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- The Current Status of Contraceptive Research Since the introduction of the pill and the IUD in the early 1960s, no fundamentally new contraceptive methods have been approved for use in the United States. This chapter discusses the new contraceptive methods currently being studied both in the United States and abroad. We try to provide an overview of promising scientific leads, and thus of methods that the public might reasonably expect to be available within the next 10 to 15 years. Unfortunately, such a general criterion is hard to apply without dispute. One person's promising new development is, for another, a preposterous idea or only a trivial modification. We have chosen to be inclusive rather than exclusive, since our aim is to provide a sense of what might be possible if the barriers to faster development were reduced. We have also included a brief overview of important modifications of existing methods to enable readers to evaluate more knowledgeably the range of potential innovations that changes in public policies could yield. RESEARCH LEADS Dramatic changes in the range of available contraceptive technology are unlikely to occur in the 1990s (Djerassi, 1987; Harper, 1983~. Most of the contraceptive methods that will be available in the United States between now and the turn of the century will constitute modest improvements to existing methods. So, although no single new contraceptive will be a panacea for the fertility control needs of all people, scientists are studying a number of promising leads that could result in the development of contraceptives that have few side effects and health risks and are more effective, more easily administered and used, and less costly. 30
CURRENT STATUS OF CONTRACEPTIVE RESEARCH 31 The acceptability of new methods or of modifications of existing methods among potential users and their effect on nonuse are difficult to predict. Advocates of new technology often exaggerate the potential impact of Innovations, while critics of new methods often underestimate the likely influence of such changes. Modest improvements in existing methods will probably not significantly increase acceptability and use. But major changes, such as that made possible by a contraceptive implant, could substantially increase the acceptability of contraceptive practice. It is extremely difficult to estimate when a particular new contraceptive will be available. The entire development process is surrounded by the uncertainties of scientific research, funding, marketing feasibility, and regulatory approval. Based on a 1980 survey of contraceptive development experts, the congressional Office of Technology Assessment (OTA) named nine fertility control methods as "highly likely before 1990" (OTA, 1981~. Only three of these technologies triphasic pills, the Copper T3 80A intrauterine device, and the Today contraceptive sponge- were available in the United States as of June 1989. Two steroidal methods, long- acting injections (e.g., Depo-Provera) and implants (e.g., NORPLANT@), are available in other countries. (A New Drug Application for NORPLANT~ to be used in the United States has been feed with the FDA.) Four methods improved ovulation~etection methods, vaginal rings, luteinizing hormone-releasing hormone (LHRH), and prostaglandin analogues are being studied but will not be available in the near future. None of the 11 technologies designated by OTA as "possible by 1990 but prospects doubtful" is likely to be available for several years, and some could take an additional decade or longer to be developed or could, indeed, not be developed at all. Given the problems encountered in previous efforts to identify the range of potential new contraceptives, we do not argue strongly for our list of possible contraceptive innovations. Instead, we want to emphasize that significant developments are possible and are being studied and that, in some cases, couples in other countries are already benefiting from new methods not yet available in the United States. Each new method represents possible improvement over existing methods, either because of new drugs or materials or because of a more effective, safer, or more convenient mode of administration. Because some of the methods being studied use drugs or other substances already approved by the FDA, the approval process for them may be less cumbersome, time-consuming, and costly than for a totally new method. Female Methods New methods of delivering contraceptive steroids are being evaluated in clinical trials, and some are expected to be available for general use during the 1990s. These new delivery systems include injections, implants, ~ansdermal patches (through the skin), vaginal suppositories and rings, and sublingual tablets
