3
Workshop Summary and Analysis

This workshop arose from the belief that reviewing the experience with the development and introduction of the contraceptive implant, Norplant, would be illuminating. As the first real contraceptive innovation in over two decades and as a long-acting method requiring clinical intervention for its application and removal, the method raised a range of issues that could offer valuable lessons about the challenges to be addressed if other new technologies are to enter the contraceptive marketplace, so as to make the entry of those technologies as positive and trouble-free as possible.

The workshop had three objectives:

  • to review newly available data on Norplant's efficacy, safety, and use;

  • to extract lessons from diverse aspects of the method's development, introduction, use, and market experience; and

  • to explore approaches to developing and introducing new contraceptives based on learning from the Norplant market experience.

The workshop consisted of these elements: 17 formal presentations; two organized dialogues, one on consumer perspectives, the other on strategies for developing and introducing new contraceptive technologies; and extensive discussion among subcommittee members, presenters, and invited participants on the information presented and its implications. The dialogues were led by panels of individuals with perspectives from women's health advocacy, reproductive ethics, and the clinic. The subcommittee then met in executive session to analyze the workshop proceedings and develop a list of lessons and points for further consideration or action.



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3 Workshop Summary and Analysis This workshop arose from the belief that reviewing the experience with the development and introduction of the contraceptive implant, Norplant, would be illuminating. As the first real contraceptive innovation in over two decades and as a long-acting method requiring clinical intervention for its application and removal, the method raised a range of issues that could offer valuable lessons about the challenges to be addressed if other new technologies are to enter the contraceptive marketplace, so as to make the entry of those technologies as positive and trouble-free as possible. The workshop had three objectives: to review newly available data on Norplant's efficacy, safety, and use; to extract lessons from diverse aspects of the method's development, introduction, use, and market experience; and to explore approaches to developing and introducing new contraceptives based on learning from the Norplant market experience. The workshop consisted of these elements: 17 formal presentations; two organized dialogues, one on consumer perspectives, the other on strategies for developing and introducing new contraceptive technologies; and extensive discussion among subcommittee members, presenters, and invited participants on the information presented and its implications. The dialogues were led by panels of individuals with perspectives from women's health advocacy, reproductive ethics, and the clinic. The subcommittee then met in executive session to analyze the workshop proceedings and develop a list of lessons and points for further consideration or action.

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The following section presents: a data review, consisting of brief summary statements on key points presented at the workshop; the subcommittee's analysis of those lessons learned that it considered most crucial for the future; and areas for consideration and action. DATA REVIEW Efficacy Data were presented from two 5-year-long studies of major short-to medium-term side effects of implant contraceptives not identified in clinical trials: the Postmarketing Surveillance of Norplant led by WHO and pre-introductory studies led by the Population Council. The evidence from those studies was that both Norplant and the two-rod levonorgestrel implant system are highly efficacious, with failure rates under 1 percent per year, thus providing reversible contraceptive protection essentially equal to that of permanent methods, that is, tubal ligation and vasectomy. Safety As with all hormonal methods, the contraceptive implant is unsuitable for some women and those contraindications are detailed in its labeling. The Postmarketing Surveillance and Population Council studies found serious adverse events to be extremely rare among implant users over 5 years of study and concluded that, in the settings where those studies were carried out, the method proved to be safe and well-tolerated. The studies presented at the workshop on the biocompatibility of the polymer known as "silicone rubber" used in the implant produced the following information. First, while the capsules do provoke a typical local foreign-body reaction, the character of the biomaterial and its interface with tissue are not associated with pathological problems. Second, the silicone gel in breast implants is not the same, chemically or biologically, as the silicone rubber used in Norplant, and there are no data that indicate that the silicone elastomer used in Norplant acts as an adjuvant that could potentiate autoimmune disease. A question that has been asked about the safety of the hormonal implant is whether its progesterone-like effect might, in human beings, produce the same thinning of vaginal epithelium and increased transmission of immunodeficiency virus effected in a monkey model. The report to the workshop was that at present, the quality of the available data does not permit any such conclusions but that until better human studies become available, clinical management of high-risk clients should emphasize protection from sexually transmitted infections through condom

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use and other safe sexual practices, with optimal contraceptive protection accorded secondary priority. User Profiles The characteristics of the women in international samples differed too substantially from country to country to permit easy generalizations. In the United States, the 1995 National Survey of Family Growth points to two groups of Norplant users. The largest consists of predominantly young, single, minority women of lower socioeconomic status and educational levels, with one or more children, less likely to live in rural areas or in the northeastern portion of the country, and using the method primarily for spacing. A smaller group of older women of higher parity appears to be adopting the method as a long-term reversible alternative to tubal ligation. Side Effects Contraceptive implants produce side effects for many women, as described in the product labeling. By far the most common are changes in menstrual patterns, predominantly prolonged or irregular menstrual flow or increased bleeding. These tend to be frequent during the first 6 to 9 months of use, stabilizing by the end of the first year at a level that becomes acceptable to a majority of continuing users. The method also has non-menstrual side effects which manifest with different frequency and relative importance in different populations and at different time points, but primarily include headache, vaginal discharge, weight gain, acne, pelvic pain, and mood alterations. The studies presented suggest that the simple presence of menstrual side effects does not reliably predict decisions to continue or discontinue implant use, but there are differences between continuers and discontinuers with respect to non-menstrual side effects. Discontinuation rates associated with non-menstrual side effects seem higher than those for menstrual side effects but no single side effect, menstrual or non-menstrual, is consistently associated with decisions to discontinue use. Continuation and Discontinuation In studies to compare method use, implant continuation rates tend to be high relative to those of other reversible contraceptives. The overall pattern is that continuation rates are generally high through the first 2 years of use and not strikingly dissimilar from sample to sample, except in those studies that found discontinuation correlated with negative media coverage. Although there are great differences by country and although the data for the United States are scanty (partly because of low utilization), by the end of Norplant's approved 5-year term of use, approximately one-half of those who originally chose it were

