Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (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

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. The recent advances in understanding the neurobiology of AD offer unprecedented opportunities to discover new treatments for AD. However, despite these scientific advances the development of effective AD therapies has been challenging, as is evidenced by the recent string of disappointing clinical trials. Consequently, the failure to translate scientific advances into new therapies, coupled with increased R&D expenditures, has largely dampened enthusiasm for AD drug development, leaving little hope for millions of AD patients and their families. To catalyze drug development for AD, the NIA is reissuing, with this Funding Opportunity Announcement (FOA), the Alzheimer's Drug Development Program (ADDP), which offers researchers funding for drug development activities that can be conducted in their own laboratories, in collaboration with contract research organizations (CROs) that specialize in various drug development activities including medicinal chemistry, pharmacokinetics (PK), Absorption, Distribution, Metabolism, Excretion, Toxicology (ADMET), formulations development, efficacy in animal models, chemical synthesis under Good Manufacturing Practices (GMP), Investigational New Drug (IND) enabling safety-toxicology and initial Phase I clinical testing

The overarching goal of the ADDP is the development of a broad range of therapeutic agents for AD including small molecules, natural products, and biologics, which broadly include therapeutic modalities such as peptides, proteins, oligonucleotides, gene and cell therapies. The program is not designed to support research on basic mechanisms of disease, development of biomarkers, devices, non-pharmacological interventions (e.g., exercise, diet, cognitive training), repurposed drugs and combination therapies or activities such as high throughput screening.

Projects can enter the ADDP either at the Early Stage to optimize the agent's potency, drug-like properties, specificity, pharmacological properties, ADMET properties and undergo Investigational New Drug (IND)-enabling safety toxicology, or at the Late Stage, to advance development candidates through (IND)-enabling toxicology studies and initial Phase I clinical testing.

Applicants are encouraged to contact NIA Scientific/Research Staff regarding the suitability of their projects for the ADDP and to clarify which entry stage is most appropriate for their project.

Early Stage Entry Criteria for Small Molecule Projects

Projects should meet the following qualifications prior to entering the Early Stage:

1) A bioactive compound, in hand, that will serve as a starting point for optimization with proof of identity and purity (typically >95%, as determined by, e.g., NMR, melting point, or LC/MS, with no single impurity > 0.5%);

2) In vitro biological activity (typically < 1 M in biochemical assays and <10 M in cell-based/phenotypic assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound;

3) Selectivity for the intended target over closely related targets, if desired (and when the target is known);

4) Availability of primary and secondary in vitro bioactivity assays that can be used or optimized for driving Structure Activity Relationship (SAR) studies;

5) Availability of animal and/ or cell-based model(s) that can be used to assess in vivo efficacy or target engagement (measurement of target binding or proximal downstream effects);

6) Availability of selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts;

7) Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project;

8) Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient to justify advancement criteria in a testing funnel;

9) No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development.

Early Stage Entry Criteria for Biologics Projects

Biologics projects should meet the following qualifications prior to entering the Early Stage:

1) Applicants should have one or more therapeutic lead(s) from which a candidate can be derived;

2) The therapeutic lead(s) should be sufficiently characterized so that the parameters to be optimized can be quantitatively specified;

3) Applicants should have pre-existing data demonstrating that the key in vitro and in vivo assays proposed to optimize the leads are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories;

4) Availability of animal and/ or cell-based model(s) that can be used to assess in vivo efficacy or target engagement (measurement of target binding or proximal downstream effects);

5) No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent (s) using the proposed assays and models for research purposes and/or commercial development.

Late Stage Entry Criteria for Small Molecule Projects

Small molecule projects should meet the following qualifications prior to entering the Late Stage:

1) A strong package of data linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease;

2) Proposed compounds should have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen) and outcomes.

3) A data package showing a clear and convincing demonstration of efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement at the clinically intended site of action.

4) A data package that includes Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.

5) A data package that demonstrates the degree of selectivity for the intended target over closely related targets.

6) A data package that includes counter-screening aimed at determining selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is also required.

