6
The Translators: Sectoral Roles in Contraceptive Research and Development

The Role of Industry in Contraceptive Research and Development

The Pharmaceutical Industry

Stage I: The First Contraceptive Revolution and the Primacy of Industry (1951-1972)

Since the 1950s, the involvement of the pharmaceutical industry in contraceptive research and development has passed through three stages, and it is now in a fourth stage whose future pace and direction are unpredictable. The character of that involvement has shifted in each phase in response to factors in the external environment that are peculiar to the field of contraceptive research and development and, perhaps, to the entire area of women's health. Although this chapter emphasizes the history and contemporary dynamics of the U.S. pharmaceutical industry, it incorporates information about firms outside the United States that are involved in some aspect of contraceptive research and development and raises issues deriving from the ongoing processes of industrial globalization.

Stage I, "the contraceptive revolution," can be said to have begun in 1951 more or less officially, when Carl Djerassi at Syntex filed a patent for norethindrone; it ended in the early 1970s. During this period, most contraceptive research and development was sponsored and carried out by large pharmaceutical companies, especially U.S. firms. The field was "pushed" by advances in steroid chemistry and the emergence of an array of complex plastics, neither of which



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--> 6 The Translators: Sectoral Roles in Contraceptive Research and Development The Role of Industry in Contraceptive Research and Development The Pharmaceutical Industry Stage I: The First Contraceptive Revolution and the Primacy of Industry (1951-1972) Since the 1950s, the involvement of the pharmaceutical industry in contraceptive research and development has passed through three stages, and it is now in a fourth stage whose future pace and direction are unpredictable. The character of that involvement has shifted in each phase in response to factors in the external environment that are peculiar to the field of contraceptive research and development and, perhaps, to the entire area of women's health. Although this chapter emphasizes the history and contemporary dynamics of the U.S. pharmaceutical industry, it incorporates information about firms outside the United States that are involved in some aspect of contraceptive research and development and raises issues deriving from the ongoing processes of industrial globalization. Stage I, "the contraceptive revolution," can be said to have begun in 1951 more or less officially, when Carl Djerassi at Syntex filed a patent for norethindrone; it ended in the early 1970s. During this period, most contraceptive research and development was sponsored and carried out by large pharmaceutical companies, especially U.S. firms. The field was "pushed" by advances in steroid chemistry and the emergence of an array of complex plastics, neither of which

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--> had had human contraceptive uses as their original objectives. The developers of these first-phase contraceptives were well aware of cultural sensitivities about contraception and the consequent possibilities of corporate risk, but the perceived technological potential and market demand were overriding. A number of firms became engaged in the development and production of the new oral contraceptives (OCs). In the United States, those were Syntex, Searle, Upjohn, Wyeth, Merck Sharpe and Dohme, and the Syntex-Ortho partnership. Other U.S. firms were engaged in the development and production of the first modern intrauterine devices (IUDs): Ortho, Schmidt, American Caduceus Industries, Searle, and A.H. Robins. In Europe, the first firms to be involved in contraceptive research and development were Schering AG, Ciba, and Organon; British Drug House entered with two OC compounds in the early 1960s, and firms in Canada, Switzerland, and France with improved intrauterine devices in the early 1970s. Upjohn and Schering AG also presented the injectable contraceptives, Depo-Provera and Noristerat, for regulatory approval in this time period. All this unfolded in a climate of general enthusiasm for the postwar "pharmaceutical revolution," and receptivity to effective, reversible, coitus-independent fertility regulation was rapid and enthusiastic. Regulatory requirements were fairly lenient, particularly for the IUD, and clinical studies were less sophisticated than they are today; thus, R&D time was shorter and effective patent life was longer. The taking of a daily pill over a goodly proportion of the reproductive life promised a large market, and the smaller size of the market for the longacting IUD seemed not to be a problem (Gelijns and Pannenborg 1993). Only one firm abandoned the field during this time: Parke-Davis, whose management was worried about negative consumer reaction and conflict with company values. Stage II: The Rise of the Public and Nonprofit Private Sectors and a Worldwide Orientation (1973-1987) The second stage of contraceptive research and development began early in the 1970s, its onset marked by negative reports in the medical and lay press on OC side effects. Senate hearings in 1970 received some sensational press coverage and OC use declined noticeably. At roughly the same time, there were reports of side effects of the IUD, primarily the Dalkon Shield, and Robins took the device off the market in 1974. The period also saw more stringent regulatory requirements, resulting in the extension of R&D time to between 10 and 17 years and, as a consequence, much greater R&D costs and reduction in effective patent life. The eruption of litigation against Robins spilled over onto other IUDs, as well as to oral contraceptives, and public perceptions of the pill and IUD became quite negative. Although oral contraceptives accounted for just under 4 percent of the prescription drug market as the 1980s began, there were more liability suits associated with that method each year of the new decade than for any other drug product (Djerassi

