Contraceptive Research and Development: Looking to the Future (1996)

This chapter first speaks briefly about those contraceptive options that are available today. It then turns to options that are-all things being equal-likely to be developed or become available sometime during the decade that is beginning now, that is, between 1996 and the year 2006. The term "all things being equal" refers to the fact that the entry into the market of any new contraceptive method is not just a function of scientific innovation. It is also a function of the contextual dynamics addressed in other chapters in this report. Those dynamics encompass the character of the need and demand for contraception; the various economic and political factors that may prevail as a product advances from bench to shelf; and the social, cultural, religious, and personal variables that, in market terms, shape the need and demand for contraceptives and the extent to which they are, or are not, supplied. Chapter 4 deals with the science landscape in a more distant future, and with the concepts and mechanisms that are the most probable antecedents of very new and innovative contraceptive alternatives, for women and for men. These new possibilities are affected by some of the same dynamics that affect today's contraceptive methods; those are discussed in Chapter 6 and Chapter 7.

Because of the varying states of development of the technologies under consideration, Chapters 3 and 4 are organized differently. Chapter 3 is based on presentations made at the December 1994 Institute of Medicine workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science, conducted as part of this study activity (Institute of Medicine [IOM] 1995). It consists of two parts, as follows:

• Current Options: This section sets the stage for discussion of new approaches to reversible contraception over the next decade and beyond. The section is organized by categories of methods that are presently available, that is, existing, named formulations that work through a variety of mechanisms and delivery systems. Table 3-1 summarizes these methods, their mechanisms of action, failure rates under typical and perfect use, advantages, disadvantages, side effects, and potential complications.
• Contraceptive Options in the Next Decade, 1995-2005: This section focuses on approaches that are at least in phase I of trials. For the most part, these are either improvements or novel applications of approaches that are already well known. These, too, are considered as methods and are organized in the same way as current options, in order to point more clearly to where improvements are under way. We recognize that, in some categorical instances, the boundary between prospects for the next decade and prospects for the years beyond is often blurred. This is a function of technology and of the degree of advance. In the first instance, a technology that seems promising disappoints in trials. In the second, there may be one or two advances that have become "available methods," but the contraceptive category to which it belongs is otherwise largely empty; good examples are barrier and postcoital methods and contraceptives for men.

Chapter 4 and its appendixes constitute the committee's efforts to respond to its charge to review the state of the relevant basic science and identify a range of potential areas and targets that would provide a foundation for fresh endeavor in contraceptive research and development. The chapter is based not only on the December 1994 workshop but on a set of authored papers found in the appendixes to this report. The chapter has three sections: (1) areas of inquiry or specific targets in the development of contraceptive methods for women, that is, "female methods"; (2) areas of inquiry or specific targets in the development of contraceptive methods for men, that is, "male methods"; and (3) an area that holds promise for the development of various contraceptive methods for both females and males, "immunocontraception," which subsumes the topic of "mucosal immunity'' and its potential for generating new anti-infective and/or contraceptive barrier methods. The internal organization of each of these categories was determined by physiology and by the stage of scientific understanding. Because the stages of the female reproductive cycle are critical from both the technologic and policy perspectives, this particular section is organized according to that cycle. Because of the diversity in the levels of scientific advance, the sections of Chapter 4 that deal with methods for males and with immunocontraception are, necessarily, a mix of specific molecular targets and modes of action.

The reversible contraceptive options that are available today, almost all of

which are for women, fall into the following broad categories: oral contraceptives, including emergency contraception; implants; and injectables; intrauterine devices; barrier methods; and non-commodity-based methods.

Although the past decade has seen the introduction of levonorgestrel subdermal implants (Norplant) and depo-medroxyprogesterone acetate (Depo-Provera or DMPA), these are technical variations of existing hormonal methods; they have new and/or different advantages and disadvantages, but they do not represent truly new physiologic concepts. The same can be said for some of the new female barrier methods, which, while their configurations are novel and represent a great deal of research, are still not manifestations of completely new ways of thinking about contraceptive technology. Currently available methods of emergency contraception, while receiving fresh attention, use existing products, although expansion of their availability and utilization would be, in itself, an important novelty.

Beyond new delivery systems and minor modifications in active ingredients, hormonal methods of contraception have changed little since the birth control pill was first introduced, although research on lower-dose formulations has been a steady theme in the field. Today's hormonal contraceptives—consisting of various combinations of estrogens and progestins—can be delivered in the following ways: as pills taken orally, as implants, and as injectables.

Hormonal contraceptive methods work through a variety of mechanisms. The dual action of estrogen and progestin in combined oral contraceptives (COCs) serves both to suppress ovulation and change the nature of cervical mucus, making it less permeable to sperm. A fact that is very imperfectly recognized is that COCs have definite non-contraceptive advantages, including protection against ovarian and endometrial cancer, fibrocystic breast disease, benign ovarian cysts, ectopic pregnancies, and symptomatic pelvic inflammatory disease. And, with lower doses of estrogen, their disadvantages are infrequent.

Because of their established and good record of safety and efficacy, particularly in the modem formulations, there would seem to be scant incentive to improve OCs (Hatcher et al. 1994). However, the appearance of the injectable methods spurred competitive response in the market, as did the perception of needs in special subpopulations (e.g., older women) for whom some reformulation might be attractive (Hatcher et al. 1994). Taken conscientiously, oral contraceptives seldom fail.

The marketing of progestin-only pills (POPs, often referred to as minipills¹) began about 10 years after combined oral contraceptives were introduced. Although there are now a number of these preparations employing a variety of progestins, they account for a small portion of the OC market (Hatcher et al. 1994).

