A strategic action framework for multipurpose. prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent

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1 The European Journal of Contraception & Reproductive Health Care ISSN: (Print) (Online) Journal homepage: A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV Bethany Young Holt, Laura Dellplain, Mitchell D. Creinin, Kevin J. Peine, Joseph Romano & Anke Hemmerling To cite this article: Bethany Young Holt, Laura Dellplain, Mitchell D. Creinin, Kevin J. Peine, Joseph Romano & Anke Hemmerling (2018) A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV, The European Journal of Contraception & Reproductive Health Care, 23:5, , DOI: / To link to this article: Published online: 24 Sep Submit your article to this journal Article views: 256 View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at

2 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 2018, VOL. 23, NO. 5, REVIEW ARTICLE A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV Bethany Young Holt a, Laura Dellplain a, Mitchell D. Creinin b, Kevin J. Peine c, Joseph Romano a,d and Anke Hemmerling a,e a The Initiative for Multipurpose Prevention Technologies, Public Health Institute, Sacramento, CA, USA; b Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, USA; c USAID Global Health Fellows Program, Office of Population and Reproductive Health, US Agency for International Development, Washington, DC, USA; d NWJ Group, Wayne, PA, USA; e Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA ABSTRACT Objective: Multipurpose prevention technologies (MPTs) are an innovative class of products that deliver varied combinations of human immunodeficiency virus (HIV) prevention, other sexually transmitted infection (STI) prevention, and contraception. Combining separate strategies for different indications into singular prevention products can reduce the stigma around HIV and STI prevention, improve acceptability of and adherence to more convenient products, and be more cost-effective by addressing overlapping risks. Methods: This article outlines a strategic action framework developed as an outcome of a series of expert meetings held between 2014 and The meetings focused on identifying opportunities and challenges for MPTs that combine hormonal contraception (HC) with antiretroviral drugs into single products. The framework aims to present an actionable strategy, by addressing key research gaps and outlining the key areas for progress, to guide current and future HC MPT development. Results: We identified eight primary action areas for the development of impactful HC MPTs, and includes aspects from epidemiology, pharmacology, clinical trial design, regulatory requirements, manufacturing and commercialisation, behavioural science, and investment needs for research and development. Conclusion: Overall, the challenges involved with reconciling the critical social-behavioural context that will drive MPT product use and uptake with the complexities of research and development and regulatory approval are of paramount importance. To realise the potential of MPTs given their complexity and finite resources, researchers in the MPT field must be strategic about the way forward; increased support among policy-makers, advocates, funders and the pharmaceutical industry is critical. ARTICLE HISTORY Received 10 May 2018 Revised 11 July 2018 Accepted 31 July 2018 Published online 24 September 2018 KEYWORDS Action framework; contraception; HIV; MPTs; multipurpose prevention technologies; prevention Introduction Multipurpose prevention technologies (MPTs) are an innovative class of products that deliver varied combinations of human immunodeficiency virus (HIV) prevention, other sexually transmitted infection (STI) prevention, and contraception [1]. Despite progress in recent decades in reducing sexual and reproductive health-related morbidity and mortality for women and girls worldwide, significant challenges remain [2]. Globally, 85 million unintended pregnancies occur every year, and each day 830 women die from preventable causes related to pregnancy and childbirth [3]. HIV infects 900,000 women annually, and AIDS remains the leading cause of death among women aged [3,4]. Genital infections with sexually transmitted pathogens other than HIV affect hundreds of millions of women [5]. Improved prevention options to address these health concerns are needed, as many women face barriers to access and use of existing methods including condoms and contraceptives, particularly long-acting reversible contraceptives, as well as pre-exposure prophylaxis for HIV prevention [6,7]. Combining separate strategies for different indications into singular prevention products can reduce the stigma around HIV and STI prevention, improve acceptability of and adherence to more convenient products, and be more cost-effective by addressing overlapping risks. The MPT development pipeline has grown substantially over the past decade in spite of the technical complexities of combining active pharmaceutical ingredients (APIs) such as a hormonal contraceptive (HC) and antiretroviral (ARV) drug into a single product [1]. Recognising the need for a range of options to meet women s needs, the MPT development pipeline includes different drug configurations, delivery mechanisms, designs, and indication combinations [1]. For example, drugs preventing pregnancy and STIs can be co-formulated and delivered topically (e.g., intravaginal ring, vaginal gel, vaginal insert, vaginal film) or systemically as either daily oral or longer-acting formulations (e.g., injectable depot preparation, patch, intrauterine device CONTACT Bethany Young Holt byh@cami-health.org The Initiative for Multipurpose Prevention Technologies, Public Health Institute, 1825 Bell Street, Suite 102, Sacramento, CA 95825, USA ß 2018 The European Society of Contraception and Reproductive Health