7) No obvious legal (e.g., intellectual property) constraints to pursuing the proposed small molecule(s) using the proposed assays and models for research purposes and/or commercial development

Late Stage Entry Criteria for Biologics Projects

Biologics projects should meet the following qualifications prior to entering the Late Stage:

1) A data package demonstrating completed optimization and final characterization of the candidate, such as structure/identity, selectivity, bioavailability stability, formulation, manufacturability, sufficient purity, clinically intended route of administration, minimal effective dose, optimal effective dose, time and duration of treatment, as determined in relevant in vivo assays using clinically relevant functional and/or pathological outcome measures, and/or in vivo target engagement assays

2) In vivo study results that include assessment of pharmacokinetics, bioavailability at the relevant site of action, and pharmacokinetics-pharmacodynamics relationship

3) Details concerning special formulations if proposed (i.e., slow release, liposomes, nanoparticles, etc).

4) Rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS)

5) A data package showing a clear and convincing demonstration of efficacy. The data package can include in vivo efficacy in an established AD animal model and/or in vivo target engagement at the clinically intended site of action.

6) No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent (s) using the proposed assays and models for research purposes and/or commercial development

Supported Early Stage Activities for Small Molecule Projects

Examples of Early Stage activities for small molecule projects include but are not limited to the following:

• Establishment of the structure activity relationship (SAR)
• Testing of analogs in bioactivity assays and animal models
• Testing of analogs in selectivity and counter-screening assays
• Assessment of efficacy and /or target engagement
• Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, pharmacokinetics [PK] in multiple species).
• Scale-up synthesis
• Compound stability studies
• Pre-formulation studies
• Multiple dose rodent pharmacokinetic (PK) testing with pharmacodynamic (PD) correlations if possible
• Dose-range finding toxicology studies
• Initial IND-enabling toxicology

Supported Early Stage Activities for Biologics Projects

Examples of Early Stage activities for biologics projects include but are not limited to the following:

• Optimization of leads for improvement in potency, specificity, bioavailability and suitability for human testing
• Selection of the best promoter or viral serotype for a gene therapy product
• Humanization of a mouse monoclonal antibody
• Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, post-translational modifications, sequences, viscosity, stability)
• Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
• Assessment of efficacy and /or target engagement
• Assessment of in vivo pharmacology such as determination of dose range, dosing regimen, duration of treatment
• Assessment of pharmacokinetic/pharmacodynamic (PK/PD) properties
• Evaluation of metabolism
• Minimizing a predicted or previously encountered toxicity
• Optimization of delivery systems and special formulations (i.e., slow release, liposomes, etc.)
• Optimization to have better suitability for the route of administration
• Developing a production plan
• Dose-range finding toxicology studies
• Initial IND-enabling toxicology

Supported Late Stage Activities for Small Molecule Projects

Examples of Late Stage for activities for small molecule projects include but are not limited to the following:

• Scale-up synthesis
• Salt and polymorph screening
• Compound stability studies
• Pre-formulation studies
• Multiple dose rodent PK testing with PD correlations if possible
• Dose-range finding toxicology studies
• Metabolite identification
• IND-enabling toxicology, with toxicokinetics, if applicable
• Pre-IND meeting
• IND document preparation (the PD/PI will be responsible for the submission of the IND application and scheduling meetings with the FDA)
• GMP manufacturing of material for phase I clinical testing
• First in human Phase I clinical trial (single dose study to characterize safety, PK, and PD)

Supported Late Stage Activities for Biologics Projects

Examples of Late Stage activities for biologics projects include but are not limited to the following:

• Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working cell banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology tests
• PK evaluations in species relevant for toxicology or human dose-prediction
• Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
• IND-enabling toxicology, with toxicokinetics, if applicable
• Tumorigenicity evaluations particularly for gene therapies and cell therapies
• Immunogenicity evaluations
• Biodistribution studies
• Pre-IND meeting
• IND document preparation
• GMP manufacturing of material for phase I clinical testing
• First in human Phase I clinical trial (single dose study to characterize safety, PK, and PD)

Projects Not Appropriate for this Announcement

Projects Not Appropriate for this Announcement include:

• Basic research and studies of disease mechanism
• Animal model development
• Screening to identify hit compounds
• Projects that propose to develop generic or off-patent compounds for AD.
• Projects that propose to repurpose, or develop new formulations or drug delivery systems for compounds that have previously been approved for another indication by FDA or any other worldwide regulatory agency
• Projects that propose to develop and/or test combination therapies
• Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers
• Development of diagnostics and diagnostic devices
• Studies directed beyond Phase I clinical testing

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

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (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.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 SF424 (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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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, including Supplemental Grant Application Instructions 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.