Progestin-only products are members of a family of progestin-only contraceptives which, in addition to being administered orally, may be administered by injection, implants, intrauterine devices, and vaginal rings. They prevent pregnancy through several modes of action: by inhibiting ovulation; thickening and decreasing the amount of cervical mucus (making it more difficult for sperm to penetrate; creating a thin, atrophic endometrium; and/or premature luteolysis (McCann and Potter 1994). Like regular oral contraceptives, progestin-only methods provide little or no protection against sexually transmitted infections, including HIV. Given perfect use, progestin-only pills have slightly higher rates of unintended pregnancy than combined OCs and cause sporadic bleeding in some women (Hatcher et al. 1994).

The first implant introduced onto the world market was Norplant, developed through a long process of intersectoral collaboration. When initially introduced, Norplant was remarkably successful. This long-acting contraceptive slowly and steadily diffuses a small amount of progestin through six slim, flexible rods inserted subcutaneously in a woman's upper arm and produces in most women the same cessation of ovulation and other physiologic changes that are associated with all progestin-based methods. Despite the somewhat cumbersome need to insert the rods, the method's long-term convenience (five years of protection in its present formulation) and low unintended pregnancy rates led initially to its quick adoption by many women in many countries, including the United States.

As with all contraceptives, Norplant has side effects for some women, primarily menstrual irregularities and, in some instances, weight gain. Experience of these sequelae led some women to request discontinuation within the first year of use. However, if not inserted properly, removal of the implants can be difficult in some instances, so that there were cases of difficult removals. As a consequence of adverse publicity about those experiences, as well as an alleged (but totally unproven) effect from the silicone in the rods, there was a widely publicized series of class action suits. Choice of this method dropped precipitously and requests for removal mounted, even in women who had been satisfied with the method (White 1995). These issues are discussed in Chapter 7 in the context of legal and regulatory issues.

The underlying mechanism for the injectable contraceptive, Depo-Provera, is similar to that of progestin-only hormonal methods. It does not, however, have to be taken every day, but is effective for three months. For women who may wish to change their minds, this time commitment may or may not be a disadvantage, depending on the urgency with which they wish to reestablish fertility. For women who wish to continue with an injectable method, the need for quarterly injections can also be a problem if there are constraints on access to an appropriate health provider, although the method is somewhat forgiving since it has a variable grace period. Its contraceptive efficacy is very high and, again, like all progestin-only methods, Depo-Provera can be used by lactating women. The method is approved for use in over 90 countries, including the United States where it was finally approved in late 1992, its approval having been delayed because of its effect on dogs (Hatcher et al. 1994) (see Chapter 7). Several other injectables are available outside the United States, for example, Noristerat and Cyclofem.

Two intrauterine devices are currently available in the United States, the progesterone T (Progestasert System), which must be inserted and removed annually, and the Copper T 380A (CU T380, or ParaGard), which is effective for at least 10 years.² The levonorgesterol IUD (LNg IUD), not yet licensed in the United States, has a manufacturer-recommended duration rate of five years. There are also other IUDs available outside the United States, for example, Multiload and Nova-T.

All newer IUDs have very low failure rates (1 percent or less, equal to sterilization), and fewer side effects (bleeding and pain) than earlier devices. Although the exact mechanism of action of the IUD has been uncertain until quite recently, it now seems that fertilization and implantation rates are both decreased. All IUDs that have been tested experimentally or clinically induce a local inflammatory reaction in the endometrium that changes the cellular and humoral components of the fluid contents of the uterine cavity; in humans, the entire genital tract then appears to be affected by the inflammatory fluids from the uterine lumen. This in turn affects the function and viability of gametes, thus decreasing the rate of fertilization, either in the altered tubal milieu or in the uterine cavity (Bardin 1996).³

Barrier methods of contraception fall into two, sometimes overlapping, categories: (1) physical barriers (male and female condoms, and diaphragms and cervical caps for women), which differentially prevent the passage of sperm and other constituents of semen to the partner's genital tract; and (2) chemical barriers, a more varied class of products and delivery systems. Chemical barrier methods contain a spermicide, which kills or immobilizes sperm (and other cells). The delivery vehicle can be a cream, gel, foam, film, or other formulation. A combined barrier approach involves using a physical barrier with a spermicide; the diaphragm and cervical cap are examples of this combination. The spermicidal agent in most products sold in the United States is nonoxynol-9, a nonionic detergent or surfactant.

There is renewed public interest in barrier methods, since they constitute the only category of contraceptives now available that can reduce the risk of transmission of sexually transmitted diseases (STDs). However, because they are coitally dependent, their effectiveness depends upon consistent and correct use. And, since cultural and motivational factors influence that use, their efficacy varies widely. Prevalence of use of most barrier methods has been increasing in recent years; still, they are used by less than half of all sexually active couples engaging in behaviors that put them at risk of transmitting or acquiring an STD.

The principal barrier method currently in use is the male condom, whose utilization has increased steadily since the late 1980s in response to growing consumer concern about sexually transmitted infection. That same concern has provoked interest in developing new condoms for males that are impermeable to virus and thinner but stronger, and to place control of self-protection in women's hands by developing a female condom, called Reality in the United States and Femidom elsewhere. The concern has also generated a tension in approval processes at the U.S. Food and Drug Administration (FDA) which must weigh the urgency of the public health and individual need for protection from sexually transmitted disease, on the one hand, and the need to assure that new products are safe as barriers against conception and infection, on the other. In addition, the ethical and physiologic challenges of product testing are large and complex. Studies of spermicides and drugs to protect against HIV infection are particularly difficult, since failure could result in either unwanted pregnancy, the transmission of a potentially life-threatening sexually transmitted disease, or both (Russell 1996b).

Some of these problems have already affected the availability on the market of both Reality and Avanti, a new male condom. Avanti is the first condom available for use by individuals allergic to latex (the material used for the overwhelming majority of currently available male condoms) and the first male polyurethane condom to be approved by the FDA. Avanti went onto the U.S. market in a limited number of western states in the fall of 1994, approved by the FDA before the agency began requiring manufacturers of medical devices to perform extensive clinical testing prior to marketing. Although it is actually made of a synthetic material that is similar to the material used for Reality, the FDA determined that Avanti was ''substantially equivalent" to the latex condom instead. The effect of this ruling was to exempt Avanti from the more rigorous clinical testing that had been required for Reality. However, the thinness of the material used for the first Avanti to go on the market produced breakage rates judged to be unacceptable. A thicker material is now being tested in clinical trials under the aegis of the National Institute of Child Health and Human Development (NICHD) (American Health Consultants 1995; Contraceptive Technology Update June 1995).