3 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 327 [IUD], subcutaneous implant). Some MPTs in development combine prevention of two or more STIs, or combine contraception and non-hiv STI prevention. However, development of MPTs that combine contraception and HIV prevention have been prioritised by a range of stakeholders in several MPT expert consultations [8,9], resulting in a broad pipeline of MPTs combining HCs and ARVs, with the most advanced products expected to reach later-stage clinical trials by 2020 [1]. These include two 90-day intravaginal rings containing the contraceptive progestin levonorgestrel and ARVs such as dapivirine and tenofovir, both of which have advanced into phase I clinical trials [10,11]. Given the complexities of MPT product development and finite funding resources, strategic thinking is essential in order to address research and development challenges and prioritise which attributes in future products would be most valuable and appropriate for advancement to later-stage clinical trials and product licensure. This approach must outline and provide a method for carefully balancing explorations that are of scientific merit, but not vital to product development, against fundamental research that must be addressed to achieve regulatory approval. The Initiative for MPTs (IMPT; a product-neutral global collaboration that advances the field of MPTs, was founded in 2009 by researchers, policy-makers, funders, and advocates working across the spectrum of women s global health to help facilitate this strategic thinking. This article outlines a strategic action framework that was developed during a series of expert meetings focused on combining HCs with ARVs for HIV prevention held between 2014 and These meetings included family planning and HIV prevention experts, MPT product developers, and MPT funders [8,9,12]. As part of its 2013 strategic planning process, the IMPT asserted that it was a top priority for the field to successfully identify and address the research questions and technical complexities for MPTs combining HC and ARVs. This prioritisation initiated the formation of a dedicated work stream for HC MPTs, which included members of the Contraceptive Clinical Trials Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), other family planning experts, HIV prevention experts, MPT product developers, and MPT funders tasked to develop an action plan. To work towards this aim, the IMPT in collaboration with the NICHD s Contraceptive Clinical Trials Network convened a series of expert consultations. The first, in September 2014, began the process of identifying priority research areas for HC MPTs, each with existing evidence and remaining gaps [12]. The second consultation in May 2015 refined these priorities, to track advances in each research area and to reach an updated consensus on gaps [8]. The IMPT and Contraceptive Clinical Trials Network convened a third HC MPT expert consultation in September 2016 to develop recommendations for a strategic action plan in order to address these identified and vetted research priorities [9]. The resulting framework outlined below aims to present an actionable strategy, including the identification of key research gaps and priorities, to guide current and future MPT development that combines HCs with ARVs into single products. Strategic action framework The strategic action framework consists of eight primary action areas to facilitate the development of impactful MPTs that provide contraception and HIV prevention. It includes aspects from pharmacology, clinical trial design, regulatory requirements, manufacturing and commercialisation, behavioural science and investment needs for research and development (Table 1). Action area 1: Identifying the HC MPT target population and their product preferences To support higher uptake and consistent use of marketed MPTs, lessons learnt from the microbicide field suggest that assessments of primary target population preferences should be conducted during early clinical development [13,14]. Available data indicate that young women in Sub- Saharan Africa have the highest unmet need for a product preventing both HIV and unintended pregnancy [3,15]. Since this is a heterogeneous population, refining the primary target populations in regions where HC MPTs will have the greatest health impact will enable the MPT pipeline to focus on products tailored to that population s needs and preferences. Previous work has begun to document and visualise where intersecting risks of unintended pregnancy and STIs suggest the greatest need for MPTs [16]. Building on this work, the IMPT is using epidemiological data to identify subnational geographical hot-spots where HIV prevalence and contraceptive need among young women overlap in 10 Sub-Saharan African countries. An interactive geographic information systems mapping tool of the prioritised MPT regions is in development to further refine the prioritised target populations for MPTs, inform MPT preferred product characteristics, guide the selection of MPT clinical trial sites, and inform programme planning in regions where uptake/ rollout of MPTs can be most impactful. The tool includes HIV and contraceptive epidemiological data. Once the primary target populations for MPTs have been identified, assessments of their preferences should be conducted early in clinical development. These assessments can inform MPT product attributes that are conducive to product uptake, as well as product introduction planning and rollout, including messaging, packaging, and delivery [5]. Action area 2: Selecting effective and appropriate APIs A product s end goal shapes the approach to its API selection and design, beyond the API s potential for reliable protection with few risks and adverse effects. In the context of HC MPT development, compounds currently dominating the pipeline have safety and efficacy data for use as single APIs [17 19]; however, this evaluation process is more complicated for drugs that are co-formulated with more than one API. Complexities include competing metabolic

