Historical Interviews
 

These remarks, by persons involved with the silicone breast implant controversy, reflect only a sample of the strong emotions aroused by the episode. This month the entire issue of the new Epi Monitor is devoted to an interview with scientists involved with the silicone breast implant controversy at Dow Corning. This topic has been in the news throughout 1992 because of questions raised about the safety of this medical device which has been on the market for about 30 years. The reported lack of satisfactory safety data has outraged many citizens and scientists, and many have found it difficult to understand how we could have come to be in the situation we now face with this product.

Since Dow Corning employs epidemiologists, and most recently hired well-known epidemiologist Ralph Cook from Dow Chemical, the Epi Monitor interviewed Dr. Cook and his colleagues to get their perspective on the controversy and how and why it developed. Included in the interview were Robert LeVier, PhD, Technical Director for the Health Care Business, who has been at Dow Corning for 20 years and Myron Harrison, MD, the Corporate Medical Director, who just joined the company. Most recently, Dow Coming has withdrawn from the market, and the FDA has banned the use of the implants except in special studies. We trust readers will find this interview fascinating and will come away better prepared to deal with similar challenges in their specialty areas if and when they arise.

Epi Monitor: What is the key piece of information or the key database that the company is or was relying on to assert that breast implants have been safe?

LeVier: The answer is ordinarily quite long, but I’ll try to compress it the best I can. Dow Corning has something like 10,000 safety studies of silicone of which 329 were included in the Pre-market Approval Application (PMAA) as having direct and strong relevance to the safety of the material that was used in the breast implant. Those studies really show three events that are noteworthy. One is that there is always a foreign body reaction to these materials, just as there are to all known medical materials like polyethylene and metals and so on. By foreign body reaction I mean there is an acute inflammatory stage followed by a chronic inflammatory state that transitions over a few weeks or months to the formation of a scar or capsule around the implant. All materials do this. The second event is that, at least in rodents in life-time studies, sarcomas are generated at the implantation site immediately around and adjacent to the implanted material. That’s been known since 1941, for all materials that have been tested. Finding it for silicone was not a new event, and in fact, the FDA recognized upon reviewing our data that that was the case. Thirdly, is the absence of something. That is, there is an absence of systemic toxicity across a very broad range of studies and through several species. So overall when we looked at those 329 studies, our conclusion on the basis of laboratory work is that silicone is like other synthetic materials. They are not truly and absolutely inert—the body does recognize them as foreign and responds to them as I’ve just indicated.

Excuse me, I missed one point. We also have evidence that very small amounts of mobile components of implants distribute in the body; for example, polydimethyl siloxane goes where you would expect it to go, namely to the reticulo-endothelial system, as is the case for polystyrene microspheres and carbon particles and other things. Those are the laboratory data. The other supporting evidence comes really from the medical literature. There are case reports of adverse effects like infection and contracture and hematoma, and of course, some apparent rheumatic disease. All these reports taken together in our opinion indicate that the incidence of adverse effects is largely known, and is not particularly unexpected in most cases...

Epi Monitor: Can I interrupt you there...You say taken together they suggest the incidence is low?

LeVier: For example, let’s take infection. The incidence of infection is down around the one to three percent range, virtually like what you would expect from other procedures in hospitals. The rate of contracture is higher than any of us would like, but it is known and surgeons know what that rate is and what the corrective measures are. The data in the literature provides no evidence whatsoever that these implants, for example, cause breast cancer. I would cite the Deapen-Brody Study as reasonable evidence that there’s not an excess of breast cancer. The most contentious area is the rheumatic disease issue. But I would point out that since 1964, the Miyoshi paper from Japan, there are about 50 or so case reports of women with silicone breast implants analyzed with rheumatic disease. Over a 28 year period that would not strike us as necessarily different than a normal background.

Epi Monitor: If I’m following the thrust of your answer here, it’s a little different than the question I asked in the sense that you’re really answering what is the basis for the company’s assertion that the devices are safe. You’re going over two major categories of evidence—329 lab studies and case reports from the literature which you interpret as reassuring overall. Is that right?

LeVier: I think those are the major ones. But I could add that our understanding of the chemistry of the materials is also instructive and has bearing on expectations for biological activity. Just to cite one example, the chemistry used here is inherently not pyrogenic. If there should be pyrogenicity as an issue, it would undoubtedly come from a non-silicone source, such as bacterial contamination during manufacturing or surgery, or something like that. You indicate that I’m not quite answering your question...