Other plastic condoms for males that are not polyurethane have also been developed. Carter-Wallace is bringing one to market and Smart Practice has developed the Tactylon condom. Core issues for any male condom are not only concerns about breakage, but concerns about the viral permeability of any material of which they are made.

The female condom has been on the market too short a time to assess its acceptability. Recent focus group research shows a positive response at about the 50-60 percent level; it is quite novel and will require familiarity with its use, on the part of men and women. Cost will continue to be an issue for many women, especially since reuse is not advised. While Reality is not without its limitations, it provides women with much more autonomy than other available methods, although it still requires some discussion with the male partner (WHO 1995b). A washable, reusable female condom would seem to be a useful area of improvement.

There are several approaches to contraception, often grouped as "traditional methods," that have undergone scientific scrutiny in recent decades, resulting in newly rediscovered, reliable, and efficacious methods of family planning that do not require dependence on the contraceptive technologies of the type described above. These methods rely on time-based barriers to conception, behavioral based barriers to conception, or both. Time-based barriers to conception are methods that allow coitus at times when a conception cannot occur, while behavioral barriers are actions that prohibit semen from entering the vagina. Both are

receiving more attention as a result of greater interest in reducing human exposure to drugs and artificial materials.

LAM, the newest method in this category, is an effective postpartum introductory family planning method based on breastfeeding's effect on a woman's fertility. LAM's efficacy depends on three parameters: a woman's menstrual period has not returned postpartum; she breastfeeds frequently, day and night; she gives her baby no other food or liquid regularly; and her baby is less than six months old. A change in any of these requires initiation of another method. LAM has shown up to 99.6 percent efficacy in clinical trtials (Pérez et al. 1992); other clinical studies have found only 1 to 2 pregnancies per 100 women in the first six months after delivery, by life table analysis (Labbok et al. 1994).

LAM's mechanism of action is based on the hypothalamic-pituitary-ovarian axis and its response to the suckling stimulus. Suckling sends neural signals to the hypothalamus. This mediates the level and rhythm of gonadotropin releasing hormone (GnRH) secretion. Early postpartum breastfeeding also affects pituitary responsiveness to GnRH. Since GnRH influences pituitary release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), the hormones responsible for stimulating follicle development and ovulation in the ovary, frequent breastfeeding suppresses adequate ovulation and follicle development. In this manner, the woman's body is kept from producing eggs and becoming fertile in the early months after childbirth.

These methods provide instruction about the timing of ovulation during the ovulatory cycle and the days of potential fertilization of the ovum, and require abstinence at those times (Queenan and Labbok 1992). In recent decades several techniques have been developed, often referred to as "natural family planning (NFP) methods"; they have been comprehensively defined by the WHO as "methods for planning or preventing pregnancies by observation of naturally occurring signs and symptoms of the fertile and infertile phases of the menstrual cycle" and the practice of abstinence at those times.

Calendar Rhythm Although, worldwide, calendar rhythm remains the best known and most commonly used periodic abstinence method, new methods have been developed which allow abstinence decisions to be made in closer relationship to the actual physiology of the cycle in question. The two most widely taught methods are (1) ovulation (or cervical mucus) method, based on observations of changes in cervical mucus; and (2) the symptothermal method, which

uses primarily basal body temperature changes in addition to calendar or observations of changes in cervical mucus. An estimated 2-5 percent of married American women exposed to the risk of pregnancy currently rely on these methods. Theoretically, these methods should provide reasonable efficacy; however, published figures on efficacy vary widely. Calendar rhythm generally is not prescribed today but may serve as an effective adjunct to newer methods.

Cervical Mucus , or Ovulation Method This method relies on the sensation and/ or observation of mucus, observed vaginally or at the vulva, to identify its characteristics over time. The scientific basis for these signs and symptoms is clear: The changes in the mucus reflect normal physiological reaction to the dynamic estrogen and progesterone levels of the menstrual cycle which can be used to approximate the time of ovulation. Use of this method generally includes maintenance of a daily record, often in a monthly format, to aid in assessment of the phase of the cycle; charts have been developed using colored tabs or symbols to indicate different signs and symptoms.

The Symptothermal Method The symptothermal method provides a multiple index approach and is based on the use of at least two indicators to identify the fertile period: the basal body temperature (BBT) shift, and either cervical mucus or calendar rhythm. The relationship between temperature and ovulation was identified as early as the 1920s: BBT, reflected in the temperature registered orally, rectally, or vaginally before rising in the morning, will rise slightly (about 0.2°-0.4°C, or about 0.4°-0.8°F) in concert with the increasing progesterone levels of the early luteal phase of the menstrual cycle. Generally, the shift is said to occur when the BBT reading is more than 0.05°C (0.1°F) higher than the highest of the previous six postmenstrual readings, although there are other acceptable approaches; a slight drop in temperature (about 0.1 F) may be noted around the time of ovulation. Interpretation of BBT charts may demand considerable education.

Fertility Awareness Methods "Fertility awareness" is a term used when signs and symptoms are taught as part of general reproductive health and family planning or family life education. The term "fertility awareness method," on the other hand, generally applies when either periodic abstinence or a barrier method is used only for pregnancy avoidance during the fertile phase, as that is identified using any of the three periodic abstinence methods listed above. Thus, periodic abstinence may be a part of practicing a fertility awareness method or of natural family planning, but the philosophies behind the two approaches are different.

