Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

NIH Blueprint for Neuroscience Research

National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title

Alzheimer's Disease Therapeutics Program (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-AG-13-014

Companion Funding Opportunity

NoneNone

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.866, 93.273, 93.853

Funding Opportunity Purpose

The goal of this Funding Opportunity Announcement (FOA) is to provide support for investigators to develop new drugs for the prevention or treatment of Alzheimer’s disease (AD). Specifically, this initiative is aimed at researchers who have promising small molecule compounds but lack outside drug development expertise and infrastructure support to advance these compounds to the clinic. This Alzheimer’s Disease Therapeutics Program adjunct to the NIH Blueprint Neurotherapeutics Program will allow investigators access to a “virtual pharma” network of contract research organizations, technical and regulatory experts and project managers, with extensive biopharma-industry experience.   The long-term goal of the Alzheimer’s  Disease Therapeutics Program is to advance projects from medicinal chemistry optimization through Phase l clinical trials and facilitate industry partnership for their further development.

This FOA responds to the recommendations of the May, 2012 NIH Alzheimer’s Disease Research Summit (http://www.nia.nih.gov/newsroom/alzheimers-disease-research-summit-2012-recommendations), which was convened as part of the strategic planning process for implementation of  the National Alzheimer’s Project  Act (NAPA: http://aspe.hhs.gov/daltcp/napa/). 

Key Dates
Posted Date

October 31, 2012

Open Date (Earliest Submission Date)

December 14, 2012

Letter of Intent Due Date

December 14, 2012  

Application Due Date(s)

January 14, 2013, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

April, 2013

Advisory Council Review

August, 2013

Earliest Start Date(s)

October, 2013

Expiration Date

January 15, 2013

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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

A. Background

Alzheimer’s disease (AD) is one of the most common age-associated diseases, and because of the aging of populations worldwide this disorder is predicted to reach epidemic proportions, with an enormous human and economic burden by the year 2050. To avert this public health crisis effective therapies that prevent AD, slow its progression or treat its cognitive and behavioral symptoms are urgently needed. There are currently no therapies that meet this need.

Over the past three decades significant progress has been made in understanding the neurobiology of AD. Notwithstanding these advances the development of effective AD therapies has been challenging, as is evidenced by the recent string of disappointing clinical trials. This has led to the perception that the biopharmaceutical industry is not properly developing AD therapies. Many factors contribute to the lack of progress in developing an effective AD therapy including: the complexity of the disease, the lack of animal models that accurately recapitulate the disease, the paucity of well validated biomarkers that correlate pathophysiology with clinical disease stages, and the strong possibility that AD drug candidates have failed in the clinic because they are designed to ameliorate a pathology that is already too advanced at the time patients are treated.  In addition to scientific factors, there are legal, regulatory and new economic factors that have hindered the development of AD therapies and have created the so-called “Valley of Death”.

As a consequence of the failure to translate scientific advances and increased R&D expenditures into new drug approvals, there is the increased threat that the biopharma industry will re-strategize and pull out of the AD field entirely, leaving little hope for millions of people with the disease and their families.   To address the unmet needs of millions of AD patients and to catalyze AD drug development, the NIH Blueprint for Neurosciences has created, with this FOA, an adjunct Blueprint AD Therapeutics Program. 

B.  Overview and Objectives

To expand and support AD drug discovery by the neuroscience community, the NIH Blueprint for Neuroscience Research is establishing the AD Therapeutics Program. This new program will utilize the ‘virtual-pharma’ network of contract service providers and consultants established by the NIH Blueprint for Neuroscience Research-Grand Challenge for Neurotherapeutics. The types of contract research organization (CRO) support provided on an in-kind basis will be for: medicinal chemistry optimization, Absorption, Distribution, Metabolism, Excretion and Toxicology (ADMET), Investigational New Drug (IND) enabling safety-toxicology, and Phase l clinical trial.

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. Awarded researchers will, in collaboration with the Blueprint consultants and NIH staff, design and implement a drug development strategy through clinical Phase l.

Applications will be considered from investigators with small molecules, that are at either of two stages of the drug discovery process: 1) hit-lead stage compounds that require iterative medicinal chemistry optimization to improve potency, pharmacological and chemical/physical properties, ADMET, IND-enabling safety-toxicology and Phase l clinical studies; 2) IND candidate- stage compounds that require IND-enabling preclinical clinical studies and subsequent Phase l clinical studies. The long-term goal of this program is to advance a pipeline of drug candidates through technical and feasibility milestones to produce at least one novel AD drug that successfully completes Phase l trials.

