International Journal of Technology Assessment In Health Care, 8:4 (1992), 658-668. Copyright © 1992 Cambridge University Press. Printed in the U.S.A.
CONTRACEPTIVES On Their Own Lisa Kaeser Jacqueline Darroch Forrest The Alan Guttmacher Institute
Allan Rosenfield Columbia School of Public Health
Abstract Despite the need for more safe and effective contraceptive drugs and devices, enormous barriers to contraceptive research and development have been raised in the United States. The designation of contraceptives as orphan drugs, with concomitant incentives, may be warranted to encourage private manufacturers to reenter the field.
Contraceptives are among the drugs and devices most widely used by people of reproductive age in the United States. Yet despite the enormous need for safe, effective, and easy-to-use methods, the legal, social, and economic barriers have been raised so high as to seriously impede the development and dissemination of new or improved contraceptive technologies. This paper discusses the possibility that these barriers have become sufficiently entrenched in the perceptions of private industry that a radically new way of viewing contraceptives — as orphan drugs —may be warranted. ORPHAN DRUGS Orphan drugs generally are understood by the pharmaceutical industry and policy makers to include those drugs which, when developed and marketed, would be used to treat or prevent only certain diseases or conditions in relatively small populations. Section 5 of the Orphan Drug Act of 1983 (16) created incentives for the development of certain drugs by providing federal funding through the Department of Health and Human Services (DHHS) to defray the costs of developing drugs and medical devices for "rare diseases or conditions," defined as (in the case of a drug) those that affect less than 200,000 persons in the United States or that may affect more than 200,000 persons but for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such a disease or condition can be recovered from sales. (The latter part of this definition does not apply to medical devices or foods.) Those pharmaceutical companies that are first to develop a drug that qualifies as an orphan are eligible for grants, tax credits, and seven years of market 658
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exclusivity. While current law permits more than one company to be granted orphan status during the development stage (for grants and tax credits), only one company ultimately is approved for marketing. Thus, whichever company obtains approval from the U.S. Food and Drug Administration (FDA) first—even if only by days —wins exclusive marketing rights for that drug or device for seven years, allowing it to recoup its research and development costs without concern for competition. Legislation that would have allowed shared exclusivity (to prevent windfalls for certain manufacturers should the affected population treated by their drugs prove to be larger than expected) and that would have revoked exclusivity when the patient population exceeded 200,000 was vetoed by President Bush in 1990. The president's budget for fiscal year 1992 proposes another alternative: that manufacturers whose products have received orphan drug approval be given temporary tax credits for 50% of the costs of the clinical testing, which must be completed before the drug's manufacture and distribution are approved by the FDA (2). The actual determination of whether a drug or device qualifies as an orphan is made based on "the facts and circumstances" as of the date of the manufacturer's request to the FDA prior to or during the development of the drug (16). The determination of the size of the affected population is made at the same time and cannot be revised after the drug's approval. Most of the drugs that thus far have been determined to be orphans fall under the first part of the definition by assisting fewer than 200,000 people nationwide. Many more are in the final stages of development, including 32 to treat rare diseases in children (15). Far less common is a determination by the FDA that the costs of developing certain drugs are so much higher than what consumers can pay to purchase them that even if substantial numbers of people would benefit from their use, manufacturers are reluctant to invest the resources that are necessary for their development because they cannot recoup the costs of research and development. A strong case can be made for considering contraceptive drugs as orphan drugs under the latter part of the definition. While unintended pregnancy certainly cannot be considered a disease, it is a condition that can seriously affect the health and wellbeing of a woman. Unfortunate rises in both the numbers and rates of sexually transmitted diseases in the United States may affect not only a person's immediate health but possibly his or her future health and fertility as well. Several contraceptive methods are available in the United States, but none is perfect; it is likely that the ideal contraceptive—extremely effective, reversible, safe, easy to use, and widely accessible — will never be achieved. In fact, standards are especially high for contraceptives. A drug or device (in the case of a medical device, the definition would have to be expanded legislatively) that can treat a rare disease or condition with an 80% effectiveness rate may be acceptable; a contraceptive with a failure rate of 20% may not. The ideal contraceptive, or one closer to the ideal, appears to be impractical to produce from a manufacturer's point of view because the criteria for success are so high and the development and marketing costs are so great. Yet at the same time, this country is faced with unacceptably high unintended pregnancy rates, with severe consequences for the individuals involved and our society as a whole. The prospects are not encouraging. Most U.S. pharmaceutical companies - once the world's leaders in this field—either have severely restricted new research in this area, concentrating instead on improving currently available methods, or have dropped out of the field altogether (11). In addition, the little training of young researchers in this field, due in part to stagnant federal research funding in this area, has been focused within the disciplines that relate to the development of new contraceptive methods. Nonetheless, when balancing the societal benefits, including the economic INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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benefits, of preventing unintended pregnancy and sexually transmitted diseases against the monetary interests of pharmaceutical manufacturers, the scales seem heavily weighted toward the value of offering every possible incentive to those companies to consider reentering the field.
CONTRACEPTIVES-THE DEMAND AND THE NEED In its landmark report, Developing New Contraceptives: Obstacles and Opportunities (12), a National Academy of Sciences (NAS) and Institute of Medicine (IOM) panel recognized that while a broad array of contraceptive drugs and devices is required to meet the varying needs of men and women at different stages of their reproductive lives, many subpopulations are not well served by the methods that are now available to them. Particularly ill-served groups include teenagers, who often use contraceptives sporadically, if at all; mothers who are breast-feeding their infants; and comparatively older couples with completed families who do not yet wish to undergo sterilization (12). The contraceptive choices that are available also limit the opportunities for men, who might otherwise do so, to effectively share responsibility for contraception with their partners (12). Although contraceptive use is widespread in the United States, many people lack access to methods that they consider appropriate for their particular circumstances. Each currently available method has some drawbacks; collectively, current contraceptive choices leave significant gaps in the ability of people to control their fertility safely, effectively, and in culturally acceptable ways throughout their reproductive lives. Woman and couples in the United States today appear to be largely disappointed with their limited range of contraceptive choices (4). Opinions regarding various reversible contraceptive methods that are available change with a person's age, type of relationship, number of children, and plans for future children; they also may change on the basis of a person's experience using the method. In 1982, 61% of U.S. women said that no method is completely satisfactory (5). By 1987, among women in general, only four methods received more favorable than unfavorable ratings: oral contraceptives, condoms, vasectomy, and female sterilization (5). However, while just under 9 in 10 women who depended on sterilization were satisfied with it, 1 in 10 said that she or her partner wished to have the procedure reversed (5). Only one-third to onefifth of all women had positive opinions about the diaphragm, the IUD (intrauterine device), foam, and the sponge, although (depending upon the woman's marital status) those ratings were considerably more positive among actual users of the individual methods (5). Among women ages 15-44 who have ever had intercourse, 95% have used one or more contraceptive methods (5). Although this portion of sexually active people who have ever used contraception is high, so too are the rates of contraceptive failure and discontinuation. About 90% of the women who are currently at risk of unintended pregnancy use some method of birth control. Contraceptive failure among these approximately 35 million couples was responsible for more than half of all unintended pregnancies —1.7 million unintended pregnancies in 1987 — including half of all of the abortions that occurred in that year. In contrast, the smaller group of women who are at risk of unintended pregnancy and use no contraceptive — about four million women — accounted for 1.9 million unintended pregnancies, including half of all abortions (8). Disturbingly, the level of nonuse is even higher among young, unmarried,