32 DEVELOPING NEW CO=~CE~~ES (under the tongue). Because most of the new delivery systems release the drug into the bloodstream at a constant and slower rate and in smaller doses than existing oral contraceptives, they may have fewer adverse health effects than the pill. Such delivery systems are also more convenient for some users than oral tablets. In addition to the injectables already available in other countries, new formulations of injectables using rrucrospheres and nucrocapsules are undergoing human trials and may become available by the early to mid-1990s, assuming there are no major problems or delays in clinical testing (Liskin and Blackburn, 1987~. Similar in concept to time-released cold capsules, these injectables consist of one or more hormones encased in biodegradable capsules and suspended in a sterile solution. The capsules release hormones gradually to block ovulation. Depending on the formulation, one injection can provide contraception for one, three, or six months. The most promising microspheres contain one of the progestins, norethindrone WEIR or norgestimate. A disadvantage of this approach is that, once administered, it cannot be removed or reversed. Injectable microspheres with NET have been tested in nearly 200 women, and more extensive clinical trials are under way (Beck and Pope, 1984; Rivera et al., 1984; Liskin and Blackburn, 1987~. The pregnancy rate is expected to be similar to that of oral contraceptives, but the incidence of side effects may be lower. Irregular menstrual bleeding and the absence of menses are the main side effects found in the clinical trials to date. Two formulations of progestin-estrogen combination once-a-month injectable contraceptives have been developed by the World Health Organization's Special Programme in Human Reproduction. A large Phase III multicenter study has been completed and has confirmed their high efficacy as well as the regular vaginal bleeding patterns associated with their use. Plans are being made for introductory field studies in Latin America and Southeast Asia. Biodegradable pellets are similar to the new spastic contraceptive implants (see below), in that they are a long-acting, slow-release contraceptive. But unlike the implant, the pellets can be removed only within the first few months of insertion. The rice-size pellets, which are inserted under the skin in the hip or -upper and, slowly release progestins, thereby inhibiting conception. The pellets themselves are absorbed while the hormones are being released. The two types of pellets currently undergoing clinical trials are effective for one to one and a half years. The main side effect identified to date is irregular menstrual bleeding, particularly in the first few months of use (Program for Applied Research on Fertility Regulation, 1985~. It is estimated that they could be available for general use in the mid-199Os. The inability to remove the pellets, once administered, is a disadvantage. The vaginal ring consists of a silicone rubber ring about the size of a diaphragm that continuously releases steroids to suppress ovulation and thicken the cervical mucus, thereby preventing sperm from entering the uterus. Vaginal rings have the
CURRENT STATUS OF CONTRACEPTIVE RESEARCH 33 advantage of being user-controlled and readily reversible. Depending on their formulation, vaginal rings are worn continuously for three months and then replaced, or for three weeks at a time and then removed for one week to allow monthly bleeding. The rings may be removed for a few hours without reducing their effectiveness and do not need to be in place during intercourse (Harper, 1983~. Vaginal rings do not need to be specially fitted, but f~rst-time users should be screened and instructed in proper use. Research is most advanced on a continuous-wear vaginal ring containing levonorgestrel, the same progestin used in some oral contraceptives. However, the pregnancy rate observed in clinical trials of the ring was higher than that of oral contraceptives. In one Dial involving about 1,000 women, there were 3.5 pregnancies per 100 woman-years of use (WHO, 1985b). Similar to other progestin-only methods, the main side effect associated with the levonorgestrel vaginal ring is irregular menstrual patterns. Clinical trials have been completed, and an application for marketing approval in the United Kingdom has been submitted. Introductory studies are expected to follow validation of the ring's manufacturing process. Other vaginal rings containing progesterone and both progestins and estrogens are being tested. Some experts estimate that these other rings may be available in the early 1990s. The progesterone ring could be very useful for breastfeeding women, because it would not affect breast milk. Transdermal patches constitute another delivery system that could provide slow, consistent release of contraceptive steroids to the bloodstream through the skin. Now being used to provide estrogen-replacement therapy to menopausal women, the transdermal patches can be worn on the body and replaced by the user as needed (ALZA Corporation, 1988b). In one system, three patches (each effective for seven days) would be worn consecutively for three weeks, followed by a week during which no patch or a placebo patch would be worn to allow menstrual bleeding to occur. Early clinical teals of this system were completed in 1988 