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continuing use, with a significant proportion of those who discontinued having done so to start a pregnancy. And while explicitly comparative data are also scant, continuation rates for the implant are high compared to those for other reversible methods. Much remains to be understood before making broad assertions about reasons for continuing and discontinuing use of the contraceptive implant and about how those reasons differ from population to population over the reproductive cycle. Menstrual disturbances and other medical reasons are undeniably important yet, overall, reasons for retaining or removing Norplant are a complex blend of personal experience of side effects, "other-directed" variables like the wishes of partners, and broader social influences, the passage of time, and changes in life plans. At least some women who stay with Norplant seem motivated to trade off side effects, even when burdensome in number or severity, for the convenience and efficacy they believe essential to greater control over their lives. User Satisfaction Information on user satisfaction is scarce. Data from clinic-based studies presented at the workshop found most women continuing Norplant use to be very satisfied with the method, while noting that they had not found it easy to get used to; their satisfaction level was slightly below satisfaction levels for Depo-Provera and the pill. The large majority of women continuing Norplant use would recommend it to others, a slightly smaller majority than for the other two methods but still high. Perceptions among those discontinuing use were much less positive: Very few of those discontinuing use indicated that they had been "very satisfied," compared to sizable minorities of those who had discontinued use of Depo-Provera and the pill. Both women continuing use and those discontinuing saw the best features of Norplant as its convenience and effectiveness; fewer Depo-Provera and pill-users, whether they were continuing use or had discontinued, cited those attributes as those methods' best features. Postmarketing Surveillance The report from the 5-year Postmarketing Surveillance of Norplant confirmed its value not only as a source of knowledge on adverse effects that cannot be identified in clinical trials, but as evidence that large-scale, longer-term surveillance studies using cohort methodology can now be considered feasible in developing countries.

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Cost-Effectiveness A "savings" model indicated that all forms of contraception, including dual-method use, are far less costly in the United States than an unintended pregnancy. In that array, the implant was shown to rank very high in terms of cost-effectiveness compared to other contraceptive methods, saving almost $14,000 over a 5-year period of use. In sum, no good scientific reasons emerged in the workshop for not making Norplant available to all women for whom its use is not counterindicated in labeling. LESSONS LEARNED In its postworkshop analysis of the workshop proceedings, the subcommittee was struck by the amount of agreement on the overarching lessons from the Norplant experience. Variability in workshop participants' perspectives on those issues were differences of emphasis, for example, what had mattered most or first in the sequence of events involving the method. Yet, at end of day, views on what is needed for the future were not widely disparate, although differences can be expected around implementation practicalities, roles and responsibilities, and financing. While some of the lessons may be particular to long-acting contraceptive methods, they are not exclusive to such methods and still point clearly to areas where there are lessons to be applied to the development and introduction of new contraceptive technologies as a general matter. In fact, a primary value of the workshop was that it effectively named the issues to be put promptly on the table as preparation for the next contraceptive, as both cautionary and positive guidance. The full committee's extensive analysis of the field of contraceptive research and development, which culminated in its 1996 report, led to some conclusions that are appropriately repeated here as preface to this report's closing sections. First, while contraception is frequently used and new contraceptive technologies seem to be much needed and desired, as an area of human health it has certain intrinsic complexities. Perhaps the most important of these are that contraceptives are used, often for long periods of time, by presumably healthy individuals, who are less inclined to accept limitations and side effects. Second, contraception is also closely linked to social, cultural, and personal norms and values that, varying by setting, require considerable sensitivity. Third, the likelihood in the foreseeable future of a single contraceptive that will be perfect for all potential users across their lifetimes, totally effective yet totally free of side effects, is small. Fourth, like all pharmaceuticals, the development, production, and distribution of contraceptives are in varying ways connected to, if not dependent on, a commercial market with needs and expectations that do not inevitably coincide with those of public health. Finally, the subcommittee concluded that just as there was no single prime cause for the difficulties that have surfaced regularly in the field of contraceptive research and development and which have had such impact on Norplant's experience, there is no single, prime solution for those difficulties.

