Intrauterine Devices. Technology Opportunity Assessment. Prepared for the Merck for Mothers Program. February 2012. www.path.org

February 2012 Intrauterine Devices Technology Opportunity Assessment Prepared for the Merck for Mothers Program MAILING ADDRESS PO Box 900922 Seattle, WA 98109 USA ADDRESS 2201 Westlake Avenue Suite 200 Seattle, WA, USA TEL: 206.285.3500 FAX: 206.285.6619 www.path.org

Copyright 2013, Program for Appropriate Technology in Health (PATH). All rights reserved. Cover photo credit: PATH/Mike Wang. Funding for this technology assessment was provided by Merck.

Intrauterine Devices Summary The intrauterine device, or IUD, is a device inserted into the uterus which releases either copper or a progestin hormone to prevent pregnancy. It is a long-acting and effective contraceptive method appropriate for women wishing to limit childbearing, as well as to space births, thus potentially playing an enormous role in reducing maternal deaths. Statement of Need Improving access to effective family planning methods offers numerous health and development benefits to women and families. Research suggests that between 1990 and 2005, an estimated 1.2 million maternal deaths were averted because of declining fertility, largely due to increases in contraceptive use. 1 Family planning improves maternal health by reducing births among women who are too young or too old, births that are spaced too closely, and high-parity births (4 births or more). Use of family planning also contributes to broader health and development goals; educational and employment opportunities for women improve, and social and economic development goals are easier to achieve. Use of family planning methods also has an impact on other health outcomes. For example, increased use of condoms for contraception reduces transmission of HIV and other sexually transmitted infections. 2 Globally, more than 215 million women have an unmet need for contraception. 3 An estimated 31 million women in India 4 and 35 million women in sub-saharan Africa have an unmet need to space their pregnancies (spacing) or to stop having children altogether (limiting). 5 Based on women s preferences, unmet need for spacing is higher than unmet need for limiting in sub-saharan Africa, while in India unmet need for limiting is slightly higher than unmet need for spacing. 6,* Many factors influence the use of family planning methods, including cultural norms that favor large families, religion, poverty, lack of access to information, provider bias, and spousal disapproval. Some contraceptive users find available contraceptive methods to be unacceptable, while others confront challenges using a method consistently because of limited availability of supplies and services. In many developing countries donors pay for a significant proportion of the cost of contraceptives, which means that funding constraints further limit contraceptive supply levels. At a minimum, any contraceptive method should be both safe for the user and effective at preventing pregnancy. Ideally, each user should also be able to select a method that suits his or her personal preferences and lifestyle. * MEASURE DHS Demographic and Health Surveys uses the following definitions of unmet need, spacing, and limiting in all country reports: Currently married women who are not using any method of contraception, but who do not want any more children, are defined as having an unmet need for limiting; those who are not using contraception, but want to wait two or more years before having another child, are defined as having an unmet need for spacing. 1

The intrauterine device (IUD) is an appropriate method for women wishing to limit childbearing, as well as to space births, and potentially plays an enormous role in reducing maternal mortality. When countries have low levels of contraceptive use, about half of all births are parity four and higher, and thus high risk; however, as contraceptive use increases to 80%, this percentage shrinks to almost zero.1 When women have access to contraception enabling them to limit their family size and the IUD is a prime example of such contraception the result is a substantial reduction in maternal mortality. Worldwide, there is great demand for methods that are long acting or permanent (LA/PM), including IUDs, implants, and sterilization. Nearly 50 million married women living in developing countries (excluding China) desire no more children and yet are not using family planning. 7 While 59% of those women live in Asia, there is considerable unmet need for limiting births even in sub-saharan Africa. An analysis of Demographic and Health Surveys (DHS) data from 15 sub-saharan African countries identified 7.6 million women as the potential market for LA/PMs, in addition to 750,000 current LA/PM users. 8 Technology Solutions Landscape and Gap Analysis In the developing world, about 14% of married women of reproductive age use the IUD to prevent pregnancy. 9 While there are moderate to high levels of IUD use in China (36%) and Vietnam (37%), the five Central Asian Republics (25% 56%), and some countries of the Near East and North Africa Jordan (24%), Turkey (20%), Lebanon (17%), Egypt (37%), and Syria (16%) in most other countries the IUD is not widely used. IUD use in India is about 2%, in sub-saharan Africa prevalence is less than 1%, and no country exceeds 3% use. 10 The TCu-380A (marketed as the ParaGard in the United States), is the most widely used IUD in the world because it is safe, low cost, easy to use, long acting, and highly effective. IUDs are considered an underutilized technology that could greatly benefit women s reproductive health. But effective IUD provision requires an organized service delivery system that includes the infrastructure for aseptic IUD insertion, skilled medical providers that receive ongoing training (including training in counseling for the management of side effects), and a strong referral system. Health system capacity for IUD provision is weak throughout much of the developing world, and these weaknesses underlie the very low IUD prevalence in sub-saharan Africa. In India, the low use of IUDs stems in part from a disproportionate emphasis on sterilization in the national program, which provides little motivation to health care providers to offer alternatives for women wishing to limit childbearing. 11 From a demand perspective, the IUD has been plagued by persistent myths about its safety and by service delivery guidelines and provider practices that are inconsistent with World Health Organization (WHO) Because of its widespread use, the TCu-380A IUD will serve as the benchmark against which the LNG IUS is evaluated. 2