4 328 B. Y. HOLT ET AL. Table 1. Action areas for HC MPTs. Action area Next steps 1. Target populations and product preferences Identified young women in Sub-Saharan Africa with highest unmet need for MPTs Developed mapping tool to identify geographic hot-spots of overlapping HIV prevalence and unmet contraceptive need 2. Combining APIs Initially focused on progestin-only HC (primarily LNG) in MPTs because of good safety profile, but brings unpredictable menstrual bleeding patterns as potential deterrent for users For MPTs, a monthly drug pause like in HC would allow withdrawal bleeding, but ideally need continued HIV protection despite short half-lives of many ARVs 3. Pharmacokinetics and drug drug interactions Growing evidence suggests certain ARVs induce liver cytochrome P450 metabolism and decrease HC serum concentrations Epidemiological evidence describes range of possible HC and ARV interactions, but there are limited robust clinical data to date 4. HC target dose High body mass index associated with low LNG HC serum levels, potentially impacting contraceptive efficacy New surrogate markers tested to evaluate ovulation and cervical mucus changes as predictors of pregnancy risk (cervical mucus, disruption of oocyte maturation, endometrial changes) 5. HC and susceptibility to HIV acquisition 6. Pre-clinical and clinical strategies Epidemiological data suggest that certain contraceptives (DMPA injectable) may affect susceptibility to vaginal HIV acquisition in high-risk populations, but more information is needed ECHO study currently comparing risks of HIV acquisition for specific drugs and routes of administration (DMPA injectable, LNG subdermal implant and copper IUD) Identified key development elements for each MPT configuration, which will need to include milestones, go/no-go decisions, and use of appropriate comparator groups, outcome measures, study sequencing, best trial populations 7. Commercialisation potential Recognised that early stages of product development should include market and user understanding, manufacturing and distribution considerations, policy and advocacy parameters, and regulatory pathways 8. Optimising investments Since 2014, a supporting agency committee has aimed to optimise MPT funding by information-sharing and collaboration in MPT research and development Funding for HC MPT development has increased since 2013, but funding is not adequate to ensure value potential of MPTs LNG: levonorgestrel; PrEP: pre-exposure prophylaxis. Assess product preferences among MPT target populations early in product development to inform desirable MPT product attributes, product introduction and rollout (including messaging, packaging and delivery) Develop MPTs using new APIs or devices that combine compatible drugs, including new HCs beyond LNG Develop non-hormonal and non-arv APIs as well as new delivery mechanisms Develop ARVs with high potency and long half-life for long-acting administration and continuous HIV protection Use existing licensed drugs and devices to create new MPT combinations to accelerate licensure and market entry Implement pharmacokinetic and drug drug interaction studies to inform the selection of API combinations and delivery mechanism Develop reliable, standardised and reproducible pharmacokinetic and drug drug interaction measurements in plasma, cervicovaginal fluid, cervical and endometrial tissue, and cervical mucus Establish serum level threshold zones for HCs and administration modes to serve as contraceptive surrogate markers to help adjust HC dosing in MPTs Develop new local and systemic contraceptive surrogate markers Invest in basic science research, epidemiological and clinical research to determine the role of selected HCs on HIV acquisition Assess impact of HC on vaginal microbiome and vaginal, cervical and endometrial tissues, and the impact of microscopic mucosal injury on HIV acquisition risk Consult relevant regulatory agencies, social-behavioural scientists and marketing experts to inform early in product development go/no-go decisions and guide trial design With expanding availability of PrEP, trial design for future phase III efficacy trials may be large non-inferiority trials without placebo groups Explore alternative regulatory pathways, such as bioequivalence studies, as suitable surrogates for efficacy trials Develop individual commercialisation strategies for each MPT, including impact on the HIV epidemic, cost-effectiveness, service delivery requirements, volume and profits Assess the investments to address prioritised action areas, and opportunities for expanding or repurposing existing research projects to help address field-wide gaps Tailor needed future research to specific priorities of different MPT funders across the fields of family planning, HIV prevention and STI prevention Engage new funding partners to leverage existing support for assessment of end-user preferences, cost-effectiveness assessments, epidemiological research, basic science research to advance non-hc and non-arv APIs, and eventual larger-scale and costly clinical trials Develop MPT value proposition, or investment case, to demonstrate the financial and public health rationale for MPTs in order to encourage investment in MPT development