Epi Monitor: What I wanted to get at was, can you point to one or two or three studies as the most key pieces of evidence for the assertion that the implants are safe? In other words, what does the assertion ultimately hang on? Maybe you feel it hangs on too many things to be able to say that two or three are very key. That’s what I was trying to get at.

LeVier: Well, I think the latter is absolutely the case. The full body of evidence provides a spectrum of information that is most valuable here, but let me try to respond to your question, nonetheless, in the way in which you’ve posed it. If I think about pivotal studies, I would think of a group of six studies we did on the effects of silicone on the immune system—well done, GLP (Good Laboratory Practices) controlled, essentially state-of-the-art studies—that conform in every way to what the National Toxicology Program protocols would expect to be done.

Epi Monitor: These are laboratory studies?

LeVier: Yes, they are. Secondly, trying to stay with the spirit of your question, I would cite a set of two studies. Our own animal studies showing sarcomas, coupled with the Deapen-Brody Studies showing an absence of apparent translation to humans.

Epi Monitor: An article I read quoted one of your company’s consultants who said that there were five key studies—that the crux of the company’s case was based on doctors’ records of about 1,000 patients showing five percent with complications, and less than one percent with serious complications. These studies apparently were of records not of women per se. So I wondered, in your own opinion, what were the key studies, what was the crux of the matter from your point of view, and I think that’s what you're answering now.

LeVier: You bring up a good point. We do have clinical studies, a total of five, as I recall that add up to a bit over 1,000 women. What I’m not including are three studies that are still underway. And that body of 1,000 plus women is pivotal and instructive, and it is important in regards to characterizing complications. I suppose in my own mind, I didn’t list that as core, simply because there are so many studies in the literature that are fundamentally supportive of that conclusion, as well as the studies done by other manufacturers. It is important but there are many other studies that come to bear on it.

Epi Monitor: There are sometimes many studies, but for a variety of reasons, they’re not done optimally and when something is considered to be established, people often say, “well, it’s the Smith Study, or it’s the Jones Study that really nailed this down,” either because it was the largest study, or because it looked at the most important variables or it had the best control group, whatever. When they have to go back and say “what really established it?”, “what really proved it?” they always fall back on that particular study. I was looking to see if, in the mind of the company scientists, there was a key study. If there is, I think it would be interesting and important to get that out.

Cook: But aren’t you discussing the other side of the coin, the key study that showed lack of cause and effect? I think when you’re talking about lack of cause and effect, you’re in that sort of catch-22 in that you can’t prove a negative in a sense, but you’re looking at the preponderance of data. And I think that’s really what Bob is saying, that if you look at the preponderance of data and the consistency and the coherence of the data, it seems to lead us in the direction that these are safe materials.

Epi Monitor: You can have a key negative study just as well as a key positive study...

LeVier: In regards to the cancer issue, I think we could fairly categorize the Deapen-Brody Study as pivotal at this point, although additional studies are underway and still other ones will be done.

Epi Monitor: Is this the one that was done in California?

LeVier: Yes. First reported, I think in ’86 and followed up every five years. They just published their most recent update in the April Journal of Plastic and Reconstructive Surgery.

Epi Monitor: What are the most outstanding gaps or the greatest weaknesses in the available information that we do have?

Cook: From my perspective, I think there is an issue having to do with immunological/connective tissue and that seems to be focusing on systemic scleroderma. That’s one of the reasons we moved ahead the University of Michigan study under David Schottenfeld to really address that issue.

The difficulty in these issues is that the concerns and/or allegations can come fairly rapidly, but the research can take three to five years. I think there is an anticipation gap between what the public expects—they almost expect push-button epidemiology—and what the reality of the discipline is, the data collection, all the logistical problems, the analyses, development of the protocol, etc. So, I’m not sure I view it as a weakness in this sense, but rather what is the next level of investigation that needs to be done, and that’s the scleroderma case-control study.

Epi Monitor: How long has this suspicion been around?

