CLINICAL OBSTETRICS AND GYNECOLOGY Volume 00, Number 00, 000–000 Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Contraceptive Technologies: Looking Ahead to New Approaches to Increase Options for Family Planning

LISA B. HADDAD, MD, MS, MPH, JOHN W. TOWNSEND, PhD, and REGINE SITRUK-WARE, MD The Population Council, New York, New York

Abstract: With persistently high global rates of unin- Key words: user-controlled methods, vaginal rings, non- tended and contraceptive nonuse, nonad- , male contraception, multipur- herence and discontinuation, new contraceptive pose prevention technologies, development pipeline methods must address the needs of women and men who seek alternatives to their current options. Methods Approximately half (49%) of all pregnan- under development aim to reduce potential side effects, improve access and ease of use, ensure safety, increase cies around the world are unintended, secondary benefits associated with method use and with recent estimates from 2015 to 2019 expand options for both women and men. Develop- of 121 million unintended mental approaches employed to enhance current meth- annually.1 Elimination of the global un- ods utilize new delivery systems and novel active met need for contraception, comprising of pharmaceutical ingredients. This will improve overall user satisfaction with the methods used while expand- an estimated 218 million women, would ing the number of options available to provide choice prevent 76 million unintended pregnan- and value user autonomy in the highly diverse contra- cies, $6.6 billion costs associated with ceptive markets around the world. pregnancy care for these pregnancies, and 70,000 maternal deaths.2 Further- Correspondence: Lisa B. Haddad, MD, MS, MPH, more, it would fulfill the global commit- The Population Council, Center for Biomedical ment to reproductive justice enshrined in Research, 1230 York Avenue, New York, NY. E-mail: the Sustainable Development Goals for [email protected] 2030 by ensuring reproductive health and L.B.H., J.W.T., and R.S.-W. are all employed by the Population Council and are involved in the development reducing related inequalities across social of several of the products discussed in this manuscript. and national groups.

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 00 / NUMBER 00 / ’’ 2021

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Inadequate access to safe, effective, cost of product development. In pursuit of and acceptable contraception is a key greater market penetration globally, contributor to this unmet contraceptive developers are employing user-informed need. However, even when contraception design approaches to shape the ultimate is relatively accessible, rates of unin- profile of the methods they are developing tended pregnancy can remain high, for to maximize their benefit and deliver a example, in North America (48%) and product that priority clients want to use. Europe (43%).1 Currently, available con- End-user engagement is crucial to ensure traceptive options are not adequately that product characteristics that can meeting many women’s needs, as is evi- be modified during product development dent by high levels of typical use failure, are considered before the final design of method nonuse, switching, and discont- the product. inuation.3 New methods are needed to The development of contraceptive support the reproductive health needs of methods remains a priority at several both women and men, recognizing that nonprofit, academic, governmental, and these needs may change over their repro- nongovernmental organizations. The ductive life-course. Methods under devel- Population Council, a global nonprofit opment aim to reduce potential side research organization, has been a pioneer effects, improve access and ease of use, in the field of contraceptive research and ensure safety, increase secondary benefit development for over 60 years and devel- associated with method use. Moreover, in oped a number of highly effective long- developing countries, some products may acting reversible contraceptives (LARC) provide relief for overburdened supply including implants, Norplant and Jadelle chains by offering longer term methods (Bayer OY, Turku, Finland), intrauterine that do not demand regular resupply, may devices (IUDs) such as the copper IUD be obtained through pharmacy networks, ParaGard (The Cooper Companies Inc., and are also highly safe and effective. This San Ramon, CA) and medicated intra- will improve overall satisfaction while uterine systems such as Mirena (Bayer expanding the number of options avail- OY) and Annovera 1-year contraceptive able to provide choice and value patient vaginal system (TherapeuticsMD Inc, autonomy globally. In addition, there is a Boca Raton, FL). move towards making newer “green” FHI360 has improved access to highly methods where their potential environ- effective methods in low- and middle- mental impact is minimized during income countries (LMICs) is by reducing manufacturing through packaging, trans- costs of contraceptive products with Sino- portation and supply chains, delivery, implant (II), a 2-rod use, and disposal.4 implant Similarly, Medicines360 is pro- There are many products at different viding an avenue for extended access with stages in the contraceptive development their lower cost levonorgestrel containing pipeline. An ongoing database main- IUD