D Remains Stagnant Despite Scientific Advances

SIDEBAR: Mired in Politics: Emergency Contraceptives And Abortifacients LITTLE PROGRESS NOTED: "Why should a pharmaceutical company take these risks?" asks pioneer Carl Djerassi. Although the molecular biology revolution is in full swing and potential new products abound, basic methods of birth control have changed little in the 36 years since the contraceptive pill was introduced. Indeed, some scientists believe that political and economic pressures will keep most contraceptive advances -- even those now available in Europe -- from ever reaching the United States market. The introduction of the pill was a major milestone in contraceptive research, writes Carl Djerassi in his book From the Lab Into the World: A Pill for People, Pets, and Bugs (Washington, D.C., American Chemical Society, 1994). Djerassi synthesized norethindrone, the first progestational oral contraceptive, while working for Syntex S.A. in Mexico City in the early 1950s. "The only new developments have been chemically minor variations on the compound that we synthesized in 1951 and on new sustained-delivery methods of these steroids," he notes. Products available in the U.S. today fall into one of three categories. There are steroid hormone-containing methods based on progesterone compounds, such as Norplant and Depo-Provera; the intrauterine device (IUD); and barrier methods, which include the female condom and the discontinued sponge. The notable exception is RU 486, an anti-progestational drug that is used with prostaglandins to induce abortion; however, RU 486 is not used as a true contraceptive (see story on page 5). The causes for this dearth of new contraceptives are many, according to an Institute of Medicine (IOM) report released in May (P.F. Harrison, A. Rosenfield, eds., Contraceptive Research and Development: Looking to the Future, Washington, D.C., National Academy Press, 1996). The political climate in the U.S. often is hostile to contraceptive research and use, the report states. Fiscal austerity -- in both the private and public sectors -- tends to limit research funds. And few niches that could be filled by a new contraceptive product actually exist, which makes development economically unattractive to pharmaceutical firms. Perhaps the most stifling reason for the lack of new contraceptives is the existence of product-liability laws that discourage companies from investing in innovative technology. Such is the case with the intrauterine device (IUD), the most prominent "new" technique other than hormonal contraceptives. The device has had a rocky history since its introduction in the 1960s. The most notable controversy surrounding the IUD has been highly publicized litigation over the Dalkon Shield. As pointed out by Sylvia Law, a professor at New York University School of Law, the Dalkon Shield went on the market in February 1970, prior to the Food and Drug Administration (FDA) requirement that medical devices be approved. In fact, Law says, the case of the Dalkon Shield was the impetus for the FDA requirement that medical devices go through the approval process. The string hanging from the Dalkon Shield in the vagina was made of a material that allowed pathogens to travel upward into the uterus and pelvic cavity. Women using the shield who became pregnant -- it had a failure rate of about 5 percent -- risked septic abortion and even death. Thousands of liability lawsuits were filed against A.H. Robins Co., a Richmond, Va.-based pharmaceutical company that had bought the rights to the product. Robins eventually was forced to pay millions of dollars in punitive damages. CLINICAL TRIALS: Nancy Alexander of NICHD cites problems. As a result of the Dalkon Shield litigation, "both Searle [a pharmaceutical firm based in Chicago] and Ortho [Pharmaceutical Corp. of Raritan, N.J.] removed their IUDs from the U.S. market because of the fear of litigation, but the Progestasert [manufactured by Alza Corp. in Palo Alto, Calif.] remained on the market," states Nancy Alexander, chief of the Contraceptives Development Branch of the National Institute of Child Health and Human Development (NICHD). The Dalkon Shield case hangs like the sword of Damocles over the heads of all interested in developing new contraceptives based on modern biomedical research. Thus, scientists and the general public have stayed with tried-and-true methods. GLOBAL IMPACT: Mahmound Fathalla says female sterilization is the most common method worldwide. Worldwide, the most popular contraceptive method is surgical female sterilization, notes Mahmoud F. Fathalla, senior adviser for biomedical and reproductive health research and training for the Rockefeller Foundation in Assiut, Egypt. According to the statistics released in 1994 by the United Nations Department for Economic and Social Information and Policy Analysis, Population Division, female sterilization accounts for 17 percent of world contraception use. The IUD is the next most popular contraceptive method worldwide at 12 percent. Owing to the bad press and excessive consumer fears, however, IUDs are used by only about 2 percent of American women using birth control, according to the May IOM report. The pill -- usually combinations of estrogen and progestins -- is used by 8 percent of women worldwide. Mired In Politics: Emergency Contraceptives And Abortifacients When the United States Food and Drug Administration (FDA) made an unprecedented announcement