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--> Summary This study began with three questions. The first was: Is there really a need for new contraceptives and, if so, why? The second was: If, as has been said, the field of contraceptive research and development has somehow lost the energy that characterized it at the time of what is called the ''first contraceptive revolution," are there new prospects in the science that could reenergize it? The third was: Given such prospects, would they be sufficient to accomplish that revitalization? The committee sensed early in its deliberations that, as exciting as scientific opportunity might prove to be, the climate for development would constrain it. Thus, the committee opted not only to explore the prospects in the new science, but to examine the context for collaboration between the public and private sectors that would be essential to meeting the need and demand for new contraceptive options. The Existence of Need and Some Fundamental Concepts Other questions surfaced early in the committee's work: Was there really a need for new contraceptives, why, and what kind of contraceptives? The committee pressed itself to answer those questions and concluded that there is not only a need for new contraceptives but evidence of a real market for them. While the existing array of contraceptive options represents a major contribution of science and industry to human well-being, it fails to meet needs in significant
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--> populations and the costs of that failure are high, for societies, for families, and for individuals. Throughout its work, the committee sought to frame the issues around contraceptive research and development in a way that might offer a fresh outlook on the subject. Four concepts seemed to merit integration into such a framework: the idea of a "woman-centered agenda," the challenges of unintended pregnancy, consideration of contraceptives from both the perspective of need and market demand, and new possibilities for collaboration between the sectors. The Idea of a "Woman-centered Agenda" For many years, women's health groups and advocates, as well as some researchers, have called for more safe and effective contraceptives that would better meet the needs of both women and men. In 1989, Carl Djerassi, a major figure in the development of the first contraceptive pill, suggested a list of priorities for new contraceptives. In order of descending priority, they were: (1) a new spermicide with antiviral properties, (2) a "once-a-month" pill effective as a menses-inducer, (3) a reliable ovulation predictor, (4) easily reversible and reliable sterilization for males, (5) a contraceptive pill for males, and (6) an antifertility vaccine for males or females or both. Over the half-decade since then, a construct referred to as a "woman-centered agenda" has evolved, its source an expanding dialogue within a number of national and international women's groups, and between some of those groups and scientists working in reproductive and contraceptive research. The agenda reflects a more expansive view of contraception that attempts to integrate concerns for contraceptive efficacy into concerns for the overall reproductive health and general well-being of the primary users of contraceptives, that is, women. The notion of a woman-centered agenda for contraceptive research and development does not imply that there is some "universal woman" or some necessary, unitary view of women's preferences; it is simply that the field should refocus itself toward approaches in areas where the needs of women are still unmet by existing methods. At the top of that agenda are three types of methods that were included in that 1989 agenda. Slightly restated, these are contraceptives that are also protective against sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV); menses-inducers and monthly methods targeted at different points in the menstrual cycle; and contraceptive methods for males that would both expand their range of contraceptive choice and their sharing of the responsibility for contraception. There is also a subtext for the agenda that has two themes: One is women's concern for control over their own bodies, including control over the occurrence and timing of pregnancy; the other concern is for equity in terms of physical safety and well-being. The basic message from research around these topics is
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--> that, as a general matter, women want contraceptives that are safe and efficacious, with minimal side effects. However, some women also assign value to methods that are discreet, easy to use, and nonsystemic. For still others, it is important that they themselves control method use, in other words, methods that are not controlled by a partner or unduly dependent on a provider. And, as reflected in the agenda, many women want full protection against sexually transmitted infection. No single contraceptive can ever satisfy all these criteria simultaneously. Nor is that required since individual needs will always vary personally and situationally. At the same time, the present array of contraceptive technologies does not respond adequately to these criteria for many women and couples, many of whom would be willing and able to pay were there a fuller range of contraceptive options. In more and more societies, rich with technological diversity and replete with seemingly endless permutations of consumer goods, it is odd indeed that these particular options, central to the lives of so many individuals, families, and societies, are so limited. The Challenge of Unintended Pregnancy A recently published report by the Institute of Medicine made the following its lead recommendation: "To begin the long process of building national consensus around this norm, the committee recommends a multifaceted, long-term campaign to (1) educate the public about the major social and public health burdens of unintended pregnancy; and (2) stimulate a comprehensive set of activities at the national, state, and local levels to reduce such pregnancies." Similar objectives have motivated public statements by the United Nations Population Fund and the Alan Guttmacher Institute that underscore concerns about unintended pregnancy as a global problem. This committee finds the central ideal of this proposed campaign—"every child a wanted child"—compelling, for women, for children, and for families. Attainment of this ideal is far too critical to be left to chance or the passage of time. It requires a thoughtful and deliberate response, a pivotal part of which must be the increased, careful, and consistent use of some form of contraception or, for the highly motivated, the exercise of periodic abstinence. Thus, greater knowledge about reproductive health and, in that context, contraception, is essential for providers, consumers, and the public at large, if fully informed, free, and appropriate choices are to be made about fertility regulation and sexuality. In turn, the proper use of contraceptive technologies for fertility regulation is linked both to the availability of quality contraceptive services providing a full range of safe, approved methods of contraception and an earnest and continuing search for more and better methods for more people. In this connection, the committee finds understanding both in the United States and the developing world about the extent, causes, and consequences of