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--> 1989). As for the IUD, even though the copper-releasing and medicated devices were major improvements in safety, liability insurance had become essentially unavailable in the United States; even firms with FDA-approved IUDs left the market—and contraceptive research and development—altogether. Research indicating that IUD risks had been overestimated, together with improvements, motivated numbers of European and some developing-country women to return to the method. However, in the United States, only Alza's Progestasert was able to stay on the market and the IUD became virtually a nonoption for American women, never to regain its market share (Gelijns and Pannenborg 1993; NRC/ IOM 1990). Contraceptive research and development became what it continues to be today: highly politicized, with consumer advocates and some women's groups arguing that developers and policy makers have been generically heedless of the needs and safety of women, and opponents of fertility control arguing against any contraceptive research and development whatsoever. There was little mistaking the growing reluctance of U.S. industry to invest in contraceptive innovation; the barriers were everywhere. As something of a substitution effect, growing interest in family planning in developing countries drew the U.S. Agency for International Development (USAID) into the field, accompanied by funding that motivated research activity in universities and nonprofit organizations, especially those with strong international networks. The Center for Population Research at the National Institute of Child Health and Human Development (NICHD), motivated by U.S. domestic concerns, also became a major source of funding for contraceptive research during this stage. In 1972, the World Health Organization's Special Programme of Research, Development, and Research Training in Human Reproduction was established. Among the nonprofit entities that were either created or that became more active during this stage were the Population Council's Biomedical Research Center, Family Health International (FHI), and the Program for Appropriate Technology in Health (PATH). There were also over two dozen university-based research programs, some of which also took on roles as intermediary funders of research at other universities, for example the Institute for International Studies in Natural Family Planning (IISNFP) at Georgetown University, the Program for Applied Research in Fertility Regulation (PARFR) at Northwestern University and its successor, the Contraceptive Research and Development (CONRAD) program at Eastern Virginia Medical School. Wyeth, Schering AG, and Organon, recognizing the long-term profit potential of developing-country markets, set up manufacturing facilities in over 20 developing countries, including Bangladesh, Egypt, India, and Indonesia (PATH 1994). Second-generation lower-dose and multiphasic oral contraceptives, minipills, and more selective progestins reduced side effects and revived the reputation of oral contraceptives; when the secondary health benefits of the method also began to be appreciated, the structure of demand shifted back in their favor. And, owing to the sophistication, greater safety, and lower relative cost of endoscopic

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--> techniques, sterilization became by 1982 the most commonly used method in the United States. In the 1988 National Survey of Family Growth (NSFG), male and female sterilization together exceeded OC use and, in the 1990 telephone resurvey, sterilization by itself was the most commonly used method (Peterson 1990), even though, as a one-time permanent method with a limited pricing range and much subsidy, it did not offer industry a growing and profitable market niche. However, the profits that ensued from the other therapeutic and diagnostic uses of endoscopy were considerable so that the technology itself, overall, proved quite lucrative (Gelijns and Pannenborg 1993). Yet the net result of the dynamics of Stage II was that, by the end of the 1980s, women in the United States had one effective reversible method, the pill, and one effective permanent method, sterilization. Stage III: The Exodus of U.S. Industry and the Entry of Smaller Firms (1987-Present) Beginning in the late 1970s, all but two of the U.S. pharmaceutical companies that had engaged in contraceptive research and development over the previous two decades had, to all intents and purposes, ceased any significant involvement in that field: Syntex, Searle, Upjohn, Mead Johnson, Parke-Davis, Merck Sharp and Dohme, Eli Lilly, and Wyeth all withdrew, although some remained involved in production. Of the nine large U.S. pharmaceutical firms that had entered contraceptive research and development in Stage I, all but two-Ortho, a subsidiary of Johnson and Johnson, and Wyeth-Ayerst-had exited by the end of Stage III, although Syntex, Searle, Upjohn, and Parke-Davis continued to produce and distribute the products their firms had developed. By the end of the 1980s, innovation in contraceptive research and development in the pharmaceutical industry resided largely in Europe, in the hands of Organon, Schering AG, and Roussel-Uclaf, a Hoechst subsidiary (Gelijns and Pannenborg 1993). Another significant Stage III phenomenon was the entry into contraceptive research, development, production, and distribution by smaller companies. In Europe, this category has included firms like Gedeon Richter (Hungary), Alphatron (The Netherlands), Bioself (Switzerland), Cilag AG (Germany), Leiras (Finland), and Theramex (France) (see Table 6-9). In the United States a new pattern evolved, one of collaborative effort among public and private organizations: funding agencies, basic research facilities, university-based scientists, clinical trials organizations, nonprofit organizations, and smaller pharmaceutical companies, some of which were outside the U.S. (see Bronnenkant 1994). These organizational arrangements were unlike the standard model in the two preceding decades, that is, the single, large, integrated pharmaceutical company with, at most, one industry or nonprofit partner. In those years, basic research had been as likely to come out of industry as it was to emerge from the academic research community. In contrast, the multisectoral arrangements of the 1980s were flex-

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--> ible, opportunistic, varied, and complex, and the industry component was just one of several and as likely to be a smaller firm as a larger one. Almost all of these collaborations were focused on modifications of and new delivery systems for existing or improved compounds, namely: VLI (purchased by Whitehall Laboratories), National Institute of Child Health and Human Development (NICHD): vaginal sponge (Today) 1 Medisorb (formerly Stolle Research and Development Corporation), Ortho, World Health Organization (WHO), Contraceptive Research and Development Program (CONRAD), Family Health International (FHI): injectable microspheres Finishing Enterprises, Population Council, World Health Organization, Rockefeller Foundation, Ford Foundation: Copper T intrauterine device Wyeth-Ayerst, Leiras, Population Council, FHI, Program in Appropriate Technology in Health (PATH), individual clinical researchers worldwide: Norplant implants Ortho, Salk Institute, Medisorb (Stolle): LHRH analogues Alphatron, Vastech Medical Products, Population Council: nonsurgical vasectomy devices Upjohn, Dow Corning, Population Council, Battelle Institute, London International, Roussel UK: hormone-releasing vaginal rings London International, National Institute of Child Health and Human Development, Family Health International: polyurethane male condom (e.g., Avanti) Tactyl Technologies/SmartPractice, Contraceptive Research and Development (CONRAD) program: nonlatex (Tactylon) male condom Wisconsin Pharmacal, CONRAD, FHI, Reddy Health Care: female condom (Reality) YAMA, CONRAD, FHI: Lea's Shield. Stage IV: The 1990s and the Biopharmaceutical Industry The global pharmaceutical industry of the 1990s is composed of a great array of corporations devoted to the discovery, development, and commercialization of new pharmaceuticals. Over the years since the introduction of oral contraceptives, the industry has evolved and changed in response to a number of factors that are highly relevant to further advances in contraceptive research and development. Those factors include increases in the regulation of pharmaceuticals; a changing economic environment that has driven industry restructuring and stressed a global view of pharmaceutical markets; and—importantly—dramatic growth in the scientific tools and understanding of biology available to assist in the development of new pharmaceuticals. This understanding and these tools have spawned a whole new subset of the industry that is called the biotechnology

