Opinion ID: 2367601
Heading Depth: 1
Heading Rank: 3

Heading: The development of hormone replacement therapy

Text: In 1942, Wyeth introduced Premarin, an estrogen hormone used to treat menopausal symptoms. By the 1970s, the medical community had recognized a potential link between the use of estrogen and endometrial cancer. Wyeth's Premarin sales dropped. In 1976, Wyeth's internal documents show that its researchers knew that the presence of both estrogen and progestin in a tumor indicates that the tumor had responded to hormones. In the late 1970s, a published scientific article recommended adding progestin to an estrogen regimen to avoid the risk of developing endometrial cancer. Consequently, physicians began prescribing estrogen and progestin. Respondents' physicians prescribed them Wyeth's Premarin with another manufacturer's progestin. In 1983, Wyeth sought approval from the FDA to study and market the combination of estrogen and progestin. The FDA allowed Wyeth to study the drugs' combination, but rejected its application to market the drugs together. The FDA specifically told Wyeth that a large, long-term study was first needed to evaluate the drug combination's safety. An internal Wyeth document shows, however, that the company viewed such studies as costly and lengthy, with unpredictable results. In 1988, Wyeth was approached for funding to conduct a study that consisted of reviewing data of women who had already been taking estrogen and progestin for a number of years. Wyeth declined to fund the study. In fact, Wyeth's documents showed that it had a company policy of not supporting breast cancer studies. Starting in the late 1980s and early 1990s, independent studies were published that linked an increase in breast cancer risk to the estrogen-progestin hormone therapy regimen. For example, in 1989, a study was published in the New England Journal of Medicine that showed a 4.4 relative risk [5] of breast cancer in premenopausal women. The study characterized the risk as a slightly increased risk of breast cancer among women who took estrogen plus progestin for a long time. The 1989 study was followed by another study shortly thereafter confirming those results. In 1990, another independent study showed an increased risk of developing breast cancer when the hormone therapy regimen was estrogen plus progestin. Internal Wyeth documents show that it responded to studies suggesting a possible breast cancer risk by downplaying the risk through public relations campaigns and its sales representatives' interactions with physicians. Wyeth also created an internal task force to counteract such findings. In 1992, the FDA's advisory committee noted that there was insufficient data to determine whether adding progestin to estrogen increased the breast cancer risk. Wyeth's internal documents revealed that it was pleased that its efforts resulted in the FDA's conclusion that the risk was uncertain. That same year, Wyeth provided its drug to the National Institutes of Health, which was conducting a study called the Women's Health Initiative (WHI). The WHI consisted of 27,000 postmenopausal women grouped into two substudies to assess the risks and benefits of taking estrogen plus progestin or estrogen alone as compared to a group taking only placebos. This long-term study was halted in 2002 because a significant number of women on the estrogen-progestin combination had developed cancer. In 1994, Wyeth sought approval from the FDA to market Prempro. Along with its request, Wyeth submitted at least 14 different breast cancer studies, including a quantitative statistical analysis of 31 breast cancer studies performed at Wyeth's request. The FDA, relying on the studies, approved Prempro as safe and effective. Its approval, however, was conditioned on Wyeth conducting a large-scale clinical trial on bone mineral density and the breast cancer risk to obtain comprehensive answers about breast cancer. The breast cancer issue was highlighted as the most important issue concerning hormone therapy drugs. The FDA also recognized that it would take many years of studying the drug before the relationship between estrogen, progestin, and breast cancer could be definitively determined. Prempro's approval was also conditioned on precise warning-label language. The FDA modified Wyeth's proposed warning label. The modified warning informed readers that [s]ome studies have reported a moderately increased risk of breast cancer. The label noted that [t]he effect of added progestins on the risk of breast cancer is unknown, although a moderately increased risk in those taking combination estrogen/progestin therapy has been reported. The label also stated that the rate of breast cancer that showed up in Wyeth's own human study did not exceed that expected in the general population. Wyeth, however, never conducted its own human study. With the launch of Prempro, Wyeth became the first pharmaceutical company to combine estrogen and progestin into one pill. Although Wyeth knew there were no long-term studies on the safety of estrogen plus progestin, it recommended Prempro's use for all women for life. A 1996 published European study showed that the estrogen-progestin combination increased the breast cancer risk for thin or lean women. Following that study, Wyeth updated its European label warning, but did not update its warning label in the United States. Wyeth specifically cautioned its Breast Cancer Working Group to keep the article confidential, [and] not discuss [it] with anyone outside of Wyeth. Testimony indicated that Wyeth developed a plan to minimize the study and divert attention from it. Wyeth contended, however, that the marketing strategy to counter this European study was never utilized. By 1997, Wyeth had not begun a comprehensive clinical trial, as required by the FDA. Even so, Wyeth requested and the FDA agreed that Wyeth could rely on the WHI study to fulfill its commitment. By 2000, a number of published scientific articles linked hormone replacement drugs to an increased risk for breast cancer. Evidence showed that Wyeth responded to these articles by creating a task force and adding $40.4 million to its large yearly marketing budget to counter rising consumer awareness about the relationship between breast cancer risk and hormone replacement therapy. Wyeth also began promoting Prempro's unproven, and later debunked, heart and mental health benefits in television advertisements and informational pamphlets, guides, and textbooks. The promotional materials failed to mention any breast cancer risk. The FDA admonished Wyeth for recommending its drugs for unapproved benefits as a violation of FDA regulations. As it pertained to those promotional materials, Wyeth disregarded the admonition, and the FDA never sanctioned Wyeth for the improper practices. In another situation involving different promotional materials that Wyeth intended to send to its hormone therapy consumers, Wyeth complied with the FDA's warnings to omit information about unapproved benefits. Over the years, Wyeth sponsored 51 medical articles by selecting different physicians to author the articles, when in fact Wyeth personnel wrote the articles or provided the substance for the articles. Wyeth's involvement with those articles was never identified. Published under independent doctors' names, the 51 ghostwritten medical articles touted the benefits of hormone replacement therapy while minimizing the breast cancer risk. In July 2002, the Prempro arm of the large-scale WHI study was terminated because the data showed an increased risk of invasive breast cancer, coronary heart disease, and stroke. The WHI study also concluded that estrogen plus progestin did not provide any cognitive benefit for women 65 and older, but actually caused a decline in cognitive functioning. Respondents' epidemiological expert testified that the use of estrogen plus progestin caused approximately 8,000 to 15,000 extra breast cancers each year for women between 50 to 69 years of age. After the WHI study results were released, prescriptions for the standard dose of estrogen plus progestin dropped by 80 percent. Similarly, the number of diagnosed hormone-receptor-positive breast cancers  cancers in which tumors show an active hormone receptor  also fell. Following the WHI study, Wyeth introduced a new, lower dose estrogen-progestin pill called Prempro Low. This lower-dose treatment is recommended only as a second-line treatment and for the shortest duration necessary. It also carries the strongest warning possible  a black box warning  and informs the consumer that the risk of breast cancer increases with prolonged use. With this background in mind, we discuss the procedural posture of the underlying district court case.