Avibela, Sayana Press, a subcuta- tained by the Contraceptive Technology neous depot medroxyprogesterone ace- Innovation Exchange provides a tool to tate, is an important advancement to access knowledge on contraceptives in provide an option for self-administration development (https://pipeline.ctiexchan on a progestin-only contraceptive. These ge.org). With over 200 results, this data- newer advancements are proving critical base highlights the many products in to enhancing individuals’ access, specifi- development and the diverse approaches, cally in LMICs, where new technologies and broad but clearly insufficient invest- are often initially a substantial barrier to ment occurring in this arena given the full broad distribution. We aim to provide an www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 3 overview of contraceptive technology METHODS FOR WOMEN development approaches while highlight- ing some of the methods in the develop- Enhancement of Existing Hormonal ment pipeline, as well as some of the Contraceptives obstacles that must be overcome to get Multiple products under development new methods into the hands of users in aim to enhance existing methods by im- dramatically diverse cultural and eco- proving the product profile for women. nomic contexts. One approach is altering the hormonal composition of existing methods to devel- op products with improved safety. This can be done by lowering doses of the same Development Approaches hormonal formulation, for example, hav- Contraceptive developers are pursuing ing a lower dose of ethinyl in different avenues to address user needs newer formula- that are not filled by currently available tions, or by including a safer steroid. contraceptive options. Developers are For example, newer formulations with seeking to improve upon the profile of potentially safer , such as estra- existing methods to increase acceptabil- diol (E2) or estetrol (E4), could poten- ity and reduce side effects while control- tially decrease venous thromboembolic ling the costs of goods, facilitating global risks or reduce hemostatic changes in distribution, and eventually securing af- comparison to ethinyl estradiol.5–7 Newer fordable prices to users in highly diverse progestins may have reduced side effects markets around the world. New technol- due to less androgenic activity of these ogies under development will increase progestins.8,9 A new intravaginal ring options including methods for women (IVR) currently in a phase 2b trial has with contraindications to hormones, replaced the ethinyl estradiol with 17β- methods for men, and will expand sec- estradiol, the endogenous that is ondary medical benefits, such as preven- less potent with decreased impact on tion of human immunodeficiency virus clotting factors. This ring combines estra- (HIV) or other sexually transmitted in- diol and segesterone acetate (trademark fections (STIs). In addition, new delivery name Nestorone), which is a potent pro- systems can expand the way individuals gestin with no androgenic properties.9 receive contraception, favoring user-con- New progestin-only options, such as trolled methods to allow easy access in progestin-only patches and IVRs, are regions, such as LMICs, where access to under development. While progestin-only health providers trained for LARC in- approaches expand access for women sertion or removal may be limited. Ex- with contraindications to estrogen- amples of such an approach is Annovera, containing methods, the altered bleeding a 1-year, the user-controlled intravaginal profiles that occur with these methods system recently approved by the Food may not be acceptable to all users. Fur- and Drug Administration (FDA) in the ther, progestin-only options may be able United States, and the 3-month proges- to promote breastfeeding, especially crit- terone vaginal ring (PVR) for birth spac- ical in LMICs, while extending the inter- ing among breastfeeding women pregnancy intervals. The PVR is used to included in the World Health Organiza- extend the contraceptive effectiveness of tion(WHO)ListofEssentialmedicines among breast- and most recently approved by regula- feeding women, which is favorable for tory agencies in Nigeria and Senegal many women. The PVR is a donut- (see below). shaped, soft, flexible silicone ring;

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58 mm in outer diameter and 2.4 mm in and paraprofessionals with small case- cross-section, containing 2 g micronized loads provide the bulk of clinical family releasing ∼10 mg/d. Proges- planning services. IUDs are a great exam- terone enhances the prolactin response to ple where significant investment is work- breast suckling that suppresses ovarian ing toward enhancing the design for a function.10 It also thickens the cervical range of clients including adolescents and mucus, inhibiting penetration into women immediately postpartum and al- the uterus. Clinical trials have demon- tering the formulation to reduce side strated that the PVR is 98.5% effective in effects and improve safety. One approach preventing pregnancy when used cor- is altering the delivery profile for copper rectly, is safe for mother and baby, and by lowering the doses or release of does not affect a woman’s ability to copper ions from the IUD or integrating produce breast milk, unlike estrogen- copper nanoparticles in the device to containing oral