Introduction

This report is about the need for new contraceptive technologies, the potential of contemporary science to respond to that need, the context in which that need will or will not be met, and the prospective roles of the private and public sectors in meeting it. The study that culminated in this report responded to a request that the Institute of Medicine explore these questions as an element of the Rockefeller Foundation's "Contraception 21" initiative: a search for ways to set the research agenda for the contraceptives of the twenty-first century and to mobilize the resources of all sectors toward a "second contraceptive revolution."1

The First Contraceptive Revolution

A pivotal dimension of family and child well-being and of female reproductive health is the ability to regulate fertility. A critical component of that ability is the availability of safe and effective contraceptive methods, both reversible and irreversible. Before 1960, that availability, for men and for women, was limited to the irreversible options of male and female sterilization and the reversible methods of the condom and withdrawal for men, a few barrier methods for women, and periodic abstinence, all of which had relatively high failure rates when not used consistently and carefully. The "contraceptive revolution" which began in the 1950s changed that picture with the invention of oral contraceptives and the reintroduction2 of intrauterine devices, innovations which, for the first time, separated reversible contraception from the act of coitus (Rockefeller Foundation 1993).

The 1970s and 1980s brought infusions of funding for contraceptive research



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--> Introduction This report is about the need for new contraceptive technologies, the potential of contemporary science to respond to that need, the context in which that need will or will not be met, and the prospective roles of the private and public sectors in meeting it. The study that culminated in this report responded to a request that the Institute of Medicine explore these questions as an element of the Rockefeller Foundation's "Contraception 21" initiative: a search for ways to set the research agenda for the contraceptives of the twenty-first century and to mobilize the resources of all sectors toward a "second contraceptive revolution."1 The First Contraceptive Revolution A pivotal dimension of family and child well-being and of female reproductive health is the ability to regulate fertility. A critical component of that ability is the availability of safe and effective contraceptive methods, both reversible and irreversible. Before 1960, that availability, for men and for women, was limited to the irreversible options of male and female sterilization and the reversible methods of the condom and withdrawal for men, a few barrier methods for women, and periodic abstinence, all of which had relatively high failure rates when not used consistently and carefully. The "contraceptive revolution" which began in the 1950s changed that picture with the invention of oral contraceptives and the reintroduction2 of intrauterine devices, innovations which, for the first time, separated reversible contraception from the act of coitus (Rockefeller Foundation 1993). The 1970s and 1980s brought infusions of funding for contraceptive research

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--> by the U.S. government and other governments, motivated by demographic concerns. Support was made available for improvements in the delivery of hormonal contraception, as well as for the development of new delivery modalities such as implants and injectables, so that the quality and range of contraceptive options were considerably enhanced. Contraceptive use in the developing world rose from less than 10 percent of couples (31 million) in the early 1970s to current levels of 50-60 percent (446 million) by the late 1980s (United Nations, forthcoming). Use of the technologies emerging from the first contraceptive revolution accounted for the great preponderance of that increase: Despite significant regional differences, as of 1995 most of the world's women who use any contraception are selecting modern contraceptive methods (Guttmacher Institute 1995a). The Changing Structure of Contraceptive Needs While currently available contraceptives are obviously adequate for many individuals, there is ample evidence that they can only inadequately respond to the changing structure of contraceptive needs. The character of those needs, as we will discuss in detail in the next chapter, is variable, complex, and different in several important ways from the needs that characterized the period of the first contraceptive revolution. The fact that those needs are presented sequentially in the following paragraphs should not be interpreted as evidence of priority; all are of great importance and each is in some way related to the others. First, there is the sheer volume of need. Minimum estimates of what is defined as "unmet need" range from 120 million to 238 million women worldwide who are at risk of unintended pregnancy because of nonuse of contraception, misuse, or contraceptive failure (Guttmacher Institute 1995a; Institute of Medicine [IOM] 1995a; Robey et al. 1992). Nearly half of the pregnancies defined as "unintended" in the United States as of 1987 had occurred among the 90 percent of women who were, in fact, using some contraceptive method (Forrest 1994). Second, there are the 52 million pregnancies that women decide to resolve in abortion, approximately 28 percent of all pregnancies worldwide (Guttmacher Institute 1994; WHO 1994). Somewhere around 21 million of those abortions are performed under unsafe and septic conditions, and the burdens of mortality and morbidity they generate are high (WHO 1994). In the United States, of the 6.3 million pregnancies estimated to have occurred in 1987, over half were unintended at the time of conception and, of those, approximately half ended in abortion (Harlap et al. 1991). In the current array of contraceptive methods, there is no method that is explicitly intended to prevent pregnancy in women who have been exposed to unprotected sex, thereby obviating the possible need to confront the dilemmas of abortion. Third, there is the high proportion of women who opt for sterilization, now the most used method in most of the world's regions, including the United States