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TABLE 3-1 Lessons Learned The Delivery Side of the Health Care Equation Is a Commanding Factor The principal lesson concerning Norplant was that when used in a medically controlled environment, it proved to be a highly effective and safe contraceptive method, responsive to the needs of significant numbers of women. However, as the most technologically complex contraceptive method so far introduced onto the market and as one dependent for its provision on health care systems, Norplant's utilization in large populations was never going to be simple, even though its introduction had been preceded by many years of basic and clinical research. Like all the most effective contraceptives now on the market, the method was designed to be applied in contexts requiring specific standards and, as the most technologically challenging of those methods, it demanded authentic competence in a minor surgical procedure in a clinic setting of good quality. These optimal contexts were not always secured: Extension of the method from limited populations to larger domestic and international settings was associated with shortcomings in application that confounded the value of the method with the quality of its delivery. The great preponderance of the method's difficulties were those that have to do with larger, systemic difficulties in assuring provider training and evidence of competency, delivery system capacity for assuring the quality of all required services, the adequacy and appropriateness of counseling and communication, and the character and timing of consumer involvement. Providing and Receiving Training in New Contraceptive Methods Are Equally Critical Complicated implant removals were the basis, in 1994, of the first lawsuit involving Norplant and the subsequent flood of media coverage and litigation. This occurred despite the efforts by the method's distributors and non-profit intermediaries to train large numbers of providers in the technology. Those efforts were affected by a range of factors. each discussed in the course of the workshop and reflected in this report in the section on "Training for Insertion and Removal," including, most importantly: • fast, high-volume program takeoff; • insufficient appreciation of the importance of proper insertions for easy removals; • limited practice in removal technique and predicting and preparing for complications; • lack of participation in training on the part of some providers who did insertions: health care system structures that made uniformity of practice and assurance of competence difficult; and • insufficient sensitivity to the social, cultural, and personal dimensions of contraception, especially those particular to long-acting. "provider-dependent" contraceptives. The workshop material provided by presenters indicated that approximately 95 percent of removals were successful and without significant problems. While these were research sites and might be expected to have higher success rates, they indicate a potential that can be achieved and possibly improved.

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Counseling and Communication Are Pivotal Case material indicated that intensive counseling was associated with better acceptance and continuation rates, partly because women deciding to use the contraceptive implant were carefully identified at the outset, partly because they were provided with enough information to choose freely, and partly because they acquired more complete understanding of what to expect in the form of side effects. There is anecdotal evidence that clinical response to management of side effects was less evenly successful and that women's concerns about side effects were sometimes not given proper attention. The lesson here is a description of what communication about contraceptive choice would ideally be: a continuum spanning appropriate and intelligible product labeling; adequate provider training, collaboration between provider and client at the point of method choice; and support for clients in dealing with side effects and possible discontinuation, all the way to removal on demand or as approved efficacy ends and a new contraceptive choice must be made. This would optimally occur as truly two-way dialogue; information exchanged and necessary understandings would be complete and unconstrained by time; dialogue would be ongoing across the full course of contraceptive use; client participation in contraceptive choice would be truly voluntary; and the hierarchical distinctions between provider and client would be muted to the extent necessary for all this to happen. Taking Context into Careful Account Is Essential Experience with Norplant highlighted the fact that long-acting, provider-dependent contraceptive methods require special regard to ensure that decisions for their election and continued use are freely made and well informed. Failures in this respect not only have ethical implications but more broadly affect the proper utilization of the technology in question and its reputation. For example, although all such efforts failed, legislative and judicial attempts made in the United States to use Norplant coercively were perceived by some panelists and the constituencies they represented as evocative of some past attempts to restrict reproductive freedom that had disproportionately affected minority women. This had added to a residue of suspicion and affected objective assessment of the method. Lack of free choice, in method election and continuation, was also an issue in some developing countries, where it also led to negative public perceptions of the method overall, thus discouraging its use for many women for whom it would have been appropriate. Costs Matter The topic of cost-effectiveness raised questions for further consideration, importantly the meaning of costs, to both consumers and providers, for contraceptive availability and utilization. Real or imagined costs did act as barriers to Norplant use, notably in connection with removal for some women in some clinics. Workshop participants agreed that the entire subject of costs requires more creative thinking—about the cost of the method and its financing, about how to assure removal, and about clear policies of removal upon demand that are more effectively communicated to women considering the method.

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NEXT STEPS: AREAS FOR CONSIDERATION AND ACTION In analyzing what learning from Norplant's experience indicated for the future, the subcommittee identified nine areas for further consideration or action that could conceivably make the terrain for new or improved contraceptive technologies more hospitable than has been the case for Norplant. Of those areas, some are matters of broad context, while others relate to specific parts of the processes of contraceptive research, development, and introduction. Some would expand or deepen work now informed by that experience; others would involve new effort. Together, these areas can be viewed as critical pieces of a strategy whose most immediate application might be to the introduction of other implant formulations and, later, to the full span of the development and introduction of any new contraceptive technology. The text that follows presents these areas in two groups. The first consists of areas where the science indicates that more answers are needed or where strengthening or expansion would build on the positive learning from the Norplant experience. The second group consists of areas in which the Norplant experience revealed clear deficits and where new and, in some cases, bold initiatives will be critical for a different future. The subcommittee offers all these elements as options and propositions for further discussion, consensus-building, and action-signposts on the way forward. Areas for Strengthening or Expansion 1.Clinical Research Data reported at the workshop pointed to two areas where more fundamental research is needed to strengthen the position of implantable contraceptives in the array of contraceptive options: research on vaginal response to hormones, including cyclic hormonal effects, and on the use of progestins in contraceptives on the incidence of sexually transmitted disease, importantly including HIV; and research on the causes of hormonal side effects that, in addition to their implications for the users of hormonal methods, also affect the ability of providers to manage and treat those events clinically.