guidance. For example, in many developing countries, providers tend to recommend IUDs only for use by women who already have children, who are married, who are HIV negative, or who are menstruating at the time of the clinic visit. They may also require unnecessary follow-up appointments. Increasing IUD use will require training to overcome provider bias, and information and education will be needed to increase demand for IUDs among the substantial number of women who want longer-term protection. 10 The development of a levonorgestrel-releasing IUD or intrauterine system (LNG IUS) by the Population Council and Bayer Schering Pharma 12 has the potential to inject new life into the IUD market and allow more women to achieve their fertility intentions, if the above-mentioned barriers that challenge the adoption of IUDs in general can be overcome. The LNG IUS, marketed under the brand names Mirena, Levonova, and Levonelle, has been available in Europe since 1990, was approved by the US Food and Drug Administration (USFDA) in 2000, and is registered for use in more than 120 countries. Testing of the LNG IUS technology, which has largely involved the Mirena, shows that it is at least comparable to the ParaGard in efficacy. 13 Its efficacy is also comparable to female sterilization, but it is entirely reversible with a return to fertility in two to six months. 9 The LNG IUS has side effects common to progestin-based hormonal contraceptives, which tend to be mild and transitory. Approximately 1% to 2% percent of women discontinue the method due to these side effects. 14 Changes in menstrual bleeding are more common and can be problematic in some contexts. Most LNG IUS users experience decreased menstrual bleeding and eventually amenorrhea. Within a year, 17% of users will become amenorrheic, increasing to 35% after two years, and up to 60% over the long term. 14 The LNG IUS insertion technique is slightly different from that required for the ParaGard. A United States study reported that providers found the LNG IUS device to be easier to insert than the ParaGard; 95% of first-time insertion attempts were successful and 99% were successful after two attempts. 15 However, because the insertion technique is different, even trained IUD providers will require more training. In terms of its acceptability, continuation rates for the LNG IUS are variable across different contexts and depend largely on the quality of client counseling. 16 Continuation rates in the United States are comparable for the LNG IUS and the ParaGard, with 80% and 78% continuing with the device beyond the first year of use, respectively. 17 Other studies that followed women for a longer period of time found lower continuation rates for the LNG IUS relative to the ParaGard. 10 While women in some contexts might welcome amenorrhea, it is also a principal cause of LNG IUS discontinuation; increases in menstrual bleeding and pelvic pain contribute to discontinuation among ParaGard users. 18,9 Though continuation rates for either type of IUD are high relative to other methods, there is nonetheless a need for provider training in client counseling if women receiving the LNG IUS are to understand that amenorrhea is not a dangerous side effect, a symptom of declining fertility, or a sign of pregnancy. 3

