and Human Services (HHS)
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Participating Organization(s) |
National Institutes of Health (NIH) |
NIH Blueprint for Neuroscience Research National Eye Institute (NEI) |
|
Funding Opportunity Title |
NIH Blueprint for Neuroscience Research Grand Challenge: Developing Novel Drugs for Disorders of the Nervous System (U01) |
Activity Code |
U01 Research Project Cooperative Agreements |
Announcement Type |
Reissue of RFA-NS-11-002 |
Related Notices |
|
Funding Opportunity Announcement (FOA) Number |
RFA-NS-12-002 |
Companion FOA |
None |
Catalog of Federal Domestic
Assistance (CFDA) Number(s) |
93.213, 93.389, 93.867, 93.866, 93.273, 93.286, 93.865, 93.173, 93.121, 93.279, 93.113, 93.859, 93.242, 93.853, 93.361 |
FOA Purpose |
The National Institutes of Health (NIH) announces a unique opportunity for investigators working with small molecule compounds to gain access to a robust virtual pharma drug development network to develop neurotherapeutic drugs. Successful applicants to this FOA will become collaborative participants in this network, receiving both funding and no-cost access to contracted drug development services that are not typically available to the academic research community. Funding will be provided through a U01 cooperative agreement mechanism to conduct biological testing of compound analogs in disease assays and models in the investigator s laboratory. No-cost drug development services will also be provided, including medicinal chemistry optimization, IND-directed pharmacology and toxicology, and Phase I clinical testing. Researchers in possession of disease assays and small molecule compounds that show promise for treating nervous system and psychiatric disorders, but that are not yet suitable for clinical testing, are strongly encouraged to apply. |
Posted Date |
March 16, 2011 |
Open Date (Earliest Submission Date) |
May 10, 2011 |
Letter of Intent Due Date |
May 10, 2011 and November 15, 2011 |
Application Due Date(s) |
June 10, 2011 and December 15, 2011, by 5:00 PM local time of applicant organization. |
AIDS Application Due Date(s) |
Not Applicable |
Scientific Merit Review |
September, 2011 and April, 2012 |
Advisory Council Review |
January, 2012 and May, 2012 |
Earliest Start Date(s) |
April, 2012 and July, 2012 |
Expiration Date |
December 16, 2011 |
Due Dates for E.O. 12372 |
Not Applicable |
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission
Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
Many devastating disorders affect the nervous system, including neurological diseases, psychiatric disorders, age-related dementias, developmental disorders, visual and hearing loss, chronic pain, alcohol dependence, and drug addiction. In 2010, the sixteen NIH Institutes, Centers, and Offices that comprise the NIH Blueprint for Neuroscience Research announced a Grand Challenge for Neurotherapeutics to address the paucity of effective treatments for disorders of the nervous system (http://neuroscienceblueprint.nih.gov/blueprint_basics/about_blueprint.htm). A long-term goal is to produce at least one novel and effective medication for a disorder of the nervous system that is currently poorly treated or untreatable.
Recent advances in neuroscience offer unprecedented opportunities to discover new treatments for nervous system disorders. However, most promising compounds identified through basic research are not sufficiently drug-like for human testing. Before a new chemical entity can be tested in a clinical setting, it must undergo a process of chemical optimization to improve potency, selectivity, and drug-likeness, followed by pre-clinical safety testing to meet the standards set by the Food and Drug Administration (FDA) for clinical testing. These activities are largely the domain of the pharmaceutical industry and contract research organizations, and the necessary expertise and resources are not commonly available to academic researchers.
To enable drug development by the neuroscience community, the NIH Blueprint for Neuroscience Research is establishing a virtual pharma network of contract service providers and consultants with extensive industry experience. This Funding Opportunity Announcement (FOA) is soliciting applications for U01 cooperative agreement awards from investigators with small molecule compounds that could be developed into clinical candidates within this network. This program intends to develop drugs from medicinal chemistry optimization through Phase I clinical testing and facilitate industry partnerships for their subsequent development. By initiating development of up to 20 new small-molecule compounds over two years (seven projects were launched in 2011), we anticipate that approximately four compounds will enter Phase 1 clinical trials within this program.
