.

What kind of performance are we expecting from mammography? Well, this is a good question. I'm not sure we have the absolute answer, but in the American Health Care Policy Research Manual from 1994, we do have benchmarks that were established by a variety of experts in the field suggesting that with routine screening, we should be able to achieve detecting of the majority of cancers at Stage 0 or Stage 1, over 50 percent, and that node positivity should be under 25 percent of the patients diagnosed, and overall sensitivity of mammography on the order of 85 percent should be achievable.

I think that last number may be a little optimistic. There have been multiple studies showing performance. In practice it's closer to 78 to 80 percent detection of breast cancer, allowing for a variety of factors, including errors in interpretation.

Next slide, please.

These are the references on which I have drawn, the literature that does exist on implants and breast cancer detection.

Next slide, please.

There's a lot of information here, but just to summarize, you can see across these studies very small numbers of patients, and I think these are patients who had augmented breasts with usually silicone implants and were not undergoing annual mammographic screening. So this is simply at the time of detection looking at results.

They had ten patients, six patients, seven who had implant displacement views, as well as routine views, a total of 41 patients in the study of Silverstein, but all small numbers of patients in these studies.

Overall, the degree to which cancers were visible mammographically ranged from 55 percent up to a high of 86 percent. Overall palpability of the lesions detected was quite high across all these series. The lowest was the first study here with Leibman and Kruse, where six out of ten cancers were palpable at presentation, but the vast majority of the cancers in these studies were palpable, and again, this may reflect the lack of routine screening in these patients.

Nodal positivity was also higher than that benchmark of 25 percent across most of these series. One study in particular I want to call your attention to was that of Laurie Fajardo and colleagues done at Arizona. At the time 18 patients all had implant displaced mammography views, as well as routine views, and in that series the sensitivity was only 67 percent, and in fact, 39 percent had positive lymph nodes at presentation.

Next slide, please.

So to summarize, the majority of patients in these studies that have been done to date had only routine mammographic views without implant displacement, and we've already shown, I think, that it's mandatory that the implant displacement views be obtained in order to adequately evaluate the parenchyma.

More cancers were palpable at diagnosis than in general. We expect that number to be about 40 percent palpable at presentation. In these series it was from 80 to 90 percent in the majority of the studies.

The stage distribution of cancers, however, in the papers that had control groups was not found to be significantly different in women with implants, nor was the survival found to be different.

Okay. Next slide, please.

Overall, where it could be assessed, 66 percent of cancers were visible on mammography with implants, and when implant displacement views were included, again, very small numbers, but 72 percent of those cancers were then visible on mammography.

That's lower than the expected sensitivity, as I mentioned.

Next.

I think of greatest concern though, it's difficult to make recommendations because the performance of mammographic screening in women with saline implants or any other implants, for that matter, has really not been adequately evaluated, particularly with high quality mammography and implant displacement views.

We can suspect from the data that does exist that there's at least a ten to 20 percent decrease in mammographic sensitivity, and that alone, even that relatively conservative number, has the potential for delayed diagnosis of cancer in 20 to 40,000 women.

Are there other alternatives to mammography? Very briefly, yes, there are, but they all have their limitations as well. Ultrasound is being used more and more widely. It has a clear role in evaluating palpable abnormalities in all patients, including those with implants. We also use it when there's a mammographic density that we're concerned about.

It's easy to guide biopsy lesions as we see under ultrasound, but the problem is screening ultrasound is less sensitive to the very early carcinomas, particularly ductile carcinoma in situ, than is mammography.

Further, it's technically extremely demanding. It requires a lot of expertise on the part of the person doing the ultrasound, usually requires a physician to perform the task, and at least in the United States the costs of screening ultrasound are on the order of $300 per patient compared to approximately $75 for mammography.

Further, lesions behind the implant will not be well seen even on ultrasound.

Next.

Just another slide that illustrates a cancer adjacent to the implant on ultrasound.

Next slide, please.

It has been suggested that MRI may be appropriate in these patients. In fact, one recent reference suggested it's the modality of choice for detection of primary breast cancer in the augmented breast.

Well, it's clearly a very sensitive test. The implant does not obscure detection of lesions. However, it does require injection of intravenous contrast. It's extremely expensive. A billed cost is about $1,000 for a contrast enhanced MRI.

It's difficult to guide biopsy lesions seen only on MRI. It's technically very demanding and not widely available.

Next slide, please.

Just to illustrate though, it is very nice to demonstrate cancers on MRI. We have here an implant at the lower right-hand corner of the slide, and you can see the area of enhancement just above it is a spiculated mass with associated rim enhancing lesion, and these were two adjacent cancers that were nonpalpable in a woman with implants.

Next slide, please.

MRI done improperly, however, still doesn't help obviously and it can be very demanding. This is a woman that we saw in our practice with a saline implant, some periprosthetic fluid inferiorally; several cysts in the breast, but no contrast had been administered and, therefore, no lesions were detected of significance, and she had a breast cancer that went undetected for another year.

Next slide, please.

One other potential method for screening would be nuclear medicine techniques, such as Sestamibi or Miraluma, as it's more commonly known. However, again, the sensitivity is not very good. It's an expensive test, again, and in particular, I call your attention to the statistic that nonpalpable lesions under a centimeter, only 48 percent of these were detected.

And so I don't think there are very many good alternatives to mammography, in summary, but I think we also have at least reason to consider that there may be some limitations of mammography in patients with implants.

Thank you for your attention.

CHAIRMAN WHALEN: Do any of the panel have questions for Dr. Berg?

DR. ROBINSON: I have a question.

CHAIRMAN WHALEN: Yes.

DR. ROBINSON: Just a question. How do you think MRI will evolve as an imaging technique in the evaluation of women with implants or one where you really cannot get good imaging by your other --

DR. BERG: I think more and more we're finding from data from international studies and grant sponsored research trials now that it is an extremely effective method at finding early cancer. I think the problem is going to be who's going to foot the bill.

It's an extremely expensive test. It's very demanding, and if insurance companies will foot that bill, great, we can do the test. But I think that as a society, we really can't afford to screen women with breast MRI at this point. So we've got that double edged sword.

DR. ROBINSON: What numbers would be involved if you weren't screening them per se, but just doing women where you could not get good imaging by another technique?

DR. BERG: Well, again, I think you're looking at at least probably 30 percent of women with implants where you've got significant limitations. You've got women with dense breasts, women who are at high risk. We're probably looking overall at the population of maybe, again, probably 30 percent of the overall population who has mammography routinely where MRI would stand to benefit them.

It is routinely done in women who are at high risk at some centers already, and it's being more and more widely used.

DR. ROBINSON: Yeah, that's what my impression was.

The last question. I'm sorry. For lesions behind implant, is spherical CT or helical, anything in that area going to have any implication?

DR. BERG: I thought about including CT. The reason I did not is that it's got very high radiation dose to the patient, on the order of two to three rads as opposed to mammography is on the order of .2. You don't want to irradiate the breast with tenfold as much radiation. You're going to be causing a significant number of cancers.

So it also is not -- it's clearly not as sensitive a test for certainly not in situ disease and may pick up invasive cancers with the injection of contrast, but, again, I don't think anybody wants to advocate CT for that purpose.

Any other questions?

DR. BURKHARDT: I have a question. Most of the studies that you quoted here are of necessity a few years old.

DR. BERG: Right.

DR. BURKHARDT: In the last five years or so, there's been a tremendous shift in the placement of these implants in the plastic surgery community. They're almost all put behind the muscle now --

DR. BERG: Right.

DR. BURKHARDT: -- in nonreconstructive cases.

DR. BERG: That's right.

DR. BURKHARDT: Do the ACR standards still require double the radiation dose?

DR. BERG: Yes, they do. I think it's very explicit. I looked in the most recent ACR standards that I have, which is 1998, and it does require the implant displacement views be obtained as part of routine practice, and I think you'd be very hard-pressed to defend if you missed a cancer as a result.

It's very difficult. Even with subpectoral implants it's very difficult to adequately compress the entire tissue, depending how much tissue the patient has.

DR. BURKHARDT: Do you have any sense of what percentage of women in the eligible and in the recommended cancer screening group actually have mammograms according to the ACR standards?

DR. BERG: Good question. I was thinking about discussing that. I don't really have good data on that, but I can tell you that many women with implants hesitate to have mammography even once they become of that age because it's a painful exam, and it's more involved.

DR. BURKHARDT: How about women without implants?

DR. BERG: Well, without implants, we know it's about 60 to 70 percent who do under -- have had a mammogram within the last two to three years.

DR. BURKHARDT: Thank you.

DR. BERG: Un-huh.

CHAIRMAN WHALEN: Ms. Brinkman.

MS. BRINKMAN: For routine screening mammography, does insurance pay for the extra views then for the displacement of the implant?

DR. BERG: As a rule, insurance does pay the additional cost, although oftentimes a woman will still have a deductible and still bear a greater cost as a result of having to have a diagnostic mammogram on a yearly basis for what amounts to screening.

CHAIRMAN WHALEN: Thank you, Dr. Berg.

We are now going to proceed to the review of the first PMA, and that is going to be the one of Mentor Corporation. So I would ask those who are going to be making that presentation to come forward.

I would like to remind all of the public observers at this meeting that while this portion of the meeting is open to your public observation, you as public attendees may not participate unless there were to be a specific request of the panel.

We now turn it over to Mentor Corporation who, if necessary, can take upwards of a full hour for their presentation.

I'm being outvoted by the mutiny here. I was going to hold off on the break until afterwards, but it seems that all of the panel has bladders the size of walnuts --

(Laughter.)

CHAIRMAN WHALEN: -- we will take about a seven minute break and then resume.

(Whereupon, the foregoing matter went off the record at 2:43 p.m. and went back on the record at 3:04 p.m.) CHAIRMAN WHALEN: And, again, we are now going with the sponsor's presentation. So we turn the table over to Mentor Corporation.

MR. GETTE: Thank you, Mr. Chairman and distinguished members of the advisory panel.

I am Anthony Gette, President and CEO of Mentor Corporation.

For more than 30 years, Mentor has been dedicated to the research, development, and marketing of innovative and effective medical devices that meet the needs of patients and physicians. We sell products in more than 60 countries around the world. These products include devices used in plastic and reconstructive surgery which we will present here; products to treat urological disorders, such as for prostate cancer, bladder cancer, erectile dysfunction, and pelvic flora disorders; and a variety of consumable products, primarily for the management of urinary incontinence.

All of our products are designed to improve the quality of life for patients who use them. Today we focus with you on our saline filled breast implant products. The heart of our presentation is data that we believe confirms that our implants are both safety and effective and warrant your recommendation of approval of our PMA to the FDA.

For breast implants, our goal is to provide a safe and effective option so that women can choose whether to restore the breast following cancer, trauma, or correct a deformity, and also to choose a more satisfying breast appearance through augmentation.

Saline breast implants have been available for more than 25 years. There is a large body of information based on such a long history. Reports from prestigious scientific organizations, such as the Institute of Medicine and others, have provided invaluable information with respect to the long term safety of breast implants.

For a number of years we have worked closely with the FDA to develop the preclinical and clinical information contained in our PMA submission. We will present some of the results of this comprehensive effort this afternoon.

We believe that our PMA application clearly demonstrates safety, defines the localized risks of implant surgery, and for the first time quantifies the effectiveness and benefits of saline filled breast implants.

Our commitment is that the implants we manufacture are safe, effective, and are appropriately supported by scientific studies. We are proud of our pivotal trial, the saline prospective study, or SPS, and believe it will significantly advance the clinical knowledge about breast implants.

Our job does not end there. We are committed to continuing research and to the development of ever better products.

Our presentation today has four parts. Mr. Bobby Purkait, Mentor's Senior Vice President for Science and Technology, will describe our preclinical testing program.

Ms. Pamela Powell, Manager of Mentor's Clinical Programs Department, will describe the clinical trials we have sponsored, including our pivotal trial, the saline prospective study.

Dr. Bruce Cunningham of the University of Minnesota will describe the results with regard to clinical safety.

Dr. Rebecca Anderson of the Medical College of Wisconsin will then describe the effectiveness and benefits of Mentor's saline filled breast implants.

At the conclusion, Mr. Purkait will summarize our presentation and lead our response to your questions. He will also introduce our question and answer response team at that time.

It is now my pleasure to introduce Mr. Bobby Purkait. He is a polymer science engineer, and for the past 15 years has led Mentor's research and development efforts. He has been the primary coordinator of Mentor's preclinical and clinical submissions on the saline filled breast implant.

Mr. Purkait.

MR. PURKAIT: Thank you, Mr. Gette.

Good afternoon, Mr. Chairman and members of the panel. I'll be presenting an overview of our preclinical data today.

In that overview I'll be describing the devices which are seeking approval today. I'll be also describing the separate issues that we have considered in our evaluation, and in that evaluation we have conducted various testings, such as biological, chemical and mechanical and manufacturing. I'll be describing some of those testings and the findings from those test results, and finally I'll summarize.

These pictures represent the Mentor's family of saline filled mammary prosthesis. There are two saline filled mammary prosthesis. The one on the left-hand side is a fixed polymer prosthesis, which has been filled at the time of implantation. The right-hand side is an adjustable volume prosthesis. It's filled intraoperatively or postoperatively.

These two devices come either in smooth or textured surface and also can be found in round or contoured shapes, and the sizes vary from 125 to 700 cc's. All the variations of these sizes and shapes are denoted by styles number, which has been given in our PMA.

These schematic diagrams furthermore illustrate the design and the materials that we have used in our devices. These two devices, one on the left-hand side, has elastomer silicone shell, and the right-hand side the adjustable one also has silicone elastomer shell.

These silicone materials are being used commonly in many other medical devices, and a large body of data exists both in Mentor data bank, as well as in the open literature.

The left-hand side, the fixed volume one, has a valve called diaphragm valve on the anterior surface of the device, and the right-hand side, the adjustable volume prosthesis called Spectrum has a kink valve which is used to fill intraoperatively or postoperatively.

All variations of these devices have same materials, have been manufactured under similar conditions, tested and released under same requirement and specification.

In our preclinical safety issues we have considered safety assessment by two different ways. First, we concentrated on the toxicological safety assessment by chemical characterizing our device and materials, and also conducting some various biological battery of testings.

To assess the performance and durability of these devices, we have done mechanical testing and also developed information from manufacturing process and quality of the products information.

In the toxicological safety assessment, we have used the biomaterial toxicity risk assessment paradigm. From that paradigm we have done a chemical characterization of the device material and also we have characterized the toxicity of those materials. We also have developed information regarding exposure to the constituent materials in the course of the device.

Now I want to share with you some of the chemical testing that we have conducted. This particular slide shows a battery of testings, and these testing demonstrate in case of biodegradation we found a device or material, stable and nonbiodegradable, under the exposures of harsh conditions of enzyme, peroxides or lipids.

When we look into the surface, we found the surface composition is made solely from polydimethosol siloxin (phonetic), and those surfaces were examined by various different instrumentation techniques, such as IRS, SIMs, SEM, to say some of those instrumentation techniques.

When you look into the state of the cure of our shell, we found it is fully polymerized, and the cure is 100 percent cured there. PCBs are not detectable in our devices. When we looked into the metals and extractables, we found all levels are below the toxicological concerned.

This shows the total battery of our chemical calculation of a device and our materials.

Similarly we have done a significant battery of biological safety testings, and this particular site, we present those testings. The results from those, we have not found any reproduction or developmental toxicity problem, no pyrogenicity with our materials or our devices, no genotoxicity.

The biostability of our device was found to be excellent. No chronic toxicity and carcinogenicity, and when we look into the immunological response, no adverse reaction from those either. This represents the total battery of testings for our device and materials.

As we move on and characterize these materials under mechanical testings, these are the test batteries that we have conducted on a device and materials.

We recognize that this device would be used in clinical settings, and in that use there will be -- it will be subjected to mechanical load and stresses in order to establish an evaluative behavior of a device and materials under various mechanical conditions. We subjected the device to the various mechanical testings.

Now I will share some of the test results with you now. As you look into the basic mechanical properties of our material and device, we conduct ASTM testing, such as tensile, ultimate elongation, tear/break force, et cetera, and we found our device and materials exceed ASTM specification.

When you look into the joint testings, we also found it meets the specification as defined by ASTM. Active material, what we use in our device, has excellent abrasion properties. However, when it has been upgraded (unintelligible), we found no silicone materials were found on the surface.

When looking at the expanded devices, some of the devices were implanted up to six years, but when we test those, we found the mechanical properties have not significantly changed.

Fold flaw was determined by the explanted devices. When we examined those devices, we found the fold failure was primarily due to the concentrative force that was onto the fold.

The fatigue testing has been applied to our devices. Through this testing we have established the F and N curve (phonetic), and that has demonstrated a large safety factor against rupture.

I'll share with you an example of our test mechanism and test set-up where we used in a laboratory. This particular device shows the procedures or the set-up, what we use to understand the mechanism of rupture failure. There's a device sitting in the bottom of this cage. There's the foam. This is the case. The whole thing has been emersed into 37 degree saline solution, and we have applied the load conditions of 30 to 85 pounds and cycled those many, many times.

Here is an example for ten million cycles, no failure.

We looked into the static impact testing. Our devices can withstand a significant amount of energy on our device exceeding in excess of three times that one might experience in a car accident for 35 miles an hour collision.

I'll show you an example of those test mechanisms again. Here the prosthesis is sitting in the bottom under the saline solution at 37 degrees, and the weight has been dropped from 9.2 feet, with a load factor of 35 pounds and then 45 pounds. Impact energy generated on this device, about 444 to 570 and no rupture was noted.

However, this device also cycled even before this for ten million cycles, indicating a great assistance to rupture of these devices.

This particular impact test has been shown previously. Again 35 pounds, 45 pounds load were impacted on these devices and no failure was achieved or seen.

Static rupture is also an important phenomenon for our device to understand. When we can place our devices to a load of 162 to 344 pounds of weight, we can practically get this device into a pancake shape without noting any particular rupture or crack on the particular device.

Looking at the valve competence test, we found this internal pressure of this valve exceeds in excess of the in vivo use.

Looking into the radiolucency testing, we found the radiolucency is significantly higher in comparison to the silicone gel.

As we complete this battery of mechanical testing, we conclude that our devices and materials survive mechanical stress that exceeds the clinical use conditions.

We looked into our manufacturing process extensively. We have a rigorous manufacturing process and a quality system. The process validation system has been done extensively to understand our processes table, and we produce consistent quality product. We have a significant amount of in process and other testing throughout the operation. We do not release any product without having any finished device specification being met.

We believe that our manufacturing provides a good, consistent, reliable product, and the conclusion from our operation of the evaluations of the results are devices are produced using a validated process and equipment under GMP, which meet quality standards. We have a well documented quality system that insures that we have a safe, reliable, and quality products.

I'd like to summarize our preclinical testings by this way. We have done an extensive preclinical testings which has been documented to understand the behavior of our materials and device by the state of the art methods.

We have characterized the potential extractables, identified and quantified those which are found to be below the toxicological concern. Our device materials and devices are stable and nonbiodegradable. A total battery of biological testing documented no toxicity testing issues, and devices and materials survived mechanical stress testing that exceeds clinical use conditions.

Now I would like to invite Ms. Pamela Powell to describe our clinical studies. She will be primarily talking about the design and the design parameter of our studies.

Ms. Powell.

MS. POWELL: Thank you, Mr. Purkait.

Mr. Chairman, panelists, I will present the clinical studies that Mentor has undertaken in support of the saline PMA and focus primarily on the three year saline prospective study.

Mentor is seeking approval for the indications of cosmetic augmentation, breast reconstruction following mastectomy or trauma, asymmetry, ptosis, aplasia, hypoplasia, replacement or revision of unsatisfactory implants, and combined breast and chest wall deformities.

Mentor has funded or conducted five clinical studies, two prospective and three retrospective. The prospective studies include Mentor's three year saline study of 1,680 patients and the large, simple trial, a one year study of 2,400 -- excuse me -- 2,347 patients.

The three retrospective studies include Mentor's study of 822 patients with ten years of follow-up, the SEER study with 1,159 patients with ten years of follow-up, and the Cunningham study with a minimum of ten years of follow-up on 450 patients.

These results will be presented by Dr. Bruce Cunningham.

With the data of the prospective study unavailable until its completion in 1998, FDA wanted safety data on a large population in a short period of time. The large, simple trial was designed to meet those needs and consists of one year of follow-up on 2,347 augmentation, reconstruction, and revision patients, with the safety objectives to assess infection, deflation, and capsular contracture.

The patients were seen at baseline four to six weeks, six months and one year.

The saline prospective study or pivotal clinical trial is a comprehensive study designed to look at both safety and effectiveness. The primary safety objective was to assess short term complications, such as infection, seroma, deflation, capsular contracture, and nipple and breast sensitivity.

The secondary objective was the detection of calcification surrounding the implant.

The primary effectiveness objective was change in breast size. The secondary objectives were patient satisfaction and quality of life.

Dr. Rebecca Anderson will be presenting these results.

At the baseline visit, study parameters, benefits and risks of the implants and procedure itself were discussed with patients. A history and physical and rheumatology assessment was done by the plastic surgeon, and the patient completed the quality of life questionnaires.

Complication information or adverse reactions occurring or reported at scheduled or unscheduled visits were also reported to Mentor.

The saline prospective study was conduct at 153 centers throughout the United States, providing a broad geographic and demographic diversity of clinical sites. Sixteen hundred and 80 patients were enrolled in the study; 1,264, or 75 percent, augmentation and 416, or 25 percent, reconstruction, with over 80 percent of the patients returning for their two year visit.

The augmentation patients were between the ages of 20 and 40, with about one half married and 30 percent single. The educational level of the patient population was representative of women throughout the United States.

The majority of the reconstruction patients were between the ages of 30 and 60, 63 percent marries and 15 percent single. Most had some college.

Based on the demographic data and other characteristics presented here, we believe that the saline prospective trial population was a representative cross-section of women who were seeking breast implants for augmentation, reconstruction, and revision.

Now I am pleased to turn the presentation over to Dr. Bruce Cunningham, the Medical Director of the three year saline study, professor and chair of plastic surgery at the University of Minnesota. Dr. Cunningham is also former chair of Silicone Implant Research for the Plastic Surgery Educational Foundation for the American Society of Plastic Surgeons.

Dr. Cunningham.

DR. CUNNINGHAM: Thank you, Ms. Powell.

Mr. Chairman, panelists, my name is Dr. Bruce Cunningham. I'm a professor of surgery at the University of Minnesota and also conduct a busy clinical practice. I'm the paid Medical Director for the study that Mentor is presenting today, and in addition, have been contracted to do research for Mentor and the McGhan Corporation, which will be presented by McGhan.

I want to address some of the issues of clinical safety. The goals of my presentation are to characterize and quantify the clinical risks defined by the large, prospective study and other clinical data to demonstrate the method and extent of physician and patient information and education, to place the clinical risks in perspective with the medical literature for similar devices and indications, and then to summarize.

There are four types of major safety concerns which have been raised with respect to saline filled breast implants. The first of these, and most important, is systemic disease, and this has been addressed by the Institute of Medicine and other scientific panel reports.

Local complications are a special area, highlighted by the Institute of Medicine, and will be addressed by the large simple trial and the saline prospective study.

Durability or the survivability of the devices in vivo will be addressed by the Cunningham ten year, multi-center, retrospective outcome study, as well as the prospective study.

And then cancer detection and treatment issues are very important, and Dr. Lenore Iverson, our breast radiologist, can address those during the question and answer session.

The recent reports of the multi-specialty review panels have drawn some major conclusions. Three scientific review panels, two in America and one in the United Kingdom, have concluded that there's no evidence for systemic disease associated with these devices. We believe this is not an issue of major concern at this time.

These panels have also concluded that breast feeding is safe and beneficial for the child, and that there are no second generation effects on children of women with breast implants.

The large, simple trial goals have been addressed. The data provided the FDA with assurance that during the short term, while the long term three year data is being collected, that there were no major serious risks and complications of the procedure.

I want to move now to the saline prospective study, the goals of which were recounted, and this is the signal study that's being presented by the Mentor Corporation today.

There were a number of statistical methods which were applied to this data set. Most of them are survival analyses which are statistical methods to examine the time to occurrence of various complications. We felt that the best way to represent this was with the Kaplan-Meier analysis, which is used to provide the estimate of cumulative incidence for each complication by indication.

In some incidences we performed other analyses, such as a Cox proportional hazards model to examine for risk factors of individual complications and a logistic regression analysis to examine the risk factors for breast and nipple sensitivity.

The prospective study includes two distinct clinical populations with different objectives and different complication rates. So we will present them separately.

First, the augmentation patients. The devices that were placed are shown here. The majority of them are the textured SILTEX devices or the textured adjustable volume SPECTRUM device. The remaining third of them are smooth devices.

The location of placement is three quarters in the submuscular position, which is beneficial for mammography, and also gives a better shape and feel to the device. Only 28 percent were placed in the subglandular position.

I want to spend a moment on this slide because it will serve as a template for the data slide which follow. This is the standard Kaplan-Meier analysis, and in this case for infection. To make it easier to depict, the curve always shows one minus the survival curve, and the scale is pretty consistent at 40.

The graph typically shows the incidence, cumulative incidence at 36 months, banded by the 95 percent confidence interval, and in the upper right-hand corner in this book, we will cite the relevant statistics from the medical literature.

So in this case, the cumulative incidence in the augmentation patients who are receiving elective, noncomplicated surgery is 1.7 percent for infection, which is a cumulative over three years, and in a situation where the curve is flat or the graph is flat, this does not mean that this is the incidence which is continuing to occur each year, but a flat graph rather means that there are no new occurrences of the complication.

Every time we generated a number or a complication from the data, we wanted to make sure that it was reflected in the patient and physician information. Here's the citation of the data reflected in the product information data sheet which is given to physicians, and here it is in the product information sheet which was given to patients, citing the data right out of the study.

I won't continue to show these, but for every data point we've reflected it in the product information.

Here's the Kaplan-Meier analysis for a significant concern, which is Baker II and IV capsular contracture. A Baker I classification contracture is essentially a normal breast. So we wouldn't report that. The Baker II classification is a firmness which is basically detectable by the patient, and it's only when you get into the III and IV level complications, grades of capsular contracture that the presence of the implant might be detected by someone else.

This is the Level III, Baker III classification, 6.9 percent, and the Baker IV at .6. We feel that the Baker III is not a significant clinical problem and rarely results in reoperation, but we wanted to check that out.

So our statistics show that of patients in this classification of three and four capsular contracture, only 23.5 chose to have surgical release of this scar tissue contracture.

We also had a group of patients who had capsular contractures which are classified as unknown. In order to show the most adverse possible analysis, we included these patients as though they all had Baker III and IV grade classification, and that results in a classification for augmentation patients of nine percent.

Let's look at deflation among this augmentation group. The incidence, cumulative incidence at three years of deflation of the implants is 3.3 percent. We did, however, want to know whether this is a trend that continues or what the long term deflation rate is, and to address that, the Cunningham study was commissioned.

This is a multi-center, retrospective cohort outcome study. The study design was consistent with the recommendations made by the FDA epidemiology panel. The study included 450 patients and 882 devices, with a minimum of ten year follow-up. Ninety-four percent of these patients were augmentation. So it seems appropriate to include this at this point in the presentation.

Well, I'm going to deal with the Mentor devices in a moment. The deflation rate for devices made by the current manufacturers, which are McGhan and Mentor, was 5.8 percent. This is 5.8 percent cumulative incidence at three years. It does not mean that it is an annual incidence of 5.8 percent. It's a cumulative incidence.

With respect to the Mentor devices, 86 percent of the devices in the study were Mentor devices, and we could isolate them as we look back at the data.

The incidence of deflation per device for Mentor or Heyer-Schulte Model 16 devices was 3.7 percent cumulative incidence at ten years. For comparison, the saline prospective study, when looked at on a per device incidence, is 1.9 percent.

Other significant findings from this long term, ten year retrospective study include an overall patient complication rate of 27.6 percent and an overall patient reoperation rate of 25.8 percent.

However, despite these two complications and the number of reoperations, 93 percent of patients were satisfied or very satisfied with their implants.

The Kaplan-Meier analysis for augmentation patients undergoing reoperation is shown here. The incidence is 13.2 percent. We wanted to look behind this number a bit and see what were the causes for this, and here are the causes for reoperation.

These are a good assortment of causes and indications which we would expect to see in a group of patients having elective surgery, and I'll address this other classification in a moment.

There were a number of patients in this augmentation group who had their devices removed, 8.1 percent, in fact. And again, we wanted to know why was this occurring. Was there a clinical reason for it?

And when we look at that, we find that there are the usual things that we are citing as complications, but also in terms of this number, patient request alone, and this indicates for most patients that they're choosing to change the volume of their implant, and in fact, the critical finding is that 72 of the 88 patient implants that were removed were replaced again at the same surgery, indicating that this was an elective procedure, perhaps a size change that the patient chose.

Other complications are shown. One of the goals of the study was to reflect the incidence of calcifications in this patient, which is extremely low, less than one percent.

Cancer detection is a significant issue, as Dr. Berg pointed out. The clinical issues are: do breast implants interfere with mammography? Is cancer detection delayed? And is clinical outcome compromised by the presence of the devices?

The data to be presented can be drawn from the SPS study results. However, it's important to realize that this was not a study design goal, and this data is anecdotal.

The population based research conclusions we feel are very important and will be drawn from papers that were included in the PMA submission. First, let's look at the data from the study.

There were two breast cancers detected by mammography among this augmentation cohort. The first patient had treatment which was effective for a small lesion with a very favorable outcome.

The second patient unfortunately had a very aggressive cancer. This was detected in the first six months following implantation with her device, and unfortunately the patient expired five years later. She expired outside of the terms of the study time frame, but we felt it was important to present her data nonetheless.

There are two major studies that I would like to address. First is the Birdsell study from Alberta, Canada. This is a population based study design which we feel is much more significant and powerful study design than the case study reports which have been cited.

The study group was 41 women with cosmetic breast implants who had developed breast cancer. The control group was 13,000 women with breast cancer, but who did not have breast implants.

In terms of the findings, the women with implants were diagnosed at a younger age than controls. The study population tumors were smaller. Lymph node and distant metastases occurred equally frequently in the two groups, and the distribution of tumor histological types was not significantly different.

Of greatest importance, however, is the fact that the five and ten year Kaplan-Meier survival rates did not differ between the implanted and the control groups.

Another significant study was reported by Dr. Deapen in 1997. This is another population based study using the cancer registry from Los Angeles County. It looked at women who were implanted between 1953 and 1980. The study group consisted of 31 breast cancer patients in 3,182 women with breast implants.