in July that, absent standard FDA-approval procedures, oral contraceptive pills in high doses are safe and effective for emergency contraception -- the so-called morning-after pill -- it was giving its imprimatur to a well-established use (T. Lewin, New York Times, July 1, 1996, page A1). An Institute of Medicine (IOM) report released in May (P.F. Harrison, A. Rosenfield, eds., Contraceptive Research and Development: Looking to the Future, Washington, D.C., National Academy Press, 1996) states that both combined estrogen/progestin and progestin-only pills are used as emergency contraceptives up to 72 hours post-coitus. The report also notes that mifepristone (RU 486) dosage and insertion of a copper-T intrauterine device (IUD) are given for emergency contraceptive use. However, success rates for these treatments are markedly low, ranging from about 1 percent for both mifepristone and the IUD to 25 percent for the pills. But IOM reports that clinical trials with drug combinations have yielded very high success in averting pregnancy in women whose menstrual periods were as late as 10 days. Mifepristone, however, has another, much more visible use: in combination with prostaglandin administration, as an early abortifacient. Approved in France and China since 1988, the drug, produced by Roussel-Uclaf of Romainville, France, has been licensed to the Population Council in the U.S. to keep Roussel and its parent, German pharmaceutical giant Hoechst, away from the ire of the U.S. anti-abortion movement. Sources close to FDA who request anonymity expect the drug to be approved for abortion induction within the month. Nancy Alexander of the National Institute of Child Health and Human Development explains that antiprogestins like mifepristone have other uses for women's health-for example, to treat endometriosis (M. Watanabe, The Scientist, Jan. 24, 1994, page 14). "All these other uses make [the compound] not [merely] 'the abortion drug,'" Alexander says. The controversy surrounding use is so great that a recent hearing in which a panel of advisers suggested that FDA approve the drug was held in secrecy. Even those attending were not told where they were being taken. "You had to take a van from a nearby hotel," recalls Gloria Feldt, executive director of the Planned Parenthood Federation of America Inc. "The van had to go through two security checks on the way to the building. The building was unmarked. It had no windows. It had metal garage-type doors." There was another security check at the building, Feldt adds. "If there were bathrooms in the building, you were not allowed into them; they put up portable toilets outside in the rain. Electronic devices were scrambled." Feldt is appalled: "What struck me is, it's 1996; this is the United States of America." What should have occurred, she says, was a straightforward discussion on an issue of women's reproductive health. "Instead, it was shrouded." -M.E.W. Other hormonal methods include the injectable Depo-Provera, a progestin compound administered through a single injection every three months, and Norplant, six progestin- compound- containing silicone rods that function for five years after implantation. Alexander notes that use of Depo-Provera is increasing, but "Norplant insertions have gone down astronomically." She says that a small clinical trial of Depo-Provera and Norplant funded by NICHD is being attempted, but researchers have complained that "they can't get the Norplant patients to conduct the study." Both Norplant and Depo-Provera's side effects include bleeding. And Norplant, which is implanted subcutaneously, has proved difficult to remove in some cases. Litigation is pending against St. Davids, Pa.-based Wyeth-Ayerst Laboratories, which markets and distributes Norplant. Law says that plantiffs allege physical harm from the silicone in the implant, side effects, injuries resulting from implant removal, and lack of informed consent. Such litigation has caused pharmaceutical firms to drop contraceptives R&D and marketing in droves. According to the IOM report, by the mid-1980s only one U.S. and three European drug companies had significant contraceptives R&D programs. The lack of pharmaceutical company development has prompted government agencies such as the U.S. Agency for International Development and the National Institutes of Health as well as private organizations to pick up that research. Now, instead of pharmaceutical firms developing a contraceptive, a nonprofit like the New York-based Population Council may develop a product, then search for a drug company to manufacture and distribute it. The Population Council, for example, developed Norplant for the U.S. market. However, as the IOM report notes, the lack of funding is impacting contraceptive development. Beverly Winikoff, director of reproductive health for the Population Council, points out that the council doesn't "have the kinds of resources that large companies can throw at development of new products." Her organization relies on funds from foundations and private sources for its research. The continual threats to federal funding for contraceptives research could have a worldwide impact. "There clearly is a problem now, particularly for the agencies that are funded by AID [Agency for International Development, a part of the U.S. Department of State]," says Henry Gabelnick, director of the Contraceptive Research and Development Program (CONRAD), an AID-funded group that subsidizes