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--> unintended pregnancy and sexually transmitted disease to be seriously incomplete. The committee views this distressing situation as due largely to three relentlessly interacting factors: a welter of conflicting messages about sexuality and responsibility, inadequate education, and constrained access to a range of contraceptive alternatives that are suitable for those who most need them. The committee agrees that the large numbers of unplanned and unwanted pregnancies in the world are not due solely to inadequate contraceptive methods. It is surely true that substandard health services; lack of public education; inadequate provider training; misunderstandings about risks and poor understanding of how people calculate risk; and social, cultural, and religious influences on family planning behavior, all can play a role in whether contraception is used and whether it is used appropriately and properly. Still, the committee finds ample indication that new technologies would improve the overall effectiveness of contraception in ways that currently available contraceptives do not and in ways that enhanced access and education, in themselves, alone, cannot. Need and Market Demand There are two categories of need for new contraceptive technologies. These overlap somewhat, but each has distinctive implications. The first category comprises public health needs that, left unanswered, generate further problems that are often quite costly, to individuals and to societies. Yet, as irrefutable and sizable as these needs may be, for a number of reasons they may not evoke a disposition, either by societies or individuals, to pay for their satisfaction. The second category consists of needs that are recognizable in public health terms and, in addition, can elicit a disposition, either by society or individuals, to invest in resolving them. In other words, again for a number of reasons, these needs are of enough concern to produce market demand. Indicators of Public Health Needs Unintended Pregnancy Unintended pregnancy is both a fundamental notion underlying the rationale for contraception and a measure of a fundamental public health need in today's world. Nearly 60 percent of all pregnancies in the United States and anywhere from 24 to 64 percent of all pregnancies worldwide are unintended, either because they were mistimed or because they were not wanted at all. Despite reigning stereotypes, unintended pregnancies are not confined to adolescents, minorities, or developing countries. While a majority of pregnancies among teens under age 19 are unintended, women of all ages and marital status—everywhere—face difficulties planning and preventing pregnancy. In the United States, of the 6.3 million pregnancies in 1987, 3.5 million were unintended; of these, 2 million occurred among women over age 20. Half of those unintended pregnancies occurred among women who had unprotected sex de-
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--> spite having no intention to become pregnant; slightly under half occurred among women who were, in fact, using contraception that either failed or was used improperly. The committee contemplated the prospect of attempting to discern what portion of the unintended pregnancies in the world might be averted by new contraceptive technology. While not a totally impossible task, it is certainly a large and difficult one, well beyond the committee's mandate and capabilities. The task of determining what percentage of women who used no contraceptive at all would have done so had there been new technologies available is particularly daunting; one would have to know that the reason no contraceptive had been used was rejection of the available methods. It may be more informative to consider those women who were contracepting but became pregnant because the method failed or because it was used improperly. Either case may reflect lack of knowledge or some limitation in the efficacy and ease of use of a method; in some instances, both kinds of deficiency are at work. Abortion Approximately one-third of the 190 million pregnancies in the world in 1995 ended in abortion; that same proportion applies in the United States. Clearly, those millions of women who choose to terminate a pregnancy, many submitting to unsafe and illegal procedures that can be life-threatening, attest to the need for improved access to and utilization of existing contraceptive methods and the need for new and improved contraceptive options. Furthermore, the evidence is overwhelming that, in most countries, children from unwanted conceptions, and their mothers, tend to be at greater medical risk and may become socioeconomic burdens—on society, on their families, and on their own life chances. In developing countries, unsafe abortion is a leading cause (perhaps as high as 20 percent) of the more than 500,000 maternal deaths that occur annually. Contraception is the first line of defense against unintended pregnancies, and any contraceptive option that will diminish the proportions of mistimed and—especially—unwanted pregnancies should be considered essential to societal and individual well-being. Population Growth A focus on women's reproductive health and a woman's agenda for contraceptive research and development does not mean that other consequences of contraception suddenly do not matter. Family planning is an option for individuals that may benefit the larger community as well. Slower population growth is believed by many to contribute significantly to the healthy sustainability of the planet. Were only unwanted births prevented, the global number of live births would fall from 139 million a year to 122 million and the global rate of population growth would drop by 19 percent. There is also growing and powerful evidence that users can drive the demographics: It has been suggested that family planning programs that truly enable individuals to achieve