The control group was the Los Angeles County cancer surveillance program, and the patients were demographically matched as closely as possible to the women without implants.

The median follow-up was 14.4 years. The findings showed that the stage at diagnosis did not differ between the implanted and the control groups. In fact, there was a lower than expected incidence of breast cancer with 31 observed cases against an expected rate of 49.2.

This data has been further elaborated on by a recent study that Dr. Deapen published this month. In that study, he points out that cancer detection was not delayed in the group of implanted patients and treatment was not compromised.

Let's look now at the reconstruction cohort. Reconstruction patients are a special population. They have more extensive initial surgery. In that case breast tissue and skin is removed, and flaps or skin grafts may be required just to close the wound.

Additional procedures and interventions are frequent, and the general health of the patient may be severely affected by adjunctive treatment, such as chemotherapy or bone marrow transplantation.

A special clinical problem exists for plastic surgeons treating patients for breast reconstruction. Symmetry is much more difficult to achieve than a simple enlargement of the breast. Complications have to be compared to the chief alternative to implants, and not to the augmentation group that we've just discussed.

The major alternative to breast implant reconstruction are major flaps and major surgery, and when flaps fail, they have a significant morbidity and impact on the patient's life.

The reconstruction patients were implanted by and large, a significant majority, with textured, contoured, textured devices, the SILTEX. The SPECTRUM device was used in 44 percent of patients, and this is a unique device which is specifically applied and of great use to plastic surgeons in reconstruction because it can serve as a soft tissue expander and as a permanent implant, allowing many patients to have the reconstruction in one stage.

Most of the devices were placed in a submuscular position. Some were subglandular, perhaps in patients who were having lumpectomy and radiation.

The Kaplan-Meier analysis for infection shows an incidence of 9.1 percent cumulative at 36 months, which is three times the amount in augmentation patients. This is in a group of complication prone individuals who are receiving adjunctive treatments and much more significant surgery.

The Baker Grade III and IV capsular contracture is significantly higher, 24.1 percent capsular Grade III and 6.7 percent capsular Grade IV. Again, the question arises: how significant is this and what kind of impact does it make on the patient's life?

And of note, only 27.8 percent of patients chose to have the capsule released with surgery.

Deflation is a significant problem in this group of patients, again, almost three times as frequent as in the augmentation group. However, this is a group of patients who are having subsequent treatment, biopsies, needle aspirations, radiation, chemotherapy to treat their primary underlying disease, and this can easily account for this increased complication of deflation among this group.

We looked at the reoperation rate, which is higher than the ten year retrospective study and is at 40.2 percent. We want to look behind the number. What are the causes for this, and it's important to note that many of the causes for this operation in this group have to do with the underlying tumor problem, lymphadenopathy, breast cancer or mass, necrosis, which is probably related to the flaps at the time of the mastectomy, or delayed wound healing, again, related to healing at the time of the mastectomy.

There are a lot of patients who are undergoing operations as a part of their reconstruction, either a staged reconstruction or a nipple/areolar complex or some other part of the breast mound is being built or for asymmetry many of these patients were recorded, although they had surgery on the contralateral breast, such as a reduction or a mastopexy.

So there are a number of good clinical reasons not related to the implant for these subsequent operations.

The Kaplan-Meier analysis of explantation shows that 26.8 percent of patients have their implants removed, but a lot of them were elective and were being done to release scar capsular contracture or infection or, again, to deal with the problems related to their breast cancer.

Of this group, 60 of the 97 percent of implants were replaced at the same time that they were removed, indicating that this was not a group of patients, by and large, who gave up or abandoned their reconstruction, but rather were a group of patients who were electively trying to fine tune or complete their reconstruction.

The revision after explantation, which is the revision group that the sponsor is seeking approval for, the data is shown here. It's a difficult group to categorize because it includes both augmentation and reconstruction patients, and the variance, statistically significant variance, from the previous initial operation is shown with the augmentation cohort and the reconstruction cohort and the difference in the variant.

This is a summary slide of the short term risks and complications similar to what was presented in the large simple trial for augmentation and reconstruction. This is presented on a per patient basis. The revision was always presented on a per implant basis. So we can only give you a qualitative assessment with respect to incidence.

Additional statistical analyses were done, and this is one of the major benefits of the study because it will provide significantly important clinical information for plastic surgeons and for the patients. Cox proportional hazard models were used on factors contributing to deflation to understand them, and logistic regression analysis was done to determine factors affecting breast and nipple sensitivity.

Here are all of the risks factors that were identified and reported in this large group of patients, and the ones which had clinical statistical significance are noted on the right. Let's take a closer look.

In the group of patients who had -- this is an analysis with respect to deflation, and when the augmentation is used as the reference, immediate reconstruction patients had a significantly higher rate of deflation which, again, would go with the fact that they are having subsequent interventions, biopsies, aspirations and things to treat their underlying problem, and the delayed reconstruction patients who have by and large completed that process have a lower rate of deflation.

The unilateral versus bilateral simply reflects the statistical chance of having two implants versus one, and this is a clinical interest. The average incision size is the reference, and incision size below reference of three sonometers results in a two times risk factor for deflation of the device, indicating that surgical choices and surgical technique have a definite impact on the outcome of the durability of the device.

Of great significance is the effect of Betadine, a common antibiotic irrigant which is used by many plastic surgeons, despite the face that the product labeling specifically interdicts such use, to attempt to prevent an infection. Patients who have their devices bathed or irrigated with Betadine had a 3.5 times risk factor for deflation of the device. This is clearly information that needs to be in the hand of every plastic surgeon so that this practice is abandoned.

We wanted to look at breast and nipple sensitivity. Above the yellow line show patients who had increased sensitivity. Below the line are patients who had less sensation carried out to 36 months. We wanted to know if there were any factors that impacted clinically on this incidence of change in sensation.

When we look at the inframammory incision as the reference site and compare it to periareolar or transaxillary incision sites, there are statistically significant findings. Periareolar patients had a significantly greater risk of diminished or changed sensation than the inframammary site patients, and this would follow from an intervention that occurs close to the insertion of the nerves in the end sensory organs.

The transaxillary patients had a significantly lower risk of change in sensation, obviously being operated on from a more remote site. This is good information that will allow plastic surgeons and their patients to make better informed choices.

So what does this all mean? What's the impact of this amount of data?

First, the clinical risks and local complications have been effectively defined and quantified by the data presented today. Physicians and patients are fully informed about the risks and complications, and that's based on the study data directly.

The risks are consistent with those reported in the medical literature for similar devices and indications. Augmentation patients have a lower risk consistent with their elective surgery.

Reconstruction patients have a higher risk, but they also have greater potential emotional and physical benefits from the implants.

Revision patients experience similar or somewhat higher complication risks than that of their primary indication, and population based studies have shown that breast implants do not delay detection or compromise treatment of breast cancer in implanted women.

It's now a pleasure to turn the podium over to Dr. Rebecca Anderson. She's a full-time Ph.D. clinical psychologist in the Department of Plastic Surgery at the Medical College of Wisconsin in Milwaukee. She actively counsels patients undergoing plastic surgery, and many of those are patients having implants.

She also occupies a unique role within plastic surgery as being one of the key players in the outcomes movement within plastic surgery, which is funded by the Educational Foundation.

Dr. Anderson.

DR. ANDERSON: Thank you, Dr. Cunningham.

Members of the panel, guests, I'm Rebecca Anderson, and I'm here today as a paid consultant for Mentor Corporation. I have no other financial interest in the company.

As a psychologist in an academic plastic and reconstructive surgery practice in a university setting, I have the opportunity to speak with thousands of women who have undergone or who plan to undergo breast surgery. I see both augmentation and reconstruction patients in my clinical practice.

Women report seeking implants to restore the breast following cancer, trauma, or deformity, or to achieving a satisfying breast appearance through augmentation.

When I see breast reconstruction patients, I generally see them at least once prior to their surgery in an effort to discuss their adjustment to the diagnosis of cancer. I often see these patients during their hospitalization and again for follow-up as long as the situation dictates.

When I see augmentation patients, I generally see them prior to their surgery to discuss body image issues and expectations of the surgery. I also try to see these patients at least once following their surgery to discuss their level of satisfaction.

Today I will discuss motivations and expectations of women seeking implants. I will review the results of the primary and secondary objectives of the saline prospective study, and I will present a summary of the clinical findings.

The effectiveness objectives of the saline prospective study included a primary objective, which was to evaluate a change in breast size. The secondary objective was to evaluate patient satisfaction and quality of life outcomes.

As Dr. Cunningham mentioned, the breast augmentation and reconstruction patient are really two distinct patient populations, and for that reason I will also discuss the results separately for these two population groups.

Women report seeking augmentation mammoplasty to improve body image and self-confidence; to enlarge the size of the breast; to make the breast more proportionate with the rest of the body; to regain size and shape following pregnancy and lactation; or to correct severe asymmetry.

In the saline prospective study, in an effort to address the effectiveness in the augmentation mammoplasty patients, the following assessments were provided. Breast size was assessed by looking at a change in bra cup size, a change in chest circumference, and the use of a breast dimensional analysis measurement.

Quality of life outcomes were assessed by use of the breast evaluation questionnaire, which was specifically designed and validated for use in this study. Additionally, the multi-dimensional body self-relations questionnaire and the Tennessee self-concept scale were used.

With respect to breast size, a bra cup size change was demonstrated in the augmentation patients with 96 percent of the patients experiencing at least a one cup size bra cup increase.

Breast size was also demonstrated when we looked at chest circumference. From the preoperative to the postoperative assessment, there was a statistically significant increase in chest circumference of 7.2 centimeters for the augmentation patients.

Based upon these size measurements, it is clear that breast size was increased by use of the implants in the augmentation patients.

Quality of life issues were assessed in the augmentation patients. The breast evaluation questionnaire, which was developed for this study, assessed satisfaction with a number of aspects of breast size, shape, firmness, and general appearance. The breast evaluation questionnaire utilized a five point scale. Patients were asked to respond rating their satisfaction from very dissatisfied to very satisfied.

And as you can see, preoperatively the majority of the patients reported being somewhat or very dissatisfied with the general appearance of their breast. However, postoperatively the majority of the patients reported being somewhat or very satisfied with the general appearance of their breast.

The BEQ looked at size, shape, and firmness of the breast and patient satisfaction with these attributes across three settings: intimate, social, and professional. And as you can see, with respect to breast size, preoperatively patients reported low levels of satisfaction, whereas postoperatively there was a statistically significant improvement in satisfaction with breast size, with well over 80 percent of the patients reported being satisfied or very satisfied with breast size.

The same was true with patient satisfaction regarding breast shape. Preoperatively, low levels of satisfaction were reported, and again, postoperatively at the 36 month follow-up there was a statistically significant improvement with, again, over 80 percent of the patients reported being satisfied or very satisfied with breast shape.

The trend also continued when we looked at breast firmness with the patients reporting a statistically significant improvement in their satisfaction with breast firmness. Again, over 80 percent of the patients were satisfied or very satisfied.

This is not only statistically significant. It's clinically relevant to the patient with respect to their satisfaction of attributes of their breast.

The multidimensional body self-relations questionnaire was also used with the augmentation patients. The MBSRQ is a frequently used body image assessment. When taking the MBSRQ, the patient is asked to record their agreement with statements on a five point Likert (phonetic) scale.

And as you can see, from the preoperative to the 36 month follow-up there was a statistically significant increase in satisfaction with general appearance on the scale of the MBSRQ which assess satisfaction with general appearance.

We looked at a statement on the MBSRQ, "I like the way I look without my clothes," and again, you can see that there was a statistically significant improvement in agreement with that statement from the preop. into the 12 month follow-up, and that improvement was maintained through 36 months.

With respect to the statement, "I like the way my clothes fit me," there was also a statistically significant improvement in agreement with that statement from the preop. to the 12 month follow-up, and again, that was maintained at 36 months.

Based upon the results of the MBSTQ, we see that there is a clinically significant increase in satisfaction with body image, which is statistically significant and clinically relevant to the patient.

In summary, regarding effectiveness for the augmentation patients, we see that there was an increase in breast size. This was demonstrated by an increase in bra cup size and an increase in breast circumference.

Patient satisfaction and quality of life outcomes were also demonstrated. Satisfaction with breast attributes increased, and comfort and satisfaction with appearance also increased among these patients.

The breast reconstruction patient faces a number of emotional and physical challenges. Today one in eight to ten women faces a lifetime risk of developing breast cancer.

Once diagnosed with breast cancer, the patient will have a number of decisions to make, and her life will be changed. For women who face mastectomy, implants may provide the only reconstruction option.

Women report the following motivations and expectations of reconstruction: to feel whole again after breast removal; to avoid the need of an external prosthesis; to improve body image and self-confidence; to put the cancer behind them; to wear more clothing styles; to regain a sense of femininity; and to correct deformity.

In the saline prospective study, breast size and quality of life measures were also assessed with regard to effectiveness. Regarding breast size, a chance in chest circumference was used as a measurement, as was the breast dimensional analysis measurement.

Regarding the secondary objective, which was to look at quality of life outcomes, the multidimensional body self-relations questionnaire, the Tennessee self-concept scale, the functional living index of cancer, and the Beck depression inventory were used.

An increased in chest size was demonstrated in the delayed reconstruction patients. There was a statistically significant increase in breast size from the preoperative to the 36 month follow-up of 3.8 centimeters. This is indicative of restoration of the breast mound in these patients.

There was no need to assess change in breast size among the immediate reconstruction patients because the breast mound was created at the time of the mastectomy.

The functional living index of cancer is a widely used assessment which evaluates patient adjustment following the diagnosis of cancer. Higher scores reflect improved physical and psychological adjustment, and as you can see on the functional living index of cancer, the immediate and delayed reconstruction patients both experienced a statistically significant improvement in physical and psychological functioning.

The Beck depression inventory is a widely used outcome measure for assessing symptoms associated with depression. Lower scores reflect lower symptoms associated with depression. The immediate reconstruction patients experienced a statistically significant decrease in symptoms associated with depression. There was a decrease in symptoms associated with depression among the delayed reconstruction patients. It was not statistically significant. However, it does represent a trend in the desired direction.

The Beck depression inventory evaluates various levels of clinical depression. For example, a score of ten or greater represents a low level of clinical depression, with scores from ten to 16 indicating mild depression. Higher scores indicate moderate to severe depression.

We looked at 196 patients for whom we had data, both preoperatively and at 36 month follow-up on the Beck depression inventory, and as you can see, at the preoperative assessment, 43 patients reported scores of ten or greater on the Beck depression inventory, whereas at the postop 36 month follow-up, only 26 patients reported scores of ten or higher on the Beck depression inventory, which is indicative of a statistically significant decrease in symptoms associated with depression in this population.

In summary, with respect to the effectiveness for the reconstruction patients, an increase in breast size was demonstrated. Chest circumference increased in the delayed reconstruction patients, which was indicative of restoration of the breast mound on these patients.

Patient satisfaction and quality of life outcomes were also demonstrated. Physical and psychological adjustment in cancer patients increased, and symptoms associated with depression decreased.

So what does this all mean? The Mentor saline filled mammary prostheses are effective and beneficial. In the augmentation patients, an increase in breast size was demonstrated. In the reconstruction patients, the breast mound was restored.

The saline prospective study and the professional literature demonstrate that the risk and benefits are well defined and documented, and these results are consistent with the quality of life benefits reported in the professional literature.

Despite possible complications, patients report high levels of satisfaction and improved quality of life.

And finally, many women facing reconstruction or desiring augmentation have a wealth of information available to them as they make their decisions, and they continue to choose implants.

Mr. Purkait will return for concluding remarks.

MR. PURKAIT: Thank you, Dr. Anderson. Thank you, Dr. Cunningham, and thank you, Ms. Pamela Powell.

I'd like to summarize our presentation today. First, we have shared with you the preclinical findings. We have submitted our scientific study data in our PMA to show the safety and effectiveness of our product.

In the toxicological safety assessment, we have shown that our materials and devices are extractables below the toxicological concern.

In our durability and performance assessment, we have shown that our devices can withstand excessive forces equal to the interval used.

As you look through our clinical findings, we have established risk and complications, and we have shown that the long term durability of our implant through the retrospective study to be over ten years.

In our studies we also have well characterized risks. We have shown that our product improved the quality of patients and this information and education materials will be provided to both patients and physicians for their decision.

Thus, we believe that we provide a safe and effective option for women who want to restore the breast following cancer, trauma, or deformity, or to achieve a satisfying breast appearance through augmentation.

Finally, we recognize that there are no objective measures or standards by which the relative risks and benefits of these devices can be weighed against each other. On the patient and individual can make the decision and will be the judge, and this decision is different from each person.

Mentor provides the necessary information to the patient and their physician so that a patient can make a truly informed decision.

We thank you for your attention.

CHAIRMAN WHALEN: Thank you fry much.

For those members of the panel who now may have any questions of the sponsor. Dr. Blumenstein.

DR. BLUMENSTEIN: When you compute the Kaplan-Meier estimates of risk, how did you handle the explantation event for the computation of the Kaplan-Meier curve for something like infection or contractures, and so forth? Were these for patients who had an explantation censored in those curves?

MR. PURKAIT: You know, I have not had a chance to share with you our Q&A team, but in order to address that, I'd like to invite our biostatistician, Dr. Gene Poggio to explain our Kaplan-Meier analysis on those.

If I could just request one thing and show you our Q&A team so that all the questions that will be coming to us, we'll be able to tell you exactly who's answering what.

We have Dr. Wally Grant in our hand to address or answer questions about material testings.

We have Dr. Gene Poggio who will be addressing primarily the biostatistics related questions.

We have Ms. Pamela Powell who will be talking about the clinical protocol designs or implementations.

We have Dr. Noel Rose at hand to answer any questions on the immunology.

Mr. Clark Scherff from the manufacturing.

And Phil Yang for the preclinical data.

We also have Dr. Mark Allen for any particular testings, long term testings.

Radiology, Dr. Leonard Everson.

And Dr. Roger Wixtrom on the safety assessment.

Thanks for your attention, and we'll be addressing your question now.

DR. POGGIO: Mr. Chairman, Panelists, my name is Gene Poggio. I'm a biostatistician. For the last 15 years, I've directed the biostatistics group at Apt Associates.

Apt Associates has contracts with Mentor Corporation to do analysis, data management reporting of clinical studies. Apt has no other financial connection with Mentor, and I personally have no financial connection with Mentor.

To address your question, as laid out in the original analysis plan for the study, we did censor patients, with one exception which I'll mention in a moment. We censored patients at the time of explantation. We thought it was very important to do so because -- for two reasons.

The patients who are not reimplanted, we felt that we've used a conservative strategy because to keep patients in the denominator for incidence estimates when they no longer have an implant we would think would bias the estimates.

And then for patients getting new implants, complications that might occur. It could be a different device, a different manufacturer's device, and we wouldn't be able to attribute it to a given device.

So we thought the cleanest approach was to censor them at the moment immediately after the explantation, if you will.

The one exception I mentioned is we did do some analysis to look at the issue of revision patients, and for those that was, if you will, the baseline for revision patients. But aside from the exception or aside from revision patients, they were censored at the moment immediately after the explantation.

DR. BLUMENSTEIN: One more question. Did you do analyses in an attempt to try to characterize the patients who did not have follow-up at various time points following the original, following baseline?

DR. POGGIO: I mean we basically have a quite high response rate. I believe it's off the top of my head about 80 percent at two years. We could pull those numbers up if you want.

We didn't specifically compare the ones who did drop out to the ones who did not.

CHAIRMAN WHALEN: Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: Yes. I have a related question to Dr. Blumenstein's. It may also go to you.

This involves the quality of life and effectiveness analyses. At the three year visit, my understanding is that those analyses, any summary statistics excluded individuals who were lost to follow-up up to that point, and that that loss to follow-up included a relatively substantial number of explantations; is that correct?

DR. POGGIO: It is true in the analyses when we looked at simply the 36 month value, they would have been excluded, but we did have summary measures looking at the average change across all visits.

There is generally a very consistent pattern of one level at baseline and a very different level, especially for the primary efficacy measures or primary effectiveness measures, the one level at baseline and a quite different level consistently for all the visits after it.

DR. BANDEEN-ROCHE: But to summarize, the people at that different level would comprise people who had not had explanations, correct?

DR. POGGIO: Yes, for all analyses. Yes, for all analyses after explantation, patients were excluded from those analyses aside from the revision patients that I mentioned for separate analyses.

DR. BANDEEN-ROCHE: Thank you.

CHAIRMAN WHALEN: Dr. Li.

DR. LI: Yes, I'm not sure who can take this question.

My question is when you were doing your either retrospective study or your prospective study, how you counted deflations. Perhaps you can correct me if I'm wrong, but am I reading patients were scored as having deflation as a reason for explantation when that was the primary identified cause for the revision, but if you went in to revise somebody for contracture and found the device deflated, it was not counted as a deflation; is that correct?

DR. CUNNINGHAM: The saline devices, unlike the gel devices, are readily apparent when they deflate. The saline comes out. Either in the study that I did, the retrospective study, the majority of patients noticed a significant loss in volume over a period of days or perhaps one week. Some of them noted it over a longer period of time, but mostly it's a short term, dramatic event.

So I think that going to some other intervention and then finding an incidental deflation is not anything that was reported in our study, and I'm not aware of it being reported in the saline prospective study.

The reason for reoperation would be to correct, replace a deflated implant. It wouldn't be something that would be discovered incidentally at another operation.

DR. LI: Thank you.

Just a follow-up question, if I could. There was a difference in deflation rates between those patients where the surgery was done for augmentation versus reconstruction. You outlined perhaps several maybe interventionally related reasons why there was that difference in deflation rate.

However, can you discount the fact that in the reconstruction group there was four time as many SPECTRUM devices as there were SILTEX, and coincidentally the incidence of deflation was on that order?

So I guess my question is: how sure are you that it's completely interventional and not device related?

MR. PURKAIT: Perhaps if you could just repeat that question for me so I can truly understand. Are you asking that --

DR. LI: Let me simplify it for you.

MR. PURKAIT: -- if the SILTEX has higher deflation rate than the non-SILTEX or the smooth? Is that the question?

DR. LI: I'll take that. I'll start with that one. Go ahead.

DR. CHANG: Could I rephrase that question? Would you be asking the same question I was going to ask? Was there stratification in terms of deflation rate for either augmentation or reconstruction? Could you tell if it was a valve leak or puncture or failure of the shell?

Was that stratified as an explanation of deflation?

MR. PURKAIT: Yes, we have that information we will share with you. Dr. Gene Poggio will show you that information.

DR. POGGIO: I think the Cox proportional hazards model we used perhaps might be the best answer that we have to the question you're raising. We looked at deflation rate. Probably most of the panelists know this, but in case anyone doesn't, just the Cox proportional hazard model is the most standard way to look at time to occurrence of an event, in this case a complication where you have varying lengths of follow-up and you want to look at various risk factors, either to adjust for confounding factors or to evaluate the various risk factors.

So the factors we have on the left are the various factors we took into account in the model. You'll notice indication reconstruction versus augmentation or specifically immediate and delayed reconstruction, augmentation, and so forth.

And so the only factors that were found to be significant are the four shown there, indication whether it was unilateral or bilateral, incision size, and Betadine use, and so you'll see that we also have valve type and surface type and implant shape there, and none of those were significant in that model, and it's adjusting for the other variables in the model.

DR. LI: I don't see in there a split though between SPECTRUM and not SPECTRUM, for instance.

DR. POGGIO: Well, this is characterized by device characteristics, and the SPECTRUM is characterized principally by the surface type of a texture. You're correct, but it's characterized by a textured surface and a specific valve.

So if SPECTRUM was different, you would expect to see the difference in the valve type or the surface type, and/or the surface type.

DR. CUNNINGHAM: There are only two value types, the diaphragm valve and the kink valve, and the kink valve only exists in the SPECTRUM device. So the valve is a marker in effect for the product with respect to this analysis.

DR. LI: Right, but then the whole argument would hold only if the valve was the source of the leak?

DR. CUNNINGHAM: Perhaps I can address that more fully. Two, two, 16 would be the slide I would like. Go ahead.

This is a breakdown of the occurrence of deflation that the manufacturer can actually analyze. There were 74 devices that deflated, and 37 of them were returned to Mentor, and here are the breakdown after physical examination of the devices based on what the final concluding reason was for failure.

There were three valve leaks or tears. There were 18 or there are, rather, eight iatrogenic failures which in most cases were needle biopsy or nicking with a suture or hitting with a scalpel.

There were 18 shell tears, which are very difficult to evaluate. It almost certainly is a surgical event related to surgical technique, perhaps as it was being removed or explanted.

And then there were six in which no abnormalities were found. So to answer Dr. Chang's question, the valve does not seem to be, at least in the group of devices that could be examined, the major cause for deflation.

CHAIRMAN WHALEN: Does that answer your question, Dr. Li?

DR. LI: I'm not sure. Let me work on it for a second. I'll come back.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: I have two questions. The first is for Dr. Cunningham.

A reoperation rate of 25 percent -- and I tried to follow this when you were presenting it -- is that 25 percent of patients or 25 percent of implants?

DR. CUNNINGHAM: That is a per patient analysis.

DR. BURKHARDT: So 25 percent of patients who had implants had to go back for surgery. On the face of it, that would seem to be extraordinarily high, and I couldn't quite understand the breakdown. You said 72 of 88 were removed and replaced. Were the 88 all -- did that represent all of the patients who were reoperated?

DR. CUNNINGHAM: That represented the patients who were explanted. So what I was using was the -- if we could go back to that slide.

DR. BURKHARDT: I'm just concerned. One out of four patients is an awful lot to go back for a second surgery.

DR. CUNNINGHAM: So there are two different analyses that we showed. One was the reoperation rate, which you're referring to. The other was the explantation rate, and the patients that were replaced, that statistic was on patients who had an explantation and a replacement at the same time.

So in effect, one of the main causes for reoperation in this group was an elective desire to change the size of the device because a large proportion, almost three quarters of them, had the device replaced at the same time that they had the previous one removed.

Sometimes that may have been removing the device to treat for an infection or capsular contracture and then replacing it with a new device, but many of them in the augmentations were to perhaps change the size of the device.

DR. BURKHARDT: For those patients who had an elective change of the device for size purposes only, can you tell us how many wanted to go larger and how many wanted to go smaller?

DR. CUNNINGHAM: We would have to find that data for you. I don't have any --

DR. BURKHARDT: Do you have any impression?

DR. CUNNINGHAM: I do not.

DR. BURKHARDT: Thank you.

DR. CUNNINGHAM: One of our statisticians says that the majority of them were to increase size.

DR. BURKHARDT: Is this an appropriate time to ask about the information that's provided with the implant or do you want to wait until Wednesday?

CHAIRMAN WHALEN: You mean in terms of labeling? This is an appropriate time to ask any questions of the sponsor that you feel is appropriately answered by the sponsor.

DR. BURKHARDT: Mr. Purkait, I have a question about the brochure that is provided with the implants by Mentor. When you go to implant shape, you have a rather carefully constructed sentence that says, "Round implants are thought to give a fuller shape to the breast, while contoured implants are designed to offer a more anatomical shape."

And I'm sure that's correct, and then when I look at the pictures that you have, if they weren't labeled, I couldn't tell the difference between the round and the anatomical shaped implant. Do you have any basis for believing that the use of one implant variety over the other implant variety makes a difference that can be detected by a blinded observer?

MR. PURKAIT: I would like to see Dr. Cunningham. Could you please address from your experience on the anatomical versus the level implant with the difference in cosmetic application?

DR. CUNNINGHAM: I don't believe that we broke down or at least I have not seen a breakdown of the data that Dr. Anderson presented, namely the chest circumference measurements by shape, and if we do have it, perhaps we can get it put up.

But my personal clinical feeling is that contour devices particularly in reconstructed patients do not confer a significant difference in total outcome of shape than do round devices.

DR. BURKHARDT: How about in augmentation patients?

DR. CUNNINGHAM: Again, my personal clinical belief is that when these devices are placed in the submammary position in a thinner woman with a lot of extra skin, it's possible that the shape of the device could be conferred to the overlying breast parenchyma and the skin envelope.

However, the majority of these devices are placed underneath the muscle, and my personal feeling and clinical observation is that underneath the muscle they all become essentially round, and any shape that might be conferred by the implant design is overridden by the forces of the muscle.

DR. BURKHARDT: Thank you.

CHAIRMAN WHALEN: Dr. Li?

DR. LI: Yeah, I thought about it. I think I need a simpler answer to this.

Could you just simply tell me out of those devices that were deflated how many of them were SPECTRUM? That's the answer I'm looking -- that's the question I would like to have answered.

MR. PURKAIT: Sure. I think we have the data. Can I just come back to you while I was just getting those information?

DR. LI: Sure, and I have a separate question. Dr. Cunningham alluded to it and some of your literature alluded to the fact that depending on the shape of the device and where you place it or maybe even the size of the incision, that that affects the outcome of the device.

So my question is that seems to imply that seems to imply that there's some kind of extra stress or extra loading or extra some kind of kinematic application to the device that somehow is not advantageous to the device if you don't put it in in the appropriate fashion.

My question is: do you have any biomechanical data that would suggest, for instance, if you make the incision two centimeters smaller what that increase in stress actually is, or if you use the wrong profile and put it in the wrong place and the stress is too high, do you have any biomechanical information, again, that tells you exactly what that increase in stress is, or is it stress or is it sheer or is it something else?

MR. PURKAIT: We have some information that shows that when you do apply load, regardless of what incision site and where you're placing, if you take an implant and if you apply certain types of load, we have measurement that shows that what type of internal pressure you can generate.

Now, do we have information between the subglandular or some muscular? At this point in time I couldn't tell you, but we have a general information if we have a certain amount of load or if certain types of women sleeping on the chest, what sort of stress would be -- internal stress would be developed?

We have that information.

DR. LI: I've read that information. I guess what I'm looking for is the link between the laboratory data for those calculations of pressure under those different conditions to your instruction to the surgeon that says, "Put it in this way or the stresses will be too high."

So my question is versus your laboratory data under different conditions where you generate different internal pressures, compare that to your instruction to surgeons that say don't do this or the stress will be too high. What's the comparison, numerical comparison, between those laboratory stress data and then the stresses you think are being generated in the patient at least to the level where you're concerned enough that you're instructing the surgeon to watch out for it?

DR. BOYKIN: I'd like to follow that before you answer with a similar question because your mechanical data indicates when you have looked at the environment of the implant that a, as you define it, stiffer tissue surrounding the implant significantly lowers the pressure per square inch. I believe it goes below two pounds per square inch in this model.