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and poor women. Nonuse among poor women is 15% among those under 200% of poverty income level, compared to the 8% nonuse rate of higher-income women who are at risk of unintended pregnancy (6); poor women are approximately twice as likely as higher-income women to become pregnant while using a contraceptive (9). This challenging situation has been further complicated by the prevailing attitudes of Americans toward reproductive issues. Although it is difficult to measure, the chilling effect of the ongoing political controversy over abortion on contraceptive research is undeniable. The NAS/IOM panel found that the seemingly permissive and sexually liberated lifestyles in the United States (particularly as evinced by television) in actuality mask "remarkably conservative" attitudes toward reproduction and the use of contraceptives (12). Governmental restrictions (such as the obsolete Comstock obscenity laws) on contraceptive products and information can be traced back to the country's religious roots and traditional views of family and sex. Moreover, views regarding the availability and use of contraceptives also may have been affected by attitudes toward sterilization and abortion. Contraception and abortion often are linked politically, both by groups that oppose abortion as well as by those that support contraceptive practice and a woman's right to choose abortion. Contributing to the confusion is the attempt on the part of legislators to form policy around indefinite science, such as the determination of when individual methods of contraception act to prevent pregnancy and, more fundamentally, the determination of when life begins. With such pressure to base scientific findings on political expediency, it is not surprising that relatively little federal research has concentrated in this area. Not even the law of supply and demand has translated into increased support for contraceptive development. Possibly because of the perception that discussing these issues is embarrassing or uncomfortable, no loud demands on the part of most consumers for more options can be heard. Some of the groups that would be expected to support the wide-scale provision of the broadest possible array of methods, such as some consumer and feminist groups, are also among those who are the most suspicious and critical of the newer drugs and devices as being dangerous or unhealthy. Early concerns about high-dose oral contraceptives and the disastrous consequences of the Dalkon Shield IUD in the 1970s never have been completely alleviated. And finally, the urgency that is attached to the development of a drug or device to cure a specific illness or treat a certain condition simply is absent when performing research on a preventive measure. Nonetheless, the benefits of careful, if imperfect, contraceptive use are well established. Women and their partners reduce their risks, not only of unintended pregnancies and abortions but also of the health problems that are related to too-frequent pregnancy and childbirth; moreover, adequate spacing of children may have beneficial effects on the entire family's health. In addition to the benefit of reducing unwanted pregnancies and their consequences, contraceptive use also provides noncontraceptive health benefits. Some contraceptives help reduce the risk of contracting sexually transmitted diseases, and others reduce certain kinds of cancers. However, the preventive benefits —not only of unwanted pregnancy, but of abortion and health risks that are associated with pregnancy—have not been sufficiently taken into account when informing public policy. In part, contraceptive development has been slowed because the full benefits to the individual, as well as to society, of additional contraceptive drugs and devices have not been properly recognized (12).
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Kaeser, Forrest, and Rosenfield THE CURRENT STATUS OF CONTRACEPTIVE RESEARCH IN THE UNITED STATES
Few fundamentally new contraceptive methods have been approved for use in the United States since the advent of the Pill and the IUD. (The new subdermal implant, Norplant, was approved for use in this country in December 1990.) Most new methods have been improvements or variations upon existing technologies. Predicting when even these variations might become available has been difficult because of the uncertainties of scientific research, funding, procedures for regulatory approval, and marketing feasibility. For example, the NAS/IOM committee pointed out that in a 1980 survey of contraceptive development, experts named nine birth control methods that they considered likely to become available by 1990; however, only three of these (triphasic pills, the Copper T38OA IUD, and the sponge) were actually on the market in the United States by 1990 (14). Another, Norplant, is only now becoming more widely available, at least to the women who can afford it. However, the committee report also emphasized that, given the right environment, significant new developments would be possible before the year 2000; in some instances, new drugs or devices already are being tested or used in other countries. In the 1970s, the pharmaceutical industry, encouraged by the success of the oral contraceptive, was enthusiastically pursuing the development of other methods; at least eight of the 13 companies worldwide that were performing research in this area were based in the United States (11). As the 21st century approaches, however, clinical research on new contraceptive methods has slowed considerably, and only one major private U.S. company (Ortho) remains active. The United States used to hold a leadership role in the field; now new contraceptive methods are being developed and used overseas for years before being introduced—if at all—onto the American market. Private pharmaceutical companies face ongoing decisions about which avenues of research are most likely to provide a profitable return on their often substantial investments of time and resources. These decisions are affected by the likelihood of making significant discoveries that will lead to patentable products that meet consumers' needs and by the prospect of not only covering research and development costs but also making a profit from marketing the product. The development of a new product "from scratch" entails large costs, no matter what the size of the potential market. And few contraceptive innovations, with the exception of oral contraceptives, have offered a potential market that, in pure economic terms, justifies the heavy development costs involved. Still, the breadth of resources that are available to the large private pharmaceutical companies could expedite the process if they were applied to the development of new contraceptive methods. Private nonprofit, public sector, and small companies (or some combination), have emerged to partially fill the research gap (12). Nonprofit research firms, funded for the most part by private foundations and the federal government, have been able to carry out important new research with less regard for the bottom line than have the large private companies that are primarily responsible to their own stockholders. Norplant was tested and shepherded through the FDA approval process by the nonprofit Population Council. Small firms tend to limit their involvement to the marketing and introduction of new or improved methods rather than perform the basic and clinical research themselves; others fund their activities based on licensing agreements with larger companies. Some of the smaller firms, however, also are pursuing new contraceptives to fill niche markets in the United States rather than work on products to meet the needs of a mass market, which is a far more complicated proposition. Moreover,
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some small firms, although focusing on methods that are primarily intended for use by people in less developed countries, discover domestic benefits as well. Although their funding also has dropped in comparison with the heyday of contraceptive research in the 1970s, federal agencies, specifically the National Institute for Child Health and Human Development (NICHD) and the Agency for International Development (AID), are now among the only sources of support for contraceptive development remaining in the United States. Traditionally, NICHD has focused its efforts on products for domestic use, and AID has focused on new technologies that would serve the contraceptive needs of the developing world; however, the needs, and therefore these efforts, increasingly overlap. However, while AID remains almost exclusively supportive of applied research, NICHD's traditional emphasis upon basic research alone has broadened. Specific congressional direction called for the formation of four new applied research centers under the auspices of NICHD in 1991, two of which would focus on contraceptive development (17). These centers, which are intended to coordinate the expertise of several disciplines to create new contraceptive drugs and devices, are as yet politically fragile and underfunded. Whether they can fulfill the promise that their supporters envision remains to be seen. A fair number of new contraceptive methods —or variations upon current methods — are in the research pipeline, but the lack of concentrated research efforts has slowed the process considerably. Thus, it is unclear how quickly these new drugs and devices can be readied for clinical trials. The very nature of research, which requires pursuing innumerable leads to achieve a drug or device to be tested, demands a heavier commitment of resources than most research entities are able to command. For the foreseeable