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POPULATION COUNCIL, ORTHO AND GYNOPHARMA STUDYING HORMONAL AND COPPER IUDs: ORTHO EYEING REENTRY INTO U.S. MARKET; GYNOPHARMA’s FLEXIGARD IN PHASE III

Executive Summary

The Population Council, Ortho Pharmaceutical and Gynopharma are developing new intrauterine devices (IUDs) employing hormonal drip and copper-bearing systems, R. W. Johnson Pharmaceutical Research Institute's Christine Mauck, MD, told a Feb. 26-28 contraception R&D conference sponsored by the National Institute of Child Health and Human Development, the Rockefeller Foundation and the Center for Population Research. The Population Council's levonorgestrel device is a likely candidate for near-term approval, Mauck predicted. The IUD, which has been on the market in Finland since 1991, is a traditional T- shaped device featuring a "reservoir of levonorgestrel put on the vertical stem," Mauck said. She added that the amount of levonorgestrel in the device is equivalent to about "two regular Norplant capsules." Studies show that blood levels of the hormone are "about half that of Norplant users," and ovulation is suppressed in somewhat less than 50% of women. Clinical trials using the device have been conducted outside the U.S. during the last 10-20 years, with follow-up of some cohorts of women for up to seven years, Mauck said. An NDA may be submitted soon. IUDs are regulated by FDA as drugs. The Finnish firm Leirias Oy and The Population Council are codevelopers of the product; Leirias would seek to negotiate a licensing agreement for the U.S. market. In a head-to-head trial with the copper-bearing 380-AG IUD, also developed by The Population Council, the efficacy of the levonorgestrel IUD was found to compare "very favorably," Mauck reported, noting that the device's efficacy is due to "local and systemic effects of progestin." Because the levonorgestrel IUD suppresses ovulation, "eventually it could be shown to be more effective," she added. Overall, the levonorgestrel IUD has a "much higher rate of amenorrhea, and a slightly lower discontinuation rate due to pain and bleeding" when compared to the 380-AG, Mauck said. Regarding any possible protection the device might offer against sexually transmitted diseases (STDs), she commented that theoretically, "because it thickens cervical mucus and causes less bleeding, [the levonorgestrel IUD] should result in a lower incidence of [pelvic inflammatory disease], but we haven't really seen that yet." R. W. Johnson researcher Loretta Itri, MD, told the conference that Ortho is continuing "work on a copper-bearing IUD." She indicated that Ortho has found a consumer interest in IUDs again in surveys. Itri commented that "for women who cannot, should not, or just plain don't want to use the pill," the IUD "is an equally reliable method and a good alternative to the pill." She added that, according to a recent company survey, IUD user satisfaction rate was found to be in the high 90%-range, compared to 92% for the pill. She noted that 1.8 mil. women in the U.S. are still recorded to be IUD users. In Ortho's 23rd annual birth control survey released last Aug. 20, IUDs were reported to be used by 1% of women surveyed ("The Pink Sheet" Aug. 26, T&G-10), compared to 28% of women in the U.S. population estimated to use oral contraceptives. Gynopharma's Cu-Fix, or FlexiGard, IUD is another candidate for U.S. approval, Mauck told the conference. The IUD is in Phase III clinical trials in the U.S. Developed in Belgium, FlexiGard consists of a monofilament onto which six copper sleeves have been strung, for a total of 330 mm of copper. Unlike other T-shaped IUD frames, FlexiGard is inserted and "suspended from the fundus [base part of the cervix]," Mauck said. The absence of a frame is "supposed to lead to less pain and bleeding," she added. A fourth IUD, the Cu-Safe 300, developed in Germany and in clinical trials there, has less copper -- 300 mm. The design is a variation on the copper T, with the arms bent downward to "reduce imbedding," Mauck said. She noted that Cu-Safe 300 has a "narrow insertion tube," which could potentially make it easier to insert than other devices. Studies show that the efficacy rate is promising, while the expulsion rate, like that of Cu-Fix, is "very low," she stated. Cu-Safe 300's developer, Karl Kurz, is negotiating with various U.S. companies to start clinical trials here. Analysis of continuation rates among women using the three devices show that the levonorgestrel IUD has a "good continuation rate -- a little low at five years, but not bad," Mauck stated. First-year continuation rates of the Cu-Fix and Cu-Safe 300 IUDs are "very high," but further long-term data are needed, she said. Regarding the issue of HIV infection and IUD use, Mauck cautioned that "it could be argued that [women with AIDS] are at greater risk of transmitting infection to the male due to the increased blood flow." Also, "because the mechanism of action of IUDs probably relies to some extent on a foreign body reaction, women who are immunocompromised perhaps have lower contraceptive efficacy associated with IUDs -- and in this group of [infected] women, that is a very serious concern." She concluded that "all of this makes IUDs contraindicated in women with HIV infection," further noting that immunocompromised women may also be at "greater risk of" pelvic inflammatory disease. Reanalysis of data from various studies on the relationship of PID and IUDs indicates that the highest risk probably occurs shortly after insertion, Mauck said. "It probably makes sense to go ahead and use prophylactic antibiotics," she commented. In more fundamental studies of IUDs conducted during the last decade, researchers have shown that the devices "act primarily as contraceptives," Mauck stated. For example, in animal and human studies, "eggs that were found were rarely fertilized," she said, and there were "fewer degenerating embryos [and] fewer ectopic pregnancies than in non-contraceptors." Earlier, it had been thought that the primary mechanism of action of IUDs was to prevent implantation of fertilized eggs in the womb.
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