5 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 329 pathways, differing drug release patterns in devices (i.e., intravaginal rings) used to combine APIs with different chemical properties (i.e., hydrophobic and hydrophilic), and API compatibility with the polymers used in devices [20]. In addition, regulatory requirements for combination drugs and devices mandate the assessment of safety and efficacy in the combination product, and that the combination be at least as effective as the single agent products. Large-scale manufacturing capabilities need to be carefully considered, as well as patent agreements. All these factors will impact the complexity of each MPT product s regulatory pathway, manufacturability, cost, and feasibility. A current focus for the contraceptive agent in MPT development is levonorgestrel, based primarily on its long history of safety [10,11]. Although progestin-only HCs such as levonorgestrel-only are safe and effective, unpredictable menstrual bleeding patterns are common and can be a significant deterrent for sustained contraceptive use, especially in settings that restrict women s activities during menstruation [21,22]. To mitigate this, progestins are often combined with estrogen such as ethinylestradiol or estradiol [23], but contraindications and adverse effects such as an elevated risk of deep vein thrombosis need to be considered [24]. To minimise intermittent spotting, hormones used in oral contraceptives and intravaginal rings typically include a monthly drug pause of 4 7 days to allow for withdrawal bleeding while women remain protected against pregnancy. Regimens for MPTs combining HC and ARVs that can accommodate a drug pause of several days are complicated, because the pharmacokinetics of many of the current ARVs, with their short half-lives [25], may not allow for extended drug pauses of several days and need to be administered without interruption to maintain HIV protection. There are two distinct paths forward to advance this area of work. The first is to accelerate the development of new MPTs using newly developed APIs or devices that are purposefully designed to combine chemically compatible drugs in a delivery system that meets specific behavioural and biophysical characteristics. To this end, it is critical to explore alternative HCs beyond levonorgestrel for future MPT products, such as alternative progestins. Additionally, the importance of developing non-hormonal APIs (e.g., new spermicides or copper IUD), non-arv APIs, as well as new delivery mechanisms, such as the use of biologics or nanotechnology, has been acknowledged by the MPT field. ARVs with higher potency for systemic or local administration and ARVs with a long in vivo half-life are needed, especially to provide adequate continuous HIV protection during the window of vulnerability caused by a drug pause (e.g., during intravaginal ring removal or missed doses). The second path could be considered as the lowerhanging fruit because it focuses on using existing licensed drugs and devices to create new MPT combinations with multiple indications. This could accelerate the regulatory pathway and market entry, but chemical properties, existing safety and efficacy data, and delivery, regulatory and manufacturing requirements need to be carefully assessed in order to select the most suitable candidates, and design studies to generate the missing safety and efficacy data required for licensure. Appropriate candidates for MPT development using approved APIs could be contraceptives such as etonogestrel and segesterone acetate, as well as the highly potent ARV tenofovir alafenamide for HIV prevention. Action area 3: Evaluating pharmacokinetics and drug drug interactions of candidate HC MPTs For MPT development, it is paramount to ensure that the high efficacy and/or safety of contraceptives and HIV prevention methods are not compromised when APIs are coformulated. For any product that concurrently administers more than one API, a thorough evaluation of interactions between the different APIs is required for regulatory approval [20]. Drug interactions on shared metabolic pathways, such as in the liver or kidney, could boost or slow drug pharmacokinetics and consequently accelerate or prolong drug elimination, resulting in drug levels that are either too low to be efficacious or high enough to be toxic [26]. Interactions of HC with APIs other than ARVs are also a growing concern in the medical community and among regulators [26], and have been reported for several other drugs, including psychotropic drugs [27,28] and anti-epileptic drugs [29]. However, caution is needed when interpreting studies that measure systemic or local drug levels, as the results may depend on modes of delivery. For example, an intravaginal ring may produce higher drug concentrations in vaginal fluids compared with plasma levels [30]. Of primary concern is the growing evidence that certain ARVs that induce liver cytochrome P450 metabolism seem to decrease HC serum concentrations, which in turn may increase pregnancy risk [30,31]. Recent systematic reviews explored epidemiological evidence across the range of possible HC and ARV interactions, demonstrating that while HCs generally