future and to a limited extent, the federal government and private foundations are likely to bear most of the costs of development. As was the case with Norplant, nonprofit or government-funded research programs that are involved in developing new methods with public funds will generally turn them over to private companies for introduction and distribution in the United States. While this sort of collaboration has been born of necessity, there are several serious problems with the current situation. Only the methods that are predicted to be profitable and which carry relatively low risks are likely to be picked up by private firms. Consequently, methods that are viewed as controversial, that are appealing to only small segments of the population, or that are expensive to produce, still may never reach the U.S. market. Truly new methods often require extensive professional and public education before becoming acceptable to enough individuals to make their marketing worthwhile. Even more problematic are the emerging concerns about making any new methods available to low-income women, either in the United States or overseas. Although better contraceptive methods carry the potential for tremendous impact on women here and overseas, private pharmaceutical companies are unlikely to see a sufficient return on their investments to develop new methods for use in developing countries. Recognition of this economic reality resulted in the formation of U.S. government-funded research entities (CONRAD, PIACT) and nonprofit agencies such as the Population Council and Family Health International, which may devote serious attention to methods that serve those populations, some of which may never be available to U.S. women. This approach is failing those who need a wider range of contraceptive options in the United States. Even the methods that are being developed with public funds (if their development has not been retarded by political pressures) and then turned over to private firms for disseminations here may be sold at such high prices that they INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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cannot be offered by family planning clinics serving low-income women and their partners, thereby creating two tiers of contraceptive availability. THE OBSTACLES TO CONTRACEPTIVE DEVELOPMENT
The approval for use of the new contraceptive implant, Norplant, in December 1990, capped an arduous process for the Population Council. Even now, it is unclear how many women in this country—the 17th to approve the method —will be able to take advantage of its availability, given its current high cost (13). Some women may already have been discouraged from trying it due to highly publicized cases of involuntary use. Norplant was heralded as the first truly new contraceptive to become available on the U.S. market in years; the questions remain: how many more years will it take before others are researched and approved, and how many other countries will have them first? Even if new methods are introduced in this country, will they be inaccessible to those with possibly the greatest need for help in preventing unintended pregnancy? The existence of serious impediments to contraceptive research and development in the United States has been generally established; the nature of those obstacles is not particularly controversial. The NAS/IOM panel cited four of the most daunting barriers: the organization of and resources available for research, the attitudes of the public, federal regulations, and product liability (12). Because these obstacles may never be entirely eradicated, other means must be found to entice private pharmaceutical companies back into the area of research and development. Funding
In real dollars, worldwide spending for contraceptive development by both government and industry has declined by nearly one-quarter since its peak in 1972 (1). By 1983, only about US $57 million was being spent for 384 research projects involving some 70 variations of potential contraceptives (1). Thus, expenditures amounted to approximately $800,000 per method. During the 1980s, NICHD only spent around $8 million annually for contraceptive development; by 1991, includingthe new centers, that total had risen to less than $11 million. In stark comparison, recent estimates of the cost to a pharmaceutical company of bringing a new method from the laboratory to the marketplace have been approximated at $231 million over a 10-year period (3). While data are unavailable to measure the specific impact that the lack of funding has had on the frequency of contraceptive innovation, the minuscule number of options that have entered the market in recent years indicates a lack of fiscal incentive. The results of such low levels of funding are many. Private and nonprofit researchers alike are more apt to spend the bulk of their available funds on modifications of existing methods, as opposed to new breakthroughs. Funding constraints slow the pace of research by limiting the formulations that can be tested simultaneously, thus lengthening the development process and jeopardizing its ultimate success. Declining or sporadic funding from foundations and the government, as well as a lack of promising positions within the large private companies, also has contributed to a reduction in the number of scientists who are being trained in fields that relate to reproduction. The lessened interest of pharmaceutical firms has resulted in fewer research opportunities, and those scientists who might have contemplated careers in contraceptive research have been deterred. Moreover, the controversial nature of contraceptive research has been made the field less attractive, resulting in increasingly sparse literature on each new method or development. While the costs of training have risen in recent years, 664
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the expected benefits and career opportunities have fallen; other areas, such as AIDS and genetic engineering, show far more promise for the budding scientist. The granting of orphan status to contraceptive drugs and devices might result in more private companies placing renewed emphasis on their reproductive research programs and encourage them to offer salaries that are geared toward motivating scientists to consider once again a career in this field.
Product Liability
The concept of liability requires an injured party to be compensated, unless that individual has used that product with the full knowledge that it was contraindicated. If negligence or fraud on the part of the manufacturer is shown, punitive damages also may be awarded. When the FDA approves any drug or device, it does not guarantee that the product is 100% effective or that it poses no risk but rather that the benefits of the drug or device in question, for most users under most circumstances, outweigh the risks. People are generally willing to take risks if dramatic benefits, such as the cure of a severe disease, can result. However, the NAS/IOM committee noted that the FDA's requirements for the approval of proposed contraceptives have been much more demanding than for other drugs because the agency views contraceptives as intended for use by healthy women and their partners, most of whom have alternative birth control options (even if they are limited) (12). Yet the benefits of contraceptives are less tangible than those from other drugs and devices; it is difficult to assess the value of avoiding unwanted pregnancy, especially as it is more important to some women to not become pregnant than it is to others. Some women may be willing to take greater risks to avoid pregnancy and would be better off using methods that are far more effective but which may carry more side effects. Furthermore, psychological and economic benefits may weigh in as important considerations—considerations that the FDA is ill-equipped to determine. During the 1980s, the number and size of jury awards in product liability suits were perceived to have increased, with no immediate relief in sight (12). Despite the fact that conduct meriting punitive damages (as opposed to compensatory damages) was arguably infrequent, such damages were sought and awarded by sympathetic juries to compensate injured persons; pharmaceutical manufacturers were frequent targets. As a result, liability insurance — covering both the conduct of clinical trials and the use of FDA-approved contraceptive products — became prohibitively expensive and, in some cases, almost impossible to obtain. Contraceptive development was badly damaged by the insurance crisis of the mid-1980s, and the field has not yet recovered. The disastrous experience with the Dalkon Shield — an IUD that substantially increased the risk of pelvic inflammatory disease in its users and, through the malfeasance of the manufacturer, led to enormous numbers of women being permanently injured or infertile—made insurance companies shun the coverage of any IUD and perhaps other contraceptive methods as well. Fear of large awards and the lack of obtainable insurance led to already approved products being withdrawn from the market and to some manufacturers leaving the field of contraceptive technology altogether. Some contraceptive methods, like oral contraceptives, have a large enough profit margin to effectively insure themselves. However, longer-acting methods like the IUD, Norplant, and injectables (widely used outside of the United States but not approved for contraceptive use in the United States) (7) have much smaller money-making potential, so that funds cannot be reserved so easily in preparation for litigation. The liability problem has also partially paralyzed clinical research on new methods, as those INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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that are in the research stage generate no profits from which they can be self-insured and outside insurance for testing new contraceptives on human subjects is often unobtainable. Without immediate prospects for easing the situation concerning the assessment of punitive damages, even those manufacturers who wish to remain in the field must continue to give special consideration to the prospects of extended litigation, given the time and costs that are involved in developing new contraceptive methods. While clearly not a panacea for the problems that are posed by the U.S. tort-law system, giving orphan drug status to contraceptives might go far in alleviating some of the component concerns. In particular, the possibility of financial assistance during the development process, as well as the assurance of exclusive marketing rights to the product for seven years, may provide the incentive that private companies need to redirect their thinking toward this area. FDA Approval Procedures