To be accepted into the network at the hit-lead entry point, 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 virtual-pharma network (see Entry Criteria below for more details).

To be accepted at the IND-candidate entry-point applicants must have the compound in hand and must provide the following information: a target product profile, medicinal chemistry optimization performed to date including identified liabilities, evaluation of pharmacokinetics (PK) and pharmacodynamics , evaluation of ADMET properties including products of metabolism, microsome stability and CYP profile, in vivo efficacy evaluation, including dosing (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) access, at no cost, 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 discovery consultants identified by NIH. The budget of the U01 application will support only the work in the investigators’ laboratories.

Each drug discovery project will be directed by a collaborative Lead Development Team, co-chaired by the U01 Program Director/Principal Investigator (PD/PI) 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 NIH program is structured to allow the PDs/PIs’ institutions to retain ownership of intellectual property for compounds developed within the network. The PIs' institutions therefore fully retain the responsibility for the ultimate commercialization of compounds developed through this effort.

C.  Entry Criteria

Applicants seeking support through this program must have available small-molecule compounds that are considered high quality from a druggability perspective, with validated biology relevant to the pathophysiology of AD.  

For entry at the hit-lead stage, compounds must have the potential for optimization through iterative medicinal chemistry. In addition, hit-lead stage projects, applicants must have the capabilities and resources to conduct the bioactivity and efficacy testing including validated cellular or animal efficacy models to assess compounds synthesized in the development process.

The minimal entry criteria for IND- candidate stage projects is a high quality Developmental Candidate (defined below). The entry criteria for the Blueprint AD Therapeutics Program are detailed below.

1.  Biological Rationale

Hit-lead and IND-candidate compounds entering the program must be well-supported by biological rationale data that is sufficiently compelling and rigorous to justify the entry into the program. Applicants should include a brief statement of the therapeutic hypothesis in a Projected Product Profile that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.

While it is not necessary to know the precise molecular target of the compound, the applicant should briefly summarize what is known about the compound’s mechanism of action and whether the compound engages a disease-relevant pathophysiological mechanism.

For compounds with known targets, the applicant should summarize the evidence that validates the drug target from cellular or animal models and clinical studies, provide a brief summary  of the rationale for  the selection of the target, the level of agreement in the field regarding the target’s role in disease pathogenesis and clinical relevance of the target, including the optimal disease stage (asymptomatic, mild cognitive impairment (MCI), mild, moderate or severe AD) to pharmacologically engage the target.

Applicants proposing to develop multi-target compounds should summarize the cumulative pathogenic pathways that the drug is proposed to engage and provide a strong clinically-relevant rationale for this approach. In addition, describe the small molecule (see below), its impact on the target, and the rationale for selecting the compound over similar entities (if they exist).  

Applicants should discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured and levels of activity observed are likely to be clinically relevant. In addition, applicants should discuss plans to incorporate any translatable, clinically-relevant biomarkers into their preclinical development program.

Studies using animal models presented to justify the choice of therapeutic target or compound must be sufficiently powered, controlled, and replicated to lend a high degree of confidence in the results (examples of critical elements of a well-designed study are summarized at http://www.alzdiscovery.org/wp-content/uploads/2011/01/alzheimersbestpracticesguidelines.pdf).

2.  Compounds Proposed for Development

Hit-lead stage compounds

Compounds entering the Blueprint AD Therapeutics program at this stage of development must provide information in the following areas:

IND-candidate compounds

Compounds entering this stage should be considered Development Candidates (optimized lead compounds). Applicants proposing the development of IND-candidate compounds should provide a brief summary of the current state of the project including description of medicinal chemistry performed to date, remaining liabilities and potential for further optimization; ADMET properties, efficacy in an accepted animal model; any known or suspected drug liabilities or challenges related to their drug candidate.

Applicants proposing development of IND-candidate compounds should provide information on the following areas:

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

D.  Projects Not Responsive to this Announcement
E.  Timeline of Drug Development and the U01 Investigator’s Role

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 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 for development of a hit-lead compound (activities 1-4) and IND-candidate compound (activities 3 and 4). This section also outlines the roles of the NIH Blueprint Neurotherapeutics Network and the U01 investigator in each stage of the pipeline.

1. Exploratory chemistry/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 No human studies should be included in the direct costs requested in the application..

F.  Milestones

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

G.  Intellectual Property

The ultimate goal of the Blueprint AD Therapeutics Program is to bring new AD drugs to the market. Therefore, the creation and protection of biotechnology and pharmaceutical industry standard intellectual property (IP) are significant considerations in designing research strategies and prioritizing projects for funding. The NIH allows the U01 awardee institution to gain and maintain assignment of intellectual property rights until the awardee institution licenses or transfers the IP to another institution. The awardee institution will maintain full responsibility for funding and managing the patents of the project as it advances, and will exclusively control the patent prosecution and licensing negotiations. 