contraceptives research in developing countries. In the continuing resolution on the FY 1996 federal government budget, the House and Senate cut AID's Office of Population's budget by 35 percent. This was a compromise between those legislators in the House who totally oppose contraceptives research and those in the Senate who may oppose abortion but realize that effective contraception can eliminate abortion. They stipulated that none of this money could be spent prior to July 1, 1996, and then could be meted out only at one-fifteenth of the budget per month through FY 1997. Gabelnick says this has wreaked havoc with programs supported by CONRAD and other organizations that receive AID funding for contraceptives research, including Family Health International in Research Triangle Park, N.C., and the Population Council. From October 1995 through July 1 of this year, the organizations essentially had to work with leftover funds or money they could raise from private sources. "The immunocontraceptive area is one that we've really cut back on," Gabelnick states. "Not knowing what we would get, we stopped doing new projects." Cutting off money for contraceptives research is the goal of many conservative groups. "I believe our position would be that we oppose federal funding," says Gracie Hsu of the Family Research Council in Washington, D.C. "When contraception is introduced into a relationship, it has a possibililty of breaking down a marital bond because [it] could be used outside marriage." POLITICAL REALITIES: Planned Parenthood's Alexander Sanger knows conservatives' criticisms. Alexander C. Sanger, president of Planned Parenthood of New York City and grandson of contraceptives pioneer Margaret Sanger, comments on Hsu's explanation: "I've heard this before. I believe that family planning, including the use of contraception, is of benefit to individuals, marriages, and families. When couples can plan and space their children, it creates a stronger and better family." As continued federal support is debated, private sources are stepping in to fund research, observes Michael J.K. Harper, director of the CONRAD Consortium for Industrial Collaboration in Contraceptive Research (CICCR). The Arlington, Va.-based consortium-funded jointly by U.S.-AID, the Rockefeller and Andrew W. Mellon foundations, and industry-gives grants for feasibility studies to determine if a method is valid. It then will find a for-profit partner for the development of the method, says Harper, an IOM committee member. CICCR also is providing "matching grants to investigators at not-for-profit institutions that have a good idea and have been able to recruit a partner in industry," he states. Despite the lack of R&D by pharmaceutical companies in the U.S., the IOM report devotes several sections to current research in contraception and possible methods that may be on the horizon. DEVELOPMENTS: Population Council Elof Johansson says European methods may come to the U.S. Methods already available in Europe and most likely to soon be approved for use in the U.S. include "low-dose combinations in oral contraceptives with 20 µg of ethynylestradiol, third-generation progestins," and an IUD that delivers levonorgestrel, a progestational compound, explains Population Council vice president Elof Johansson. "This [IUD] acts locally in the uterus and with very high efficacy in preventing pregnancy and also in reduction of blood loss during the menstrual period." This device, he says, "has been available in Scandinavia since 1990 [and] generally in central Europe as of this year." Also in the works are vaginal rings that function as a progestational compound delivery system that requires no medical intervention to stop or start. "You can leave it in all month; you can take it out during sex," explains NICHD's Alexander. "Unlike Depo-Provera and Norplant, a woman could change her mind and take it out." NICHD also has been involved in developing a three-month injectable steroid for women. Norplant II, in which only two instead of six rods with progestin hormones will be implanted, "is about ready" to hit the market, states Alexander. She expects that nonlatex polymer condoms will also enter the market. Latex poses a problem because people become allergic to it, according to Alexander. And the amount of released latex antigen is increased from condoms packaged with spermicide. Alexander predicts that shortly after the turn of the century, there will be spermicidal and microbicidal creams, gels, films, and foams. No currently available product is both spermicidal and able to kill most of the organisms that cause sexually transmitted diseases. IMMUNIZATIONS: Donald Patrick McDonnell predicts immunocontraception products are coming. Antiprogestins, like RU 486 (mifepristone), are synthetic steroids. They bind to progesterone receptors and thus can cause termination of pregnancy, prevent fertilization of the ovum, or prevent implantation of the fertilized egg. IOM panel member Donald Patrick McDonnell, an associate professor of pharmacology at Duke University Medical Center in Durham, N.C., predicts that such molecules, including RU 486, "will definitely be looked at both as a contraceptive and menses inducer." McDonnell's recent research on antiprogestins was published in the Proceedings of the National Academy of Sciences (B.L. Wagner et al., 93:8739-44, 1996). A male contraceptive, the one unfilled niche, is likely to be available within five