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--> their reproductive objectives actually have more impact on reducing fertility than do programs driven solely by demographic goals. Unmet Need and Unserved and Underserved Populations While contraceptive prevalence has risen impressively worldwide, new analytical approaches to the definition and measurement of the "unmet need" for family planning have produced estimates of from 120 million to 228 million women who can be defined as lacking effective contraceptive protection. These are the women most critically in need, that is, who do not want to be pregnant but who are not using any kind of contraception or who are using methods that are, for one reason or another, problematic. The available contraceptive array is limited in the extent to which it can respond to variability in individual and family situations, to cultural differences, to specific health problems and shifting personal preferences, and to life cycle stages and changing reproductive intentions across those stages. Nor does the present array respond to the lengthening of the time during which women are at risk of unwanted conception, a lengthening that has resulted from earlier initiation of sexual relations, multiplicity of partners, and smaller family size ideals. The contraceptive needs of adolescents, sexually-active single or postpartum women, women who are lactating or in their later reproductive years, and—very importantly—men of any age, remain substantially unmet. Adolescents are of special concern, not only by virtue of their youth and vulnerability but because the contraceptives that are most appropriate to their age and health status are few in number and require meticulous use to be fully effective. The fact of these unserved and underserved populations is an indicator of both public health needs and market demand. Indicators of Market Demand Contraceptive Side Effects, Failure, and Discontinuation Like any medical intervention, all contraceptive methods have side effects, some of which are burdensome, some unacceptable. The most popular forms of reversible contraception are hormonally based, namely, oral, injectable, and implant contraceptives. Although these are safe and have many benefits and few risks, they also have side effects that result in frequent discontinuation of their use. These side effects are generally not life-threatening complications, but rather symptoms such as spotting and irregular bleeding, weight gain, nausea, and mood changes, annoying to some women, very distressing to others. Together with myths and rumors about methods, side effects account for much of method discontinuation or misuse and will persist as obstacles to more widespread and effective use of reversible hormonal contraceptive methods. Somewhat different, but equally difficult problems lead to much less use than might be expected of the very effective intrauterine devices (IUDs) currently
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--> available. These include the very negative impact that endures as a consequence of the publicity generated by the infections and deaths attributable to the Dalkon Shield IUD, misconceptions about IUDs and their association with infection, and side effects of bleeding and cramping experienced by some women. Furthermore, except for sterilization, IUDs, implants, and injectables, the factors of inherently low efficacy and/or imperfect use limit the contraceptive effectiveness of most of the currently available methods, although in widely varying measure. It is unrealistic to expect that there will soon be a contraceptive technology that is fully efficacious, with no side effects, for all users, under all conditions. Still, each additional method expands the spectrum of possibilities to an ever-larger number of users, as does the series of improvements that are inevitably made to all medical technologies after their first market introduction. Sterilization Sterilization is the most used contraceptive in virtually all the world's regions, including the United States. While the method is most satisfactory for individuals who consider their families complete, many women are resorting to sterilization at unexpectedly early ages simply because they have found no reversible method to be satisfactory. Sterilization is clearly an excellent choice for women and men who are certain that they wish no more children; it is unsuited to the great majority of younger individuals. Studies have clearly demonstrated that the younger a man or woman is when a sterilization procedure is performed, the greater the chances that there will be later regret and a request for a reversal of the sterilization, a procedure that is complex, costly, and subject to failure. More effective and acceptable reversible contraceptive methods would allow for sterilization procedures to be used primarily by those who have truly completed childbearing. While sterilization can stand as an indicator of willingness to spend a considerable sum to terminate childbearing, that reading is somewhat compromised by the fact that, in many cases and particularly in the United States, some third-party payer is willing to assume the costs for the intervention, yet not willing to assume the costs for provision of reversible contraceptives. Sexually Transmitted Disease, Including Human Immunodeficiency Virus (HIV) An important focus in this study was on the science and policy implications of the interface between sexually transmitted disease (STD) and contraception, since sexual contact, usually sexual intercourse, is necessary for both. In the past, attention to these two sets of concerns has generally proceeded on parallel tracks, guided by the correct perception that sexual activity and reproduction do not inevitably coincide and the incorrect perception that the populations requiring protection from STDs and from conception are utterly distinct. The STDs were viewed as a matter of no concern for the normative majority, that is, married couples creating families, for whom the risk of sexually transmitted infections was considered trivial. The facts of today's world must persuade us that this norm is much eroded and that the dynamics producing the erosion have altered
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--> the composition and greatly increased the size of the global population at risk, of which a sizable proportion is—simultaneously—vulnerable to possibly unwanted conception and surely unwanted infection. Though it is true that there are important biologic and behavioral differences between STDs and unintended pregnancy, it is hard to justify continued separation of the two, either programmatically or scientifically. Because of the spread of heterosexual transmission beyond groups typically considered high risk, because of greater female physiological vulnerability to infection and to more severe sequelae, and because of the potential of vertical transmission from mother to fetus, both society and individuals confront very high costs as the prevalence of sexually transmitted disease (STD) rises. Only the condom provides protection against both conception and STD transmission. Because the female condom is not yet widely used and research has not yet been completed on the protection it provides against STDs, the single method now available for protection against both STDs and conception is the male condom—a method not controlled by women. Nor is there yet any single noncontraceptive technology that eliminates the risk of infection by the full gamut of pathogens that are transmitted sexually. Growing double-method use and increases in condom sales volumes indicate that the risk and urgency of this large problem are more appreciated and that individuals are willing to pay for protection. The market signals would seem to be quite clear. Costs Almost all the world's health systems are being driven to contain costs and look far more attentively