Interest in methods for emergency contraception is gaining momentum in the United States, although they have been available in Europe and the United Kingdom for over a decade. These methods are used after an act of unprotected intercourse, either because of method failure or failure to use a method. Emergency contraceptive approaches include the use of standard combination oral contraceptives (COCs) containing estrogen and progestin in a postcoital regimen to prevent pregnancy, a regimen of progestin-only minipills, or insertion of a copper-T intrauterine device. Mifepristone (RU 486) has been used as an emergency contraceptive in research trials but is not yet available for that purpose in any country.

When standard COCs are used for emergency contraception, they are called ECPs (emergency contraceptive pills). Though commonly known as the "morning after" pill, ECPs may actually be taken immediately after unprotected intercourse and up to 72 hours beyond; dosage and timing of administration vary according to formulation. Minipills are contraceptive pills that contain only progestin (and not estrogen). Their side effects (nausea and vomiting) are far less common than with COCs, but the window of use is narrower: The time limit for postcoital administration is 48 hours. The copper-T IUD can be inserted up to seven days after unprotected intercourse, is significantly more effective than either ECPs or minipills, and can be left in place to provide continuous effective contraception for up to 10 years. However, like any IUD, it requires skilled insertion using antiseptic practice and is not ideal for women at risk of sexually transmitted diseases (Hatcher et al. 1995).

In Europe, the main hormonal method used is the "Yuzpe Regimen," the sequential administration of higher-than-usual doses of estrogen and progestogen, marketed by Schering AG under the brand name PC4 and licensed in the United Kingdom and some European countries. The Hungarian company, Gedeon Richter, markets the progestogen-only product "Postinor" as a postcoital contraceptive in eastern Europe and some countries of the Far East (Hughes 1995).⁴

Each of the three methods that are available in the United States requires a prescription and all are currently marketed as regular methods of ongoing contraception; none is marketed as an emergency contraceptive, primarily because no pharmaceutical company has applied to the FDA to market emergency contraceptives (Kaiser/Harris 1995). Without FDA approval, manufacturers cannot market or advertise these products for postcoital use, so the normal educational function of drug promotion is absent (Hatcher et al. 1995). As a consequence, most women and many clinicians do not know about emergency contraception, even though a clinician may legally prescribe an approved drug for an unlabeled

purpose ("off-label use") and even though considerable research demonstrates that emergency contraceptives are safe and effective (Grossman and Grossman 1994; Trussell and Ellertson 1995).

While dramatically new approaches to contraception may take decades to develop (see Chapter 4), some areas of research and development have advanced and, all things being equal, could produce new contraceptive formulations within the next 10 years (PATH March 1993, June 1993, 1995). It takes a tremendous amount of time—a minimum of 15 years—to develop and market any new pharmaceutical from start to finish. For that reason, approaches considered here include only products that are already in some stage of the drug development process, even if that stage is relatively early.

Thus, this section is about transition, from the universe of existing contraceptive methods to the universe of shifting emphases indicated by the women's agenda and new targets that might permit response to those emphases and to the general public health need for a fuller range of contraceptive options for women and for men. The categories reviewed are: (1) improved methods for women, including improved oral contraceptives, new delivery systems, postcoital methods, and better barrier methods; and (2) more methods for men.

Throughout the period during which oral contraceptives have been used—nearly 40 years—continually better formulations have been introduced, with improvements focusing on development of new progestins and lower levels of hormone content, both estrogen and progestin. Work continues in areas of further refinement.

One line of current OC research and development focuses on designing new regimens for taking the drug. These include shortening the pill-free interval and changing the sequence of administering estrogen and progestin (the so-called priming regimen). The purpose of these changes is to reduce the dose of the drugs without sacrificing what has been achieved in efficacy and cycle control.

Incorporating new estrogens into OCs—either natural estrogens or, further down the road, synthetic ones—is another area of current research. The goal is to reduce some of the drug's current undesirable side effects. These include, in some women, weight gain, mood swings, unfavorable bone and lipid effects, and increased blood coagulability, which occasionally can lead to thromboembolism and stroke.

New progestogens also offer hope for reducing the current liabilities of OCs. Moreover, they may allow researchers to develop contraceptives targeted specifi-

cally to a subset of the general pill-taking population, for example, OCs designed specifically for smokers, overweight women, or teenagers who are prone to acne.

While not as advanced, there is considerable research being conducted on the development of tissue-selective steroid hormones. The hope in this area is to come up with a steroid that specifically targets key reproductive tissues. Researchers may also be able to develop nonsteroid molecules that interact only with specific estrogen or progesterone receptors. Both of these advances could reduce the occurrence of unwanted side effects elsewhere in the body.

Because many women taking progestin-only formulations experience bleeding problems, a high priority in OC research today has become the mechanism of uterine bleeding. If it were better understood and these problems were prevented, women might more often choose and continue with this effective method of contraception. This is an area where basic science still has work to do.

Another area of work is predicated on the hormone responsible for seasonal breeding cycles in most mammalian species, melatonin, which has been found to combine with ovarian hormones to shut off the hypothalamic center directing ovulation. This line of inquiry has been pursued by a small pharmaceutical company, Applied Medical Research, which has developed "B-Oval," a new generation estrogen-free oral contraceptive containing a patented formulation of 75 mg melatonin and 0.5 mg norethindrone, the most widely used progestogen over the last 20 years. The product is in the preliminary stages of phase III clinical trials in the United States (Executive Briefing 1995).

Research into the areas mentioned above could provide significant improvements in a relatively short period of time. The consideration of recent scientific advances supports this notion. Our increasing understanding of the molecular mechanisms through which steroid hormones function, the development of molecular models for some of these mechanisms as well as effective screens for steroid receptors, and the recent identification of steroid receptor subtypes and their associated proteins provide a broad knowledge base. New developments in combinatorial chemistry and high-throughput screening allow researchers to make, and screen, enormous numbers of new chemical compounds in a very short period of time. The combination of this new knowledge with these relatively new techniques could make for a relatively short development period.