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 activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Lorenzo M. Refolo, Ph.D
Telephone: 301-594-7576
Fax: 301-496-1494
Email: refolol@nia.nih.gov

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Applicants and their collaborators should demonstrate the appropriate experience and training to prosecute the work and, are well suited to the project. If established, the applicant and collaborators should demonstrate an ongoing record of accomplishments that have advanced their respective fields. If the project is collaborative or multi-PD/PI, the applicant should demonstrate that the investigators have complementary and integrated expertise.

For Late Stage projects, the applicant should demonstrate that there is sufficient clinical expertise to define the goals of the therapy development effort for the intended stage of AD, even if the trial will be conducted by contractors.

All instructions in the SF424 (R&R) Application Guide must be followed.

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.

The budget request may include travel costs for one or two trips per year to attend meetings.

It is expected that the PD/PI will dedicate at least 20% level of effort (2.4 calendar months) to managing the U01 project.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

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

Specific Aims: The Specific Aims section should include Aims delineated either for the Early or Late Stages of the project. For proposed Phase 1 clinical trials, define the aims of the study (e.g., safety, dose-range).

Research Strategy: The Research Strategy section should include the following subsections:

• Clinical Impact (Significance)
• Biological Rationale and Profile of the Therapeutic Agent (small molecule or biologic) (Significance)
• Early or Late strategy (Approach)
• Innovation
• Milestones
• Intellectual Property

Clinical Impact (Significance):

- Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.

- Provide a Target Product Profile (TPP) that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy.

- Discuss how the drug would be an improvement over the currently available therapies. Indicate target clinical population and specific stage of disease in which the treatment would be most efficacious.

- Describe possible clinical trial endpoints. Indicate if biomarkers are available in animal models and humans to detect if the drug engages the target.

- Discuss how the proposed project relates to therapeutics development efforts underway in academia and industry.

Biological Rationale and Profile of the Therapeutic Agent (Significance):

- Applicants 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

- Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed stage of AD.

- 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 therapeutic agent must be sufficiently powered, controlled, and replicated to lend a high degree of confidence in the results.

- For small molecule projects present evidence that the therapeutic candidate(s) meet the entry requirements for the proposed project stage (Early or Late).

- For biologics projects present evidence that the therapeutic candidate(s) meet the entry requirements for the proposed project stage (Early or Late).

- For Early Stage projects, show that the therapeutic candidate proposed as the starting point for optimization alters the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.

- For Late Stage projects, show that the proposed development candidate has clinically relevant in vivo activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.

- For Late Stage projects describe the in vivo (animal model) efficacy study design in detail, including the power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were replicated

- For Late Stage projects show the data that demonstrate the relationship between compound exposure and activity and explain how these data support the clinical dosing regimen proposed in the TPP.

Testing Strategy (Approach):

- Specify whether the project is proposed for entry at the Early or Late Stage.

- Clearly indicate which activities will be conducted by the PD/PI and associated personnel and which activities will be conducted by contractors. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by contractors should be outlined in general terms that will indicate the expected deliverable

- Include a Gantt chart that lays out each step in the critical path of the project (e.g., Optimization of drug-like properties, Optimization of bioactivity, Pharmacology profiling, Toxicology profiling, Efficacy in animal models, GMP synthesis, formulations development, and IND-enabling studies, PH I clinical trial).

- Include a table with yearly milestones and quantitative success (Go-NoGo criteria)

For Early Stage projects:

- Present a table that lists all of the in vitro and in vivo assays that will be run by the PD/PI and associated personnel. The table should include descriptive names of the assays, the assay throughput, and the proposed advancement criteria for each assay.

- Explain the rationale for the choice of assays, assay design, and advancement criteria, and clarify how these relate to the desired drug properties presented in the Target Product Profile.

- Show assay validation data or present plans to optimize and validate assays.

- If requesting funding to conduct all of the assays for SAR studies, including ADMET, provide a testing funnel that shows how these assays will be ordered and grouped into testing tiers.

- If requesting funding for medicinal chemistry, describe the SAR strategy that will be used.