Cook: I don’t really view it as Shazam! We now have a suspicion. What you’re talking about is you get a case report of a particular type of disease. Is that first case report the initiation of the suspicion? Probably not. And then you start looking at a pattern of case reports, or somebody does, and this whole issue, if you will, of passive post-marketing surveillance, and the tide sort of rises. And I think in this particular issue, it was exacerbated by some of the publicity about some of the process, and so I think a lot of people’s attitude, even about the scleroderma is that— “gee, there’s not a lot of evidence for it,” —but if it’s anything, that’s probably the one that should be investigated.

Epi Monitor: Based on some kind of theoretical considerations more than what’s been reported in the case reports?

Cook: No, based more on the fact that if you look at the case reports, that’s where the case reports seem to be clustering. But even there you’re talking about maybe a half a dozen to a dozen case reports in the literature having to do with scleroderma. Now, I would pose the question back to you: In say a million women, would a dozen case reports of any particular type of outcome be suspicious? I think what you have to do is you have to start looking at that total picture.

Epi monitor: Well, this is one of the big issues that has been part of this controversy all along. It seems like we don’t have a clear definition for what is a trigger. And the company, it appears, has not felt that the threshold or the trigger had been reached for investigating some of these allegations, or case reports. When the publicity began about the breast implants, it made it seem like the trigger or the threshold had been reached a long time ago, and that the company was lax in not addressing some of these conditions sooner. And exactly where the trigger is, is ultimately a matter of judgement because it is not clearly defined. So I was just trying to get a sense about how long-standing the suspicion about scleroderma has been around, not necessarily the date of the first case report, but how long has there been an expectation that this should be investigated?

Cook: Aside from what I’ve already said, I’m not sure how to answer that. We certainly have been looking at the issue of protocols. The company put out an RFP about two years ago, and the studies were initiated some time in 1991. So I think if you go back in the literature you can look at some of this having surfaced years ago perhaps in Japan, but when you start looking at that you find that— “jeez, this wasn’t even silicone, it was injections of paraffin” —or it was injections of silicone that were purposely mixed with something else to get the capsule and so what we’re viewing now as a complication was, in fact, viewed in years past as a laudable event, because it was part of the process of the use of the silicone. So public expectations have changed over time, and I think, quite frankly, that’s driven part of this too.

Epi Monitor: In your opinion, from the company’s point of view, have all serious, suspected consequences been investigated in a timely fashion?

Cook: I think you’re putting some qualifiers in there, from the point of view of “all” and “serious” and “timely.” I see us moving forward and we have a research agenda in place. In one of your previous issues, Mary Ann Woodbury laid out some of the things with the NYU study, and with the University of Michigan study—we’re very aggressively now looking at a variety of databases to see whether or not there are some secondary data analyses that can be brought to bear to address this issue. So in the sense of could it have gone faster? I suppose so. Is it unreasonable? My estimation having been here this period of time is probably not. The timing is not unreasonable.

Epi Monitor: Were there ever any epidemiological studies that the company sponsored, either cohort or case control studies, to look at some of these safety issues?

LeVier: Certainly the cancer issue, we are a sponsor of the Deapen-Brody work. We have not co-sponsored epidemiologic studies of rheumatic disease, until the one we now have going for about 10 months for all the reasons that Ralph just pointed out.

Epi Monitor: So the major, if not the only, epidemiologic study has been this one by Brody that you referred to for cancer.

Cook: I don’t mean to be nit-picking on all of this, but what constitutes an epidemiological study? If what you’re talking about is clinical investigations, the company has been involved in a number of clinical investigations over a number of years.

Epi Monitor: I would define it pretty narrowly to mean...

Cook: In a more purist sense from the point of view of cohort, case-control, or ones that address statistical power—that type of thing?

Epi Monitor: Yes. That’s what I mean. The only one like that is the Brody one, right.

LeVier: Dow Corning also encouraged participation, financially only, in the Calgary study by Dr. Birdsel, which is also a cancer study. [to be published]

Epi Monitor: If you’ve identified the questions around scleroderma as the most important unanswered questions, and the University of Michigan study is designed to address that, are there others? If so, can you say where they are, or what type of studies they are?

Cook: One of the other things that’s happening with the NYU study is that we will also be looking at a variety of other outcomes besides cancer. Obviously the NCI is doing some work also. They’re going to be looking at a cohort of about 12,000, so all of those are also going to bear on this whole issue.