at preventive approaches and economies of scale. The short- and long-term costs of unintended pregnancy and sexually transmitted disease are high; the cost-effectiveness of all contraceptive methods is excellent. Furthermore, availability of a good method mix has an independently positive effect: The addition of even a single major method to a family planning program can account for significant increase in contraceptive use-prevalence and reduction in crude birth rates. As health systems worldwide restructure and, hopefully, recognize the savings to be derived from prevention, contraception as an integral part of reproductive and family health should attract greater support. Beyond this, there are benefits to health that are less easily quantifiable but no less real, including substantial benefits from contraceptive methods themselves, such as protection against ovarian and endometrial cancer, benefits which can have a positive bearing on consumer decision-making. In less precise but commonsensical terms, experience indicates that a larger number of options will enhance overall acceptability and greater utilization across a wider range of individuals from different cultural backgrounds. In sum, this committee finds an authentic need for development of new contraceptives and related reproductive health technologies. It believes that the nature of some of the need for such technologies is such that it represents a large and potentially profitable market. The committee also finds an agenda for contra-
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--> ceptive research and development that is "woman centered" to be reasonable, just, and also market worthy. The challenge is to find creative ways to elicit the best response from the scientific and industrial communities in a conducive climate that protects the integrity of inquiry and the safety of consumers. The issue of climate is central. The aspects of context that press on every effort to provide safe and effective contraceptive technologies are complex and reflective of deeply rooted differences and deeply held beliefs. In addition, there is the current atmosphere of fiscal austerity in so much of the world, an atmosphere that cannot be ignored. At the same time, what is to be done about real, urgent, and unmet needs that affect public health and well-being everywhere? The committee has opted for a set of recommendations that are neither glamorous nor sweeping. They are, instead, unified by their practicality, located in the middle ground of policy, and intended to respond to what seem to be the needs of a significant majority. The Prospects Of The Science The next question was whether there are possibilities that have been generated through the insights and mechanisms unfolding in contemporary science that would offer fresh, exciting, and plausible leads for a whole new generation of contraceptives. The committee dedicated vigorous effort to this question, reviewing a large body of evidence and expert testimony about possible leads to new contraceptive technologies, with special emphasis on those that respond to priority needs and might also evoke market demand. It is the nature of science to pursue lines of inquiry that may turn out to be unrewarding for all sorts of reasons, no matter how plausible or broadly enticing they may have seemed; the ability to predict such eventualities is always limited. Nevertheless, basic research has been the wellspring of all quantum leaps in contraceptive technology so far and it will continue to be the wellspring for any significant innovations in the future. It is of interest in this regard that emphasis in AIDS and cancer research has very recently been retargeted toward fundamental issues in cell and immunobiology. New technologies, such as computer modelling, combinatorial chemistry and rational drug design, in vitro screening systems, and molecular biology, now provide tools for pursuing new leads in a meaningful and perhaps more rapid fashion. This gives hope that the progress of contraceptive development can be accelerated, that previously intractable problems will be much more susceptible to solution, and that discriminations can be made further upstream. The committee concluded that there are, indeed, good prospects in the science that fit—or can be made to fit—the environment of both need and demand. Some of this promise could be realized in the nearer term; some, as is always the case early in the discovery process, must be seen as more distant possibilities. There is, however, no dearth of ideas, no lack of potential targets.
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--> Criteria for Decision-making A Woman-centered Agenda Women—and men, if they are to share more of the responsibility for contraception and protection of themselves and their partners against infection—have many different requirements. These will vary according to many factors, including age, the nature of intimate relationships, ability to pay for methods, and access to health services, but the overall need is great and urgent. The committee has concluded that a vigorous and honest attempt to be responsive to a woman-centered agenda fulfills objectives that have potential benefits to all parties. At the same time that there is no "universal woman" to whom the information in this report and its recommendations are meant to apply in some inevitable, culture-blind fashion, there are two principles that are arguably universal: (1) the goal of enhancing women's control over their own bodies, including control over the occurrence and timing of pregnancy; and (2) equity for women's physical safety and well-being. Recommendation 1. The committee recommends that priorities for new research be assessed against the preference criteria presented in a new "woman-centered agenda" and that existing public sector contraceptive research and development portfolios be reassessed similarly. Such an approach highlights the need for improvements and new advances in contraceptives for women, and in areas where there are few or inadequate options, namely: • Methods that act as chemical or physical barriers to conception and to transmission of sexually transmitted diseases, including the human immunodeficiency virus (HIV); • Menses-inducers and once-a-month methods targeted at different points in the menstrual cycle; • Methods for males that would expand their contraceptive choices and responsibility. It is also the case that some existing contraceptive methods, such as the current oral contraceptives, condoms, and spermicides, have major health benefits above and beyond those produced by contraception. In strategies for future contraceptive development, the possibility of other health benefits should be assessed and, where such can be identified, those methods should be accorded priority. It is clear, however, that it may be difficult to establish a priori that there will be any such benefits. However, new contraceptive methods for which such benefits cannot be predicted should not be discarded from consideration when they meet the criteria of need, efficacy, safety, and acceptability.