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--> sector and, in fact, suggest that the industry can be thought of as the "biopharmaceutical industry." The emergence of the biotechnology sector, together with what some analysts have referred to as a "structural revolution," are producing an ever-wider range of companies that differ greatly in size and organization; in the variety of their product development focus; and in the extent to which they either address the entire drug development process from basic research through to the marketing and sale of approved products or, instead, focus on one or more individual steps within that process. The Demography of the Biopharmaceutical Industry Numerous parameters can be used to define the companies that comprise the biopharmaceutical industry. One common metric is market capitalization, or the value that the market places on a company. Market capitalization is defined as the number of shares outstanding multiplied by the price per share. Clearly, since market capitalization varies with price per share, this metric is most easily determined for public companies whose shares trade on public securities exchanges. Figure 6-1 shows the market capitalization distribution of 232 pharmaceutical/ biotechnology companies that are traded on U.S. exchanges. These companies range in market value from over $5 billion (e.g., Merck, Glaxo-Wellcome) to under $25 million (many small, public biotechnology companies). Absent from this chart is information on over 1,200 private small biopharmaceutical companies in the United States and Europe which tend to have market capitalizations of less than $100 million and most of which do not yet have any product revenues. Figure 6-2 shows the annual net sales distributions of 244 pharmaceutical/ biotechnology companies that trade on U.S. public exchanges. The bulk of revenues produced by these companies is generated by a minority of large corporations. To emphasize this point, the accounting firm of Ernst and Young has calculated the "Merck/Biotech Index," an assessment of the entire developing biotechnology industry as compared with Merck's ethical pharmaceutical business. According to the latest Ernst and Young survey in 1995, Merck had reported $15 billion in revenues, compared to $12.7 billion in revenues for the entire biotechnology industry for the 12-month period ending June 1995. During the same period, while Merck invested $1.2 billion in research and development and had a workforce of 47,500, the biotech industry invested $7.7 billion in research and development and had a work force of 108,000. In other words, R&D investment, while intense throughout the biopharmaceutical industry, is most heavily concentrated in the emerging company subsector. Industry estimates are that, despite the large investment of public funds in disease-specific areas, 92 percent of all drugs approved between 1981 and 1990 trace their origin to private sector R&D programs. The growing importance of the R&D effort within young entrepreneurial companies is emphasized by statistics that show that even in R&D-intensive large companies such as Merck, 50 percent of all

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--> Figure 6-1   Market capitalization distributions of public   pharmaceutical/biotechnology companies. B = billion;  M = million. Source: Disclosure Annual Industrial Database, 1995. products presently in clinical trials were licensed from small companies and, to a lesser extent, universities. Contemporary Industry Dynamics There is little disagreement that the years since the late 1980s have brought profound transformations in the marketplace for human health products. The prospect of health reform accelerated a reorganization of the health care marketplace that was, in some respects, already under way. The precipitating factor was the relentless run-up in health care expenditures in the United States and the sense of urgency about the need to contain costs and shift from fee-for-service arrangements to managed care systems. The competitiveness and profitability of such systems depend on their cost-effectiveness. As a result, fixed-fee and capitation schedules, protocols, and guidelines have been implemented or recommended. In the same vein, there is growing interest in formularies and a consequent burgeoning of pharmacy benefit management organizations (PBMs) as

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--> Figure 6-2   Annual net sales distributions of public pharmaceutical/biotechnology  companies. M = million. Source: Disclosure Annual Industrial Database, 1995. ways to control the costs of pharmaceuticals. Health care purchasers in the 1980s, who were primarily physicians, tended to be generally cost-insensitive. Pharmaceutical profitability in the 1980s had exceeded all other industry sectors and drug companies had been able to grow almost entirely owing to price increases. It is now clear from different challenges to industry pricing that this strategy is no longer viable (Easton 1993; Pollard 1993). The pharmaceutical industry has been adapting to these realities by essentially reconfiguring itself. Some firms are moving toward domination of a small number of specialty areas, some toward vertical expansion throughout the health value chain. Some are increasing their size in the belief that greater critical mass will drive success, others are aiming at being total disease-management companies in which drugs are just a part of total health care solutions. The specter of shrinking profit margins has also motivated companies to view market share—that is, the percentage of sales within a particular market segment—as the most important determinant of near- and long-term success. The sense is that market share leaders will be the most cost-efficient players, whose cost-efficiency will yield them savings for reinvestment in research or for the sourcing of higher-value products (Easton 1993). Companies are attempting