For many years, clinicians have recognized the additional benefits to reproductive health that OCs can provide, although women themselves have not (American College of Obstetricians and Gynecologists 1994 and 1985; Russell 1996b). As indicated earlier in this chapter, depending on a woman's age and health status, these benefits can include protection against ovarian and endometrial cancer, pelvic inflammatory disease, fibrocystic breast disease, ovarian cysts, ectopic pregnancy, iron-deficiency anemia, dysmenorrhea, and osteoporosis. As today's mandate for combining effective contraception with methods to improve women's health grows, this aspect of OCs should be considered in all future research and development decisions.

From a market perspective, there are two sets of arguments for the continued investment in improvements in oral contraceptives. One is that the pharmaceutical industry has an enormous amount of money and expertise already invested in this product line. In addition, with some exceptions, for instance, China, where IUD use is more common, and Japan, where the marketing of oral contraceptives is prohibited, oral contraceptives are the most frequently used method of reversible contraception in the world and thus constitute a large and established market. Furthermore, many of the liability issues that affected oral contraceptives in the past are now resolved, so that future risk is attenuated although, at least in the highly litigious climate in the United States, that risk is ever-present.

An alternative perspective is that there are enough highly effective oral contraceptives already on the market and improvements are likely to be quite marginal, so that further work in this field has low priority compared to the need for new products to meet new priorities. This leaves the question of whether, if funding were to be removed from OC research and development, it would then be shifted into other areas of contraception. Absent positive incentives, some companies currently in the field might dismantle their contraceptive research teams and devote the freed-up resources to other, less risky areas of research and development. There is also the matter of negative stimuli, one of which is the fact that the USFDA considers all oral contraceptives as belonging to a single class of drugs. Such "class labeling" prevents manufacturers from differentiating among products so that they can charge more for some formulations than others.

The principal focus of innovation in drug delivery systems for contraceptives has been on implants and injectables, a focus that includes not only attempts to improve the mechanisms of delivery but the pharmacological content of what they deliver. Implants and injectable contraceptives offer a number of advantages over other methods of contraception. Perhaps the most important is that they have a high degree of efficacy, combined with narrow margins for failure. Furthermore, the fact that they are, almost by definition, long-lasting—the most commonly used formulations range from three months (Depo-Provera) to five years (Norplant) in duration of efficacy—is seen as attractive by a number of women. Others, who do not want to be dependent on having to see a clinician, do not find these methods appropriate.

Current implants and injectables for women all contain progestins which, as noted earlier in this chapter, work by blocking ovulation and increasing the thickness of cervical mucus so that sperm have difficulty moving through the system. The pioneer in this area was Norplant; its successor, Norplant II, releases the same amount of levonorgestrel as the present Norplant formulation but through two rather than six implants, making insertion and removal easier. It is worth noting that the two-rod presentation might well have superseded the six-

rod system that came onto the market, except for the fact that production of the original elastomer for the Silastic tubing was halted, requiring a shift to another elastomer and thereby slowing the approval process in the United States.

Other new implant systems are in various stages of development, again with emphasis focused on reducing the number of capsules, varying the length of effectiveness, and offering biodegradability. Considerable work is being done on single-rod implants, including Implanon, Uniplant, and a device using the progestin Nestorone (ST-1435). By reducing the number of rods implanted, the new products should make this long-lasting form of contraception more appealing to users. Now in phase III clinical trials, Norplant II and Implanon are the most advanced of the new possibilities (Coutinho 1993; Singh et al. 1985 and 1989).

Implant manufacturers are engaged in development of single-rod implants and, probably further into the future, biodegradable implants that will eventually dissolve in the body but will be removable, and hence reversible, for a while (Alexander 1995). Primate studies conducted by researchers under the aegis of NICHD suggest that the possibility is not far-fetched and that a levonorgestrel-containing biodegradable implant (Capronor) can provide adequate contraception for up to two years; however, the biodegradability aspect of this method remains challenging (Darney 1994) and we are still speaking of animal models. Other biodegradable formulations under study include norethindrone pellets (implants [e.g., Annuelle, Endocon]) and norethindrone microspheres (injectable).

Another product that should be available relatively soon is the vaginal ring, a doughnut-shaped ring that fits in the vagina and releases either progestin alone or a combination of estrogen and progestin. The progestin-only rings can be worn continuously; the combination rings would be removed for one week in every four to allow for menses. While less long-lasting than implants, these products offer advantages over daily pill-taking or insertion of another contraceptive product; at the same time, they are under the immediate control of the user, an important feature for many women. Researchers are also working on development of a vaginal ring for lactating women that would last for three months; efficacy and acceptability have been demonstrated in large multicenter trials (Landgren 1994; Mishell 1993).

Also well advanced is a new IUD that releases a progestin for up to five years. Already available in some European countries, this new device seems to have fewer side effects—for instance, cramping, blood loss, and increased risk of pelvic inflammatory disease—than traditional IUDs and has a very low pregnancy rate (WHO 1994b). The expectation is that new implants for women that are more easily inserted and removed, as well as a hormone-releasing vaginal ring, will be available by the year 2000; the progestin-releasing IUD should be available in the United States by the year 2005 (Alexander 1995; WHO 1995a).

The only contraceptive injectable for women on the U.S. market so far is Depo-Provera (although others are available elsewhere in the world). A number of institutions are working to develop new injectable contraceptives such as

levonorgestrel butanoate (WHO 1995a) and, as mentioned above, norethisterone microspheres. Some of these products do contain estrogen as well as progestin, thereby overcoming the bleeding side effect.

While ranking high in efficacy, one problem with all implants on the market and most that are under development today is that they contain only progestin (as opposed to a combination of estrogen and progestin). In many users, progestinonly products cause irregular uterine bleeding as a side effect (particularly in the early stages of use), which limits their acceptability.

Although research on implants and injectables has focused on developing products for women (as has most contraceptive research), there are a few products that fall into this category that are now under development for men. These are discussed below in the context of new contraceptive methods for males.