Epi Monitor: Just by way of summary...the key epidemiologic studies of the major unanswered questions involve Michigan, NYU and the NCI study?

Cook: We’re working with another group up in Cambridge, Abt Associates—what we’re calling the complications study. Now, I would anticipate that there are a variety of other groups that are also going to be looking at this, like NCI, the Canadian government, maybe other groups...I know that some of the people up at Mayo have certainly surfaced on this issue, and whether they intend to do something further, I don’t know.

Epi Monitor: What about the other two manufacturers. Are they involved, do you know?

Cook: Yes. They are co-sponsors on some of the work that we are doing. We also are seeking opportunities to identify databases whereby we might be doing some secondary data analysis. This interview is in a sense an REP, because if some of the readers are particularly interested or have some suggestions we’d be very happy to hear from them.

Epi Monitor: Well, we can make a point of that. Let’s be clear then. What is it that you’d like to bring to people’s attention? That you’re looking for databases that people know of that might be suitable for secondary analyses for either immune system or cancer-type outcomes?

Cook: Immune system or cancer-type outcomes that might bear on the issue of silicone.

LeVier: Before we leave this, let me add that while all this work at the clinical level is going on, we also have studies underway and we’ll do additional studies at the laboratory-level on both the cancer and immune issues to test hypotheses. To test for the apparent plausibility of various mechanisms that have been proposed. That work will be going on for some years to come.

Epi Monitor: To some extent, the level of activity you describe could be viewed as rather high for a company that has withdrawn from the market. I know the company has said that it would continue to investigate this, so I would like you to just take a minute to describe how you see the future, how long you see the company in this, how much money and staff are really going to be devoted to this, and for how long...Just so readers can get an idea of what role the company will be playing even after it has withdrawn this product.

Cook: To answer your questions in turn, long, lots and lots...

Epi Monitor: Long time, lots and lots of money?

Cook: Long time, lots and lots of money and lots and lots of personnel time.

Epi Monitor: When you said “lots and lots of money” were you talking about possibly more than the $10 million the company has set aside?

LeVier: I think the position is that we’ve set aside $10 million, and if we need more than that, it will be made available.

Cook: That $10 million is $10 million for research. I think it is probably a very conservative estimate of what the company has committed to spend as far as expanding the scientific database in this whole process.

Epi Monitor: Do you see yourself using some of that $10 million to start up other studies in the future, similar say to Michigan or WU, or do you see it more perhaps to expand those studies?

Cook: Let me put it this way. This morning, Bob, Myron and I sat down and we started going through 87 proposals that we currently have. And we’re anticipating that we will be receiving more. If we’re not going to consider additional research, we would not be going through those proposals.

Epi Monitor: Is that in response to a specific RFP or because of publicity? Are these epidemiologic studies or what?

Cook: No, they’re not all epidemiologic studies. They cover the gamut. We’re trying to go through there and see what are the questions that we view as important, what are the questions that others are viewing as important, and we’re not in this alone. As you probably know, the Public Health Service under Dr. Mason has convened a breast implant task force to look at the research needs.

Epi Monitor: I wasn’t aware of that. That’s interesting. Who’s chairman of that?

Cook: There are actually two co-chairs: Dr. Adamson, from the NCI and Dr. Henney from the FDA.

Epi Monitor: Have they gotten off the ground yet?

Cook: Oh, yes, they’ve had a series of meetings.

LeVier: We are also receiving proposals directly that are unsolicited.

Cook: Yes, I just got a telephone call today from somebody on the west coast.

Epi Monitor: Are you encouraging that?

Cook: Personally, I would like to encourage it—but with some trepidation. But I think if people have good ideas, we certainly would like to hear from them. We are actively soliciting the opportunity to identify databases that we might use for secondary data analysis. Our orientation there is to see whether or not we can interest the primary investigator into moving this type of analysis high on their agenda. Or, if not, whether they would be willing to make the database available to some other party. The idea would be to try to promote a marriage between the primary investigator and the person doing the analysis, perhaps to the extent of funding some of those analyses, or whether some of these databases might be made available to us, and we could do the analyses in-house. So we’re looking at a variety of different options. We’re open to suggestions.

Epi Monitor: About the registry—there’s been a lot of talk about that in the media, and I’d just like to clarify what is going to happen. How is that expected to work?