The complex, expensive, and time-consuming premarketing requirements that are imposed by the FDA have delayed the availability of many contraceptive methods in the United States until long after consumers in other countries have benefited from them. These extensive requirements have also discouraged pharmaceutical companies, because the longer the time spent on research and testing of a new drug or device, the shorter the time remaining under which the product is protected by a patent and therefore better able to earn a profit (10). Although patents grant the developer of a drug 17 years of exclusive rights, the patent generally must be approved long before FDA approval allows the new products to be placed on the open market. Even if widespread testing takes place in thousands of patients over a period of years, many reactions occur so rarely that normally only some of a drug's adverse reactions can be discovered before the drug is on the market. Some organizations have suggested that increased emphasis on postmarketing surveillance may better protect consumer health than an unrealistic emphasis on absolute safety before approval (12). The average time that it takes a product to wind its way through the FDA approval process has increased over the past two decades; yet in more recent years, new pressures have been placed on the FDA to approve drugs that relate to HIV on a faster track than ever before, due to the critical nature of the disease itself. However, the concomitant pressures to "guarantee" that all of the drugs and devices that are approved by the FDA are perfectly safe and effective have created something of a trap for the agency. Five states have adopted statutes that offer manufacturers involved in a product liability lawsuit the "FDA defense" to punitive damages, i.e., if a product has been duly approved by the FDA, and if the manufacturer did not materially misrepresent the drug or device to the FDA during the approval process — and did not withhold any new information that was obtained after FDA approval —the manufacturer cannot be held liable for the punitive damages to an injured party (10). (Note that the injured person could still recover compensatory damages from the manufacturer.) A similar provision was proposed by the NAS/IOM committee for contraceptive drugs and devices, with the same caveats, and has also been proposed (without success thus far) at the federal level for any FDA-approved drugs or devices (12). Its proponents claim that the manufacturers of new products (including contraception) might be less wary of entering or staying in the field with this protection. However, many consumer groups oppose the idea, stating that it is far too difficult for one individual or small group to marshal the funds or the information necessary to prove fraud on the part of the manufacturer. 666
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CONTRACEPTIVES AS ORPHAN DRUGS The ideal contraceptive is a poor product risk from a manufacturers' point of view: easy to use, long-acting, inexpensive, reversible, and extremely safe even with longterm use—for everyone who wishes to use it. At one end of the scale is the need for better and safer contraceptives that at least approach the ideal, both in the United States and overseas. While unintended pregnancy is not a disease, contraceptives can serve to fundamentally enhance the quality and direction of people's lives. Every new method that is developed will benefit at least a portion of those women and their partners who are of reproductive age, and the potential public health costs of not making a new method available are staggering. At the other end of the scale is the reality that many who most need help preventing unintended pregnancy can pay relatively little, especially because they need protection throughout most of their reproductive lives. Orphan drugs in the classic sense are not money-makers, because they are used by only a relatively small number of people to cure a specific illness — people who in all likelihood cannot afford to assume the entire bill for the research and development costs of making them available. It is equally apparent that the most ideal contraceptive drugs and devices cannot be profitable if they must fully cover research and development costs, especially the longer-acting methods. The factors that are delineated in this paper — the social benefits of contraception, the complex relationship of contraceptive-related risks and benefits, the ongoing difficulties in evaluating the health-related impact of long-term use, and the deleterious effects of inconsistent and unsupportive public policies — interact in such a way as to make the field of contraceptive development extremely uninviting to many pharmaceutical companies. None of these factors is dispositive; together they contribute to the near void in contraceptive research. The standard of supply and demand cannot be relied upon because of current attitudes toward these products that prevent consumer demand from clearly being voiced. At the same time, there is not just one but many markets for contraceptive products. Many of the individuals who need new methods cannot afford to pay the prices that are set by the manufacturers who, in turn, set high prices to cover the cost of development, liability insurance, and profit. Yet the vast number of people who would benefit from heavier public and privatesector commitment in this area dictate a public policy that is aimed at creating incentives for such research. One such incentive would be to make whatever classifications are necessary in the law and public perception in order for contraceptives to be recognized as orphan drugs. Not only would the overall goal of providing a broader range of contraceptive options be met, but in all likelihood, individuals' use of their chosen methods would improve greatly. By changing or interpreting the definition of orphan drugs to accommodate contraceptives, the public also may become more educated regarding the risks and benefits that are involved in deciding whether to use them. Moreover, advances in technology that are discovered through contraceptive research can be applied to and benefit other types of medical technologies. Establishing such a public policy change would not only somewhat alleviate the extraordinary problems facing the field of contraceptive research and development but would allow additional safe, effective, acceptable, and affordable contraceptives to be developed, expanding the limited range of options now available and preventing the need for women and men who are of reproductive age to make far more difficult choices. REFERENCES 1. Atkinson, L., Lincoln, R., & Forrest, J. D. Worldwide trends in funding for contraceptive research and evaluation. Family Planning Perspectives, 1985, 17, 196-207. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Kaeser, Forrest, and Rosenfield 2. Budget of the United States Government: Fiscal Year 1992, Part 3-31, Washington, DC: United States Government Printing Office. 3. Crooks, G. Pharmaceutical discovery and development. Presentation before the National Institute of Child Health and Human Development, January 28, 1991. 4. Forrest, J. D. Has she or hasn't she? Family Planning Perspectives, 1987, 19, 133. 5. Forrest, J. D., & Fordyce, R. R. U.S. women's contraceptive attitudes and how they have changed in the 1980's? Family Planning Perspectives, 1988, 20, 112-18. 6. Forrest, J. D., & Singh, S. The sexual and reproductive behavior of American women 1982-1988. Family Planning Perspectives, 1990, 22, 206-14. 7. Gold, R. B. Depo-Provera: The jury is still out. Family Planning Perspectives, 1983,15,78-81. 8. Harlap, S., Kost, K., & Forrest, J. D. Preventing pregnancy, protecting health: A new look at birth control choices in the United States. New York: The Alan Guttmacher Institute, 1991. 9. Jones, E. F., & Forrest, J. D. Contraceptive failure in the United States: Revised estimates from the 1982 National Survey of Family Growth. Family Planning Perspectives, 1989, 21, 103-09. 10. Kulik, B., & Kingham, R. The adverse effects of standardless punitive damage awards on pharmaceutical development and availability. Food, Drug, and Cosmetic Journal, 1990, 45, 699-xx. 11. Lincoln, R., & Kaeser, L. Whatever happened to the contraceptive revolution? Family Planning Perspectives, 1988, 20, 20-24. 12. Mastroianni, L., Donaldson, P. J., & Kane, T. T. (eds.). Developing new contraceptives: Obstacles and opportunities. Washington, DC: National Academy Press, 1990. 13. Nazario, S. Breakthrough in birth control may elude the poor. Wall Street Journal, March 4, 1991. 14. Office of Technology Assessment. World population and fertility planning technology: The next twenty years, Washington, DC: OTA, 1981 (as cited in the NAS/IOM report). 15. Pediatric products in U.S. development. SCRIP, November 7, 1990, No. 1564, 24. 16. P.L. 97-414 Sec. 5(a) 1983. 17. Senate Subcommittee on Labor-Health and Human Services-Education. Committee report on H. R. 5257, Appropriations for Fiscal Year 1991.