The barrier methods of contraception that are now available are either mechanical (male and female condoms, diaphragms, and cervical caps), chemical (spermicides and other formulations), or some combination of both, all of which are inadequate to needs. Recognition of this inadequacy has motivated movement toward research to correct it, involving efforts by a number of public sector entities, including the World Health Organization's Special Programme of Research, Development and Research Training in Human Reproduction (WHO/ HRP) and the Human Immunodeficiency Network (HIV/NET); the NICHD's Center for Population Research; and Family Health International and the Contraceptive Research and Development (CONRAD) Program, both supported by the U.S. Agency for International Development (USAID). The driving objectives of these efforts are to improve product safety and efficacy, formulations, and configurations; to widen the spectrum of barrier methods that women can control and use discreetly (Mauck et al. 1994, Stewart 1994); and to determine acceptability prior to decisions about market launch.

One especially active area of research is in efforts to combine contraceptives with effective mechanical barriers to sexually transmitted diseases (STDs). Included in this category are methods developed for contraception, some of which may provide protection against STDs. These include Lea's Shield and FemCap. Lea's Shield is a "one size fits all" device that blocks the cervix but has a valve that allows passage of cervical secretions and facilitates insertion. FemCap is a new cervical cap with a design that increases apposition to the cervix and vaginal wall and is sized based on parity. Both devices could become available within a few years. Their efficacy against pregnancy or infection is still unknown and their present costs would be prohibitive for many women. The usefulness in

much of the developing world of any such coitus-dependent method that is both costly and dependent on access to privacy and clean water remains questionable.

In addition, manufacturers have developed a new vaginal sponge, Protectaid, which incorporates three spermicides that have a synergistic spermicidal and microbicidal effect and is designed to provide STD protection without irritating the vaginal epithelium (Psychoyos et al. 1994). The sponge contains a compound spermicide, microbicide, and virucide that, in laboratory studies, has inactivated HIV as well as chlamydia and trichomonas. With the withdrawal from the market of the Today sponge in 1995, there is no other comparable product available in any market.

The spermicides that are now on the market are not very effective against either sperm or pathogenic organisms. This may be due to weaknesses in certain characteristics of these products. Due to their short period of activity and messiness, many of these formulations are not seen by users as particularly desirable. While some spermicides, specifically nonoxynol-9, can kill HIV and bacteria in laboratory studies, there is concern that, as a detergent, it may also kill cells and irritate the vaginal epithelium, thereby possibly elevating susceptibility to HIV transmission. This has led many researchers to suggest that research should now focus on noncytotoxic rather than cytotoxic methods of stopping sexually transmitted pathogens.

Any potential new barrier method should not compromise natural defenses and, if possible, should strengthen them. Defense mechanisms include a thick epithelial lining and mucus secretion during certain stages of the menstrual cycle, both of which provide a physical barrier. The vagina and cervix are also equipped to mount antibody and cell-mediated immune responses against pathogens, and secretions from these areas contain several nonspecific antibacterial and antiviral defense agents, including lysozyme, polyamines, zinc, hydrogen peroxide, lactoferrin, and B-defensins. Finally, the natural flora of the vagina, that is, lactobacilli, keep the vaginal pH low (Larsen 1993), creating yet another deterrent to microbes. Current research focuses on developing a chemical barrier that would be nontoxic and nonirritating to these beneficial microbes and at the same time capable of killing or disabling invading pathogens.

Researchers at Johns Hopkins University are working with the support of the NICHD and the National Institute of Allergy and Infectious Disease and, most recently, with the HIV/NET component of the Global Programme on AIDS, on development of buffer gels⁵ that can maintain vaginal acidity even in the presence of semen and cervical mucus. The gels are created with nonmetabolizable polymers that should produce only minimal perturbation of the normal vaginal flora. Because the cell membranes and the vaginal epithelium are not permeable to polymers, they can provide high buffer capacity without producing the toxicity

or irritation caused by high concentrations of membrane-permeable weak acids (e.g., lactic and acetic acids). Indeed, the gel simply increases the buffer capacity of vaginal fluids sufficiently to overcome the neutralizing action of semen and cervical mucus. Furthermore, compared with other broad-spectrum microbicides, an acidic buffer is less likely to irritate or disturb normal vaginal microflora.

This combination of characteristics suggests that the gels can be used to create new methods for vaginal protection against pregnancy and STDs and could also serve as drug-delivery vehicles for vaginal therapy (e.g., during menses and menopause, for vaginal bacteriosis). They may also help prevent the onset or relapse of vaginal and urinary tract infections. More specifically, the Reprotect gel formulation also has excellent qualities as a sexual lubricant; is inexpensive, colorless, and odorless; and its constituents are in products already approved by the FDA for vaginal use or that are generally recognized as safe. Pilot experiments using the mouse/HSV-2 model demonstrate that the gel's acidic-buffer action blocks vaginal and genital skin transmission of genital herpes infections, which suggests that it might also be effective against HIV infections. The gel will go into phase I trials in Boston, Malawi, India, Zimbabwe, and Thailand in 1996 (K Whaley, personal communication, February 1996). Another vaginal gel formulation, PC 213, comprised of sulphated polysaccharides, has completed Phase I vaginal irritation studies, under the aegis of the Population Council (Stein 1995).

Another possibility is a vaginal product containing squalamine, a natural substance that appears to be spermicidal as well as microbicidal. Isolated from animals, squalamine is thought to protect them from a wide range of diseases. Further animal studies are being conducted prior to doing safety studies in women, under a Cooperative Research and Development Agreement between NICHD and Magainin Pharmaceuticals (N Alexander, personal communication, 1995; Russell 1996a).