It makes me wonder if that could be translated into some instructions for the surgeon who's trying to optimize the length of the implant. I think that's what he's getting at because you have data about this pressure on the implant in the environment that it's in. How does that translate to what we can do to improve the lifetime of it while it's there?

The other question I'd like to pose is was there any investigation of the possible presence of clinical capsular contracture before implant deflation. I didn't see that listed as a cause, but did you go back to find out was there a capsule before it inflated, or it might be subjective data, but did anybody try to look at that possible correlation?

DR. CUNNINGHAM: Could I have Slide 109 while I answer the first question?

The first question really has -- if I understand it correctly, you're asking is there a good, effective way to model in the preclinical testing the kinds of forces and effects that would result not from the daily use and activity of the device when it's in the woman's body, but rather that mimics the condition of actually placing the device.

DR. LI: Yes, that would be the global question, yes.

DR. CUNNINGHAM: Right. Perhaps one of the materials people can answer that, but let me say that from a clinical point of view, the devices are placed in deflated so that they are, you know, in a very small volume when they're placed through the incision.

So that it would be hard to model that accurately, except for tear or sheer characteristics, which of course have been recorded.

Surgeons vary so widely in their techniques. Some surgeons fill the implant partially so that they can then aspirate the air bubble and then put it in partially inflated. Other surgeons put it in completely empty. Some surgeons place it in through a remote incision site, such as the axilla. There are some surgeons who wad it up and place it through a long tube through the umbilicus.

You know, certainly these different techniques would have different stresses and different strains applied to the device. I think it would be very hard to model.

With respect to the question of the associations of risks with the deflation event, this is the series of potential things that we felt could affect the -- these are the factors that we looked at that could affect deflation, and capsular contracture is not one of them.

And these are the things that were found to be statistically significant.

DR. BOYKIN: Well, I understand that, but I guess what I'm asking is that obviously when it's deflated, it's deflated, but could you -- did anyone ask the patient or the physician if there was any indication that a contracture may have been present or developing at that time?

I mean that's just kind of a retrospective analysis.

DR. CUNNINGHAM: I think from my personal clinical observation of how these devices function, it's clear that we had a higher deflation rate in reconstructive patients. Reconstructive patients also had a significantly higher Baker Grade III, Baker IV capsular contracture rate. In many cases personally I believe that this is reported as a capsular contracture rate when, in fact, what is actually going on is that there is tissue inadequacy. There has been tissue that's been removed.

So if I understand your question, it's dealing with does a tight, confining space in somehow or in some way predispose an implant to fail, and I think the data would indirectly bear that out because the higher degree of capsular contracture reported in the reconstructions parallels a greater deflation rate, and you could understand that that is a more adverse environment. The implant is going to be more likely to be folded on itself, and so it's not as -- it's a more adverse environment than underneath an unoperated pectoralis muscle.

DR. BOYKIN: Right. This is really conjecture, but the reason I was curious about the data, the PSI and the firm environment is because what you might be describing is a situation in, which the submuscular pocket which by virtue of the nature of the tissue is a stiffer environment, is probably causing this lower load on the surface of the implant. If it is significantly lower, does this correlate with the decreased contracture rate? Does this correlate with an increased lifetime, life span of the implant?

And if this information is variable, it could be correlated to some pressure reading through a remote valve that we could do clinically and perhaps look at some U curve with the bottom being the optimum side. When we get past that point we need to make some changes.

So I'm just talking about the information you've got and how we can use that clinically.

MR. PURKAIT: Dr. Li, we're still getting your data. We'll come back to you.

CHAIRMAN WHALEN: While we're still getting that, Dr. Morykwas.

DR. MORYKWAS: Yeah, I just had a couple of things, and one is actually related.

MR. PURKAIT: Dr. Li, sorry. I'd like to answer if I could, please, and show these data. The deflation of SPECTRUM versus SILTEX versus the smooth and the SPECTRUM versus the smooth.

Gene.

DR. POGGIO: I have a very specific answer. I hope this -- you asked how many SPECTRUM. There were 21 SPECTRUM had deflation out of 472 devices.

DR. LI: So that's 21 out of the 74 that Dr. Cunningham alluded to?

DR. POGGIO: It is devices. So 21 devices out of 472.

DR. LI: So then would that translate, Dr. Cunningham, to 21 out of your 74? Oh, that was 37 that he had. He had 74 deflations, 37 of which they analyzed.

MR. PURKAIT: That's right. The 57, I suppose, are total deflations. That's what we've seen. We received the 37 to examine that was what the cause for the deflation.

DR. LI: Right, but is the 21 out of the 74 total or is the 21 out of the 37 that you analyzed?

MR. PURKAIT: I believe it's the total, 24 out of the total 37 or 57, 57 or 74.

DR. LI: Seventy-four.

MR. PURKAIT: Right.

DR. LI: Okay. So most of them then were the prefilled, not SPECTRUM devices; is that right?

MR. PURKAIT: I couldn't tell you exactly. Most like from the data, it looks like that, yes.

DR. CUNNINGHAM: And there are no prefilled devices. They're all filled at the time of surgery.

DR. LI: So sorry. Thank you.

DR. MORYKWAS: Well, I guess I had a couple of questions, and one is related to the implantation. Since a lot of surgeons now do for augmentation -- not a lot, but some do the perienvolicol (phonetic) insertion. Since you have presented data that shows that the length of the incision appears to be related, are you going to discourage surgeons from using the perienvolicol or would that be something you would consider?

DR. CUNNINGHAM: Well, I personally -- and I'll let someone else speak to the product labeling as it exists -- but I personally feel that that is a very strenuous and risky thing to do to an implant, and I would not feel comfortable doing that in a patient of mine. I don't think that the benefits outweigh the risks of the device deflating, and I would feel strongly that it should certainly be an interdicted use of the device.

MR. PURKAIT: Yeah, to answer your question, this information as we have found in our study we have submitted to the agency. As these things are approved and discussion occurs, we will put in the patient information as well as the physician information, yes.

DR. MORYKWAS: then I had a question about your infections and how that was related. You also had a delayed wound healing.

Now, the infections that you reported, were they later infections? Did the incision had healed and the breast had just swelled or developed a draining tract or was it also just a nonhealing incision that pus was coming out of at the time of surgery?

DR. CUNNINGHAM: There could be several events reported at the same time, such as delayed healing and infection at the same time, but the infections were all reported either with a positive culture or with a positive clinical assessment.

There are times where the implant is in place. A patient might have some symptoms of redness or malaise, and there are times when you can treat that effectively by intravenous or oral antibiotics. So those are situations where you would not be able to get an actual tissue culture positive, but it's certainly your clinical impression that that's what it is.

If you're able to treat it successfully, the patient is not encumbered with an operation, and it would be dangerous to try to needle aspirate it simply to get a culture. So there are certainly cases where it's clinically strong indication, but not culture document.

DR. MORYKWAS: Sure, and then there are also indications where the patient might have been double reported as nonhealing or delayed healing plus infection.

And then the last thing is you had a very small number of patients that were other. Are those the combined smooth and textured implants?

DR. CUNNINGHAM: You're talking about the pie chart of types of devices?

DR. MORYKWAS: Yes. In one it was .2 percent, and in another pie chart it was a one percent and it just said "other."

DR. POGGIO: Just in rare instances there were different devices in the two breasts, and it reflects the mixture of one device in one breast and one in another.

CHAIRMAN WHALEN: Ms. Dubler.

MS. DUBLER: I'd like to pursue a little further the relationship between your findings and your communication with physicians and with patients. The findings on the Betadine washing are quite startling, and when did you make those findings, and what's happened to that information since it developed in your database?

MR. PURKAIT: The Betadine findings approximately we came to know about this about a year, a year and a half ago. As soon as we came to know about this, we immediately contacted the agency with that information to correct the patient information, as well as the physician information.

So that was being done even long before the clinical study results came to us.

MS. DUBLER: And do you state your findings in a similar fashion in your patient information and your physician information communications?

MR. PURKAIT: I believe definitely I recall that we do that in a physician's information on this. I would have to check and get back to you about the patient and so on.

DR. CUNNINGHAM: There would probably not be a reason to inform the patient about this. It's something that occurs while the patient is asleep. I suppose in a best case circumstance the patient might ask the doctor, "Do you do this?" but it may be more information than they can clinically use.

They're bombarded with a lot of information as they try to make this decision.

MS. DUBLER: I agree, but there are some very interesting examples of instances in which giving patients information brought change in practice and giving physicians information didn't. So that's the background of my question.

DR. CUNNINGHAM: Certainly the reference to the hand washing and patients being aware of that and encouraging their physicians to do that is very good, and hopefully this is something that will come up on Wednesday when we discuss or on Friday, rather, when we discuss this more fully.

CHAIRMAN WHALEN: Dr. Robinson.

DR. ROBINSON: A couple of question. Mr. Purkait, in your fatigue impact studies, just to give me a better perspective, what does that -- I know it may be impossible to translate into real time, and that's unfortunate, but can you give me an estimate of what you think that translates to in real time? Is that falling off a ten foot wall? Is that an air bag inflation? What do those maximum values tell you about your device?

MR. PURKAIT: Yeah, sure. I'd like to share with you some test data and show that to give you a better understanding what it really means, and I'll take about two minutes of your time. I'd like to invite Mr. Phil Yang and Dr. Mark Allen to show you some of the data and the test.

MR. YANG: I'm Phil Yang. I'm Vice President of Technical Studies and Submissions for Mentor Corporation.

The fatigue data is really comparing to fatigue activities that you normally see in someone's body. We've modeled this as someone walking. A breast implant would go up and down. So we're comparing it to those types of small, relatively small effects that continually happen to a person in a cyclic manner. So those are what we're comparing to.

In order to understand how we do the testing very quickly and what it means in terms of numbers, I'd like Dr. Mark Allen to come and explain it.

DR. ALLEN: I'm Dr. Mark Allen, Mentor Corporation, Science and Technology Laboratory Manager.

I would like to provide a very brief overview of the fatigue testing that Mentor conducts for an estimation of the in vivo lifetime prediction or, more appropriately, an assessment of long term durability of the implant.

To do this, as indicated on the slide, the in vivo fatigue testing methodology, both consideration of the fixture and experimentation, include an assessment of the in vivo environment, the stress magnitude and distribution on the implant, and the physical activity associated with typical daily routine.

This then can be used to develop safety factor and lifetime prediction for an endurance limit, safety factor calculation, Basquin relation or the Gerber relation.

This slide indicates that the device, when implanted, the posterior region is adjacent to the chest wall, and accordingly is subject to minimal stress, whereas the annular and anterior region of the device is probably that which is exposed to load distribution.

When considering the activity of an individual and the loads that might be imposed upon the device, one can consider the at rest condition or the emotion condition. If this is done at rest, typically one assigns the mass of the device as the stress induced on the mammary and the regions indicated. In motion, one would consider jogging perhaps and equations can be shown which will allow derivation of a magnitude of load of approximately two times the mass of the device.

With these considerations then, in vitro testing can be conducted, and this illustrates the schematic of the test fixture. I believe Bobby showed this earlier.

This design includes a hemispherical ram which is used to load the device. The device is held or supported within a steel spring cage. The steel spring cage actually allows for the anterior region of the device to protrude between the springs so that during this test under compression loading, both the annular region and the anterior region are subjected to loading for us, which is consistent with the in vivo environment.

The testing that's typically conducted for this kind of experiment, some of the conditions are listed here, and as I mentioned previously, a typical load that might be experienced by a device in vivo is on the order of three pounds. The loads that are used here for two different types of experiments range anywhere from 40 to 80 pounds, which is extremely excessive relative to the in vivo condition that's typically encountered.

The failure analysis is then used to construct the S-N curve. On the other hand, endurance analysis is used to determine the load in which failure will not occur.

A typical S-N curve is shown here. This is derived from the data which results in failure, not endurance. However, if one were to construct a horizontal line along a stress amplitude consistent with that measured for the endurance limit, that would define an elbow region of the curve.

DR. LI: Excuse me. Could I just interject one?

DR. ALLEN: Yes.

DR. LI: Could you define for us what the failure point is? At what point do you decide the implant has failed?

DR. ALLEN: Catastrophic rupture defines the failure for the data which is presented here, and with that catastrophic failure, the failure mode is measured and recorded, including the location, dimensions, and thickness of the shell at the site of failure.

DR. LI: Thank you.

DR. ALLEN: So all of these are catastrophic failures that are incurred. They're induced intentionally to develop the S-N curve data.

From these types of experiments then, one can derive a safety factor. One of the most straightforward approaches is the endurance limit safety factor which uses, again, that stress amplitude that I mentioned, which does not result in a failure of the device, a catastrophic device from this cycling. That occurs at ten to the seventh cycles or ten million cycles.

And then that can be compared to the in vivo stress amplitude, which I identified previously, approximately three pounds for a 325 cc mammary. This allows for the construction of a safety factor, and that yields in this case for a 325 value of about eight.

Unfortunately, this only assesses the safety factor of the device without failure. An alternative approach to develop a safety factor relies upon an equation based upon the Basquin relation, and this allows incorporation of a time even, as indicated below, the time event which would be consistent with activity, daily routines such as jogging and walking.

An this case five hours of activity a day were considered with one cycle per second for events, and typically this would calculate to be about seven million cycles per year.

If one assigns a ten year life then and incorporates this value into the Basquin equation, a stress amplitude results which is about 28 psi. This then can be used with the in vivo stress amplitude and yields a safety factor of about 8.6, which is very consistent with the endurance limit safety factor and would offer then a reasonable lifetime, if you will, or long term durability of the implant under these conditions.

One additional relationship that can be used relies upon the Gerber equation, and that allows also for the incorporation of ultimate tensile strength of the shell to be included in the calculation, and as you can see, a similar safety factor is developed from that.

DR. ROBINSON: Could I try it a different way? The real time part is missing.

What would be your conjecture if a woman was sitting in the passenger side and an air bag inflated?

DR. ALLEN: If I recall correctly -- maybe I'm not the person that should be answering this question -- but the impact testing resulted in a value which is approximately three times that of a car collision.

DR. ROBINSON: Okay.

MR. YANG: The air bag situation we model as impact testing, not as fatigue testing.

DR. ROBINSON: I have one more for Dr. Cunningham.

CHAIRMAN WHALEN: Please.

DR. ROBINSON: Dr. Cunningham, towards the end of your presentation you had a group of patients that were explanted and then reimplanted. I think there was 60 of them if I remember correctly. I may be a little bit off on that. I may have missed it.

Is it too early to comment on those 60 that have been reimplanted?

DR. CUNNINGHAM: You're referring to the revision group?

DR. ROBINSON: I believe so. It was towards the end of your presentation, yeah.

DR. CUNNINGHAM: We can discuss the revision group.

MR. PURKAIT: Before we start the revision group, one question to answer Ms. Dubler about that, no, we have not had that incorporated in the patient level. We would be doing that, the information about Betadine use.

And to answer your, Doctor -- I can see your --

DR. ROBINSON: Robinson.

MR. PURKAIT: -- Robinson, about the safety margin, the question that you have on fatigue, I'd just like to conclude that by saying the model that you have shown here is fatigue testing only to show the safety margin in terms of the load factor that it can take over a time period.

The question that you have is data impact. We have tested against a model called 35 miles per hour collision. If somebody had the amount of impact energy, it would be on the chest, whether it would withstand the breast or not, and we found that our product, it takes about three times more than impact energy to cause rupture.

So I just want to clarify that.

DR. ROBINSON: That's what I was looking for. Thanks.

MR. PURKAIT: Thank you.

To answer the question on the other areas, I'd like to call Dr. Gene Poggio to show some of the information, and then I'll have Dr. Cunningham explain the clinical data on that.

DR. POGGIO: This actually connects with what I mentioned at the beginning when I said there was one exception to when we discontinued the patient to explanation. We did for all of the analyses except for these analyses where we actually used that as the data, if you will, as a baseline for the next set of patients.

So I'll run through this focusing on the saline perspective part, but revision patients are basically defined by the FDA as patients that are replacing their original implant regardless of whether your original implant was for augmentation or reconstruction.

And in the saline prospective study -- and I must apologize here. The 196 is actually the number of devices. It's 124 patients, and the 215 in the large, simple trial is, indeed, the number of patients.

Next slide.

This slide showed the complication rates in the LST for revision patients with 95 percent confidence intervals, in the "large simple trial," I should say, and this is on a per patient basis at 12 months.

And the next slide.

And now we're looking on a per device basis at 36 months, and we did actually so that we have the estimated rates for the major complications here with 95 percent confidence intervals, and we tested whether there was a significant difference between -- and I'm sorry. This is for prior, where the previous implant was for augmentation. The next slide is the reconstruction.

We compared whether there was a statistically significant difference between these estimated rates and the rates per the original augmentation, and there was no significant difference with the exception of explantation, which was somewhat higher.

Next.

And then for reconstruction, again, the same five major complications with estimated rates, complication rates, and 95 percent confidence intervals, and again tested for significant difference between this, and in this case the original reconstruction, and we have two significant differences, one up and one down.

And then we also have information on effectiveness, and I think I'd rather turn that over to Dr. --

MR. PURKAIT: -- show the complication rate and then Dr. Anderson will show the effectiveness.

MR. POGGIO: Okay.

DR. CUNNINGHAM: It was of interest to me to try to determine or theorize why these rates of clinically significant changes in these patient cohorts over their primary indication for implantation, and to come up with a clinical story that explains it.

The explantation group, which is higher after the revision, the causes for explantation, the second explantation, are capsular contracture, deflation, and infection, and I think what we're seeing here is a group of patients who had an intervention to try to solve a problem. They had a capsular contracture. They had some other problem and had an implant placed in an attempt to solve that problem.

And I think this increased explantation rate shows that the problem was attempted to be solved, but was not, in effect, solved. So a patient who in a clinical situation, as we were discussing earlier, might have the signs and symptoms of a cellulitis, you try to deal with it with intravenous or oral antibiotics. It does not resolve. You offer the patient the choice.

The choices are: we remove your device, let you have no device for a period of time while you heal, and then replace the device. That's one option that we offer patients.

Another option that we offer patients is we can go in, we can take out the infected device, we can clean the space, we can put you on oral antibiotics or IV antibiotics, and we can try and save you a third operation or another operation and put the implant back in at this time.

And I think what we're seeing here is that there are times where we try to do that and were not successful.

With respect to the reconstruction patients, I think the decreased number of capsular contracture Baker Grade III or IV that we see after reimplantation indicates the opposite story, but this is a group of patients where we were able to successfully treat a problem, namely, that of capsular contracture, by operating on the patient, taking out the scar capsule contracture, dividing through the scar capsule, whatever, and that this decreased number indicates we've been successful.

With respect to deflation, it's a more difficult question to answer for me clinically as to why this group has a slightly greater risk of deflation than when they originally had their device placed, and I feel that I have to come back to the sense that it's a more adverse environment.

Perhaps if the surgery was done for a capsular contracture and the contracture continued to exist for some reason, we know that that might be associated with a greater incidence of rupture.

Now, the bigger question is: how do patients who have already undergone a frustrating experience? They've had high hopes of success. The operation has been done, and it hasn't worked out. They've had to have another implant placed. So a very significant question is: how do they take this? How do they respond to it? What's their satisfaction level?

And I would like to ask Dr. Anderson to spend a second or two talking about that.

DR. ANDERSON: We had used the breast evaluation questionnaire to assess patient satisfaction in the saline perspective study. So we decided to look at patient satisfaction in this revision group of augmentation patients on the three aspects, size, shape, and firmness.

And as you can see, despite the fact that they experienced revision procedures, they still reported very high levels of satisfaction at the 36 months follow-up with respect to size, shape, and firmness.

CHAIRMAN WHALEN: Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: I believe --

CHAIRMAN WHALEN: Excuse me one second.

On that same issue?

PARTICIPANT: No.

CHAIRMAN WHALEN: We're going to someone else and then I'll get to you.

DR. BANDEEN-ROCHE: I believe my question series is for Dr. Anderson: concerns about the quality of life data, and certainly include the lack of a control group.

And so first of all, just correct me if I'm wrong, but my understanding is you really don't have any true quality of life data for the augmentation patients. It's body appearance and self-esteem data rather than quality of life, is it not?

DR. ANDERSON: I suppose you could characterize it as body image.

DR. BANDEEN-ROCHE: Okay. In terms of the slight increase of self-esteem, I'll just voice my concerns, and I just want you to respond. If women went into the surgery at a particularly low point of their self-esteem, which is certainly reasonable, slight increase would be consistent with regression to the mean, wouldn't it?

DR. ANDERSON: I'm not a statistician, but, yes, I understand the concept you're talking about, and that's probably true.

Are you referring to the Tennessee self-concept scale?

DR. BANDEEN-ROCHE: Yes, I am.

DR. ANDERSON: Okay. With respect to that scale, we've acknowledged that that scale is maybe not the best assessment to have been utilized, and that's one of the reasons I didn't present it in my presentation, even though we did achieve clinical significance. We didn't know if the results were -- I mean statistical significance -- we didn't know if the result were clinically meaningful.

DR. BANDEEN-ROCHE: Okay. Thank you.

My next question goes to the reconstruction patients. So you noted increases in quality of life on the FLIC. I'm just going to state something, and just correct me.

My impression is that those increases are not distinguishable from increases that could have happened anyway just because they've recovered from their cancer.

DR. ANDERSON: It's very possibly true that they would have over a period of three years adjusted to their cancer and shown an improvement. In my clinical experience, however, I do see that there is a tremendous amount of satisfaction with restoration of the breast in these patients.

DR. BANDEEN-ROCHE: Thank you.

CHAIRMAN WHALEN: Ms Brinkman.

MS. BRINKMAN: Yeah. Along that same vein, I'm interested in your Beck depression inventory because in reconstruction patients, you say, you know, that their scores have decreased, but, I mean, is that a decrease, and how do you know the difference whether it's a decrease due to the fact that they've finished cancer therapy treatment or whether it's actually the fact that they've had an implant?

How do you separate that?

DR. ANDERSON: Well, you know, it was relatively nice to see that they weren't a real depressed group of patients to start with, which is consistent with one of my studies, which looked at psychological adjustment in breast reconstruction patients, and I suppose that it is theoretically possible that levels of depression would have decreased over time in these patients.

Again, I relate to my clinical experience. These patients are overwhelmingly satisfied and pleased to wake up from surgery with a breast mound.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: I wasn't going to open the door to Betadine, Dr. Cunningham, but it's already been opened, and I think I have to walk through it.

My recollection is that Mentor initially sent out a flyer to users of breast implants saying that Betadine was a problem with the integrity of the implant, and that was from a study in which Betadine had been placed within the device, and the problem at that time was a valve failure.

And then there was some furor about it within the plastic surgery community, and as I recall, Mentor did another study or perhaps a parallel study with the implant immersed in Betadine solution and found no problems with that in vitro.

Now, is my memory of that correct?

MR. PURKAIT: Some of them, correct, and some of them -- if I may have your indulgence, I'd like to kind of go and kind of give this.

When we looked into the Betadine, this was brought to our attention by many different surgeons. They are the one who called us and said, "Look. Maybe you should take a look at it because some of the implants are showing failure because of some reason we do not know."

Well, when we started looking into their information and the data, we realized that there was a large amount of Betadine was used with our implants in all conditions, whether it has been soaked or put inside the cavity or put inside the implant.

We initiated our internal investigation and studies to understand was there any relationship between the Betadine and the implant failure. We have done several experiments three different times, one with the solution inside, one with the soaking, and also to match up the acidity of this particular one to make sure that the acidity doesn't have anything to do with it.

So the series of experiments have indicated that, one, either the implant does fail even with the contact, and when we learned that --

DR. BURKHARDT: I'm sorry. I didn't understand when you said that. That the implant does fail?

MR. PURKAIT: Failed, yes. The implant failed. When I said "failed," it means the pads tends to come out of the shell or the shell itself, the surface of the shell looks like getting weaker, and you can easily probably break through that. Those are the kind of observations we have seen.

And when we saw that, we realized that any way we want to do it -- in other words, if we can go back and probably do some more experiments to tease out exactly what conditions and what time, we kind of felt that this is our responsibility to contact the agency with that information, and we did so, and at that point in time, the agency and ourselves decided that we should put that immediately with the patient information, with information that with even the slightest contact will provide or will probably fail or show the loss of integrity of the implant in the future.

So that's where it is.

DR. BURKHARDT: For Dr. Cunningham, were the failures that you observed with the Betadine irrigation, were they valve failures or were they the usual fold flaw failure, or do you know?

MR. PURKAIT: We have the failure, the deflation, as we have shown you before. We only saw two fold flaw failure. We did see some failure because of the tear of the shell. That's the largest number.

Now, it's very difficult sometimes to exactly identify the tear was already there or it was the loss of the shell thickness for some reason. So we couldn't really identify that very well.

DR. BURKHARDT: Thank you very much.

CHAIRMAN WHALEN: Dr. Morykwas.

DR. MORYKWAS: I just wanted to ask a follow-up question of Dr. Cunningham on the infection that I brought up before, and just to simplify things, I'll say an early infection is one that is apparent before the incision is totally healed, and a late infection is one after the incision is healed.

Do you have the percentage of early versus late, and was it at all correlated to the surface type of the implant, the smooth versus textured?

And I guess as a follow-up, did you use any of the partially textured implants?

MR. PURKAIT: The last question first. Partially textured implant was not used to understand that phenomenon, but as far as the breakdown of those, we'll talk to Dr. Gene Poggio to see if he can tease out the information for you.

DR. MORYKWAS: Okay.

DR. POGGIO: I can answer part of your question pretty readily. Looking overall, across augmentation and reconstruction, and I have it separately for those if you'd like, in the first year -- this is using the Kaplan-Meier estimates and looking at changes from year to year. So how much happened in the first year and then how much increased; did it increase between the end of the first year and the end of the second year?

So infection overall, 2.8 percent in the first year, 0.5 percent in the second year, and 0.16 percent in the third year. So it's almost all in the first year.

DR. CUNNINGHAM: But in terms of teasing out, I mean you're asking for a time frame of one or two weeks, and the first interval follow-up were data reported as four to six weeks, and these would presumably be detected earlier than that, but they would be, you know reported as they accumulated.

I think in clinical practice they occur most frequently within the first two weeks, and it's a little bit different than a wound infection without a device because most plastic surgeons, as Dr. Burkhardt has teased out, try to use antibiotics, Betadine, whatever they can, to make this complication go as close to zero as possible.

So there are times where the -- plus giving prophylactic antibiotics -- so there are times where the time course is shifted or delayed out into the future than in a wound where there is, you know, no prophylactic antibiotic, not as much irrigation, but clinically my impression is that they almost all are most apparent within the first two to three weeks, and it's very rare that you see a late complication associated with, say, some dental procedure or some other seeding.

Here's the time to occurrence. Four to six weeks is 53 percent, which is the majority. Six months is 24 percent. Twelve months is 17 percent for reconstruction patients, and then in terms of the infection by device, the textured device, both the SILTEX and the SPECTRUM, are more likely -- it looks like about 85 to 90 percent -- are more likely to have an infection.

CHAIRMAN WHALEN: Dr. Change.

DR. CHANG: I'm going to quote Dr. Burkhardt again because it is my concern that on the face of it, although in the ten year retrospective study patient satisfaction rate was high, 93 percent, could you help me out? And I presume you're looking at infection, significant capsular contracture and deflation rate. Could you help me out and in your own words, how would you explain to a consumer, to a patient that despite one in four complication rate at ten years, that this is, indeed, a safe product?

Overall complication rate is 27 percent.

DR. CUNNINGHAM: I can speak to, you know, what I see clinically, and perhaps Dr. Anderson can speak to that as well.

First of all, no plastic surgeon wants a surprised or unhappy patient, particularly when we're doing elective surgery, aesthetic surgery. So I think one of the ways to explain the fact that despite a one in four risk for complication or reoperation patients are generally satisfied goes to the degree to which they are informed.

If I as a plastic surgeon whitewash the possible complications and have the kind of risk of complications that we've demonstrated today, I'm going to have a lot of very unhappy, surprised patients saying, "How could this happen to me?"

Whereas if I go as far as I can to stress what the risks are, make clear what things could go wrong, and make clear that the patient understands that and we're not pretending that it's not going to happen to them, we're saying it could happen to you; I think that sets an expectation set that makes anything that does occur more acceptable to a patient and not something that's going to diminish their overall result.

But I think when we ask the patients to rate themselves on a strongly dissatisfied, dissatisfied, satisfied, very satisfied -- I can't remember what the fifth one was -- the vast majority of them also when we asked them would you do it again, the 90 percent range was, yes, they would.

So I think part of it is they're well informed, and so they tolerate the complications.

CHAIRMAN WHALEN: Ms. Dubler.

MS. DUBLER: I'd like to pursue that just a little bit because I have an epistemological problem. In the context of research where IRBs have to weigh the risk and benefit, there's an articulate, although not the majority of scholars who argue that the informed consent process can cure the defects in the risk-benefit ratio; that it doesn't really matter what the risk-benefit ratio is. If you can tell the patient and the patient can make an informed choice, it solves your problem.

But in the context of the FDA's finding that something is safe and effective, I'm not sure that an informed consent response solves the underlying problem. So we have a 27.6 overall complication rate.

I don't know. I think women want it. I think they're satisfied. Your data seems to show that, but I don't know how we can find it safe. Now, maybe that's a question for the company. Maybe it's a question for the FDA, but that's a problem for me.

DR. CUNNINGHAM: Well, I think --

(Applause.)

DR. CUNNINGHAM: You know, I think we wouldn't want to try to make the assessment for the patient. We are constantly asking them what their assessment is. That's the basis of the data that Dr. Anderson presented. It's the basis of the data that I presented.

I think there are two different risk-benefit sets. There's obviously a different set for the augmentation patient versus the one for the reconstruction patient.

I think another thing that we haven't really talked about extensively here is that we're not just counting pieces of chalk marking on a blackboard. The complications that we talk about, some of them are significant and impact definitely on a patient's life, and some of them are things that they can control and determine themselves.

For instance, the patient who wants to change their size is recorded as a reoperation, but it's not an obligatory reoperation. It's something that they choose to do to improve their result.

So it's not exactly the same model as some of the others that you might be looking at because the patient is in so much control of the process relative to, you know, you need a heart valve, you need a pacemaker, this you need. It's a different situation.

A lot of these operations are things that patients choose to do.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: Yes. Dr. Cunningham, I forget exactly what the figures were. Seventy-two of 88 implants that were removed were replaced at the same time, and the problem was apparently size. So rather than being a concern about the integrity of the device or anything, it does raise some question about how the size is picked in the first place.

How did you do that in your study?