do not seem to impact ARV blood concentrations and effectiveness, ARVs containing non-nucleoside reverse transcriptase inhibitors, specifically efavirenz, may interact with combined oral contraceptives and progestincontaining subdermal implants [30,31]. These findings should be interpreted acknowledging the absence of robust clinical data exploring these ARV HC interactions. In general, there is a need to perform pharmacokinetic and drug drug interaction studies early in the development pathway to inform the selection of API combinations and delivery mechanism. Reliable, standardised and reproducible pharmacokinetic and drug drug interaction measurements also need to be developed. First, depending on the API and mode of drug administration, plasma, cervicovaginal fluid, cervical or endometrial tissue, or cervical mucus may be the most suitable sampling to measure topical or systemic hormone levels. Second, measurement validity must be ensured for variability in sampling, such as sampling hormone levels at different time points within the menstrual cycle when endogenous hormones naturally vary

6 330 B. Y. HOLT ET AL. greatly. Additionally, each regulatory approval process will require drug drug interaction assessments for the specific API and device combination and are the responsibility of the drug sponsor. Although pharmacokinetic studies in humans will always be required and should be performed early in the MPT development pathway, redundant and expensive pharmacokinetic measurements in clinical studies may be minimised with the development of appropriate in vitro studies and pre-clinical animal studies assessing vaginal pharmacokinetics for various HCs that are then used to inform in vivo human studies. Importantly, drug drug interaction studies with specific HC and ARV combinations can help inform product development efforts across alternative dosage forms and strategies. Action area 4: Selecting an effective target dose for HC To determine contraceptive efficacy, the US Food and Drug Administration (FDA) has for decades used the Pearl Index as the main efficacy outcome variable, measuring pregnancy occurrence during product use. Researchers do not routinely measure HC serum levels in contraceptive efficacy trials, and no thresholds have been established for HC concentrations necessary for reliable pregnancy protection. The question of necessary HC concentrations is especially important for combination drugs, because potential drug - drug interactions may require an HC dosing adjustment to correct for pharmacokinetic changes, and it is critical to know what HC serum levels are needed [32,33]. However, such a threshold level, or transition zone, will be different for each progestin, and pharmacodynamic effects may not consistently correlate with HC serum levels. Additionally, different HC delivery methods may have different mechanisms of action (e.g., systemic versus local), and consequently the required HC target dose levels will depend on the specific administration mode. While some HCs such as oral contraceptives, intravaginal rings or injectables largely function systemically by suppressing ovulation, other topically administered methods such as vaginal films and IUDs may work by creating unfavourable local conditions for sperm penetration, sperm capacitation and fertilisation [34]. Data are emerging that show that women with a high body mass index often experience lower HC serum levels compared with normal weight women with some progestins (such as levonorgestrel) which could potentially impact contraceptive efficacy; thus, HC dosing may have to be increased for these women to remain protected against unintended pregnancy while still avoiding adverse effects [35]. In addition to relying on the Pearl Index for measuring contraceptive efficacy, other pharmacodynamic surrogate markers have been tested to evaluate whether ovulation or changes in cervical mucus quality might be reliable future predictors of pregnancy risk [34]. This work targets the development of new, reliable local and systemic surrogate markers that could predict contraceptive efficacy. For instance, local surrogate markers could be based on the assessment of changes in cervical mucus during the menstrual cycle, such as amount, consistency and ability to allow or prevent sperm penetration, measure these changes in relation to HC concentration delivered to the cervix with topical devices such as intravaginal rings or IUDs. For systemic surrogate markers, inhibition of ovulation and disruption of oocyte maturation could be measured in relation to serum progesterone levels. Fluctuations in histology and immunohistochemistry cause changes in the endometrium throughout the menstrual cycle and prevent or facilitate the implantation of a fertilised egg, but they are not routinely assessed. It is important for the development of effective and safe MPTs to establish robust serum level thresholds, or transition zones, for different HCs and administration modes. Those could serve as future surrogate markers for contraceptive efficacy and help adjust HC dosing for combination drugs or in women with a high body mass index. Moreover, continuing the development of robust new local and systemic surrogate markers for contraceptive efficacy will be critical. Action area 5: Evaluate role of HC in susceptibility to HIV acquisition With important caveats, some preliminary research has suggested that use of certain HCs, specifically depot medroxyprogesterone acetate (DMPA), may increase HIV acquisition risk in high-risk populations. This finding is primarily based on an updated (2016) systematic