The primary purpose of this announcement is to support and facilitate multidisciplinary approaches to the development of new and/or improved contraceptive methods for both men and women through the formation of a Contraceptive Research Center. This FOA also allows the inclusion of translational studies to facilitate the pre-clinical to clinical transition and increase the likelihood of clinical success, and also behavioral and social science research projects to study contraceptive use and non-use of marketed products or products in clinical development. The Center will serve as a national resource for development of early stage investigators electing to pursue careers in contraceptive research.
Since 1994, the Eunice Kennedy Shriver National Institute of Child Health and Human Development NICHD has been directed by federal law to establish three research centers ‘for the purpose of improving methods of contraception’ (42 USC 285g-5).
The objective of this FOA is to develop new or improve existing methods of contraception for men and women using a multidisciplinary approach. This FOA supports method development projects (‘Contraception Development Research Projects’). It also allows the inclusion of translational studies (‘Contraception Translational Research Projects’) to facilitate the pre-clinical to clinical transition and increase the likelihood of clinical success, and behavioral and social science research projects (‘Contraception Behavior Research Projects’) to inform on contraceptive use and non-use of marketed products or products in clinical development. The ideal application must have two or more highly meritorious Contraception Development Research Projects and may integrate behavioral and/or translational projects that together form a scientifically aligned, conceptually integrated and cohesive center focused on the development of new or improved methods of contraception.
The funded Center will be expected to establish or maintain an organizational infrastructure with the scientific and administrative capabilities to support the proposed research.
Applications of high program priority include:
- Applications focused on the late stage preclinical development or clinical development of a single contraceptive product (i.e., drug or medical device);
- Applications for the development of a product (i.e., drug or medical device) which demonstrate current industry interest/support (e.g., advisory).
Contraception Development Research Projects of high program priority are:
- Male or female contraceptive development based on non-steroidal action;
- Non-hormonal multipurpose prevention technology (MPT) products with both contraceptive and anti-infective properties;
- Pre-coital ‘on-demand’ contraception.
Contraception Development Research Projects appropriate for this FOA include, but are not limited to, the following:
- Non-hormonal small-molecule lead discovery and optimization for modulation of validated male or female contraceptive targets (e.g., high throughput screening and virtual screening);
- Development or improvement of vehicles (implants, films, transdermal, etc.) for delivery of non-hormonal contraceptive compounds;
- Clinical trials to assess safety and/or efficacy of new agents with promising contraceptive properties.
This FOA requires that applications include data demonstrating that the mechanism proposed for development is validated. Validation, as defined in this RFA, is the demonstration in a mammalian species that the modulation proposed in the application to achieve a contraceptive effect, whether specific (e.g. antagonism of a single specific enzyme) or non-specific (e.g., sperm motility inhibition by exposure to a high molecular weight polymer) results in contraception. Subfertility is not sufficient to constitute validation. Subfertility, as defined in this RFA, is the generation of live animals from in vivo mating trials and/or an in vivo or in vitro fertilization rate greater than zero.
Validation is not required for applications focused on the development of devices for the delivery of nonhormonal contraceptive agents.
Examples of research projects and acceptable forms of validation:
For applications focused on modulation of defined molecular targets:
Proposed contraception research projects focused on the modulation of specific molecular interactions between an administered molecule (e.g., chemical, antibody) and a defined molecular target(s) (e.g., enzyme, transporter, ion channel) to achieve modulation of the target (e.g., agonism, antagonism) leading to a contraceptive effect (i.e., infertility). Reversibility does not need to be demonstrated to support validation justification for defined molecular targets.
- Examples of validation include but are not limited to:
- Targeted deletion of the gene encoding the target to be modulated, resulting in infertility;
- Development of an antibody that binds specifically to the target and inhibits fertility in a concentration dependent manner in a relevant model (e.g., in vitro fertilization);
- Specific inhibition of RNA corresponding to target to be modulated leading (e.g., vivo morpholinos) to inhibition of gametogenesis or loss of gamete function as demonstrated by histology, mating studies or in vitro fertilization.
For high molecular weight polymers:
It is generally accepted that natural or synthetic high molecular weight polymers that interact with cells and inhibit transport or motility (e.g., sperm motility) act via multiple non-specific binding events. Validation of these molecules requires (1) supporting evidence that their action is mediated by non-specific binding, (2) demonstration that the agent can achieve a contraceptive effect, and (3) lack of observed toxicity at or above the dose and duration of contact expected to be used to achieve contraceptive effect in a relevant model. If in vivo mating studies were used to demonstrate validation for high molecular weight polymers, then reversibility must be demonstrated as part of the validation justification.
- Examples of validation of high molecular weight polymers include but are not limited to:
- Use of the agent in a mammalian animal model resulting in reversible infertility and lack of toxicity;
- Use of the agent to inhibit sperm motility in vitro to a level consistent with reversible infertility at concentrations consistent with expected in vivo use without demonstrated in vivo toxicity at those doses;
- Use of the agent to inhibit in vitro fertilization when the product is at concentrations consistent with in vivo use without demonstrated in vivo toxicity at those doses.