contraceptives. decrease the burst of copper release.12,13 The PVR was added to the 2015 Another approach is to add an additional updated WHO Medical Eligibility Crite- active pharmacologic ingredient (API) ria (fifth edition) and to the WHO Model with the goal of improving the bleeding Essential Medicines List. In a recently profile, either in terms of volume, fre- published 1-year study conducted in In- quency, or predictability. An example of dian family planning research centers this is a copper IUD that releases comparing the PVR with the Copper-T indomethacin,14 a nonsteroidal anti- IUD in postpartum breastfeeding women, inflammatory drug. Another approach is efficacy and safety outcomes were com- to include a progesterone receptor modu- parable among women in both groups. lator in a small reservoir to prevent Continuation rates for the PVR, a wom- bleeding associated with IUDs. An uli- an-controlled method, were lower than pristal acetate-Copper IUD was tested in IUD rates while PVR users maintained a proof-of-concept dose-finding study and lactational amenorrhea significantly lon- confirmed the feasibility of decreasing the ger than IUD users. Infant breastfeeding expected copper-associated bleeding and growth patterns/well-being were fa- (Brache V, Vieira CS, Plagianos M, Lan- vorable in both groups.11 The PVR can siaux M, Merkatz R, Sussman H, Cochon address the unmet need for birth spacing L, Tejada AS, Kumar N, Loeven D, among lactating postpartum women Blithe DL, Aprem AS, Williams ARW, while encouraging breastfeeding that is Kannan A, Bagchi IC, Sitruk-Ware R, essential for infant’s health in many coun- revision under review). Advancing mod- tries including LMIC where breastfeeding els that employ new materials, such as up to 1 year is popular. nitinol where shape memory and elasticity properties offer a theoretical advantage in Enhancement of Existing Contraceptives terms of retention, ease of insertion or For nonhormonal contraceptives, includ- comfort over the current models or differ- ing , diaphragms, and IUDs, ent shapes and sizes may overcome some developers are exploring different materi- of the side effects or resistance to existing als, shapes, and designs to enhance the methods, especially among sexually active user experience and better facilitate in- youth. Veracept low-dose Copper IUD sertion and prevent adverse events, such and Levocept IUS currently in clinical as uterine perforation or expulsion. Com- trials exemplify this approach.15 Another plications like these are more likely to example is the intrauterine ball, where the occur in delivery systems where task- classic T-shape is replaced by a series of shifting requires that general physicians copper “pearls” on a frame that are www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 5 inserted and through shape memory de- as dissolution of the needles or as hollow velop the shape of a ball.16 Last, new needles to deliver the drug from a reser- inserters are designed to simplify insertion voir in the patch that is removed after and reduce risks of pain and perforation, application. These are user-administered, including those with single-handed and and appropriate for community distribu- 2-handed inserters as well for immediate tion along with products under develop- postpartum use.17 Enhancing the ease and ment for vaccination, HIV prevention safety of IUD placement can further as well as recently for contraception. support task-shifting to increase access Individuals in theory would place the in LMICs, while in-service training op- patch for a few minutes and then remove portunities increase the development and it. This interesting approach may be maintenance of required clinical skills. preferred by women who favor discreet options over the classic transdermal Novel Delivery Systems patches that remain in place and visible. New delivery systems can potentially Also, there is no risk of patch detaching enhance user control and increase the from the skin in high humidity areas. duration of contraceptive effectiveness to Different progestin-based products under reduce the need for repeat clinical visits development include an on-demand and associated barriers associated with patch that would provide protection for some methods. Examples of newer deliv- 5 to 7 days and a long-acting patch that ery systems include biodegradable contra- would provide pregnancy protection for ceptive implants and longer acting several months. injectable methods that can provide The advancement of IVR technologies extended periods of contraceptive effec- are allowing for newer approaches to tiveness without the need for a trained include multiple drug moieties in a single provider for removal. Longer acting in- device. Oak Crest Institute of Science and jectables under development allow the its collaborators have developed a novel user to go 6 months or 1 year between pod IVR: a core IVR in which multiple injections compared with current prod- API reservoir “pods” are contained with- ucts every 1 to 3 months, yet provide a in the IVR scaffold. The ring scaffold rapid return of fertility. Recent donor is an unmedicated supporting structure interest in MedinCell’s18 BEPO technol- for the pods and can be composed of ogy may make it possible for a subcuta- silicone elastomers or thermoplastics like neous injectable to deliver the optimal ethylene-vinyl acetate and polyurethane. therapeutic