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--> to retain market share for the drugs now coming off patent by converting them into over-the-counter (OTC) drugs; by building relationships with pharmacy benefit management organizations; by limiting price increases; or by responding to competition from generic drugs, either by building their own generic businesses, licensing out generic conversions of their drugs, or acquiring generic companies outright. Some industry analysts argue that there will be an inevitable decline in the number of new drugs, for two reasons. One is that the science is more complicated; the other is that providers will increasingly depend on drug formularies to control costs. Furthermore, there is evidence that patients may have a much more powerful voice in determining managed care buying practices. Selection, addition, and substitution of formulary products will be based on product price and the amount of therapeutic or ''user value" added, so that product improvements that are merely incremental are likely to be far less important than in the past. Yet, while "me too" and "incremental" products will be less attractive in the future, the opportunity for cost-effective "breakthrough" products for unmet medical needs remains. As a consequence, pharmaceutical companies will not just need to be more cost-efficient inventors, developers, and marketers to make more products pay off for shareholders; they will also have to be disciplined in focusing their research investment on a smaller, more select group of therapeutic categories. Speed to market, always important, will become more so. Established, experienced pharmaceutical companies will have an advantage because they have the best scientific understanding of what is needed in the field and the greatest resources to buy the innovative research required to develop the truly novel drugs that can break into formularies. Thus, despite pressure to cut prices and reduce profit margins, innovation and heavy R&D investment will continue to fuel the industry, with high rewards for novelty and being early to market with products that lower the cost of health care (Burrill and Lee 1993; Pollard 1993). For the large pharmaceutical companies ("big pharma") and for biotechnology firms, "pharmacoeconomics," or the linking of quality-of-life and outcome measures with efficacy data in the design and conduct of clinical trials, will be essential; it will be crucial in the development of products for "difficult audiences." The need of the large pharmaceutical industry to purchase technology in some form is highly significant for the biotech industry and there is a sense that the redefinition of the pharmaceutical industry offers biotechnology a much wider set of opportunities to prove its value. As noted above, because biotechnology firms essentially invest all of their assets in research and development, they are far from losing their identity as the incubators of much of the progress in human health care (Lee and Burrill 1995). Table 6-1 depicts different dimensions of the way the pharmaceutical industry is being reshaped, its likely future directions, and the way innovative products might be expected to fit into that picture.

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--> The Biotechnology Industry Industry Structure Most analysts trace the emergence of the "biotech industry" to the late 1970s/ early 1980s, with the foundation of a series of companies (Cetus, Genentech, Amgen, Biogen) that were started to exploit the commercial potential of recombinant DNA (rDNA) and monoclonal antibody (MAb) techniques. The former involves transferring genetic information from one organism to another, splicing and "gluing" it onto a vector molecule, and replicating or cloning it for a variety of purposes. MAb technology takes advantage of antigens on the surfaces of invading agents to trigger immune-system recognition and response in the form of antibodies, proteins that attach themselves only to the foreign antigen and nothing else, signaling subsequent processes that then destroy the invader. It is the specificity of MAbs, as well as the fact that they can be enlisted as transport mechanisms, that makes them so valuable in the development of diagnostics, therapies, and vaccines. The techniques, once seen as arcane, have become commonplace. Yet the tradition of novel technology deployed to define and address problems in human health care, agriculture, and animal health remains the hallmark of biotech companies. Thus, new technology stories are often the hallmark of new companies, so that gene therapy, xenotransplantation, genomics, and the like have been fostered first in biotech companies and then been transferred to "big pharma" via partnership, acquisition, or adoption. From its birth, the biotechnology industry has confronted a set of factors or "hurdles" whose confluence is seen as unique: massive breakthroughs in science and technology (but quite upstream in the R&D process); enormous capital needs with a long horizon to payback; financial markets and investor expectations that turn alternatively hot and cold; a regulatory hand that is seen as heavy; uncertainty about intellectual property rights; and a cost crisis in its primary market, which is health care (Burrill and Lee 1993). Financial analysts are unable to describe public biotech companies to their investment clients using standard financial parameters because the majority of these companies are essentially R&D operations without products, revenues, and earnings. The financial community has therefore adopted a categorization of companies that describes where they are in the product development and company development process. A jargon has emerged that divides companies into first-tier, second-tier, and third-tier. The first-tier companies have products and product revenues and can be judged using standard financial criteria (e.g., Chiron, Amgen, Genzyme). Second-tier companies have products that are new or close to the market and have established the business infrastructure needed to be a self-supporting entity (e.g., Cephalon, Matrix Pharmaceuticals). The third tier has the biggest population and generally consists of companies that went public in the last three years, with

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--> TABLE 6-1 Trends, Worldwide Pharmaceutical Industry, 1970s and Beyond Early 1970s-Mid-1980s Mid- 1980s-Mid- 1990s Mid- 1990s and Beyond Consolidation Further Consolidation   Many small companies Fewer, larger corporations Few, large corporations Small boutiques Domestic focus Technology driven Global focus Technology dependent Sales/service/distribution driven Competitive pricing Lower profitability Increased government regulation Global reach Technology dependent Sales/service/distribution driven Competitive pricing Potential to increase profits Increased government regulation Managed care Managed Care and the Pharmaceutical Industry   Past   Future Approvable products (safety/efficacy)   Marketable products (pharmacoeconomic outcomes) Cost-based pricing   Positioning on value Mega sales force   Multiple distribution techniques Customer service   Customer alliances * Disease management * Outcomes studies * Education * Customized phase III and IV clinical trials Science/sales driven   Customer/market driven