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--> Specificity of Targets The committee is sensitive to the global atmosphere of austerity and pressures for cost containment, as well as the ambivalence toward basic science in the United States. It sought, therefore, to establish some foundation for making some a priori judgment about priorities for new directions. One area of consensus was around the matter of specificity of targets. Another had to do with points of intervention in the menstrual cycle and how the most controversial of those might be addressed. The committee and the panel of scientists at the workshop it convened on New Frontiers in Contraceptive Technology had reservations about pursuit of targets that make for interesting biology but are less likely as candidates for attack because they are not specific enough. At the same time, there are likely to be many genes whose products are truly specific; that is, the interruption of these products will not affect anything but that cell. In this connection, the committee noted the particular concerns of some women's groups about immunocontraception and its long-term, systemic effects on other aspects of reproductive function. For these and related reasons, it would seem desirable that priority be given to new directions that focus on peripheral rather than central processes, since products that act centrally, such as oral contraceptives, are already available and specificity is more likely to be achieved by concentration on peripheral targets. Recommendation 2. Modern scientific methods now exist that can identify genes whose products are involved solely in reproduction and are therefore prime targets for inhibition of conception. Fundamental research on the cells, tissues, and organs that contribute to conception can now be carried out with a new and incisive precision using tools of modern biology. The committee recommends, therefore, that priority be accorded to work with genes whose products are truly specific and urges attention to the fact that investment in basic research in contraception will be essential if work with these elements is to proceed with reasonable dispatch. Absent such investment, it is hard to see where innovative new approaches to contraception will come from. The science is also potentially responsive not only to the requirements of contraception but to the additional imperative of addressing the mounting burden of the sexually transmitted diseases, including HIV. Because sexual relations can ''transmit" both conception and infection, the design of new reproductive technologies must consider how to protect women against both, sometimes independently and sometimes together. The technologic and practical challenges of simultaneous protection against conception and infection are daunting. Clinical trials will present special technical and ethical challenges for developers, regulators, and trial participants, and industry will have to make some hard market
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--> The significant difference between the industrialized and developing countries in this regard is that, as in the case of new vaccines, translation of scientific potential into new products that can meet the needs of these markets is difficult at the prices consumers (or governments) are typically able to pay. The characteristic solution has been that international bilateral and multilateral external assistance programs procure large quantities of contraceptive commodities from developers or manufacturers at a public sector contract price sufficient (given large volumes and low distribution and marketing costs) to cover developers' costs, with a modest profit. Prices charged to developing country governments, however, can be substantially lower, thus ensuring substantial demand and overcoming economic impediments to widespread adoption of these products in those countries. Creation of some sort of multilateral "purchasing pool" for new contraceptives could rely on industrialized-country agencies or firms to fund a two-tiered pricing and distribution system that would be profitable for pharmaceutical firms and feasible for developing economies. Manufacturers could compete to develop and produce pilot lots of contraceptives that met specifications developed by these agencies as especially relevant to the needs of developing countries. The winning firms would be eligible for large-scale purchases of their products by the sponsoring agencies for distribution at a lower price in developing economies. The prospect of a large procurement commitment should attract the interest and, possibly, entry by firms not now pursuing the development of contraceptives for industrial or developing country markets. Recommendation 7. The committee recommends that consideration be given to a multilateral approach that would enlist the participation of public agencies and private philanthropic organizations toward support for an extension of the Global Contraceptive Commodity Programme that would create incentives for the development of new contraceptives. Since contraceptive procurement is already tiered and since both purchasers and vendors appear to accept that as a fact of life, an additional tier might be constructed for volume commitments for procurement of new contraceptives at prices that would constitute an incremental attraction to industry and still be feasible for countries able and willing to expand the range of contraceptives available to their populations. Direct Funding for Contraceptive Research and Development The committee recognizes the difficulties international agencies face in obtaining additional funding for contraceptive research and development at a time of fiscal austerity. Still, the committee's scrutiny of funding for contraceptive research and development over the past 15 years indicates that it has, at best, remained flat in constant dollars and may actually have diminished. This means that cuts of any size have major implications, since targeted financial support
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--> from the public sector, notably on the part of the U.S. Agency for International Development and the National Institute for Child Health and Human Development, has been critical in drawing U.S. university and not-for-profit institutional researchers into the field of reproductive biology and in catalyzing and sustaining the creative research partnerships that produced the advances in contraceptive research and development over the past two decades. The public sector also has particular strength and expertise in supporting the later stages of contraceptive research and development, for example, the clinical trials necessary to obtain the data required by the drug regulatory process. An increasingly frequent pattern of work in the contemporary pharmaceutical industry is a sequence of "virtual partnerships" and contract research arrangements at different junctures in the research and development processes. This is not an unfamiliar pattern for contraceptive research and development; in fact, the willingness of small companies to risk engagement, and the willingness of the public and non-profit sectors to venture along with them, have been pivotal in advances in the field. It is possible that the power and speed of combinatorial chemistry and high-speed computer modelling of compounds may make it more plausible for these sorts of collaborations to occur earlier in the research sequence. The partial nature of such early commitments might be attractive to biotechnology companies and might also mean that large pharmaceutical companies, wary of involvement in full product launch, would be willing to engage in different kinds of collaboration "closer to the bench." Any function that can expeditiously catalyze these sorts of ad hoc mechanisms across and within sectors could provide considerable value added. The reverse is also true; that is, any function impeding the healthy growth of such mechanisms is value lost. Recommendation 8. The committee strongly endorses continued public sector support of, first, basic research in innovative areas of reproductive biology as a source of new leads for contraceptive research and development and, second, in the applied research that will bring the most promising leads to fruition. The committee believes that the greatest value added will accrue to strategies focused on attracting investment in those smaller domestic and foreign firms able and willing to do early-stage research in contraceptives or in a fundamental reproductive mechanism of particular promise. In this connection, the committee calls attention to the new Consortium for Industrial Collaboration in Contraceptive Research, whose purpose is to catalyze funding for feasibility studies and matching industry investment in early-stage contraceptive research and development in priority areas of the woman-centered agenda. The committee believes this initiative to be a creative and potentially high-payoff mechanism for sponsor investment.