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2.Market Research In its 1996 report, the full IOM committee* concluded that the clear priorities in the ''women's agenda" set forth at the 1994 International Conference on Population and Development, along with dramatic advances in the science that make response to those priorities far more feasible, add new dimensions to the landscape for contraceptive and anti-infective research and development. However, implementing an agenda driven more intensely by what women want underscores the importance of fortifying pioneering efforts to engage consumers much earlier than has been customary, doing more with the kinds of research typical of commercial markets, and proceeding in as cross-sectoral a manner as possible. To do that would require development of more explicit and systematic public-sector strategies for: early, purposive, and systematic interactions among product developers and marketers, non-profit intermediaries, and representatives from key consumer and provider groups, beginning with product design and subsequently at key points in the development, pre-introductory, and introductory phases; and utilization of a full range of quantitative and qualitative market research techniques throughout. 3."Pre-introduction" Three consecutive sets of experience with Norplant's introduction, each building somewhat on the one before, highlighted the many utilities of inserting what amounts to a "pre-introductory" phase that permits various assessments prior to full-scale product introduction, thus diminishing possibilities of later difficulties. "Introduction" was thoughtfully utilized by the Population Council as a bridge from research and development and from the successful completion of clinical trials, to Norplant's entry into national family planning programs. The key mechanism was introductory trials in a limited set of facilities that then became centers for extension of training after national product registration; their purpose was to identify management and technical issues affecting method delivery and to develop and refine guidelines, standards, counseling materials, and training programs for clinical management. In the United Kingdom. the principal mechanism was premarket research focused on provider attitudes and delivery system issues that might present problems, in order to take those into account in training and actual scaled-up introduction. The WHO Strategic Approach then significantly expanded such pre-introductory questions by stepping back and asking first whether a new method should be introduced at all in certain countries until the *   The references made in this section to "the Committee" are to the Institute of Medicine's Committee on Contraceptive Research and Development and its full report on the state of the field (see Endnote 1).

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necessary systems are strengthened sufficiently to accommodate the addition of a new technology. The WHO Approach has three stages, the first proceeding to the next only when and if the decision is made to introduce the new method: Stage 1: assessment of need, in a specific country family planning program, for an additional contraceptive technology, including initial assessment of existing method mix, service infrastructure and capability, program policies, potential user demand, cost-benefit to user/program, and logistics management. Stage 2: introductory trial, service delivery research, and user perspective research, in an integrated sequence. Stage 3: analysis and participatory review of research results, decision-making on next steps, and strategy development. The subcommittee, while mindful of the issues of cost, time, and sustainability attached to adopting this strategy as a standard approach, regards this three-stage framework as "best practice" for the future, with further experience expected to make such processes more efficient. 4.Informed Decision-Making Informed decision-making is a general concern for the clinical management of any new medical technology, but the Norplant experience underscored the fact that all long-acting, provider-dependent contraceptives have special characteristics and therefore require special attention. The questions the workshop participants flagged as of greatest concern were: how mechanisms for informed decision-making are to be developed and by whom; the distinctions and connections among the kinds of information needed in the experimental stages of product development, compared to what is needed in the introductory phases and in routine clinic settings; the purposes and practical implications of labeling, informed consent documents, and clinical guidelines for informational and decision-making purposes; what is essential as opposed to discretionary information; and the impact of all the above on participation in contraceptive research and development. If and when new long-acting, provider-dependent contraceptive products are developed and introduced, each of these concerns would ideally be part of a systematic strategy for informed decision-making, to then be tested and refined in the product's clinical trial and pre-introductory phases. The subcommittee felt that development of core guidelines and clinical materials for possible new products

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would be an effective way to catalyze and focus the necessary thinking about these concerns, as well as any potential areas of difficulty, in an organized and concrete way. 5.Postmarketing Surveillance The concerted public-sector effort to carry out postmarketing surveillance underscored the value of such surveillance as a source of knowledge of adverse effects that cannot be identified in clinical trials. It also proved that such studies are feasible in developing countries. Postmarketing surveillance might also become an integral component of new product liability legislation. At the same time, such surveillance adds to costs which, in the case of Norplant, were defrayed by the World Health Organization and private foundations. This raises a general question about future financial support for such studies by the public sector, as well as a specific question about the responsibility for financing them were they to be required as a component of a federal standards defense. Both need to be addressed. Areas for New Initiative 6.Credentialing A significantly problematic aspect to Norplant's introduction derived from the fact that requirements for reasonable competence in surgical procedure are uneven across clinical facilities worldwide. This is especially problematic when new technologies are introduced rapidly, as was the case with Norplant despite major investment in provider training. While this situation is likely to persist, it could be susceptible to a thoughtful, individual-case approach. Accordingly, the subcommittee concluded from the workshop discussions that collaboration with professional medical societies and major managed care organizations on strategies for training and assuring provider competence would be a critical preparatory step in introducing the next new provider-dependent contraceptive technology, most immediately the LNG two-rod implant. 7.Core Guidelines for Long-Acting Contraceptives A key to any serious attempt to implement informed decision-making in clinical situations is helping providers to actually make it possible. This suggested to the subcommittee that a most effective route to such implementation would be, again, to enlist the cooperation of the pertinent professional medical societies. The tasks would be to develop a collaboration among representation from those societies and a range of consumer groups to recruit necessary additional expertise, and to work on fashioning core guidelines for the introduction and clinical

