Contraceptive Research, Introduction, and Use: Lessons From Norplant, Summary (1998)

In its post-workshop 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.

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.

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.

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, nonprofit intermediaries, and representatives from key consumer and provider groups, beginning with product design and subsequently at key points in the development, preintroductory, and introductory phases; and

• utilization of a full range of quantitative and qualitative market research techniques throughout.

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 “preintroductory” 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 preintroductory questions by stepping back and asking first whether a new method should be introduced at all in certain countries until the 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.

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 preintroductory phases. The subcommittee felt that development of core guidelines and clinical materials for possible new products 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.

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.

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.

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 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.

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.

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 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 IOM 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 compli

ance 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.

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.”