I am pleased to have the opportunity to testify as President of The National Research Center for Women and Families. Our nonprofit research and education center does not accept contributions from companies that make medical products that we evaluate, or competing companies, and so I have no conflicts of interest.
Our Center is dedicated to improving the health and safety and adults and children, and we do that by scrutinizing medical and scientific research to determine what is known and not known about specific treatments and prevention strategies, and to compare their safety and effectiveness.
In addition, I am a fellow at the University of Pennsylvania Center for Bioethics, and a board member for two nonprofit organizations that work to improve resources for the FDA: the Alliance for a Stronger FDA, and the Reagan Udall Foundation.
I was trained in epidemiology at Yale Medical School; I have worked on federal health policy issues in Congress, the White House, the Institute of Medicine, and for nonprofit organizations for 25 years; and I have testified at FDA advisory committee meetings on numerous safety issues for almost 20 years.
Osteoporosis is a serious disease. Fortunately, there are numerous treatments available, and those options should help the FDA determine whether the risks of this drug, Fablyn, outweigh the benefits.
I have examined the data that were made available to you, I have reviewed the FDA’s summary of the data, and I have listened to the presentation today. The data from The PEARL Study indicate that Fablyn at .5 mg significantly decreases the risk of new or worsening radiographic vertebral fractures by about 50% — but that is only from 2% to 1% during the first year and from 4.6% to 2.2% during the first two years. Over three years, the risk reduction is somewhat lower, from about 6.4% to 3.8%.
However, most of those fractures were asymptomatic. The results were not significant and were much less impressive for clinical vertebral fracture – from only 1.7% to 1.2% through the third year.
Since Fablyn’s reduction of vertebral fracture seems to decrease over time for radiographic fractures and is not significant for symptomatic fractures, it is very unfortunate that no 5-year data were made available for FDA analysis. Preliminary data are not adequate to judge this product.
The safety data from the same study are apparently available through the 5th year, and the risks are significant. Women taking this osteoporosis drug were significantly more likely to die during the 5 years of the study. Surprisingly, it seems that at 3 years the death rate was similar for either the .5 mg dose or the .25 mg dose, but at 5 years the death rate was higher for women taking the lower dosage (.25 mg) than the .50 mg. Even so, the death rate was higher for women taking Fablyn than for the placebo group, and these findings are obviously worrisome. The increased risk of death was primarily from cancer, stroke, and other non-coronary vascular causes – which is consistent with mortality data from women taking other SERMS.
In addition, the number of serious adverse reactions also is higher among women taking Fablyn, especially for those classified as “treatment-related.” These include pulmonary emboli, uterine polyps, and deep vein thrombosis.
What does this mean for women?
Clearly, the benefits of this drug are quite small – primarily in preventing new vertebral fractures that can be diagnosed with x-rays but have no symptoms of pain or discomfort. In contrast, women taking this drug were more likely to die, and slightly more likely to have serious adverse reactions, such as pulmonary emboli and gynecological symptoms requiring invasive procedures.
As you consider what this would mean for women in the U.S., not in a research study, keep in mind that there were very rigorous exclusion criteria for the major study of Fablyn. If you look on page 18 of the FDA memo, there is a long list of exclusions, such as atrial fibrillation, history of breast cancer or DCIS, history of various types of hip or vertebral fractures, or stroke or MI within the last 6 months. In addition, only women with specific bone mineral density levels – not too high and not too low – were included in the study. It is not likely that the women excluded from the study would be excluded from taking Fablyn if it were sold in the U.S., and we don’t know what impact that would have on safety or efficacy, or the likely risks vs. benefits.
Osteoporosis can be a serious and debilitating disease, but there are other treatments available.
In the ideal world, we could tell patients what the risks and benefits seem to be for each medication, and let them decide. In the real world, however, that doesn’t work well for several reasons.
#1: In our experience, many doctors don’t know all the details of research findings and are not at all likely to recall all the exclusion criteria that were used in this study.
#2: Even those doctors who know the details of research findings don’t do a good job of explaining them to patients.
#3: Just under 1% of the women in the study are black. The 18% who are Asian women are primarily living in India, not the U.S. So, we don’t know if the risks or benefits would be different for African American women or other Asian women. And, although 5 % of the women are Hispanic, they were apparently from Argentina and other countries, not the U.S. Since most of the women in the study are not from the U.S., and many from countries such as Croatia and India where diet and exercise might be quite different than the U.S., and that would affect osteoporosis, we don’t really know what the impact of Fablyn would be on the mortality of women living in the U.S.
#4: The data from these studies are short-term. We don’t know the long-term risks or benefits. For cancer, for example, one would not expect risks to show up within 3-5 years, and certainly they would not be statistically significant. In the U.S., women live an average of 80 years, and women who have already lived to be post-menopausal live even longer. So, it is not enough to know the 3-5 year risks and benefits for women who could live another 20-30 years after they start taking an osteoporosis drug.
In conclusion, the data on Fablyn are incomplete to draw the conclusion that the benefits outweigh the risks, and the data thus far suggest that the risks probably outweigh the benefits.
It is the job of the FDA, with your help, to determine if this drug is safe and effective, and if the benefits outweigh the risks. Those decisions should be based on science, not wishful thinking. It is not enough to say “this drug will probably decrease breast cancer” or “this drug will probably continue to reduce fractures over time.” For example, we know that other SERMS, such as tamoxifen, are only effective for 5 years, and not after that. We need more data to determine if this drug does more good than harm for women suffering from osteoporosis.