Cook: My sense is that you’re probably going to see sometime in the future at least two types of registries. One is going to be a retrospective registry. The other one is going to be a series of prospective registries. The prospective registries obviously are going to be associated with continued implanting of these devices and therefore they would be largely driven by the two companies that are currently still in the business, Mentor and McGhan. The retrospective registry—some of those discussions are really focusing back on what are the ultimate objectives for this type of registry because I think everybody realizes that we had better be very clear on our objective going into both the retrospective and the prospective registry.

Epi Monitor: Do you expect that there will be RFPs for those registries, or how will that work? Is this something epidemiologists might anticipate bidding on in the future or how do you see that playing out?

Cook: I can’t speak for Mentor and McGhan, I would have to punt back to them.

Epi Monitor: What about your retrospective registries? Would that be something you might contract with a group to do?

Cook: I think that’s in the process of discussion right now. Certainly the idea of perhaps using a contract group has been discussed, there’s a lot of advantages to it.

Epi Monitor: Ralph, can you comment on how long you expect to be involved with these activities at Dow Corning? Has that been fixed in time? I think some of the readers who know you might be curious to know how long you might be expected to be involved with this work.

Cook: Well, I am a full-time Dow Corning employee. I anticipate this is my full-time job for the foreseeable future. I hope sometime in the not too distant future to retire, my hair is greying fast. Some of that has to do with age, some of that has to do with issues, but I would anticipate that I’m going to be involved in Dow Corning both from the point of view of this issue, and quite frankly, I’m in the process now of figuring out ways that we’re going to be implementing a comprehensive occupational epidemiology program within the company to augment some of the things that have already been done in the past by Mary Ann Woodbury and some of the other people that have worked here. So, I’m going to be involved in a variety of different issues.

Epi Monitor: From the point of view of the scientists or the epidemiologists that have been at Dow Corning and have gone through this episode—I’d like to hear what you would candidly offer as lessons learned. What comments would you care to make to other epidemiologists or scientists who are now working for other companies and who will be in the news in six months or 12 months from now? Would anyone like to take a crack at that?

LeVier: I’ll try to say something about it. Some of the lessons are almost obvious and they’re very simple but they’re worth repeating. One of the things that I think has been hard for us to learn has been to speak plain English on every occasion—that we have to make sure that surgeons, other physicians, consumers are communicated to by us in simple, plain English. I think we’ve been, as so many scientists will be, a little bit obtuse from time to time. Secondly, I think that a scientist, like myself, can look at issues that arise and say comfortably to himself, “Oh, that’s not biologically plausible, so I’m not going to think about it.” I have found for myself that’s a mistake. You have to take all these issues that arise seriously in the beginning and not conclude so quickly that just because it’s not biologically plausible that you don’t have to worry about it. You do have to worry about it. So, that’s a big lesson. And thirdly, I suppose is to put our own materials in context at all points in time with all the materials that are out there. Not to study just our own. Because one of the peculiar things that happens here is we’ve got a huge amount of data on silicone. There’s a lot less on other materials and that provides a certain opportunity for questioning and having issues arise with this material that I think are undoubtedly relevant to all materials. Maybe I’ll stop there, but as a scientist, those are some of the issues.

Cook: There’s a couple that come to my mind. One is the techniques in post-marketing surveillance have to be looked at and perhaps the whole science of post-marketing surveillance is overdue for further development. That’s one area. I think the other issue that I see, and that we’ve talked about in the past, is the importance of industrial scientists publishing their work. Because I think there is an important check and balance that’s involved in that whole process. You know, obviously we’re getting very aggressive at this stage at doing a lot of work and putting a lot of work out into the literature hopefully as fast as we can. So I think that’s another point that I think epidemiologists and industrial epidemiologists have to think about.

Epi Monitor: So you say perhaps the company in the past has done work that was not in the literature, that could have been, or should have been?

Cook: Well, I mean we have 10,000 studies, as Bob said. And we have considerably less than 10,000 publications. And I think that one of the problems that we’re dealing with in this particular issue is a lot of vague allegations and concerns. When our scientists look at the body of evidence that’s available, in totality, it doesn’t seem to support that, and yet I’m sympathetic perhaps to people on the outside who don't have access to that same body of evidence because it’s not readily available in the peer reviewed literature. In fact, even the 300+ studies that are in the PMAA, for example, I would suspect many people would not have ready access to that. So there’s an issue of access there that I think we need to take a longer, harder look at.