To be accepted into the network, applicants to this FOA must have in hand the starting compounds for chemical optimization and bioactivity assays for testing new analog compounds generated through the Blueprint Neurotherapeutics drug development network (see Entry Criteria below for more details). Successful applicants under this FOA will receive 1) funding for biological assessment of compounds in their laboratories, 2) no-cost access to drug development resources that typically reside in the pharmaceutical industry, including iterative medicinal chemistry optimization, pharmacokinetics, toxicology, manufacture and formulation services, and Phase I clinical safety testing and 3) strategic guidance from experienced drug development consultants, identified by NIH. The budget of the U01 application will support only the work in investigators laboratories, which will involve testing of compounds in biological assays and models related to the target disorder.
Each drug development project will be directed by a collaborative Lead Development Team, co-chaired by the U01 investigator and a consultant with extensive industry expertise identified and supported by the NIH Blueprint for Neuroscience Research. The team will also include consultants with additional expertise, supported by NIH, and NIH staff. Work will be guided by this team, with oversight from the Blueprint Neurotherapeutics Steering Committee and, ultimately, the NIH Blueprint for Neuroscience Research Institute and Center Directors.
This program is structured to allow the principal investigators' institutions to retain ownership of intellectual property for compounds developed within the network. The principal investigators' institutions therefore assume responsibility for the ultimate commercialization of compounds developed through this effort.
To be eligible for the Blueprint Neurotherapeutics Network, a project must focus on a nervous system condition that falls within the mission of one of the Blueprint Institutes or Centers (http://neuroscienceblueprint.nih.gov/blueprint_basics/about_blueprint.htm). Applicants must have available small-molecule compounds with strong evidence of disease-related activity and the potential for optimization through iterative medicinal chemistry. Applicants must also be able to conduct bioactivity and efficacy testing to assess compounds synthesized in the development process and provide all pre-clinical validation for the desired disease indication. The entry criteria for the Blueprint Neurotherapeutics Network are detailed below.
1. Biological Rationale
Compounds entering the program must be well-supported by biological data that is sufficiently compelling and rigorous to justify the initiation of a multi-million dollar drug development effort. However, it is not necessary to know the precise molecular mechanism of action of the compound; for the purposes of this FOA, a 'drug target' may be defined as a specific molecule, pathway, or cellular phenotype.
Applicants must provide compelling biological rationale for their proposed therapeutic strategy, including:
2. Compounds Proposed for Development
An application may propose development of more than one chemical scaffold, provided that the same testing strategies and assays are utilized for all of the proposed scaffolds. To be suitable for medicinal chemistry optimization, compounds proposed for entry into the Blueprint Neurotherapeutics Network should possess the following attributes:
Compound structure. The compound must be of a size and structure that can be readily synthesized and chemically modified. This program is not designed to support the development of biologics, including oligonucleotides and proteins, or the iterative optimization of complex natural product scaffolds. Small peptides of fewer than ~6 amino acids may be acceptable; applicants should contact NIH program staff regarding small peptides and other complex chemical structures to determine suitability for optimization within the network.
Activity in primary and secondary/confirmatory assay(s). For biochemical assays, compounds generally should show activity at 1 M or below. For cell-based assays, an IC50 or EC50 of <10 M is desirable. Activity in the primary screening assay should be confirmed by repeat dose-response testing.
Determination of identity and purity. The starting compound(s) should have proof of identity and purity (typically >90%, as determined by, e.g., NMR, melting point, or LC/MS) and biological activity should have been demonstrated with more than one batch of compound.
Compound target selectivity. In cases where the molecular target of compound action is known, the applicant should demonstrate the degree of selectivity for the intended target over closely related targets. Counter-screening to determine selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is desirable, but not required.
