Silicone, science and settlements: breast implants and a search for truth.

• Author: Stine, Krista R.

IN APRIL 1992, the U.S. Food and Drug Administration banned the further use of silicon breast implants, once the third most common form of plastic surgery in the United States, except for limited use in research settings. FDA Commissioner David Kessler stated that the ban was not imposed because the implants were known to pose a risk, but rather because the manufacturers had not fulfilled their legal responsibility of collecting data on the question.(1)

During the first two years following the FDA ban, more than 16,000 lawsuits were filed on behalf of women claiming injuries from their breast implants. Facing one product liability case after another, manufacturers, while maintaining that the devices are safe, eventually agreed to a class action settlement establishing a set aside fund of $4.25 billion. Some 440,000 women joined the class. action settlement, while more than 7,000 others opted out to file individual suits. The result was too many claims and too little money. The original manufacturer, Dow Corning, was drived into bankruptcy, and the remaining manufacturers - Bristol-Myers Squibb, Minnesota Mining and Manufacturing Co. and Baxter Healthcare Corp. - have entered into negotiations for a new settlement.

When the FDA made its decision in 1992, however, there had been no systematic studies of the adverse effects of breast implants.(2) The fact that implants occasionally leaked or ruptured, causing local problems, has been conceded by both manufacturers and researchers.(1) These include localized pain, scar formation, inflammation, enlarged lymph nodes, and misshapen breasts caused by shifting or hardening of the silicone gel.

There have been instances in which the silicone gel core material has escaped from the restrictive confines of the silicone rubber envelope, causing silicone to enter the body. There are two ways by which this can occur. First, the envelope of the breast implant can rupture. This is often caused by trauma to the area or closed capsulotomy. Second, research has shown that even in the absence of a rupture, the implant can "bleed," and minute quantities of the gel can move through the envelope and into the body.

These localized complications, however, have not been the basis of the public scare. Rather, it has been the allegation that the leaking silicone causes connective tissue and rheumatic diseases such as systematic lupus, rheumatoid arthritis and scleroderina. Because these are chronic disorders not easily diagnosed, and because they also may occur in women without breast implants, the postulated associations have been very difficult to evaluate.

Since the FDA action, numerous scientific studies have been done using a variety of epidemiological techniques. In the wake of what has become the "monster" of product liability cases, published medical studies have failed to find any correlation between silicone breast implants and any of the connective tissue diseases alleged. Nevertheless, lawyers representing women with implants have created an avalanche of litigation, and women have received awards.

This article addresses the scientific evidence that exonerates the silicone implants, the subsequent settlement and litigation that has seemed to fly in the face of the evidence, and the effect of the evidence on the new settlement and opt out litigation.

1995 HARVARD STUDY

Development of connective tissue disease in women with breast implants does not by itself constitute evidence that the implants caused the disease. Each year approximately 100 women with breast implants can be expected to develop lupus or scleroderma by chance alone.(4) Because these types of diseases may occur in women with and without breast implants, the only way to examine whether breast implants actually contribute to the diseases is to show that the incidence of disease is significantly higher among women with breast implants than in those without implants.

This has not been shown. The research done by the Harvard Medical School, the Harvard School of Public Health and the Brigham and Women's Hospital of Boston and reported in the New England Joumal of Medicine found no, link between the implants arid any connective tissue diseases or symptoms.(5)

1. Sample and Variables

   There are two basic types of epidemiological studies: (1) a prospective or cohort study and (2) a retrospective or case control study. Cohort studies (the focus here) are those in which the incidence of connective tissue diseases among groups of persons exposed to silicone implants is compared with the incidence in groups of persons not exposed. Case control studies start with a group of persons who have the disease in question (cases), match this group with another group without the disease (controls) and compare the frequency of exposure to the chemical or drug among the cases and controls.(6)

   In the Harvard study, researchers analyzed data from 14 years of follow-up of the Nurses' Health Study Cohort, which was assembled in June 1976. Questionnaires were mailed in 1992 to all registered nurses who were female, married, age 40 to 55 and living in one of 11 states. The researchers included questions on breast implants in a biennial questionnaire sent to all 109,750 women still participating in the study. Responses were received from 89,376 including 88,153 who responded to questions about breast implants.

   After the exclusion of women about whom implant information was missing or who were diagnosed with connective tissue disease before 1976 or after May 1990 - cut-off date chosen to eliminate possible bias because widespread news media coverage of a possible association of implants with the diseases began in December 1990 - the study focused on 87,507 women. During the 14-year period, 1,181,244 person-years of follow-up were accrued. The number of person-years was calculated from 1976 until May 31, 1990, or until the date of diagnosis of any connective tissue disease, whichever came first.

   The results of the Harvard study are based on responses from registered nurses, 95 percent of whom were white. The sample, nevertheless, is likely to reflect a general population. In 1989, a national survey of 40,000 households in the United States found that approximately 60 percent of breast implantations were performed for cosmetic reasons, and that 95 percent of those receiving them were white.(7)

   The reported data were classified into four case types or variables: (1) self-reported disease, (2) self-reported signs or symptoms, (3) documented signs or symptoms of disease and (4) definite connective tissue disease. Most significant here are the data on cases of "definite" connective tissue disease. These are undisputed cases of anti-immune or connective tissue diseases that were carefully evaluated and free from biased diagnosis.

   The other three case types should not be discounted, however, since the classification criteria for connective tissue diseases excluded women with milder or atypical cases, and thus could have underestimated the true incidence rate. Self-reported cases included women who reported a rheumatic disease on any biennial questionnaire. Self-reported signs or symptoms included women who had a positive screening, as defined on the connective tissue disease questionnaire. Documented signs or symptoms of disease included women who had any one of 41 signs, symptoms or laboratory features of a connective disease.

   Analysis was further broken down as to women with no implant history, women with any type of implant history, including silicone gel-filled, saline-filled, double-lumen, or poly-urethane-coated, and women with silicone gel-filled implants.

2. Statistical Analysis

   Epidemiological studies do not provide direct evidence that a particular woman developed a connective tissue disease because of a silicone breast implant, but they can provide circumstantial evidence of cause and effect through a process known as hypothesis testing. Epidemiologists begin their study in an attempt to falsify the "null hypothesis," which is that there is a relative risk of one.(8) The null hypothesis postulates that there exists no association between two studied variables. Significant here is the null hypothesis that there is no association between silicone breast implants and an increase in connective tissue disease.

   Epidemiological studies use sample groups such as the nurses' cohort employed in the Harvard study. The experiences observed within such a sample, however, may differ from those of the entire relevant population. Thus, a showing of association between silicone breast implants and connective tissue disease within the sample group could be the product of chance and not indicative of the general population. This discrepancy is referred to as "sampling effor" and causes researchers to reject suggested associations unless they withstand the test of "statistical significance," a statement that enables the researcher to determine if the deviation between samples represents a true difference between populations or is the result of the sampling process.

   The statistical significance test postulates the probability that the observed difference is due to chance if the null hypothesis is true - that is, there is no association. If that probability is sufficiently small, .05 (or 5 percent) being the most common used level, then the null hypothesis is rejected and an association is found. On the other hand, if the probability is greater than 5 percent, the null hypothesis is accepted and no association is found.(9)

   In the Harvard study, the analysis of data was based on incidence rates. Relative risk, the measure of association, is defined as the incidence rate of connective tissue disease among women with breast implants divided by the corresponding incidence rate among women without implants. Researchers used confidence intervals to describe the reliability of the sample results as compared to the entire relevant population...