Epi Monitor: I’d like to use a quote to introduce the next question. It is from Noel Rose from Johns Hopkins who said “I just don’t have a good feel for why we are left 20 years on, still saying we are sorry, we wish these things would have been looked at 20 years ago.” I think it’s an interesting question that a lot of us have who read about this. How is it that we came to be in this situation now?

LeVier: Keep in mind that more studies have been done on silicone than any other synthetic material ever to my knowledge, and by the very fact of doing that gives the opportunity to raise questions that wouldn’t even exist in anyone’s mind for the other materials that have not been looked at. That’s an important point. The second point is that for a number of societal and regulatory reasons, regulatory expectations change at a very rapid rate. We fully expect to honor that, conform to that, with our present and future products in every way. But I think it’s a little bit ludicrous to point at us or at any other company as somehow being at fault for a regulatory environment that didn’t even exist; it’s all really quite new in many ways.

Epi Monitor: You’re raising the issue that the regulatory environment changes and sometimes at a very rapid rate, and so...

LeVier: Now I am not trying to give the FDA itself a really bad time. Consider that the FDA is under extreme pressures to deal with all manner of claims and charges in the evolving societal expectations, I think they’re doing the very best they can to deal with this. But the public debate has put most of the weight for dealing with the change on us. And I don’t think that’s right or wrong, it just doesn’t answer it. I think there are other players here, such as the agency.

Cook: In my mind, what you’re doing is getting some really rapid shifts in societal expectations. I think that we are doing our best to adapt to those, to anticipate those, to put into play processes and programs that will adequately address those, but the questions can come faster than the answers just because of the nature of the process.

Epi Monitor: One explanation given for this situation is that no clear standard had to be met. This was best expressed to me in a quote from Alan Magazine, and he put it this way: “It is as if they said they will penalize you if you don’t obey the speed limit, but then they don’t tell you what the speed limit is.” So, there was no clear standard that had to be met. Do you agree or disagree?

LeVier: I’ll agree with that because the FDA had no power to regulate devices before 1976, and reacted as quickly as they could. They virtually didn’t have regulations until 1978. So there was a very long period of time when certainly reasonable people could disagree about what standards ought to be met.

Epi Monitor: I’m not sure I get your answer. In other words, if there were regulations by 1978, then isn’t that saying that there was a standard as of ’78?

LeVier: There was an evolving standard which was quite rudimentary at the time and we and other companies conformed to those standards and they’ve evolved since then. As I said earlier, they’re changing at an incredible rate. Remember this product was first sold in 1963 or 64, and there simply were no regulations at that time.

Epi Monitor: So the standard that you’re trying to conform to now has been the standard since when?

LeVier: I’m hesitating on that because, as the agency deals with this very difficult situation, where there are political pressures and societal pressures and so on, the apparent regulatory requirement is changing literally by the month.

Cook: For example, it’s unclear to us as to whether or not a retrospective registry is in fact mandated by regulation. But nonetheless, we’re spending a fair amount of time on trying to figure out how we would go about implementing a retrospective registry, what the objectives are, how the logistics would work, etc, and yet maybe a year, two years, five years down the line, retrospective registries may be required by regulations. Now, what’s the starting point on that one?

LeVier: In addition, I’ve just been reminded that the 515 (b) (a regulation for the device industry) which defined the requirements for breast implants appeared in final form in April 1991.

Epi Monitor: The second explanation I’ve read about, which is what I think we’ve been saying is: there has been a clear standard, but this standard was changed and made more rigorous recently. I suppose that’s what you’ve been saying, it’s been evolving and being made more rigorous.

LeVier: Well, I think we would agree with that, although I would offer a caution. I wouldn’t want you to think that we think there is some sort of capriciousness or unilateral behavior on the part of the agency. They are faced with a Herculean task.

Epi Monitor: The third explanation I have is also related to this: There has been a clear standard, but no clear timetable by which the standard had to be met. I guess you would disagree with that because you would say that a timetable is not so much the issue, it’s more the issue of an unclear standard, or a changing standard.

LeVier: Yes, I’d agree with the timing issue, but I think it’s really a little subpart of the previous item that you cited.