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--> with great variety, despite the fact that contraception has become an accepted fact of life for millions of individuals worldwide and despite major changes in attitudes concerning women's rights to equity and choice. At the heart of controversy reside two fundamental clusters of issues: beliefs about human sexuality, especially female sexuality, and beliefs pertaining to abortion. In many parts of the world, sometimes as a correlate of economic reversals, controversy may be expressed in a resurgence of conservative ideologies regarding women, their sexuality, and their rights, a resurgence that may originate in religious fundamentalism, ethnic nationalism, or social conservatism in reaction to concerns about excessive sexual and personal freedom (IWHC/ UWI 1994). Sexuality The United States is no exception. One scholar quoted in the recent IOM study of unintended pregnancy (IOM 1995b) notes that "Few if any societies exhibit a more perverse combination of permissiveness and prudishness in their treatment of sexual issues" and adds that the U.S. popular media are "filled with sexual material, while, on the other hand, there is a noted absence of equal attention to contraception, responsible personal behavior, and values in sexual expression." Other analysts point to the deep strains of ambivalence about contraceptives among some groups in the United States. In some cases, the ambivalence is rooted in economic inequality, racial discrimination, and a history sometimes marked with coercive or punitive uses of contraception (Samuels and Smith 1992; Segal et al. 1994). In others, it derives from the asynchrony between a tradition of high demand for technologic solutions, particularly in health, and the broad strain of technologic minimalism born in the 1960s. Another dimension of this line of thought includes worries about the "hypermedicalization" of women's health and the high priority that is placed by some women's advocacy groups on the need for women to have total control over their own fertility. A more specific ambivalence springs from disappointments as limitations and, in some cases, real deficiencies of new contraceptives are revealed in use in large populations (Forrest 1994b). Finally, there is an underlay of cynicism about the profit motives of the private sector, currently fueled by attention to issues of pharmaceutical pricing and the privatization of health care. All these areas of dissonance necessarily affect the exchange of accurate information about sexual behavior, contraception, and the avoidance of unintended pregnancy (Chen 1995). At the same time, the disjoints foster dissatisfaction with current contraceptive methods and, somewhat ironically, strong support for continued research and development of new ones (Forrest 1994b).

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--> Abortion The other major element of this conceptual environment has to do with beliefs about childbearing and the relative rights of parents and offspring, with definitions of the beginning of viable life ex utero, and with the ways abortion and contraception are seen to overlap. This overlap, real or not, matters greatly, whether or not abortion is defined as in itself a contraceptive method; whether it is defined as a last recourse in case of contraceptive failure; whether a specific method is defined as having abortifacient effect, even though science may provide evidence that no such effect is in play; or whether artificial contraception is seen, in itself, to be morally wrong. The resurgence of abortion as a central theme in the current U.S. political campaign, attempts to reverse Roe v. Wade, and efforts to eliminate the national family planning program are ample indication of the durable, penetrating character of these matters. For example, the State of Pennsylvania just, for the first time, appropriated state funds for contraceptives but excluded Norplant, Depo-Provera, and IUDs from being provided because they are considered abortifacients, a definition that is scientifically incorrect. There appears to be more clarity about current methods of emergency contraception, which are well accepted by medical and legal authorities in the United States and Europe as not being abortifacients, but as methods that either prevent fertilization altogether or stop the fertilized egg from implanting in the uterine wall. In other words, methods that prevent implantation from occurring, or perhaps even completing, are appropriately regarded as contraceptives, not abortifacients (Holt 1995).16 The same clarity of perception may be less likely in connection with the antiprogestins, since these offer potential for a number of interventions across the whole menstrual cycle, before and after implantation, a matter that will require special consideration. Revisiting the Analogy with Vaccines Issues of regulation and liability were also central in the years of discourse around vaccines (IOM 1985 and 1993). Vaccines and contraceptives are alike in that neither is a curative drug for people who are already ill; rather, both are administered to healthy individuals to prevent a condition they may never get. As a result, adverse reactions are much more noticeable and less tolerated by the vaccine (IOM 1993), so that both product categories have been especially susceptible to "superlitigation" (Djerassi 1989). However, as discussed earlier in this chapter and in Chapter 3, the vulnerability of the pediatric vaccines to litigation has been much attenuated by the National Vaccine Injury Compensation Program (NVICP) in the United States and was already less of an issue in the European countries, many of which had instituted some kind of vaccine injury compensation program (IOM 1985). The vaccines market, after decades of modest, birth-driven growth, entered a

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--> phase of dramatic expansion beginning in the mid-1980s. As of 1995, global vaccines sales reached approximately $2.5 billion, a market size close to that of the global market for contraceptives (FIND/SVP 1996).17 Part of the expansion is attributed to industry's gradual appreciation of the potential of the NVICP (Day 1996) and part to a confluence of other policy decisions, importantly the establishment of pediatric vaccination as part of the health care regimen for all newborns in most developed countries and intensification of vaccination campaigns in developing countries under the guidance of the World Health Organization (FIND/SVP 1996). WHO efforts were pivotal in raising immunization coverage of the developing world's children from about 10 percent in the late 1970s to 80 percent in many countries by the late 1980s. These efforts received further impetus from the 1990 World Summit for Children, where most of the world's nations committed themselves to achieving 90 percent national coverage by the year 2000 (UNICEF 1992). Consequent to the Summit, WHO, in conjunction with other United Nations' agencies, the World Bank, and the U.S. Agency for International Development, established an International Children's Vaccine Initiative (CVI) that is working toward development of a multivalent pediatric "supervaccine" that would require just one or two doses administered orally and would be heat stable, affordable, and have a low rate of side effects (IOM 1993). The vaccines market was further driven by development of new, genetically engineered vaccines (HiB-related meningitis, hepatitis A, and hepatitis B), as well as efforts to develop vaccines for such key needs as prevention of AIDS (FIND/SVP 1996). Analysts also attribute vaccine market growth to recognition of the emergence and resurgence of diseases, appreciation of infectious etiologies for some chronic diseases, and mounting drug resistance (IOM 1992). Greater awareness of the cost-effectiveness of vaccines is also considered a factor (FIND/ SVP 1996) and by subsidized bulk procurement for vaccine provision to developing countries that has been able to evoke positive commercial response (Mercer Management Consulting 1994). The bottom line is that there are over a dozen new pediatric vaccines in development, 18 in addition to almost two dozen diseases targeted for preventive vaccines for adults.19 To these must be added efforts at developing therapeutic vaccines, obviously including AIDS, cancer, and herpes, and work in novel delivery systems, including liposomes, microspheres, and nanoparticles. However, vaccines are not about human sexuality nor have they confronted anywhere near the diversity of public opinion that swirls around contraception. Furthermore, vaccines are not generically blurred as technologies qua technologies, nor are issues around their delivery as culturally fraught. Vaccines are what they are: They prevent disease and their modes of action are not confused by the public with any other purpose or effect. In addition, it is understood that vaccines are to be delivered by a provider in a formal health system and, while they may be required by law, they are not perceived as coercive except by small minorities who resist vaccination for their children largely on religious grounds. In contrast,