dose of a progestin-based This novel design has successfully deliv- contraceptive for 6 months. The possible ered hydrophilic APIs (small and large drawback of such long-acting methods is molecules) and small-molecule hydropho- that it could not be withdrawn if someone bic APIs. Each API is encapsulated in its is dissatisfied with the method or in case own pod, the polymers/excipients of of a serious adverse event requiring im- which can be tailored to the properties mediate removal. of the drug, and each pod is coated with a Microneedle (or microarray) patches release-controlling polymer membrane are being developed to provide an alter- with the core content released through a native approach for the delivery of hor- delivery window in the ring scaffold. The monal contraception. These differ from potential for combining multiple APIs typical transdermal patches as they con- with different properties opens new ave- tain an array of microneedles built into nues for multipurpose prevention tech- the patch that can release drug through nologies (MPTs) and products combining the dermis via differing approaches such different active ingredients that had

www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 6 Haddad et al previously been challenging to coformu- methods. This is a common challenge late. This pod-ring approach is being with on-demand approaches, where the pursued at the Population Council as an typical use effectiveness is much lower MPT combining hormonal components, than perfect use effectiveness largely due ethinyl estradiol, and , with a to challenges in adherence. Nonetheless, nonantiretroviral lectin with potent anti- many women seek an on-demand HIV activity, Q Griffithsin, to address the approach.21 New approaches aim to im- concerns of women and policymakers prove the delivery of on-demand methods aiming to reduce both unwanted preg- to enhance acceptability and provide an nancy and unwanted transmitted infec- extended window of effectiveness by using tions without increasing antiretroviral a combination of different APIs with drug resistance.19 differing mechanisms of action in one Microchip technology is under develop- method. Electrospun drug-eluting fibers/ ment as a long-acting, user-controlled fabrics can combine several molecules approach for pregnancy prevention. The delivered at different doses and pace. goal of the microchip is to have an Laboratory tests showed a steady delivery insertable device with a controlled drug from different fibers delivering levonor- release that can be turned off and on gestrel and tenofovir from a fabric to be through a remote device. The Bill and used vaginally.22 Fast-dissolving inserts Melinda Gates Foundation recently in- are a solid dosage form that are placed vested in funding the development of a inside the and quickly dissolve to device that would release levonorgestrel form a viscous gel that can deliver the with activity up to 16 years, that can be active agents, without leakage that may turned off when someone wants to con- be observed with vaginal gels. Fast- ceive or is abstinent and turned back on dissolving inserts are inexpensive, dis- postpartum or when one resumes sexual crete, and portable with demonstrated activity. Innovations such as these have the high acceptability in surveys and with potential for reducing the current burden use in currently marketed products for on supply chains and potentially may other indications.23,24 Bioadhesive films lower the long-term costs of method use. can be placed within the vagina and This approach, however, is not without maintain protective activity for a longer controversy as it raises concerns regarding period of time by adhering to the mucosal security, the extent of reliable user control, wall.25–27 These discrete approaches can and contraceptive coercion.20 expand options for user control with no While there are some on-demand meth- interference with the woman’s cycle, a ods for use around the time of intercourse minimal effect on the bleeding profile, that may be sought by individuals with and the potential for added secondary infrequent sex where the use of a daily pill benefits such as HIV or other STI pre- or LARC is undesirable, the current vention. options are limited, and the effectiveness is lower than desired. Phexxi (Evofem, MPTs San Diego, CA), a nontoxic As discussed above, some of the methods that maintains the pH within the vagina under development aim to incorporate at levels < 5 to immobilize and kill sperm drugs that have activity against HIV and/ and likely many sexually transmitted or STIs. There is an undeniable need for pathogens. However, the MPTs in many parts of the world. In 2019, of this method is higher than usually ∼1.7 million people became newly infected required by regulatory authorities or ex- with HIV, > 3 times the target 2020 goal pected by clients desiring highly effective set by the 2030 Agenda on Sustainable www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 7