DR. CUNNINGHAM: I think we left the size determination to the surgeon's individual practice. There's no way that the company could help the surgeon decide what size the patient would need for the patient to be happy, and I think certainly I have seen in my own clinical practice where a patient might come in with one set of expectations before they have any surgery, and then as time goes on, their expectations and their desires change after the operation.

So there are times when patients come in and demonstrate or discuss a certain look or appearance, and then after the surgery they say, you know, "I would like to enhance that further," and that's part of what we see when the implants are changed, particularly for a larger size.

DR. BURKHARDT: I guess my point would be that as I understand it, then that doesn't reflect deficiency of any sort on the implant, only in the decision making process as to the size originally.

DR. CUNNINGHAM: I think what you're reflecting is a communication issue or a change in communication or change in desire on the part of the patient, not an implant related problem.

DR. BURKHARDT: Thank you.

MS. DUBLER: Could I follow up with that, please?

CHAIRMAN WHALEN: Yes.

MS. DUBLER: I just want to follow up this discussion because I think it's very interesting, and that is the Betadine discussion and perhaps the reoperation to put in a larger prosthesis reflects on the quality of the practice of the surgeons more than it does on the device itself.

So, again, it's hard for me to separate out how much of this reoperation and overall complication rate is related to the device and how much of it is related to surgical patterns of practice, and how we allocate or understand that I think makes a difference in this context.

DR. CUNNINGHAM: I take that as more of a statement than a question.

MS. DUBLER: Okay.

MS. BRINKMAN: I just have one question. You're talking about your ten year study, your follow-up. You're using the SEER data for that?

MR. PURKAIT: That's what the cancer patients primary.

MS. BRINKMAN: And that sample size is a little over 200? That's about it, of saline?

MR. PURKAIT: No.

DR. CUNNINGHAM: No, the ten year data that I presented is not the SEER data. The SEER data was another part of the way of looking at the reconstructed patients and what their failure rate was, their deflation rate.

MS. BRINKMAN: But in the SEER data, the saline implant population number was about a couple hundred for the reconstruction?

DR. CUNNINGHAM: That data set, I think, was complicated by the fact that it was a retrospective study. A lot of charts were looked at, and there were definite incidences, and perhaps Dr. Poggio or one of the others can pull that out, where devices were recorded as implants, but clearly as you look back over the medical record, they were not ever meant to be permanent devices. They were soft tissue expanders, not implants.

So I think the large number of those that were soft tissue expanders and not implants kind of clouds that whole data set for us and it makes us very hard for us to interpret what is the actual failure rate in the SEER data for reconstruction patients.

CHAIRMAN WHALEN: Are there other members of the panel who have questions for the sponsor?

PARTICIPANT: One quick one.

CHAIRMAN WHALEN: Well, I'm asking only because I've been asked to move the rest of the questions to a later point in time, but if indeed, we're done, we're done. But if there are others, we are going to move on now to the FDA presentation, and there will be time later for more sponsor questions, which I would project, looking at the schedule, should be some time before 2:00 a.m.

(Laughter.)

CHAIRMAN WHALEN: So we will move on to the FDA presentation, and I thank the sponsor for their presentation.

For all my fellow panel members, as the FDA is coming up for their presentation, please be aware it is past 5:00 p.m. We now are on overtime, which means that Jim Dillard will thank us twice on Friday instead of once for our work.

PARTICIPANT: -- other questions later on?

CHAIRMAN WHALEN: Not at the table, sir, because the FDA will be coming up, but please if you could stay in this vicinity, that would be good because there will be questions, and also you have a summation period later on.

(Pause in proceedings.)

DR. BERKOWITZ: I'll present the FDA presentation of the Mentor saline filled and SPECTRUM saline filled breast implants.

I'm David Berkowitz, the lead reviewer, and I will give an overview of the status of the preclinical testing, and then I'll finish with a one slide summary of the medical device reports for the Mentor prostheses.

And then we'll hear from Sahar Dawisha, who is the clinical reviewer and will review the clinical results.

And then we'll hear from Phyllis Silverman, who is the statistical reviewer.

To describe the device first, the saline filled device is available in six styles. The styles are determined by two things. One is the shape, like the round, the profile or the contour, and the other is the nature of the surface. The surface is either smooth or textured, and SILTEX is the Mentor name for textured. So SILTEX implies textured, and the surfaces are either smooth, SILTEX or SILTEX PT, which is a partially textured device.

The saline filled device has a diaphragm, an anterior diaphragm valve, and of course, it's filled with physiological saline, and both devices, obviously the shells are made from silicone elastomers.

The SPECTRUM device differs from the saline filled device in that it can be postoperatively adjusted. The volume can be postoperatively adjusted, and when the desired volume is reached, the little valve for postoperative filling can be removed under local anesthesia.

The SPECTRUM device has a posterior kink plug value, and like the saline filled, obviously the filler is also saline.

The indications for use are augmentation, reconstruction, asymmetry, ptosis, aplasia, hypoplasia of the breast, replacement, and combined breast and chest wall deformities.

Mentor has done extensive chemical analyses on the device. They've looked at the levels of the volatiles, extractables, and metals, and these are important because, one, they characterize the materials present in the device and, secondly, they determine what is there and how quickly those things can diffuse out of the device to cause either local or systemic toxicity.

These are some of the toxicology testing. The pharmacokinetics testing came from the literature, but also relied upon the chemical determinations sine by knowing how much is present and how much could leak out, we know what the dangers are.

So, in fact, it turns out in terms of systemic toxicity, even if all of the low molecular weight components present in the device leaked out immediately, it would still be a wide margin of safety between the levels, say, the blood levels obtained and the toxic levels.

The middle group of things that were determined are all the, I think, quite commonly done biocompatibility things that are tested on most devices, and I just want to mention at the end that the immunotoxicity is important for these devices, and it was quite extensive.

That is, in addition to doing simply the hematology and counting cells, they enumerated, you know, the B and the T cells and the T cell subsets. They enumerated the killer cells, for example, and they also estimated the effects of implanted shell material on killer cell activity and on things like the mixed leukocyte response.

So various aspects of the immunology were broadly tested.

The remaining, these toxicological things have to do with mutagenesis and in bacterial testing and in mammalian cells, and finally culminating in a two year rat carcinogenicity study which demonstrated no carcinogenicity.

The company also did a reproductive toxicology and teratology study, and that was also negative, which would have been expected.

The mechanical testing, on the other hand, is not complete. Mentor has done some mechanical testing on each of these topics, and we have also received some recent data which have not yet been reviewed. But with all the testing we now have, we think that the data are not yet sufficient to make a recommendation for all the implant styles proposed in the PMA.

So we are still going back and forth with Mentor on the mechanical testing.

Finally now, to change topics, I'd like to put up a slide summarizing the medical device reporting for Mentor, and this slide summarizes the medical device reports that FDA has received for the Mentor saline filled breast implants during the last three year period.

The first column, that is the Maude reports -- oops, I missed the slide -- the first column, the Maude reports, the Maude system received reports directly from patients, health care providers, practitioners, and from manufacturers.

The second column lists the five most frequently reported adverse events that are reported in summary form by Mentor on a quarterly basis. So these are the sums of the reports for the last -- for over the three years shown above.

So that's all I'll say about this, and I think now I'll ask Dr. Dawisha to come and begin the clinical report.

DR. DAWISHA: Good afternoon. I am Sahar Dawisha, a Medical Officer in the Division of General and Restorative Devices, and I will be presenting FDA's clinical perspective of the information provided in the Mentor Corporation's saline filled breast implant PMA.

The clinical studies reported in the PMA are summarized on this slide and consist of a retrospective assessment of implant removal from the SEER data base, a one year large, simple trial, or LST; the saline prospective study, or SPS; and the Mentor retrospective study.

The SEER and LST were conducted in response to suggestions from FDA in 1994 on the type of information needed for PMA approval submission. The SPS is a prospective clinical study which was approved by FDA in 1995 after all augmentation and some reconstruction patients had already been enrolled.

Because the saline prospective study contains the main safety and effectiveness information, I will focus on this study summarizing the SEER and LST only briefly. I will not be discussing the Mentor retrospective study because the patient population in this study is highly selected and because data ascertainment bias severely limits the conclusions drawn from this study.

The sponsor funded a retrospective analysis of implant removal in a breast cancer population cohort from the surveillance epidemiology and end results or SEER program of the National Cancer Institute because they were having difficulty enrolling reconstruction patients in their clinical studies. Women with a diagnosis of breast cancer in the years of 1983, '85, '87, and '89 with any type of breast implant, including silicone gel filled, saline filled, and tissue expanders, were asked to respond to a questionnaire regarding implant removal.

The results of this study are shown here. The nonresponse rate was 20 percent overall. Of the 1,375 total implants removed -- I'm sorry. Of the 1,375 total implants, 32 percent were removed.

Of the 252 saline implants, 43 percent were removed.

There was information provided based on the reason for removal, and excluding the 28 saline implants removed as part of planned reconstruction -- these are the tissue expanders that Dr. Cunningham was referring to -- the reasons for saline implant removal are shown.

Capsular contracture constituted the single most common reason for implant removal, 35 percent of implant removal.

The large, simple trial was designed as a prospective study of a large number of patients followed only for the safety endpoints of capsular contracture, infection, rupture, deflation, and explantation for a total of one year. The sample size of 3,000, and 5,000 patients was proposed by the sponsor to estimate complication rates with a precision of one to two percent.

The LST results at one year are shown here on a by patient basis. The analysis method used here is the Kaplan-Meier survival analysis, which shows a risk of a first occurrence of a complication, along with a 95 percent confidence interval, which is shown in parentheses.

Not that for the total group, which is in this column, the confidence interval are all within one to two percent as proposed by the sponsor. However, the intervals for the reconstruction and revision patients are much larger, and in some cases there was insufficient information to estimate the proportion.

There were a total of 2,373 patients enroll with the majority as augmentation, and the follow-up rate at one year was approximately 47 percent.

Of the four complications studied here, capsular contracture, Baker Grade III or IV was generally the complication encountered with the greatest overall frequency.

Furthermore, you can see that for the two complications in which there was sufficient information, which would be explant and capsular contracture Grade III or IV, the revision patients generally have rates between those of augmentation and reconstruction.

With the exception of this study and the implants in the SPS in which there was replacement and follow-up information, the sponsor has not collected safety and effectiveness information on revision patients.

You'll be asking the panel questions to discuss the revision indication.

Before I discuss the SPS in detail, I would like to show you the implant style studied in Mentor Corporation's clinical studies, as well as those not studied for which the sponsor is seeking approval.

Note that the sponsor is no longer manufacturing implants with an oval shape or with a leaf valve. The implants with a contour profile shape have a greater contouring than those that are contoured, and the major difference here is the partially textured devices. These implants appear to be unique from all others in that they are textured only on the posterior surface. The texturing is more pronounced. The posterior textured layer is an additional vulcanized layer, and this layer is made from a different, softer silicone.

The sponsor has been asked to clarify how this new texturing differs from the type of texturing in their clinical studies and to explain whether and how the clinical performance can be inferred from this new texturing method.

The saline prospective study was initiated in 1993 and approved in 1995 after augmentation and summary construction patient enrollment. The study is a prospective, open label, multi-center study with three years of total follow-up for patients seeking primary augmentation and primary reconstruction.

Safety was based on local complications, and effectiveness was based on breast dimension changes, patient satisfaction, and quality of life measures.

The sponsor collected lactation and reproduction history at baseline and connective tissue disease, or CTD, symptomatology and breast conditions at baseline and at follow-up.

A sample size of 1,200 to 1,500 patients with at least 20 percent of these as reconstruction was proposed to estimate the 95 percent confidence interval precision for complications.

The patient disposition at three years is shown here. Of the 1,265 augmentation patients enrolled, approximately 76 percent completed their three year visit. For reconstruction, the completion rate was 66 percent at three years.

Of the patients who were withdrawn, the majority for augmentation were lost to follow-up. For the majority of reconstruction patients who were withdrawn, the majority were explanted. The 15 patient deaths reported in this study were not implant related. For the 49 augmentation and 75 reconstruction patients who underwent explantation, subsequent complications are not included in the Kaplan-Meier complication rates to follow.

The three year cumulative Kaplan-Meier rates of first occurred and 95 percent confidence intervals for selected complications are shown here on a per patient basis for the patients in the saline prospective study. You can see that the largest 95 confidence intervals are plus or minus three points for augmentation and plus or minus five points for reconstruction.

Note that the capsular contracture shown here includes both Baker Grade III or IV and Baker Grade unknown or unreported, and that the category of any complication here includes reoperation.

The cumulative risk of a first occurrence of a complication is 43 and 73 percent, respectively, for augmentation and reconstruction. Although only the three year rate is shown here, the cumulative rate of first occurrence of any complication increases over time and has not leveled off by three years of follow-up.

The cumulative risk of at least one reoperation for any reason over the three year period is 13 percent for augmentation and 40 percent for reconstruction, and these rates, as well, are increasing over time.

In general, the complication rates for reconstruction are three times greater than for augmentation.

The cumulative rates of first occurrence of leakage/deflation, implant removal, breast pain, wrinkling, and nipple changes, which includes both loss of nipple sensation and intense nipple sensitivity, are shown here as well.

The most common types of reoperation procedures performed through three years is shown here based on the number of procedures. Percentages do not sum to 100 because I have omitted infrequently performed procedures from this table.

There were 358 and 353 reoperation procedures performed in the augmentation and reconstruction patients, respectively, through three years. For the category of removal with replacement, I combined the following categories reported in the PMA: implant size exchange, secondary augmentation, replacement, and revision.

Scar/wound revision includes skin adjustment and wound management. Capsule related procedures include capsulotomy and capsulectomy.

The most commonly performed procedure for augmentation patients was removal with replacement, 32 percent of the procedures performed in these patients. And for reconstruction, it was a capsule procedure, 28 percent of the procedures.

Not shown here are the nine implant removals without replacement and augmentation and 40 in reconstruction patients.

The information shown on this slide was provided subsequent to the PMA submission at the agency's request, and it shows the reasons for implant removal through three years on a by implant basis. If an implant was reported to have been removed for multiple reasons, the hierarchy for categorization into this table is shown in the footnote below the table.

Cosmesis includes asymmetry, ptosis, wrinkling, and scarring. Of the 136 augmentation and 116 reconstruction implants removed over the three years of follow-up, other than a patient request for a size or shape change, the single most common reason for augmentation implant removal was due to leakage/deflation.

Twenty-three percent of all removed augmentation implants were due to leakage/deflation. Infection and capsular contracture constituted the most common reasons for reconstruction implant removal, each at 26 percent of all reconstruction implant removal.

For both augmentation and reconstruction, if you were to take the complications and sum those, you would see that the majority of implants were removed due to a complication rather than due to patient request for a size or shape change.

In an effort to characterize the complication rate in revision patients, the sponsor was asked to provide the cumulative Kaplan-Meier first occurrence complication rate on a by implant basis for those implants which were removed and replaced during the study and for which there was follow-up information.

This table summarizes this information through three years of follow-up. Because the sample size and follow-up is lower than for the primary implantation in the SPS, the confidence interval for this table are much wider than reported for the primary implantation group.

Note that the capsular contracture here, as well as in the other table I showed you, includes both Baker Grade III/IV and Baker grade unknown or unreported, and the any complication category here includes reoperation.

The risk of a first occurrence of any complication for this group is similar for these implants compared to primary implantation. However, for the major complications of reoperation, implant removal, capsular contracture, and leakage deflation, the rates are higher than for primary implantation and lower than for primary reconstruction, which is similar to the revision complication rate reported in the LST.

For most other complication the rates are similar or lower than for primary implantation. You'll be asked to address a revision indication in the panel questions.

The sponsor performed Cox regression analysis for several patient at implant variables which they showed you and for the complications of infection, capsular contracture, deflation, reoperation, and removal, and selected associations are shown on this slide.

There were no associations with infection. Implants with leaf valves had two times higher capsular contracture than those with diaphragm valves. Recall that the sponsor is no longer manufacturing implants with leaf valves.

Surgical pocket irrigation with Betadine was associated with a three and a half times greater risk of deflation than without,a nd implants with SPECTRUM valves were associated with a twofold higher risk of both implant removal and reoperation than those without.

With respect to other safety issues, the sponsor collected breast cancer and connective tissue disease information at baseline and at follow-up. Of note, there were two augmentation patients who developed breast cancer during the course of the study, one patient two years and the other patient five months after implantation. At any follow-up visit complaints of fatigue, generalized achiness and/or joint pain were reported infrequently in patients without such a report at baseline.

There were six confirmed and 31 unconfirmed cases of connective tissue diseases reported over the course of the study. The six confirmed cases are shown here with the indications shown as well.

There were two patients with osteoarthritis and one with an undetermined arthritis and one with ankylosis spondylitis in the reconstruction group.

In the augmentation patients, there was one patient with systemic lupus erythematosus and rheumatoid arthritis reported during the course of the study.

Without a control group of sufficient numbers of similar types of patients followed for the same duration, conclusion regarding the association of the CTDs shown here with these implants cannot be made.

With respect to effectiveness, the augmentation patients and delayed reconstruction patients experienced an increase in breast size. Augmentation patients were generally satisfied, and they experienced small, but statistically significant improvements in one of the ten subscales of the multidimensional body self-relations questionnaire, or MBSRQ, and small but statistically significant improvements in the Tennessee self-concepts scale.

Reconstruction patients experienced statistical improvements in the functional living index of cancer scale, or FLIC, and immediate mastectomy patients experienced improvements in the Beck depression inventory.

There were no statistical improvements in the MBSRQ or in the Tennessee self-concept scale for reconstruction patients.

Recall that the SPS was initiated in 1993 prior to FDA approval in 1995. Shortly after FDA approval, the sponsor was informed that continued follow-up beyond three years would be advisable. The sponsor contacted patients who were still participating in the SPS at that time to solicit continued follow-up in the form of a yearly postcard assessing for deflation.

Of the 1,045 augmentation patients in the SPS at that time, 519 or 50 percent agreed to the four to ten year follow-up. Of these 519, 362 patients returned postcards, a 70 percent response rate, and in these 362, there were 36 deflations reported or a rate of ten percent.

Of the 375 reconstruction patients in the SPS at this time, 186, or 45 percent, agreed to the four to ten year follow-up. Of the 186, 144 returned their postcards, an 86 percent response rate, and deflation was reported in 17, or 12 percent, of these patients.

You'll be asked in the panel questions to address the duration and type of follow-up information needed to fully characterize the long term safety of these implants.

In summary, the cumulative risk of a first occurrence -- of a first complication is 43 percent for augmentation and 73 percent for reconstruction; is increasing with time; and has not leveled off by three years.

Cumulative complication rates of reoperation and removal have not leveled off as well at three years.

Although cumulative local complication rates are increasing, the types of local complications are well characterized, and the rates are precisely defined. In augmentation patients, most reoperations are implant removal. For both augmentation and reconstruction, most implants are removed due to a complication rather than due to a patient request for a size or shape change.

Breast size benefits were realized for augmentations and quality of life changes were evident, but small. For reconstruction patients, quality of life measures generally improved.

You will be asked to discuss these safety and effectiveness issues in the panel questions to follow.

Thank you.

I'd like to now introduce Ms. Phyllis Silverman, who will be discussing the statistical perspective.

MS. SILVERMAN: Good afternoon, or perhaps I should say good evening. I'm Phyllis Silverman, the statistical reviewer for the Mentor PMA.

The statistical sections of this PMA are well written, comprehensive, and address nearly all of the requests put forth in the draft guidance for breast implants. The sponsor's PMA contains safety and effectiveness data from five studies.

Since the saline prospective study is the only one that utilizes the device in question, includes all of the endpoints of interest, and fulfills the recommended follow-up, I consider it to be the primary study, with the others lending various degrees of support.

Because of the approximate 50 percent loss to follow-up with the large, simple trial, the ability to draw meaningful conclusions from this trial is limited. Therefore, my comments will focus on the saline prospective study.

Because there was no control group and therefore no claims of superiority or equivalence, the safety and effectiveness results for this device must be evaluated by way of descriptive statistics. Complication rates, implant survival curves, and effectiveness parameters must be evaluated from a clinical perspective.

As a statistician, my role is not to judge the acceptability of these rates, but to evaluate the validity of the data presentation as well as point out any weaknesses in the study design and analysis. I will start with some comments on sample size.

Because there were no null and alternative hypotheses for the primary endpoints, hence making statistical power a non-issue, the adequacy of the sample size was determined by the desired precision around the estimates of complication and reoperation rates. The larger the sample size, the smaller the width of the 95 percent confidence intervals which are used to represent the precision.

We wanted to insure that the width of the confidence intervals would be no more than about plus or minus four and a half percent when rates were high, for example, a 40 or 50 percent complication rate, and only about one to two percent when rates were low.

The sponsor's enrollment of 1,265 augmentation patients and 425 reconstruction patients resulted in a three year accountability sufficient to meet this precision. Therefore, I feel the sample size was adequate.

This brings me to the Kaplan-Meier curve. The sponsor used Kaplan-Meier curves to estimate the occurrence of complications and adverse events. This technique allows women who were not followed for the entire three years to contribute information to the, quote, survival curve for the time that they were in the study. They either experienced the event in question or they are, quote, censored at their last follow-up, which means they are dropped from the denominator at that point.

I feel that this is the best technique that the sponsor could have used for this type of data. There are, however, three weaknesses with this methodology as applied to these particular data. The information collected reflects prevalence and not incidence, and thus, new cases of infection or contracture, for example, could not be distinguished from continuing cases.

Therefore, survival curves are based on the time to the first occurrence of each complication and multiple occurrences could not be analyzed.

Secondly, because a patient explanted or revised will be censored from the table and not be in the pool to experience other complications, there is the issue of competing risks which can add an uncalculated bias to these rates.

And, thirdly, with the exception of deflation, explant, and reoperation, the exact time of onset of a complication could not be known, but would generally have been noted at the next scheduled follow-up.

This interval censoring as it is called can add an additional unknown bias to the data. Therefore, the curves are not as exact as if one were measuring an endpoint like mortality in days.

A summary of the Kaplan-Meier rates for the primary safety endpoints is reiterated on the next slide. It can be seen from the table that the complication rates in the reconstruction group are about three times what they are in the augmentation group. Because of considerable difference between the augmentation and reconstruction cohorts, these rates must be considered separately by indication and evaluated from a risk-benefit perspective.

Is a three year explant rate of almost 27 percent or a re-op. rate of 40 percent acceptable for re-com. patients? As you can see from the slide, the 95 percent confidence intervals were plus or minus two percent or less for the augmentation patients and plus or minus three to five percent for the reconstruction patients. This is consistent with the guidelines.

Now, I would like to discuss some possible biases with the data. There are several sources of possible bias with this data. With three year follow-up missing for approximately 25 percent of the cohort, there could be a non-respondent bias in that women who were having problems were more likely to return for follow-up than those who were happy with their implants. This would result in an overestimation of complication rate, or there could be the opposite scenario. Patients with complications were not returning for follow-up because they were seeking help elsewhere. This would result in an under estimation of complication rates.

A key assumption for the Kaplan-Meier analysis is that the censoring distribution is independent of the survival distribution. What this means in English is that whether or not a patient returns for follow-up should be unrelated to their level of satisfaction with their implants.

Since we do not know to what degree this is true or the reasons for patients not returning, we cannot ascertain this bias. We can only acknowledge that there probably is some, and the complication rates must be evaluated with this in mind.

Because many of the complications are self-reported, there is likely also to be some recall bias, especially with the reporting of connective tissue disease and the rheumatology screening. This bias could go either way. That is, it could inflate or decrease the rates, depending on how a patient's memory compares to reality.

This is a weakness of a study design where follow-ups are infrequent and medical conditions are not always confirmed by a physician.

The last bias I wish to discuss is investigator or site bias. With a study design of 153 sites, it is virtually impossible to justify pooling on a statistical basis, and the sponsor did not attempt it.

Although there is always the possibility for difference in follow-up or results among sites, I feel that any site or investigator bias would probably be minimal, especially compared to some of the other variables that emerged as related to outcome.

For example, surgical approach, valve type, and implant shape are significantly associated with contracture, and valve type is also associated with explant and reoperation.

Incision size and use of Betadine irrigation was significantly associated with deflation. The sponsor presented an extensive analysis of co-variables, such as valve type, implant shape, laterality, incision size and surface type by use of Cox regression.

Surface type was not significantly associated with contracture, the very thing it was meant to reduce.

Of the three biases discussed, my belief is that the nonrespondent bias is of most concern, and that the other two are probably minimal. This brings me to effectiveness.

The sponsor presented a very thorough analysis of effectiveness by way of descriptive statistics resulting from numerous surveys administered and objective breast measurements.

In addition, before and after comparisons of some effectiveness endpoints showed statistically significant changes. However, I question the interpretation of the phrase "statistically significant increase in breast size." It does not appear to mean anything from a clinical perspective.

The data must be looked at in the broader sense. The data indicate to me that even though there were some dissatisfied patients, breast implants are overall effective from both a physical and emotional perspective.

Conclusion. In summary, I found the data analysis presented in this PMA to be comprehensive. The sponsor's analysis was consistent with the methodologies laid out in the guidance. The complication rates must not be taken as exact, but rather as estimates subject to the biases discussed earlier.

I would like to close just by presenting a few more statistics. Because there could be multiple complications per patient, and even correlations between adverse events, for example, contracture and pain, I would like to leave you with the complication free rates at one, two, and three years. These rates are not subject to the problem of competing risk and would be of particular interest to a prospective patient in making an informed decision.

Although some complications are more serious than others, the data show the complications are, indeed, frequent. Approximately 57 percent of augmentation patients are complication free at three years, as opposed to only 27 percent of reconstruction patients. If breast implants are deemed acceptable for market, women must be presented with these figures so they can make an informed decision from their own personal risk-benefit perspective.

Thank you for your attention.

CHAIRMAN WHALEN: Thank you, Ms. Silverman and the entire team.

Well, our next order of business would be to have the FDA entertain questions from the panel. We have a sort of unscheduled break that we must take because apparently part of this room is not reserved for this block of time. So we're all going to get a little bit closer, too.

So if we would please take a 15 minute break while they resize this room and hopefully that will be sufficient time for them to do what they have to do.

(Whereupon, at 5:53 p.m., a recess was taken, to reconvene at 6:15 p.m., in the same place.)

E-V-E-N-I-N-G S-E-S-S-I-O-N

(6:15 p.m.)

CHAIRMAN WHALEN: I would like to ask that at the real conclusion of the FDA presentation that Dr. Berkowitz review for us the FDA questions that are going to be posed to the panel as the next step.

DR. BERKOWITZ: Question one, while the sponsor provided no long term clinical data on their implant, fatigue testing and fold flaw testing provides some information in the long term rupture leakage of the implants. Please comment on the sponsor's methodology and results for each of these tests.

CHAIRMAN WHALEN: Dr. Berkowitz, if you could just read all of the questions, we're not going to go into the deliberation upon each one just yet.

DR. BERKOWITZ: All right. Question two, given the data for augmentation patients in the SPS and other data provided by the sponsor, is there reasonable insurance as defined in 21 CFR 860.7 that the product is both safe and effective for augmentation patients?

Question three says given the data for reconstruction patients in the SPS and the other information provided by the sponsor, is there reasonable assurance as defined in 21 CFR 860.7 that the product is both safe and effective for reconstruction patients.

Question four, with the exception of the LST one year follow-up and the implants in SPS in which there was continued follow-up after explantation, the sponsor has not collected safety and effectiveness information for the cohort of revision patients. Yet the sponsor proposes revision as an indication for use. Given that this cohort typically represents at least 30 percent of the patients presenting for breast implantation, please discuss whether there is sufficient safety and effectiveness data to include revision as an indication and whether the sponsor should evaluate the safety and effectiveness for revision patients as a condition of approval.

Please also comment on the information that would be useful to collect in a post approval study.

Question five, given that the sponsor's data show increasing cumulative rates per year for the majority of complications for both reconstruction and augmentation patients, please comment on whether there is adequate follow-up data to characterize the frequency and types of long term adverse events.

Please address the following pertaining to long term adverse events: (a) the minimum duration of follow-up; (b) the type of visit, i.e., active or passive, and (c) which types of complications should be assessed.

Question six, the sponsor's SPS study was not designed to provide information in the following long term issues of pertinence to women with implants: one, the interference on the ability of screening mammography to detect tumors in breasts with implants; two, the interference with lactation; and, three, the effects on offspring from women with implants.

Please discuss whether the sponsor should evaluate these issues as a condition of approval. If so, please discuss the appropriate methods for addressing these issues.

And the last question is: given the heterogeneity of surgical practices and post operative management of mammary implantation, please comment on the important issues which should be included in physician training.

CHAIRMAN WHALEN: Thank you.

We now, therefore, proceed to the panel discussion and review of FDA's seven questions, and we will start that off by having three of the panel members in specific areas as lead reviewers make comments in their areas of expertise. Those three will be Dr. Li in mechanical testing, Dr. Burkhardt on the clinical study, and Dr. Blumenstein on statistical considerations.

First, for mechanical testing, Dr. Li.

DR. LI: Thank you.

Let me first say as an overall comment that it appears that mechanical failure of this device in the form of leakage or rupture is one of the primary reasons for revision and reoperation, and this is purely a mechanical failure in my view of either some combination of material, design and environment, and it's unfortunate that that's actually the one area that was the most incomplete in your PMA.

The FDA has done a nice job summarizing their comments regarding your testing in the deficiency letter I believe you have received, and in general I agree with virtually all of your comments, but let me highlight a couple of them, I think, that are more important perhaps than the others.

One is, I think, you need to provide data for all models that you intend to market and not just the ones that you have selected. This goes for all the sets of testing.

The other is that most of the data, as I understand it, was done with the material of construction that you refer to as PTC, RTC, silicone. Yet the final products are made with Sytech (phonetic) silicone, and although you make some comparisons of basic material property similarities, I believe this argument is insufficient to merely make a material swap in those raw material properties alone.

For instance, one of your own data points suggests that, in fact, Sytech and PTC are not equivalent in terms of if you look at one of your numerous tables that showed the elongation and break strength of Sytech versus PTC on dry heat. The Sytech silicone actually has improved properties of elongation and break strength. However, if you do that same comparison and the components are gamma sterilized, the order is reversed, and in fact, the Sytech is less strong and has less elongation.

So certainly I think your claim that the materials are equivalent is not supported.

That raises an odd issue. It appears through the literature that you have one particular Model 1600 which apparently from my reading may or may not be gamma sterilized, which is a little confusing to me. I'm not sure when you choose to gamma sterilize it and when you choose not to gamma sterilize it, and this might be important because basically all of the gamma sterilized material properties are significantly less than those that were heat sterilized.