The intellectual property position of each drug project will be evaluated at multiple points throughout the program.  The awardee will be expected to provide written reports to the NIH on the patent program as it progresses. Failure to build a standard patent estate world-wide may be a reason for project termination by the NIH. Each U01 application is expected to address intellectual property issues related to the proposed compounds and assays, including any infringement of other third party patents, with input from the institution's technology transfer.  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.  The U01 awardee institution will be encouraged to identify potential licensing and commercialization partners early in the drug development process. The PD/PI will be encouraged 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.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH 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

NIH intends to commit up to a total of $1 million for FY 2013; to fund up to 5 awards in FY 2013. In addition, in FY 2013 NIH intends to commit up to a total of $3M in in-kind drug development services. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are limited and need to reflect the actual needs of the proposed project. For hit-lead stage projects applicants are encouraged to keep direct costs to no more than $125,000 per year for the in vitro bioactivity screening in the early years of the project.

For IND-candidate projects applicants are encouraged to keep direct costs to no more than $50,000 per year for time/effort in participating in Lead Development Team activities and attending semi-annual  Steering Committee meetings. (see Section VI.2)  

Award Project Period

For hit-lead stage projects the duration of the award can be up to five years.  For IND-candidate projects duration of the award can be up to two years.

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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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 Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

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(s)/PI(s)) 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 6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

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:

The letter of intent should be sent to:

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 (20819 for express mail)
301-594-7576
Email: refolol@mail.nih.gov

Required and Optional Components

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 submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

SF424(R&R) Other Project Information Component

Facilities & Other Resources

Applicants should use this section to describe 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-PD/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 PD(s)/PI(s) and institutions involved in the U01-supported work.

R&R Budget Component

For hit-lead stage programs the U01 award is intended to support the disease-focused biology studies proposed by the Program Director(s)/Principal investigator(s) (PD(s)/PI(s)). This includes work done in the PD(s)/PI(s) laboratory, such as assaying compounds through the screening assays detailed in the application.  For IND-candidate stage programs the U01 is intended to support the PD/PI and Co-PI/consultants for time/effort involved in participating in Lead Development Team (LDT) activities during the time of the award.  The time/effort requested for LDT activities should not exceed 10% of the PI(s)/PD(s) or Co-PI(S) total time/effort. For both hit-lead and IND-candidate projects the U01 budget may include one or two trips per year, for PI(s)/PD(s)/Co-PI(s), to attend meetings of the Blueprint Neurotherapeutics Network Steering Committee.

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). 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.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims

For hit-lead stage projects the Specific Aims section should focus on the goals of medicinal chemistry optimization and the biological work to be conducted under the U01 grant. For IND-candidate projects the Specific Aims should focus on specific pre-IND activities that are needed to advance the compound to IND status and aims of the Phase 1 trial (safety, dosage- range).

Research Strategy

Within this section, the following subsections should be included:

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 modification:

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 Institutions

Foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.

6. Other Submission Requirements and Information

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(s)/PI(s) 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 System for Award Management (SAM). 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.  

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.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115, with the following modifications:

Concurrence from the Authorized Organization Representative (AOR) of the applicant organization is required.

Section V. Application Review Information

1. Criteria

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:

Overall Impact

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).

Scored Review Criteria

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(s)/PI(s), 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 discovery expertise, is the experience with biological testing sufficient to support and inform a drug discovery 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?

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?

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?

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?

Additional Review Criteria

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

Additional Review Considerations

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.

2. Review and Selection Process

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:

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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 these awards. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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’s 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, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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 has 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.

3. Reporting

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 the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

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 301-435-0714
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

Scientific/Research Contact(s)

Lorenzo M. Refolo, Ph.D.
National Institute on Aging (NIA)
Telephone: (301) 594-7576
Email: refolol@mail.nih.gov  

Rebecca M. Farkas, Ph.D.
National Institute of Neurological Disorders and Stroke
Telephone: 301-496-1779
Email: farkasr@mail.nih.gov 

Qi-Ying Liu, MD, MSci
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism
Telephone: (301) 443-2678
Email: liuqiy@mail.nih.gov

Peer Review Contact(s)

Ernest Lyons, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
6001 Executive Boulevard, Room 3201, MSC 9529
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

Financial/Grants Management Contact(s)

Tijuanna E. DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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.


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