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--> the provider role in contraception is frequently brought into question (Forrest 1994b; Richter 1994). Concluding Comment Despite the imperfection of the analogy between vaccines and contraceptives, the vaccine experience does inform us that the issues around particularly controversial medical products, whatever the sources of controversy, tend to be incremental and systemic in their resolution. The vaccine experience 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; and, in lesser measure, from the decision of a major international procurer of commodities to seek professional assistance in assessing its processes and their impact. 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 any "silver bullet" solution to the dilemmas faced by the field of contraceptive research and development, but that each piece of the dilemma will need to be considered and addressed as part of a coherent strategy. References AH Robins Company. 1988 Annual Report and Form 10-K. Richmond, VA: AH Robins Company. 1988. AIDS Alert. Barriers to better condom "killing people"; regulatory, political hurdles stifle development. Atlanta, GA: American Health Consultants. 1994. American Law Institute (ALI). Restatement (Second) of Torts §402A. 1977. Associated Press. FDA Defends Its Drug Program. Washington, DC: 12 December 1995. Baker FD. Effects of products liability on bulk suppliers of biomaterials. Food and Drug Law Journal 50:455-460, 1995. Bankowski Z, J Barzelatto, AM Capron, eds. Ethics and Human Values in Family Planning: 22nd CIOMS Conference, Bangkok, Thailand, 19-24 June 1988. Geneva: WHO Special Programme of Research, Development and Research Training in Human Reproduction and Council for International Organizations of Medical Sciences. 1989. Barnett AA. FDA criticized by Republicans despite success. Lancet 346:16-17, 1995. Biotechnology Industry Organization (BIO). FDA Regulatory Reform: A Proposal by the Biotechnology Industry Organization. Washington, DC: BIO. 27 February 1995. Bruce J, A Jain. A new family planning ethos. The Progress of Nations. New York: UNICEF. 1995. Bulatao RA, RD Lee. An overview of fertility determinants in developing countries. IN Determinants of Fertility in Developing Countries, Vol. 2. RA Bulatao, RD Lee, eds. New York: Academic Press. 1983. Carpenter PF. Informed choice as a way to reduce risks and prevent injury. IN No Fault Compensation in Medicine: Proceedings of a Joint Meeting of the Royal Society of Medicine and the

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--> Macklin R. Ethics and human values in family planning: Perspectives of different cultural and religious settings. IN Ethics and Human Values in Family Planning: 22nd CIOMS Conference, Bangkok, Thailand, 19-24 June 1988. Z Bankowski, J Barzelatto, AM Capron, eds. Geneva: WHO Special Programme of Research, Development and Research Training in Human Reproduction and Council for International Organizations of Medical Sciences. 1989. Mathieu M. New Drug Development: A Regulatory Overview, 3rd ed. Waltham, MA: Parexel International Corporation. 1994. Mayer CE. Getting personal on product liability: Two lawmakers' opposing views stem from their own painful experiences. The Washington Post, pp. D1-4, 7 March 1995. Mercer Management Consulting. Summary of UNICEF Study: A Commercial Perspective on Vaccine Supply. New York: Mercer Management Consulting. 1994. Merrill RA. Regulation of drugs and devices: An evolution. Health Affairs 13(3):47-69, 1994. National Institutes of Health. Fiscal Year 1997 Legislative Proposal: Products Liability Exemption for PHS IND and IDE Research. Bethesda, MD: National Institutes of Health. 1995. National Institutes of Health (NIH). Long-term Effects of Exposure to Diethylstilbestrol (DES), NIH Workshop, Falls Church, VA, 22-24 April 1992. National Research Council and Institute of Medicine. Developing New Contraceptives: Obstacles and Opportunities. L Mastroianni Jr, PJ Donaldson, TT Kane, eds. Washington, DC: National Academy Press. 1990. National Women's Health Network. Memorandum to Dockets Management Branch, Food and Drug Administration: Vaginal Contraceptive Drug Products for Over-the-Counter Human Use (Docket No. 80N-0280). Washington, DC: National Women's Health Network. 2 June 1995. Newbille CI. The "injectable contraceptive"-Depo Provera: Cause for alarm, not celebration. Health and Fitness 1:6, 1993. Peterson MA. Civil Juries in the 1980s. Santa Monica, CA: Rand Institute for Civil Justice. 1987. Prichard JRS. Canadian FeralProvincial/Territorial Review on Liability and Compensation Issues in Health Care. Toronto: University of Toronto Press. 1990. Prosser W, P Keeton. Prosser and Keeton on Torts, 5th ed. St. Paul, MN: West Publishing. 1984. Reisman EK. Products liability: What is the current situation and will it change (and how) when more women are included in studies? Paper presented at the Women in Clinical Trials of FDA Regulated Products Workshop, Washington, DC, Food and Drug Law Institute, 5 October 1992. Richter J. Beyond control: About antifertility vaccines, pregnancy epidemics and abuse. IN Power and Decision: The Social Control of Reproduction. G Sen, R Snow, eds. Cambridge, MA: Harvard University Press. 1994. Robertson JA. The law of institutional review boards. UCLA Law Review 25:484-549, 1982. Samuels SE, MD Smith, eds. Norplant and Poor Women. Menlo Park, CA: The Henry J. Kaiser Family Foundation. 1992. Sathyamala C. Depot-medroxyprogesterone acetate and breast cancer: A critique of the WHO's multinational case control study. Medico Friend Circle Bulletin 220:1-5, 1995. Scheper-Hughes N. Death Without Weeping: The Violence of Everyday Life in Brazil. Berkeley: University of California Press. 1995. Schrage M. Shielding companies from suits is just industrial policy in disguise. The Washington Post, p. B3, 10 March 1995. Schwartz GT. Reality in the economic analysis of tort law: Does tort law really deter? University of California at Los Angeles Law Review 42:377-444, 1994. Schwartz J. FDA revises biotechnology rules: Changes are designed to consolidate and speed approval process. Washington Post, Federal Page, p. A19, 13 November 1995. Segal SJ, GP Talwar, RG Edwards. The Agenda for Contraceptive Research. Paper prepared for the Ad Hoc Group on Population of the International Council of Scientific Unions (ICSU). New York. 1994.