So my questions would be: why do you do this? How do you decide when they're gamma sterilized and when they're not? And more importantly, does the physician at the end of the line know when he buys a 1600 component if it's gamma sterilized or not and that there's, in fact, a material property difference?

In a more general sense, the thing that I was most taken back is these implants have been around for decades and the leakage and deflation has always been a key complaint or indication for revision, but none of the testing actually directly addressed this particular mode of failure other than your fatigue test, which as you describe it, is a catastrophic failure under extremely high loads and high cycle, which is some indication of leakage, but certainly not any mirror of what happens clinically apparently in these leakage phenomena.

So on the fatigue testing, there is a high variation in your results. If I can just quote a couple of your numbers in general, for your Model 2600 of the 175 milliliters volume and an 80 pound load, your cycles to failure varied from 3,000-something to over 32,000-something, a factor of ten from the best to the worst.

If you take that same model and do the 325 milliliter sample at 75 pounds, again you get about a factor of ten difference, from 16,000 for the worst to 126,000 for the best.

And lastly, if you take the Model 2400 at the same volume and load, it actually fails at 850 cycles rather than the thousands mentioned previously. So although your average graph looks very good, if you factor in the actual cycle fatigue for each individual product, there's at least a factor of ten from best to worst for every component, and then the gamma sterilized version, the 1600 which would be expected to have the worst values, is not done.

You do do a lifetime survivorship in a couple of different ways. I don't dispute the methodology. However, everybody should be reminded that that safety factor is for that particular test. So if the end use was, in fact, that kind of cyclic high speed loading in your test rig, then that safety factor would, in fact, be appropriate.

But I think it's undoubtedly true that that particular mode of failure is not what happened clinically. So I think it's not supported at all that a safety factor is, in fact, carried over to the clinic.

A technical detail, I think, that carries through all of this is the variation of properties and final results as a function of the percent of fill. I couldn't see actually on your reports that I saw how you exactly filled each one. Were they filled to the same volume? Were they filled to the same pressure? I wasn't that exactly sure how that was done.

And also in subsequent device tests, there might be cases where the worst case scenario is a device that's under inflated, and in another test scenario, the worst case scenario might be where it's slightly over inflated, and I see no addressing of the issue of inflation percentage at all, and this actually might be one of the surgically related phenomena that Dr. Cunningham alluded to.

A bothersome thing on the load thing is this. It seems to be a belief by yourself and Dr. Cunningham that how the surgeon puts it in, in fact, makes a difference on the outcome. In fact, there's even a general agreement that somehow that provides higher stresses. Maybe there's folds; maybe there isn't; maybe it's puncture; maybe it isn't. But absolutely none of those particular factors are addressed in any of your testing components, so basically remains anecdotal even after 30-plus years of use.

The other tests are -- I guess I don't know what to do with them. You do a static and dynamic rupture test, which is either dropping of weights on something or just squeezing it until it breaks, and those are interesting kind of device tests, but I'm not actually sure how clinically relevant either one of those particular tests are unless you're going to tell me car accidents are actually one of the reasons that some of those devices fail.

The abrasion test is even more peculiar. I'm not actually sure what the clinical consequence of where is. Are you projecting that the clinical consequence of where is that the device thins and, therefore, is more likely to rupture or are you worried about where and the fact that it creates some kind of particulate debris that goes on to cause some kind of systemic effect?

But in either case neither one of those particular issues is addressed, and you also use a Tabor abrasion test for which panel they stick a flat piece of membrane on a device and then rub against it a very roughened surface. In the crudest sense, sometimes it's a piece of sandpaper, and again, it's a relatively crude test. They're only testing a portion of the device, and again, I don't really know what to do with the device, nor am I sure that particular method of where it is, again, clinically relevant.

The tear test let's me get into the area of retrieval analysis. Depending on what numbers we see, the number of devices that were deflated varies somewhere from maybe three percent to, you know, some relatively much higher number at the end. So even if it's a five percent deflation rate and you've implanted 500,000 of these, there's 25,000 retrieved deflated devices somewhere, and I only see a report that you provide that looks at ten of these devices that were retrieved for either deflation and/or wear, which is a little confusing because you didn't tell me which of the ten were retrieved for deflation and which were wear, and I didn't know if the ones that you called wear were also deflated.

So be that as it may, you did look at where -- tried to assess where the flaws were that caused the leakage, and the short answer is they appear to be everywhere. They may or may not be around folds. Some of your retrieved implants had folds, permanent folds. Others did not.

In most cases the cracks that you associated with leakage were nowhere near the folds. There were a couple that were on the folds, but I don't know if this is just a statistical chance that that's where the crack and the fold happened to meet, but certainly you can have folds without leaks, and certainly you could have cracks in areas without folds.

So your tear testing was a cruder sense. The cracks that you identified in retrieval run the size of hundreds of microns, very small, sometimes even microscopic sizes, but your tear test is relatively gross when we take a big piece of material and you just try to pull it apart.

So I'm not quite sure of the relevance of this more macroscopic tear test to the crack initiation or propagation that you've identified as failure modes in the retrieved implants.

So, again, you've done a lot of tear testing, but I actually have no idea how to relate that to the clinical situation, and you also tore it only in one direction, and multi-directional tears and then assessments of you might have survived the tear test, but I didn't see you look at the samples as closely as you looked at the retrieved devices to see if, in fact, you created creases or cracks that may not have failed as a tear, but may have caused pinholes or whatever bit enough to cause a leakage.

I'm almost done. Bear with me.

The next to the last item is this issue of fold flaw. I think it's certainly a reasonable hypothesis that somehow that these permanent folds that end up in this device are somehow related to the failure, but it's an interesting thing.

If you take a brand new implant and try to fold it and you just fold it in half and let it go, the fold doesn't stay there. It goes away, but just because it's a piece of nice, resilient rubber, but in these retrieved devices, that fold line is often rigid and hard, which indicates either a chemical and/or structural change in material along that fold. That's why that fold is permanent as opposed to if you take a brand new implant, fold it up, do some kind of fatigue test. The chemistry and the structure of the two folds, I believe, are completely different.

So I'm not quite sure that the fold flaw tests, as difficult as they are to run, again, have a clinical relevance.

And then an item that I didn't put much weight to until today's discussion is what for lack of a better term let me call reverse diffusion. It seems as if somehow the inside of these bags get infected somehow and microorganisms find their way inside, and perhaps a mechanism for that is there's got to be a way for the bacteria to get into the device.

One of the earlier speakers even suggested that the valve, in fact, might be two way in the sense that you can let liquid in as well as liquid out, but, again, I see none of your testing that addresses that.

So in summary, I would say that the testing you have done actually has been rather extensive as far as the number of samples and effort that you've put in, but unfortunately hasn't really helped me answer the question at all, is that will this implant leak; how often will it leak; where will it leak; and there's this big mystery in my mind of the mechanism of why the implants fail more in reconstruction than they do in the original augmentation.

There's got to be a biomechanical reason. This is a mechanical failure, and you ought to be able to define how that happens and develop a test to address that issue.

So in the end of it all, I believe that the FDA is correct in saying that the tests are incomplete and they should be completed, and additionally I think the reoperation rate due to inflation -- I find if I carry it over to the devices I normally work with are alarmingly high.

To have a device fail in the two to three year period mechanically is extremely surprising, and it's also amazing to me that it seems to be tolerated as just something that you just have to live with in these implants, and I don't really see how the design and the materials change or the testing really addresses that issue.

Let me stop there.

CHAIRMAN WHALEN: Thank you, Dr. Li.

I should point out to all the panel members, lead reviewers and the rest of the panel, that this is the appropriate juncture when, if there are any further questions for the sponsor or any specific questions to the FDA presenters that these questions be raised.

That being said, there were probably too numerous to count questions, but some of them were rhetorical. Some of them were comments, and some of them were questions that perhaps an answer is needed, and so with that preface specifically for you, Dr. Li, among those questions you raise or any others that you have, would you like to direct any question specifically to sponsor or FDA at this juncture?

DR. LI: Let's see. Well, I guess I would like to -- well, I'm not exactly sure because the question is kind of broad ended. I'm struggling with asking kind of a non -- all of my specific questions might be kind of trivial, and the big question I'm not sure we can get into.

CHAIRMAN WHALEN: Well, there also will be a closing summation, about ten minutes for each, the sponsor and the FDA, that we'll get to eventually where anything that has been raised during this discussion can be addressed, although no new data will be raised.

DR. LI: Let me ask one general question then.

MR. PURKAIT: (Inaudible.)

CHAIRMAN WHALEN: Well, the point I was making is if I were to say to you right now could you answer each of his questions, we'd all have to get cots because it might take the night.

DR. LI: Well, let me ask you one general question then. Do you believe that with all the testing that you have provided that you can a priori determine what the leakage will be? Because you clearly have some idea of things that you think are important, for instance, surgical placement, just to bring up another issue, where the size of the incision that you at least feel anecdotally are related to the performance of the device.

Yet I was frustrated by that because you don't have a hard number, biomechanical data that says, you know, when you make the incision this small, the force goes up 30 percent and the stress goes up this high and this leads to this and this leads to that.

I really kind of -- I don't see that particular sequential kind of argument that we normally apply to a device failure and every other medical device that have been in being applied to this particular device.

So what makes you -- what gives you the confidence or the belief that if you change, for instance, as an example, from PTC to Sytech or from something to partially textured, which you have not clinically proven; what leads you factually to believe, other than your personal belief, but in terms of data that would you believe that the leakage rate is going to be the same, smaller or bigger than your previous device?

MR. PURKAIT: I think -- let me go try to see. You have about -- I don't know -- 15 different areas that you have questioned, which is quite interesting because you get me going for the next two hours I probably can do that, but let me see if I could summarize and try to answer those, the simple question first and then go to the complex one.

You asked a question about the differences between the sterilization of dry heat versus gamma. Right now we all do dry sterilization. So one issue about gamma is out right now.

Now, the question was: why did you do the gamma nd dry heat and how would one --

DR. LI: If it's out, you don't have to answer the question.

MR. PURKAIT: Okay. Good. So that was simple.

DR. LI: It's in the application though, as I understand it, right?

MR. PURKAIT: The second question you had about the PTC active versus --

DR. LI: Just to clarify that, I raised the issue of that particular one because it was highlighted and takes up many pages in your PMA application. So you're now withdrawing that particular --

MR. PURKAIT: No withdrawing. You see any manufacturer operation always have an optional sterilization procedure because you cannot rely upon one particular type of sterilization. We do qualify both dry heat and gamma sterilization, and as we have established the process, validation of the dry heat, we have converted all of the sterilization to dry heat.

In case that there be a need in the future we probably will do gamma sterilization, but this is not a withdrawal of the gamma sterilization.

DR. LI: Well if you're going to do it at all, then I think you need to answer the questions.

MR. PURKAIT: The gamma sterilization and the dry heat sterilization, we have compared the data, and that has been submitted in the PMA, and if you look carefully in the PMA, you will see that the gamma sterilization does reduce to some extent the mechanical properties in comparison to dry heat.

However, the range of the properties, what we see by the gamma, is far superior to the expected results that we believe we are going by, such as the ASTM standards. For example, if you have a 350 percent elongation, that's what we kind of maintain. Our product shows consistently over 350 percent elongation.

You might question, well, what does this 350 percent elongation mean, you know. Remember in a body when you put this thing in a cavity, we have a liquid elastomer which goes up to 700 percent elasticity. Now, here we are testing for 350 percent. In a body probably under all loads we know that we can measure, this probably wouldn't extend more than 20 percent to 30 percent.

So, you know, to look into the proper perspective, the elastomer elasticity in this case is much superior or much more higher than is reported in the body.

DR. LI: Well, let me stop you here. This is my general problem, I guess, with the testing. First of all, the ASTM methods for those of you who aren't into ASTM methods are proposed standard ways of doing tests, and there's not an ASTM method yet that I've read that doesn't have a disclaimer in there that if you meet these standards, it has nothing to do with projected clinical performance.

So if you followed the ASTM standard, you're basically telling me you're following a standard test, but as the ASTM itself says, it's not performance related.

And this is the general problem or concern I've got with all of your testing.

MR. PURKAIT: I understand that.

DR. LI: It performs to some standard, but I can't make the connection to the clinical case where maybe 19 percent are failing by leakage. Your tests suggest that.

MR. PURKAIT: I agree with you. The ASTM is not our Bible; that we follow ASTM, therefore, everything is good. The ASTM is a standard that's accepted across the country, across all product lines, all devices that exist. So we do follow their standard.

At the same time, we supplement many other tests to show that not only do we meet ASTM. We also have other tests to show that we go beyond that. So ASTM is not the only study that we do to say that our product --

DR. LI: I understand that, but at the end of the day, you still have a 19-plus percent, up to a 19 or more percent leakage rate.

MR. PURKAIT: Now you talk to my heart. If you look at the in vitro versus in vivo situation, unfortunately we are at a loss to exactly simulate what happened in the body process in vitro.

For example, you have seen in our data today that if somebody used Betadine, if somebody used different incision size, if somebody used a bilateral, if somebody used a different valve type, there are some clinical indications that will occur. A clinical problem will occur that it cannot replicate every time in vitro.

I'm not saying that we're not going to try for that. However, at this point in time we took into consideration the best we can, and we continue to study that all the time.

DR. LI: I'm not saying that you didn't do your best. What I'm saying is that there's a disconnect for me between the data you generated and the prediction of in vivo performance. I mean I'm not disputing the hard work that you put into it or you sincerity in doing --

MR. PURKAIT: Well, I'm not going to argue on that. I'm trying to make the point that some of the test conditions, what we have used, does have some real meaning behind it.

That includes one of the areas you also have addressed the fact that our fold flaw or the leakage things -- let me address the leakage one.

To understand the deflation or leakage in a body, we considered that there are three ways, primarily three ways that it can fail: rupture of the shell, the valve failure, or maybe fold flaw, or maybe other reasons in the clinical.

The rupture in the shell, we try five testings, such as fatigue, the static rupture, the static impact, and so forth. For the valve competence, we have three different tests for valves. We have valve burst test. We have valve special test. We have valve -- the flow properties test.

For the fold flaw, we believe that the fold flaw test is very unpredictable because you cannot predict where and when, how the fold will be formed. That has a lot to do with how it has been implanted and how these devices have been put there.

And the other question I think previously asked about, the special inferences in different locations, initially all of these implants are folded and put inside the cavity and then has been placed and then been inflated.

So the pressure generated there, whether you put it in submuscular or subglandular, is really determined by what location you're putting and, regardless whatever the pressure is, we always test for the worst case condition. We always test for the extreme conditions. So, therefore, we believe that even if it is within the range, it will maintain the properties.

DR. LI: Maybe one last -- I'll try to make it a last response.

If I were to take your data at completely face value, I think I would walk away with the impression that this device is near bulletproof. I mean you have to go in your testimony to rather extreme conditions to get rupture, fatigue. Nothing happens in the fold flaw.

Now, if I look at all of your tests, it actually looks extremely good, except for the --

MR. PURKAIT: It is good.

DR. LI: But you get 19 percent failure rate, and over 40 percent of them are revised.

MR. PURKAIT: But over 40 percent of those --

DR. LI: Which is an enormously high number.

MR. PURKAIT: If you break it down into cosmetic versus non-cosmetic --

DR. LI: Okay. So 20 percent. Take half.

MR. PURKAIT: Okay.

DR. LI: It's still a high number in three years. So that's the disconnect that I'm going after, right?

I mean your data looks excellent, right? I mean if I just looked at your data in and of itself, I would say from a materials and design standpoint it looks excellent. Okay? In the absence of any clinical data, you know, I'd probably have a completely different view, right? But the problem is I do have a clinical --

CHAIRMAN WHALEN: Just to focus upon this for a moment --

DR. LI: Yeah.

CHAIRMAN WHALEN: -- in the interest of the flow of things, I don't think we're talking about mechanical testing per se anymore. We are talking about a highly clinically significant issue.

DR. LI: Well, I think they have to be linked to be meaningful.

CHAIRMAN WHALEN: Indeed, and we're going to proceed to other clinical issues. I guess refocusing, is there something specific that you would like to inquire about in terms of other mechanical testing that could have or should have been done?

DR. LI: Well, I guess, for instance, why haven't you looked at the effect of percent fill on the results as an example?

MR. PURKAIT: How do you mean?

DR. LI: In other words, doing a fold -- pick a test. Pick a dynamic test, fatigue, fold, whatever.

MR. PURKAIT: Let's say you mention about --

DR. LI: And then do an under fill -- do a 20 percent under filled, 20 percent over filled, and then --

MR. PURKAIT: Well, we don't suggest anybody to under fill. In our label copy, we clearly say, please, please, please don't.

DR. LI: So are you going to say that never happens?

MR. PURKAIT: I don't know, but we say that's what is supposed not to happen. We can't control this. We test in the nominal volume. That's the way they come in there.

You mentioned something. Just to clarify, the 2600 model, 2400 model, they were failed about 3,332 cycles, 16,118, those failures if you're looking back in the data was intentionally done to understand at what pressure and at what load that we can make a failure so that we can make a model. Those does not show a premature failure of those materials or those devices.

DR. LI: That wasn't clear in the application then in that case.

DR. CUNNINGHAM: If I could address your under fill issue from a clinical point of view, there is a body of information within plastic surgery medical literature which I think would have almost all plastic surgeons feel very strongly that they should not under fill these devices because of the predilection for possible folds, fold flaws.

So I think most plastic surgeons know that there is a small range of fill which these devices are meant to perform within, and in fact, the way you determine what size implant you want to use is fairly precise because there are sizers which are connected with a tube and have the same footprint and dimensions as the implant which you place in, fill with saline until you reach the look or appearance that you think is appropriate for that patient and conforms with the discussions that you've had with that patient, and that gives you the amount of saline and allows you to choose which device to use.

So that surgeons are able to choose within that narrow fill range exactly which device is appropriate for the patient. So I think in clinical practice the real world is in this case perhaps more precise than the kind of range of testing that you might think we would have to do.

DR. LI: Well, in their own literature, in their PMA document, they said that -- I don't remember the exact phrase -- but that 20 percent over fill would be something that they would consider as an upper end of what might happen clinically.

So at 20 percent over fill, why weren't things tested at 20 percent over fill if that's what they stated as an over fill potential level?

MR. PURKAIT: I'm not sure I recall that, but maybe you are referring to the SPECTRUM product where you can go for adjustment purposes as we allow in our particular product.

DR. LI: Right.

MR. PURKAIT: Yeah, that is okay for the SPECTRUM, not for the regular fixed volume one.

DR. LI: Well, the other medical -- again, I hate to harp upon other medical devices, but typically in these there's a zone where you want the surgeon to be or the physician to be in the implantation of this device, but for reasons either by skill or by necessity, the person's anatomy or something beyond the physician's control, they can't always hit that exact target, and they might have to do something, make a decision to go out of that extreme.

It happens. Right? It happens. You know you don't want it to happen. Most of the time it doesn't happen, but it happens. Right?

And you're faced with a case here where you have a very high number of failures and an alarmingly little analysis of those retrieved devices, right? And with the absence of that information of how the device actually deflates, I don't really know how you can discount any possible mechanism.

CHAIRMAN WHALEN: Any other questions, Dr. Li?

DR. LI: I think I'm done.

DR. ALLEN: Will I have an opportunity to respond?

CHAIRMAN WHALEN: Actually at the summation period if you wish, yes, but no.

And I'll get to your question in a moment. We're going to do the lead reviewers first and then we're going to go to general questions from the panel, but we're going to -- okay. Dr. Burkhardt is here for the clinical study.

DR. BURKHARDT: That was all just on question one?

CHAIRMAN WHALEN: Actually we've not done question one yet.

(Laughter.)

DR. BURKHARDT: How do you want me to do this? Do you want me just to address question one?

CHAIRMAN WHALEN: No, no, no. This is just a general clinical study review, not with reference to any of the particular seven questions.

DR. BURKHARDT: Oh.

CHAIRMAN WHALEN: An overview.

DR. BURKHARDT: Okay. My thoughts on the clinical trial are, first, that -- my thoughts on this whole thing, I think is what you're driving at.

CHAIRMAN WHALEN: Yes, sir.

DR. BURKHARDT: The question of systemic illness and second generation problems, the reports are experiential. We don't have any scientific data on that, and what we have doesn't support it, and I think they have to be disregarded.

What we have to worry about is local complications, and I'm not enough of an engineer to understand what happened, why this incidence was as high as it was, but my understanding is that if you eliminate needle punctures, which are there, and valve failures, that the major problem here is fold flaw failure, and my understanding of that -- you correct me if I'm incorrect -- is that that occurs because of abrasion, internal abrasion at the end of a fold.

In other words, it's not material fatigue. Am I correct about that? Because that's what I've been told.

MR. PURKAIT: To some extent fold flaw, that what we know of, we can speak for, could occur, could fail in at least three or four different ways. One of the mechanisms may be abrasion. The other would be, as I mentioned, a localized stress concentration. It's a creep factor.

If you have a two fold (phonetic) and some weight has been there for a long time, the material crimps, and that might give a pinhole, and it will fail.

And the other probably would be a multiple fold that causes abrasion with different surfaces, and that might be a problem there.

DR. BURKHARDT: Thank you.

But the underlying problem is that they're going to fold. If you take an oval, three dimensional or round three dimensional thing with an oval cross-section and you stand it on its end, which is what we see in these patients when they stand up, for instance, they're going to get folds in them. The material is not perfectly elastic, and there's no way that I know of that you can get around that.

DR. LI: But, Dr. Burkhardt, perhaps to clear it up, there's some pictures that were difficult to see in black and white, but the FDA gave me the color versions. These are ten retrieved devices that Mentor supplied a photograph. They did a very nice job on these particular set of ten.

But if you look through these photographs of ten, the cracks which may have been the leak are delineated in black, and on Figure 6 there, you actually see running across the horizon a white line that's a fold flaw, and you notice the two cracks that probably caused the leak are nowhere near it.

And if you look at the ten all the way through, more often than not the cracks and the pin holes that they identified were nowhere near the fold.

Now, in two cases, I think they were, but in the other eight they were not. So my point is this generation of these small cracks is not mimicked in any of their testing that I've seen.

DR. BURKHARDT: Well, these are implants that are removed, right? And --

DR. LI: For leakage.

DR. BURKHARDT: Yeah, for leakage, and what you're saying is that there's no permanent fold there that you can see now.

DR. LI: Well, on Figure 6 there's kind of a ghostly white line that runs across the horizon. I think it's Figure 6, the page I handed you. Now, some of them you'll see like a white line that goes across a gray background. That white line is the permanent fold, and the black lines that they've delineated are where the cracks and pin holes are, and you'll see that oftentimes, most times that white line -- and sometimes it runs in all different directions -- is nowhere near the black lines that they identify as the source of the crack or the leak.

So in other words, this fold flaw thing still, after 30 years, may or may not be the reason these things leak based on the data that they've supplied.

DR. BURKHARDT: Well, I see some big black lines on here, but these were not cracks in the implant. Am I correct?

DR. LI: Yes. Yes, the short ones are all --

DR. BURKHARDT: Well, now let's find out about that before we decide that.

DR. CUNNINGHAM: I'm not sure exactly what picture --

DR. BURKHARDT: You've got big, long black lines in these pictures. Were those the cracks?

DR. LI: The long ones are wear. The short ones are cracks. If you see a really long black line -- and correct me if I'm wrong -- but if I know your nomenclature, there is some implants that have very long black lines in them. Those are wear lines.

Other ones are very short black lines. The short black lines are cracks and holes.

DR. BURKHARDT: Okay, and so I guess I don't understand the point.

DR. LI: Well, the point is it is not so simple as you would like to make it, that if there's a fold it's bad, and if there's no fold, it's good, right? Because some of those have fold --

DR. BURKHARDT: Why not?

DR. LI: Because you've got the data right there. If folds and leaks were directly associated, the black line, the small black marks to indicate holes should be right on all of those ghostly white lines that are folds, and they are not.

DR. BURKHARDT: I think I'm not sophisticated enough to follow that line of reasoning. If the black lines are wear lines, which I would interpret as being the convex lines of the wear --

DR. LI: So, for instance, we're looking at Figure 6 in your report. This line here, this off white, that's a fold line as I understand it, and these two lines are where the cracks are.

If the fold line was a source of cracks, these crack lines should be right on that line, and they are not.

DR. BURKHARDT: The black lines are described as wear lines, not cracks.

DR. LI: "Location of cracks in relation to the wear lines." Right. There's cracks and wear lines, right.

DR. BURKHARDT: There's a red line for a crack and black lines for the wear lines.

DR. LI: The problem is on this one unless --

CHAIRMAN WHALEN: In the microphone, please.

DR. LI: I guess the problem on this one is unless Mentor can say that the wear lines are not leak lines, I assume that when you had a wear line it may or may not be the source of a leak; is that correct?

So some of those wear lines may leak and some of those wear lines may not; is that correct?

MR. PURKAIT: That's correct.

DR. LI: Okay.

MR. PURKAIT: But I'm not sure which picture and what you are talking there because it's hard for me to really --

DR. LI: I understand. I'm just trying to fill in for Dr. Burkhardt how I was looking at those photos.

DR. BURKHARDT: Okay. Where were we? Nobody under fills these implants with any knowledge. You can't really legislate physician behavior, but --

DR. LI: But you could design for it.

DR. BURKHARDT: Well, maybe you can design for it, and again, I don't know. Maybe these could be improved, and that's your jurisdiction more than mine.

The leakage rate that is generally reported from fold flaw failure is in the five to ten percent range, and I don't remember the slides that you showed that brought it up to 19 or why it got to be so high.

Questions were raised about the texture to implant. I think it would be worthwhile for everybody to know why these implants were textured and what gave rise to the origin of the textured implant because it didn't have anything to do with easy insertion through a small incision.

A number of years ago a polyurethane covered implant came out from another company that was called the MIM (phonetic). It was widely accepted in plastic surgery and short term had a very small incidence of hardness or capsular contracture. Long term there's some question about what happened. Most of us think they all got hard.

At that time the companies that were producing the silicone implants, the silicone shell implants could not use a polyurethane covered implant because it was patented. So they had to try to do something to compete economically with the success of the polyurethane covered implant, and the response was to texturize the surface of the silicone implant.

Most of us who are in the field thought that that wouldn't accomplish anything at all, but there have been a number of outcome studies now that show that for some reason that we do not understand that it was helpful.

Another reason for the folding that I think everybody needs to understand is that if you put this sort of flat device which is oval in cross-section in a pocket that then begins to contract and so that the device is now compressed into more of a sphere, it's going to fold, and I don't know any way that the manufacturer or anybody else can really prevent that.

In regard to reverse diffusion, that was brought up today. There was no evidence that I could detect that I was aware of that it was a significant problem and no evidence presented that it was a problem.

If there is diffusion of that sort, it would be through the valve, but there's no reason to believe that's significant.

Local complications. Contracture is the big problem, and everybody should understand what happens with contracture. There's a membrane that forms around the implant and for some reason that we do not completely understand, the membrane contracts.

It often happens unilaterally. It is not a systemic response, and the most prevalent theory at the present time is that it is a low grade bacterial infection from the breast ducts, which may explain why we get better results in the retromuscular position, and it also explains the use of Betadine, which I think is one of the things that has surprised a lot of people here, because that wasn't brought up. And Betadine is used in an attempt to sterilize the pocket.

There are questions that have been brought up about the shelf life of saline. Saline per se, so far as I understand it, has an indefinite shelf life. All it is is salt water, and I think that the expiration date that has been presented here, it really refers to the container more than to the saline itself.

Fungal growth in saline, I think most of us have seen that. The situation has changed a lot since those cases were initially presented. We used to use an open tray to fill the implants. In other words, we would pour saline to an open tray on the Mayo stand, take the saline out with a syringe, and use it to fill the implant. That was pretty much the standard of care.

I think what has happened is that there's airborne fungi, and they would get into the open tray and then be put into the implant. There's no reason to believe that that contamination comes from the patient herself, and the method of filling now that so far as I know everyone uses is a closed method of filling from an IV bag with a three-way valve, a three-way stop cock to the syringe. So I don't think that that's the issue that it once was.

Rippling is going to occur, specially in the thin breast. It's going to be seen. There's no way to get around that at the present time because the implants are going to ripple.

The information we have in our literature suggests that sensory changes in the nipple and the areolar area are related not so much to the location of the incision as to the position that the implant is placed, whether it's behind the muscle or in front of the muscle, and I realize that that doesn't correspond with what was just presented here, but I think we need to be aware of that.

Mammography may be made more difficult without any question whether the implant is behind the muscle or whether it's behind the breast, but all of the studies we have fail to show any difference in the tumor stage when detected or in the long term survival. So so far as an outcome is concerned, it doesn't seem to be a major issue.

That's mine.

CHAIRMAN WHALEN: Thank you, Dr. Burkhardt.

Actually unless there's specific questions that we'll raise from time to time, you needn't necessarily reside at that table. We'll just ask you to come up to the podium if we do have a question to ask you.

Thank you.

For statistics, Dr. Blumenstein.

DR. BLUMENSTEIN: Well, when I thought about this, I found myself thinking of how I would respond if the information given to me were given to me as an article to be reviewed for publication in a peer review journal, and so a lot of what I'm going to say here has to do with holding the information to that standard, but there's also the standard of trying to be informative to the potential recipient of an implant.

The theme of what I'm going to say has to do with the presentation of the data; do not take into account the censoring and, therefore, the conditional probabilistic aspect of what's going on in the presentation of the data. I'll make that a little bit clearer as we go along.

The Cox regression analysis, Cox proportional hazard regression analysis looks like it's somewhat useful. However, I would point out that that would be very difficult for the consumer or physicians to understand.

Also, for someone who wants to talk to me later, I would have some ideas about how time dependent covariance might be brought into that analysis in order to improve some of the precision of the analysis.

However, I want to go on and talk about the data itself, that doing Cox proportional hazard regression on data that's kind of smelly might not be the best thing in the world.

I want to talk about several methodologic issues that are more technical in nature, and the first thing I want to say is, of course, and as has been pointed out before, these studies are not randomized clinical trials. They don't come even close to that, not to propose that anybody could do a randomized clinical trial, but just in terms of weighting the evidence we don't have that kind of evidence here. We don't even have control groups, and so these data should be very carefully interpreted.

Some of the plots that were presented and some of the language that was used tried to represent the individual risks as cumulative incidents. That's absolutely wrong. They are not cumulative instances. One minus a Kaplan-Meier curve is not a cumulative incidence curve. That is a cumulative conditional probability curve. I have some references if someone wants to look at them. We must have these things labeled correctly to the patient.

I would suggest that you do look at real cumulative incidence methodology as a means of presenting the risk data and those same references would address that.