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--> where over one-third of women using contraception have made that choice (Forrest and Fordyce 1993; Ingrassia et al. 1995; Marquette et al. 1995; Mosher and Pratt 1990). Women may elect this essentially irreversible method, even at unexpectedly young ages and earlier than they themselves might wish, because no alternative reversible method is seen as satisfactory. Fourth, there remain large subpopulations whose contraceptive requirements remain insufficiently addressed, significantly those of males in general, to whom the first contraceptive revolution brought no new reversible contraceptive options, as well as the requirements of special times and circumstances across the female life span, notably adolescence, lactation, and the perimenopausal period.3 Fifth, there is the virtually undisputed reality that no existing contraceptive method can meet the requirements, intentions, and preferences of all individuals in all circumstances over entire reproductive lifetimes. Nor can any method be totally without side effects, risks, or trade-offs in terms of safety, efficacy, convenience, usability, and appropriateness (Fathalla 1994). In fact, it is difficult to envision any prospective method that could respond to all these variable requirements. Furthermore, for many women it is also important, even vital, that their contraceptive method be "user-controlled," that is, that it permit them to be the primary decision-makers about utilization. All this argues for the broadest possible range of available options. Sixth, of particular concern in the United States, is the fact that the range of contraceptive options, rather than becoming more generous in an era when so many other medical technologies are proliferating, is actually narrowing and, in fact, is more constrained than in other industrialized countries. The reasons for this are diverse and complicated, their net effect most worrisome. Seventh, and of mounting urgency, there is the need to address the growing burden of the sexually transmitted diseases and the ways in which they intersect—or do not intersect—with contraception. At present, only abstinence from sexual intercourse provides absolute protection against both infection and conception. For those choosing to be sexually active, while some forms of contraception reduce the possibility of either pregnancy or infection, they do not eliminate it. The male condom can provide good protection against both, but its efficacy depends on perfect use and on decisions which do not inevitably rest with women. New Concepts: Reproductive Health And The "Woman-Centered Agenda" Over the past 15 years, as a consequence of thought and advocacy on the part of internationally oriented activist groups, funding agencies, research organizations, and policy makers concerned with women's health, the concept of "population control" has moved toward a perspective which contemplates contraception within the more ample framework of "reproductive health." That framework is a comprehensive, more inclusive model of female health and well-being that

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--> encompasses fertility and infertility, contraception, abortion, childbearing, maternal morbidity and mortality, sexuality, sexually transmitted diseases, menstruation, and menopause and, for some theorists, child survival and male reproductive health as well (Behrer 1993; Dixon-Mueller 1993; Ford Foundation 1991; Germain and Ordway 1989; Lane 1994; Ruzek 1993). At its most expansive, the model also takes into account the social, political, and economic context of reproductive health and women's general empowerment (Lane 1994) and the ways in which each of these complements and reinforces the others (Bongaarts 1994; Germain and Kyte 1995; Guttmacher Institute 1995b; UNFPA 1994).4 The central themes informing this framework, that is, the concepts of women's control over their own bodies and equity for women's physical safety and well-being, have now taken root in the United States. The general subject of the health of U.S. women is now a focus of priority concern and has provoked attention to the necessity of including women in clinical trials for new preventive and curative therapies, long focused mainly on men. In response, the U.S. National Institutes of Health established in 1990 an Office of Research on Women's Health and recently launched a ten-year Women's Health Initiative. All this has fueled the interest of pharmaceutical companies, several of which have established female health care research departments (Bhargava 1992). A significant component of this new rationale and, within that, contraception, is the accumulated body of evidence that just meeting the individual family planning desires of women (their ''unmet need") would go a good distance toward meeting the demographic goals of those countries that have set such goals (Sinding 1994). The principal reason for this dynamic is that family planning approaches that are "woman centered," dedicated to quality of care, provision of a full range of contraceptive options and the informational basis for making informed choices among them, and generally satisfying clients are simply more effective in terms of adoption and continuation (Bongaarts and Bruce 1995; Bonnie et al. 1991; Bruce and Jain 1995; Germain 1987; Potts and Rosenfield 1990). It is individual women, with full access to better information and better tools, who determine the outcomes of population programs, rather than population programs determining women's behavior (Miller and Rosenfield 1996). This represents a shift away from the rationale that drove much of public funding for contraceptive research during the 1970s and 1980s, rooted as it was in the demographic concerns of governments (Brown 1995). It also lies at the heart of the Programme of Action that was articulated at the 1994 United Nations International Conference on Population and Development in Cairo. In this context, individuals decide to limit or space births for a variety of personal and family reasons, even though many individuals may well include among those reasons a recognition of the societal implications of having very many children. Finally, the shift has laid the foundation for a new "woman-centered" approach, not only in services but in deciding on priorities for contraceptive research and development (R&D)(Fathalla 1994; Khanna et al. 1994). At the most

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--> general level, the approach calls for an agenda centering on methods more directly under women's control so as to enhance their autonomy, enable them to shield themselves from sexually transmitted disease, diminish their dependence on the medical system and on the agreement of a partner for use of a contraceptive or anti-infective, and provide them with entirely new access to a range of methods that can be used postcoitally. While it might seem counterintuitive, another component of that agenda is development of contraceptive choices for men that will permit them to share more of the responsibility for contraception. There does appear to be consensus on these broad areas as appropriate and necessary orientations for new contraceptive research and development. There also seems to be agreement that the current array of available contraceptives must be expanded, though the point is often made that it is necessary to improve the availability of those contraceptive methods that presently exist, as well as the ways in which they are made available. Important among those ways is assuring much better informed contraceptive users. At a more specific level, however, there is no "universal woman," nor is there some unitary view of women's contraceptive preferences. There are differences among women's health advocates—as well as between those advocates and scientists—about the meaning of each of these focal areas, their relative importance, and the proper criteria for setting research and development priorities (Barroso 1994; Correa 1993; Dixon-Mueller and Germain 1993; Germain 1987; Marcelo and Germain 1994; WHO/HRP 1991; Women's Global Network for Reproductive Rights 1993). Most of the energy in the debate centers on perceptions of the risk and benefits of contraceptive technologies and on the definitions and relative weights of their safety, efficacy, affordability, and acceptability (Snow 1994). The details of this debate are reflected in Chapter 2 and Chapter 5 of this report since, as significant features in the current climate surrounding contraceptive research and development, they affect the determination of needs in the field and, by extension, the market. Contraception and Sexually Transmitted Disease A question raised before this committee was the appropriateness of including the sexually transmitted diseases (STDs)5 in a study of the current scientific prospects for contraceptive technology. The question is natural enough: The fields of family planning and the prevention and cure of STDs, including HIV/ AIDS, have traditionally operated independently, surely in the case of research and development, only slightly less so in the delivery of clinical services (Cates 1994). The operating assumption has long been that the STDs have to do with sexual activity, and contraception with reproduction. The implication was that the STDs were not a concern for the normative majority, that is, married couples creating families, for whom the risk of sexually transmitted infections was considered trivial.