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--> Sivin I. International experience with NORPLANT® and NORPLANT®-2 contraceptives. Studies in Family Planning 19(2):81094, 1988. Smith SD. The critics and the "crisis": A reassessment of current conceptions of tort law. Cornell Law Review 72:765-798, 1987. Snow R, P Hall. Steroid Contraceptives and Women's Response: Regional Variability in SideEffects and Pharmacokinetics. New York: Plenum Press. 1994. Spayd L. America, the plaintiff: In seeking perfect equity, we've made a legal lottery. The Washington Post, Outlook section, 5 March 1995. Squires S. DES daughters and their children. The Washington Post, February 19:14. 1991. Steyer R. Searle nearing end of lawsuits over Copper 7 contraceptive. St. Louis Post-Dispatch, p. 1E, 15 October 1995. Swenson S. Depo-Provera: Loopholes and double standards. Hastings Center Report 17:3, 1987. Trussell J, K Sturgen, J Strickler, R Dominik. Comparative contraceptive efficacy of the female condom and other barrier methods. Family Planning Perspectives 26(2):66-72, 1994. United Nations Children's Fund (UNICEF). The State of the World's Children 1992. New York: Oxford University Press. 1992. United States Congress, House of Representatives. Impact of the high cost of long-term contraceptive products on federally sponsored family planning clinics, welfare reform efforts, and women's health initiatives. Hearing before the Subcommittee on Regulation, Business Opportunities, and Technology of the Committee on Small Business, 103rd Congress, 2nd session. Washington, DC, 18 March 1994. United States District Court for the Eastern District of Texas, Beaumont Division. Memorandum Opinion and Order Granting Plaintiffs' Motion to Remand (Case No. 1:94CV5006). Beaumont, TX, 17 March 1995. Wadington W. Breaking the silence of doctor and patient (review of J. Katz's The Silent World of Doctor and Patient). The Yale Law Journal 93(8):1640-1651, 1984. Washington Post. Editorial: Drug Regulation and Reform. 5 December 1995 . White K. Contraceptive makers chilled by court challenges. Journal of Women's Health 4(3):223-224, 1995. World Health Organization. Creating Common Ground: Women's Perspectives on the Selection and Introduction of Fertility Regulation Technologies-Report of a Meeting Between Women's Health Advocates and Scientists, 20-22 February 1991. Geneva: WHO/Special Programme of Research, Development and Research Training in Human Reproduction and the International Women's Health Coalition. 1991. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Depomedroxyprogesterone Acetate (DMPA) and Cancer: Memorandum from a WHO Meeting. Bulletin of the WHO 64(3):375-382, 1986. Zabin LS. Addressing adolescent sexual behavior and childbearing: Self esteem or social change. Women's Health Issues 4:93-97, 1994. Notes 1.   Although Depo-Provera was manufactured and marketed by a U.S. company (Upjohn), the U.S. Food and Drug Administration (FDA) did not approve it for routine contraceptive use until 1993 because, among other reasons, the FDA concluded that other contraceptives were equally or more convenient, safe, and effective. This decision made the drug unavailable to countries with a "country of origin approval rule" even though, unlike the United States, some of those countries had no alternatively available or appropriate contraceptives (Cook and Dickens 1989). At the same time, there was much debate around the fact that the drug was eventually licensed for contraceptive use in over 90 countries while the FDA continued to withhold approval, a circumstance considered by some analysts as constituting an "ethical double standard" (Swenson 1987). At the same time, other