Solubility. Compounds should have reasonable aqueous solubility, typically >1 g/mL at pH7.4.
Structure-activity relationship (SAR). Demonstration that chemical analogs of a proposed compound show similar biological activity is desirable but not required. Limited SAR information may have been derived from activity of analogs in a screening library or from testing of commercially available analogs.
3. Proposed Assays
This initiative is not intended to support development of new bioactivity assays, thus the applicant must have in hand well-characterized assays and models. Applicants should have three types of assays that can form the basis of a bioactivity testing funnel: 1) a moderate throughput primary screening assay, 2) one or more secondary assays for confirmation of activity and potential efficacy and 3) counter screening assays for target selectivity, where necessary. The testing funnel must include at least one cell-based assay. For each type of assay, the parameters that should be discussed in the application are outlined below.
Primary screening assay. This must be an assay with moderate throughput or better, e.g., a reporter assay, which will be used to perform routine weekly screening of compounds synthesized for iterative medicinal chemistry. To inform the medicinal chemistry design, the assay must be sufficiently robust and reproducible to reliably rank compounds with similar activities. The primary screening assay should meet the following criteria:
Secondary confirmation assays. The applicant must have one or more secondary assays with sufficient biological validation and reproducibility to confirm the activity of compounds identified in the primary assay and demonstrate potential efficacy in the target disorder. These may be low to moderate throughput assays. Ideally, at least one secondary assay would be capable of generating dose-response data for multiple compounds simultaneously.
Selectivity and counter-screening assays. Where the molecular target of drug action is known, e.g., a particular kinase, it may bear similarity to other cellular targets. In these cases, the applicant should describe criteria for compound specificity for these targets and propose a strategy for using screening assays to determine that specificity. Where aspects of the screening approach are prone to unwanted activities or artifact, or mechanism-based or compound-based side effects are anticipated, counter screens should be proposed to rule out these unwanted activities. Proposed counter-screening and selectivity assays should have demonstrated reliability and adequate throughput for their proposed use in the development program.
Directing compounds through the drug development pipeline will be a collaborative effort. After award, a Lead Development Team (LDT) will be formed to collaboratively manage and coordinate the progress of compounds through the development pipeline. The team will be co-chaired by the U01 investigator and a drug development consultant identified and supported by the Blueprint Neurotherapeutics program. The team will include other consultants as needed at each stage of the project to advise on chemistry, biology and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) study design and interpretation. The first responsibility of the Lead Development Team will be to establish a drug development plan involving the Blueprint Neurotherapeutics Network contractors. This plan will define activities and advancement criteria for a series of stages through which compounds will progress during development.
This section outlines the stages and timeline of work that will be conducted throughout the development pipeline, beginning with the entry of a well-characterized hit compound and ending with a novel candidate drug with demonstrated safety in humans. This section also outlines the roles of the NIH Blueprint Neurotherapeutics Network and the U01 investigator in each stage of the pipeline.
1. Exploratory chemisty/feasibility (for budget purposes, assume 6 months). Each project will undergo a feasibility phase in which investigators will validate their primary screening assays for SAR studies and test a collection of approximately 50-100 chemical compound analogs. These will be supplied to the investigator by NIH Blueprint Neurotherapeutics contractors. Work in this phase will be directed toward determining whether the compounds and assays are amenable to medicinal chemistry optimization. If ADMET properties of the parent compound have not been characterized at the time of submission, preliminary studies of PK and toxicological properties also will be conducted during this phase.
2. Medicinal chemistry optimization (for budget purposes, assume 2 years). If the outcomes of the feasibility studies are successful, compounds will enter a full-scale, iterative medicinal chemistry optimization phase to improve bioactivity, potency and pharmacological properties. This process of understanding the structure activity relationship (SAR) between the compounds and the desired drug properties typically requires dozens of rounds of compound synthesis and testing. The ultimate goal of the SAR effort is selection of a pre-clinical candidate compound with sufficient bioactivity and drug-likeness to proceed to IND-directed pre-clinical safety assessment.