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--> The epidemiologic and sociologic facts of today's world must persuade us that this norm is much eroded and that the dynamics producing the erosion have altered the composition and greatly increased the size of the global population at risk, of which a considerable proportion is—simultaneously—vulnerable to possibly unwanted conception and surely unwanted infection (Brunham and Embree 1992; WHO 1995). This is so despite the fact that sexual activity is not necessarily concurrent with reproduction or contraception: sexual activity continues much longer than reproductive activity, may occur during pregnancy and lactation, and may involve a variety of partners and types of sexual activity that do not have reproduction as their primary objective. The dimensions of these phenomena are discussed in Chapter 2 from the perspective of needs for new technology, and in Chapter 3 from the perspective of the market. Another point of relevance is the existing technologic intersection between contraception and disease prevention. The condom has long been used as a contraceptive and as a barrier to STDs. While other contraceptives have also been found to provide some protection against infections, none protect against all STDs; any protection is highly dependent on perfect use and is variable by gender; double protection is ideally required; and some contraceptives, individually and used concurrently with other methods, may even enhance susceptibility to the risk of certain infections. Unfortunately, those contraceptives that best prevent pregnancy provide minimal protection against STDs. In all instances, there are many unanswered questions which jointly affect the fields of sexually transmitted disease and family planning and involve questions of safety, contraceptive use, and the nature of the need for new contraceptive methods (Antrobus et al. 1994; Cates and Stone 1992). The fact that some existing contraceptives—barrier and non-barrier—bestow any protection at all suggests that scientific exploration of this intersection is not only necessary but plausible (Claypool 1994; Elias and Heise 1993; Stratton and Alexander 1993). The Need for a Second Contraceptive Revolution By the late 1980s, many of the factors that had been driving the research agenda of the 1970s and 1980s had changed drastically. The mission's clarity had become blurred by the debate about whether it was population growth, or inequitable access to economic and social opportunity, that was the world's major problem. There was also the widespread misconception that, with oral contraceptives, the "problem" had been solved. From the standpoint of the science, the promise of reproductive endocrinology was diminishing, funding opportunities were decreased, and new scientists were not being attracted by the field. And, largely for legal, political, sociocultural, and ultimately economic reasons, there was relentless retrenchment from the field of contraceptive research by most major pharmaceutical companies. In the 1960s, a dozen large pharmaceutical companies had been active in contraceptive research and development; nine of

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--> those were in the United States. By the mid-1980s, just four such firms continued to have significant contraceptive research and development programs; three were in Europe, just one in the United States.6 Had it not been for public sector commitment during these years, the field might well have fallen into utter scientific oblivion (NRC/IOM 1990; Rockefeller Foundation 1993). The net effect of this stalling of the first revolution was that there has been no real scientific breakthrough in contraceptive technology, for either men or women, in over three decades. The sole exception has been the antiprogestins, arguably the greatest breakthrough in fertility regulation technology since the discovery of oral contraceptives (Brown 1995; IOM 1993b). Modification of hormonal contraceptive delivery through injectable and implant technologies and dramatic improvement in intrauterine devices (IUDs) were significant developments, but they were not significant breakthroughs from the perspective of fundamental science. Because development of new contraceptive technologies typically takes 10 to 20 years, contraceptive products that are now emerging from the pipeline tend to fit the earlier demographically driven paradigm and respond only in a limited way to newer thinking (Brown 1995). Although recent surveys of contraceptive research and development indicate that there are close to 100 product leads being pursued around the world, most are incremental improvements—modifications in dosage, form, or delivery—and all but one are hormonally based (PATH 1993). Such improvements have been important and necessary but the argument might be made that, absent any shared, coherent set of priorities, large gaps will persist in contraceptive research and development. At best, contraceptive needs will be filled erratically and slowly, impairing wise and effective allocation of resources under conditions of increasingly probable scarcity (IOM 1993a). In sum, the advances in cell and molecular biology and biotechnology that have been opening new frontiers in other areas of the medical and biological sciences have been exploited in only limited ways in contraceptive research. There are at least two possible explanations. One is that the new science, as much as it has contributed to innovation in other domains, is not, in fact, as applicable to development of novel contraceptives and the new leads that have been identified are not scientifically enticing enough to industry. The other is that there are other historical and current factors, outside the science, that are holding back contraceptive research. This study explores both possibilities. The Environment for Contraceptive Research and Development and the Objectives of this Study In January 1990, the Committee on Contraceptive Development of the National Research Council (NRC) and the Institute of Medicine released a report on two years of analysis of barriers facing the development of new contraceptive methods.7 The committee concluded that contraceptive development was indeed