The issue of interval censoring has been brought up before. I'm not sure what to do about that. That's a difficult problem here. I suspect it's a matter of simply pointing it out in the publication as a source of bias, as has been previously discussed.

One of the very difficult issues that's here is that the confidence intervals that are presented are confidence intervals that represent the experience of a group of patients and do not represent the uncertainty of the estimates that pertain to an individual patient's risk. This is a problem that exists everywhere wherever risks are trying to be presented. It's a difficult problem, and I don't have an answer for it other than in certain specific situations.

Now, there's a number of data issues, and all of them are related to what I call informative censoring, and I think it's absolutely wrong that the data have been presented here without any analyses to show the characteristic, to try to characterize the patients who are not followed for specific time points.

There is information that the types of patients who are dropped out over time could be biasing the data significantly. You could be comparing demographics. You could be comparing whatever reasons for dropout you might have. You could be comparing baseline assessments in terms of some of the measures of quality of life or some of the mechanical measurements and so forth.

So essentially what I'm saying is you can compare the baseline data between patients who are included in an analysis for a subsequent point in time to the patients who are not included. It's just a very minimalist approach to trying to get a handle on whether the data from patients who are not included in subsequent time points are different from the data that are there.

This kind of informative censoring applies to the efficacy data, the quality of life data, and the risk data. It applies to everything in this kind of study.

Dr. Bandeen-Roche pointed out that especially in the quality of life data the patients who were explanted are not represented in the subsequent, the late time point analyses of these data. This is an extreme limitation and misrepresents the data unless you point it out and very carefully document that that's exactly what you're doing.

It's wrong to represent that as being an unconditional quality of life assessment.

The follow-up for the data here are just too short, and I will, I'm sure, talk about that later. In short, my take on all of this is that I cannot accept the accuracy of any of the data here because of the limitations that I'm pointing out. It may be that we do have some rough idea, some very crude idea of the relative size of these risks and ranking of the risks, but 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.

CHAIRMAN WHALEN: Thank you.

With apologies for twice having put you off, Ms. Domecus, if you have a question.

MS. DOMECUS: I just want to go back to Dr. Li's criticisms regarding the mechanical testing study design. As I understand it, it seemed like he thought there was a disconnect between the laboratory testing study design and how that could mimic what was seen clinically, and I was just wondering if you had any suggestions on how those tests could be designed at this point or maybe later, but I think that might be helpful to the manufacturer since, as you suggest, they've done an awful lot of testing, put a lot of effort in, and if it doesn't kind of hit the mark for you, if you had some suggestions, I thought that would be helpful.

DR. LI: Well, I suppose I do, but it probably would take a long time. We'd have to sit down for a long time and work that out, but I think one suggestion that I could definitely make though is to continue the type of retrieval analysis that they've begun to do because I think that is going to be the proof in the pudding.

In other words, in other devices that I work on, the whole purpose of our laboratory is to try to develop an in vitro test that where at the end of it it looks like the failed device, and the closer you can get to that, the better off you are in developing an apparatus or a test that would say, "Look. If I improve the properties this way, I can measure it and it will be better or worse clinically than what I've got."

So in the absence of knowing the exact mechanism for the failure, I'm not exactly sure what test to suggest.

CHAIRMAN WHALEN: Did you also have a question from earlier of the sponsor that --

MS. DOMECUS: It got answered.

CHAIRMAN WHALEN: Thank you.

Do any of the other panel members have any questions first of the sponsor before we go on to attempt to answer the FDA questions?

DR. BURKHARDT: I have one more question for the sponsor. When these failures occur, Mr. Purkait, don't they usually occur at the end of a fold?

MR. PURKAIT: Sometimes they do.

DR. BURKHARDT: Sometimes?

MR. PURKAIT: Yes.

DR. BURKHARDT: But not consistently?

MR. PURKAIT: Not consistently.

DR. BURKHARDT: Thank you.

CHAIRMAN WHALEN: Dr. Chang.

DR. CHANG: Also, was there any relationship between thickness of the implant and sell failure? Was that ever measured or considered?

There's a variability in the thickness of the models or range of thickness?

MR. PURKAIT: Yeah, we have range of thickness for the smooth and the SILTEX, which is textured. We have information that shows that regardless, within the same model type, whether it's the smooth or SILTEX, within the same specification any of those tests show the same results. So thickness does not cause problem.

DR. BOYKIN: Could I ask one more question while you're there?

A comment in the summary, and I don't think we've really talked about this, is that within one device there could be a variation of almost the entire thickness at the thinnest point of the shell, like from 17/1000 to 34 or 35/1000 of an inch; is that correct?

MR. PURKAIT: That's correct.

DR. BOYKIN: Now, this reflects the inherent difficulty in fabrication of the device, that you can't control the tolerance of the limits any closer than that?

MR. PURKAIT: To some extent that's exactly true. The way the shell works is that these are all done by the dipping process, and if you take a particular viscous material and if you dip the mandrel, and if you turn it over, normally those things tend to drip down there. So you get a variable thickness from the top to the bottom. That's why you see the 14,000 to 38,000 is the difference.

But I just wanted to point out that most of our test data though we target for the area of the thinnest possible shell.

CHAIRMAN WHALEN: Dr. Morykwas.

DR. MORYKWAS: I just had a thing where you commented on the white line on the implant is interesting, and if you could, with the repeated folding have you analyzed any of those where the white line is for the induction of crystallization or crazing or anything in the polymer material itself that might change some accountable properties?

MR. PURKAIT: We did previously some of those. We have looked into some of the explants. One thing I just want to bring to the attention that explant is very difficult because by the time we get the explant, this particular explant has been altered a few times because they go through sterilization; they go through the wash process; they go through various different handling procedures.

Therefore, by the time we really actually do that, we probably have not seen everything that's coming out of the body. Nevertheless, we do try to characterize as best as we can.

To answer your questions, we did not see per se any creasing effect or super crystallization on those areas because of the stress there.

CHAIRMAN WHALEN: Thank you.

Are there any questions of any of the panel members for any of the three FDA presenters?

(No response.)

CHAIRMAN WHALEN: Seeing none, we will being to attempt to answer FDA's questions.

Dr. Berkowitz, would it be possible to re-project those questions sequentially as we try to deal with them?

And for --

PARTICIPANT: (Inaudible.)

CHAIRMAN WHALEN: You will have a comment period, sir, shortly.

On many of these questions I will poll the entire panel. On come I will be somewhat more focused, and the first question which we see projected is one of these more focused ones that Dr. Li is our subject matter expert on, and we'll begin with him.

DR. LI: Well, in general, I think the fatigue testing and fold flaw testing are incomplete in that they either did not test all the models and/or did not test the final materials that ended up in the commercial device, the last issue being the reference to switch to the Sytech silicone from the original PTC, which is the bulk of their data. So it is at best incomplete.

The fatigue testing and the fold flaw testing I do not believe provide any long term information to us to the rupture and leakage of the implants. I think looking at their data, I would have no way to predict when they switch, for instance, from the PTC to the Sytech whether or not the rupture leakage rate will be the same, better or worse. So I guess my comment on the sponsor's methodology and results is that the methodology, although it represents some construct testing -- oh, actually one important thing. Correct me if I'm wrong, but most of your fatigue and rupture data did not have the valve in the implant; is that correct?

PARTICIPANT: We did have the valve.

DR. LI: They did have the valve. Okay. Fine.

So in general I think the methodology, although presents some device testing, I don't think any of it is reflective of what we could expect to happen in the patient. So I think what they've got unfortunately is a little incomplete, and I don't know what to do with the information as far as projecting what the long term rupture and leakage of the implants will be.

CHAIRMAN WHALEN: So in regard to our first question on this testing, are there other members of the panel that would like to address that?

Just to remind everyone on the panel and in the audience, the way this will proceed is that when the panel has attempted to answer the question, I will then attempt to summarize, although there was only one responder in this case, to Dr. Witten on behalf of the FDA what the panel's answer is, and then if Dr. Witten finds that a satisfactory answer, we'll proceed to the next question.

Dr. Witten, in regard to question number one, it is the panel's opinion that at best we are given incomplete testing, and that specifically in regard to fatigue and fold flaw testing, that while the methodology and the results were exposed to us, that there seems to be little or no correlation with the long term clinical actualities that are witnessed.

Is that sufficient for your answer?

DR. WITTEN: Yes. Thank you.

CHAIRMAN WHALEN: Thank you.

If we can go to question number two on the projection screen, this is one of the questions that I will ask that everyone comment upon the question, and this has to do with the issue for patients who are receiving the implants for augmentation.

Given what has been presented to us by the sponsor, do we find in accord with the federal regulations that the product is both safe and effective for augmentation patients?

I will begin going around with Dr. Chang.

DR. CHANG: Certainly the analysis presented by Dr. Anderson gives credence to the fact that with respect to change in size and for some of the parameters of quality of life that the device is effective for augmentation patients.

I want to qualify my comments about safe, safe with qualifications, in that several of the complications listed, and in fact, the high number of complications listed is not in the purview of the manufacturer; that it is dependent on the practice of the physician. So it's a very qualified safe product.

And the remaining question in my mind is that 5.8 percent deflation/leakage rate.

So for effectiveness, yes, in augmentation; for safe, a qualified yes, given parameter that are actually in the control of physician, not the manufacturer.

CHAIRMAN WHALEN: Thank you.

Dr. Morykwas.

DR. WITTEN: Excuse me. Can I clarify before you go around the room? Yes?

The way that 21 CFR 860.7, we're asking you actually about reasonable assurance of safety and effectiveness. So it's not an absolute safe and effective. The definition is reasonable assurance of safety and effectiveness.

CHAIRMAN WHALEN: Thank you.

DR. MORYKWAS: I would just like to also agree that I think the product has been shown to be effective, and I will just somewhat parrot some of the conclusions of Dr. Chang, that several of, I think, the safety issues aren't really the responsibility of the device itself. It is more the physician or the physicians who are implanting it. So there are concerns there.

And some of that, I guess, is out of our purview. I don't think we can legislate how the surgeon will do that.

But still with -- well, again, I'll get back to Dr. Li also -- his comments that it is relatively safe, yes, but still there is a high degree of deflation that doesn't seem to gibe with in vitro data.

CHAIRMAN WHALEN: Thank you.

Ms. Dubler.

MS. DUBLER: I do think the effectiveness, which is largely measured by the response and satisfaction rates of the patients themselves, is impressive and provides reasonable assurance that it is effective.

I'm troubled by the combination of factors that are either under the control of the manufacturer or part of the practice patterns of surgeons or, in the third place, part of the body's reaction to these devices, and it's hard for me to sort them out.

I'm not sure I agree that we can't legislative how surgeons go. I don't think we can legislate it, but I think the notion of best practice is a very powerful one, and I think that if there are better ways to use these devices, that has to be very, very clear in how they're marketed and who uses them and under what conditions.

But I am concerned about the 5.8 deflation rate and by the reported 43 percent complication rate and 73 percent complication rate in reconstructive patients. I think that's very, very high, and the combination of all of that makes we reluctant to say that we can provide reasonable assurance that, in fact, they're safe.

CHAIRMAN WHALEN: Dr. Robinson?

DR. ROBINSON: I believe that the product is effective, with the word "reasonably," "reasonably safe," I'm worried that no matter what type of ex vivo testing we suggest, there won't be a link between that testing and prediction of what happens clinically. So we may be getting into a situation where we're looking at more and more ex vivo testing and still coming back and asking the question what does it mean clinically.

But the use of the word "reasonably" is fine with me. It's reasonably safe.

CHAIRMAN WHALEN: Thank you.

Ms. Brinkman.

MS. BRINKMAN: Well, in regard to effectiveness, obvious it's perceptual. It's true then that deflation can't be considered effectiveness because I would think if I had an implant and it deflated I would not think it was very effective.

But anyhow, as far as safety goes, I think it's appalling that for an elective procedure for augmentation that there is 43 percent, first complication rate of 43 percent, and it continues. I mean, it never levels off. It continues to grow.

And so I guess I feel negatively about the safety of the product, even though I know that there are many women who want them, and I think the manufacturer does what they can.

CHAIRMAN WHALEN: Ms. Domecus.

MS. DOMECUS: I think effectiveness has clearly been shown. I guess when I look at the individual adverse event rates they all look reasonable, but the 43 percent number does seem high, especially for a cosmetic indication, and in my experience I don't know that I've ever seen a medically indicated product have that high of a complication rate and have it be a favorable risk-benefit ratio. So that would be concerning to me.

CHAIRMAN WHALEN: Dr. Li.

DR. LI: I agree with everyone on the effectiveness of the implant.

I think the reasonably safe part, I think, would come down to whether or not you believe 5.8 material or design failure of the device is a reasonable level. I think for my own purposes, for the short length of time these devices were followed, that's an alarmingly high what I'll characterize as the design and material failure, and although the surgeon may have a large input on this, and I never intend to legislative surgical behavior and skill, I think part of what we are able to do is either to design or test for the variations that one would expect a physician to apply in the implantation of this device, and I don't believe that particular range of possible surgical procedures has been explored.

So I would say although I would say it's effective, I would have to come that it was unreasonable for safeness.

CHAIRMAN WHALEN: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: I agree that it appears that there's some efficacy here in terms of the intended purpose of augmentation. I think the safety issue is largely dependent on how well the risks could be communicated to the potential recipient of one of these implants.

And I think accuracy has part of that, and so forth. I think the best overall representation to the potential recipient is the time to first bad thing, which has been already characterized here as being the best measure.

CHAIRMAN WHALEN: Dr. Boykin.

DR. BOYKIN: I would agree that we have evidence that the device is effective, and I would like to underscore the comments concerning the environment that this whole process is taking place in.

This operation is an invasive surgical procedure, and it is associated with an inherently dynamic process that occurs around this static, inanimate object, and this is also affected by the patient's own chemistry in terms of how they heal, the drugs they're taking, whether or not they smoke cigarettes, where they live, and how they live their lives.

These are generally considered the surgeon's complications, if you will, and not necessarily the device's.

We've seen a disparity between the mechanical testing and the clinical evidence of failure which to me just basically means we need to go back and redesign some tests.

Overall, however, I believe what we can say about the safety is that we understand probably better than ever before what these factors are, what the patient will be faced with, but that to a fairly great degree, I believe that a lot of these complications are away from the domain of the device itself, and I think that it is reasonably safe.

CHAIRMAN WHALEN: Thank you.

Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: Let me just first say this is an appropriate time for me to read into the record that I'm not a regular member of this panel, that I was asked to serve on this panel because I'm very highly qualified to evaluate the strength of epidemiologic evidence and had a substantial experience with self-reported health function and quality of life data, but not because I have particular specialty in plastic surgery or implants.

That having been said, in terms of safety, my reading of the epidemiologic evidence in its total is that the devices are reasonably safe, if safety is defined as a very hazardous event, such as death, systemic diseases, that sort of thing.

In terms of effectiveness, I believe that the device has been shown to satisfy rather narrow definition of effectiveness, that is, increasing of bust size, some evidence of increase in body image. I did not find any strong evidence for increases in self-esteem.

Quality of life was not really assessed, and I agree with Ms. Brinkman in that in my mind efficacy also has to do with complications, you know, reoperations, cosmetic complications that occur at a high enough rate that I don't feel that I can give a blanket reasonable assurance in terms of high probability of a desired outcome and, therefore, effectiveness.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: I believe the safety in surgery is always qualified. It always comes with qualifications, and this particular operation is no exception.

My comments about physician behavior and the probability of being able to change that through the mechanism of this particular agency are perhaps colored by my knowledge of how training works and the fact, and probably most people are unaware of this.

Once you are licensed in a state as a physician, you are legally entitled to do any operation that you can do, provided you do it in your own environment, in your office or whatever. There are no restrictions legally regarding what any physician may do with any particular patient, and we're in a situation now where we're seeing more and more of this with people who are not plastic surgeons or who define themselves as plastic surgeons but don't meet the usual qualifications are doing this kind of surgery.

And all I'm saying is that that's going to be very difficult to control through this agency or by any action of this committee.

I believe that the --

CHAIRMAN WHALEN: Excuse me, Dr. Burkhardt. Dr. Witten was just addressing this.

DR. WITTEN: Yeah, I think we want to focus on for this product.

DR. BURKHARDT: I understand that. I understand that, but that was brought up, and I felt that I should respond to it.

I think that so far as I can see these have been proven to be effective, and I think they're reasonably safe.

CHAIRMAN WHALEN: Thank you.

Dr. Witten, in regards to patients receiving this device for augmentation purposes, in attempting to answer whether or not we the panel deem it to be reasonably safe and effective, I believe there is near unanimous opinion that it is effective within the important constraints of defining effectiveness as we have viewed it today, but there is less than consensus on the issue of safety inasmuch as nearly everyone on the panel is significantly troubled by the complication rates that have been reported by the sponsor, but there are various interpretations upon the significance of those complication rates inasmuch as they relate to the definition of safety.

Does that answer your question?

DR. WITTEN: Yes. Thank you.

CHAIRMAN WHALEN: We go on to the third question which has to do with the same issues of reasonable safety and effectiveness, but this time as regards those patients who receive this implant for reconstructive purposes, and we'll skip over and begin with Dr. Morykwas.

DR. MORYKWAS: Well, again, I think that we can or at least in my opinion the device has proved to be effective, and then coming to the issue of safety, the complication rate does increase significantly for this patient population, but some of that is to be expected just due to the nature of the patient and their systemic conditions which has caused them to need to be reconstructed.

But I would believe that this device would be reasonably safe even with the higher complication rate.

CHAIRMAN WHALEN: Thank you.

And I would just interject before Ms. Dubler gives us her answer everything that was said the last time was insightful and important, and I'm not reflecting upon anything anybody said, but if you just simply agree with what you said the last time, it's perfectly acceptable to say, "I feel the same as I did last time."

Sorry.

MS. DUBLER: Actually I think there's another factor when reconstruction is at play, and for me, as I think the choice for a woman is different under those circumstances, I would wonder what her options would be. In other words, if all of the options for the prosthetic devices have the same complication rate, I might still say that for a woman facing reconstruction that that might be safe enough under those circumstances.

Aside form that, I ditto what I said before.

CHAIRMAN WHALEN: Thank you.

Dr. Robinson.

DR. ROBINSON: Ditto what I said before.

CHAIRMAN WHALEN: I may have started a trend.

Ms. Brinkman.

MS. BRINKMAN: Unfortunately I cannot do a ditto.

I think this becomes even a much more devastating issue for me. Unfortunately we just haven't studied a large enough number of patients for me to agree that it's safe and effective.

CHAIRMAN WHALEN: Thank you.

Ms. Domecus.

MS. DOMECUS: Again, going back to the risk-benefit ratio, I would feel comfortable saying that for this indication that safety and effectiveness have reasonably been shown. Even though the risks are higher, I think there's a unique benefit here, and the risk-benefit ratio, I think, is favorable for this patient population.

CHAIRMAN WHALEN: Thank you.

Dr. Li.

DR. LI: Same answer as before.

CHAIRMAN WHALEN: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: I would like to put just one qualification on the answer here. It really applies to what I said before as well as this, and that is that I want to make sure that the characterization of effectiveness provides adequate data on quality of life benefits appropriately analyzed, and so forth.

CHAIRMAN WHALEN: Thank you.

Dr. Boykin.

DR. BOYKIN: No change.

CHAIRMAN WHALEN: Thank you.

DR. BANDEEN-ROCHE: My comments on safety and complications are unchanged.

With regard to the quality of life, I think it's even a more narrow definition of effectiveness in this case. No evidence that the implant affected quality of life and not just recovery from surgery, other than anecdotal evidence.

Thank you.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: Effective and reasonably safe.

CHAIRMAN WHALEN: Thank you.

Dr. Chang.

DR. CHANG: Effective and reasonably safe.

CHAIRMAN WHALEN: Thank you.

Dr. Witten, in regards to patients who receive this device for reconstruction as regards reasonably safe and effective, generally the same opinion that was voiced to you in the prior question is reflected with perhaps two important exceptions, and that is that the effectiveness as regards the frame of reference of indications is different in this particular subset of patients by virtue of what options the patients may have, and that the single subject matter expert with the best expertise as regards quality of life type of data feels that that has not been sufficiently answered by the sponsor's presentation.

Does that answer your question?

DR. WITTEN: Yes. Thank you.

CHAIRMAN WHALEN: Thank you.

We proceed to question number four. With the exception of the one year follow-up data in the implants and the FBS study, FDA asserts that the sponsor has not collected safety and effectiveness information for the cohort of revision patients, and yet the sponsor is proposing revision as an indication for use.

Since this is about 30 percent of patients who present for this operation, we are asked to discuss whether sufficient safety and effectiveness data, to include revision, as in a mentioned stated indication and whether the sponsor should evaluate the safety and effectiveness for revision patients as a condition of approval. Please also comment on the information that would be useful to collect in a post approval study.

Ms. Dubler.

MS. DUBLER: I find this a very hard question because it builds on the uncertainties of the two that preceded it. Given my lack of comfort with the first three questions, I would request that the sponsor investigate revision in a more detailed fashion, although it's beyond my capacity to make specific suggestions.

But I think before they could include revision, they would need to collect more data and be very certain what their measures were.

CHAIRMAN WHALEN: Thank you.

Dr. Robinson.

DR. ROBINSON: Since I believe it's a reasonably effective device, I think revision should continue as an indication and perhaps some discussion could be on a post approval continuing to collect data in this particular group of patients.

CHAIRMAN WHALEN: Thank you.

Ms. Brinkman.

MS. BRINKMAN: I believe there's a lack of safety and follow-up data.

CHAIRMAN WHALEN: Ms. Domecus.

MS. DOMECUS: Again, is revision here meaning revision for any reason, not just for cosmetic reasons?

CHAIRMAN WHALEN: Well, inasmuch as we're really sort of focusing it upon a labeling application here and since the word revision is there and not necessarily with qualification.

MS. DOMECUS: I would think we wouldn't want to preclude patients from undergoing a revision procedure if they wanted to, especially if they're doing it for a complication. So even if there isn't as much data as we'd like to see in it, I think that it should be part of the approval, where many issues can be done post approval.

CHAIRMAN WHALEN: Maybe I would ask Dr. Witten if a little clarification here would be in order. If we don't mention revision in the indications, that would not in and of itself preclude a patient receiving this device for revision. However, it would more focus what the standard set of indications for using this device would be. Am I correct in saying that?

DR. WITTEN: That's correct.

CHAIRMAN WHALEN: Dr. Li.

DR. LI: Yeah, with that clarification I'll say there's not enough information to accept it for safety as revision. The thing that sets me off a little bit on that is that it's a little bit surprising and somewhat unexplained why in the reconstruction case the deflation rate is so much higher, and now we have a revision series in which we have no information hardly at all.

It's unclear how you would predict what that would be. So I think I would definitely ask for a follow-up.

CHAIRMAN WHALEN: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: Well, I feel like that the patients who are undergoing revision will be a lot more informed than the patients who are undergoing their first implantation. And so with that condition, I feel that there's a little bit less of a concern about informing patients, although other things can happen besides what happened the first time.

So I feel that more data need to be collected, but I would go along with the indication.

CHAIRMAN WHALEN: Thank you.

Dr. Boykin.

DR. BOYKIN: I believe clinically speaking this indication really falls in between the two areas that we've looked at. It should, I believe, at least from my experience, be considered a continuum of the spectrum.

While there is relative paucity of data, I believe that this could be continued as a post approval study and that the complications that have been investigated should continue to be documented.

CHAIRMAN WHALEN: Thank you.

Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: While I agree that the data collection needs to continue hopefully along many of the same parameters that have already been collected, it is very conceivable to me that medical and biological and mechanical analogy would be sufficient to approve this for revision if we're approving it for the other things, and I would defer to the other subject area experts on that.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: That's such a fuzzy question I still can't understand it. I cannot imagine a situation in which you would have a patient who has had a safety and effective implantation primarily, needs a revision, and then say, "Well, it was okay for the first time, but not for the second time."

And I can't imagine that an implant that would be judged safe and effective for an initial procedure would not be judged safe and effective for a revision procedure, and I believe it should be included as safe and effective.

CHAIRMAN WHALEN: Thank you.

Dr. Chang.

DR. CHANG: I'll be consistent and leave it on as an indication and ask for post marketing study, follow-up.

CHAIRMAN WHALEN: Thank you.

Dr. Morykwas.

DR. MORYKWAS: I'll also agree that it should be approved with post market approval because you also could run into the situation where a woman with bilateral implants has a unilateral explantation and then couldn't be revised, and that's a peculiar conundrum that would be in there.

So I would recommend a yes.

CHAIRMAN WHALEN: Thank you.

Dr. Witten, there is not a unanimity of opinion on this particular subject. However, it is, I think, the clear preponderance of the panel's opinion that there should be a directive for further data to be collected upon this issue of patients who receive this device for revision.

On whether or not this should be a part of the labeling, there is pretty much a division 50-50 of opinion on this particular topic.

DR. WITTEN: Thank you.

CHAIRMAN WHALEN: Thank you.

Going to question number five, this is sort of a side point of what we were talking about a little bit earlier in terms of the complications, but it focuses upon long term adverse events, and I would ask that those in responding address the three lettered subpoints of question number five, and we, I believe, start with Dr. Robinson.

DR. ROBINSON: The increasing rates per year for a device, I mean, devices over time have increasing rates of complications, I think, for most. So I'm not too surprised there are increasing rates.

The minimal duration of follow-up to look at them, I think I would have to defer to the statisticians. I'm not sure I have even a gut feeling for what that should be in terms of a number.

The type of visit, I'd have to ask for some clarification. Active versus passive, what exactly is meant by that?

Pardon?

DR. WITTEN: Do you want clarification from us or --

DR. ROBINSON: Yeah, please.

DR. WITTEN: Yeah, meaning does the patient come in for, you know, to be seen. Is it a postcard follow-up? Is it a visit with the physician?

DR. ROBINSON: So active would be they're physically present.

DR. WITTEN: Yeah. In other words, what mechanism? You know, there's a range of ways of getting information from follow-up.

DR. ROBINSON: If you're going to continue to do long term follow-up, you should od it in a serious manner, and it should be active.

And which types of complication should be addressed? They should be serious complications, complications like connective tissue diseases, and things like that that I think have been laid to rest by multiple studies should not be included on these serious complications.

CHAIRMAN WHALEN: Thank you.

Ms. Brinkman.

MS. BRINKMAN: Well, I believe that the FDA in '95 asked for a minimum of ten years for patient follow-up, at least for deflation, and so certainly a minimum of ten years, although I am not a statistician. So that's my only off the top of my head, non-expert opinion.

Certainly an active visit would be preferred, but I'm not sure I believe that's realistic, and so in light of not being able to get that, then some sort of at least survey or by mail thing or the best that someone can get.

Obviously what types of complications, capsular contraction, infection, deflation, breast nipple sensation, leakage, rupture, reoperation, the whole list of complications that we've discussed to this point.

CHAIRMAN WHALEN: Thank you.

Ms. Domecus.

MS. DOMECUS: Again, I'm not sure if this question refers to preapproval or just any data that's there.

CHAIRMAN WHALEN: Actually you can phrase your answer in whichever way you desire.

MS. DOMECUS: From a preapproval standpoint I think the sponsor has more than met the typical standards for what would be required prior to FDA approval. So that any of this data I think should be a post approval setting.

The ten year stipulation that's already present, I think, is very stringent already. So I think that should not be extended.

Active or passive? I think either is probably a fine way to collect the data. In terms of wish complications, I think all complications should be followed for the duration of the study.

CHAIRMAN WHALEN: Thank you.

Dr. Li.

DR. LI: I guess I would leave, again, the minimal follow-up to the statisticians, although the, again, short term performance of these things as far as deflation goes, to me I still consider to be quite high, but I certainly would like to follow that up for a little longer, at least the ten year suggested FDA.

I'd like the follow-up to be active. I think if we could include perhaps so that it would be a little easier to ascertain after the fact if there is a deflation or some mechanical failure that there would be some easy way to ascertain the model, the sterilization method, or the details of that particular device, and then we could answer the question is there a material and design correlation or is there not with this, and try to answer that question once and for all.

And maybe this is outside the purview of a survey, but I certainly would encourage either the companies or some academic institution to embark on what other implant devices do and have retrieval collections and analysis because I think in the absence of that we're never going to get to the actual factual answer that will make us all happy.

CHAIRMAN WHALEN: The drum roll for the first of our statisticians, Dr. Blumenstein.

(Laughter.)

DR. BLUMENSTEIN: So I've been set up here. I have to say the number of years, huh? No way.

I think a long term follow-up, active follow-up would be very useful here for the reasons just cited, and in particular to address this issue of informative censoring, you need to know why patients are not coming back for their follow-up visits and whether that has something related to do with failures or particular types of failures.

So I think that an active long term follow-up study until that Kaplan-Meier curve starts to flatten out a little bit.

CHAIRMAN WHALEN: Thank you.

Dr. Boykin.

DR. BOYKIN: I believe the ten year period is a reasonable minimum requirement, and that if at all possible, if at all reasonably possible, the patient should be enrolled in an active follow-up phase and that the complications that we have looked at, capsular contracture, infections, asymmetry, breast feeding complications, nipple sensation, recent review of the mammography I think would also be important and maybe review of the trauma and illnesses that have occurred while the patients had the implants as well.

CHAIRMAN WHALEN: Thank you.

Another statistical opinion, Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: Well, I would like to punt a little bit and say that in my opinion statistics can't answer the question about duration if this is more than establishing the precision. If it were then we could determine number of events and do a power calculation, but it's a matter of establishing the natural history of the device. So that's medicine and lots of things other than the statistics.

That having been said, I agree with Dr. Blumenstein's recommendation.

CHAIRMAN WHALEN: Thank you.

Dr. Burkhardt.

DR. BURKHARDT: I think that the present study has an adequate follow-up and adequate follow-up for pre-market approval. I would agree that it might be nice to get a ten year active follow-up, but pragmatically it's not going to happen, and you will be very lucky if you get a ten year passive follow-up on a significant percentage of these patients.

This is a highly mobile population, and unless you have data like they do in Canada where you can trace these people by their Social Security numbers or whatever, you're not going to get them back for follow-up for ten years.

CHAIRMAN WHALEN: Dr. Chang.

DR. CHANG: I would agree with Dr. Burkhardt's comments that it would be important to get data regarding deflation rates, but it is not practical to expect an active follow-up, and we should not not get the data and record it because of someone having a passive -- passively giving us this information.

CHAIRMAN WHALEN: Thank you.

Dr. Morykwas.