Development and articulated in the United more, recent studies conducted both in the Nations General Assembly 2016 Political United States and in Sub-Saharan Africa, Declaration of Ending acquired immuno- have highlighted that women will likely deficiency syndrome (AIDS).28 Uptake of prefer and use an MPT product that preexposure prophylaxis has been slow prevents pregnancy and STI/HIV acquis- particularly among women in developing ition over a product that prevents only countries. While STIs including HIV are pregnancy or only STI/HIV.31,32 These found worldwide, the bulk of new HIV recent findings are of high relevance for infections and cases of AIDS are reported women who desire an STI/HIV prevention in East and Southern Africa. For example, product that could be used discretely adolescent girls and young women (ages 15 (either not noticed by the partner or where to 24) account for about 25% of new HIV contraception could be the stated/dis- infections in sub-Saharan Africa, despite closed reason for product use). making up only 10% of the population, One approach towards advancing and AIDS is the second leading cause of MPTs is combining an approved contra- death among this population. There are ceptive with another approved STI or over 1 million new cases daily of curable HIV prevention strategy. Currently, only STIs worldwide29 with treatment costs Truvada is approved for preexposure exceeding $2 billion annually.2 Despite HIV prophylaxis for women, thus devel- national efforts to reduce STIs, the STI opers are aiming to combine this molecule epidemic in the United States has experi- with a hormonal contraceptive pill to enced steep and sustained increases for the develop one pill for dual prevention. With fifth consecutive year, reaching an all-time additional HIV prevention options soon high in 2018 with 1.7 million cases of becoming available to women, including chlamydia (increased 22% since 2013) and a ring delivering dapivirine and a long- 555,608 cases of gonorrhea (increased 67% acting cabotegravir injectable, new ap- since 2013).30 Increasing antibiotic resist- proaches for combination products are ance exacerbates these concerning trends.19 becoming feasible in the foreseeable fu- STIs have a broad-reaching impact on ture. An example of this approach is an women’s health and maternal-child health, MPT IVR that delivers dapivirine and including increasing the risk of HIV ac- levonogestrel.33 As with other family quisition and transmission, chronic pelvic planning approaches, offering different pain, infertility, and preterm delivery, the delivery approaches is imperative to en- leading cause of infant morbidity and hance uptake by providing choice to the mortality. MPTs that can reduce the risk user and enhancing efficiency in service of STI acquisition have huge potential for delivery for providers. public health impact as they aim to tackle these overlapping burdens. Unfortunately, Nonhormonal Methods condoms – a method plagued by low Nonhormonal contraceptive technologies adherence and poor typical use contra- are being developed to address the needs ceptive effectiveness – are the only MPTs of women who want to avoid pregnancy currently available. without using hormonal approaches. The It is anticipated that combining these varied reasons women may want to avoid prevention strategies will not only increase hormonal methods include contraindica- uptake of interventions that can reduce tions and/or increased health risks asso- the global burden of these diseases but ciated with ethinyl estradiol use (such as also increase adherence, where the moti- venous thromboembolism, thrombo- vation to prevent one outcome can help philias with increased risk of thrombosis, drive the prevention of another. Further- migraines with aura, and breast cancer),

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Unauthorized reproduction of this article is prohibited. 8 Haddad et al concerns regarding hormonal methods family planning for women, particularly during the postpartum period or while for those who completed their family breastfeeding, a general dislike of these either at an early age or over age 35. methods, side effects and/or fear of Inadequate availability of surgical facili- adverse effects related to hormones. ties and trained personnel in overbur- There are also women who desire predict- dened health systems present significant able regular menses without unscheduled barriers to access that may contribute to or irregular bleeding experienced with the the unmet need for permanent contra- use of some progestin-only methods.34 As ception in many low-resource settings.36 the only nonhormonal options are pro- Research is ongoing to develop an effec- vider-dependent copper IUDs, which tive and safe nonsurgical approach that have the risk of increased monthly bleed- could improve access and even allow task- ing, or pericoital approaches with low shifting to allow skilled midlevel providers typical use effectiveness, such as condoms to perform permanent contraception pro- or , it is critical to fill this gap cedures without compromising appropri- in the method mix. ate counseling, informed consent, or the Expanded technologies for on-demand quality of the clinical outcome. methods will increase the number of op- tions in the future. In addition to Phexxi, METHODS FOR MEN polyphenylene carboxymethylene, is being The only current options for male contra- explored by Yaso Pharmaceuticals as a ception, condoms, withdrawal, and vasec- potential on-demand nonhormonal ap- tomy, limit choice for half of the world’s proach. Another such approach is through population. Studies indicate that > 50% of a nonhormonal vaginal ring under devel- men say they would be interested in an opment which releases ferrous gluconate