The major role of the U01-funded investigator in this process is to conduct primary biological assessment of compounds on a regular, one-to-two week schedule to inform the design of subsequent iterations of compound synthesis. In addition to a regular testing schedule in the primary assay, the PD/PI will provide confirmation of the activity of select compounds in secondary assays and possibly animal models relevant to the drug target.
NIH Blueprint Neurotherapeutics contractors will produce compound analogs for SAR testing and provide standard screening services to assess in vitro and in vivo ADMET characteristics of the compounds.
In the first year, medicinal chemistry will be in a hit-to-lead phase, focusing heavily on optimizing activity and potency of compounds in the primary and secondary disease assays. In the subsequent lead optimization phase, SAR will increase emphasis on ADMET properties of the compounds, with continued monitoring and optimization of bioactivity. If compound testing in in vivo animal models is proposed, this should be limited to testing a small number of selected advanced compound analogs (e.g., 3) in year 3.
3. IND-enabling studies (for budget purposes, assume 1.5 years). If a therapeutic candidate is identified which meets the target criteria for activity, efficacy, and favorable physicochemical and ADMET properties, it will move into IND-directed pharmacology and toxicology studies. Blueprint Neurotherapeutics contractors, with direction from the Lead Development Team, will conduct the preclinical safety studies, GMP synthesis, formulation and other activities required to ready a compound for human testing. Blueprint Neurotherapeutics contractors will provide data and reports in a format suitable for inclusion in an IND application and will assist in the development of the application. The U01 investigator will be responsible for the submission of the IND application and scheduling meetings with the FDA.
4. Phase I clinical trial (for budget purposes, assume 1 year). Once an IND has been submitted successfully to the FDA, a Phase I clinical trial, typically in healthy volunteer subjects, will be conducted by a Blueprint Neurotherapeutics contractor. The development of the protocol and conduct of the trial will involve input from a Clinical Development Team, which will include the U01 investigator, clinical consultants identified by the NIH, and Blueprint Neurotherapeutics staff. Costs associated with the conduct of clinical trials will be supported outside the U01 and should not be included in the requested budget. In most cases, Phase I human studies will be conducted under a contract in the NIH Blueprint Neurotherapeutics Network.
Because drug development is an inherently high-risk process, it is anticipated that there will be a significant attrition rate as projects move through the pipeline. Go/No-Go milestones will be agreed upon at the start of each project and, in consultation with the Lead Development Team, investigators will produce milestone progress reports for independent evaluation by the Blueprint Neurotherapeutics Steering Committee. Please note that milestones do not need to be proposed in the application.
If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project and access to Blueprint Neurotherapeutics contract resources may be discontinued unless an additional source of funding is identified (see section VI.2.)
Since the ultimate goal of the Blueprint Neurotherapeutics Network is to bring new drugs to the market, the creation and protection of appropriate intellectual property is a significant consideration in designing research strategies and prioritizing projects for funding. This program is structured so that the U01 awardee institution can gain assignment of intellectual property rights (and thereby control the patent prosecution and licensing negotiations) for drug candidates developed through the Blueprint Network. The goal is for the U01 awardee institution to take responsibility for patent filings and licensing toward eventual commercialization.
To this end, the NIH has structured the medicinal chemistry contract to ensure that the U01 institution will receive assignment of rights to inventions for analogs and methods of use of such analogs, generated through the chemistry contract, that are directly related to the U01 institution's starting materials. In addition, the U01 institution will retain its proprietary rights in its starting materials. Inventorship will be governed by U.S. patent law, so that contractor chemists will be listed as inventors on patents, as appropriate. However, the contracted chemists must abide by the royalty-distributing policies of the U01 PD/PI's institution. The medicinal chemistry contractors will retain ownership of inventions on methods of manufacturing or synthesis but must provide broad licenses to the U01 PD/PI's institution to enable subsequent development of drug candidates. Drug development consultants hired by the NIH must agree to an intellectual property arrangement with the U01 PD/PI's institution before advising on the project.