DR. MORYKWAS: I'll just also agree that I think in the real world a ten year active follow-up is not possible and even passive follow-up in the last five years from years six to ten is doubtful, but I would agree with the other -- with (c) for all complications.

CHAIRMAN WHALEN: Thank you.

Ms. Dubler.

MS. DUBLER: Ideally an active follow-up for ten years. If that isn't possible, a passive follow-up for ten years, and in any event, I think we should track as many complications as we can in that period of time, and with a special focus on the leakage and deflation.

CHAIRMAN WHALEN: Thank you.

Dr. Witten, the panel in attempting to answer these questions feels that with the consensus, the ideal follow-up should be active and ten years-plus, which is really in line with what FDA has already required and/or suggested, but an asterisk perhaps on that should be that some seasoned cynicism or realism, depending upon how you want to put it, thinks that that may or may not be achievable.

And that finally, in terms of complications, clearly all of those complications that we have rather extensively discussed already today should be tracked inasmuch as they have not plateaued over the period of observation, and any and all other serious complications should be as well.

Does that answer the question?

DR. WITTEN: Thank you.

CHAIRMAN WHALEN: Thank you.

Going to question number six, in regard to design of the study of the sponsor in providing information on certain long term issues, we are asked to comment, and I would specifically point out that this is as a condition of approval, although if there is some further editorialization that any of the panel wish to make about post approval, then please do so.

And those three issues, as you see posted and before you, have to do with interference of the ability of screening mammography to detect tumors when implants are present, interference with lactation and effects of offspring from women with implants.

And I believe, Ms. Brinkman, you're up.

MS. BRINKMAN: I think these issues are going to take good education and information. Certainly that physicians, radiology techs, mammography techs, and patients need to know the importance of good clinical breast exams, that when compression techniques are available, MRIs aren't practical; that according to Dr. Berg, that we're going to see double in radiation costs and doubles in radiation doses; that people need to know where the placement of the implants are and how that affects the mammogram; that implants can hide breast tissue; that certainly the viewing may be limited by contractures and difficult to visualize.

And I think all of those issues need to be made available in provider patient information and education.

CHAIRMAN WHALEN: Just in follow-up though, should there be anything specifically as a condition of approval or prior to approval in any of those things that you feel needs to be done?

MS. BRINKMAN: Other than those are included in our information and education in the labeling.

CHAIRMAN WHALEN: Okay. Thank you.

MS. BRINKMAN: Are we going to address lactation or are we going to just do these one at a time?

CHAIRMAN WHALEN: All three. Yes, please address all three.

MS. BRINKMAN: Okay. The same for lactation, that the ability to nurse a child may be certainly affected by having an implant, and the effects on offspring from women with implants, I don't know that there's any data out there that says that it affects babies born of mothers that had implants.

CHAIRMAN WHALEN: Thank you.

Ms. Domecus.

MS. DOMECUS: I'm not sure that I'm qualified to design the studies to address these, but I did have a couple of comments.

I think question number one about this interference with mammography, I think that it was Dr. Berg presented data on that. So I think that that's probably been sufficiently addressed, and that the sponsor shouldn't have to do that post approval.

The IOM report addresses interference with lactation and addresses that positively. So that seems like an issue that doesn't need to be further addressed.

The only comment that I'd make on that though is that one of the presenters in the open public section this morning talked about how it could actually reduce the amount of milk even if it didn't put contamination into the milk, and that's something that maybe a nursing mother, if she didn't ever use a breast pump, would not be aware of. The baby could not be gaining weight, and you could have some, you know, failure to thrive issues.

So maybe I think it's an informed consent issue that nursing mothers need to realize their milk volume may be less if, in fact, the presenter earlier this morning was factual in his statements.

And as far as effects on offspring from women with implants, the IOM suggests that that is something that should be further studied.

CHAIRMAN WHALEN: Thank you.

Dr. Li.

DR. LI: I'll defer to my more learned colleagues on this.

CHAIRMAN WHALEN: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: I've been waiting for a place to say this all day, and I've finally figured it out. I think that these are very important issues and are very difficult issues to address in any kind of study or surveillance system.

Just as an idea, maybe insurance providers or managed care might have data that would be obtainable that would address these issues, and I would encourage the FDA and the sponsor to investigate those as possible sources of data addressing these issues.

CHAIRMAN WHALEN: Thank you.

Dr. Boykin.

DR. BOYKIN: I agree that it would be important to continue to collect information. I think the IOM studies, study, rather, has given us some comfort at least in terms of the problems related to mammography and the interference with lactation.

And I think that an informed consent process could be developed by the manufacturer and perhaps reviewed by the FDA as a way to take care of this.

CHAIRMAN WHALEN: Thank you.

Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: I don't believe that the current study is well designed to rigorously investigate any of these issues. I certainly support collecting data in long term follow-up. You know about events that occur, but I would not say that further rigorous investigation is a condition for approval.

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: I believe that we have all the information we need for pre-market approval.

CHAIRMAN WHALEN: Thank you.

Dr. Chang.

DR. CHANG: I don't believe any further study is required regarding these questions before approval.

CHAIRMAN WHALEN: Thank you.

Dr. Morykwas.

DR. MORYKWAS: I also don't believe any other information is required.

CHAIRMAN WHALEN: Ms. Dubler.

MS. DUBLER: I don't think the information is required before approval, were all other problems solved, but I think these three areas should be flagged to women as areas of some complexity and uncertainty, and that long term follow-up studies should be encouraged.

CHAIRMAN WHALEN: Thank you.

Dr. Robinson.

DR. ROBINSON: As I understand the question, the sponsor to evaluate these issues as a condition of approval, so the answer to two and three would be, no, we have adequate data on that. That should not be a condition of approval.

One, no, it should not be a condition of approval, but somewhere the panel will have to address the fact that some patients in rare instances will need additional imaging studies, and we should address that if for nothing more to give patients leverage on their payers to support those studies.

CHAIRMAN WHALEN: Thank you.

Dr. Witten, in regards to the three questions, the panel does not collectively feel that any of these issues would need to be evaluated by the sponsor prior to consideration of approval of their application, but nevertheless, I believe there is a preponderance of concern about several of the issues, and specifically mostly centered upon that of the possible interference with mammography, and that this should be something that would need to be studied in the future.

Does that answer the question?

DR. WITTEN: Yes, thank you.

CHAIRMAN WHALEN: Thank you.

And finally, question number seven, and this, I believe, is the other one that we can be a little bit less formal about going around the table, has to do with heterogeneity of surgical practice and recommendations for what issues should be included in physician training vis-a-vis this particular device and its implantation.

Does anyone wish to comment upon that?

Ms. Dubler.

MS. DUBLER: I'm impressed by some of the discussion of the importance of surgical technique in these sorts of surgeries, and I'm also impressed by the fact that this is a growing field, and cosmetic surgery is now described as one of those fields outside of the restrictions of managed care, and therefore, lots of people are finding it attractive, and that makes me very anxious about some of the people who will be engaged in these surgeries.

And, therefore, I would expand this topic not only to address surgical training, but to also address potential patients and tell them to be aware of the fact that surgical training varies in these areas, and it's one of the discussions they ought to have with a prospective provider.

CHAIRMAN WHALEN: Ms. Domecus.

MS. DOMECUS: I guess as a follow-on to that, I think that physician training should not just involve the surgical techniques and information about the device, but apparently information about the informed consent process.

This morning session, that was the most alarming part of all that to me, was how many of these patients didn't feel like they got adequate information or any information on the risks and benefits to make an informed decision, and so I think that the sponsor could go a long way in helping its physician customers understand what an adequate informed consent process looks like.

CHAIRMAN WHALEN: Dr. Witten, in an attempt to answer this question and perhaps even taking the purview of the chair and editorializing a little bit myself as a Program Director in general surgery, I think there is concern about what practitioners do, and there is concern about both physician training and how much the public who is interacting with these physicians knows about such issues, but I would add myself that I don't know that there's anything that we can impose upon this or any other sponsor which is going to be a requirement vis-a-vis that particular aspect of the training.

Does that answer the question?

DR. WITTEN: Well, I do have one follow-on question, and just to see if anyone has anything to add, which is have we learned anything from the study and the information the sponsors provided that leads us or leads you all to recommending anything specific in the label regarding surgical practices and post operative management with this particular product based on the information that was provided from the studies.

CHAIRMAN WHALEN: Dr. Burkhardt?

DR. BURKHARDT: The information provided in the studies shows that you can't push one of these things through a small hole without maybe injuring it, and I would think that it would be reasonable to suggest to the FDA that they advise against insertion through a long, small tube by way of the umbilicus.

DR. WITTEN: Thank you.

DR. CHANG: And I think that this issue of Betadine perhaps changing the integrity of the device, and particularly the length of incision, may be added in the labeling.

DR. BURKHARDT: Could I speak to that issue?

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: The two major problems we have are deflation and capsular contraction. There is new evidence that is presented here that the Betadine may make deflation more common. There is evidence in the literature that it may make capsular contraction less common.

And I would suggest to you that this should not be an issue of device approval, but should be left up to the judgment of the operating surgeon.

CHAIRMAN WHALEN: I guess the only response I would have to that is ultimately it's going to be anyway, isn't it? Ultimately it is going to be up to the surgeon, and the surgeon is going to do whatever he darn well pleases no matter who tells him anything.

Some of you probably think since we answered all seven questions that we're now going to vote. You're wrong.

(Laughter.)

CHAIRMAN WHALEN: We will now proceed with the second open public hearing session of this meeting. All those and only those who have signed up for this -- there are four people -- who will address the panel should speak clearly into the microphone as the transcriptionist is dependent upon this means of providing an accurate record of this meeting.

The instructions from this morning still apply, and to briefly encapsulate those, we would ask that you disclose if anyone is paying for your trip or accommodations; if you have any financial ties to industry or health professional societies. We would also ask that you disclose whether you are a witness or party to any lawsuits related to breast implants or whether you derive any of your income from medical procedures involving breast implants or symptoms attributed to breast implants.

Each speaker in this session, unless there's a loud outcry, was originally going to be allotted ten minutes, and in view of the hour, the chair is going to ask that you confine that to five minutes, and we only have time for the four scheduled speakers.

The first one is Lale Goddard.

MS. GODDARD: (Inaudible.)

CHAIRMAN WHALEN: If you feel that it's so critically important, then please proceed.

I'm sorry. Just for the timer's sake then, ten minutes on this please.

MS. GODDARD: My name is Lale Goddard.

Now can you hear me better? I don't need to holler, right?

Okay. My name is Lale Goddard. Thank you very much for the opportunity to appear before you today.

I paid my own travel and accommodations. I do not have financial ties with industry or health professional societies. I am the plaintiff to a pending lawsuit related to breast implants. I derive no income from surgical procedures.

I'm here today because scientific literature states that particulate wear debris generated from implanted medical devices may not be biocompatible. Long term implantation of various medical devices, such as breast implants and joint implants, can generate particulate wear debris.

White blood cells, called macrophages, can be stimulated or activated when they ingest silicone elastomer particles. Activated macrophages can synthesize and release various inflammatory mediators, such as the pro inflammatory cytokines called tumor necrosis factor alpha.

Tumor necrosis factor alpha induces the production of another inflammatory cytokine called interleukin-1. Tumor necrosis factor alpha and interleukin-1 are both potent and biologically active protein molecules. They act as signals between cells to regulate the immune response to injury or infection.

Biological properties of interleukin-1 suggest that its effects often mimic host response to infection, inflammation, injury or immunological challenge.

Once released into the circulation, interleukin-1 can induce systemic systems, such as fever, muscle aches, arthralgia, headache, lassitude, sleepiness, changes in metabolism, and hematological dysfunction.

Tumor necrosis factor alpha and interleukin-1 can be toxic in vivo. Inflammatory cytokines produce at the site of chronic granulomatous for a body reaction can move through the blood stream and activate cells at a distant site. There is growing evidence that the tumor necrosis factor alpha is involved in the onset of inflammatory arthritis, whereas the cartilage and bone destructive process is mainly interleukin-1 driven.

Interleukin-1 is responsible in the production of cyclooxygenase, an enzyme that helps make prostaglandins, the substance largely responsible for the pain and inflammation of arthritis. When scientists injected the inflammatory cytokines into rabbits, the animals developed signs of inflammatory arthritis and join erosion.

Tumor necrosis factor alpha and beta are potent stimulators of bone resorption in vivo.

Orthopedic implant manufacturers and surgeons have known about the adverse cellular responses to particulate wear debris for decades, and they call it a chronic granulomatous foreign body reaction or particle disease.

Scientific literature states that silicone elastomer particles can cause erosive or destructive arthritis that mimic rheumatoid arthritis. Long term benefits of silicone elastomer use in joint implants probably far outweigh the risks of complications and adverse reactions for most orthopedic patients.

The cosmetic and psychological benefits of long term breast implants made with silicone elastomer shell in healthy women may not outweigh the possible risks and complications. The FDA recognized standards for biological evaluations of medical devices and guidance documents do not require the manufacturers to do testing for cellular responses to silicone elastomer particles.

The particle testing could be done in less than three weeks, according to an article published in the May 1996 issue of Orthopedic Hand Surgery. The title of the article is "In Vivo Inflammatory Response to Silicone Elastomer Particulate Debris," published by Dr. Sanjiu H. Naidu and his colleagues.

The article abstract states the following: "Silastic silicone elastomer polymers, polymethylmethacrylate particles, monosodium urate particles smaller than 10 microns were injected into a rat subcutaneous air pouch lined with synovial membranelike cells. Inflammatory exudate from the air pouch was retrieved at 6 hour, 24 hours, 48 hours, and 72 hours after injection. White blood cell count, tumor necrosis factor, and prostaglandin E₂ were measured in the exudate. White blood cell and tumor necrosis factor levels in the exudate were the highest for the silicone group in 24 hours. Prostaglandin E₂ was significantly higher in the silicone group at 24 hours. We concluded that acute inflammation is particle-type specific and that silicone elastomer particles are acutely inflammatory."

In 1998, American Society for Testing and Materials developed two particle testing standards. One is titled "Testing for Biological Responses to Particles in Vitro," and the other is titled "Standard Practice for Testing the Biological Responses to Particles in Vivo."

Both standards state the following: "it is well recognized that the biological responses to particles could be different from those to solid materials. The interaction of the particles with cells in the tissue, notably macrophages and other phagocytic cells, is the key to final biological responses."

The standards describe techniques used to detect soluble cell products, such as tumor necrosis factor alpha, interleukin-1, interleukin-1 receptor antagonist, and interleukin-6 due to interaction of phagocytic cells, such as tissue macrophages and synovial lining cells with particles.

For consumer safety sake, please consider making the following recommendations to the FDA.

One, the FDA to recognize the American Society for Testing and Materials standards titled "Testing for Biological Response to Particles in Vitro" and the "Standard Practice for Testing the Biological Responses to Particles in Vivo."

Two, the FDA to updated and include the two particle testing standards in the guidance document.

Three, the FDA to not approve silicone inflatable breast implant manufacturers' pre-market approval application or product development protocol until the manufacturers comply with the revised guidance document.

Four, the FDA to analyze the explanted elastomer shells to determine the amount of material lost.

Five, if the FDA approves breast implant manufacturers' PMAs and PDPs without the testing for cellular responses to silicone elastomer particles, then the FDA should inform the public that the particle testing was not required for the PMA and PDP approvals.

Please do not vote for the approval of breast implant manufacturers' PMAs and PDPs without the requirement for testing for cellular responses to silicone elastomer particles. Particles to be tested should be smaller than 13 microns or small enough to be ingested by macrophages or other phagocytic cells.

Manufacturers should inform doctors and patients about the cellular responses to silicone elastomer shell particles and cytokine production.

Thank you very much, and my written statement is also available at my Web page, jps.net/joseeefus/.

Have a good evening.

CHAIRMAN WHALEN: Thank you.

Next we will hear from Ms. Rosmary Locke on behalf of the Department of Defense Military Hospital Beneficiaries.

MS. LOCKE: Thank you.

It's been a long day, but I really do appreciate the opportunity to speak to you after one of the manufacturers presented and the FDA made the comments.

My name is Rosmary Locke, and I have no personal financial involvement with manufacturers or health care providers. I'm not involved in a legal issue, and I'm not being reimbursed.

However, I am a volunteer for Y-ME national breast cancer organization, and it's my understanding in the past they did receive small donations from one manufacturer. The bulk of our -- that's all public record in our annual reports -- the bulk of our money comes from individual donors and some pharmaceuticals who support our work.

I am a breast cancer survivor of 15 years with implants. I'm a military spouse and a health care advocate for military beneficiaries. I'm also a past president of the National Military Family Association.

Eight years ago I was a member of your advisory panel when it reviewed the PMA on gel implants. Though I believed that gel implants were safe, I concurred with the other panelists that the scientific information was lacking for gel approval.

Since then a large body of science has emerged showing that breast implants do not cause systemic disease. The National Academy of Science's IOM review of the science, its conclusions and recommendations now provide us with knowledge based on sound science.

Saline implants are a very important option for women who face breast cancer. At diagnosis, treatment options must be considered and difficult decisions made with the hope that disease can be controlled and a more normal life resumed.

That is why it's so important to have a full array of treatment options. It gives the cancer patient some sense of control and restoring her health and quality of life.

While saline breast implants generally do not produce the desired aesthetic results of gel in reconstruction, saline offers mastectomy patients the only unrestricted option left since the FDA's restrictions in 1992.

Saline is the only implant option for breast cancer patients or long term survivors treated in military hospitals, and access to gel for reconstruction is a problem for many women in the civilian sector.

And I know because time is limited you're probably not going to ask any questions on why that is, but it is a significant problem for military beneficiaries.

I urge this panel to stick to the science, consider the exhaustive and definitive review of the IOM of all of the existing research. The IOM found that there's no evidence that silicone breast implants cause disease or cancer. Yet the FDA restrictions on gel remain, denying access or causing delays for some women seeking them for reconstruction.

Look at the fear and the litigation that happened after the 1992 PMA on gel. FDA cannot and should not act in a vacuum.

Now, there have been many other reviews that were spoken of today, and each found similar findings to that of the IOM. The research shows no increase in primary or recurrent breast cancer. Indeed, though we've heard from a number of women who have a wide range of medical conditions they attribute to breast implants. Their health needs cannot be ignored.

The FDA, however, cannot make regulatory decisions based on personal anecdotes. It must stick to the science.

Of course, a woman considering reconstruction should seek in depth information about her cancer and her reconstruction. Now, the National Cancer Institute, FDA, IOM, and many medical institutions have excellent information in print and Web pages, and many women find it helpful to talk to other cancer patients.

Consumers need to know that no medical device is risk free. No medical device lasts forever. And there are risks associated with all surgical procedures. That makes informed consent central to the process. It's absolutely essential for doctors to advise their patients on the risks and benefits of any medical procedure.

Though quite sobering, we welcome the information coming from the manufacturers on the nature and frequency of complications and reoperations.

We also appreciate the opportunity by the FDA to make comments on informed consent and labeling, and we ask to be able to make a statement on that.

In summary, I ask that breast cancer treatment decisions should be made on how best to treat cancer, not on disfiguring surgery, and breast implants offer an important option to women with breast cancer.

I urge this panel to base its recommendations on sound science and studies with reasonable endpoints, a process FDA uses in evaluating all other effective medical devices and therapies.

Thank you.

I did cut my time. It may not seem like it with the red light going.

CHAIRMAN WHALEN: Thank you.

We next will hear from Dr. Diana Zuckerman from the National Center for Policy Research for Women and Families.

DR. ZUCKERMAN: Is this a good height? Oh, towards me? Is that better?

I'll be brief if you stay awake. That's the deal.

(Laughter.)

CHAIRMAN WHALEN: Hunger is a wonderful motivator. Please continue.

DR. ZUCKERMAN: Thank you.

I just want to briefly say that I come to be here -- oh, I should start with my conflicts of interest. I'm donating my time, and my transportation here all the way from Bethesda, and my answers to the other conflict of interest questions are no.

My background is in epidemiology and psychology, and I've also talked to hundreds of women with breast implants of the last ten years, and so my goal today is to put those two things together.

I know that we as scientists are not supposed to focus on anecdotes, but sometimes when we listen to patients, it tells us something important, and when we tie that in with what the research does or doesn't tell us, I think it can be very important and give us some insights into where we go next.

I'm very concerned about the loss of patients to follow-up in the studies that you've heard about, and I'm particularly concerned about it because I've talked to a lot of implant patients who have told us, told me personally of experiences where they try to tell their doctor that they have problems.

And it isn't getting registered in the studies that they are supposed to be in, or they get so turned off by doctors who do not seem to believe that their health problems can possibly be related to their implants that they stop seeing those doctors and go find other doctors.

And so I think it is not a minor issue that there is this loss of patients to follow-up, and several of you have raised that question, and then I feel it's sort of gotten lost. It's the long day and it's the end of the day, and so I want to bring you back to that issue, that perhaps part of the reason why the women who had problems sound one way and the research seems so entirely different is because some of those women at least are getting lost.

And of course, we don't know how many there are, and that's very important, and I think that's a big issue, certainly for me, and I hope it will be for you.

I also want to talk a little bit about the quality of the data, and that ties in again. I mean obviously a study of depression that has no comparison sample or control group, I mean it reduces the credibility of the whole package to me to have something like that be supposed to be evidence that these women are getting better because, of course, women who have just had surgery for breast cancer are going to be depressed.

I used to do research on depression. I promise you that's true. They are going to feel better, and without a comparison sample, you don't know anything about how effective this particular treatment is for those women.

I also have some concerns about whether all of the right questions were asked in these studies. Pain is a big issue for a long of the women I talk to. I'm not at all convinced that the research that was presented today really deals with pain in a meaningful way.

Obviously if women say they're really satisfied with their implants, you have to assume that pain is not a big problem, but let's remember that the follow-up was quite short for these studies. Three years is not a very long time.

When I've talked to women, most of these women have been very happy with their implants for the first few years. It's only after three or four or five or six or more likely seven or eight years that they start having serious problems.

And let me also mention that part of that is that when they do have problems initially their doctors say, "Don't worry. It's going to get better," and so they have this hope, and they may feel quite satisfied because they think that the problems that they have of pain or numbness in the nipple area or whatever it might be, that those problems are going to go away and they're going to feel better soon.

If you follow them for a longer period of time, they might feel quite differently about how satisfied they are and how they feel about it.

Let me briefly say I'm on the Scientific Advisory Committee for the NCI study of breast implants. I was very surprised that that study wasn't mentioned here today. I Know that the data are not -- nobody knows better than me the data are not public yet.

I would have thought FDA would have asked for those data. I would have thought they would have presented those data to you. Although it's not published yet, some of those data are already analyzed, and one of the people at FDA is a co-author of those studies.

Those are studies of cancer, breast cancer and other cancers, and a study of connective tissue disease. Those are relevant data. Those are important data. It's a very large study, the largest study that's ever been done, and I don't understand why you didn't get it, and I hope that FDA will ask for it and look at those data before any kind of final decision is made.

I'm almost done here.

There's one thing I just have to address, and that's the issue of connective tissue disease. When I was asked to speak today and all the other public comment people were told stick with saline implants, and I'm happy to do that, but the studies on connective tissue disease do not do that.

I may be one of the few people in America who's actually read all of these epidemiological studies on connective tissue disease and breast implants. Here they are. I've read all of the. I've done a review of them.

And let me tell you that of the 17 studies that are most often quoted in the Institute of Medicine report, as well as other reports that have been done, only one, one study looked at saline breast implanted women and analyzed them separately. None of the other studies did.

Most of the studies had no women with saline implants or very small numbers that were not analyzed separately. If you want to assume that the data on silicone gel implants are relevant to saline, that's a decision to make, but it's kind of an unusual decision to make. Usually you would study, you know, one product at a time and base your decision on that one product.

Finally, I just want to say that there is a lack of long term data. I think that's serious, and I commend your concern about that and your asking for more data.

As someone who's done survey research, I don't think there's any way in the world you're going to get questionnaire data ten years out. You may say it's impossible to get, you know, actively women coming back in, but you're sure never going to get questionnaire data like that.

If you think that long term data are important -- I personally think they're very important -- I don't know how you're going to create an incentive for the manufacturer to do that if you approve these devices. If they haven't done it up till now when they had all these years to do their studies, what's going to give them the incentive to do it in the future?

And my understanding is that FDA does not have post market surveillance resources or perhaps authority for medical devices. So if you think that the data that's been presented are not sufficient to prove safety, and I know that some of you have said that here today, then you have to think very carefully about how you're going to make sure that happens when I think there is actually no other way to make sure it happens.

And my last comment is just to say that breast cancer patients are a special case, and Dr. -- not doctor -- Ms. Dubler and I commend your concern about them, and I share it.

I've worked with a lot of breast cancer activists, and I actually met with them very recently to talk about this issue, and there's a wide range of feelings among the breast cancer community about breast implants. Most groups have been neutral on the issue. They all do want good data.

We do women no favor, whether they're breast cancer patients or any other patients, we do them no favor by leaving something on the market that is not proven safe for them.

Thank you.

CHAIRMAN WHALEN: Thank you.

Finally we have -- Dr. Zuckerman, if you'd stay at the podium, there's a question.

DR. ZUCKERMAN: Sure.

DR. BLUMENSTEIN: This NCI study, I did not know about it, and I think that it has a possible impact on what other kinds of data we require of the manufacturers, and I would like to know some more details about it.

CHAIRMAN WHALEN: Well, before you go into any details about that, Dr. Witten, would you like to comment upon the whole process we're about in terms of what PMAs are and what we can review?

DR. WITTEN: Yeah. I just want to reiterate what I had mentioned this morning, which is we want you to base your safety and effectiveness assessments on the information contained in the PMAs, and in addition, your scientific knowledge, including, you know, what you know from publicly available scientific literature.

CHAIRMAN WHALEN: Which is what we are mandatorily directed to do.

DR. WITTEN: Which is what we're directed to do.

DR. ZUCKERMAN: No, and I understand that, but I have heard people say, "We don't have to worry about cancer or connective tissue disease because the studies show there are no problems," and I am not at liberty to say what's in those studies even though I have seen them. I am not allowed to talk about them.

I'm only saying I think that that would be something that FDA would want you all to look at and would want to look at.

CHAIRMAN WHALEN: Thank you.

Finally, we have Ms. Jill McClure from the National Alliance of Breast Cancer Organizations.

MS. McCLURE: Good evening. Thank you for your time.

My name is Jill McClure. I'm a health educator and a breast cancer information specialist. It's my pleasure to represent the consumer and professional constituencies of the National Alliance of Breast Cancer Organizations and to offer a point of view to the members of the panel.

My travel expenses have been paid for by internal NABCO funds earmarked for advocacy activities. Neither NABCO nor I have any financial ties to implant manufacturers or marketers. NABCO does not receive any funding from any current implant manufacturers. Neither NABCO nor I are part to any implant related lawsuits.

The reason I phrased it current implant manufacturers, I know, for example, Bristol was an implant manufacturer, and they're somebody who has supported a publication of ours this year. So I want to be absolutely clear on that.

I would like to emphasize that my remarks will be confined to use of these devices for reconstruction for women who have had breast cancer or breast disease or who have had a prophylactic mastectomy due to an established risk for breast cancer.

NABCO cannot and does not comment on the cosmetic use of breast implants of any type.

NABCO is a not for profit, information and education resource on breast cancer. It is also a network of over 400 member organizations and a nationally recognized voice for the needs and concerns of women with breast cancer, women at increased risk for the disease, and their friends and family.

NABCO's professional staff members are frequently called upon by providers and health professionals to serve as patient advocates and advisors in medical and policy deliberations and in clinical decision making.

We also frequently translate scientific developments and advances into understandable and compelling language for print and broadcast media.

We're comfortable taking on these roles and responsibilities because NABCO's mission and program areas offer us constant exposure to a large and varied constituency.

I work in NABCO's Information Services Department where our Web site and toll free number are NABCO's front line for serving the public and where we handle hundreds of weekly contacts with many segments of patient and survivor communities.

Callers express their breast cancer and educational needs, and as we fulfill those needs with materials, resources, and referrals, we've often heard misinformation, confusion, and concern, but also some reassurance and relief surrounding the emotionally volatile subject of breast implants.

Without question, saline implants are not ideal since they can leak, be subject to capsulary contracture, and are less sturdy, require higher maintenance, and are often less aesthetically acceptable than their silicone filled counterparts.

We at NABCO hope and expect that the FDA will address the availability of silicone filled breast implants, again, for breast cancer patients and survivors at some point later this year, but until these devices are open for discussion, we wish to make several points about saline breast filled implants.

Safe, well tested, saline filled breast implants must continue to be available in as many types and forms as feasible so that options and choices for women with breast cancer are maximized. The alternatives of autologous tissue reconstruction and external prosthesis are not appropriate for every woman, and as individuals differ and vary, so much their options.

Like any medical device or procedure, saline breast implants should be considered and selected by a woman and her medical team after careful discussion and consideration with a full information exchange that includes the risks and benefits.

Saline filled implants have been available and, as such, have not been subject to the more stringent and highly regulated informed consent provisions and requirements of clinical trials.

However, there still remains confusion about implants, and for this reason NABCO calls upon the device manufacturers and the medical specialists and providers who use these implants to make special additional efforts.

Women who are considering saline implants should receive an exceptionally thorough, comprehensive, and understandable information review about the devices from their physicians, be given time to ask questions and have those questions answered.

Information conveyed should not only include what to expect when the saline implants are first received, but how the devices will behave over time both under normal circumstances and under unusual circumstances.

NABCO encourages giving women contact information for organizations that can offer accurate and balanced information about implants and breast health in general. Understanding and working with her implant is a woman's lifelong commitment and part of the decision to choose an implant.

It should be made clear that replacement of a saline implant is not only possible, but likely, and the woman shares the responsibility with her physician for keeping up with developments about implant improvements, advances, safety, and this idea of maintenance.

Women with saline implants need to know the special considerations and requirements for breast examinations for early detection of breast cancer. MQSA regulations have specified certain procedures for imaging women with implants, and these must be taken into account at the time a woman has an implant in place or -- I'm sorry -- and the type of implant the woman has in place.

Breast self-examination techniques should be reviewed with the woman after the implant has resolved to its ultimate size and resting place. The breast cancer survivor should be particularly vigilant about breast examinations and the possibility of recurrence.

Finally, NABCO urges the FDA to move forward with communication of scientific findings about breast implants, and that all types of these devices be discussed using factual scientific and evidence based information rather than relying on or giving consideration to emotional, personal, and anecdotal experiences.

Women who have survived breast cancer are particularly able to weigh the risks and benefits, understand that no medical intervention is risk free. Having become informed patients by selecting the treatments that would extend their lives, patients and survivors need and deserve similar choices even if they seem difficult or challenging, including breast implants and any other regulated aspect of recovery that may improve the quality of their lives.