and studies on improved patches were scheduled to begin in the United States in 1989. The technology of osmotic pills could also be used for controlled release of contraceptive steroids. Osmotic pills allow for a gradual release of a drug encased in a semipermeable membrane. Because the drug is released continuously at controlled rates, lower and less frequent dosages are possible, thereby reducing the potential adverse effects associated with oral formulations that are absorbed quickly (ALZA Corporation, 1988a). Many researchers believe that, in the long term, a vaccine could be the ideal contraceptive because it could be highly effective, long-acting, and eventually reversible. Three types of vaccines are currently being studied. One would immunize a woman against human chorionic gonadotrophin (hCG), a placental hormone that is needed in early pregnancy; the second would immunize against the hormone in the zone pellucida of the egg; and the third would work against the sperm (Harper, 1983a). Following an initial series of injections to establish
34 DEVELOPING NEW CO=~CE~~ES . immunity, a woman would need a periodic (probably annual) booster shot to prevent the return of fertility. Research on vaccines is at an early stage, and there are many technical problems to overcome. Nonetheless, it is possible that at least one version of the hCG antipregnancy vaccine could become available for use in some countries around the turn of the century (Segal, 1989~. In 1988 the FDA approved the initiation of clinical research on a contraceptive vaccine in the United States. One alternative to the contraceptive methods based on analogues of estrogen and progesterone is the use of luteinizing hormone-releasing hormone (LHRH) analogues, which control reproduction by affecting the pituitary gland (Schally et al., 1971; Guillemin et al., 1971~. In early clinical trials, LHRH analogues have been effective in suppressing ovulation, and ovulation returned quickly once the drug was discontinued (Eloper, 1983~. It was originally thought that LHRH analogues could be administered by injection or nasal sprays; other possible modes of administration include suppository, cheek insert, or oral capsule (OTA, 1981~. Researchers believed that LHRH analogues might have fewer side effects than combined oral contraceptives. However, clinical work has revealed many difficulties. LHRH analogues also block production of estrogen and progesterone in the ovaries; if these hormones are replaced by drug therapy, the resulting side effects might negate any advantages LHRH analogues have over existing steroidal methods (Wiedhaup, 1988~. Male Methods Although sperm antigens have been tested for use in women, their use in a reversible vaccine for men is not considered feasible because destroying sperm production capability would lead to permanent sterility (Harper and Sanford, 1980~. Animal studies using sperm antigens found an increase in tumors in male mice and more atherosclerosis in male monkeys (Alexander and Anderson, 1985~. Because so much more research is needed to develop and test suitable antigens for a male vaccine, a male vaccine-reversible or permanent will not be available for general use in this century. Inhibin, a peptide derived from the testis, is thought to regulate production of follicle-stimulating hormone (FSH). More research is needed to understand the biology and to develop the specific form of inhibin needed for sperm suppression and to develop a specific regimen for its use. Nevertheless, animal studies suggest that an ESH-inhibiting drug might be effective without changing libido or potency. Scientists are also studying ways to interfere with the fertilizing capacity of sperm as they mature while passing through the epididymis. In the 1960s, gossypol, a derivative of cotton seed, was found to cause male infertility in China. Although the rigor and documentation of many Chinese studies of gossypol are uncertain, the antifertility action of gossypol has been studied extensively and its
CURRENT srATUS OF CONTRACEPTIVE RESEARCH 35 effectiveness has been clearly demonstrated. Two major side effects threaten its potential usefulness: it can deprive the body of potassium (needed for normal muscle function), and its antifertility effect appears to be irreversible in some cases. Reduced sperm count can take two to three months to achieve, and the return of fertility may take at least three to four months (Harper, 1983~. To date, no clinical studies of gossypol have been initiated in the United States. However, the principles underlying research on gossypol should enable scientists to explore other important areas in search of a nonhormonal, nonendocnne contraceptive method. Modifications of Existing Methods Significant modifications of oral contraceptive formulations have recently been introduced in Europe. Three new compounds-desogestrel, gestodene, and norgestimate-allow significant reductions in dosage compared with oral contraceptives currently on the market in the United States (Wiedhaup, 1988~. A new oral contraceptive containing gestodene, for