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management of long-acting contraceptives. Addressing the potential for inappropriate use and how to prevent it would be an integral component. An ancillary task would be development of a strategy for dissemination of those guidelines in the corresponding professional communities. These core guidelines could then be modified culturally or linguistically for specific populations as needed. While such guidelines would be particularly important for introducing long-acting contraceptives into contexts where past attempts to use such methods had been problematic, they would also be valuable for introducing any new contraceptive method into environments where educational level, language, culture, or socioeconomic status have the potential to constrain well-informed decision-making. 8.Costs Real or imagined costs did act as barriers to Norplant use, notably in connection with removal for some women in some clinics. Systematic understanding of the effects of price on initial adoption is lacking. At the same time, in the subcommittee's view, Norplant's history raises a separate and complicated question that is likely to arise in the future. That question is how to develop pricing structures in cases where a large proportion of R&D costs have been borne by the public and quasi-public sectors, at the same time that industry profit requirements and risk exposure are appropriately taken into account. The issues around Norplant's costs raise other issues that merit prompt and systematic analysis and discussion that is focused on actionable outcomes: public-sector cost constraints; political and economic tensions around tiered pricing structures; the role of health insurance coverage of contraception and health plan formularies; diversification and expansion of the market for contraceptives in general: and different meanings of cost-effectiveness for consumers, countries at varying levels of development, and delivery systems. Each has implications for what constitutes a market share that might be appealing to industrial investment as contraceptives grow in variety and, as Norplant user profiles suggest, may increasingly become niche products. 9.Product Liability The Norplant experience provides further grounds for the perception that product liability, or simply the anticipation of liability, stifles industrial investment in development of new contraceptives. The most immediate example is the fact

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that the improved two-rod, three-year implant that is significantly easier to insert and remove is not being introduced in the United States by its European manufacturers, apparently owing to litigation concerns related to Norplant, so that it may not become available as a contraceptive option for American women. A related concern is the current controversy around silicone products and its potential effects on the supply of biomaterial not only for implant contraceptives but for other medical devices, some of which—for example, cerebrospinal fluid shunt systems and pacemaker leads—are essential to life. The subcommittee and workshop participants again voiced support for the conclusion of the 1990 and 1996 Institute of Medicine committees concerning the potential importance of enactment of a product liability statute. Broadly stated, such a statute would make FDA approval of contraceptive drugs and devices available to manufacturers as a defense against punitive damages, assuming proper compliance with FDA regulatory requirements. The subcommittee recognizes that the complexities and ramifications of a defense of this nature are many, so that a crucial—and urgent—area of work will be systematic, very practical conceptualization of alternative configurations of such a defense as a foundation for possible legislative work. FINAL COMMENT The purpose of this workshop was to learn from the many years of intersectoral activity dedicated to the development and introduction of Norplant. The fact of emphasis on barriers and problems should not obscure the considerable positive learning from the Norplant experience that, consolidated and refined, can only make the advent of new contraceptives smoother. At the same time, there were social and cultural aspects of Norplant's market experience that were negative to an extent that overwhelmed the best of those efforts. Some of these aspects will change slowly, if at all; others may be at least partly susceptible to new areas of initiative discussed in the workshop and highlighted in the preceding section. A pivotal challenge will be determining how those initiatives are to be pursued and by whom. The workshop participants and the subcommittee agreed that contraceptive research and development have fallen behind in the great advances propelling the rest of medicine, including all other areas of women's health, and that, without attention to these areas of major impediment, contraceptives will continue to compete poorly when industries contemplate alternative new directions for their investment portfolios. They agreed as well with the conclusion of the full Committee "that there is not likely to be a 'silver bullet' solution to the dilemmas faced by the field of contraceptive research and development. Each piece of the dilemma will have to be tackled in cumulative fashion as part of a coherent strategy, each resolution improving matters somewhat and eventually amassing enough weight to tip the balance in a more positive direction."

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ENDNOTES 1.   Institute of Medicine. Contraceptive Research and Development: Looking to the Future. PF Harrison, A Rosenfield, eds. Washington, D.C.: National Academy Press, 1996. The study was supported by the Rockefeller Foundation, the Andrew W. Mellon Foundation, the National Institute of Child Health and Human Development, the Contraceptive Research and Development (CONRAD) Program, and the United States Agency for International Development. 2.   The workshop and this report are supported by a grant from the Henry J. Kaiser Family Foundation. 3.   Medical officer NDA review. NDA#19-897. Rockville, MD: Food and Drug Administration, 1990.—Grubb GS, D Moore, NG Anderson, et al. Pre-introductory clinical trials of Norplant® implants: A comparison of 17 countries' experience. Contraception 52:287-296, 1995.— Sivin I. Contraception with NORPLANT® implants. Human Reproduction 9:1818-1826, 1994. 4.   Patient labeling for Norplant is organized by risks, warning signals, precautions, and side effects. Provider prescribing information is organized by contraindications, warnings, precautions, and adverse reactions. For Norplant, the FDA sorted the last group into four subcategories: (a) conditions associated with Norplant during the first year of use; (b) conditions that occurred more frequently among Norplant users than among a control group of IUD users, with differences in incidence great enough to attain statistical significance as being probably related to Norplant use; (c) conditions occurring with a frequency of 5 percent or more during the first year of use in clinical trials and judged to have possibly been associated with its use; and (d) conditions observed in Norplant users postmarketing but for which there is no basis for judging a causal relationship (Food and Drug Administration. Norplant® Implants Revised Labeling: Information for Providers [Draft], March 1995). 5.   Affandi B, SSI Santoso, Djajadilaga, W Hadisaputra, FA Moeloek, .I Prihartono, F Lubis, and RS Samil. Five-year experience with NORPLANT. Contraception 36:417-428, 1987. Akhter H, TR Dunson, RN Amatya, K Begum, T Chowdhury, N Dighe, SL Krueger, and S Rahman. A five-year clinical evaluation of NORPLANT contraceptive subdermal implants in Bangladesh acceptors. Contraception 47:569-582, 1993. Brache V, F Alvarez-Sanchez, A Faundes, AS Tejeda, and I, Cochon. Free levonorgestrel index and its relationship to luteal activity during long-term use of NORPLANT implants. Advances in Contraception 8:319-326, 1992. Chompootaweep S, E Kochagarn, S Sirisumpan, J Tang-ushu, B Teppitaksak, and N Dusitin. Effectiveness of NORPLANT implants among Thai women in Bangkok. Contraception 53:33-36, 1996. Crosby UD, BE Schwarz, KL Gluck, and SF Heartwell. A preliminary report of NORPLANT implant insertions in a large urban family planning program. Contraception 48:359-366, 1993. Cullins VE, PD Blumenthal, RE Remsburg, and GR Huggins. Preliminary experience with NORPLANT in an inner-city population. Contraception 47:193-204, 1993. Cullins VE, RE Remsburg, PD Blumenthal, et al. Comparison of adolescent and adult experiences with Norplant levonorgestrel contraceptive implants. Obstetrics and Gynecology 83:1026-1032, 1994.