Epi Monitor: The fourth point that was brought up was: additional studies were considered by the company as being too expensive, therefore you didn’t do them for that reason.

LeVier: Well, I don’t know what those studies are. Obviously when you’re in business, cost and expenses are a practical issue. I’m not aware of studies that we’re not doing because of reasons of cost.

Cook: Let me respond to that a little differently. Here we are sitting, for example today, with 87 proposals. Now, in one sense some people would not understand why we would not rush to fund all 87 of those. And others would fully understand why we might winnow through those and decide on one, two, five, half a dozen. Now is that an issue of cost, or is there some other dynamic that’s going on? The discussion having to do with some of the studies that we are currently funding certainly took place during a period of time before we funded them but we are funding them, and we are moving ahead with them.

Epi Monitor: The other explanation is that there was concern that new studies would more likely discover new hazards rather than prove that the implants were safe, and the company did not want to hear bad news about implants.

Cook: I’m not sure how we would comment on that over and above saying obviously we are very aggressively looking at a variety of studies at the present time.

Epi Monitor: Here is a comment made by someone in the newspaper: “Sometimes you can have a mind set that a drug will be very commercially important”—I guess you could substitute implant here—“you don’t want to hear bad news about it, you don’t really develop or acknowledge some problems.” Do you think any of that was going on in the company?

LeVier: I would suppose there are a couple of answers. One is the record of studies we’ve done that indicates that we certainly try to pay attention and do a lot of work. It’s also true in human nature that it’s difficult to maintain vigilance. I suppose that’s true of everyone. But our primary assertion is, we have conducted more studies on silicone than anyone I think has ever conducted on any implantable material. Could we have done a better job? I suppose in some way the answer to that is always yes, but I think we’ve done fairly well.

Epi Monitor: The other comment I’ve read had to do with the problems that called for additional study. They were not judged common or frequent enough to warrant full-scale investigation. We talked about that in the past, this whole issue of threshold, but this suggests that the problems that called for additional study were just not considered to be common or frequent enough. Was that operating at all?

Cook: You mean is judgement operating at all? Well, the answer would be yes. Judgement is operating at multiple different levels. I would anticipate that there’s probably a spectrum of scientists out there that are looking at this whole issue and saying, if you will, that this is being driven by less than four dozen case reports, and what a waste of resources. We could be spending all of this money on investigations of AIDS. And there’s probably others that are saying in those four dozen case reports, there were two cases of X disease; therefore, you should mount a full study of X disease. So you’re dealing with that spectrum. It seems as though people are expecting a black and white answer to what, in the statistical sense, is a continuous variable.

Epi Monitor: That gets back to the point we were talking about earlier, that what exactly constitutes a trigger is not black and white, it’s a matter of judgement. Another explanation for the current situation is that there were large amounts of women who were very satisfied with the implants; therefore, it was unlikely that such an acceptable product could have any serious problems associated with it. I wondered to what extent that might have held sway in the minds of some of the people in the company?

LeVier: Well, I think I can only speak for the scientific community here, but typical scientists are not overly impressed with a bunch of people that are happy, and are telling you that there aren’t potentially any difficulties. I think there always could be. That’s why we’ve continued to do research. People finding that as the explanation is really quite inappropriate and inaccurate.

Epi Monitor: How about the notion that the company was aware of safety problems, but was seeking to hide information, not collect more? I think you've sort of alluded to that already. Do you want to comment any more?

LeVier: Only to say that I disagree. Absolutely. As I’ve said publicly before. I think there’s no basis for that comment.

Epi Monitor: From talking with you, my sense is that we’re in the situation that we’re in because it’s been an evolving process. Over time our own expectations have changed. The expectations that we’re saying that we’re failing to meet today, it’s not that they’ve been there for 30 years as long as the product has been with us. But they have been more recent; therefore, the reason that we’ve failed to meet all of our expectations is that those expectations have not been constant.

LeVier: I think that applies to the entire spectrum of the device industry, not just silicones. It’s the fundamental issue that applies to the entire industry.

Cook: I don’t think it’s confined just to the device industry. I think we’re seeing that happening on a whole variety of things. I think you’re seeing it happen in clinical medicine, for example. People’s expectations about what to expect out of a visit to their doctor is driving a lot of the issue on health care costs. There are all sorts of societal dynamics that are coming to play. We happen to be involved in one part of it, but it’s certainly not exclusively ours, or exclusively the device industry’s, or even exclusively medicine’s.