example, contains only about one hundredth the amount of contraceptive steroid contained in the first oral contraceptive marketed in the United States in the early 1960s (Segal, 1989~. If the European manufacturers file for FDA approval, these new oral contraceptives may become available in the United States in the l990s. The main focus of research on natural family planning methods has been devicesforpredicting ovulation or detecting when ovulation has occurred in order to pinpoint more accurately the time for periodic abstinence. In some Western countries, the first models of a "personal rhythm clock," which uses a high- precision thermometer and calculator to interpret daily fluctuations in body temperature, and an "ovutimer," which analyzes changes in cervical mucus, are on the market. Practical biochemical methods for prediction of ovulation, and therefore for improvements in natural family planning, can also be anticipated in the l990s. Research on new monoclonal antibodies, which can be used to detect hormones produced by the ovary, is far advanced. Reliable detectors for ovulation based on urinalysis are already on the market. Research is also under way on ovarian markers of follicular growth and urinary estrogen assays to monitor follicular development (Institute for International Studies in Natural Family Planning, 1988~. Research has also been carried out on the use of salivary electrolytes and glucose as an indicator of the fertile period (WHO, 1988~. New hormone-releasing IUD s and modifications to copperIUDs have recently been developed and tested (Sivin and Tatum, 1981; Luukkainen et al., 1987~. A long-lasting copper IUD, which has a pregnancy rate of less than 1 percent, was introduced in the United States in June 1988. These methods provide highly effective long-term protection at relatively low cost with little risk for most women.
36 DEVELOPING NEW CO=~CE~~ES The search for new sperr~ucides, especially those with virucidal properties, has taken on new importance as a consequence of the dramatic increase in sexually transmitted diseases. Several researchers are trying to develop new spermicides. Preliminary studies have found that propranolol, a beta blocking agent widely used in the treatment of cardiovascular disease, is an effective spermicide. One study involving 198 volunteers found a pregnancy rate of 3.9 pregnancies per 100 woman-years of use (Sherris, 1984~. However, more work needs to be done on formulation and on research to increase effectiveness. Disposable diaphragms containing spermicide have been developed but are not being vigorously pursued. One disposable diaphragm manufactured by G.D. Searle and Co. was approved by the FDA in the late 1970s but was withdrawn in 1980 when test marketing sales were low (Sherris, 1984~. The FDA refused G.D. Searle's request for approval to market the product for sale without a prescription. GynoPharma is currently evaluating a new vaginal barrier very similar to the disposable diaphragm. A female condom, developed in Europe in the early 1980s, is being tested in both Europe and the United States. Made of polyethylene plastic, the female condom consists of two flexible rings and a loose-fitting sheath that lines the vagina so that sperm cannot enter the cervix (International Planned Parenthood Federation, 1988~. The larger ring at the open end secures the device outside the vagina, while a smaller ring at the closed end is inserted into the vagina and placed at the cervix. It is larger than a male condom, its use is controlled by the female, and the method may provide greater protection against sexually transmitted diseases. Recently the FDA Medical Device Center allowed the marketing of two condoms: the "minicondom," a shorter version of a condom using adhesives (in 1988), and the "panty condom," a condom constructed so that it can be worn by the woman (in 1987~. Because these products were considered to be substantially equivalent to products already on the market, no clinical studies of efficacy and safety had been required for FDA approval. In 1989 the status of both products changed: before the minicondom can be marketed, pregnancy rates must be included in the package labeling; and clearance for the panty condom was rescinded pending FDA reevaluation because of a change in the product's design. Considerable work is also under way to develop a new type of male condom that substitutes synthetic materials such as silicone and polyurethane for latex. These materials could provide greater strength, uniformity, and durability and increased sensitivity compared with latex products. Another research lead involves sterilization procedures. Current female sterilization procedures can be reversed only through use of complex microsurgery, which is expensive and not always successful. Researchers have been exploring various techniques for reversible female sterilization, but there are no major leads on the horizon. Clips, bands, fimbrial hoods, and plugs to obstruct the fallopian tubes have been tested, but none has proven to significantly increase reversibility.