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CONTRACEPTIVES On Their Own Lisa Kaeser Jacqueline Darroch Forrest The Alan Guttmacher Institute
Allan Rosenfield Columbia School of Public Health
Abstract Despite the need for more safe and effective contraceptive drugs and devices, enormous barriers to contraceptive research and development have been raised in the United States. The designation of contraceptives as orphan drugs, with concomitant incentives, may be warranted to encourage private manufacturers to reenter the field.
Contraceptives are among the drugs and devices most widely used by people of reproductive age in the United States. Yet despite the enormous need for safe, effective, and easy-to-use methods, the legal, social, and economic barriers have been raised so high as to seriously impede the development and dissemination of new or improved contraceptive technologies. This paper discusses the possibility that these barriers have become sufficiently entrenched in the perceptions of private industry that a radically new way of viewing contraceptives — as orphan drugs —may be warranted. ORPHAN DRUGS Orphan drugs generally are understood by the pharmaceutical industry and policy makers to include those drugs which, when developed and marketed, would be used to treat or prevent only certain diseases or conditions in relatively small populations. Section 5 of the Orphan Drug Act of 1983 (16) created incentives for the development of certain drugs by providing federal funding through the Department of Health and Human Services (DHHS) to defray the costs of developing drugs and medical devices for "rare diseases or conditions," defined as (in the case of a drug) those that affect less than 200,000 persons in the United States or that may affect more than 200,000 persons but for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such a disease or condition can be recovered from sales. (The latter part of this definition does not apply to medical devices or foods.) Those pharmaceutical companies that are first to develop a drug that qualifies as an orphan are eligible for grants, tax credits, and seven years of market 658
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exclusivity. While current law permits more than one company to be granted orphan status during the development stage (for grants and tax credits), only one company ultimately is approved for marketing. Thus, whichever company obtains approval from the U.S. Food and Drug Administration (FDA) first—even if only by days —wins exclusive marketing rights for that drug or device for seven years, allowing it to recoup its research and development costs without concern for competition. Legislation that would have allowed shared exclusivity (to prevent windfalls for certain manufacturers should the affected population treated by their drugs prove to be larger than expected) and that would have revoked exclusivity when the patient population exceeded 200,000 was vetoed by President Bush in 1990. The president's budget for fiscal year 1992 proposes another alternative: that manufacturers whose products have received orphan drug approval be given temporary tax credits for 50% of the costs of the clinical testing, which must be completed before the drug's manufacture and distribution are approved by the FDA (2). The actual determination of whether a drug or device qualifies as an orphan is made based on "the facts and circumstances" as of the date of the manufacturer's request to the FDA prior to or during the development of the drug (16). The determination of the size of the affected population is made at the same time and cannot be revised after the drug's approval. Most of the drugs that thus far have been determined to be orphans fall under the first part of the definition by assisting fewer than 200,000 people nationwide. Many more are in the final stages of development, including 32 to treat rare diseases in children (15). Far less common is a determination by the FDA that the costs of developing certain drugs are so much higher than what consumers can pay to purchase them that even if substantial numbers of people would benefit from their use, manufacturers are reluctant to invest the resources that are necessary for their development because they cannot recoup the costs of research and development. A strong case can be made for considering contraceptive drugs as orphan drugs under the latter part of the definition. While unintended pregnancy certainly cannot be considered a disease, it is a condition that can seriously affect the health and wellbeing of a woman. Unfortunate rises in both the numbers and rates of sexually transmitted diseases in the United States may affect not only a person's immediate health but possibly his or her future health and fertility as well. Several contraceptive methods are available in the United States, but none is perfect; it is likely that the ideal contraceptive—extremely effective, reversible, safe, easy to use, and widely accessible — will never be achieved. In fact, standards are especially high for contraceptives. A drug or device (in the case of a medical device, the definition would have to be expanded legislatively) that can treat a rare disease or condition with an 80% effectiveness rate may be acceptable; a contraceptive with a failure rate of 20% may not. The ideal contraceptive, or one closer to the ideal, appears to be impractical to produce from a manufacturer's point of view because the criteria for success are so high and the development and marketing costs are so great. Yet at the same time, this country is faced with unacceptably high unintended pregnancy rates, with severe consequences for the individuals involved and our society as a whole. The prospects are not encouraging. Most U.S. pharmaceutical companies - once the world's leaders in this field—either have severely restricted new research in this area, concentrating instead on improving currently available methods, or have dropped out of the field altogether (11). In addition, the little training of young researchers in this field, due in part to stagnant federal research funding in this area, has been focused within the disciplines that relate to the development of new contraceptive methods. Nonetheless, when balancing the societal benefits, including the economic INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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benefits, of preventing unintended pregnancy and sexually transmitted diseases against the monetary interests of pharmaceutical manufacturers, the scales seem heavily weighted toward the value of offering every possible incentive to those companies to consider reentering the field.
CONTRACEPTIVES-THE DEMAND AND THE NEED In its landmark report, Developing New Contraceptives: Obstacles and Opportunities (12), a National Academy of Sciences (NAS) and Institute of Medicine (IOM) panel recognized that while a broad array of contraceptive drugs and devices is required to meet the varying needs of men and women at different stages of their reproductive lives, many subpopulations are not well served by the methods that are now available to them. Particularly ill-served groups include teenagers, who often use contraceptives sporadically, if at all; mothers who are breast-feeding their infants; and comparatively older couples with completed families who do not yet wish to undergo sterilization (12). The contraceptive choices that are available also limit the opportunities for men, who might otherwise do so, to effectively share responsibility for contraception with their partners (12). Although contraceptive use is widespread in the United States, many people lack access to methods that they consider appropriate for their particular circumstances. Each currently available method has some drawbacks; collectively, current contraceptive choices leave significant gaps in the ability of people to control their fertility safely, effectively, and in culturally acceptable ways throughout their reproductive lives. Woman and couples in the United States today appear to be largely disappointed with their limited range of contraceptive choices (4). Opinions regarding various reversible contraceptive methods that are available change with a person's age, type of relationship, number of children, and plans for future children; they also may change on the basis of a person's experience using the method. In 1982, 61% of U.S. women said that no method is completely satisfactory (5). By 1987, among women in general, only four methods received more favorable than unfavorable ratings: oral contraceptives, condoms, vasectomy, and female sterilization (5). However, while just under 9 in 10 women who depended on sterilization were satisfied with it, 1 in 10 said that she or her partner wished to have the procedure reversed (5). Only one-third to onefifth of all women had positive opinions about the diaphragm, the IUD (intrauterine device), foam, and the sponge, although (depending upon the woman's marital status) those ratings were considerably more positive among actual users of the individual methods (5). Among women ages 15-44 who have ever had intercourse, 95% have used one or more contraceptive methods (5). Although this portion of sexually active people who have ever used contraception is high, so too are the rates of contraceptive failure and discontinuation. About 90% of the women who are currently at risk of unintended pregnancy use some method of birth control. Contraceptive failure among these approximately 35 million couples was responsible for more than half of all unintended pregnancies —1.7 million unintended pregnancies in 1987 — including half of all of the abortions that occurred in that year. In contrast, the smaller group of women who are at risk of unintended pregnancy and use no contraceptive — about four million women — accounted for 1.9 million unintended pregnancies, including half of all abortions (8). Disturbingly, the level of nonuse is even higher among young, unmarried,