As their advocates, we have confidence that these women will make wise choices that are right for each one of them based on full disclosure.

Thank you for your time.

CHAIRMAN WHALEN: Thank you.

I'd like to thank all of those for taking time out of their schedules to testify at this panel meeting.

Is there any further comment from anyone in the FDA?

DR. WITTEN: No, thank you.

CHAIRMAN WHALEN: Thank you, Dr. Witten.

Will there be any further comment from Mentor Corporation?

Seeing that there will be, I'd like to remind you beforehand that this will be for ten minutes. I would ask that the timer be run to that accord, and also remind you that this is not to present new data, but just to comment upon anything that has already taken place.

MR. PURKAIT: Thank you, Mr. Chairman.

Thank you, members of the panel, for your time and the thoughtfulness and seriousness that you have shown to consider our PMA today.

There are some issues that I saw or we saw here you panel members are struggling about the data, specifically on the complication rates. I'll take only a few seconds or minutes jut to show that some of this data that we presented did not show the complication rates increasing over time.

I'd like to call these slides here, please.

This is from the augmentation patients. I wouldn't take much time to explain each of those data. I just want to draw your attention to the fact that the year one, year two, year three, you can see the year one they are higher, as it goes down in year two and year three. All categories go down except the reoperation, what we have explained before.

Slide number two please.

Similarly on the hematoma, seroma, necrosis breast pin, and the others, what we have calculated through the Kaplan-Meier, which we have submitted also, that shows that the year one, year two, year three decreasing, not increasing.

Similarly, on the reconstruction patient, please. On the reconstruction patients, I'd like to also point out that infection goes high at the year first and goes decreasing rate over two and three. Similarly on the deflation, deflation probably is in the higher scale, which we have explained the reason behind it. Reoperation rate and explantation goes high in case of the reconstruction.

Similarly, in the other areas of complication, the hematoma, necrosis, seroma, all of them shows higher rate at the year one, year two, and year threes on the decreasing.

This one, the extrusions and the rest of the other complications, this is an example to show that what you're struggling before about the safety issues related to the fact that this goes over -- increase over time. I like to present this to keep the record straight that this doesn't really.

The second thing that I'd like to mention is that in case of the division patients I request strongly to the panel members to consider this carefully because the division patient groups are in between, and I do not like to see that division patient groups have a cloud over their head that they can get an implant one time, but the next time they can't because there is some problem with the devices.

Also I'd like to mention that out SPS study is quite full of data, we believe rich, and has a lot of new information that we recently uncovered and discovered, and we are understanding, and we believe that as those data are being disseminated and been shared with both physician and FDA, it will be provided in the patient as well as the physician-patient information in such a way that we'll be able to provide a better information than before, previously, to the whole community.

With those notes, again, I thank you very much for your consideration, and I believe that this will give you a pretty good idea about our PMA's data and will help you to understand this data and vote on it.

Thanks.

CHAIRMAN WHALEN: Thank you.

Dr. Krause will now read the voting instructions for the panel.

DR. KRAUSE: Thank you, Dr. Whalen.

I'd now like to read the voting instructions for the panel.

The medical device amendments to the Federal Food, Drug, and Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows the Food and Drug Administration to obtain a recommendation from an expert advisory panel on designated medical device pre-market approval applications that are filed with the agency.

The PMA must stand on its own merits, and your recommendation must be supported by safety and effectiveness data in the application or by applicable publicly available information.

Safety is defined in the act as reasonable assurance based on valid scientific evidence that the probable benefits to health under conditions on intended use outweigh any probable risks.

Effectiveness is defined as reasonable assurance that in a significant portion of the population the use of the device for its intended uses and conditions of use, when labeled, will provide clinically significant results.

Your recommendation options for the vote are as follows.

First option: approval if there are no conditions attached.

Second option: approvable with conditions. The panel may recommend that the PMA be found approvable subject to specified conditions, such as physician or patient education, labeling changes or a future analysis of existing data. Prior to voting all of the conditions should be discussed by the panel.

Third option: not approvable. The panel may recommend that the PMA is not approvable if the data do not provide a reasonable assurance that the device is safe or if a reasonable assurance has not been given that the device is effective under the conditions of use prescribed, recommended, or suggested in the proposed labeling.

Following the voting, the chair will ask each panel member to present a brief statement outlining the reasons for their vote.

CHAIRMAN WHALEN: Thank you, Dr. Krause.

Does one of the panel members wish to make a motion?

DR. BURKHARDT: Yes, Mr. Chairman. I move that the panel recommends approvable with conditions for this PMA, and that those conditions should include post approval studies specifically consisting of some of the mechanical in vitro engineering concerns that have been expressed by Dr. Li.

In addition, I would attach labeling revision concerns, specifically including a revision of the comments regarding the shaped implant and labeling to discourage periumbilical insertion.

CHAIRMAN WHALEN: As to the motion that there be a recommendation that this be approvable with conditions -- and we will discuss those conditions shortly -- but as to that motion, is there a second to the motion?

DR. LI: Second.

CHAIRMAN WHALEN: We will now consider each of the conditions which have been stipulated by the motion, and if you could once again please read for us, Dr. Burkhardt, or refresh for us what the first stipulation would be.

DR. BURKHARDT: The first stipulation was that additional mechanical testing be performed in cooperation with the FDA to address some of the concerns that have been raised.

CHAIRMAN WHALEN: Thank you.

Is there any discussion of that stipulation? Dr. Li.

DR. LI: Do you want specific suggestions? Is that where we are?

CHAIRMAN WHALEN: Well, just in support of that being a condition or not.

DR. LI: Yes.

CHAIRMAN WHALEN: Or amplifying or --

DR. LI: I'm obviously fully in support of that. Is that all you want now or do you want the actual conditions for approval?

CHAIRMAN WHALEN: I'm not trying to be a ventriloquist. You can either talk about it as much as you wish or just say you approve it and leave it there.

DR. LI: Oh. Well, I would approve it with -- surprisingly, I would actually approve it with conditions perhaps. I think minimally you need to complete the testing of all the models that you intend to sell, and I think it's important that you test them with the materials that you intend to sell in the sterilization conditions in which you sterilize them at.

So if you're going to consider gamma sterilization as a potential fall-back manufacturing process, I think it is imperative that you test it in those conditions.

Further, we didn't mention it before, but gamma sterilization raises the whole issue of shelf aging and things like that, which are probably much less important for dry heat.

I think there needs to be either a modification or perhaps even just a further description of your fatigue test results. In other words, to help me close that gap between your fatigue test and what happens clinically, perhaps a description of what and where and how your devices fail and fatigue.

For instance, if you're generating giant holes in your fatigue test when it blows out that look nothing like your retrievables, then that test is far less meaningful than it is if you're actually generating similar types of behavior as found in retrieved devices.

I would encourage further analysis of retrievables, and then the closer you can mimic your laboratory test to what you actually find, the more comfortable, much more comfortable I would be, but I think it behooves you to find some cases or some tests where your implants actually do, in fact, leak and fail because they, in fact, do that clinically, and they do so even more under the reconstructive environment.

So I think it would behoove you if you wanted people to make your tests more believable that you actually run tests that actually fail in a reasonable amount of time, that somewhat mimics what happens clinically rather than some of the more extreme tests that you've provided so far.

CHAIRMAN WHALEN: Thank you, Dr. Li.

As to the first condition --

DR. DUBLER: Excuse me.

CHAIRMAN WHALEN: Okay.

DR. DUBLER: I just don't understand if we stipulate that number and specificity of conditions which are such at odds with the data that's been presented. Can that still be considered under the FDA rules for conditions of approval or does that have to go into the explanation for why the data have not been adequate and don't show safety?

CHAIRMAN WHALEN: Anyone, including of course FDA, correct me if I'm wrong, but what we're discussing and what we will shortly vote upon is that there be a condition that there be in vitro engineering testing.

Dr. Li has amplified for us some potential examples of what form that testing may take, but at the point in time when we come to vote upon that being a condition, we are being rather generic in what we are voting upon with only the specificity of the field of testing that would need to be done.

Dr. Blumenstein.

DR. BLUMENSTEIN: I have a question. There were conditions specified here, but I have additional conditions, but I have additional conditions that I would like to add.

CHAIRMAN WHALEN: And we will, indeed, get -- we're going to discuss each of the ones that have been stipulated as conditions, enlist further conditions, then vote upon each of those conditions, then vote upon the motion of approvable with those conditions that we have then approved.

Dr. Morykwas.

DR. MORYKWAS: Well, I'd like to add to that that a potential testing condition could be done. Instead of just 37 degrees saline, do it in serum or some other biological fluid in case you do get lipid incorporation. You get minor swelling of the device which may potentially alter some of the mechanical effects and just try and mimic the in vivo environment a little more in your testing.

CHAIRMAN WHALEN: And we can do that. The only response I would say to that is, as I just alluded to, we're going to be voting upon that there be further in vitro testing. If it's the pleasure of this committee that we get very specific in what that testing is, then by all means we'll do that.

But as first stipulated, we're being rather generic in specifying that there be further testing.

As regards the first potential condition of in vitro engineering testing, is there further discussion before we go to discuss any other conditions?

MS. DOMECUS: Yeah, I just wanted to clarify. I heard Dr. Li said it's pre-approval and Dr. Burkhardt say it's post approval. So I'm not sure what the condition is.

CHAIRMAN WHALEN: Dr. Burkhardt, since you had proposed that condition, did you propose it as post approval or pre-approval?

DR. BURKHARDT: I proposed it as post approval.

CHAIRMAN WHALEN: Dr. Li, do you agree with its being post approval or do you feel that this needs to be done before we can approve, which I would -- which I believe means we would not be then saying it's approvable with conditions if we're saying it's pre-approval.

DR. LI: Oh, I misunderstood. I thought approvable with conditions means we would approve it so long as they met the conditions.

MS. DOMECUS: Right.

DR. LI: And if they don't meet the conditions, then it's not approved. That's how I was interpreting. Is that --

CHAIRMAN WHALEN: Dr. Witten?

DR. WITTEN: Well, I think that's up to you to clarify in your recommendations because you can make the approval. You can make your recommendation about approval with conditions, that it's approval that some things be done before we go ahead and approve it or you can recommend that something be approved and recommend some post approval additional testing.

DR. BURKHARDT: The intent of the motion was to approve now and proceed with post approval studies.

CHAIRMAN WHALEN: With that actually having been what was proposed, do you wish to speak against that, Dr. Li, or are you agreeable to that?

DR. LI: If it's post approval, I withdraw my second.

CHAIRMAN WHALEN: Into the microphone.

DR. LI: Sorry. I misunderstood you to mean pre-approval in the sense that you would approve it before we would move on. So all of my conditions are that I would vote for approval so long as the conditions of testing are met, but not otherwise.

CHAIRMAN WHALEN: But would you --

DR. LI: So I would not approve it without those tests. Is that what you mean?

CHAIRMAN WHALEN: As Dr. Burkhardt has phrased it, we would recommend that the FDA find this approvable and then subsequently do these studies.

DR. LI: Can I ask, I guess, a procedural question? If we go that route and say it's approved first, and they do some subsequent testing, whatever that may be, and at the end of it, whatever time period, they go, "Oh, my gosh, this isn't what we should be doing," what is our course of action?

DR. WITTEN: Well, usually if you're recommending something post approval, it's to answer some focused questions. So I guess we'd have to see what that data showed, but in general it would be to answer a focused question.

DR. LI: In that case I would disagree then with Dr. Burkhardt's motion.

CHAIRMAN WHALEN: Very well. And withdraw your second?

DR. LI: And I withdraw my second.

CHAIRMAN WHALEN: Well, you withdraw the second of the motion as approvable with conditions?

DR. LI: No, his that it's approvable --

CHAIRMAN WHALEN: Yeah, we don't have to move and second each individual condition.

DR. LI: Okay, fine.

CHAIRMAN WHALEN: So the motion is still on the floor, and we're discussing this first condition.

MS. DOMECUS: I think there may be a semantics issue. Post approval means post FDA approval of the PMA application. It doesn't mean post panel approval today.

CHAIRMAN WHALEN: Correct. We don't approve anything. We only recommend.

MS. DOMECUS: Right, but I mean if you say approvable with conditions, those conditions can be met after today's panel approval, but before FDA approval of the PMA.

DR. BURKHARDT: May I comment?

CHAIRMAN WHALEN: Dr. Burkhardt.

DR. BURKHARDT: What I'm saying is I don't think we ought to take these things off the market pending these things, pending the new studies. I think we should leave them on the market at the present time and go ahead and proceed with the studies and reconsider if the studies do not turn out satisfactory.

MS. DOMECUS: But approval with conditions wouldn't take them off the market, would they? Would it?

DR. WITTEN: Well, I'm not sure. You all make a recommendation of approval with conditions, but then our action would be either to have them -- would be -- our action isn't approval with conditions. Our action is either approving it, possibly with some post approval conditions, or not approving it. So I guess, you know, it's sort of a difference between what you recommend and, you know, what we end up doing.

But we would either approve it with post approval conditions or we wouldn't approve it or we would try to do everything, you know, that you recommended within the allowed time. So, you know, that would be another option depending on how involved, you know, some of these things were.

CHAIRMAN WHALEN: Ms. Brinkman.

MS. BRINKMAN: I have a question that I don't understand. So how do you provide accountability then if you say we'll approve this with post approval conditions and the conditions are not met? So then what does the FDA do?

I don't understand. How then is the manufacturer accountable and what happens?

DR. WITTEN: Well, we work very hard with the sponsors, with them on their post approval studies. So I'd say, you know, there's accountability both on our end and on the sponsor's.

And I'll say that also I don't want to suggest to the panel what you do, but you may look at some of those specifics in the mechanical testing, and maybe differentiate those that really are pre-approval versus post approval.

I mean perhaps, you know, retrieval versus, you know, approving the ones that are tested or in other words, it may not be an all or nothing thing, some of what you're recommending. So you might look at it and say, "What do you think is really a post approval condition of what needs to be done pre-approval?"

I mean you might want to -- I don't want to tell the panel what to do, but you might want to look at the specifics of the suggestions.

CHAIRMAN WHALEN: Dr. Blumenstein and then Dr. Li.

DR. BLUMENSTEIN: I was just wondering if we could make it unspecified as to whether it's pre-approval or post approval and let that be the FDA's discretion.

DR. LI: I guess I don't mean to over complicate this, but I guess I was thinking the last panel I was on was a completely different device family, that there was a lot of additional testing we required of the sponsor, but the sponsor was not taken off the market during that time.

In other words, the FDA and the sponsor agreed on a set of tests and a time frame for which those tests should be completed, and during that time frame the company or the sponsor will still able to sell their device.

So I'm not saying you should stop selling their device until all of these tests are met was my intention.

DR. BURKHARDT: Would you like to reinstate your second?

CHAIRMAN WHALEN: Well, since we're dealing with an FDA issue, Dr. Witten.

DR. WITTEN: Yeah, I think we'd prefer to hear, you know, your recommendations about what needs to be done for approval of these products versus getting into a regular -- you know, have the panel get into a regulatory discussion about what the different terminology means.

I will just say in this case, as I mentioned in my background, we have a 180 day total time frame for review from the date on which the call for PMAs was issued, which was in August. So that by the end of that time, we will need to take a final action.

Having said that, I might say that, you know, you could perhaps want to tell us approval with conditions that some issues be addressed if you don't want to get specific and into some of the regulatory issues versus how we would handle some types of recommendations versus others.

Because I think what we really want to know from you is what you think needs to be addressed by this application, you know, rather than your regulatory assessment.

CHAIRMAN WHALEN: So if I may then, in line with what Dr. Blumenstein raised, we are now discussing the motion of approvable with conditions, the first condition of which we are now specifically discussion is that there be in vitro engineering testing.

Does anyone wish to speak further about that condition?

(No response.)

CHAIRMAN WHALEN: Seeing no one, Dr. Burkhardt, your second condition was, please?

DR. BURKHARDT: The second condition was that the comment regarding the shaped implant in the promotional material or the informational material, which technically is labeling, be revised. There is a strong implication that these implants will offer a more anatomical shape. Those are the words used, and there has been no evidence presented to support that.

CHAIRMAN WHALEN: Does anyone wish to speak to that condition?

(No response.)

CHAIRMAN WHALEN: Dr. Burkhardt, were there other conditions that you had raised?

DR. BURKHARDT: The third condition was that the company labeling, the sponsor labeling discourage periumbilical insertion.

CHAIRMAN WHALEN: Does anyone wish to speak further to that condition?

Ms. Dubler.

MS. DUBLER: I'm just distressed that if we get that particular that there might be other instructions for surgeons that would be equally important, and if we stipulate one particular one and don't do a total review of the other possible negative practices, that we will look like we have just merely identified one and approved all the others.

So that strategically makes me a bit uncomfortable.

DR. BURKHARDT: I am reluctant to put constraints on the surgeon as a rule, but here we have clear evidence that the deflation rate of these implants is increased by compression and by insertion through a small incision, and I think this is a reasonable restriction to recommend from the manufacturer.

If the surgeon wants to do it that way, they're going to do it anyway.

CHAIRMAN WHALEN: Further comment on that particular condition?

(No response.)

CHAIRMAN WHALEN: Dr. Burkhardt, were there any further conditions that you had?

DR. BURKHARDT: No.

CHAIRMAN WHALEN: Thank you.

Now, I'm sorry. Dr. Morykwas, did you have anything further?

DR. MORYKWAS: No.

CHAIRMAN WHALEN: Are there any of the panel members -- Dr. Chang.

DR. CHANG: In the data, one of the factors that also increased rate of rupture and failure of the implant was an incision smaller than three centimeters.

So I would offer a friendly amendment that if you stipulate a recommendation that the incision of insertion be greater than three centimeters, would that not take care of the practice of putting this through endoscopically or through a long tube?

CHAIRMAN WHALEN: Dr. Burkhardt?

DR. BURKHARDT: It would, but it would also preclude axillary and periareolar insertion, which are very commonly used, and I don't think we should do that.

CHAIRMAN WHALEN: Any further discussion as to that particular condition?

(No response.)

CHAIRMAN WHALEN: Are there any other conditions that any members of the panel wish to suggest?

Dr. Blumenstein.

DR. BLUMENSTEIN: I think we discussed collecting revision data before the indication of the revision data would be approved, although now that I'm reading this, I don't think that was -- I think just collect additional revision data.

CHAIRMAN WHALEN: Dr. Burkhardt?

DR. BLUMENSTEIN: Do we want to go one at a time?

CHAIRMAN WHALEN: In terms of additional conditions?

DR. BLUMENSTEIN: Yes.

CHAIRMAN WHALEN: If anyone wishes to address collection of revision data as an additional condition.

DR. BURKHARDT: I don't understand what you mean.

DR. BLUMENSTEIN: We talked about how the sample size for data on revision was small and that additional revision data would be helpful.

DR. BURKHARDT: I would accept that amendment.

CHAIRMAN WHALEN: Anyone else wish to address that condition, imposition of the necessity of the collection for revision or, quote, indication data?

(No response.)

CHAIRMAN WHALEN: Do you have something further, Dr. Blumenstein?

DR. BLUMENSTEIN: Yes. That the risk estimates either be done using true cumulative incidence methodology or that the risk estimates be appropriately labeled as to their conditional nature, as conditional probability estimates.

DR. BURKHARDT: I would accept that.

CHAIRMAN WHALEN: Does anyone wish to discuss that condition further?

(No response.)

CHAIRMAN WHALEN: Are there any further conditions?

DR. BLUMENSTEIN: Redo the analyses showing a demonstration of the potential for informative censoring of missing data related to dropouts affecting biasing the results.

CHAIRMAN WHALEN: I'm sorry. Can you elucidate that a little further for me again?

DR. BLUMENSTEIN: That analyses be done in which the characteristics of the patients dropping out be documented.

CHAIRMAN WHALEN: Does anyone wish to discuss that?

DR. BURKHARDT: I don't understand how you'd do that.

DR. BLUMENSTEIN: You can take the baseline data, for example, age, and compare the age of the women who have follow-up data with the age of women who do not have follow-up data. This is a very simple example, and then you can do that for almost all of the baseline characteristics that one has.

DR. BURKHARDT: I understand that for age. I don't understand how you're going to collect complication data on people who don't return for follow-up.

DR. BLUMENSTEIN: No, we're not collecting complication data. We're collecting for patients who have an assessment at 12 months for a particular complication, and for the patients who do not have an assessment at 12 months for a particular complication. then you can compare their characteristics at baseline.

DR. BURKHARDT: I will accept that, assuming that the other statisticians understand it.

(Laughter.)

DR. BLUMENSTEIN: the other statistician is nodding yes.

(Laughter.)

CHAIRMAN WHALEN: The question has been raised on this last point that you raise do you wish this for the labeling.

DR. BLUMENSTEIN: Yes.

CHAIRMAN WHALEN: Okay.

DR. BLUMENSTEIN: In other words, that the labeling data be published in a way that would be consistent with publication in a peer reviewed journal. That's certainly what I'm getting to.

CHAIRMAN WHALEN: Okay. Any further conditions?

(No response.)

CHAIRMAN WHALEN: You still have the floor, Dr. Blumenstein. Is that all of yours?

DR. BLUMENSTEIN: I think I know what she's going to say.

(Laughter.)

DR. BLUMENSTEIN: I think that we also mentioned about long term follow-up data with specific attention to those patients, again, who are part of an informative -- potentially part of an informative censoring pattern.

CHAIRMAN WHALEN: Any discussion of that?

Dr. Blumenstein, would you like to take the next one? Why don't you complete whatever you need to do?

DR. BLUMENSTEIN: Well, I was going to -- this was a point that Karen raised earlier about the analyses of particularly the quality of life data being labeled in such a way that it's clear that patients who have had a revision prior to the time point in which the analysis is being done are not included in that analysis.

CHAIRMAN WHALEN: Any further discussion of that?

(No response.)

DR. BLUMENSTEIN: I'm done.

CHAIRMAN WHALEN: Karen.

DR. BANDEEN-ROCHE: I don't know how appropriate this is, but I wonder whether we could state as a formal condition that the sponsor and FDA work on a specific protocol to guarantee reasonable assurance that patients are accurately and fully informed.

And I do this meaning this in more than sort of the generic you write out a label and people have the opportunity to see the label. You know, it's not enough to leave a procure on a table. It's not reasonable to track people down and interview them in their homes, but there's got to be something in between that meets a standard of reasonable assurance of accurate and complete information.

CHAIRMAN WHALEN: Any discussion as to that condition?

(No response.)

CHAIRMAN WHALEN: Are there any other conditions?

(No response.)

CHAIRMAN WHALEN: Seeing none, we are here listed with ten potential conditions, and we will vote on each of the ten individually before we then vote on the motion. I will try to key word these conditions so that we can each vote on them.

I would remind that there are two non-voting members of the panel. So please don't vote.

Ms. Brinkman?

MS. BRINKMAN: I got a bit lost on the discussion. Did you ask for long term study to be included in the --

CHAIRMAN WHALEN: That was number eight.

MS. BRINKMAN: Thank you.

DR. BURKHARDT: Mr. Chairman, in regard to the ten conditions, would it be reasonable to ask first if anyone objects to any one of those conditions and then maybe vote on the whole bunch at one?

DR. WITTEN: That's up to you.

CHAIRMAN WHALEN: There are vigorous nods from the FDA contingent.

(Laughter.)

CHAIRMAN WHALEN: So thank you for that excellent suggestion.

Among these ten conditions, is there anyone who is going to be voting negatively against on any of them?

(No response.)

CHAIRMAN WHALEN: Seeing none, just to make it formal, as regards these ten conditions, all those who are voting members who are in favor, please signify approval by raising your hand.

(Show of hands.)

CHAIRMAN WHALEN: And all ten conditions are, indeed, unanimously approved.

Thank you.

We now go to the motion, which is that we recommend to FDA that the PMA be approvable with the ten conditions we have just approved. Would all those who are in favor of that motion signify by raising their hand?

(Show of hands.)

CHAIRMAN WHALEN: All those that are opposed?

(Show of hands.)

CHAIRMAN WHALEN: For the record then, since it is not a unanimous vote, opposed to that motion is Ms. Dubler, and therefore, approving that motion are Dr. Li, Dr. Blumenstein, Dr. Boykin, Dr. Bandeen-Roche, Dr. Burkhardt, Dr. Chang, Dr. --

DR. MORYKWAS: Morykwas.

CHAIRMAN WHALEN: It's been a long day.

-- and Dr. Robinson, and the two non-voting members have not voted.

DR. WITTEN: Dr. Whalen, you know you're going to have to go around and ask everybody --

CHAIRMAN WHALEN: I know, but I had to first read that in for the record.

DR. WITTEN: Okay.

CHAIRMAN WHALEN: Well, I've just been requested something to do that I can't do, and that is to read each of those conditions again into the record because all I did was write down key words. So if that's an obstruction, I'm sorry, but I can't fulfill it.

DR. WITTEN: Just read the key words. Can you read the key words?

CHAIRMAN WHALEN: The key -- I'll be happy to read the key words.

DR. WITTEN: Read the key words. We can get the rest from the transcript.

CHAIRMAN WHALEN: The key words of each of those ten conditions are:

In vitro engineering testing;

That the shape of the implant in the present labeling be revised from its present labeling as "more anatomic";

That the sponsor labeling discourage the use of the umbilical distant incision;

That there be accumulation of revision data;

That there be risk estimates;

That the present data be reanalyzed as to the characteristics of those patients dropping out as it pertains to labeling;

That there be accumulation of long term follow-up data;

That there be labeling which concerns itself upon those findings regarding quality of life data that has been accumulated;

And that the sponsor and the FDA work together to attempt to maximize the benefit of an accurate and fully informed consent process.

DR. WITTEN: Well, now, that's nine conditions.

CHAIRMAN WHALEN: That's because when I went to page 2 I dropped off seven. There were nine conditions.

DR. WITTEN: Okay.

CHAIRMAN WHALEN: Now, we're not done. As is our directive, we must go around the table and ask that each of the members comment upon why they voted as they did, and we will start with Dr. Li.

DR. LI: It seems quite redundant somehow, but one more time, the instruction?

CHAIRMAN WHALEN: The instruction is that you indicate to us why you voted as you did, and that is to vote for approval, approvable with the conditions as stipulated.

DR. LI: Okay. I think we have the usual case of a device which has been around a long time and has been quite effective to a large number of patient populations and has been, at least for the majority of cases, been beneficial.

I think the approval should be with conditions, however, because I think unfortunately the mechanical in vitro characterization and testing lags quite a bit behind the clinical experience, and that the testing is incomplete versus the current product line, both in terms of materials and manufacturing methods, and there is a rather large -- actually it's a disconnect between the data generated and the ability to use that data to predict or assure a certain level of clinical performance.

But I believe that gap could be at least closed or made much smaller with more complete testing and perhaps modifications of their current testing.

CHAIRMAN WHALEN: Thank you.

Dr. Blumenstein.

DR. BLUMENSTEIN: I voted yes because i feel like that there is efficacy here, and that with the conditions, there will be a movement towards a nearly adequate characterization of risk that the potential patient would be able to understand.

CHAIRMAN WHALEN: Thank you.

Dr. Boykin.

DR. BOYKIN: I agree that we have a significant level of comfort about the efficacy of the product and its reasonable safety, and that the conditions of approval, I think, reasonably reflect the deficiencies which I think can be worked through quite easily.

CHAIRMAN WHALEN: Thank you.

Dr. Bandeen-Roche.

DR. BANDEEN-ROCHE: I found the whole issue of safety and effectiveness and risk and benefit very complicated per my previous comments. I voted for approvable with conditions because I came to the conclusion that at this point the best resolution is not for me to decide on risk and benefit.

But to leave the device on the market and leave the adjudication of risk and benefit up to the individual patient, the condition being that the patient be very, very fully informed.

And I would also state that I believe that FDA has maybe more than the usual responsibility here to very vigilantly keep up with ongoing developments, as indeed we all do as scientists, and to investigate opportunities to target people with particular risk for adverse outcomes.

CHAIRMAN WHALEN: Thank you.

Dr. Burkhardt.

DR. BURKHARDT: I think the evidence clearly supports maintaining the availability of these devices; that it would be wrong to take them off the market at this time; but there are some additional housekeeping items that need to be attended to and approvable conditions was the best way to handle this.

CHAIRMAN WHALEN: Thank you.

Dr. Chang.

DR. CHANG: I think the information provided by the PMA shows that there is relative safety. There's a more clear demonstration of efficacy, and I believe the previous discussions that we have and approval conditions can be met and worked between the FDA and the sponsor.

CHAIRMAN WHALEN: Thank you.

Dr. Morykwas.

DR. MORYKWAS: Also be that the efficacy has been met and reasonable safety has been approved or has been proven, with the conditions that we have stipulated.

CHAIRMAN WHALEN: Thank you.

The anticipation is killing us. Ms. Dubler.

MS. DUBLER: It always makes me anxious to find myself odd person out, but I think, in fact, that the analysis of the data, especially as provided by Drs. Li and Blumenstein, seem to indicate that the tests that had been done that would permit patient to assess risk and benefit, the data are not there.

My question earlier went to the issue of whether there was some way to leave these on the market pending the gathering of adequate data, and the answer appeared to be no.

I don't know how to make this choice because if there were other alternatives that women could use, I would be extremely comfortable with my vote.

However, I think that given the deflation rate and the leakage rate and the very clear explanations of why the test did not, in fact, gather the sorts of data that would permit us to understand these variables, I felt I couldn't vote for the reasonable safety.

CHAIRMAN WHALEN: Thank you.

Dr. Robinson.

DR. ROBINSON: Continued access to these devices are very important for a lot of patients, and I think the PMA shows me they're effective and they're reasonably safe, and I supported the conditions, although the first one luke warmly because I strongly believe that expansive ex vivo new testing probably will not provide additional significant information, but I suppose we can try one more time.

CHAIRMAN WHALEN: Thank you.

The recommendation of the panel is that the pre-market approval application for saline filled breast prostheses from Mentor Corporation be recommended as approvable with the stipulated conditions.

We have, therefore, completed the first day's activities, and I feel very much like Bill Murray in the movie Groundhog Day when I say, "We will meet here again tomorrow morning at 8:00 a.m."

DR. WITTEN: I'd like to thank our hungry panel for bearing with us and the sponsor and the public today, as well.

(Whereupon, at 9:21 p.m., the meeting was adjourned, to reconvene at 8:00 a.m., Thursday, March 2, 2000.)

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OFFICIAL (VOTING MEMBERS) PANEL DISCUSSION
& RECOMMENDATIONS