The Opportunity
Family planning is one of the most cost-effective ways to reduce maternal, infant and child mortality and contributes to the empowerment of women and families and the expansion of opportunities for economic development. In recent decades, there have been tremendous improvements in the reproductive health of women and men in the developing world. Nonetheless, it is estimated that over 225million women in developing countries have an unmet need for effective contraception. While improving access to existing methods of contraception through program implementation is a critical pillar in efforts to reach women and address their family planning needs, technical and scientific developments in the areas of reproductive biology, endocrinology, and fertility suggest that there are also opportunities for innovation in products that would better meet women’s and couples’ reproductive needs and desires. In particular, novel methods could either address liabilities associated with current products or create entirely new types of products to meet a variety of user needs that are unaddressed by current methods.
Current contraceptive methods for women include exceptionally safe and effective options. However, not all methods are suitable for all women, and concerns about undesirable side effects remain a significant barrier to greater uptake and continued use of existing methods. As a result, women who desire to avoid pregnancy often find themselves without viable options, as seen consistently across different populations. In particular, changes in uterine bleeding patterns, either heavy bleeding, breakthrough bleeding, irregular bleeding, or amenorrhea, are associated with hormonal contraceptive methods, predominantly progestin-only methods, and contribute to high discontinuation rates for these methods (up to 40% in the first year of use for some methods) due to inconvenience, or social or religious norms and taboos. Additionally, some women have medical contraindications that prevent their use of hormonal contraception and are left with very limited options. While the concept of developing a non-hormonal pharmaceutical contraceptive modality which may have a better tolerability profile and serve as a suitable alternative to hormonal methods has been promoted through a number of research efforts and publications, such a discovery effort has not yet been reduced to practice. An alternative or complementary option for family planning includes participation of men and studies have shown that men from a number of different geographies express a willingness to use contraception, if available. However, male methods of contraception are limited to condoms, withdrawal or vasectomy; no pharmaceutical contraceptive agent currently exists for men.
As approaches to discovery of new drugs for other indications have become increasingly sophisticated, these advances have not been applied to field of contraceptives. A number of key technical barriers exist that hamper progress in this area. These include, but are not limited to:
- Lack of appropriate medium- to high-throughput phenotypic screening methodologies for identifying compounds capable of exerting a potent contraceptive effect;
- Poor understanding of contraceptive drug targets associated with key fertility pathways, and a lack of validated and scalable approaches to validate and assay potential targets;
- The inability to appropriately replicate in the laboratory a number of complex multi-cellular reproductive processes for the purposes of compound screening (e.g. ovulation, sperm maturation);
- Lack of appropriate preclinical assays (in vitro or in vivo) to assess the potential side effects of novel agents.
The Challenge
While access to a range of appropriate and desirable contraceptive methods can have a broad beneficial impact on the lives of women, men and their families, this goal is currently not being achieved. As part of a comprehensive approach to addressing the unmet need for contraception, we believe that innovative new methods, particularly those that address shortcomings of existing methods, have the potential to dramatically improve access, method uptake, use, and satisfaction. Given the relative lack of attention and funding this area historically has received, the tools and assays that would enable significant progress in this area remain underdeveloped. This call is seeking new approaches that can address these technical barriers and accelerate contraceptive drug discovery. A number of options exist (see below), but applications should focus on developing and validating tools and platforms that would enable drug discovery and how those may be broadly applicable, rather than on discovering and characterizing specific compounds, as the latter would be outside the scope of this GCE call.
What we are looking for:
This call is soliciting concepts for contraceptive discovery platforms that can contribute to development of new methods suitable for women or men living in limited resource settings. Such platforms will be essential to support the foundation’s efforts to develop new methods that would be safe and effective for long-term regular use, in the form of injectables, implants, or regular oral contraception. We are not looking for new injectable formulations or implants using existing agents, nor are we looking for methods that could only practically lead to intermittent “on-demand” or pericoital use (e.g., vaginal gels). Proposed research plans should align with this goal. Importantly, research proposed for funding should not be focused on a particular experimental agent, but rather on development and validation of a set of tools and technologies to address technical limitations in this field and that could be subsequently applied to a broader drug discovery and development program. While research related to a specific drug target or target class may be warranted if justification is provided, applications with a broader scope will be viewed favorably.
A few of the many potential examples to be considered include:
- Development of in vitro phenotypic screening methods that recapitulate key female or male reproductive processes (e.g. ovulation, follicular maturation, sperm maturation).These need not be immediately suitable for a high-throughput format, but should be focused on assays that would minimally enable screening of small compounds libraries;
- Scale up and/or automation of existing laboratory assays for medium- to high-throughput and validation on a well-characterized pilot compound set or biological probe compounds;
- Development of low-throughput in vivo screening methods using native or modified (transgenic, knockout) model organisms (e.g. zebrafish, C. elegans) to interrogate compound activity against key reproductive processes;
- Development and validation of biochemical or other target-based assays, based on a clear explanation of why the proposed female or male target(s) would be viable and high value for contraceptive discovery;
- Development of PK/PD approaches, including small animal models and in silico modeling, to enable rational medicinal chemistry;
- Identification of methods to identify adjuvant compounds that could be co-formulated with existing hormones to mitigate undesirable side effects;
- Development of preclinical in vitro or in vivo models to predict side effects (e.g., endometrial bleeding, testicular toxicity) associated with contraceptive agents
- Development of tractable and relevant in vitro and small animal models of spermatogenesis and epididymal function
We will not consider funding for:
- Applications focused on fundamental reproductive biology research;
- Applications to support the development of a specific agent, rather than development and validation of a broader platform for contraceptive discovery; use of agents for chemical validation of such platforms, however, would be desirable;
- Approaches suitable only for the development of vaginal contraceptives or barrier methods;
- Approaches based on immuno-contraception, contraceptive vaccines, or antibody-based approaches;
- Approaches focused on post-fertilization contraception
- Solutions that are not applicable to the developing world setting
- Exclusively non-technological, social interventions;