or effective reversible contraceptive meth- ascorbic acid that impedes sperm motility. od.37 Developing male contraception can Ovaprene (Daré Bioscience, San Diego, provide an opportunity for individuals to CA) under development is a monthly take control of their reproductive decisions vaginal ring with a semi-permeable poly- and improve the efficacy of existing meth- mer mesh barrier that physically blocks ods if both partners are using a contra- sperm from entering the cervical canal; ceptive. These methods also offer an releases of ferrous gluconate from the main opportunity for shared responsibility for ring body, which acts locally to impede the prevention of unintended pregnancy sperm motility. A phase 1 safety-and-toler- within the couple. ability study concluded that the Ovaprene Considering the disadvantages of the device is well-tolerated and acceptable to traditional male contraceptive methods, sexually active women and their partners35; the prerequisites for an ideal pharmaco- and Daré began a clinical trial of Ovaprene logic male contraceptive should be applied in 2018. Bayer recently entered into a independently of the sexual act, be highly license agreement with Daré Bioscience to effective, be acceptable for both partners, commercialize the product in the United have minimal interference with , States and this approach is now entering have neither short-term nor long-term clinical trials through the NICHD clinical toxic side effects, have no impact on trialsnetworksomoredatashouldsoonbe eventual offspring, be rapidly effective available on safety and efficacy. and fully reversible and be as safe and effective as comparable female methods.38 Nonsurgical Permanent Contraception Male hormonal contraception is one Globally, permanent contraception repre- approach as the efficacy of hormones sents the one of the leading methods of for suppressing is well www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 9 established. Similar to women, testoster- and 4 implants (1600 µg/d) were sufficient one levels in the testes that are required to suppress gonadotropins and spermato- for spermatogenesis are regulated by the genesis, that is, or sperm hypothalamic-pituitary axis. Exogenous counts <1 million/mL in 82% of subj- androgens alone or in combination with ects.41 Full recovery was reached between progestins suppress gonadotropin secre- 2 months and 1-year follow-up. New tion leading to reduced testicular testos- prototype implants based on a different terone production. Low testosterone elastomer technology intend to deliver a levels may lead to other effects such as higher dose of MENT to decrease the low libido, erectile dysfunction, and number of implants. This technology reduced muscle mass, thus add-back needs to be refined for further clinical testosterone is needed to reduce these trials, and users will likely face similar symptoms while maintaining sperm supp- challenges in developing country markets ression. One challenge with these ap- such as Ethiopia where women with im- proaches is a delayed onset of action, as plants have faced in getting implants it can take several weeks to fully suppress withdrawn when they chose. spermatogenesis. Several formulations Currently, a nestorone/testosterone gel are being evaluated including pills, trans- formulation is being evaluated for efficacy dermal gels, and implants. Previous trials in couples enrolled in a 1-year phase IIb have used combinations of long-acting multinational clinical study conducted in injectable or implantable forms of testos- the Male Contraceptive Clinical Trial Net- terone with , which can be work of the NICHD and in collaboration administered orally, by injection, or by a with the Pop Council and including sites long-acting implant. Such combinations from 4 continents. Efficacy is suppressing suppress spermatogenesis to zero or be- the gonadotrophins has been confirmed low the threshold required for pregnancy and the dose selected for an ongoing in 80% to 90% of men, with near- efficacy study in volunteering couples.42 complete suppression in the remainder The male pill development has been chal- of individuals without severe side effects lenging given the short half-life of oral and are always fully reversible. Progestin testosterone and the toxicity of modified coadministration suppresses gonadotro- oral such as methyl testosterone pins and increases both the rate and that can cause hepatotoxicity. However, extent of sperm suppression.39 newer androgen, such as di-meth-andro- Some of these approaches aim to em- lone undecanoate (DMAU) and 11β- ploy that are not methyl-19-nortestosterone17β-dodecylcar- metabolized via 5-alpha reductase which bonate (11β-MNTDC), may be able to may be helpful for prostate health and overcome this challenge. While DMAU male pattern baldness. An androgen with and 11β-MNTDC are similar in structure high tissue selectivity has been developed and activity, DMAU is a more potent by the Population Council for both male androgen, while 11β-MNTDC has a more contraception and treatment of hypogo- balanced androgen receptor to progester- nadism in men. MENT (7α-methyl- one receptor activity. Both have shown 19-nortestosterone) is not converted to safety when administered orally. These 5α-dihydrotestosterone and therefore promising compounds suggest that a had less effect on prostate growth in “male pill” may indeed become available different animal models.40 In the first in the next decade.43,44 clinical trial in male volunteers, MENT Another approach for men under de- acetate implants delivering 400 µg/d of velopment aims to block the passage MENT, were administered for 1 year of sperm from the testes similar to