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--> stalled; that the most problematic obstacles were the political and ideologic climate in the United States, the organization of resources available for research, some of the federal regulatory requirements, and the specter of product liability. Absent public policy changes that would lower at least some of these obstacles, the committee predicted that contraceptive choices in the next century would not be appreciably different than what they were at the time of that study (NRC/IOM 1990). The present study, undertaken over five years later, began with the premise that contraceptive development continues to be largely stalled, but that the factors previously considered formidable barriers were no longer viewed by the pharmaceutical industry as the primary deterrents to its involvement in the field. In an analysis of industry perceptions commissioned by The Rockefeller Foundation as part of its Contraception 21 initiative, the Program for Appropriate Technology in Health (PATH) determined that the major obstacles for industry are, instead, economic (PATH 1995). In general, the analysis concluded, the pharmaceutical industry does not seem to perceive either sufficiently enticing new product ideas or an adequately large, interested, and financially rewarding market that would justify the sizable investments required for development of fundamentally new contraceptive methods. It seemed logical, therefore, to put our study emphasis, first, on fresh leads that might emerge from the rapid advances in the biomedical sciences and, second, on changes in the character of the market, in the hope that, together, the science and a differently perceived market might motivate at least some industrial players to return to the field. Nonetheless, we must note that, although there have been some helpful regulatory modifications since the 1990 report, the political and ideologic climate in the United States continues to be critical in the domains of law and resource investment and remains, therefore, of high economic relevance for industry. Although the charge to the committee did not ask that we analyze that climate, it continues to so influence the field that we could not justify ignoring it. The matter of the sociopolitical climate is addressed in Chapter 7 as part of the cluster of reasons that "explains" why industry perceives engagement in contraceptive research and development as problematic, a cluster that importantly includes matters of product liability. Of comparable relevance is the fact that the technical adequacy of contraceptives does not, in itself, guarantee wide social acceptance. The decisions to use contraception, plan a family, or practice safer sex are rarely just pragmatic, intellectual matters or issues of biologic function. Rather, they are profoundly rooted in personal identity and sense of control, roles and expectations, feelings about sexuality, concepts of risk, and peer and partner influences (Hatcher et al. 1994; IOM 1995a). In turn, each of these individual factors is rooted in religious beliefs, family and group traditions, and values; knowledge and education; and the contemporary play of larger socioeconomic and cultural forces. Important among the latter are the ethnic, cultural, regional, and religious diversity within a growing

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--> number of national populations, shifting as those populations urbanize and are increasingly linked to global communications media; the effects of economic variables on fertility, perceptions of personal opportunity, family structure, and access to reproductive health care; and divergent views on sexuality and appropriate sexual behavior, gender roles and relative power, and contraception and abortion. Within each of these independently weighty variables, there is contradiction, ambivalence, and volatility which, despite a fair amount of analysis and despite a sizable literature, is neither systematically or deeply understood (IOM 1995a). We consider aspects of these variables in Chapter 5 in the context of the women's agenda and attitudes toward contraception and contraceptive methods. International and Domestic Perspectives This report is admittedly uneven in incorporating both the international and domestic dimensions of contraceptive research and development. We have done so in Chapter 2 in the contexts of unintended pregnancy, abortion, maternal mortality, the public health dimensions of sexually transmitted diseases, and male involvement in contraception. In Chapter 5, we do so in relation to contraceptive use, side effects, failure and discontinuation; sexually transmitted disease as a focus for research and development; and contraceptive commodity supply and cost-effectiveness. Chapter 6 focuses primarily on the role of the U.S. biopharmaceutical industry and public and nonprofit sectors, but does not exclude international actors and notes the relevance of the globalization of industry. Chapter 7 is oriented clearly toward U.S. regulatory and legal matters, alluding nonetheless to the far less litigious climate elsewhere; the chapter also comments on commonalities, for instance, the effects of more conservative positions and ideologies on contraception. Finally, while some of the conclusions and recommendations in Chapter 8 have to do with U.S. policy, which the IOM is chartered to inform and advise, other conclusions and recommendations do have implications well outside U.S. national borders. Study Methodology The primary objectives for the study were, first, to attempt to identify new scientific leads for the next generation of contraceptives and, second, to consider ways to attract significant involvement by the private sector, including the pharmaceutical and biotechnology components of industry, in contraceptive research and development. The audience for the study report was defined as leaders of the public-and private sector policy and scientific research communities, both in the United States and abroad; legislators and regulators concerned with the frameworks that foster or impede the movement of scientific discovery to the world community of

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--> clients; and those active in the fields of family planning and reproductive health generally. In meeting the charge, the committee and staff used several methods to gather needed information. They reviewed published data and analyses and canvassed the field of science; talked informally, during committee meetings and at other times, with experts on the various topics under study; held five meetings of the full committee over a 13-month period (August 1994 through July 1995); surveyed 170 biotechnology companies to ascertain their involvement and interest in contraceptive research and development; conducted smaller, informal surveys of scientists to refine priorities for potential research leads; canvassed a small sample of pharmaceutical companies concerning their experience with litigation concerning contraceptive methods; and developed a mini-case study as the basis for a follow-on workshop at the end of the study. Study Workshops Finally, two workshops were held. The first, in December 1994, convened two groups of scientists: (1) scientists engaged in what are considered frontier areas of contraceptive research, with emphasis on male contraception, methods protecting against sexually transmitted diseases (including HIV/AIDS), menses-inducers, and a rather loose category entitled "other, female-controlled methods"; and (2) scientists not engaged in contraceptive research but conducting cutting-edge basic biological research that might have potential for producing new leads in the next decades. The former group updated the latter about progress in contraceptive research; the latter talked about how developments in their respective fields might lead to significant breakthroughs for the general field of contraceptive research (IOM 1995b). The second workshop convened representatives from the pharmaceutical industry and from the biotechnology sector to examine the proceedings from the first workshop, reviewing areas of possible contraceptive research and development; to discuss incentives and disincentives to moving contraceptive research and development forward; and to consider how the "next dollars" might be spent most effectively and how younger scientists might be attracted toward relevant areas of research (see Appendix E for workshop agendas and rosters). The Bellagio Conference Another component of the Rockefeller Foundation's Contraception 21 Initiative, in which some committee members and IOM staff participated, was a conference on "Public/Private Sector Collaboration in Contraceptive Research and Development" held under Rockefeller Foundation auspices in April 1995 in Bellagio, Italy. The four-day meeting, which brought together a mix of representatives from the private and public sectors, 8 had three objectives: to establish and