review of the epidemiological data which concluded that, while confounding in observational data cannot be excluded, new information increases concerns about injectable DMPA and HIV acquisition risk among women in high-risk populations [36]. The link is still being investigated, and it has potentially significant implications for MPTs that combine HC and ARVs [37,38]. The mechanisms by which certain progestins may affect susceptibility to vaginal HIV acquisition have been reviewed [39]. Injectable progestins may increase the frequency of HIV target cells at the cervix and activation markers in vaginal mucosal tissues [40,41]. It is also possible that HCs play a lesser role in HIV acquisition compared with other physiological factors [37 39]. Epidemiological data published in 2012 first explored the possible link between HC exposure and HIV acquisition [38]. Building from this work, a commentary that focuses on the impact of levonorgestrel on HIV acquisition and implications for MPT development finds that the limited data which are currently available suggest that levonorgestrel is unlikely to increase HIV acquisition risk, although more information is needed [42]. A broader systematic review published in 2016 on all HC methods and HIV acquisition indicates that current evidence purports a potential increased risk (hazard ratio 1.4) of HIV acquisition for users of DMPA only. However, this review notes that

7 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 331 definitively determining causality is a challenge, given that at present the only existing evidence derives from observational data [37]. Following publication of the updated systematic review in 2017, the World Health Organisation (WHO) changed its recommendations for use of progestinonly injectables among women at high risk of contracting HIV. This change from category 1, a condition for which there is no restriction on the use of the contraceptive method, to category 2, a condition where the advantages of using the method generally outweigh the theoretical or proven risks, aimed to promote conversations between clinicians and patients regarding the potential risks and benefits of contraceptive methods [43]. The Evidence for Contraceptive Options and HIV Outcomes (ECHO) study, a large, open-label clinical trial is underway to compare the risks of HIV acquisition between users of three different highly active reversible contraceptives (i.e., DMPA injectable, levonorgestrel subdermal implant and copper IUD) [36]. It will be important to understand that the outcomes of this study will only relate to the specific drugs and routes of administration being tested. In addition to the specific regulatory requirements for each MPT, a targeted investment in solving selected basic research questions is critical for the MPT field and to direct future drug development. For example, additional epidemiological, basic science and clinical research is needed to determine more conclusively the role of selected HCs other than DMPA with respect to risk of acquiring HIV in women and will impact the entire HIV prevention field beyond MPT development. Phase I safety studies with new MPT products could be designed to address issues such as the potential impact of progestins and estrogen on vaginal microbiome composition and vaginal, cervical and endometrial tissues, and the role of microscopic mucosal injury during intercourse which could facilitate the risk of HIV and STI acquisition [44,45]. Further work should also be performed to identify concrete biomarkers for HIV acquisition risk that can be measured in earlier-stage clinical trials. Action area 6: Determining and implementing preclinical and clinical strategies for HC MPTs For the MPT field to achieve public health impact in the near term, it needs to remain disciplined and objective in identifying and prioritising data gaps for each MPT candidate (e.g., safety, efficacy and chemical properties suitable for combination with other APIs and devices). This focus will ensure that resources are concentrated on research that is critical to meeting regulatory requirements and achieving licensure, rather than on research that pursues answers to ancillary questions with possible scientific merit but no immediate relevance to advancing a product along the regulatory pathway. Early clinical phase I safety studies can help with MPT candidate selection by generating safety data as well as pharmacokinetic and drug drug interaction data, with clearly delineated milestones and go/no-go decisions. Designing later-stage clinical phase III MPT trials requires careful consideration of a range of additional complex issues including the use of comparator groups, new standards of care for HIV prevention, a comprehensive set of outcome measures, study sequencing, identifying trial populations that can best represent priority users, and ethics. Each specific MPT product will require the development of study designs, with close communication between product sponsor and regulatory authorities. The overall clinical strategy will largely depend on the dosing method and API combination and will be influenced by the regulatory status of the API selected for the MPT product. Regulatory requirements in recent studies for comparator trial designs have been devised to show non-inferiority or superiority of new products relative to oral pre-exposure prophylaxis [46,47]. This is a departure from placebocontrolled trials for HIV prevention, in light of the ethical implications of conducting new trials when effective HIV prevention already exists [48,49]. It is likely that future