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and poor women. Nonuse among poor women is 15% among those under 200% of poverty income level, compared to the 8% nonuse rate of higher-income women who are at risk of unintended pregnancy (6); poor women are approximately twice as likely as higher-income women to become pregnant while using a contraceptive (9). This challenging situation has been further complicated by the prevailing attitudes of Americans toward reproductive issues. Although it is difficult to measure, the chilling effect of the ongoing political controversy over abortion on contraceptive research is undeniable. The NAS/IOM panel found that the seemingly permissive and sexually liberated lifestyles in the United States (particularly as evinced by television) in actuality mask "remarkably conservative" attitudes toward reproduction and the use of contraceptives (12). Governmental restrictions (such as the obsolete Comstock obscenity laws) on contraceptive products and information can be traced back to the country's religious roots and traditional views of family and sex. Moreover, views regarding the availability and use of contraceptives also may have been affected by attitudes toward sterilization and abortion. Contraception and abortion often are linked politically, both by groups that oppose abortion as well as by those that support contraceptive practice and a woman's right to choose abortion. Contributing to the confusion is the attempt on the part of legislators to form policy around indefinite science, such as the determination of when individual methods of contraception act to prevent pregnancy and, more fundamentally, the determination of when life begins. With such pressure to base scientific findings on political expediency, it is not surprising that relatively little federal research has concentrated in this area. Not even the law of supply and demand has translated into increased support for contraceptive development. Possibly because of the perception that discussing these issues is embarrassing or uncomfortable, no loud demands on the part of most consumers for more options can be heard. Some of the groups that would be expected to support the wide-scale provision of the broadest possible array of methods, such as some consumer and feminist groups, are also among those who are the most suspicious and critical of the newer drugs and devices as being dangerous or unhealthy. Early concerns about high-dose oral contraceptives and the disastrous consequences of the Dalkon Shield IUD in the 1970s never have been completely alleviated. And finally, the urgency that is attached to the development of a drug or device to cure a specific illness or treat a certain condition simply is absent when performing research on a preventive measure. Nonetheless, the benefits of careful, if imperfect, contraceptive use are well established. Women and their partners reduce their risks, not only of unintended pregnancies and abortions but also of the health problems that are related to too-frequent pregnancy and childbirth; moreover, adequate spacing of children may have beneficial effects on the entire family's health. In addition to the benefit of reducing unwanted pregnancies and their consequences, contraceptive use also provides noncontraceptive health benefits. Some contraceptives help reduce the risk of contracting sexually transmitted diseases, and others reduce certain kinds of cancers. However, the preventive benefits —not only of unwanted pregnancy, but of abortion and health risks that are associated with pregnancy—have not been sufficiently taken into account when informing public policy. In part, contraceptive development has been slowed because the full benefits to the individual, as well as to society, of additional contraceptive drugs and devices have not been properly recognized (12).
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Kaeser, Forrest, and Rosenfield THE CURRENT STATUS OF CONTRACEPTIVE RESEARCH IN THE UNITED STATES
Few fundamentally new contraceptive methods have been approved for use in the United States since the advent of the Pill and the IUD. (The new subdermal implant, Norplant, was approved for use in this country in December 1990.) Most new methods have been improvements or variations upon existing technologies. Predicting when even these variations might become available has been difficult because of the uncertainties of scientific research, funding, procedures for regulatory approval, and marketing feasibility. For example, the NAS/IOM committee pointed out that in a 1980 survey of contraceptive development, experts named nine birth control methods that they considered likely to become available by 1990; however, only three of these (triphasic pills, the Copper T38OA IUD, and the sponge) were actually on the market in the United States by 1990 (14). Another, Norplant, is only now becoming more widely available, at least to the women who can afford it. However, the committee report also emphasized that, given the right environment, significant new developments would be possible before the year 2000; in some instances, new drugs or devices already are being tested or used in other countries. In the 1970s, the pharmaceutical industry, encouraged by the success of the oral contraceptive, was enthusiastically pursuing the development of other methods; at least eight of the 13 companies worldwide that were performing research in this area were based in the United States (11). As the 21st century approaches, however, clinical research on new contraceptive methods has slowed considerably, and only one major private U.S. company (Ortho) remains active. The United States used to hold a leadership role in the field; now new contraceptive methods are being developed and used overseas for years before being introduced—if at all—onto the American market. Private pharmaceutical companies face ongoing decisions about which avenues of research are most likely to provide a profitable return on their often substantial investments of time and resources. These decisions are affected by the likelihood of making significant discoveries that will lead to patentable products that meet consumers' needs and by the prospect of not only covering research and development costs but also making a profit from marketing the product. The development of a new product "from scratch" entails large costs, no matter what the size of the potential market. And few contraceptive innovations, with the exception of oral contraceptives, have offered a potential market that, in pure economic terms, justifies the heavy development costs involved. Still, the breadth of resources that are available to the large private pharmaceutical companies could expedite the process if they were applied to the development of new contraceptive methods. Private nonprofit, public sector, and small companies (or some combination), have emerged to partially fill the research gap (12). Nonprofit research firms, funded for the most part by private foundations and the federal government, have been able to carry out important new research with less regard for the bottom line than have the large private companies that are primarily responsible to their own stockholders. Norplant was tested and shepherded through the FDA approval process by the nonprofit Population Council. Small firms tend to limit their involvement to the marketing and introduction of new or improved methods rather than perform the basic and clinical research themselves; others fund their activities based on licensing agreements with larger companies. Some of the smaller firms, however, also are pursuing new contraceptives to fill niche markets in the United States rather than work on products to meet the needs of a mass market, which is a far more complicated proposition. Moreover,
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some small firms, although focusing on methods that are primarily intended for use by people in less developed countries, discover domestic benefits as well. Although their funding also has dropped in comparison with the heyday of contraceptive research in the 1970s, federal agencies, specifically the National Institute for Child Health and Human Development (NICHD) and the Agency for International Development (AID), are now among the only sources of support for contraceptive development remaining in the United States. Traditionally, NICHD has focused its efforts on products for domestic use, and AID has focused on new technologies that would serve the contraceptive needs of the developing world; however, the needs, and therefore these efforts, increasingly overlap. However, while AID remains almost exclusively supportive of applied research, NICHD's traditional emphasis upon basic research alone has broadened. Specific congressional direction called for the formation of four new applied research centers under the auspices of NICHD in 1991, two of which would focus on contraceptive development (17). These centers, which are intended to coordinate the expertise of several disciplines to create new contraceptive drugs and devices, are as yet politically fragile and underfunded. Whether they can fulfill the promise that their supporters envision remains to be seen. A fair number of new contraceptive methods —or variations upon current methods — are in the research pipeline, but the lack of concentrated research efforts has slowed the process considerably. Thus, it is unclear how quickly these new drugs and devices can be readied for clinical trials. The very nature of research, which requires pursuing innumerable leads to achieve a drug or device to be tested, demands a heavier commitment of resources than most research entities are able to command. For the foreseeable future and to a limited extent, the federal government and private foundations are likely to bear most of the