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--> promote dialogue between public sector programs and private industry; to review experiences in public- and private sector collaboration and identify constraints; and to make recommendations for promoting a partnership between the public and private sectors, all in the field of contraceptive research and development. The subject of this conference was particularly relevant to the charter of this committee, and some of the rich discussion the conference engendered is woven into this report and so identified. The primary conclusion of the conference was that private/public sector collaboration was utterly essential to accelerating action on behalf of the woman-centered agenda for contraceptive research and development, most importantly with respect to the development of woman-controlled vaginal spermicides and microbicides, male methods of fertility regulation, and menses-inducers. The consensus of the meeting was that such collaboration was necessary for mobilizing more resources from industry toward investment in these areas and for getting new, safe, and effective products into the market with maximum speed. Consensus was also reached on a set of recommended activities, all intended to enhance cross-sectoral involvement. The first was that there be a review of the research and development portfolios of public sector programs from an industry perspective, in the conviction that the current duplication of effort, continuation of work on lines that were essentially unpromising, and development of products of no potential interest to an industrial partner would do little to advance the field. The second dealt with training clinical investigators from selected developing country centers so as to expand participation of those centers in industry-sponsored clinical trials of new contraceptives to standards approved by the U.S. Food and Drug Administration. The third had to do with initiation of special studies of drug regulatory requirements for vaginal microbicides/spermicides, public sector pricing structure, and comparative analysis of product liability experiences and solutions. The final recommendation was a proposal for initiating a program of collaborative effort between the public sector and private industry in the early stages of development, when product viability is still in doubt and investment is still seen as high risk, with the rationale that risk-sharing in those stages might tip the balance in industry investment. The program will match, not necessarily on a 50/ 50 basis, the investment of industry—large and small industry, as well as industry in emerging-economy and developing countries—in research at not-for-profit research institutions in areas of priority for the woman-centered contraceptive agenda. Special consideration is to be given to developing-country centers and an affiliated consortium of donors might also provide early-stage support to those same not-for-profit entities. The hope is that this focused, directed plan might serve both to make investment by industry in the contraceptive research and development field more attractive and to prime a stream of funding from different sectors. The Rockefeller Foundation has already taken first steps toward its implementation (Rockefeller Foundation 1995).

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--> Antecedents and Relationships In addition to the Bellagio Conference, this report follows and builds on other international and U.S. domestic activities in a less direct but significant fashion. While the scale and purposes of these activities differ, all are germane to the report's process, content, and implications. These include the 1984 International Conference on Population (Mexico City); the 1993 International Symposium on Contraceptive Research and Development for the Year 2000 and Beyond; the 1993 Science Summit on World Population (New Delhi); and, most centrally, the previously mentioned International Conference on Population and Development held in Cairo in September 1994. There is also a "family relationship" with two other IOM studies. One, already mentioned, was the 1990 study, Developing New Contraceptives: Obstacles and Opportunities, a report of a study committee under the chairmanship of Luigi Mastroianni. The other, The Best Intentions: Unintended Pregnancy in the United States, was completed in May 1995 by an IOM committee under the chairmanship of Leon Eisenberg. As the reader will discover, we have profited considerably from both studies. The Cairo Conference While the entire Programme of Action that emerged from the Cairo conference is relevant to this report, the portion of the Programme that addresses "Technology, Research, and Development" (Chapter XII) is of primary relevance and we reproduce it partially here: Research, in particular biomedical research, has been instrumental in giving more and more people access to a greater range of safe and effective modern methods for regulation of fertility. However, not all persons can find a family-planning method that suits them and the range of choices available to men is more limited than that available to women. The growing incidence of sexually transmitted diseases, including HIV/AIDS, demands substantially higher investments in new methods of prevention, diagnosis and treatment. . . . In spite of greatly reduced funding for reproductive health research, prospects for developing and introducing new contraceptives and regulation of fertility methods and products have been promising. Improved collaboration and coordination of activities internationally will increase cost-effectiveness, but a significant increase in support from governments and industry is needed to bring a number of potential new, safe and affordable methods to fruition, especially barrier methods. This research needs to be guided at all stages by gender perspectives, particularly women's, and the needs of users, and be carried out in strict conformity with internationally accepted legal, ethical, medical and scientific standards for biomedical research. . . . Governments, assisted by the international community and donor agencies, the