For low weight molecules (<2000 Daltons) with contraceptive properties that do not have an identified mechanism of action:
Demonstration of validation should include (1) that the compound can achieve a contraceptive effect in a relevant model, and (2) a lack of toxicity at the dose and duration of dosing used to demonstrate a contraceptive effect. Reversibility must be demonstrated as part of the validation justification for low molecular weight molecules with contraceptive properties that act via unknown molecular interactions.
- Examples of validation for low molecular weight molecules include but are not limited to:
- Mating studies demonstrating a reversible contraceptive effect in all animals at a defined dose/duration, including pharmacokinetic analysis;
- Toxicological assessment demonstrating a lack of toxicity at the dose/duration resulting in a reversible contraceptive effect in all animals.
For projects focused on the development or improvement of vehicles for delivery of nonsteroidal contraceptive agents:
- Validation is not required for vehicles for the delivery of nonsteroidal contraceptive agents.
There are mechanisms that do not correlate to the examples above. Applicants interested in proposing research not directly aligned with the above examples are encouraged to communicate with the Scientific/Research Contact.
Research topics not responsive to this funding announcement:
Contraception Development Research Projects listed below are not within the scope of this funding announcement. Applications proposing out of scope projects are not responsive to this FOA and will not be reviewed.
- Contraception Development Research Projects not focused on a validated target, validated molecule or a new/improved delivery mechanism;
- Contraception Development Research Projects lacking a clear drug/device development plan;
- Contraception Development Research Projects not focused on the development of a contraceptive product;
- Contraception Development Research Projects based on mechanisms of contraceptive action that may act post-fertilization;
- Contraception Development Research Projects that focus on the development of a product that may act via the oviduct or uterus;
- Contraception Development Research Projects based on the development intrauterine devices/intrauterine systems;
- Contraception Development Research Projects for the development of molecules for female contraception that act via steroid receptors;
- Contraception Development Research Projects focused on female contraceptive methods based on a classical steroidal mechanism of action:
- Contraception Development Research Projects for the development of female contraceptive methods that require the administration of one or more hormones;
- Preclinical Contraception Development Research Projects research projects on male contraceptives that act via a hormonal mechanism (e.g., testosterone, androgen receptor);
- Contraception Development Research Projects focused on male or female condom development;
- Contraception Development Research Projects focused on the elucidation of biological mechanisms unrelated to a defined lead chemical molecule of interest. A lead chemical molecule is defined as a molecule either being evaluated in IND-enabling studies or selected to enter IND-enabling studies; an optimized molecule for development;
- Contraception Development Research Projects focused on target identification unrelated to a validated small molecule;
- Contraception Development Research Projects for the development of the following molecules and/or their chemical derivatives: Gamendazole; H2-Gamendazole; Adjudin; Gossypol; alpha-chlorohydrin;
- Contraception Development Research Projects focused on the development of type I-II kinase inhibitors;
- Contraception Development Research Projects focused on the development of inhibitors of Bromodomain Testis (BRDT)
- Contraception Development Research Projects focused on the development of molecules or devices that disrupt the blood-testis and/or blood-epididymal barriers;
- Contraception Development Research Projects focused on molecular targets for which there is no human ortholog;
- Contraception Development Research Projects focused on the development of a contraceptive product that act by temporary or permanent physical obstruction of the fallopian tubes;
- Contraception Development Research Projects to determine prospective patient/consumer preferences on theoretical product designs except as a specific aim of a Contraception Development Research Project;
- Contraception Development Research Projects focused on target validation, although this research may be supported by the pilot program described under ” Center Description” below.
Contraception Translational Research Projects for this FOA must be focused on one or both of the
- Contraception Translational Research Projects in support of late stage pre-clinical or early stage clinical programs to identify, validate or evaluate pharmacodynamic, target interaction, patient efficacy, patient safety or side effect biomarkers;
- Contraception Translational Research Projects for the identification and/or validation of novel models (laboratory, animal) to predict clinical efficacy.
Contraception Behavior Research Projects must be aimed at improving understanding of contraceptive acceptance/use/discontinuation and must be based on actual use of marketed products or products in clinical development. Contraception Behavior Research Projects should be motivated by and explicitly designed based on a theory of human behavior and behavior change. Examples of research projects include, but are not limited to, the following:
- Integration of existing research on the needs and expectations of women and men who report having had unintended pregnancies into the development and improvement of contraceptive research;
- Follow-up studies of clinical trials to identify the characteristics and behaviors of study participants who discontinue or are non-compliant with contraceptive methods;
- Studies to identify the specific characteristics of contraceptive products—e.g. dosing or application processes, texture, or side effects—that affect discontinuation or ineffective and/or inconsistent use of contraceptive products and examination whether reactions to specific characteristics of products differ by demographic and socioeconomic status;
- Identification of characteristics of contraceptive products that affect the ratio between the actual use Pearl Index and the perfect use or clinical trial Pearl Index; identification of characteristics of contraceptive product users that are associated with low effectiveness in actual use.