The intellectual property position of each project will be evaluated at multiple points throughout the program. Each U01 application is expected to address intellectual property issues related to the proposed compounds and assays, with input from the institution's technology transfer officials. Peer reviewers will be instructed to comment on the intellectual property landscape for each U01 application, and the NIH may assess the feasibility of developing chemical analogs with a strong intellectual property position prior to making U01 awards. This evaluation may include patent searches on chemical structures similar to that of the proposed parent compound. The project milestone plan will include commercialization milestones to protect and leverage intellectual property developed through the Network. Recipients of U01 awards will be encouraged to identify potential licensing and commercialization partners early in the drug development process. The U01 PD/PI is expected to work closely with technology transfer officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner.
Funding Instrument |
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities. |
Application Types Allowed |
New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types. |
Funds Available and Anticipated Number of Awards |
The participating ICs intend to commit up to $2,325,000 in FY 2012 to fund up to 13 awards. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.. |
Award Budget |
It is anticipated that funded projects will carry direct costs of up to $125,000 per year for in vitro and/or in vivo bioactivity screening. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. |
Award Project Period |
Project duration can be up to five years; budgets should be appropriate for the proposed work. The actual duration of individual projects will depend on successful achievement of milestones as described in this FOA. |
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions:
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For profit Organizations
Governments
Other
Foreign (non-U.S.) components of U.S. Organizations are allowed.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.
All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.
All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least four (4) weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple
Program Director/Principal Investigator Policy and submission details in the Senior/Key
Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
Descriptive title of proposed research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity
The letter of intent should be sent to:
Jill Heemskerk, Ph.D.
Office of Translational Research
National Institute of Neurological Disorders and
Stroke
6001 Executive Boulevard
Neuroscience Center/Room 2229
Bethesda, MD 20892
Telephone: 301-496-1779
Email: jill.heemskerk@nih.gov
The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for application submission. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
This section of the application should address the following intellectual property issues. Applicants are encouraged to prepare this section of the U01 application in consultation with their institutions' technology transfer officials.
Intellectual property considerations for small molecule compounds proposed for development. Applicants should describe the intellectual property landscape surrounding their starting compounds, to the extent that they are aware, and demonstrate the potential for developing chemical analogs with a strong intellectual property position. Applicants should describe any constraints of which they are aware that could impede the development of analogs of their starting compounds (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues could be addressed.
Intellectual property considerations for primary and secondary assays. Applicants should describe any constraints of which they are aware of that would impede use of the assays and models for research purposes and/or commercial development.
Intellectual property management and commercialization. Applicants should describe their institutions existing or planned infrastructure for bringing the compounds to practical application (e.g., licensing for further drug development, managing intellectual property, commercializing discoveries) consistent with achieving the program goals. For a multiple-PIPD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing intellectual property) among the institutions consistent with achieving the goals of the program. Applicants should clarify how intellectual property will be shared or otherwise managed if there are multiple PIPD/PIs and institutions involved in the U01-supported work.
The U01 award is intended to support the disease-focused biology studies proposed by the principal investigator. The U01 budget may not support drug development activities that will be conducted through Blueprint Neurotherapeutics contracts (e.g., chemistry, pharmacology, toxicology, regulatory activities and clinical testing). The U01 budget may include one or two trips per year to attend meetings of the Blueprint Neurotherapeutics Network Steering Committee. Equipment requests are allowed but not encouraged. Equipment requests should be considered only if the equipment is absolutely necessary to the success of the project and cannot be supported by any other means. This is likely to be a subject of negotiation before an award is made.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Specific Aims
The Specific Aims section should focus on the goals of medicinal chemistry optimization and the biological work to be conducted under the U01 grant. Activities that could be captured as specific aims include, but are not limited to:
Research Strategy
The Research Strategy section should include the following subsections:
Note that protection of human subjects need not be addressed in the U01 application, as phase I clinical trials will be conducted under an independent contract.