www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 10 Haddad et al as a nonhormonal male contra- impact the specific target and avoid non- ceptive. Vasalgel, currently under devel- specific activity, integrating approaches opment by Revolution Contraceptives, a such as antibodies and mRNA identifica- Parsemus Foundation’s social venture, is tion. In theory, this would lead to a very a polymer gel that is injected into each vas focused contraceptive profile avoiding deferens that blocks sperm passage, other unwanted effects. While there are however, this blockage is able to be several such targets identified and being reversed if the man desires with an in- worked on, it is likely that few will office procedure.45 advance to clinical testing. For women, these approaches are aiming to block Novel Agents and Targets for oocyte maturation or inhibit factors that Nonhormonal Contraception influence follicular rupture. For male In pursuit of nonhormonal contraception, methods, several targets have been iden- there has been high interest in discovery tified that have promise including those work that has leveraged the rapid expan- that block spermatogenesis and sperm sion in genomic and proteomic research differentiation and maturation, sperm techniques. The goal has been to identify motility, or the capacity of the sperm to targets, ideally those with a specific role bind to the ovary. Figure 1 highlights the important in male or female reproduction multiple male-specific protein or enzyme and located uniquely within the reproduc- targets being explored that can potentially tive organs, for example, testes or ovary, be antagonized to inhibit fertility by act- or on sperm. Once these targets are iden- ing at different stages of spermato- tified, researchers identify agents that genesis.46 Some of these targets,

FIGURE 1. Various factors involved in sperm production, maturation, motility, and capacita- tion processes to fertilize an egg, that could become targets for specific blockage (in blue still hormonal; in burgundy nonhormonal approaches). 11β-MNTDC indicates 11β-methyl- 19-nortestosterone17β-dodecylcarbonate; DMAU, di-meth-androlone undecanoate; GAPDHS, glyceraldehyde-3-phosphate dehydrogenase, spermatogenic; MENT, 7α-methyl-19-nortestos- terone. Figure courtesy from D. Blithe and adapted from Gottwald et al46 with permission. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 11 specifically those involved in blocking their drug discovery research and develop- sperm function and binding, may also be ment programs in contraception in the early employed as innovative vaginal female 2000s. Much of the progress especially in contraceptives as well. male contraception has been then driven by government, nongovernment and philan- thropic organizations. However, any new Challenges to Method product ultimately emerging from this non- pharmaceutical model will require consid- Approval and Expanding Into a erable financial, manufacturing, and Global Market commercialization capabilities of the phar- While there are many products in develop- maceutical industry to reach the diverse and ment, many of these will fail to advance often informal markets that service men’s due to technical, regulatory, or cost issues, health around the world. Along with this, and never get in the hands of providers or thehighcostofnewmethodsevenforthe users. These failures to progress are some- private sector will require ongoing invest- times due to issues related to safety or ment and a demonstrated market at a efficacy recognized during the course of significant scale to reduce the marginal costs drug development, however, often it is due of delivery. As the field explores the impli- to failure to obtain the needed funding cations of task-shifting and telemedicine, required to complete product development new technologies need to be developed to or manufacturing in small batches until fit the new models of delivery. Ensuring that large procurements are realized. There are new technologies are included in plans for multiple stages in the discovery phase Universal Health Coverage and emerging before a product can begin clinical trials, national health insurance plans will indeed and then once clinical trials begin, the cost be a requirement for long-term scale-up of of running these trials can be substantial delivery and complex distribution and sup- given the regulatory requirements for fe- ply chain reliability. male contraceptives to provide data for In addition to the actual cost of moving 20,000 cycles of use and 400 women these technologies forward, additional bar- completing 1 year of use for any new riers persist. Newer contraceptives tend to chemical entity or a new device. Regula- have higher Pearl indexes, a metric of tory requirements for male contraceptives contraceptive effectiveness, in comparison are not specified by regulatory authorities to methods that were previously studied as pregnancy in women is the usual end- and approved. This relates to changes in point, rather than sperm suppression, but the diversity of the populations included