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-->     groups—for example, the National Black Women's Health Project and Women of All Red Nations (WARN) in the United States, and several women's advocacy groups in India—expressed concern about Depo-Provera (Foreman 1992; Newbille 1993; Sathyamala 1995, Swenson 1987). Concerns have tended to fall into two categories: issues of side effects and the method's potential for coercive applications. 2.   Beagle dogs were found to respond differently to steroid hormones, at the receptor site and systemically, than do humans. As a result, regulatory bodies in other countries and the WHO toxicology review committee all agreed that beagle dogs were inappropriate as testing models for steroid use in humans. 3.   The NDA is the vehicle through which drug sponsors obtain FDA authorization to market a new pharmaceutical in interstate commerce. In the NDA, the sponsor proposes that a compound be approved, and uses clinical data, nonclinical data, and other information to show that the drug is safe and effective for the proposed indication (Mathieu 1994). 4.   The Supreme Court recently rejected the long-standing Frye rule, which required that any proposed scientific testimony must have received general acceptance of its reliability by the relevant scientific community before the court would admit it into evidence. In Daubert v. Merrell Dow Pharmaceuticals, the Court explained that Frye's general acceptance standard was superseded by the adoption of the Federal Rules of Evidence. Under the Federal Rules, the trial judge makes a flexible determination of whether the evidence rests on a reliable foundation and is relevant to the task at hand. The effect this change will have on the liability climate is unknown (IOM 1994a). 5.   The rule for devices is different. Courts have concluded that state tort claims relating to medical devices are preempted under a provision of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. Section 360K(a) (E. Flannery, personal communication, 1996). 6.   The term ''clinical studies" encompasses a wide range of activities. In pharmaceutical testing, it usually refers to randomized clinical trials, using either a placebo or an established therapeutic as the control. Clinical studies also include the early-phase safety studies in health volunteers, postmarketing studies to expand indications for use or investigate safety and effectiveness in special populations, and investigations of the outcome of health interventions (Flannery and Greenberg 1994). 7.   "Punitive damages" is really a term of art. The more accurate statement is that there is an element of punishment in many tort judgments for damages (W Wadlington, personal communication, 1995). We use the term, however, because it is less cumbersome. 8.   E.g., Arizona, Colorado, New Jersey, Ohio, Oregon, and Utah have passed legislation that allows the manufacturer of an FDA-approved product to assert a government standards defense in response to claims for punitive damages (Ariz. Rev. Stat. Ann. §12-701[A][1992]; Colo. Rev. Stat. Ann. §13-21-403[1] [West 1989]; N.J. Stat. Ann. §58C-5[c] [West 1987]; Ohio Rev. Code Ann. §2307.80C [Anderson 1996]; Oreg. Rev. Stat. Ann. §30.927 [1995]; Utah Code Ann. §78-18-2[1] [1995]). In addition, two states, Illinois and North Dakota, have adopted a defense to punitive or exemplary damages for products that have been approved by a state or federal regulatory agency with authority to approve the product in question (III. Rev. Stat. §5/2-2107 [1996] [state or federal]; N.D. Cent. Code §32-03.2-11 [1995] [federal]. (NRC/IOM 1990; M Powell, personal communication, July 1996). 9.   The House and Senate accepted the conference report, referred to as H.R. 956, but the President vetoed the bill and the veto override attempt failed. This was reported in the press (cf. Wall Street Journal , 3 May 1996, p. A12), too late to permit incorporation of that information into the body of this document. This outcome means that the issue remains an issue.. 10.   DES was a synthetic estrogen widely prescribed in the 1940s and 1950s to prevent miscarriage by enthusiastic physicians who overlooked large, controlled clinical trials indicating that DES was ineffective and focused instead on smaller studies in which the drug appeared to show promise (Levine 1993). In the late 1960s and early 1970s, the drug was found to be clearly causative of grave injury to the offspring of pregnant women who had taken it, primarily their female offspring (NIH

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-->     1992). The ensuing legal actions were numerous and costly, with over a thousand pending nationwide as of February 1991 (Squires 1991). Of high relevance for the area of research liability were the awards for battery made to women involved in clinical trials of DES who had not been informed that they were part of a study (IOM 1994a). The experience encouraged exclusion of pregnant and potentially pregnant women from clinical research and the writing of FDA guidelines to reinforce that practice (IOM 1994a). 11.   Dow Corning was to be the largest contributor ($2 billion) to the $4.2 billion class action settlement reached in 1994 among breast implant manufacturers (including Bristol-Myers Squibb, Minnesota Mining and Manufacturing, and Baxter International) and the approximately 400,000 women signed up to participate in the settlement. However, Dow filed for bankruptcy in May 1995 and withdrew. The settlement remains the largest liability settlement in U.S. history and, since an additional 7,000 women are filing individual suits (Kolata 1995), the costs can only rise. 12.   This failure rate is based on clinical trials with two types of Norplant capsules: the original hard capsules and newer soft capsules. Cumulative failure rates through the end of five years were 4.9 percent for the hard capsules and only 1.6 percent for the capsules made of soft tubing (Sivin 1988). Leiras Oy, Norplant's manufacturer, now only uses soft tubing. 13.   MDL = Multidistrict litigation. 14.   In February 1996, Huhtamaki Oy announced that negotiations were under way on the sale of its pharmaceutical division, Leiras, to an international pharmaceutical company. ". . . The operating environment for Leiras has changed, hence our decision to concentrate on the foods division." This may have a major impact on the availability and/or price of Norplant implants for public sector purchasers of the product. It is not clear at the time of this writing whether the decision is in any way related to the company's experience with Norplant and what that might imply. 15.   The FDA estimates that implementation of nutrition labeling required under the recently enacted Dietary Supplement Health and Education Act will cost that industry from $52 to $85 million to implement (Food Labeling and Nutrition News 1996). 16.   According to medical textbooks, pregnancy begins when the process of implantation of the ovum in the uterine wall is complete. Implantation is not generally regarded as complete until 28 to 31 days from the first day of a woman's last menstrual period, assuming regular cycles (Cunningham 1993; Holt 1995). This prevailing medical opinion has been followed by policy makers and courts in Europe and the United States (e.g. , Brownfield v. Daniel Freeman Marina Hosp. , 256 Cal. Rptr. 240 , 245 [Ct. App. 1989]; Margaret S. v. Edwards , 488 F. Suppl. 181 , 191 [E.O. La. 1980]. 17.   The pediatric vaccines accounted for over 60 percent of that market, U.S. sales for slightly under half. The market is expected to enter a period of more modest growth through the 1995-1999 forecast period, followed by a second surge after the year 2000, fueled by the introduction of vaccine products to treat diseases for which there is now no preventive vaccine, the growth of mega- or multivalent vaccines, and the WHO "supervaccine" (FIND/SVP 1996). 18.   Acute infantile gastroenteritis; DTaP-HIB; DTaP-IPV-HIB; group A and group B streptococcus; hemophilus influenzae type B; malaria; meningococcus A,B, and C; pertussis; pneumoccocal disease; polio; pseudomonas infections; and respiratory syncytial virus. 19.   Cholera; dengue fever; gonorrhea; group B streptococcus; helicobacter pylori; hepatitis A, B, C, D, E, and X; herpes virus; human B19 parvovirus vaccine; influenza; Lyme disease; rheumatoid arthritis; staphylococcus aureus infections; traveler's diarrhea; and a range of new adjuvants.