MPT trials will be required to have similar comparator designs for the HIV prevention indication. Such requirements will have significant implications on sample size, study cost and feasibility. To address near-term concerns around pathways for MPTs, several reviews of key regulatory guidance documents and their applicability to MPTs outline key development elements necessary for various MPT configurations [20,50]. The importance of robust standards for integration of enduser and market perspectives into MPT research and development to inform go/no-go decisions for advancing preclinical and clinical strategies has also been recognised and these standards are in development [51 53]. Consulting relevant regulatory agencies in the planning of each specific clinical trial can help guide careful and thoughtful trial design, including ensuring requirements reflect advances in the field. Past challenges with product adherence in microbicide trials required scrutinising traditional approaches to maximising and accurately measuring adherence [13,14]. Social-behavioural scientists and marketing experts should be consulted early to inform go/no-go decisions for advancing MPT candidates into pre-clinical and clinical strategies [51], as well as to inform critical aspects of trial design such as recruitment avenues, educational materials for end-users, high appeal of packaging and product presentation. Given the risks already identified around efficiently securing regulatory approval for MPTs, the regulatory pathway and strategy for candidate MPTs needs to be charted. Stringent regulatory agency requirements should be compared across the FDA, the European Medicines Agency, as well as the WHO pre-qualification process, and guidance from regulatory bodies can inform key regulatory strategy elements for MPTs. Later-stage development guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (www. ich.org) will be particularly important for risk assessment and quality. One regulatory area that poses a significant challenge for the HIV indication of an MPT product will be trial design for phase III efficacy trials. The expanding

8 332 B. Y. HOLT ET AL. availability of approved HIV prevention products such as oral pre-exposure prophylaxis has led to the elimination of placebo-controlled trials for new HIV prevention products and in turn dictated the need for large, expensive comparator trials [49]. Consideration should also be given to whether large multicentre efficacy studies are the most prudent trial design for MPTs, or whether alternative pathways, such as bioequivalence studies, would be suitable surrogates for efficacy and be acceptable to regulatory authorities [54]. The resource demands will be an increasing challenge for the conduct of such trials and will likely limit the number of such trials in the future. Although discussions with regulatory bodies have not led to the identification of alternative trial design strategies, continued discussions will be important in advancing MPT product development. Action area 7: Commercialisation potential The commercialisation potential of products must be a key factor in determining which MPT candidates advance and attract continued support from the limited available resources. It will not be appropriate to simply focus on technical feasibility to justify product investment; a case should be made for the market impact potential of specific MPT product investments. The United States Agency for International Development (USAID) published a guide in 2015 underscoring that early stages of product development should include not only clinical considerations but also market and user understanding (i.e., end-user and provider perspectives and preferences, and market assessments including health system burden), manufacturing and distribution considerations (i.e., shelf-life stability, scale-up manufacture feasibility and prospective competitiveness, assessment of cost of goods, and demand forecasting), policy and advocacy parameters (i.e., impact potential, cost-effectiveness, likelihood for inclusion in emergency medicines lists) and regulatory pathways [55]. These focus areas should be not only monitored during early and at key stages of research and development but also re-evaluated throughout planning, introduction and scaling of selected MPTs. These variables must be included in calculations of return on investment and long-term market potential and should be part of the business case when justifying continued investment in the candidate products [56]. Individual commercialisation strategies should be developed for each MPT product. Success of MPTs designed to prevent HIV infection and unintended pregnancy will be measured in terms of impact on the HIV epidemic. However, developers, manufacturers, and other key stakeholders should appreciate that commercial success will be based on an understanding of market issues, including volume and profits. The feasibility of individual products to achieve commercial success can be assessed by scoring such products against a broad, databased understanding of market and user considerations, manufacturing and distribution, policy and advocacy, and regulatory processes [55]. Scoring should consider a robust assessment of end-user and provider perspectives, market assessment and prioritisation with associated demand forecasts, impact and cost-effectiveness thresholds, service delivery infrastructure requirements, procurement organisation requirements, access and delivery requirements, applicability to the public and private sectors, and other key variables relevant to successful