in maybe similar with 400 couples complet- studies such as those with obesity, younger ing a 1-year trial. Upscale manufacturing participants, and the inclusion of cycles under Good Manufacturing Practice con- with documented sexual activity and no ditions is another challenge and requires other method use. This is even more commercial entities to conduct these steps challenging for on-demand products where for quality-assured, mass-manufacturing, perfect use is not reflected in this metric. and future distribution. Challenging issues For male contraceptive development, of regulatory approval, procurement, and the regulatory pathway globally is not market penetration are common with all clearly developed. A large potential barrier new technologies, particularly in develop- exists in defining what will be considered ing countries with limited human resources safe enough for a male contraceptive. for delivery. Long-term safety will need to be Several multinational pharmaceutical demonstrated and very few side effects companies abandoned a large portion of would be acceptable as users do not face

www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. 12 Haddad et al the medical risks associated with preg- Conclusions nancy; thus, the risk/benefit ratio differs. In summary, considerable effort is being We must consider the risks to the individ- expended despite extremely constrained ual versus the potential health consequen- funding to broaden the contraceptive ces in another individual. One approach to method mix. Methods are being developed alter this ratio may be developing methods to increase user control, as some individu- that have additional health benefits for als do not want to rely on a provider for men, without constraining the benefits for initiation and discontinuation, and to offer women. This may be a long-term issue as newer long-acting reversible contraception the key element for the moment is efficacy or nonhormonal choices with secondary and safety for the user and his partner. benefits, such as prevention of STIs or Male contraception has been an unfulfilled HIV. This will lead to more choices for promise for many years, so there are many users and provide options for individuals issues in the delivery of new male methods who may be currently dissatisfied with that will take a great deal of time to their method. This may be an issue in address, for example, where will men go health systems with a high turnover in for information and care? Health clinics in skilled providers such as in LMICs. As developing countries are not particularly more men are expressing willingness to designed for men, apart from emergency share the contraceptive burden, new op- rooms, so policies may have to focus on tions for men are essential. Male contra- other sources of care. ception would enable men to take For MPTs, a challenge will be to responsibility for their sexual and repro- proving effectiveness against HIV and/or ductive behavior—a critical step towards other STIs. Designing adequate studies reproductive justice and greater equity in that show reduced incidence is becoming global family planning.44,48,49 That said, more challenging to ethically conduct giv- insufficient resources are dedicated to sup- en the effectiveness of newer approaches port these endeavors and to provide the for HIV prevention and the benefits of essential ongoing commitment to get these antiretroviral therapy treatment on reduc- methods reliably to users globally. It al- ing transmission to an uninfected partner. most goes without saying that only a small New studies may need to be extremely number of these promising and potential large to prove a marginal benefit to the leads will ever get to rapidly evolving user and their partner(s), where an index of market in developed countries, and only protection, similar to the pearl index for a few will contribute significantly to meet pregnancy, will likely need to be defined. It the needs in developing markets. But there is possible that for some of these MPT is hope that improved applied contracep- products seeking regulatory approval may tive science now may have a longer benefit be complicated due to multiple indications, stream for all men and women seeking to where there may be delays in the seeking of fulfill their reproductive and health goals approval for the secondary benefit or the well into the future. This clearly is an inclusion of an active pharmaceutical in- example of a public good. gredient that does not directly impact the While great strides were achieved primary indication, for example, preg- through the public sector, nonpharmaceut- nancy prevention, may lead to challenges ical channels, these successes build off of in approval. The impact of male contra- partnerships between government, re- ception will be significant internationally searchers, and potential manufacturers. as it could reduce unintended pregnancies To get products to the market, more viable by 3.5% to 5% in the United States and by public-private partnerships are needed. > 30% in low-resource settings.44,47 And lastly, while progress is slow and many www.clinicalobgyn.com Copyright r 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Contraceptive Technologies: Looking Ahead 13 of these methods may never reach the 10. Diaz S, Miranda P, Brandeis A, et al. 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