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--> private sector, nongovernmental organizations and the academic community, should increase support for basic and applied biomedical, technological, clinical, epidemiological and social science research to strengthen reproductive health services, including the improvement of existing [methods] and the development of new methods for regulation of fertility that meet users' needs and are acceptable, easy to use, safe, free of long- and short-term side effects and second-generation effects, effective, affordable and suitable for different age and cultural groups and for different phases of the reproductive cycle. Testing and introduction of all new technologies should be continually monitored to avoid potential abuse. Specifically, areas that need increased attention should include barrier methods, both male and female, for fertility control and the prevention of sexually transmitted diseases, including HIV/AIDS, as well as microbicides and virucides, which may or may not prevent pregnancy. . . . To expedite the availability of improved and new methods for regulation of fertility, efforts must be made to increase the involvement of industry, including industry in developing countries and countries with economies in transition. A new type of partnership between the public and private sectors, including women and consumer groups, is needed that would mobilize the experience and resources of industry while protecting the public interest. National drug and device regulatory agencies should be actively involved in all stages of the development process to ensure that all legal and ethical standards are met. Developed countries should assist research programs in developing countries and countries with economies in transition with their knowledge, experience and technical expertise and promote the transfer of appropriate technologies to them. . . . (UNFPA 1994) Report Organization This report has three principal parts. The first comprises Chapter 2, with its focus on the dimensions of need for contraception and for new contraceptives, on unintended pregnancy and its consequences, and on the linkages between sexually transmitted infection and contraception. The second part of the report consists of Chapters 3 and 4. Chapter 3 discusses contraceptive technologies that, all things being equal, could conceivably become available in the relatively near future. Chapter 4 summarizes the potential that lies at the more distant scientific frontier, potential that is discussed in detail in supporting Appendices A (Female Methods), B (Male Methods), C (Immunologic Contraception), and D (Barrier Methods) and their extensive references. A glossary is also provided which defines the technical terms used in Chapters 3 and 4—though not the technical terms used in the appendixes, since we assume that the readers of those sections will be primarily scientists for whom the terminology will be quite familiar—as well as technical terms used in other chapters. The third part of the report takes up different facets of the environment

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--> around contraceptive research and development. Chapter 5 examines the current contraceptive market; the limitations of currently available contraceptives; specific contraceptive needs as market opportunities; consumer perspectives; and possible financial incentives for investment, including the role of subsidy and the cost-effectiveness of contraception. Chapter 6 analyzes the roles of the private and public sectors in contraceptive research and development, emphasizing the adaptations of the biopharmaceutical industry to health sector restructuring and the meaning of those adaptations for developments in reproductive health in general and contraception in particular. The chapter also examines patterns of funding for contraceptive research over time, beginning in 1970. Chapter 7 scrutinizes the regulatory and legal context for the field, as well as some of the sociopolitical and cultural forces which affect that context. Chapter 8 presents the report recommendations. References Alan Guttmacher Institute. Hopes and Realities: Closing the Gap Between Women's Aspirations and Their Reproductive Experiences. New York: The Alan Guttmacher Institute. 1995a. Alan Guttmacher Institute. The Cairo consensus: Challenges for U.S. policy at home and abroad. Issues in Brief, March, 1995b. Alan Guttmacher Institute. Clandestine Abortion: A Latin American Reality. New York: The Alan Guttmacher Institute. 1994. Antrobus P, A Germain, S Nowrojee, eds. Challenging the Culture of Silence: Building Alliances to End Reproductive Tract Infections. New York: International Women's Health Coalition and Women and Development Unit, University of the West Indies. 1994. Barroso C. The alliance between feminists and researchers. IN Contraceptive Research and Development 1984 to 1994: The Road from Mexico City to Cairo and Beyond , PFA Van Look, G Pérez-Palacios, eds. Delhi: Oxford University Press. 1994. Behrer M. Population and family planning policies: Women-centered perspectives. Reproductive Health Matters 1:4-12, May 1993. Bhargava SW. Finally, a healthy interest in women. Business Week, pp. 88-89, 20 July 1992. Bongaarts J. Population policy options in the developing world. Science 263:771-776, 1994. Bongaarts J, J Bruce. The causes of unmet need for contraception and the social content of services. Studies in Family Planning 26(2):57-75, 1995. Bonnie K, A Germain, M Bangser. The Bangladesh women's health coalition. Quality 3(1), 1991. Brown GF. Long-acting contraceptives: Rationale, current development, and ethical implications. Special Supplement, Hastings Center Report 25(1):S12-S15, 1995. Bruce J, A Jain. A new family planning ethos. The Progress of Nations. New York: United Nations Children's Fund. 1995. Brunham RC, JE Embree. Sexually transmitted diseases: Current and future dimensions of the problem in the Third World. IN Reproductive Tract Infections: Global Impact and Priorities for Women's Reproductive Health. A Germain, KK Holmes, P Piot, JN Wasserheit, eds. New York: Plenum. 1992. Cates W Jr. Family Planning and STDs: Some Differences Between the Disciplines. Presentation at the 31st Annual Meeting of the Association of Reproductive Health Professionals, Atlanta, GA, 6-8 October 1994.