costs of development. As was the case with Norplant, nonprofit or government-funded research programs that are involved in developing new methods with public funds will generally turn them over to private companies for introduction and distribution in the United States. While this sort of collaboration has been born of necessity, there are several serious problems with the current situation. Only the methods that are predicted to be profitable and which carry relatively low risks are likely to be picked up by private firms. Consequently, methods that are viewed as controversial, that are appealing to only small segments of the population, or that are expensive to produce, still may never reach the U.S. market. Truly new methods often require extensive professional and public education before becoming acceptable to enough individuals to make their marketing worthwhile. Even more problematic are the emerging concerns about making any new methods available to low-income women, either in the United States or overseas. Although better contraceptive methods carry the potential for tremendous impact on women here and overseas, private pharmaceutical companies are unlikely to see a sufficient return on their investments to develop new methods for use in developing countries. Recognition of this economic reality resulted in the formation of U.S. government-funded research entities (CONRAD, PIACT) and nonprofit agencies such as the Population Council and Family Health International, which may devote serious attention to methods that serve those populations, some of which may never be available to U.S. women. This approach is failing those who need a wider range of contraceptive options in the United States. Even the methods that are being developed with public funds (if their development has not been retarded by political pressures) and then turned over to private firms for disseminations here may be sold at such high prices that they INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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cannot be offered by family planning clinics serving low-income women and their partners, thereby creating two tiers of contraceptive availability. THE OBSTACLES TO CONTRACEPTIVE DEVELOPMENT
The approval for use of the new contraceptive implant, Norplant, in December 1990, capped an arduous process for the Population Council. Even now, it is unclear how many women in this country—the 17th to approve the method —will be able to take advantage of its availability, given its current high cost (13). Some women may already have been discouraged from trying it due to highly publicized cases of involuntary use. Norplant was heralded as the first truly new contraceptive to become available on the U.S. market in years; the questions remain: how many more years will it take before others are researched and approved, and how many other countries will have them first? Even if new methods are introduced in this country, will they be inaccessible to those with possibly the greatest need for help in preventing unintended pregnancy? The existence of serious impediments to contraceptive research and development in the United States has been generally established; the nature of those obstacles is not particularly controversial. The NAS/IOM panel cited four of the most daunting barriers: the organization of and resources available for research, the attitudes of the public, federal regulations, and product liability (12). Because these obstacles may never be entirely eradicated, other means must be found to entice private pharmaceutical companies back into the area of research and development. Funding
In real dollars, worldwide spending for contraceptive development by both government and industry has declined by nearly one-quarter since its peak in 1972 (1). By 1983, only about US $57 million was being spent for 384 research projects involving some 70 variations of potential contraceptives (1). Thus, expenditures amounted to approximately $800,000 per method. During the 1980s, NICHD only spent around $8 million annually for contraceptive development; by 1991, includingthe new centers, that total had risen to less than $11 million. In stark comparison, recent estimates of the cost to a pharmaceutical company of bringing a new method from the laboratory to the marketplace have been approximated at $231 million over a 10-year period (3). While data are unavailable to measure the specific impact that the lack of funding has had on the frequency of contraceptive innovation, the minuscule number of options that have entered the market in recent years indicates a lack of fiscal incentive. The results of such low levels of funding are many. Private and nonprofit researchers alike are more apt to spend the bulk of their available funds on modifications of existing methods, as opposed to new breakthroughs. Funding constraints slow the pace of research by limiting the formulations that can be tested simultaneously, thus lengthening the development process and jeopardizing its ultimate success. Declining or sporadic funding from foundations and the government, as well as a lack of promising positions within the large private companies, also has contributed to a reduction in the number of scientists who are being trained in fields that relate to reproduction. The lessened interest of pharmaceutical firms has resulted in fewer research opportunities, and those scientists who might have contemplated careers in contraceptive research have been deterred. Moreover, the controversial nature of contraceptive research has been made the field less attractive, resulting in increasingly sparse literature on each new method or development. While the costs of training have risen in recent years, 664
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the expected benefits and career opportunities have fallen; other areas, such as AIDS and genetic engineering, show far more promise for the budding scientist. The granting of orphan status to contraceptive drugs and devices might result in more private companies placing renewed emphasis on their reproductive research programs and encourage them to offer salaries that are geared toward motivating scientists to consider once again a career in this field.
Product Liability
The concept of liability requires an injured party to be compensated, unless that individual has used that product with the full knowledge that it was contraindicated. If negligence or fraud on the part of the manufacturer is shown, punitive damages also may be awarded. When the FDA approves any drug or device, it does not guarantee that the product is 100% effective or that it poses no risk but rather that the benefits of the drug or device in question, for most users under most circumstances, outweigh the risks. People are generally willing to take risks if dramatic benefits, such as the cure of a severe disease, can result. However, the NAS/IOM committee noted that the FDA's requirements for the approval of proposed contraceptives have been much more demanding than for other drugs because the agency views contraceptives as intended for use by healthy women and their partners, most of whom have alternative birth control options (even if they are limited) (12). Yet the benefits of contraceptives are less tangible than those from other drugs and devices; it is difficult to assess the value of avoiding unwanted pregnancy, especially as it is more important to some women to not become pregnant than it is to others. Some women may be willing to take greater risks to avoid pregnancy and would be better off using methods that are far more effective but which may carry more side effects. Furthermore, psychological and economic benefits may weigh in as important considerations—considerations that the FDA is ill-equipped to determine. During the 1980s, the number and size of jury awards in product liability suits were perceived to have increased, with no immediate relief in sight (12). Despite the fact that conduct meriting punitive damages (as opposed to compensatory damages) was arguably infrequent, such damages were sought and awarded by sympathetic juries to compensate injured persons; pharmaceutical manufacturers were frequent targets. As a result, liability insurance — covering both the conduct of clinical trials and the use of FDA-approved contraceptive products — became prohibitively expensive and, in some cases, almost impossible to obtain. Contraceptive development was badly damaged by the insurance crisis of the mid-1980s, and the field has not yet recovered. The disastrous experience with the Dalkon Shield — an IUD that substantially increased the risk of pelvic inflammatory disease in its users and, through the malfeasance of the manufacturer, led to enormous numbers of women being permanently injured or infertile—made insurance companies shun the coverage of any IUD and perhaps other contraceptive methods as well. Fear of large awards and the lack of obtainable insurance led to already approved products being withdrawn from the market and to some manufacturers leaving the field of contraceptive technology altogether. Some contraceptive methods, like oral contraceptives, have a large enough profit margin to effectively insure themselves. However, longer-acting methods like the IUD, Norplant, and injectables (widely used outside of the United States but not approved for contraceptive use in the United States) (7) have much smaller money-making potential, so that funds cannot be reserved so easily in preparation for litigation. The liability problem has also partially paralyzed clinical research on new methods, as those INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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that are in the research stage generate no profits from which they can be self-insured and outside insurance for testing new contraceptives on human subjects is often unobtainable. Without immediate prospects for easing the situation concerning the assessment of punitive damages, even those manufacturers who wish to remain in the field must continue to give special consideration to the prospects of extended litigation, given the time and costs that are involved in developing new contraceptive methods. While clearly not a panacea for the problems that are posed by the U.S. tort-law system, giving orphan drug status to contraceptives might go far in alleviating some of the component concerns. In particular, the possibility of financial assistance during the development process, as well as the assurance of exclusive marketing rights to the product for seven years, may provide the incentive that private companies need to redirect their thinking toward this area. FDA Approval Procedures