Clinical Impact and Feasibility: Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication. Briefly discuss available treatments and their limitations. Discuss how the proposed drug development project relates to therapeutics development efforts underway in academia and industry. Provide a Summary of Key Drug Characteristics that shows the ultimate goals of the proposed drug development effort (see guidance and table template at: http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm). This summary table should indicate the target patient population; the mode, duration and frequency of drug delivery; and standards for clinical efficacy. Explain the rationale for the minimally acceptable and ideal results. Briefly comment on the feasibility of conducting clinical trials toward these goals (e.g., availability of clinical trial networks). Identify any collaborators with clinical expertise.
Please note that each application should focus on only one disorder or disease, even if the compound proposed for development shows activity in models for more than one disorder. This is because the target patient population and intended use guides the design of the drug and of the preclinical studies, such as toxicology and formulation.
Biological Rationale: Describe the intended molecular or cellular drug target. Provide the evidence that links this target to disease progression and/or outcomes for the proposed disease indication. Provide the preclinical "proof-of-concept" data that shows the activity of the compounds proposed for development in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of model and endpoints for the proof-of-concept studies. Provide the evidence that a compound's observed activity in disease models is due its effects on the putative target. If therapeutics that target the same molecule, pathway, or cellular process have been tested in clinical trials for the proposed disease indication, explain why the proposed approach would be expected to give significantly better clinical outcomes.
Compounds Proposed for Development: Address each of the compound entry criteria presented in Section I.B. of this FOA. Include data on compound activity and potency (EC50 or IC50) in biochemical and cellular bioassays. In addition to chemical structures, information should be provided on known chemical and physical characteristics of the compound(s), e.g., drug-like properties, solubility, chemical liabilities, etc. Present the results of testing any chemical analogs and inferences about structure activity relationships (SAR). If drugs with similar structures have been tested in clinical trials for the proposed disease indication, explain why the proposed drug would be expected to give significantly better clinical outcomes.
Proposed Assays and Screening Strategy: Provide a Summary Table of Bioactivity Assays (see table template at http://neuroscienceblueprint.nih.gov/bpdrugs/apply.htm) proposed for medicinal chemistry SAR studies and to validate the preclinical efficacy of optimized compounds. This table should indicate the throughput for each assay and advancement criteria for progressing compounds from one assay to the next. Explain the rationale for the choice of models, assay design, and advancement criteria, and clarify how these relate to the desired drug properties presented in the Summary of Key Drug Characteristics. Provide data demonstrating that the proposed assays meet the entry criteria presented in section I.B. of this FOA. Provide data demonstrating correlation of results from one tier of assays to the next. Describe plans for counter-screening to address selectivity concerns and anticipated side-effects due to the compound structure or mechanism of action. Describe any potential pitfalls associated with the use of the proposed assays and approaches to their resolution.
Management Plan: Describe the roles and extent of participation of key personnel over the course of the small molecule development process, from compound optimization through Phase I clinical trials. Indicate the willingness of the PD/PI and key personnel to operate under the cooperative agreement terms and conditions outlined in section VI.2. of the FOA. If needed, describe the availability of a clinical consultant with expertise in the target disorder. Clinical experts should be sought as needed to develop the application (e.g., to determine the Summary of Key Drug Characteristics), and available after award to aid in determining the goals of the drug development program and to consult on the design of the clinical trial.
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the SF424 (R&R) Application Guide, with the following modifications:
Appendix
Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide..
Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.
Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
Important
reminders:
All PD/PIs must include their eRA Commons ID in the Credential
field of the Senior/Key Person Profile Component of the SF 424(R&R) Application
Package. Failure to register in the Commons and to include a valid PD/PI
Commons ID in the credential field will prevent the successful submission of an
electronic application to NIH.
The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.