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    Diaz S, HB Croxatto, M Pavez, H Belhadj, J Stern, and I Sivin. Clinical assessment of treatment for prolonged bleeding in users of NORPLANT implants. Contraception 42:97-110, 1990. Diaz S, M Pavez, P Miranda, DN Robertson, I Sivin, and HB Croxatto. A five-year clinical trial of levonorgestrel silastic implants (NORPLANT). Contraception 25:447-456, 1982. Frank ML, AN Poindexter III, LM Cornin, CA Cox, and I, Bateman. One-year experience with subdermal contraceptive implants in the United States. Contraception 48:229-249, 1993. Gabrielle CA, WM O'Fallon, LT Kurland, CM Beard, JE Woods, and J Melton III. Risk of connective-tissue diseases and other disorders after breast implantation. New England Journal of Medicine 330:1697-1702, 1994. Grubb G, D Moore, NG Anderson, et al. Pre-introductory clinical trials of NORPLANT implants: A comparison of 17 countries' experience. C ontraception 52:287-296, 1995. Gu S-J, I Sivin, M-K Du, L-D Zhang, L-R Ying, F Meng, S-L Wu, P-Z Wang, Y-1, Gao, X He, L-F Qi, C-R Chen, Y-P Liu, and D Wang. Effectiveness of NORPLANT implants through seven years, a large-scale study in China. Contraception 52:99-103. 1995. Gu S-J, M-K Du, L-D Zhang, Y-L Liu, S-H Wang, and I Sivin. A 5-year evaluation of NORPLANT contraceptive implants in China. Obstetrics and Gynecology 83:673-678, 1994. Indian Council for Medical Research (ICMR) Task Force on hormonal contraception. Contraception 48:1230-1232, 1993. Koetsawang S. The injectable contraceptive: Present and future trends. In Frontiers in Human Reproduction, M Seppala and L Hamberger, eds. pp. 30-42. The New York Academy of Sciences, New York (Annals vol. 662), 1991. Moreno L, and N Goldman. Contraceptive failure rates in developing countries: Evidence from the demographic and health surveys. International Family Planning Perspectives 17:44-49, 1991. Noerpramana, NP. A cohort study of NORPLANT implant: Side effects and acceptance. Advances in Contraception 11:97-114, 1995. Olsson SE, V Odlind, EDB Johansson, and M Nordstrom. Plasma levels of levonorgestrel and free levonorgestrel index in women using NORPLANT implants or two covered rods (NORPLANT 2). Contraception 35:215-228, 1987. Peers T, JE Stevens, J Graham, and A Davey. Norplant implants in the UK: First-year continuation and removal. Contraception 53:345-352, 1996. Salah M, A-G M Ahmed, M Abu-Eloyoun, and MM Shaaban. 5-year experience with NORPLANT implants in Egypt. Contraception 35:543-550, 1987. Sanchez-Guerrero J, GA Colditz, EW Karlson, DJ Hunter, F Speizer. and MH Liang. Silicone breast implants and the risk of connective tissue diseases and symptoms. New England Journal of Medicine 332:1666-1670, 1995. Singh K, OAC Viegas, YF Fong, and SS Ratnam. Acceptability of NORPLANT implants for fertility regulation in Singapore. Contraception 45:39-47, 1992. Singh K, OAC Viegas, and SS Ratnam. Acceptability of NORPLANT 2 as a method of family planning. Contraception 45:453-461, 1992.