LeVier: I would surely agree with Ralph. It applies to the environment, food, our expectations have experienced a fundamental societal shift.

Epi Monitor: That’s interesting in regards to lessons learned. Dr. LeVier was saying “speak plain English”, “Take all issues that arise seriously.” Then the one about putting materials in context with others, but I think we ought to add in there, something about staying in touch with evolving social expectations.

Cook: I think that’s valid.

Epi Monitor: When one reads about this breast implant controversy, there is this clear feeling of outrage that people experience. This, in fact, is not because people have changed their minds about what they want, but that they’ve known all along what they want and it has not been complied with. If that’s true, there really is quite a diametrically opposed view of the situation on the part of the people reading about it and on the part of the people in the company that are in the middle of it.

Cook: I would challenge that. As an epidemiologist you know that if you can define your terms and really get the specifics, then you can really start addressing it. I would say that there is a sense of outrage, there is a sense that the expectations were not addressed, but you could challenge people as to what they’re expectations were on product X for the following year. I would argue that many of the expectations articulated by people would be fairly vague. I would also suggest that their expectations, if you were able to do this in some kind of longitudinal frame, would probably change over time depending on the context of some of the changes that were going on in society. So I would agree with you that there is outrage, but I would disagree having to do with the specificity of the expectations because I view that as being in flux in our whole society.

Epi Monitor: That’s interesting because then what you’re suggesting is that people are outraged for nonspecific reasons, yet they express their outrage in specific terms.

Published May 1992 

Postscript  2000

These past eight years of dealing with the silicone breast implant controversy, initially as an epidemiologist employed by the Dow Corning Corporation (a former manufacturer of the medical devices) and more recently as a part-time consultant to the company, have been both fascinating and frustrating. The issue is complex and space is limited, so my update is brief.

The registry mentioned in the initial interview never was implemented. Registries can serve many different objectives, but no single registry can meet all of them. It became obvious that the different objectives of the disparate interest groups could best be served by other mechanisms. In retrospect, they were.

In early 1992, the federal government set up an Interagency Regulatory Liaison Group to identify the major scientific questions that needed to be answered vis-á-vis silicone breast implants. That group held a series of technical meetings and developed a final report. To the best of my knowledge, it was never made public.

Even in the absence of any centralized direction and with limited federal grant support, research exploded. Based upon the relatively large amount of information that is currently available, a number of prestigious review bodies have concluded that the evidence does not support a cause and effect relationship between breast implants and any systemic disease--neither cancer, any of the classic connective tissue diseases, nor one or more novel atypical conditions. Ironically, the most provocative hypothesis that has evolved out of this research is that silicone breast implants may be protective against breast cancer, both initial onset and recurrence. The mechanism is unknown.

Research continues on the local complications, in particular, capsular contracture (the sometimes painful hardening of the tissue capsule that naturally forms around every foreign body) and implant rupture. Implementation of rigorous pre-, intra- and post-surgical protocols have reportedly reduced the frequency of contracture ten-fold, down to about 2%. On the other hand, investigations of rupture have been complicated by the phenomenon of “silent rupture”--implant disruptions that are difficult or impossible to detect since they neither compromise the cosmetic effect nor correlate with any obvious signs or symptoms. Non-invasive detection techniques are still being developed. The clinical approach to implant rupture appears to be evolving from one of routine explantation to watchful waiting.

In spite of the scientific results, the large number of lawsuits forced Dow Corning into bankruptcy and the other major manufacturers (Baxter, Bristol-Myers Squibb and 3M) into a multi-billion dollar settlement. Dow Corning is currently awaiting court approval of a plan of reorganization which it developed in conjunction with the plaintiff attorneys. Among the many groups who were given the opportunity to vote on this plan, approximately 95% of the women with implants who voted, accepted it. The linch-pin of this plan is another multi-billion dollar settlement, paradoxically with the largest payments slated to go to women with certain systemic diseases and atypical conditions. However, in the end, those in the legal system will be the major beneficiaries of the silicone breast implant controversy. Some of the plaintiff attorneys likely will pocket tens of millions of dollars in contingency fees, orders of magnitude more than most of their clients.

Ralph R. Cook, MD

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