The following areas of Contraception Behavior Research Projects are not responsive to this funding announcement and are not responsive to this FOA and will not be reviewed:
- Re-analyses of extant data sets examining the determinants of contraceptive use in general, or the collection of new data for that purpose;
- The use of clinical or convenience samples to examine contraceptive use except when the goal is to examine the use of one specific contraceptive product with the aim of improving the acceptability of that particular product;
- Research that focuses solely on attitudes on contraceptive products is not responsive. However, research that focuses primarily on behavior but includes analysis of attitudes as they relate to behavior, is within the scope of this announcement.
The Center must include a mandatory Administrative Core and a minimum of three and maximum of four research projects. There must be at least two Contraception Development Research Projects. Funds to support one- to two-year optional pilot projects, focusing on contraception development (including validation), translational medicine or contraception behavior, may be provided as part of the Administrative Core. Technical Service Cores that support and enhance the research projects are optional.
A Center must build its overall research strategy on a scientific theme of contraception method development. If Contraception Behavior Research Projects or Contraception Translational Research Projects are proposed, they must integrate with the other projects to form a scientifically-aligned, conceptually-integrated and cohesive center focused on the development of new or improved methods of contraception. Centers can have an unlimited number of consortium agreements with institutions or organizations outside of their applicant institutions to incorporate sufficient expertise for an effective multidisciplinary approach to contraceptive research. The ultimate result should be a Center where the best and most innovative science for contraceptive discovery, development and usage will be pursued.
Technical Service Cores may be proposed. Examples of optional cores include, but are not limited to, the following:
- Medicinal chemistry core
- Chemical screening core
- Animal facility core
- Protein production core
Optional cores may be designated as closed access structure or open access
- Closed Access Structure: In this center structure, administrative and all technical service cores will be utilized by budgeted center projects only. Utilization by at least two research projects is required to justify a closed Technical Service Core facility. Percent utilization by either of the research projects justifying the core may not exceed 70 percent. No internal charge-back system is required.
- Open Access Structure: In this center structure, budgeted center research projects, as well as research projects from other Contraception Research Centers (CRCs) or laboratories within or outside of the institution may have access to Technical Service Cores. If the Center chooses to operate in an open access format, the PD/PI must have in place management policies that ensure that budgeted center research projects are given highest priority in receiving services provided by the core. In addition, a plan for fair and open access is needed for how the resource, when not in use by Center projects, will be made available to others, including an effective charge-back system. The Center must establish an internal management policy for evaluating the acceptability of proposed projects from other CRCs laboratories or laboratories within or outside of the institution to access the core facilities.
- If the Center chooses to use an open access format, it may also propose one or more technical service cores that will be utilized exclusively by budgeted center research projects. The Center, therefore, may have a mix of open and closed access technical service cores, i.e., in a closed access structure. The administrative Core in open structures may be accessed only by budgeted Center Projects.
- A Center configured as a closed access structure may, at a later time, choose to convert to an open access structure upon approval after requesting such conversion in writing to NICHD.
Other Center Requirements:
- The PD/PI must have sufficient experience, skills, and competence to oversee cooperation within the Center and across funded Centers.
- The Leads of the individual components must have sufficient experience, skills, and competence to oversee the research projects, cores, and core facilities.
- Technical resources and facilities for the conduct of the proposed projects must be available, including appropriate animal facilities.
- The applicant institution must offer an environment that is conducive to the development of early stage investigators in the field of contraception research.
- The Center must have strong departmental and institutional support and commitment.
Cooperative Agreement Structure:
The Center funded through this FOA will be expected to work cooperatively and engage in a coordinated research program involving two or more Centers with multiple interacting research projects, research support cores and core facilities. The Center Directors will work together to facilitate research efforts, as required by research goals of the funded projects.
The research priorities and metrics for success of the projects within the approved research scope will be established after discussions between the awardee and the NICHD Program Staff. Outside consultants/experts may be asked to participate in these discussions. Once priorities have been agreed upon, the awardee will assume the responsibility for implementation of research activities. The awardee and NICHD Program Staff will interact throughout the duration of the award to facilitate progress and resolve any problems that may arise.
PDs/PIs may sub-contract portions of their research they are not able to conduct at their facility or institute to outside vendors (e.g., animal studies, protein production, high throughput screening, medicinal chemistry and x-ray crystallography). Applicants interested in subcontracting facilities must obtain agreement in advance, provide for the services in the budget, and include letter(s) of support in the application. Applicants who desire assistance in identifying subcontractors for animal studies or drug development services are advised to consult the NICHD Program Official.
Deadline: February 13, 2019 (letters of intent due 30 days prior to deadline)
Filed Under: Funding Opportunities