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--> Cates W Jr, KM Stone. Family planning: The responsibility to prevent both pregnancy and reproductive tract infections. IN Reproductive Tract Infections: Global Impact and Priorities for Women's Reproductive Health. A Germain, KK Holmes, P Piot, JN Wasserheit, eds. New York: Plenum. 1992. Claypool LE. The challenges ahead: Implications of STDs/AIDs for contraceptive research. IN Contraceptive Research and Development 1984 to 1994: The Road from Mexico City to Cairo and Beyond. PFA Van Look, G Pérez-Palacios, eds. Delhi: Oxford University Press. 1994. Correa S. Population and Reproductive Rights Component: Platform Document, Preliminary Ideas. Paper prepared for the International Conference on Population and Development [Cairo 1994]. Development Alternative with Women for a New Era. February 1993. Dixon-Mueller R. Population Policy and Women's Rights: Transforming Reproductive Choice. Westport, CT: Praeger. 1993. Dixon-Mueller R, A Germain. Four Essays on Birth Control Needs and Risks. New York: International Women's Health Coalition. 1993. Djerassi C. The bitter pill. Science 245:354-361, 1989. Elias CJ, L Heise. The Development of Microbicides: A New Method of HIV Prevention for Women (Working Papers No. 6). New York: The Population Council. 1993. Fathalla M. Fertility control technology: A woman-centered approach to research. IN Population Policies Reconsidered: Health, Empowerment, and Rights. L Chen, A Germain, G Sen, eds. Cambridge, MA: Harvard University Press. 1994. Ford Foundation. Reproductive Health: A Strategy for the 1990s. New York: Ford Foundation. 1991. Forrest JD. Preventing unintended pregnancy: The role of hormonal contraceptives. American Journal of Obstetrics and Gynecology 170(5; Part 2):1485-1489, 1994. Forrest JD, RR Fordyce. Women's contraceptive attitudes and use in 1992. Family Planning Perspectives 23:175-179, 1993. Gelijns AC, CO Pannenborg. The development of contraceptive technology: Case studies of incentives and disincentives to innovation. International Journal of Technology Assessment in Health Care 9(2):210-232, 1993. Germain A. Reproductive Health and Dignity: Choices by Third World Women. Technical background paper prepared for the International Conference on Better Health for Women and Children Through Family Planning, Nairobi, Kenya, October 1987. Germain A, R Kyte. The Cairo Consensus: The Right Agenda for the Right Time. New York: International Women's Health Coalition. 1995. Germain A, J Ordway. Population Control and Women's Health: Balancing the Scales. New York: International Women's Health Coalition and the Overseas Development Council. 1989. Guttmacher Institute. See Alan Guttmacher Institute. Harlap S, K Kost, JD Forrest. Preventing Pregnancy, Protecting Health: A New Look at Birth Control in the United States. New York: The Alan Guttmacher Foundation. 1991. Hatcher RA, J Trussell, F Stewart, et al. Contraceptive Technology: 16th Revised Edition. New York: Irvington Publishers. 1994. Ingrassia M, K Springen, D Rosenberg. Still fumbling in the dark--Contraception: With all the condoms, pills and foams, why are so many women getting sterilized? Newsweek, 13 March 1995. Institute of Medicine (IOM). The Best Intentions: Unintended Pregnancy and the Well-Being of Children and Families. S Brown, L Eisenberg, eds. Washington, DC: National Academy Press. 1995a. IOM. Summary of Proceedings: Workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science, 9-10 December 1994. Washington, DC: Division of Health Sciences Policy. Unpublished document. 1995b.

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--> IOM. Applications of Biotechnology to Contraceptive Research and Development: New Opportunities for Public-/Private Sector Collaboration. Washington, DC: Division of Health Sciences Policy. Unpublished concept paper. 1993a. IOM. Clinical Applications of Mifepristone (RU 486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. MS Donaldson, L Dorflinger, SS Brown, and LZ Benet, eds. Washington, DC: National Academy Press. 1993b. Khanna J, PFA Van Look, PD Griffin, eds. Challenges in Reproductive Health Research: Biennial Report 1992-1993. Geneva: World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction. 1994. Lane SD. From population control to reproductive health: An emerging policy agenda. Social Science and Medicine 39(9):1303-1314, 1994. Marcelo AB, A Germain. Women's perspectives on fertility regulation methods and services. IN Contraceptive Research and Development 1984 to 1994: The Road from Mexico City to Cairo and Beyond. PFA Van Look, G Pérez-Palacios, eds. Delhi: Oxford University Press. 1994. Marquette CM, LM Koonin, et al. Vasectomy in the United States, 1991. American Journal of Public Health 85(5):644-649, 1995. Miller K, A Rosenfield. Population and women's reproductive health: An international perspective. Annual Review of Public Health 17:359-382, 1996. Mosher WD, WF Pratt. Contraceptive use in the United States, 1973-88. Advance Data from Vital and Health Statistics of the National Center for Health Statistics 182: 20 March 1990. National Research Council and Institute of Medicine (NRC/IOM). Developing New Contraceptives: Obstacles and Opportunities. L Mastroianni, PJ Donaldson, TT Kane, eds. Washington, DC: National Academy Press. 1990. Potts M, A Rosenfield. The fifth freedom revisited: I, Background to existing programs. Lancet 336:1227, 1990. Program for Appropriate Technology in Health (PATH). Contraceptive research and development update. Outlook (Special Issue) 13(20), June 1995. PATH. Outlook 11(2), 1993. Robey B, et al. The reproductive revolution: New survey findings. Population Reports, Series M, No. 11. Baltimore: Johns Hopkins University, Population Information Program. 1992. Rockefeller Foundation. Public-/Private Sector Collaboration in Contraceptive Research and Development: A Call for a New Partnership. Report from the Bellagio Conference, 10-14 April 1995. New York: Rockefeller Foundation. 1995. Rockefeller Foundation. Mobilization of Resources to Launch a Second Contraceptive Technology Revolution: A Concept Paper. Unpublished document. New York: The Rockefeller Foundation. 1993. Ruzek SB. Editorial: Toward a more inclusive model of women's health. American Journal of Public Health 83(1):6-7, 1993. Sinding SW. Women's demands and demographic goals. Planned Parenthood Challenges. 1994/1. Snow R. Each to her own: Investigating women's response to contraception. IN Power and Decision: The Social Control of Reproduction. G Sen, R Snow, eds. Cambridge, MA: Harvard School of Public Health. 1994. Stratton P, NJ Alexander. Prevention of sexually transmitted infections. Infectious Disease Clinics of North America 7(4):841-859, 1993. United Nations. Levels and Trends of Contraceptive Use as Assessed in 1994. New York. In press. United Nations Population Fund (UNFPA). Report of the International Conference on Population and Development (A/CONF.171/13). New York: United Nations. 1994. World Health Organization (WHO). An Overview of Selected Curable Sexually Transmitted Diseases. (WHO/GPA/STD/95.1). Geneva: WHO/Global Programme on AIDS. August 1995.