CURRENT STATUS OF CONTRACEPTIVE RESEARCH 37 Research on transcervical sterilization the placement of various chemicals into the uterus at the opening of the oviduct has been under way for 20 years. Such procedures would eliminate the risks associated with surgery, but none of them has proven very practical. Among the chemicals that have reached the stage of clinical trials are silver nitrate, quinacrine, phenol, ethanol-formaldehyde, and methylcyanoacrylate (Harper, 1983~. Most of these chemicals cause scarnng, which blocks the fallopian tubes. Researchers have also injected liquid silicone rubber into the fallopian tubes to form a barrier when it hardens. The main problems with sclerosing agents have been the high failure rates and the need for repeated installations. These techniques could also pose a greater risk of ectopic or tubal pregnancy. Reversibility is another concern, although the rubber plugs may prove to be removable Warper, 1983~. In recent years, much research has been done on reversible methods of male sterilization and nonsurgical techniques to make the procedure easier and less expensive. Various valves and plugs that are inserted into the vas deferens to block sperm transport have been tested, but it has proven difficult to anchor them in the vas, and there have been problems with vas erosion and inflammatory reactions (Harper, 1983~. The"Shug" device, which consists of two silicone plugs joined by a nylon thread, is in clinical teals in the United States. Early results are promising, but even if research continues to progress smoothly, it will be several years before the device could be approved and available (Program for Applied Research on Fertility Regulation, 1987; Contraceptive Research and Development Program, 1988~. Nonsurgical male sterilization techniques have involved the injection of chemicals, including methylcyanoacrylate, ethanol, and formaldehyde into the vas deferent. A great deal of additional research is needed to assess He efficacy and safety of these methods (Harper, 1983~. In China, a sterilization technique in which a sclerosing chemical is injected into the vas deferens has been performed on over 1 million men (Segal, 1989~. Another procedure uses the "no-scalpel" vasectomy technique developed in China, in which a small puncture rather than an incision is made in the scrotum to locate the vast METHODS AVAILABLE OUTSIDE THE UNITED STATES Couples in Western Europe and in some less developed countries have a wider choice of contraceptive methods and greater access to the latest contraceptive technology than couples in the United States. In some European countries, contraceptive implants, new oral contraceptives, injectable contraceptives, and a variety of IUD s and sterilization devices that are not available in the United States are approved and marketed. These methods have been found to be safe and effective means of contraception. Depo-Provera (depot-medroxyprogesterone acetate or DMPA), taken by injection every three months, has a failure rate of less than 1 pregnancy per 100
38 DEVELOPING NEW CO=~CE~~ES women per year. It was developed in the United States and is manufactured by the Upjohn Company in Europe. Depo-Provera has been given limited or general approval in about 90 countries, including Canada, Sweden, and the United Kingdom. An estimated 4 million women worldwide use Depo-Provera (Liskin and Blackburn, 1987~. In 1978, after nearly four years of review, FDA declined to approve Depo-Provera for use as a contraceptive in the United States (see Chapter 7~. A two-month injectable, Noriste rat (norethisterone enanthate or NET-EN), is manufactured by Schering AG in West Germany and is approved in more than 40 countries. Its failure rate is higher than Depo-Provera-about 2 pregnancies per 100 women per year. An estimated 800,000 women worldwide use Noristerat (Liskin and Blackburn, 1987~. Both Mexico and China manufacture their own one-month injectables. It is estimated that there are over 300,000 users of injectables in Mexico and and over 1 million in China (Liskin and Blackburn, 1987~. There are currently eight different injectable contraceptive compounds being marketed around the world (Kleinman, l9x8~. NOR PLANT is a progestin-releasing contraceptive implant that is placed under the skin on the inside of a woman's upper arm. The implant, which is manufactured in Finland by Leiras Pharmaceuticals, can provide contraceptive protection for up to five years. The nonbiodegradable capsules containing levonorgestrel are inserted through a small incision and can be removed by a trained person when a pregnancy is desired, when their effectiveness declines, or if the user is troubled by side effects. A six-capsule version of NORPLANT~ has been tested on more than 55,000 women in 31 countries and has been approved in at least 12 countries, including Finland in 1983 and Sweden in 1984 (Population Council, 1988~. In August 1988, a New Drug Application was filled for NORPLANT~ with the I;DA. In April 1989 the Fertility and Maternal Health Drug Advisory Committee of the FDA unanimously recommended that NORPLANT~ be approved for marketing in the United States. Wyeth has expressed interest in marketing NORPLANT@, if it is approved. A newer version containing two rods (NORPLANT@-2) and providing con- craceptive protection for up to three years has been approved in Finland; clinical trials are under way in nine other countries. Evaluation of NORPLANT@-2 has been delayed, however, because of problems with the supply of the polymer used to form Be core of the two rods. Other versions of contraceptive implants using one rod are also undergoing clinical trials (Wiedhaup, 19889. The main advantages of NORPLANT~ are its high effectiveness (less than 1 pregnancy per 100 women per year), reversibility, and convenience; in addition, because NOR PLANT provides among the lowest levels of steroids of any steroidal method, it has a low incidence of serious adverse health consequences. Its disadvantages are that it must be inserted and removed by health professionals. In addition, it typically changes menstrual bleeding patterns, and the capsule's rods may be visible under the skin.