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--> Toward a More Temperate Climate The Need for New Guidelines Inevitably, regulatory factors are taken into account when a pharmaceutical or biotechnology firm decides whether or not to proceed along a given research and development trajectory. Responses to the requirements of the U.S. Food and Drug Administration (FDA) take time, and time is money, either in the form of additional "burn time," perhaps involving the costs of more trials, or in the form of delay in being early to market. The FDA has been working on the problems of delays in its approval processes and a number of internal reforms and procedural modifications have been implemented. In its contacts with industry, the committee encountered no generalized sentiment for diluting the rigor of FDA approval processes; in fact, any possibility that pending tort reform legislation might include a federal product liability statute giving contraceptive manufacturers credit for FDA approval of contraceptive drugs and devices argued against such dilution. The committee found that, in general, industry wants clear a priori guidelines on drug regulatory requirements for new contraceptives, to reduce uncertainty and wasteful error. Because contraceptives constitute a global market, it is crucial that these regulations be internationally harmonized. Although it lacks regulatory authority, the World Health Organization has, in the past, convened cross-sectoral symposia on guidelines for contraceptives; these efforts seem to have constituted a strong contribution to guidelines development and to have been appreciated by the FDA and industry. Comparable efforts are urgently needed in the area of vaginal microbicides and spermicides, since industry will need clear guidance if it is to enter this high-priority field. The committee recognizes the difficulty of anticipating all possible contingencies in any set of guidelines, particularly in the case of truly pioneer products, but finds such guidelines to have been generally conducive to industry investment; they are not, of course, a guarantee of such investment. Recommendation 9. The committee recommends that approval guidelines be developed as quickly as possible for the high-priority area of vaginal microbicides and spermicides, as a first step toward clarifying requirements for clinical trials and monitoring of novel contraceptives in general. A consensus conference on this topic is recommended, perhaps convened by the World Health Organization. Of special concern in this specific context are guidelines for what would constitute clinically significant levels of anti-infective efficacy, as well as risk of possible fetal exposure.
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--> Product Liability Contraceptives, like vaccines, therapies for drug addiction, and diagnostics and therapies for a number of infectious diseases, particularly the diseases unique to the developing world, are ''social products." That is, their benefits, intended or unintended, go beyond the prevention and cure of disease in individuals, such that they also have considerable benefits for the health of the public. However, for various reasons, the large majority of these products do not generate enough margin of profit for industry to justify investment in their development. This is particularly so when that margin is affected by other contextual issues that not only reduce its size but produce other negative consequences such as damage to a firm's reputation, stockholder unhappiness, and threats to the prosperity of its other product lines. With respect to contraceptives, factors of this genre have generated what might be called "The Contraceptive Paradox": that is, the disconnect between the consensus around the need for the widest possible offering of contraceptive methods, and the disappearance of some contraceptive options that have made it to market. Several contraceptive advances—the Today sponge, Norplant implants, Depo-Provera, and RU 486 (mifepristone) and other antiprogestins—are either unavailable or in some way besieged. Despite major improvements that have made intrauterine devices appropriate for a large number of women, the method has not yet overcome its difficult history and regained its former acceptability, at least in the United States. The newly introduced Depo-Provera, approved by the FDA only after much controversy and opposition by several women's groups, has also come under further attack. The Today sponge is no longer on the market, and the Norplant implant, which became the method of choice for many women quite quickly after its introduction, has experienced a dramatic decline in use because of removal problems in a small percentage of women and the large amount of negative publicity deriving from widely publicized class action lawsuits related to problems with breast implants. There have also been concerns that any contraceptive made with silicone and analogous biomaterials might become scarce or disappear from the market altogether or, perhaps for a time at least, become prohibitively expensive. This could affect the new two-rod Norplant II implant system, new female barrier methods now in clinical trials, hormone-releasing IUDs made with silicone, new male and female barrier methods made with silicone and analogous polymers, and tubal ligation clips, not to mention the loss of options in connection with other conditions such as cardiovascular disease. The committee encountered mixed views on the relative impact of liability on pharmaceutical innovation, in general, and contraceptive research and development, in particular. For some firms it is more of an issue than for others, but in no case is the current tort situation in the United States considered trivial. Where it is not costly in dollar terms, it can be costly in terms of company reputation; the
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--> time, energies, and concerns of staff; and an overall disposition to enter, reenter, or remain in the field of contraceptive research and development. What is also costly—and not always taken into account—are the costs to the large majority of consumers when a product is removed from the market entirely or for long periods of time. In its 1990 report, the National Research Council and Institute of Medicine Committee on Contraceptive Development recommended that the U.S. Congress enact a federal product liability statute that would give contraceptive manufacturers credit for approval of contraceptive drugs and devices (and their labeling) by the FDA. The gist of such a defense—termed the government standards, FDA, or regulatory defense—is as follows: If it is established that an injury-causing aspect of a contraceptive drug or device was in compliance with all applicable requirements of U.S. federal food and drug law at the time that drug or device was made or sold, then a manufacturer or seller of a contraceptive drug or device would not be liable under any of the relevant legal theories (misrepresentation, warranty, negligence, or strict liability) for any injury related to design, nor liable for failure to provide adequate warning or instruction regarding any danger associated with its use, nor liable if the FDA had not asserted that the contraceptive drug or device was not in compliance. The defense would not be available if a claimant were able to establish that