See more
tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed. To be considered responsive, applications must focus on a disease or disorder that falls within the mission of at least one Blueprint-member Institute or Center, the application must propose development of a small molecule compound, and the applicant must have the proposed bioactivity assays in hand.
In order to expedite review, applicants are requested to notify the NINDS Referral Office by email at nindsreview.nih.gov@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115, with the following modifications:
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
For this particular announcement, note the following:
The market size for the proposed drug will not be considered in assessing the significance of a project.
Evaluation of the approach should focus primarily on the rationale and strengths/weaknesses of proposed bioactivity studies and compound "druggability," since all other drug development work (e.g., medicinal chemistry, PK/tox, phase I clinical testing) will be designed and implemented by NIH-provided consultants and contractors after award.
Milestones will be developed after award, in collaboration with NIH-provided consultants. Applicants are not expected to propose milestones. If milestones are included in the application, reviewers may comment on them, but milestones may not be considered in scoring the application.
Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? In particular, how would achievement of the goals laid out in the Summary of Key Drug Characteristics affect clinical practice for the proposed disease indication?
Investigator(s)
Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Recognizing that the NIH does not require the applicant to have drug development expertise, is the experience with biological testing sufficient to support and inform a drug development effort? Is there sufficient clinical expertise to define the goals of the drug development effort for the intended disease indication?
Innovation
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Is the drug target or therapeutic strategy sufficiently different from ongoing drug development programs in industry and academia? Would the proposed drug be expected to give significantly better clinical outcomes than have been observed for previously developed drugs with similar structures or targets?
Approach
Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?
Based on the evidence provided, is it reasonable to believe that a drug that meets the proposed advancement criteria for each of the proposed bioactivity assays could achieve the desired clinical outcomes described in the Summary of Key Drug Characteristics? In other words, is there a strong biological rationale for the choice of drug target, disease models, and assay design? Do the proposed compound(s) and bioactivity assays meet the entry requirements for the Blueprint Neurotherapeutics Network?
Environment
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their participation
according to the following five review criteria: 1) risk to subjects, 2)
adequacy of protection against risks, 3) potential benefits to the subjects and
others, 4) importance of the knowledge to be gained, and 5) data and safety
monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable
Renewals
Not Applicable
Revisions
Not Applicable
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
Intellectual Property
Reviewers may comment on the intellectual property landscape for the project and note any intellectual property constraints that potentially could impede drug development and/or commercialization.
Applications from Foreign Organizations
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NINDS , in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NIH Blueprint institutes contributing the funds for those awards. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to the DUNS,
CCR Registration, and Transparency Act requirements as noted on the Award
Conditions and Information for NIH Grants website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Cooperative Agreement Terms and Conditions of Award
The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
Areas of Joint Responsibility include:
Project Lead Development Team (LDT): The LDT will be co-chaired by the PD/PI and an NIH-contracted drug development consultant and will include additional members from the PD/PI’s group, consultants and NIH staff. This team will collaboratively set strategic direction and guide the work flow for the project on an ongoing basis. The LDT will meet every two weeks via teleconference to analyze and interpret data from the PD/PI and contracted laboratories and to formulate the subsequent experimental plan. The team will produce progress reports for evaluation by the BPN Steering Committee and BPN Project Team as needed.
BPN Steering Committee: The Steering Committee will be responsible for reviewing and evaluating the progress of the BPN projects in meeting their milestones and goals, and making recommendations about individual projects to the BPN Project Team and the NIH Blueprint Directors Committee (the Directors of the Institutes and Centers that comprise the Blueprint). The Steering Committee will be composed of 6-8 senior non-federal scientists who are not directly involved in the activities of the BPN. The NIH Blueprint Directors will appoint members to the Steering Committee. The BPN Program Officers, Project Scientists and BPN Project Team members may attend the Steering Committee meetings as non-voting participants.