The complex, expensive, and time-consuming premarketing requirements that are imposed by the FDA have delayed the availability of many contraceptive methods in the United States until long after consumers in other countries have benefited from them. These extensive requirements have also discouraged pharmaceutical companies, because the longer the time spent on research and testing of a new drug or device, the shorter the time remaining under which the product is protected by a patent and therefore better able to earn a profit (10). Although patents grant the developer of a drug 17 years of exclusive rights, the patent generally must be approved long before FDA approval allows the new products to be placed on the open market. Even if widespread testing takes place in thousands of patients over a period of years, many reactions occur so rarely that normally only some of a drug's adverse reactions can be discovered before the drug is on the market. Some organizations have suggested that increased emphasis on postmarketing surveillance may better protect consumer health than an unrealistic emphasis on absolute safety before approval (12). The average time that it takes a product to wind its way through the FDA approval process has increased over the past two decades; yet in more recent years, new pressures have been placed on the FDA to approve drugs that relate to HIV on a faster track than ever before, due to the critical nature of the disease itself. However, the concomitant pressures to "guarantee" that all of the drugs and devices that are approved by the FDA are perfectly safe and effective have created something of a trap for the agency. Five states have adopted statutes that offer manufacturers involved in a product liability lawsuit the "FDA defense" to punitive damages, i.e., if a product has been duly approved by the FDA, and if the manufacturer did not materially misrepresent the drug or device to the FDA during the approval process — and did not withhold any new information that was obtained after FDA approval —the manufacturer cannot be held liable for the punitive damages to an injured party (10). (Note that the injured person could still recover compensatory damages from the manufacturer.) A similar provision was proposed by the NAS/IOM committee for contraceptive drugs and devices, with the same caveats, and has also been proposed (without success thus far) at the federal level for any FDA-approved drugs or devices (12). Its proponents claim that the manufacturers of new products (including contraception) might be less wary of entering or staying in the field with this protection. However, many consumer groups oppose the idea, stating that it is far too difficult for one individual or small group to marshal the funds or the information necessary to prove fraud on the part of the manufacturer. 666
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CONTRACEPTIVES AS ORPHAN DRUGS The ideal contraceptive is a poor product risk from a manufacturers' point of view: easy to use, long-acting, inexpensive, reversible, and extremely safe even with longterm use—for everyone who wishes to use it. At one end of the scale is the need for better and safer contraceptives that at least approach the ideal, both in the United States and overseas. While unintended pregnancy is not a disease, contraceptives can serve to fundamentally enhance the quality and direction of people's lives. Every new method that is developed will benefit at least a portion of those women and their partners who are of reproductive age, and the potential public health costs of not making a new method available are staggering. At the other end of the scale is the reality that many who most need help preventing unintended pregnancy can pay relatively little, especially because they need protection throughout most of their reproductive lives. Orphan drugs in the classic sense are not money-makers, because they are used by only a relatively small number of people to cure a specific illness — people who in all likelihood cannot afford to assume the entire bill for the research and development costs of making them available. It is equally apparent that the most ideal contraceptive drugs and devices cannot be profitable if they must fully cover research and development costs, especially the longer-acting methods. The factors that are delineated in this paper — the social benefits of contraception, the complex relationship of contraceptive-related risks and benefits, the ongoing difficulties in evaluating the health-related impact of long-term use, and the deleterious effects of inconsistent and unsupportive public policies — interact in such a way as to make the field of contraceptive development extremely uninviting to many pharmaceutical companies. None of these factors is dispositive; together they contribute to the near void in contraceptive research. The standard of supply and demand cannot be relied upon because of current attitudes toward these products that prevent consumer demand from clearly being voiced. At the same time, there is not just one but many markets for contraceptive products. Many of the individuals who need new methods cannot afford to pay the prices that are set by the manufacturers who, in turn, set high prices to cover the cost of development, liability insurance, and profit. Yet the vast number of people who would benefit from heavier public and privatesector commitment in this area dictate a public policy that is aimed at creating incentives for such research. One such incentive would be to make whatever classifications are necessary in the law and public perception in order for contraceptives to be recognized as orphan drugs. Not only would the overall goal of providing a broader range of contraceptive options be met, but in all likelihood, individuals' use of their chosen methods would improve greatly. By changing or interpreting the definition of orphan drugs to accommodate contraceptives, the public also may become more educated regarding the risks and benefits that are involved in deciding whether to use them. Moreover, advances in technology that are discovered through contraceptive research can be applied to and benefit other types of medical technologies. Establishing such a public policy change would not only somewhat alleviate the extraordinary problems facing the field of contraceptive research and development but would allow additional safe, effective, acceptable, and affordable contraceptives to be developed, expanding the limited range of options now available and preventing the need for women and men who are of reproductive age to make far more difficult choices. REFERENCES 1. Atkinson, L., Lincoln, R., & Forrest, J. D. Worldwide trends in funding for contraceptive research and evaluation. Family Planning Perspectives, 1985, 17, 196-207. INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE 8:4, 1992
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Kaeser, Forrest, and Rosenfield 2. Budget of the United States Government: Fiscal Year 1992, Part 3-31, Washington, DC: United States Government Printing Office. 3. Crooks, G. Pharmaceutical discovery and development. Presentation before the National Institute of Child Health and Human Development, January 28, 1991. 4. Forrest, J. D. Has she or hasn't she? Family Planning Perspectives, 1987, 19, 133. 5. Forrest, J. D., & Fordyce, R. R. U.S. women's contraceptive attitudes and how they have changed in the 1980's? Family Planning Perspectives, 1988, 20, 112-18. 6. Forrest, J. D., & Singh, S. The sexual and reproductive behavior of American women 1982-1988. Family Planning Perspectives, 1990, 22, 206-14. 7. Gold, R. B. Depo-Provera: The jury is still out. Family Planning Perspectives, 1983,15,78-81. 8. Harlap, S., Kost, K., & Forrest, J. D. Preventing pregnancy, protecting health: A new look at birth control choices in the United States. New York: The Alan Guttmacher Institute, 1991. 9. Jones, E. F., & Forrest, J. D. Contraceptive failure in the United States: Revised estimates from the 1982 National Survey of Family Growth. Family Planning Perspectives, 1989, 21, 103-09. 10. Kulik, B., & Kingham, R. The adverse effects of standardless punitive damage awards on pharmaceutical development and availability. Food, Drug, and Cosmetic Journal, 1990, 45, 699-xx. 11. Lincoln, R., & Kaeser, L. Whatever happened to the contraceptive revolution? Family Planning Perspectives, 1988, 20, 20-24. 12. Mastroianni, L., Donaldson, P. J., & Kane, T. T. (eds.). Developing new contraceptives: Obstacles and opportunities. Washington, DC: National Academy Press, 1990. 13. Nazario, S. Breakthrough in birth control may elude the poor. Wall Street Journal, March 4, 1991. 14. Office of Technology Assessment. World population and fertility planning technology: The next twenty years, Washington, DC: OTA, 1981 (as cited in the NAS/IOM report). 15. Pediatric products in U.S. development. SCRIP, November 7, 1990, No. 1564, 24. 16. P.L. 97-414 Sec. 5(a) 1983. 17. Senate Subcommittee on Labor-Health and Human Services-Education. Committee report on H. R. 5257, Appropriations for Fiscal Year 1991.
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