commercialisation. Consequently, an effort to inform these issues broadly in parallel with individual MPT product technical development will be essential to assessing the feasibility and risks of commercial success, or value potential, for individual MPT products in development. Action area 8: Optimising investments in HC MPT development Through the product-neutral IMPT network, a committee of MPT supporting agencies was created in 2014 to optimise funding for the MPT field by information-sharing and collaborating around specific research and development questions. While not enough to adequately support all that is needed for impactful MPT development, funding for the development of HC MPTs has increased in the past 5 years [57]. Leveraging the critical support of USAID and others to the MPT field, the National Institutes of Health released three funding opportunities supportive of advancing the MPT field in 2017 [58 60]. Two of these opportunities focused exclusively on MPT development [58,59]. This growth in support is reflected in the nearly one dozen MPTs moving through clinical trials and many other technologies in earlier stages of development as well as in the increasing number of research and advocacy organisations engaged in the field. However, given the complex research and development questions that remain for the MPT field, existing support is a fraction of what is needed. An important next step is an assessment of the investments needed to address prioritised action areas and opportunities for expanding or repurposing existing research projects to help address field-wide gaps. Recognising that different MPT funders will likely have specific internal priorities, implementing appropriate solutions to the critical questions outlined in this strategic action framework will require sustained support and collaboration across the fields of family planning and prevention of HIV and other STIs for all stages of the development pipeline. It will also be important to engage new and diverse funders to leverage existing funding. Phase III clinical trials will require significant financial commitment, and, as the MPT pipeline advances, new funding strategies and partnerships must be explored [61]. At the same time, many of the action items identified above are well defined and manageable research questions that could be addressed by a new funder, or leveraged through integration into larger, ongoing research projects. For example, building upon the identification of the primary target populations for MPTs described in action area 1, new funding can support the identification of product preferences among MPT target populations early in product development to inform desirable MPT product attributes, as well as product

9 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 333 introduction and rollout. To this end, an MPT value proposition, or investment case, is recommended to demonstrate the financial and public health rationale for MPTs, encourage investment in MPT development and distribution, and inform standards by which funding decisions can be made by new and existing supporting agencies. Discussion The strategic action framework aims to address fundamental research gaps and outlines the key areas for progress aimed at ensuring successful MPT development. Overall, the challenges involved with reconciling the critical socialbehavioural context that will drive MPT product use and uptake with the complexities of research and development and regulatory approval are of paramount importance. MPTs are potentially life-changing tools that address the interlinked risks of unintended pregnancy and STIs, including HIV, and their resulting health and social consequences. To realise the potential of MPTs, given their complexity and finite resources, researchers in the MPT field must be strategic about the way forward, and increased support by policy-makers, funders and the pharmaceutical industry is needed [62]. Fortunately, the necessary infrastructure of stakeholders exists to advance this critical agenda. With more focused action and continued collaboration, MPTs that provide protection from unintended pregnancies and STIs, including HIV, may soon be available. Acknowledgments The authors would like to thank Jim Turpin, Kavita Nanda, Sharon Achilles, Megan Majorowski and Chelsea Polis for their careful review of and feedback on this manuscript. Additionally, this work would not have been possible without the support and valuable insights from Diana Blithe, Gina Brown, Nahida Chakhtoura, Daniel Johnston and Judy Manning. Finally, the authors acknowledge the valuable contributions from IMPT technical consultation participants and other partners in the MPT field in developing the ideas outlined in this manuscript. Disclosure statement No potential conflict of interests was reported by the authors. Funding Support for this work was provided by the American people through USAID under the terms of Cooperative Agreement no. AID-OAA-A The contents of this document are the responsibility of the IMPT and the Public Health Institute and do not necessarily reflect the views of USAID or the US Government. ORCID Bethany Young Holt Laura Dellplain Mitchell D. Creinin Kevin J. Peine Anke Hemmerling References [1] IMPT. MPT product development database; [cited 2017 Oct 11]. Available from: [2] Bustreo F. Ten top issues for women s health; [cited 2017 Dec 20]. Available from: [3] Sedgh G, Singh S, Hussain R. Intended and unintended pregnancies worldwide in 2012 and recent trends. Stud Fam Plann. 2014;45: [4] WHO. 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