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--> WHO. Abortion: A Tabulation of Available Data on the Frequency and Mortality of Unsafe Abortion, 2nd edition. (WHO/FHE/MSM/93.13). Geneva: Maternal Health and Safe Motherhood Programme, Division of Family Health. 1994. WHO, Special Programme of Research, Development and Research Training in Human Reproduction, and the International Women's Health Coalition. Women's Perspectives on the Selection and Introduction of Fertility Regulation Technologies: Report of a Meeting between Women's Health Advocates and Scientists, Geneva, 20-22 February 1991. Women's Global Network for Reproductive Rights. Population and development policies: Report on the International Conference on Reinforcing Reproductive Rights, Madras, India, May 1993. Newsletter 43, April-June 1993. Notes 1.   The term ''Second Contraceptive Revolution" was coined by Mahmoud Fathalla and has been adopted by the Rockefeller Foundation as a central concept in the population and environment component of its portfolio. The term has acquired a certain currency in the field and describes the hoped-for revitalization of research and investment in the development of a new generation of contraceptive technologies. 2.   The first modern IUDs were developed independently in Germany and Japan in the 1920s and 1930s, but fell into disrepute in the Western industrialized countries because of substantial numbers of cases of pelvic inflammatory disease (PID) and peritonitis. In the late 1950s, the time seemed ripe for its rehabilitation and the Population Council invested in the further development of the method (Gelijns and Pannenborg 1993). 3.   Traditionally, the perimenopausal period has been defined as the few (three to five) years around menopause. Current thinking is that it should be viewed as beginning as early as the midthirties, coincident with onset of decline in ovarian function. 4.   Bongaarts (1994) makes the point that even were family planning programs in the developing world perfectly able to supply all the unmet need for contraception, they would still not be able to reduce population growth to zero in countries where, on average, desired fertility still exceeds two children and thereby have significant effect on the momentum of population expansion. From this perspective, family planning programs are part of a set of complementary and mutually reinforcing approaches such as education, empowerment of women, implementing public health measures to reduce infant and child mortality, and delaying childbearing, that tend to raise the demand for family planning. He notes that "investment in family planning programs produce larger reductions in unwanted fertility when social conditions such as education and gender equality are favorable" (Bongaarts 1994). 5.   The reproductive tract infections (RTIs) have been broadly defined to include sexually transmitted infections and infections that are nonsexually transmitted, and comprise three types of infection: (1) sexually transmitted diseases (STDs), such as chlamydia, gonorrhea, trichomoniasis (which may or may not be sexually transmissible), syphilis, chancroid, genital herpes, genital warts, and human immunodeficiency virus (HIV) infection; (2) endogenous infections, caused by overgrowth of organisms that can be present in the genital tract of a healthy woman, such as bacterial vaginosis and vulvovaginal candidiasis; and (3) iatrogenic infections, associated with medical procedures, such as female genital mutilation, poor delivery practices, cesarean section, unsafe abortion, and improperly performed pelvic examinations and IUD insertions (Brunham and Embree 1992). Of the three types of reproductive tract infections-sexually transmitted, endogenous, and iatrogenic-the majority are sexually transmitted in direct fashion (Brunham and Embree 1992). However, the iatrogenic infections are also important because they are linked to contraception, or the lack of contraception, through sepsis during the medical procedures cited above. Of the eight major STD pathogens producing RTIs, four are bacterial (chancroid, chlamydia, gonorrhea, syphilis) and four are viral (HIV, human papilloma virus/HPV, herpes simplex type 2/HSV-2, and hepatitis B/HBV).

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--> 6.   The sole remaining U.S. firm was Ortho Pharmaceutical Corporation (a subsidiary of Johnson and Johnson); the three European firms were Organon International, Schering AG, and Roussel-Uclaf (a subsidiary of Hoechst Pharmaceuticals). The U.S. firms that for all practical purposes had abandoned significant efforts on new contraceptive research as of the mid-1980s included: Syntex Laboratories; G.D. Searle and Company; Parke-Davis and Company; Merck Sharp and Dohme Company; the Upjohn Company; Mead Johnson; Wyeth-Ayerst Laboratories; and Eli Lilly and Company (Djerassi 1989; NRC/IOM 1990). 7.   The committee that generated the report (National Research Council and the Institute of Medicine. Developing New Contraceptives: Obstacles and Opportunities. Washington, DC: National Academy Press. 1990) included physicians; public health, policy, and legal experts; pharmaceutical company executives; reproductive biologists; economists; and demographers. 8.   Public sector participants came from WHO's Special Programme in Human Reproduction and Training, the Population Council's Center for Biomedical Research, the U.S. Agency for International Development, the Contraceptive Research and Development Program (CONRAD), the Center for Population Research of the U.S. National Institute of Child Health and Development of the National Institutes of Health, the U.S. Food and Drug Administration, and the Program for Appropriate Technology in Health (PATH). The private sector was represented by eight firms: Finishing Enterprises, Ortho Pharmaceutical Corporation (Johnson and Johnson), and Wyeth-Ayerst Laboratories, from the United States; Gedeon Richter, Organon, Pharmacia-Leiras, and Schering AG, from Europe; and Silesia, from Brazil.