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    Sivin I. Contraception with NORPLANT implants. Human Reproduction 9:1818-1826, 1994. Sivin I. International experience with NORPLANT and NORPLANT 2 contraceptives. Studies in Family Planning 19:81-94, 1988. Tietze C, and S Lewit. Evaluation of intrauterine devices: Ninth progress report of the cooperative statistical program. Studies in Family Planning 1(55):1 40. 1970. Trussell J. and K Kost. Contraceptive failure in the United States: A critical review of the literature. Studies in Family Planning 18:237-283. 1987. Trussell J, JA Leveque, JD Koenig, R London, S Borden. .I Hennebarry, KD LaGuardia, FH Stewart, TG Wilson, S Wysocki, and MJ Strauss. The economic value of contraception: A comparison of 15 methods. American Journal of Public Health 85:494-503, 1995. Mosher WD, and CA Bachrach. Understanding United States fertility: Continuity and change in the National Survey of Family Growth, 1988-1995. Family Planning Perspectives 28:4-12, 1996. World Health Organization. Multinational comparative clinical evaluation of two long-acting injectable steroids: Norethisterone oenanthate and medroxyprogesterone acetate use-effectiveness. Contraception 15:513-533, 1977. 6.   The expected rate of ectopic pregnancy is derived from the rate for women who are using no formal contraceptive method but may be in lactational amenorrhea or at risk of pregnancy or pregnant following non-use. In the Postmarketing Surveillance, the rate has drifted down over the years from approximately 4 per 1,000 woman-years to a final value near 2 per 1,000, or 0.2 to 0.4 per 100 woman-years. In the U.S. population as a whole in the 1970s, the risk was 2.6 per 1,000 among non-users of contraceptives. according to estimates by the Centers for Disease Control and Prevention. Whatever value is used between 0.2 and 0.4 per 100, the relative risk to women in the Postmarketing Surveillance was only 1/7th to 1/13th of the risk of non-use of a contraceptive method. The far higher value of 0.13 per 100 in the U.S. label (written as 1.3 per 1,000 years) stems from the threefold higher pregnancy rate in the Population Council studies, a rate consequent to use of hard tubing in heavier-weight women. 7.   Rose NR. The silicone breast implant controversy: The other courtroom. Arthritis and Rheumatism 39:615-618, 1996. 8.   Naim JO, RJ Lanzafame, and CJ van Oss. The effect of silicone gel on the immune response. Journal of Biomaterial Science: Polymer Edition 7(2): 123-132. 1995. 9.   Freundlich N. Commentary: Congress should protect this medical lifeline. Business Week, 21 April 1997:120. 10.   Marx PA, Al Spira, A Gettie, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nature/Medicine 2:1084-1089. 1996. 11.   The 1995 cycle of the NSFG gathered data between January and October 1995 on a national probability sample of women aged 15-44 selected from households followed by the National Health Interview Survey, a continuous multistage household survey. Numbers. percents, averages, and other statistics reported from the NSFG are weighted national estimates that account for different sampling rates and for non-response. and are adjusted to agree with control totals provided by the U.S. Bureau of the Census. The 10,847 women in the NSFG represent the 60.2 million women in the civilian non-institutional population of' the United States in 1995. Thus, on average, each woman in the NSFG represents about 5,500 women in that population.

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12.   According to NSFG data that became available after the workshop, 64.2 percent of the 60.2 million women aged 15-44 represented by the NSFG sample (N = 10,847) in 1995 were using contraception. Among those contraceptors, percentage distributions of use were as follows: Female sterilization 17.8 Pill 17.3 Condom 13.1 Male sterilization   7.0 Withdrawal 2.0 Injectable 1.9 Periodic abstinencea 1.5 Diaphragm 1.2 Implant 0.9 Intrauterine device 0.5 Female condom 0.0 Other methodsb 1.0 aIncludes natural family planning (0.2 percent). bMorning-after pill, foam, cervical cap, Today® sponge. suppository. Jelly or cream (without diaphragm), and other methods not shown separately. Abma J, A Chandra, W Mosher, L Peterson, and L Piccinino. Fertility, Family Planning, and Women's Health: New Data from the 1995 National Survey of Family Growth (Vital and Health Statistics 23[19]). Washington, D.C.: Centers for Disease Control and Prevention/National Center for Health Statistics, May 1997. 13.   The Ortho Birth Control Studies are annual surveys by the Ortho Pharmaceutical Corporation of contraceptive attitudes and use. Random sampling is not employed and the surveys tend to underrepresent black women and households with annual incomes greater than $50,000. 14.   The term "menstrual changes" is meant to express alterations in previous patterns and includes as most significant heavier menstrual flow, greater cycle irregularity. increased spotting, longer periods, and more painful periods. 15.   According to NSFG data not available until after the workshop. as of 1995 4.5 percent of U.S. women aged 15-44 had ever used Depo-Provera and 1.9 percent were current users; those figures for Norplant use were 2.1 percent and 0.9 percent respectively (Abma et al., op. cit., 1997). 16.   Preliminary figures were presented at the workshop in support of the assertions in this paragraph but, at the time this report went to press, final figures could not be released for formal publication. 17.   The text of the recommendation reads as follows: "The committee recommends that, to make a full range of contraceptive products accessible to consumers and to increase demand for contraceptive products to something closer to the level of unmet need, there should be continued and sufficient government support of contraceptives services-for males as well as females—particularly for low-income individuals and particularly in developing countries. The committee also recommends that third-party payers, who bear the