One key advantage of the LNG IUS over nonhormonal IUDs is that it reduces heavy menstrual bleeding (menorrhagia), which helps to maintain the body s iron reserves and could lead to a lower incidence of iron deficiency anemia a contributing factor to maternal mortality. 10 While a reduction in bleeding represents a unique consideration and possibly significant non-contraceptive health benefit, additional research is needed to quantify the potential impact of the LNG IUS on anemia. Other health benefits of the LNG IUS include lessening of menstrual cramps, protection against uterine fibroids, and reduction in the severity of symptoms associated with endometriosis. 19 For women living in low-resource settings who lack access to surgical relief from menstrual abnormalities, these health benefits may represent substantial improvements to quality of life. Three factors limit the adoption of this technology: Inadequate infrastructure specifically, lack of facilities with necessary equipment and supplies. A shortage of mid-level service providers trained in aseptic techniques, competent in insertion of the LNG IUS, and conversant with appropriate service delivery guidelines. Its high cost to the user between $250 and $400 per unit. The Mirena is one of Bayer Schering Pharma s more profitable health care products, with approximately $650 million in sales in 2009. 20 Its manufacture is not automated, and it is produced at relatively low volume. Because of its cost, the LNG IUS is not listed in the WHO Essential Medicines List and the United States Agency for International Development (USAID) does not supply it. The International Contraceptive Access Foundation (ICA) was established by the Population Council together with Bayer Schering Pharma for the express purpose of providing a donated or subsidized LNG IUS on a not-for-profit basis. ICA donates up to 1% of Bayer Schering Pharma s unit sales outside of the United States and makes a subsidized product available at a public-sector price (<$40/unit) for up to 3% of Bayer Schering Pharma s international sales. Note that at the public-sector price, the cost of the Mirena is about 30 to 80 times greater than the cost of the ParaGard (~$40 vs. $0.50 $1.50). 21 Under these terms, a total of 38,740 LNG IUS have been delivered in 15 countries (including Zambia and five other sub- Saharan African countries) over a seven-year period from 2005 through September 2011. 22 Having the supply of Mirena tied to international sales on a percentage basis makes it difficult for country programs to plan ahead and build the LNG IUS into the contraceptive method mix in a meaningful way. The slow rate of distribution also suggests that wide-scale adoption of the LNG IUS technology in lowresource settings may be contingent upon the production of a generic LNG IUS, or alternatively, a second-generation LNG IUS technology. Because the patent rights for the Mirena expired in 2003 (though the inserter/delivery system is under patent until 2015), the door is open to lower-cost alternatives. 20 With respect to a new LNG IUS, a number of technologies are at various stages of development. The Femilis (and Femilis Slim for nulliparous women), developed and manufactured by Contrel Research, 4

is promising but does not yet have regulatory approval. Femilis is also levonorgestrel based but is slimmer than the Mirena and has a simplified insertion system (with arms that remain outside the insertion tube and deploy in the uterine cavity). Initial studies found that the insertion system was easy to use and that pain was either absent or mild in over 90% of insertions. 23 The advantage of a simplified insertion procedure is that insertions could be performed by nonspecialist providers and health care providers who do IUD insertions infrequently. A second promising new IUD technology is the indomethacin-releasing copper IUD, developed by Oregon Health Sciences University in partnership with a Chinese manufacturer, Yantai Family Planning Medicine and Apparatus Company Ltd. 24 This technology uses a nonsteroidal anti-inflammatory drug to inhibit prostaglandin synthesis, thereby reducing the menstrual bleeding and pain often cited as a reason for discontinuation of copper IUDs. This IUD has the advantage of having none of the common side effects associated with progesterone contraceptives and uses an active ingredient that is inexpensive, off patent, and well understood. 25 Random control trials comparing the efficacy of two types of indomethacin-releasing copper IUDs against the ParaGard suggest that the technology performs either as well or better in terms of efficacy, expulsion rates, and continuation rates. 26 The indomethacin-releasing copper IUD is on the market and available in China. A third new LNG IUS technology is a product of Medicines 360, a nonprofit pharmaceutical company founded in 2009. Medicines 360 is partnering with Uteron Pharma Operations to develop, test, and bring to market a lower-cost LNG IUS intended to improve public-sector access in the United States. Though designed to be very similar to the Mirena, it employs a different insertion system. Medicines 360 initiated Phase 3 clinical trials in 2010 to assess contraceptive efficacy, safety, side effects, and return to fertility of a new LNG IUS as compared with the Mirena. Their LNG IUS technology is approved in Europe to manage menorrhagia. Medicines 360 s focus is availability of the LNG IUS in the United States public sector, so whether or how the Medicines 360 technology would become accessible to women in lessdeveloped countries is not yet known. Gap Analysis Overall, though the LNG IUS is a promising technology that offers additional health benefits that add to the value proposition, there are some critical hurdles to overcome. The value proposition for this technology needs to be strengthened to better define where this technology will bring greatest impact and the associated cost-to-benefit ratio. First, though the LNG IUS has non-contraceptive health benefits fundamental to its value, research has not yet demonstrated that increases in menstrual blood volume will impact levels of iron deficiency, particularly in settings where anemia is multifactorial (e.g., much of sub- Saharan Africa). 10 Second, shortages of trained providers and IUD infrastructure in sub-saharan Africa challenge the wide-scale adoption of the LNG IUS (as they do for the IUD generally). Finally, its cost is likely to be higher (at least initially) than copper IUDs. 5