The BPN Steering Committee will have the following involvement:
Dispute Resolution:
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Grants.gov
Customer Support (Questions regarding Grants.gov registration and
submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov
eRA Commons Help Desk(Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov
Primary Contacts:
Jill Heemskerk, PhD
Office of Translational Research
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard
Neuroscience Center/Room 2229
Bethesda, MD 20892
Telephone: (301) 496-1779
FAX: 301-402-1501
Email: jill.heemskerk@nih.gov
Rebecca Farkas, PhD
Office of Translational Research
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard
Neuroscience Center/Room 2109
Bethesda, MD 20892
Telephone: (301) 496-1779
FAX: 301-402-1501
Email: farkasr@ninds.nih.gov
NIH Blueprint for Neuroscience Research Institute and Center Contacts:
Rosemarie Filart, MD, MPH, MBA
Division for Clinical Research Resources
National Center for Research Resources
6701 Democracy Blvd
Bethesda, MD 20892-4874
Telephone: (301) 435-0178/(301)-642-5421
FAX: 301-480-3661
Email: Rosemarie.Filart@nih.gov
Tom Greenwell, PhD
Retinal Neuroscience
Division of Extramural Research
National Eye Institute
Suite 1300 / MSC 9300
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 451-2020
FAX: 301-402-0528
Email: greenwellt@mail.nih.gov
Lorenzo M. Refolo, PhD
National Institute on Aging
Division of Neuroscience
Dementias of Aging Branch
7201 Wisconsin Ave
Gateway Bldg, Suite 350
Bethesda, MD 20892
Telephone: (301) 594-7576
Email: refolol@mail.nih.gov
Qi-Ying Liu, MD, MSci
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, Room 2053
Bethesda, MD 20892
Telephone: (301) 443-2678
FAX: 301-443-1650
Email: liuqiy@mail.nih.gov
Zhaoxia Ren, PhD
National Institute of Child Health and Human Development
6100 Executive Blvd; MSC 7510
Bethesda, MD 20892
Telephone: (301) 402-9340
FAX: 301-480-2897
Email: zren@mail.nih.gov
Nancy L. Freeman, PhD
Division of Scientific Programs
National Institute on Deafness and Other Communication Disorders
Executive Plaza South-400C
6120 Executive Blvd; MSC 7180
Bethesda, MD 20892
Telephone: (301) 402-3458
FAX: 301-402-6251
Email: FreemanN@mail.nih.gov
John Kusiak, PhD
National Institute of Dental and Craniofacial Research
6701 Democracy Blvd; MSC 4878
Bethesda, MD 20892
Telephone: (301) 594-7984
FAX: 301-480-8319
Email: kusiakj@nidcr.nih.gov
Elena Koustova, PhD, MBA
Genetics and Molecular Neurobiology Research Branch
Division of Basic Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard; Room 4292
Bethesda, MD 20892
Telephone: (301) 496-8768
FAX: 301-594-6043
Email: koustovae@mail.nih.gov
Cindy Lawler, PhD
National Institute of Environmental Health Sciences
530 Davis Dr; MSC K3-15
Durham, NC 27713
Telephone: (919) 316-4671
FAX: 919-541-5064
Email: lawler@niehs.nih.gov
Jamie Driscoll
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard; Room 7194
Bethesda, MD 20892
Telephone: (301) 443-5288
FAX: 301-451-5615
Email: jdrisco1@mail.nih.gov
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Room 3201, MSC 9529
6001 Executive Boulevard
Bethesda, MD 20892-9529
(Rockville, MD 20852 for express/courier service)
Telephone: (301) 496-9223
Fax: (301) 402-0182
E-mail: nindsreview.nih.gov@mail.nih.gov
Tijuanna E. DeCoster, MPA
Chief Grants Management Officer
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Suite 3290, MSC 9537
Bethesda, Maryland 20892-9537
(Rockville, MD 20852 for express/courier service)
Telephone: 301-496-9231
Fax: 301-402-0219
Email: decostert@mail.nih.gov
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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