- For the in vivo bioactivity study required to declare a development candidate, provide details on the study design, including power analysis and associated assumptions for sample size estimation, the process for blinding and randomization, and data handling rules, such as criteria for inclusion and exclusion of data.

- Describe plans for data analysis and interpretation of outcomes, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a go/no go decision for advancement into Late-stage).

For Late Stage projects:

-Present a synthetic scheme and experimental details (yields, conditions, reagents) for the development candidate.

-Provide a brief synopsis of the Phase I human study that includes the following:

• Planned population
• Objectives
• Study design
• Route of administration and determination of dose levels
• Safety assessments
• PK and PD assessments, with attention to demonstration of CNS penetration (if appropriate) and target engagement or modulation
• Safety management plan - all clinical trials must be performed following Good Clinical Practices (GCP) and in accord with NIA/NIH Policies for Data and Safety Monitoring

It is understood that at the time of application, some of the above may be limited or even unavailable, but an effort should be made to predict trial design when possible. Since details of the trial are likely to change in the course of therapeutic development, the overview may not reflect/include the final details of the protocol that will be implemented

Innovation:

- Explain how the project offers a novel approach to treating the stage of AD as proposed in the Target Product Profile (TPP).

- If similar therapeutic agents have been tested in AD clinical trials, explain why the proposed therapeutic agent would be expected to give significantly better clinical outcomes.

- Comment on the novelty of proposed assays or models.

Milestones:

Because drug discovery and development are inherently high risk, it is expected that there may be significant attrition as projects progress. Therefore, the application must include a table or, list of Go/No-Go milestones with quantitative success criteria for each year of funding.

Intellectual Property:

Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.

Applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (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 would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

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 IP will be shared or otherwise managed if there are multiple PDs/PIs and institutions involved

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Investigators should include a brief one-paragraph description of how research data will be shared or why data-sharing is not possible. If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.

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.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date 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 SF424 (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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

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 SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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 and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at vemuri@nia.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 our Post Submission Application Materials policy.

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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 should not be considered in assessing the significance of a project.

- Projects should not be penalized if the mechanism of action of the compound is unknown. While this may add to the risk, the increased risk may be counterbalanced by increased novelty.

- Evaluation of the approach should focus on the biological rationale, the potential for identifying a compound/biologic with drug-like properties, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI

- Work to be conducted by contractors (which may include medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis under Good Manufacturing Practices (GMP), and Phase I clinical testing) is subject to review.

- Applications that propose entry at the Late Stage but that reviewers consider better suited for the Early Stage or vice versa should nevertheless be evaluated and scored based on the entry criteria and expectations for the proposed entry stage. Reviewers can note in their comments that the project may be more appropriate for entry at a different stage.

Reviewers will provide an overall impact 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.

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?

How significant an advantage does the proposed therapeutic candidate offer over other treatments under development (in any therapeutic class)?

What is the likelihood that completion of the research objectives will lead to an AD therapy (i.e., is there a clear path into the clinic)?

How strong are the data supporting the choice of therapeutic target and compound/biologic for the proposed stage of disease?

For projects entering at the Early Stage, are the proposed candidates (compounds or biologics) sufficiently active in assays that are relevant to the proposed stage of AD?

For projects entering at the Late Stage, does the applicant have a well-profiled and fully-optimized candidate with in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use?

Has the applicant provided convincing data that the candidate is efficacious when delivered by the intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

Are the expertise and experience of the PD(s)/PI(s), collaborators, and other proposed researchers appropriate for the work they intend to conduct themselves, including chemistry, pharmacology and clinical trials, if proposed?

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?

Would the proposed drug be expected to give significantly better clinical outcomes than have been observed in previous efforts focused on the same target?

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?

Are the proposed studies appropriate, feasible and consistent with the proposed TPP, and likely to advance the project to the desired endpoint within the proposed timeframe?

Are proposed experimental designs and methodological approaches sufficiently rigorous to give meaningful results?

Are the proposed compounds suitable for SAR studies and optimization into a drug candidate?

Are the proposed in vivo studies and go/no-go criteria appropriate for declaring a development candidate?

Is it feasible to scale up the synthesis of the proposed development candidate to levels required for clinical trials?