years. Alexander reports that NIH and WHO have developed a three-month injectable containing both an androgen and a progestin. The agencies believe this is a better formula than one recently studied in clinical trials that required weekly injection of testosterone enanthate (F.C.W. Wu et al., Fertility and Sterility, 65:626-36, 1996; and WHO Task Force on Methods for the Regulation of Male Fertility, Fertility and Sterility, 65:821-9, 1996). "We need to reformulate and do more clinical studies, so it could be in about five years" when this is on the market, Alexander says. PREDICTION: IOM committee head Allan Rosenfield forecasts that future methods will be specific in action. Molecular pharmacologist McDonnell predicts that immunocontraception products will be introduced. These, according to the IOM report, may include immunization against progesterone or transient immunization against cytokines necessary for implantation or embryo growth. Obstetrician/gynecologist Allan Rosenfield, dean of Columbia University's School of Public Health and head of the IOM contraceptives committee, expects that future contraceptive methods will be "specific in their action, blocking a specific receptor at a key point in time, and thus having much fewer side effects than current methods." The current epidemics of AIDS and other sexually transmitted diseases (STDs) have created an urgent need for a new type of contraceptive: one that is both a spermicide and a microbicide. The Topical Microbicides Initiative is not new, says Penelope Hitchcock, chief of the Sexually Transmitted Diseases Branch at the National Institute of Allergy and Infectious Diseases. NIH now is supporting it at $25 million per year for the next four years, and the Centers for Disease Control and Prevention will spend $4 million on topical microbicide development. Some of these new microbicides will also have contraceptive functions. WARNING: NIAID's Penelope Hitchcock warns against using of spermicides containg N-9. Hitchcock explains that the male condoms that contain spermicides and nonoxynol-9 (N-9) are touted as both contraceptives and protectants against AIDS transmission. However, she states, the spermicides have never been tested in clinical trials. In fact, Hitchcock is alarmed that the message going out to women is to use spermicides containing N-9 to protect against AIDS. She explains that studies have shown that in commercially available doses, N-9 "causes lesions in vaginal and cervical epithelia," leaving a woman more vulnerable to HIV infection. "If I were in a relationship with someone where I was at risk for HIV or STD, the last thing I would do would be to put N-9 in my vagina," Hitchcock maintains. She advises use of a topical microbicide for people not involved in long-term, stable relationships, especially teenagers and young adults. With respect to the female condom, data suggest it may not be the most effective form of birth control. A 24 percent failure rate per year has been reported for normal use. There are no clinical studies on prevention of HIV with this device. Even though the material does not permit passage of HIV, if secretions leak around the outside, it may not provide good protection against pregnancy or infection, contends Hitchcock. Photo: Karen Tweedy-Holmes SCANT RESOURCES: Beverly Winikoff notes that nonprofits like the Population Council can't fund as much research as companies can. NIH is now conducting clinical trials of several topical products that may function as both spermicides and microbicides. One, Hitchcock states, contains octoxynol-9 -- which does not cause the vaginal irritation produced by N-9 products -- and benzalkonium chloride. Octoxynol-9 is lytic to sperm, and the benzalkonium chloride is believed to further prevent infection. Another product is an acid buffer gel that will kill sperm by preventing the increase in vaginal pH that occurs after ejaculate mixes with acidic vaginal fluid. The researchers also are looking at lower concentrations of N-9. "We're looking for the window in which it will kill sperm and prevent infection" without toxicity effects on vaginal tissue, Hitchcock says. Even here, however, there is a liability question. Not only are there no data on contraceptive efficacy of spermicides, says Hitchcock, but also there are no data on development of a fetus conceived with a sperm that has been subjected to these spermicides when they fail as a contraceptive. "Private investors are as scared as drug companies when they're talking about the future of their dollars," says the Population Council's Winikoff. "The whole area has become fraught with the fear of not making money; it's hard for many to see how the private sector can make money in this area." Lawsuits are one factor making the contraceptive market unprofitable, she contends. In addition, new contraceptives would be "competing against many products on the market." She adds that as more and more products are developed, the available market becomes smaller and smaller. Djerassi, who is now a professor of chemistry at Stanford University, tells The Scientist that "people think that just because there are roughly 100 million people a day having intercourse, this is a huge market." It is not, he states: "Why should a pharmaceutical company take these risks?" Myrna E. Watanabe is a science writer based in Yonkers, N.Y.

D Remains Stagnant Despite Scientific Advances

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