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    costs and may reap the benefits of the health status of their covered populations, include contraception as a covered service. Ideally, family planning services and the management of sexual health would be integrated components of comprehensive reproductive health services" (Institute of Medicine, op. cit., 1996). 18.   The average wholesale price of Norplant in the United States is $365 for a kit containing the six capsules, trocar, scalpel, forceps, syringes and syringe needles. skin closure, gauze sponges, stretch bandage, and surgical drapes. Implantation and removal costs bring the total to about $700. At the 1995 World Bank consultation on the status of Norplant (World Bank/Population Council/World Health Organization Special Program on Research, Development, and Research Training in Human Reproduction. International Consultation on Contraceptive Implants, 19 July 1996 [unpublished paper]. Washington. DC: World Bank, 1995), the observation was made by one of the authors of the original contraceptive cost-effectiveness analysis (Trussell) that the savings model should be considered situational. For example, it cannot be calculated in the same way for developing countries, where the costs of unintended pregnancy—the chief driver for the model—may be valued differently, and where epidemiological factors differ. The price of the basic commodity also varies; the average Norplant kit price to developing country programs is $23. To that must be added public-sector health system costs for public education, training, supervision, implantation, and removal, a sizable commitment in the aggregate for donors providing commodity and/or program support and for countries with constrained health sector budgets. 19.   From the beginning, patient labeling counseled women that while the implant should be removed at the end of 5 years when it would become less effective, it could be removed at any time before then, should the user wish to stop use for any reason (Wyeth-Ayerst Research Laboratories. Norplant® System Patient Labeling. Issued 10 December 1990.) 20.   Just as this report was going to press, the following results, highly germane to this report, became available from a Population Council study of a representative sample of 2,979 current and former Norplant users in 14 Indonesian provinces: (1.) No sizable removal backlog exists as was feared, owing to the fact that nurse/midwives had performed a large number of removals, although it was illegal for them to do so at the time, so that undercounting of completed removals and overcounting of pending removals were substantial. (2.) Of the 8 percent of the sample who had not yet had their implants removed. 26 percent saw removal cost as an obstacle. About 91 percent of the women who had had implants removed underwent the procedure immediately on request; 9 percent encountered delay and resistance. (3.) Most Norplant users obtained removals between the end of the fifth and end of the sixth year of use. Over 66 percent had continued to use the method for a full 5 years: 27 percent had undergone removal but then had a second Norplant set inserted. (Population Council News Release, 20 December 1997). 21.   "Complication" as defined in the integrated summary of safety (NDA 19-897. Amendment 2) includes: multiple incisions; failure to remove implants completely, thereby requiring more than one additional visit; pain during removal; fainting: prolonged probing: or excessive time needed for removal.

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22.   Blumenthal PD, L Gaffikin, B Affandi, et al. Training for Norplant implant removal: Assessment of learning curves and competency. Obstetrics and Gynecology 89(2):174-178, February 1997. 23.   Blumenthal PD, RE Remsburg, G Glew, et al. Usefulness of a clinical scoring system to anticipate difficulty of Norplant removal. Advances in Contraception 11:345-352. 1995. 24.   The range in removal times has been found to be substantial. The multicentered Population Council trials found a fourfold variation by clinic from 4 to 17 minutes. with a coefficient of variation of about 50 percent in each clinic (Sivin I. O Viegas. I Campodonico. et al. Clinical performance of a new two-rod levonorgestrel contraceptive implant: A three-year randomized study with Norplant® implants as controls. Contraception 55:73-80, February 1997). 25.   Nearly two dozen bills in 13 states proposed variants on Norplant use in welfare cases and four women convicted of child abuse were ordered by courts to have Norplant inserted as a condition of probation (Davidson AR, and D) Kalmuss. Topics for our times: Norplant coercion-An overstated threat. American Journal of Public Health 87[4]:550-551, April 1997). Two days after Norplant was approved by the FDA for distribution in the United States, an editorial in the Philadelphia Inquirer (Can contraception reduce the underclass? Philadelphia Inquirer, 12 December 1990: A18) elicited media commentary and public debate nationwide (SE Samuels, MD Smith, eds. Dimensions of New Contraceptives: Norplant and Poor Women. Menlo Park, CA: Henry .1. Kaiser Family Foundation, 1992-Moskowitz EH, B Jennings, and D Callahan. Long-acting contraceptives: Ethical guidance for policymakers and health care providers. Hastings Center Report 25:1 [Special Suppl], 1995.) 26.   Walker KM. Judicial control of reproductive freedom: The use of Norplant as a condition of probation. 78 Iowa Law Review 779-812, 1993. 27.   Roberts DE. Punishing drug addicts who have babies: Women of color, equality. and the right of privacy. 104 Harvard Law Review 1419, 1432 n.60. 1991. 28.   Important among these is the Institute of Women and Ethnic Studies, a non-profit. medical/community-based organization whose primary focus is the development of culturally proficient health intervention and research models. Its Women of Color Reproductive Health Forum held two workshops in 1996 that were pertinent to the work of the ''Boom and Bust Initiative": Finding Common Ground-Empowerment vs. Coercion Long-Acting Contraceptives (4-7 April 1996) and Women of Color and the Emerging Health Technologies (24-27 October 1996). The Institute has publicly stated its commitment to work with the Initiative, as well as with the Pacific Institute for Women's Health, to build consensus on culturally appropriate ethical approaches to reproductive health research, development, and marketing in order to expand the array of contraceptive options. 29.   Bolivia, Brazil, Burkina Faso, Chile, Myanmar, South Africa, Vietnam. and Zambia. 30.   Institute of Medicine, op. cit., 1996.

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