Does the Late Stage plan include all of the appropriate studies for obtaining an IND? Are the timelines realistic?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

If the PD/PI is requesting funding to conduct a clinical trial, reviewers should evaluate the general quality and appropriateness of the proposed study design, including the study population, number of subjects, duration of the clinical study, and safety, pharmacokinetic, and pharmacodynamic endpoints?

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 score, but will not give separate scores for these items.

Milestones

Are the proposed project milestones adequate and feasible?

Intellectual Property

- For Early Stage projects, has the applicant demonstrated that there are no constraints, of which they are aware, that could impede their use of compounds, assays, or models for research purposes and/or commercial development (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.)?

- For Late Stage projects, has the applicant demonstrated) that the proposed development candidate is unlikely to be blocked or impeded by intellectual property constraints?

- If there are multiple institutions proposed, is it clear how intellectual property will be shared or otherwise managed to avoid encumbering the IP, consistent with achieving the goals of the program? Are these plans acceptable

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 Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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.

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.

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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 score.

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.

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).

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) Genomic Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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{National Institute on Aging (NIA) in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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’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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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:

- Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this U01. The PD/PI is ultimately responsible for the project and will make the final decisions regarding all project plans, provided that they can be executed within NIH-approved budgets and according to NIA/U01 grant and contract policies.

- Collaboration with NIA Program Staff assisting in the development of a project milestone plan at the outset of the project.

- Submitting periodic milestone progress reports in a standard format.

- Adhering to NIA/NIH policies, including those regarding data release, intellectual property, and publications.

- Implementing all scientific and policy decisions approved by the NIA/NIH

- Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner

- Providing protocol, supporting clinical documents and regulatory documents required for administrative review prior to clinical trial.

- Registering Phase I trial on clinical trials.gov

- Production of publication for clinical trial

All data or materials generated under this U01 award and through efforts of the PD/PI will be owned by the respective awardee and the data will be considered to be confidential and business privileged information of the awardee, which nevertheless does not affect its obligations to share or deliver the material or data with the government as set forth elsewhere in the grant agreement or regulations.

NIA staff have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NIA Program Officer will be assigned to the project and will be responsible for the normal scientific and programmatic stewardship of the award. The NIA Program Officer will be named in the award notice and will be the primary contact with the PI/PD. The Program Officer will be responsible for assessing the progress of the project towards accomplishment of milestones, and for recommending the level of continued funding.

An NIA Project Scientist will be assigned to the project with substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination that is above and beyond the normal stewardship role in awards. The Science Officer will provide additional expertise that is needed for proper scientific management of the award. This includes assisting the PI/PD in the development of a project milestone plan at the outset of the project, approving the final milestone language for incorporation into the award notice, enhancing the project's progress by providing access to various NIH resources, when appropriate, providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by the U01 reside with the PI/PD

Milestones:

Because drug discovery and development are inherently high risk, it is expected that there may be significant attrition as projects progress. Go/No-Go milestones (typically a minimum of one per funding year) will be established by the PI/PD in collaboration with NIA Program Staff at the start of the project and updated as needed. The application must include milestones with quantitative success criteria for each year of funding. Each year the PI/PD must submit milestone progress reports for independent evaluation by NIA Program Staff.

PLEASE NOTE: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project may be discontinued

For a Phase 1 clinical trial the following are required for approval for trial commencement (defined as signing of informed consent by first prospective participant):

- Successful achievement of the defined preclinical development milestones;

- Submission of an IND with documentation for one of the following: 1) acceptance of clinical protocol by FDA; 2) elapse of the 30 day post filing waiting period without comment from the FDA; 3) completion of protocol changes or amendments requested by FDA.

- Submission of the clinical protocol, and supporting documents to NIA for review and notification of NIA approval;

-Submission of the data and safety monitoring plan (DSMP) in accordance with the NIA policies

to NIA for review and notification of NIA approval

- Agreement on updated timeline and milestones for the clinical trial

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

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. One member will be selected by the awardee, a second member will be selected by NIA and a third designee with expertise in the relevant area will be chosen by the other two. 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 Research Performance Progress Report (RPPR) 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.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: vemuri@nia.nih.gov

Linda Whipp
National Institute on Aging (NIA)
Telephone: 301-496-7700
Email: whippl@nia.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 Part 75.