the manufacturer should have made design modifications or given different or additional warnings or instructions; if the manufacturer or seller knew or should have known of studies showing increased risk of harm from the contraceptive drug or device that indicated increased likelihood of serious injury; or if the claimant established that the FDA was not informed of dangers regarding the contraceptive drug or device that were known to the manufacturer or seller, and that the injury to the claimant or persons sharing the claimant's medical characteristics was attributable to such dangers. The arguments for the FDA defense are that punitive elements of damage awards are meant to punish egregious behavior, not to punish companies that comply with the strict rules of the regulatory system and could not have predicted the side effects alleged to have caused the injury. The arguments against it are that the proposed legislation would protect irresponsible corporations at the expense of people victimized by faulty products. In general, manufacturers of all types of products have sought to limit their liability exposure and consumer groups have generally opposed these efforts. The pivotal issue appears to be that proposals for some kind of government standards defense have generally overlooked the widely held public belief that people are entitled to compensation for harm, particularly harm caused by negligence. Nonetheless, it is critical to note that the argument for some kind of government standards defense does not do away with liability. FDA compliance is, indeed, a shield, but noncompliance—importantly including concealment of data by the manufacturer—makes that shield worthless. The committee is comfortable in, first, arguing that liability is still a signifi-
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--> cant disincentive to contraceptive research and development and, second, in reaffirming the recommendation of the 1990 NAS committee that a government standards defense is a necessary, though not sufficient, condition for unfettering the field. The committee has noted the facilitating effect on the vaccines field of the National Vaccine Injury Compensation Act and, while that is not a fully analogous example, it does suggest that, for controversial products that contribute importantly to the public health yet produce only modest profit margins, some parameters on liability can act as an incentive to research and development. Recommendation 10. The committee reiterates the 1990 NRC/IOM committee recommendation that the U.S. Congress enact a federal product liability statute that gives contraceptive manufacturers credit for FDA approval of contraceptive drugs and devices. When the FDA has considered the relevant health and safety data on a contraceptive product, has approved the product, and has required warning and instructions to accompany it, it is sound national policy to make this approval available to manufacturers as a limited defense and not to penalize them for something they could not have known at an earlier point. Because the statute would interact with postmarketing surveillance efforts, this recommendation would be more compelling were formal postmarketing surveillance studies to be generally required. This said, the committee adds emphatically that it endorses a government standards defense only in the context of existing levels of rigor and scrutiny in approval processes and presentation of all relevant data by manufacturers. Informed Choice Since this committee was convened, the array of available contraceptives has been affected by the liability cloud around Norplant implants, the related crisis around biomaterials deriving from silicone breast implants, and the 20 years of controversy before Depo-Provera was approved for contraceptive use in the United States. At present, all three products have successfully met approval standards required by the U.S. Food and Drug Administration and regulatory agencies in many other countries. The committee also recalls the fate of IUDs in the United States after the widely publicized Dalkon Shield affair. No matter how suitable the newer IUDs have proved to be for many women, no matter how innocent of associated wrongdoing, and no matter how devoted their following, they have never regained their status in the mind of the consumer public. It seems that once there is adverse publicity about an approved contraceptive product, it is hard for that product to maintain or regain significant market share. It may also be that, in some cases, a product is used by individuals for whom it is inappropriate and/or who have expectations that there will be no risk involved in the use of that particular contraceptive method. No pharmaceutical
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--> product is right for all patients and all pharmaceutical products have side effects, slight for some individuals, significant for others; contraceptives are no exception, although they bear a special cargo of cultural freight and skepticism toward those who develop and produce them. It is also true that, as with vaccines, contraceptives are used by presumably healthy people whose tolerance for side effects is lower than it is for the products they use when they are ill. These experiences are unfortunate: for the immediate user; for developers and potential manufacturers, because of the loss of the time and resources invested; and for other putative users, for whom the method in question might be quite appropriate yet whose options are now diminished. Each such case naturally affects women's feelings about contraception and the willingness of science and industry to pursue new investments in the field. The term "informed choice" has been accumulating currency in the family planning community and among women's advocacy groups. As in legal understandings of informed consent, the principles of patient autonomy and adequacy of information are pivotal in informed choice. However, the emphasis is on information for the protection of the patient or client, a desirable objective even if there were no threat of liability. That protection is achieved by avoiding injury; injury, in turn, is avoided largely by fully informing potential users about all aspects of a product they are considering and encouraging them not to use a product if they find any of those aspects unacceptable. A key element is the informing process itself. The assumption is that provision of correct information is not enough; presentation, intelligibility, and confirmation that the information was understood are necessary to insure that individuals assess and select among options in an informed way. Concurrent with the worldwide search for cost-effectiveness in health services, including preventive interventions that are cost-effective in the shorter term, is the promotion of ideas about the "educated patient," patient autonomy, health promotion, client-centered care, and the significance of client-provider information exchange. In the context of contraceptive use and family planning, these have become standard themes. The point is often made that at least some of the failure rates associated with contraceptive methods (e.g., barrier methods) are a function of inadequate information and support or, as in the case of emergency contraception, an almost total lack of communication from provider to client. There is also ample evidence that women everywhere, to a varying extent, are inadequately prepared by providers for the possibility of contraceptive side effects, their implications, and appropriate response. The core implication of all this is that accuracy of information and its completeness, intelligibility, and overall effectiveness are more critical than ever to health care in general and to reproductive health in particular. The media through which this information must flow obviously include radio, television, and the printed page. They also include consumer education initiatives at different informational levels and at different stages of development: the international dialogue