There is other research that builds on compounds derived from plants that have exhibited spermicidal and virucidal properties. The National Institute of Immunology in India has isolated oils from the neem tree (Azadirachta indica). One formulation, Praneem polyherbal cream, combines neem seed extract with soapnut extract (Sapindus mukerossi) , and is said to induce local cell-mediated immunity. Phase II trials are reported to be under way in India. Other plant extracts being studied for their potential ability to kill sperm, bacteria, and viruses include papain from papaya and gossypol from cottonseed oil.

One unresolved and quite urgent issue concerning combination contraceptive cum anti-STD agents in the United States is how they will fare in the FDA approval processes. Guidelines from the agency will be utterly essential for research and development in this area if new methods are to make their way into a very needy market. At the time of this writing, there are no FDA guidelines for

research and development activities with respect to products in this combined category.

A rich and novel area of work in recent years has been around the antiprogestins (sometimes referred to as antiprogestogens), steroid antihormones with a unique ability to block the action of progesterone at the cellular level through binding to the progesterone receptor in target tissues (Van Look and von Hertzen 1993). Progesterone exerts well-documented effects throughout the reproductive system (including the uterus, cervix, breast, and pituitary-hypothalamic system) and plays a key role in both establishing and maintaining pregnancy. It also exerts less well-defined actions on tissues outside the reproductive system (e.g., brain, vascular endothelial cells) and on lipid metabolism (Baulieu 1993; IOM 1993).

The first antiprogestin was discovered fortuitously by scientists searching for an antiglucocorticoid, a compound that would interfere with the action of adrenal gland hormones, glucocorticoids, that are involved in the physiologic regulation of virtually all tissues in the body (IOM 1993). While several hundred antiprogestins have been synthesized, only three have been given to humans (mifepristone, lilopristone, and onapristone). Just one of those, mifepristone—RU 486—has been extensively studied in humans, most widely as a means of nonsurgical termination of early pregnancy (Van Look and von Hertzen 1993).⁶ The compound has been licensed for that purpose in France, Sweden, and the United Kingdom, and is being manufactured in China. In the United States, RU 486 is in phase III clinical trials under the aegis of the Population Council (IOM 1993).

One of the most promising potential uses of antiprogestins is as a postcoital emergency contraceptive that would reduce the chance of undesired pregnancy after unprotected intercourse around the time of ovulation. Because of the critical role progesterone plays in early transformation of the endometrium (and its possible role in follicular maturation and ovulation), researchers hypothesized that mifepristone might act as an effective postcoital contraceptive. Studies in England and Scotland have supported this hypothesis (Baird et al. 1988).

Researchers have also experimented with antiprogestins as expected menses inducers (EMIs, taken regularly just before the onset of expected menstruation) and missed menses inducers (MMIs, taken only when the menstrual period does not occur). Perhaps most promising has been work combining an antiprogestin (mifepristone) with a prostaglandin (gemeprost). In a recent study, researchers working in six countries demonstrated that a combination of mifepristone followed two days later by gemeprost-induced menstruation in 98 percent of a group

of women who were up to 10 days late getting their periods (Van Look and von Hertzen 1993).

The potential of the antiprogestins goes well beyond emergency contraception. Their role in human health and disease could be large, given their applicability to a variety of reproductive and nonreproductive conditions. Research has suggested that antiprogestins may have clinical value in treating endometriosis, uterine leiomyomas (fibroid tumors), and endometrial and breast cancers. They also appear to offer value for obstetrics and fertility regulation. The antiprogestins also have potential for use as antifertility agents by inhibiting ovulation, preventing or disrupting implantation, and/or inducing luteal regression. During the early luteal phase, mifepristone may prove to be not only an effective postcoital agent used under circumstances of emergency but as a once-a-month pill or menses-inducer. The role of antiprogestins as ovulation inhibitors could be particularly attractive, since this is already a widely accepted category of contraceptive. Antiprogestins may also have clinical utility for the treatment of several other conditions, most importantly including meningioma (tumors arising from membranes surrounding the brain) and, because of their antiglucocorticoid effects, in palliative treatment of hypercortisolism due to Cushing's syndrome, some forms of depression and glycoma, and wound healing (Baird 1993; Croxatto et al. 1993; IOM 1993; Van Look and von Hertzen 1993).

There is much research to be done in all these areas and, from this broader perspective, the antiprogestin compounds should be highly attractive to industry. However, perhaps the most striking aspect of the antiprogestins, as seen in the history of RU 486, is the extent to which medical and economic decisions about their development, clinical testing, marketing, and use are being shaped by social and political forces, centering on strongly held, powerful secular and religious values either favoring or opposing abortion (Swazey 1992). The core issue in the controversy is the use of RU 486 or future antiprogestins as abortifacients (Banwell and Paxman 1992; Swazey 1992). The range of actions of the antiprogestins, together with incomplete understanding of their mechanisms (IOM 1993), can blur distinctions between contraception and abortion, conception and pregnancy, and become entangled in the sometimes vague legislative language used to describe events in the reproductive process (Banwell and Paxman 1992; Cook 1989; Swazey 1992). Roussel-Uclaf, the developer of mifepristone, assigned the rights for production and distribution of RU 486 in the United States to the Population Council, citing a ''hostile political climate in the United States" (Roussel-Uclaf press release, cited in US Department of State 1993; Tanouye 1994) and is said to have closed its research laboratories in this area. In such a climate, it seems unlikely that any large pharmaceutical company would work in this product category, even were the financial gain to be large (Swazey 1992). Two European companies (Organon and Schering AG) have also developed effective antiprogestins, but have decided not to bring them to market.

Other than modifications of the male condom, work on alternative contraceptive methods for men has been limited largely to techniques to permit reversal of sterilization, primarily different methods for occluding the vas deferens and use of no-scalpel vasectomy. A mechanical intervention that is nearing completion in India involves injecting into the vas deferens a non-toxic polymer (styrene maleic anhydride) that blocks the passage of sperm. Unlike a vasectomy, this method is intended to be reversible. Another substance, dimethyl sulphoxide (DMSO), can be injected to dissolve the first. While early animal toxicity studies suggested that DMSO might be carcinogenic, later studies proved those fears unfounded. The product is now being tested in clinical trials with humans.

The other area of work has centered on administration of hormones to inhibit spermatogenesis, the process of sperm production that is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH). One hormonal method for men being investigated by the Population Council is a system of two implants which could provide a convenient one-year contraceptive method for men. One implant delivers an agonist of luteinizing hormone releasing hormone (LHRH) that suppresses sperm production; the other implant, required to compensate for resulting diminution of testosterone, the androgen that governs sexual function, supplies a synthetic androgen (MENT) (Waites 1992). This system is in phase I clinical trials in two countries, and entering human trials under the Population Council (WHO 1995a).

Antifertility vaccines that neutralize hormones required for sperm production or sperm maturation are also in the early stages of development, again under the aegis of the Population Council and the National Institute of Immunology (New Delhi). Phase I clinical trials were expanded in 1993 and, as of June 1995, 12 men had been immunized. The vaccine would be combined with the MENT implant to provide androgen replacement needed for normal sex drive and behavior.

In addition to the challenge of affecting spermatogenesis without impact on sexual function, there is the challenge of achieving infertility in all subjects. International multicenter studies by the WHO and CONRAD/USAID have been struggling with this dilemma and have produced considerable understanding but no product yet. Another challenge has been finding a delivery mechanism that can provide more than a week's worth of protection and there have been international collaborative efforts over the past 15 years to develop longer-acting steroid formulations. This research has focused on methods of administering testosterone, either as testosterone enanthate (TE) or testosterone buciclate, alone or in combination with a progestin such as DMPA or levonorgestrel, or anti-androgenic steroids (e.g., cyproterone acetate, CPA) to interfere with spermatogenesis (Contraceptive Technology Update, August 1995).

The problem with any method that is based on suppression of spermatogen-

esis is the two- to three-month delay between method initiation and infertility, requiring use of another contraceptive method during the initial months of use (PATH 1995). Researchers are evaluating and planning evaluations of the efficacy and acceptability of testosterone enanthate, levonorgestrel butanoate/testosterone buciclate (WHO/NICHD), 7-alpha-19-methyl-nortestosterone (MENT) (Population Council), levonorgestrel/testosterone enanthate, and desogestrel/ testosterone enanthate (University of Washington/CONRAD). Work on the latter combination is particularly promising, since it exhibits faster suppression of spermatogenesis than any testosterone formulation alone. The level of suppression approaches complete azoospermia. When the drug is discontinued, sperm counts rapidly return to normal. Some analysts predict that such a product could be available by the year 2005 (Alexander 1995).

Because of the challenges of duration, lag times in return to fertility, and hormonal balance that have been the focus in work on male methods to date, there is something of a shift in research emphasis toward an emphasis on how to interfere with sperm maturation rather than sperm production (spermatogenesis), since that would avoid disruption of the hormonal balance needed for sexual function. Eventually, new knowledge on the basic biology of reproduction should allow researchers to interfere with spermatogenesis closer to the end of the process, that is, in the testes or epididymis rather than the brain or pituitary, thereby avoiding the wide range of systemic effects. The products of such research are unlikely to be available in the next decade and are, therefore, discussed in further detail in the following chapter.

A final avenue of research focuses on plant compounds that interfere with male fertility. The best known—and most controversial—of these compounds, gossypol, is derived from cottonseed oil. Studied now for over two decades, gossypol is known to effectively suppress sperm production, but has also caused hypokalemia and irreversible infertility in a significant number of subjects. Tripterygium wilfordii, a vine that grows in southern China, has also shown promise as a possible reversible male contraceptive. Researchers have thus far identified six components of the plant with antifertility activity. While toxicology studies have not been completed, these plant compounds show particular promise because they seem to work by interfering in sperm maturation in the epididymis, thus offering a potential contraceptive without side effects involving male sex hormones.

At the outset of this chapter, we stated that there was reasonable probability that a number of improvements in existing contraceptive technologies could become available in the next decade. We also used the term "all things being equal." The case of RU 486, the tensions around the approvals of the Avanti and Reality condoms, and the still-pending fate of Norplant liability, make it clear

that all things are not, in fact, equal. At the same time, the history of the oral contraceptive and the IUD, troubled in a variety of ways, suggests that the needs of individuals worldwide to plan their families somehow, sooner or later, wins out.

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• 1.	A minipill is an oral contraceptive containing no estrogen and generally less than 1 mg of a progestational agent per pill (Hatcher et al. 1994).

• 2.

  The U.S. Food and Drug Administration (FDA) recently approved labeling changes extending the use of the Copper T380A from 8 to 10 years and made two additional labeling revisions. First, the FDA added data from studies by the WHO, Population Council, and the manufacturer indicating that the risk of PID is highest 20 days post-insertion, then declines, and remains low and constant thereafter (Farley et al. 1992). Second, a history of ectopic pregnancy is no longer a contraindication.

• 3.	This refutes the usually held perception that the major mechanism of action of IUDs in

• humans is to disrupt implantation of a fertilized ova. Thus, it would seem to be no longer tenable to propose that the major action of IUDs is to induce abortion (Bardin 1996).

• 4.

  Oral contraceptives are packaged specifically for emergency contraception use in Bulgaria, Finland, Germany, Hungary, Jamaica, Malaysia, the Netherlands, Nigeria, Pakistan, Poland, Singapore, states of the former Soviet Union, Sweden, Switzerland, the United Kingdom, Uruguay, and Zimbabwe (Camp 1994). They have been marketed for emergency contraception in England since 1984.

• 5.	The gels are currently covered by a patent application assigned to ReProtect, LC.

• 6.	Antiprogestins that have reached in vivo testing include onapristone, lilipristone, and ZK 98 734 (Schering AG); ORG 31710 and 31806 (Organon); and HRP 2000 (Research Triangle Institute)(Institute of Medicine 1993).