However, a direct cost comparison against the ParaGard may not be the most important consideration given that providing one method does not preclude providing the other. A key component of increasing the use of family planning is expanding women s contraceptive choices. Some women will prefer not to use a hormonal method or will want the additional years of protection that copper IUDs provide; others will welcome a shorter protection period and the reduction in bleeding or relief from endometriosis offered by the LNG IUS. The LNG IUS method should be thought of as a complement to the copper IUD, not as a substitute. In that vein, the initial target audience for the LNG IUS need not be public-sector IUD users, but rather higher-end consumers, until greater volume production drives down the per-unit cost. The IUD has been slow to take root particularly in sub-saharan Africa and India where less than 3% and 6% of women, respectively, 10 have ever used an IUD. The new LNG IUS will face many of the same constraints as those faced by nonhormonal IUDs, including: Health care providers that are biased against provision of IUDs. Policy and regulatory barriers that limit expansion of method choice. Commodity and equipment insecurity. Poor quality services that lack a strong client focus. Lack of trained providers who are competent and experienced at IUD insertion. Limited availability of IUD services in rural areas. Persistent safety myths and lack of awareness of the benefits of IUDs. 27 That said, introducing the LNG IUS is an opportunity to inject new life into the IUD, expand the market, revitalize consumer demand, and reshape stakeholder and provider perspectives. The recent rapid rise in popularity of the IUD in the United States (from just 2% of women using contraception in 2002 to 5.5% in 2006) coincided with the 2001 introduction of the Mirena and is a testament to the power of this new technology to rapidly generate consumer demand. 28 Investment Opportunity The introduction of the LNG IUS technology in developing countries may make the IUD accessible to women who might otherwise use less-effective methods or no method at all. Specifically, investments could focus on: Bringing the Medicines 360 technology, once approved in the United States, to less-developed countries by: o Securing WHO prequalification (as needed) and licensure in target countries. o Developing a tiered pricing structure that would be attractive to international donors and appropriate for less-developed-country settings. 6

Supporting initial introduction of the IUD in select countries, by: o Conducting formative research to identify barriers to LNG IUS adoption at the level of clients, providers, and stakeholders across different country settings. This research could take advantage of ICA s experience introducing the Mirena. Research is not part of the ICA mandate, but these introduction efforts present an enormous opportunity to inform the introduction of a bioequivalent LNG IUS. o Implementing product introduction through demonstration projects, beginning in countries with trained and experienced IUD providers, the infrastructure for aseptic insertion, demand for the IUD, and a sizeable middle- and upper-income population that could afford the initially higher price of the LNG IUS. o Graduating to introduction in sub-saharan African countries where USAID has previously invested in IUD revitalization via the Acquire Project (Ethiopia, Ghana, Guinea, Kenya, Mali, Nigeria, Senegal, and Uganda). In these countries, considerable effort has been invested in building consensus around the importance of the IUD in the contraceptive method mix. However, these settings will nonetheless require strong attention to provider training (to develop a corps of experienced, mid-level clinicians competent in LNG IUS insertion and client counseling), demand generation (to combat persistent safety concerns), and efforts to strengthen commodity security and logistics. 7

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