CURRENT STATUS OF CONTRACEPTIVE RESEARCH 39 The Multiload IUD, which is used by a large proportion of all IUD users in Europe, has never been introduced into the United States. According to the manufacturer, Organon International, they consider the costs of liability insurance and of defending possible liability claims in the United States to be too high, and the negative publicity resulting from such claims to be potentially detrimental to sales in other countries (Wiedhaup, 1988~. A variety of other IUDs are used in China and a few other countries, but they are not likely to be introduced to the American market. For more than a decade, researchers have tested various chemicals that could be used to bring on a delayed menstrual period. The most advanced antiprogesterone, RU486, currently thought to be most effective when used with prostaglandin analogues, was developed in France by Roussel-Uclaf. During the past five years, RU486 has been tested in 15 countries, including France, Sweden, and the United States (scalped, 1987~. It was approved for use in France and China in 1988. Known generally as mifepristone and marketed in France under the trade name, Mifegyne, RU486 is an antiprogesterone steroid that blocks the cells in the uterus from receiving progesterone, which is needed to support the fertilized egg. (RU486 is discussed further in Chapter 4.) The Filshie clip, made of titanium lined with silicone rubber, is a method of occluding the fallopian tubes during female sterilization. It has a low failure rate and is thought to cause less damage to the tubes, an important consideration should the woman request a reversal. The Filshie clip has been tested among more than 10,000 women worldwide and is approved for use in the United Kingdom and Canada Kristin and Rinehart, 1985~. Oarlock silicone plugs, used for female sterilization and thought to increase the prospects of reversibility, are already available in the Netherlands. CONCLUSION People in the United States currently have limited options for fertility control and fewer contraceptive choices than people in several other industrialized countries and in some developing countries as well. Some improvements in existing methods will be made in the next decade, and some highly effective new methods may become available in other countries. Some of these new methods will probably be safer, easier to use, less expensive, and more acceptable than existing methods. Other new methods will meet the needs of special population subgroups, such as lactating women or women over 35. The prospects for having one or more fundamentally new methods available in the United States by the year 2000 are negligible. Contraceptive methods that are fundamentally different from existing technology, such as a contraceptive vaccine, are likely to have a greater positive impact on the consumer and society as a whole but will take considerable time to develop.
40 DEVELOPING NEW CO=~CE~IVES Some promising new methods, such as the contraceptive vaccine, for which much of the basic research has been completed, are not being developed at a rate that scientific knowledge would allow. Other methods have been approved by one or more European countries, but additional clinical trials in the United States are needed to qualify for FDA approval. Moreover, there are continuing opportunities for basic research in reproductive biology, which may yield significant contraceptive leads. Accelerated efforts to develop and introduce new contraceptive products to the market would lead to a wider variety of contraceptive options for women and men in the United States and abroad and would result in safer, more effective, and more acceptable contraception for a much broader population than is being served by existing methods.
