DR. WHALEN: Next is Dr. Jae Hong Lee, also from the National Center for Policy Research for Women and Families.

DR. LEE: Good morning. I am Dr. Jae Hong Lee, a physician and the senior medical policy analyst at the ational Center for Policy Research for Women and Families. My response to all four questions is no.

The Institute of Medicine report on breast implant safety identified reoperations and local complications as the primary safety issue with silicone breast implants.

In light of the serious concern regarding reoperations and local complications, the post-approval studies recently released by Inamed and Mentor are extremely disappointing. Both studies are poorly designed and executed, and most likely underestimate the cumulative incidence of complications.

I will discuss just a few of the more glaring weaknesses of both studies. A major problem shared by both the Inamed and Mentor studies is the exclusion of patients who have had all their breast implants removed prior to the three- or five-year study interval. One can argue that these patients, among the earliest to have all their implants removed, are the most important group of patients to study. They certainly should be counted as women with complications.

Excluding data from these patients introduces an unacceptable post-entry exclusion bias into both studies. Since it seems likely that these patients were experiencing complications rates higher than those who did not have all their implants removed, the overall effect of this exclusion bias will be to seriously underestimate the cumulative incidence of complications.

Exclusion of these patients also invalidates the Kaplan-Meier risk estimates reported in both studies. One essential condition for using the Kaplan-Meier method is the assumption of independence between censoring and outcome. In other words, one must assume that the rate of local complications and reoperations in the excluded

patients was similar to those who remained in the study. Since the excluded patients had all of their initial implants removed for one reason or another, most likely due to complications, this is not a reasonable assumption to make. Using the Kaplan-Meier method in this situation clearly results in an underestimation of the cumulative complication rate, a fundamental flaw in both studies.

The problem is compounded when the reports continue to cite the full number of enrolled patients when discussing specific complications. For example, the Inamed study enrolled 237 reconstruction patients but excluded 97 patients by year five, for an actual follow-up of only 140 patients. Inamed then reports reoperations in 100 of the 237 patients over the five years of follow-up. The question is whey were the excluded patients counted in the follow-up cohort? Is the percentage of patients with reoperations 100 out of 237, or 42 percent, or is it actually 100 out of 140? In contrast, Inamed conveniently excludes the breast implant removal patients when calculating their follow-up rate for reconstruction patients. They calculated an expected follow-up cohort of 175 by excluding 11 patients who had died and 51 patients who had all their initial implants removed. As a result, their follow-up rate of reconstruction patients was reported as 80 percent, or 140 out of 175 patients.

As mentioned earlier, it is highly inappropriate to exclude those implant-removal patients from the study cohort. If those patients are left in, the expected follow-up cohort consists of 226 patients, not 175, and the actual follow-up rate for reconstruction patients is then a clearly inadequate 62 percent.

There are also signs that the Inamed study is statistically underpowered. For example, Inamed suggests that because most of the confidence intervals between five-year and three-year risk rates for complications overlap, the true rates may not be higher at five years. They imply that it may not be necessary to follow complications with overlapping three- and five-year confidence intervals in subsequent years.

A more reasonable interpretation of this data is that the study is too small and underpowered. Since even a small difference of three percent represents over 6000 breast augmentation patients, the post-approval studies must be large enough to detect even small differences in risk rates.

As bad as the Inamed study is, the Mentor study is even worse. The Mentor report acknowledges that low response rate and the differences between the responders and the non-responders is a major limitation of their study. I would go further and state that most of the data presented in the Mentor study is scientifically worthless due to the disturbingly low follow-up rates.

Setting aside for the moment the very serious methodological problems of both studies, we find little comfort in the reported data. Even taken at face value, the complication rates are unacceptably high. For instance, Inamed reports five-year reoperation rates of 26 percent for augmentation patients and nearly 45 percent for reconstruction patients. As a physician, I find these complication rates to be completely unjustifiable for a purely elective cosmetic procedure.

The poor quality of the studies clearly indicates that both Inamed and Mentor have failed to fulfill all the conditions of their premarket approval agreement. Furthermore, the reported complication rates in both studies reinforce the Institute of Medicine's concern about local complications and reoperations. These companies seemingly lack the motivation to perform adequate and appropriate safety studies as long as they can market and sell their products as FDA approved.

So, what should be done? At the very least, the FDA should require a black box warning on all advertisements noting that the manufacturer has not adequately completed required five-year safety studies. The panel should also recommend that patient consent forms include a statement noting the lack of reliable long-term safety data. Another option would be to temporarily suspend general distribution of these implants until better safety data become available.

The Inamed and Mentor studies leave many questions unanswered, but do make clear one important fact, right now, today, there are no adequate data demonstrating the safety of saline breast implants. Thank you.