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--> among women's groups and scientists, the U.S. campaign to reduce unintended pregnancy, and the design of informed consent and informed choice protocols for specific contraceptive methods. The committee applauds these efforts, urges support for them, and suggests one more area for development, that is, the untapped potential and often counterproductive medium of product labeling and packaging. The Role of Packaging Information The packaging and labeling of contraceptives—the "software"—could play a much more useful role in educating clinicians and consumers about contraceptive technology—the "hardware"—than they now do. At present, the labels and inserts in contraceptive packaging are daunting visually and technically, a fact often attributed to FDA demands and to concerns about liability. At the same time, the FDA only has jurisdiction to approve package inserts as accurate statements of the safety and efficacy of their contents; they are not in the business of approving new, perhaps more effective ways of informing consumers and clinicians. Labeling can be dismissed as a small matter, or at least smaller than other forces that impinge on the availability and use of contraceptives, such as the media, advocacy groups, and the ideas, information and, sometimes, misinformation that flow through them. Still, a single categorical location where intelligible, accurate information about the technical aspects of individual contraceptive technologies—their risks, side effects, contraindications, benefits, and proper use—is consistently available, could anchor the information base. It is also the case that the media pay attention to package labels; an apparent misreading of the label on the Reality female condom, published in a major trade journal, sent the manufacturer's stock plummeting. The technical complexity, regulatory considerations, legal implications, and what might be called the pedagogy and artistry of labeling are extensive. Even assuming that the method in question is physiologically and socially appropriate for use by a given population, there will always be some part of that population for whom newly accessible information will make no direct difference, either because it does not fit into the ways they calculate risk, or because they receive the information inadequately transmitted through an intermediary. Nor is there any easy way to calculate the costs and benefits of better labeling. Revising labeling in some generic way would inevitably impose costs, but these would seem unlikely to be crippling for large companies. In a clinic setting, helping individuals make informed choices takes time and effort, both at a premium for busy health care providers who may also have patient load quotas. A well-informed consumer may decide not to use a product after all, and a possible sale does not occur, yet another cost. Still, these costs must be arrayed against others: the possible harm to a user or a user's progeny, the costs of compensating that
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--> harm, the costs to the reputation of the firm, and the costs to other appropriate consumers of losing an option when a contraceptive method is withdrawn from the market. Recommendation 11. The committee believes that users of contraceptives have a right to information about them that is balanced, accurate, and intelligible. Significant sources of such information are the labels and inserts that are integral to pharmaceutical packaging. The legal, regulatory, educational, sociocultural, scientific, and even artistic aspects of these packaging elements are large and complex, so that modifying them significantly will require cross-disciplinary and cross-sectoral effort. The committee urges that this topic be addressed soon, for two reasons. First, balanced, accurate, and intelligible contraceptive packaging is of potential benefit to contraceptive users, health providers, manufacturers, and entities concerned with public health and welfare, since it could contribute to the more appropriate and wiser use of contraceptive technologies. Second, the activity in itself offers the opportunity for much-needed dialogue within and across sectors, genders, classes, and systems of belief. Closing Comment Despite the undeniable richness of the science that could be marshaled to give the women and men of the world a broader, safer, more effective array of options for implementing decisions about contraception, childbearing, and prevention of sexually transmitted disease, dilemmas remain. These dilemmas have to do with laws and regulations, politics and ideology, economics and individual behavior, all interacting in a very complex synergy that could lead to the conclusion that nothing can be done to resolve the dilemmas because everything needs to be done. This committee examined the development of vaccines for the world's children as an experience with many analogies to contraceptive research and development. That experience informs us that the dilemmas around controversial medical products, whatever the sources of controversy, tend to be incremental and systemic in their resolution. Modification of the terrain for vaccine research and development took time—two decades of working groups charged with solving "the vaccine problem," a decade of legislative attempts to construct a passable bill, and close to a decade for industry to perceive that the legislative remedy was effective. Change came from several sources—from a surge of discovery in the science, from legislative action that modified public policy, from leadership at national and international policy levels, and from the decision of a major international donor to seek outside guidance in assessing its processes and their impact.
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--> This does not mean that the same amount of time will be needed for improvement in the contraceptive landscape, nor will the solutions be the same. The central implication is that there is not likely to be a "silver bullet" solution to the dilemmas faced by the field of contraceptive research and development. Each piece of the dilemma will have to be tackled in cumulative fashion as part of a coherent strategy, each resolution improving matters somewhat and eventually amassing enough weight to tip the balance in a more positive direction. What this study committee has tried to do is identify a relatively small set of emphases and changes that, altogether, could turn the field around, but that, even partially implemented, could open up the field to freer, more equitable access to those who require its fruits.
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Representative terms from entire chapter: