It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR 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

A. Overview

This Funding Opportunity Announcement (FOA) is part of a suite of complementary programs to encourage the translation of research discoveries into new treatments for disorders that fall under the NINDS mission.

The NINDS Cooperative Research to Enable and Advance Translational Enterprises for Biologics (CREATE Bio) program is dedicated to biotechnology product- and biologics-based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies and novel emerging modalities. The program includes two tracks: the Optimization Track supports optimization in order to obtain a candidate appropriate for entering the Development Track, and the Development Track supports IND-enabling studies for the candidate.

For entry into the Optimization Track, projects must have strong scientific rationale and demonstrate relevant, convincing in vivo data of one or more agent(s) that are sufficiently profiled so that the parameters to be optimized can be quantitatively specified (see entry criteria for details) in the application. At the end of the funding period, a candidate should be identified that has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) with defined minimal and optimal doses, and other favorable properties consistent with the desired clinical application (see Scope below for details).

Projects are funded through the SBIR U44 cooperative agreement award mechanism, which involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and establishing appropriate milestones. NINDS staff will also provide assistance to academic investigators in guiding them with the therapeutic development process and the criteria needed to advance therapeutic leads to the clinic.

For more information about earlier stage translational funding opportunities and programs, visit the NINDS Division of Translational Research website and, for more information specifically about the CREATE Bio Program, visit the website. Applicants are strongly advised to read through the CREATE Program FAQs.

Projects should focus on a single disorder that falls within the NINDS mission.

The CREATE Bio FOAs focus on biotechnology products and biologics, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies and novel emerging modalities. Applicants should contact NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for this FOA.

Entry Criteria:

Applicants are encouraged to talk to NINDS Scientific/Research staff about the stage of their activity and receive advice as to which program is the best fit. Applicants cannot simultaneously submit both an Optimization and Development Track application on the same agent and disease.

To be eligible for funding through this Optimization Track FOA, projects must meet the following criteria:

(1) One or more biological agents sufficiently profiled so that the parameters to be optimized can be quantitatively specified.

Note: NINDS recognizes that, depending on the type of agent and how it was identified and characterized, projects will enter at different stages, where certain required properties may have been optimized (repurposing a marketed therapy for a new indication is an extreme example). In the case of repurposing, the applications must show feasibility to proceed to an Investigation New Drug (IND) or IND exemption application, assuming the results from the Optimization Track funding period are positive. For example, the applicants should have collaborations that enable access to existing toxicology or human trial data required by the Food and Drug Administration (FDA), and have the decision rights or partnership(s) to further the development of the agent for the proposed new indication.

2) In vivo efficacy and target engagement using existing agent(s) in relevant animal model(s) to support scientific premise that the proposed mechanism of action (MOA) and modulation of the target are likely to result in a therapeutic outcome. The agent(s) should show in vivo efficacy using clinically relevant outcome measures (e.g., anatomical, and functional when possible) and in vivo target engagement (measurement of target binding or proximal downstream effects) at the clinically intended site of action, using sufficient experimental and statistical rigor.

3) Data demonstrating that the key in vitro and in vivo assays proposed are suitable for the proposed purpose and are available in either the applicant's or collaborator's laboratories. Appropriate controls should be employed and efforts should be taken to demonstrate dynamic detection range and acceptable variability so the feasibility of conducting the proposed studies can be adequately assessed.

4) An established and engaged multi-disciplinary project team to execute the proposed pre-clinical development plan that will deliver an optimized therapeutic candidate at the end of the funding period.

At the end of this Optimization Track, successful projects should have minimally achieved the following:

(1) Optimization is finished and the final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality- specific characteristics is complete.

(2) For a candidate with sufficient purity, its minimal effective dose, optimal effective dose, and time and duration of treatment have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays. [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. The in vivo study results should also include assessment of pharmacokinetics, bioavailability at the relevant site of action, and pharmacokinetics-pharmacodynamics relationship. In particular for CNS disorders, there needs to be rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS) and available at an effective dose, or evidence that the agent can act in the periphery. Key studies should be sufficiently replicated, powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with sufficient information available about study design, execution, analysis, and interpretation.

(3) Feasibility of reproducible production of the candidate.

Only the most promising agents that have undergone rigorous preclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies in the Development Track. This Optimization Track thus affords applicants the opportunity to build collaborations, conduct comparative studies among related agents and standard of care agents, and, ultimately, advance their most promising candidate therapeutics.

Activities Appropriate for this FOA include, but are not limited to:

• Optimization of the agents, like improvement of potency, specificity, bioavailability, and suitability for human testing, etc. Specific examples include but are not limited to: optimize selectivity/specificity, selection of the best promoter or viral serotype for a gene therapy product, ideal length and/or sequence of an miRNA derivative to hone its specificity, optimization of a protein for an acceptable stability in vitro or half-life in vivo, humanization of a mouse monoclonal antibody, minimizing a predicted or previously encountered toxicity, optimization of acceptable level of production, optimization to have better suitability for the route of administration
• Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, glycosylation or other post-translational modification, number of unpaired cysteines, oxidation, deamination, isomerization, proteolytic sites, sequences, viscosity, stability)
• Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
• Assessment of in vivo pharmacology such as determination of dose range, dosing regimen, route of administration, and ideal time and duration of treatment. This includes but is not limited to assessment of efficacy and/or target engagement, pharmacokinetics, pharmacodynamic measurements (including pharmacodynamic biomarkers), relationships among pharmacokinetics, target engagement and/or pharmacodynamic measurements, correlations between in vitro and in vivo activities, bioavailability at the site of action such as blood-brain-barrier penetration
• Studies to support independent replication, appropriate powering, or an assessment of efficacy in additional animal models if necessary to gain higher level of confidence for translatability of the discovery to the clinic, along with the model in which the leads were shown to have efficacy. However, these activities are restricted to the purpose of supporting the proposed development of a therapy and should be a limited portion of the application
• Evaluation of metabolism
• Optimization of production (e.g., expression levels, purification yield, purity, yield of vector or cells)
• Process development for scale-up manufacturing
• Stage-appropriate bioanalytical assay development and optimization in compliance with regulatory requirements
• Optimization of delivery systems and special formulations (such as slow release, liposomes, nanoparticles, etc.)
• Development of regulatory strategy and stage-appropriate interactions with regulatory agency
• Validation of target engagement assays, including experiments using human specimens, are within the scope of this FOA. However, these activities are restricted to the purpose of supporting the proposed development of a therapy.

To minimize potential funding gaps between the NINDS CREATE Bio Optimization and Development Tracks, applicants of this Optimization Track FOA may propose limited initial work for the Development Track, such as starting to identify species for toxicology study or preliminary safety evaluations, preliminary biodistribution study. These transitioning activities are generally restricted to the last year of Optimization Track applications. Awardees are encouraged to apply to the Development Track FOA as soon as they are eligible while finalizing studies in the Optimization Track.

Examples of Activities Inappropriate for this FOA include:

• Developing animal models
• Basic research of disease mechanisms
• Early activities such as target identification and validation
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers. (NINDS recognizes that target engagement markers developed may evolve into predictive markers for making clinical decisions for treatment trials, but it is not the intent of this FOA to support development of predictive biomarkers.)
• Manufacture of therapeutics for clinical trials
• Clinical research and clinical trials involving human subjects, except those in scope using human samples to validate target engagement assays
• Stand-alone studies to identify, validate, or qualify a target engagement marker and other bioanalytical assays
• Activities that are supported through the NINDS CREATE Bio Development Track FOA with the exception of the transitioning activities designed to enable easy transition from the Optimization to the Development Track as described above.

Milestones are quantifiable goals that are used to monitor project progress and facilitate dialogue and go/no-go decision making between program staff and the project team to effectively manage the project. NINDS recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment.

Prior to funding an application, NINDS Program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or NINDS Program staff. A final set of approved milestones will be specified in the Notice of Award.

Progress towards achievement of the final set of milestones will be evaluated by NINDS Program staff. NINDS Program staff may seek advice from independent consults with relevant expertise as necessary. If justified, future year milestones may be revised based on data and information obtained during the previous year. Funding for the project may be discontinued if milestones are not met. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

NINDS emphasizes the importance of the rigor and reproducibility of experimental results. In some cases, conducting additional critical experiments will be important for NINDS to have confidence in making a funding decision. Therefore, NINDS Program staff, in consultation with the PD/PI, may add experiments that need to be conducted prior to or during the award as additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.

If the research contains parallel activities from an independently funded, ongoing study prior to or during the funding period, it should be noted with appropriate milestones.

Applicants are encouraged to read examples of milestones (CREATE Bio Example Milestones), and see a summary chart of a milestone timeline (CREATE Bio Milestone Summary and Timeline).

For details see the Application and Submission section below.

Since the ultimate goal of the CREATE Bio program is to bring new therapies to the market/patients, the program strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed around the therapy during the project period (see instructions on attachment of letters to address IP issues in Section IV). In compliance with the Bayh-Dole Act, this program is structured so that the awardee institution can elect to retain title to inventions; not withstanding the rights reserved by the U.S. Government if title is elected by awardee institution, NINDS/NIH does not intend to hold any additional IP rights for therapies developed in this program. NIH policy requires invention reporting in iEdison. Patents should also include a reference to NIH funding support by including the grant/cooperative agreement number in the patent. The awardee institution will take responsibility for patent filings, prosecution, and maintenance as well as licensing efforts toward eventual commercialization. PDs/PIs are expected to work closely with their institutional technology transfer/business development officials to ensure that appropriate technology transfer agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. Award recipients are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. For rare or ultra-rare diseases where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with NINDS Scientific/Research staff to get further guidance.

As an U44 cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects. Applicants and their multidisciplinary team are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget. Applicants should contact NINDS Scientific/Research staff at least 12 weeks before a receipt date.

See Section VIII. Other Information for award authorities and regulations.

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.

Only United States small business concerns (SBCs) are eligible to submit applications for this opportunity. A small business concern is one that, at the time of award of Phase I and Phase II, meets all of the following criteria:

1. Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor;

2. Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture;

3.

i. SBIR and STTR. Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these; OR

ii. SBIR-only. Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these. No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern; OR

iii. SBIR and STTR. Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with 121.705(b) concerning registration and proposal requirements.

4. Has, including its affiliates, not more than 500 employees.

If the concern is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these falls under 3 (ii) or 3 (iii) above, see Section IV. Application and Submission Information for additional instructions regarding required application certification.

If an Employee Stock Ownership Plan owns all or part of the concern, each stock trustee and plan member is considered an owner.

If a trust owns all or part of the concern, each trustee and trust beneficiary is considered an owner.

Definitions:

• Hedge fund has the meaning given that term in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The hedge fund must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Portfolio company means any company that is owned in whole or part by a venture capital operating company, hedge fund, or private equity firm.
• Private equity firm has the meaning given the term private equity fund in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The private equity firm must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Venture capital operating company means an entity described in 121.103(b)(5)(i), (v), or (vi). The venture capital operating company must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.

SBCs must also meet the other regulatory requirements found in 13 C.F.R. Part 121. Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq., are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both. Business concerns include, but are not limited to, any individual (sole proprietorship) partnership, corporation, joint venture, association, or cooperative. The SF424 (R&R) SBIR/STTR Application Guide should be referenced for detailed eligibility information.

Small business concerns that are more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these are NOT eligible to apply to the NIH STTR program.

Phase I to Phase II Transition Rate Benchmark

In accordance with guidance from the SBA, the HHS SBIR/STTR Program is implementing the Phase I to Phase II Transition Rate benchmark required by the SBIR/STTR Reauthorization Act of 2011. This Transition Rate requirement applies to SBIR and STTR Phase I applicants that have received more than 20 Phase I awards over the past 5 fiscal years, excluding the most recently-completed fiscal year. For these companies, the benchmark establishes a minimum number of Phase II awards the company must have received for a given number of Phase I awards received during the 5-year time period in order to be eligible to receive a new Phase I award. This requirement does not apply to companies that have received 20 or fewer Phase I awards over the 5 year period.

Companies that apply for a Phase I award and do not meet or exceed the benchmark rate will not be eligible for a Phase I award for a period of one year from the date of the application submission. The Transition Rate is calculated as the total number of SBIR and STTR Phase II awards a company received during the past 5 fiscal years divided by the total number of SBIR and STTR Phase I awards it received during the past 5 fiscal years excluding the most recently-completed year. The benchmark minimum Transition Rate is 0.25.

SBA calculates individual company Phase I to Phase II Transition Rates daily using SBIR and STTR award information across all federal agencies. For those companies that have received more than 20 Phase I awards over the past 5 years, SBA posts the company transition rates on the Company Registry at SBIR.gov. Information on the Phase I to Phase II Transition Rate requirement is available at SBIR.gov.

Applicants to this FOA that may have received more than 20 Phase I awards across all federal SBIR/STTR agencies over the past five (5) years should, prior to application preparation, verify that their company’s Transition Rate on the Company Registry at SBIR.gov meets or exceeds the minimum benchmark rate of 0.25.

Phase II to Phase III Commercialization Benchmark

In accordance with guidance from the SBA, HHS, including NIH, SBIR/STTR Programs are implementing the Phase II to Phase III Commercialization Rate benchmark for Phase I applicants, as required by the SBIR/STTR Reauthorization Act of 2011. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 (78 FR 48537).

This requirement applies to companies that have received more than 15 Phase II awards from all agencies over the past 10 years, excluding the two most recently-completed Fiscal Years. Companies that meet this criterion must show an average of at least $100,000 in revenues and/or investments per Phase II award or at least 0.15 (15%) patents per Phase II award resulting from these awards. This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10 year period, excluding the two most recently-completed Fiscal Years.

Information on the Phase II to Phase III Commercialization Benchmark is available at SBIR.gov.

Applicants to this FOA that may have received more than 15 Phase II awards across all federal SBIR/STTR agencies over the past ten (10) years should, prior to application preparation, verify that their company’s Commercialization Benchmark on the Company Registry at SBIR.gov meets or exceeds the benchmark rate listed above.

Applicants that fail this benchmark will be notified by SBA annually and will not be eligible to receive New Phase I, Fast-track or Direct Phase II awards for a period of one year.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, may be 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, SBA Company registry, 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.
• SBA Company Registry See Section IV. Application and Submission Information, SF424(R&R) Other Project Information Component for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a DUNS number to complete this registration. SBA Company registration is NOT required before SAM, Grants.gov or eRA Commons registration.
• 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.

Under the SBIR program, for both Phase I and Phase II, the primary employment of the PD/PI must be with the small business concern at the time of award and during the conduct of the proposed project. For projects with multiple PDs/PIs, at least one must meet the primary employment requirement. Occasionally, deviations from this requirement may occur.

The SF424 (R&R) SBIR/STTR Application Guide should be referenced for specific details on eligibility requirements. For institutions/organizations proposing multiple PDs/PIs, see Multiple Principal Investigators section of the SF424 (R&R) SBIR/STTR Application Guide.

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

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

NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.

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).

A Phase I awardee may submit a Phase II application either before or after expiration of the Phase I budget period, unless the awardee elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure. To maintain eligibility to seek Phase II or IIB support, a Phase I awardee should submit a Phase II application, and a Phase II awardee should submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively.

In Phase I, normally, a minimum of two-thirds or 67% of the research or analytical effort must be carried out by the small business concern. The total amount of all consultant and contractual arrangements to third parties for portions of the scientific and technical effort generally may not exceed 33% of the total amount requested (direct, F&A/indirect, and fee).

In Phase II, normally, a minimum of one-half or 50% of the research or analytical effort must be carried out by the small business concern. The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort generally may not exceed 50% of the total Phase II amount requested (direct, F&A/indirect, and fee).

A small business concern may subcontract a portion of its SBIR or STTR award to a Federal laboratory within the limits above. A Federal laboratory, as defined in 15 U.S.C. 3703, means any laboratory, any federally funded research and development center, or any center established under 15 U.S.C. 3705 & 3707 that is owned, leased, or otherwise used by a Federal agency and funded by the Federal Government, whether operated by the Government or by a contractor.

The basis for determining the percentage of work to be performed by each of the cooperative parties in Phase I or Phase II will be the total of the requested costs attributable to each party, unless otherwise described and justified in Consortium/Contractual Arrangements of the PHS 398 Research Plan component of SF424 (R&R) application forms.

Additional details are contained in the SF424 (R&R) SBIR/STTR Application Guide.

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR 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.

All page limitations described in the SF424 (R&R) SBIR/STTR Application Guide and the Table of Page Limits must be followed.

For this specific FOA, the Research Strategy section is limited to 30 pages.

Instructions for Application Submission

The following section supplements the instructions found in the SF 424 (R&R) SBIR/STTR Application Guide and should be used for preparing an application to this FOA.

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

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

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

Other Attachments:

1. SBA Company registry

All applicants to the SBIR and STTR programs are required to register at the SBA Company Registry prior to application submission and attach proof of registration. Completed registrations will receive a unique SBC Control ID and .pdf file. If applicants have previously registered, you are still required to attach proof of registration. The SBA Company Registry recommends verification with SAM, but a SAM account is not required to complete the registration. In order to be verified with SAM, your email address must match one of the contacts in SAM. If you are unsure what is listed in SAM for your company, you may verify the information on the SAM site. Confirmation of your company's DUNS is necessary to verify your email address in SAM. Follow these steps listed below to register and attach proof of registration to your application.

a. Navigate to the SBA Company Registry.

b. If you are a previous SBIR/STTR awardee from any agency, search for your small business by Company Name, EIN/Tax ID, DUNS, or Existing SBIR/STTR Contract/Grant Number in the search fields provided. Identify your company and click Proceed to Registration .

c. If you are a first time applicant, click the "New to the SBIR Program?" link on lower right of registry screen.

d. Fill out the required information on the Basic Information and Eligibility Statement screens.

e. Press Complete Registration on the lower right of the Eligibility Statement screen and follow all instructions.

f. Download and save your SBA registry PDF locally. The name will be in the format of SBC_123456789.pdf, where SBC_123456789 (9 digit number) is your firm’s SBC Control ID. DO NOT CHANGE OR ALTER THE FILE NAME. Changing the file name may cause delays in the processing of your application.

g. When you are completing the application package, attach this SBA registry PDF as a separate file by clicking "Add Attachments" located to the right of the Other Attachments field on the Research and Related Other Project Information form.

For questions and for technical assistance concerning the SBA Company Registry, please contact the SBA at http://sbir.gov/feedback?type=reg.

2. SBIR Application Certification for small business concerns majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms.

Applicant small business concerns that are majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms (e.g. majority VCOC-owned) are required to submit a Certification at time of their application submission per the SBIR Policy Directive. Follow the instructions below.

Applicants with small business concerns who are more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these (i.e. NOT majority VCOC-owned) should NOT fill out this certification and should NOT attach it their application package.

a. Download the VCOC Certification.pdf at the NIH SBIR Forms webpage.

b. Answer the 3 questions and check the certification boxes.

c. The authorized business official must sign the certification.

d. Save the certification using the original file name. The file must be named SBIR Application VCOC Certification.pdf . DO NOT CHANGE OR ALTER THE FILE NAME. Changing the file name may cause delays in the processing of your application.

e. When you are completing the application package, attach this certification as a separate file by clicking "Add Attachments" located to the right of Other Attachments field on the Research and Related Other Project Information form.

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

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

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

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

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

Specific Aims: List the aims for obtaining an optimized and a well characterized candidate. A scientific hypothesis is not required.

Research Strategy:

The Research Strategy should include the following sections:

A. Significance: Clinical Impact and Feasibility

Supporting Data for Entry

B. Approach: Detailed Plans for Research Strategy (Including Milestones and Timelines)

C. Team Management

A. Significance

Clinical Impact and Feasibility

Each application should focus on only one disorder or disease, even if the therapeutic proposed for development shows activity in models for more than one disorder. This is because the target patient population and intended use guide the design of the therapy, the path for an IND, and the preclinical IND-enabling studies. Levels of tolerated toxicities may also differ between different disorders especially if the proposed treatment is chronic versus acute.

• Describe the current state of knowledge of the etiology, clinical characteristics, and prevalence of the proposed disease indication.
• Briefly discuss available treatments (if any), their limitations, and how the proposed project would provide an advantage over all existing therapies, regardless of therapeutic class (i.e., discussion only on within class comparisons is not sufficient).
• If the therapy is an improvement over an earlier generation agent(s) that has not been marketed, discuss what advantages the new agent has. Include results from previous clinical trials with related agents.
• Discuss how the proposed project relates to therapy development efforts underway in academia and industry, regardless of therapeutic class. What are the distinct advantages to the new, proposed therapy considering other investigational agents that might be entering the clinical pipeline soon?
• Provide a Target Product Profile (TPP) based on the FDA guidance (see CREATE Bio Example: Target Product Profile (TPP)) that shows the ultimate goals of the proposed therapy development effort, such as disease indication and stage, patient population, delivery mode and dosing regimen, treatment duration, and standards for clinical efficacy.
• Briefly, also explain the rationale behind the TPP minimally acceptable and ideal parameters for the clinical population and feasibility for future clinical efficacy evaluation should the candidate therapy be tested (for example describe how you would have access to the appropriate patient population, and what clinical endpoints are meaningful). The TPP embodies the notion of beginning with the goal in mind. Therefore, the TPP provides a statement of the overall intent of the drug development program and is a dynamic summary that changes as knowledge of the potential therapeutic agent increases. In conclusion, the proposed experimental plan should be consistent and reflect the objectives of the TPP.

Supporting Data for Entry

The Supporting Data for Entry section contains, but is not limited to, data that support the scientific premise, that justify that the application meets the entry criteria, as well as data that demonstrate the feasibility of conducting studies to address the specific aims.

1. Scientific Rationale

• Make a strong case for the choice of target (can be molecular, cellular, or system). Indicate whether evidence from multiple groups supports this is a compelling target for the disease. It is not absolutely necessary to know the precise molecular target, but knowledge of the mechanism of action is helpful to anticipate potential toxicities and essential to assess target engagement.
• Show evidence that the agent(s) modulates the target(s) in vitro and in vivo.
• Show relevant, convincing in vivo evidence that the agent(s) impacts the disease. Efficacy should be measured using clinically relevant outcome measures and in vivo target engagement, with sufficient detail to allow reviewers to critically evaluate the findings. NINDS encourages discussion of robustness and reproducibility of the observed results. These include:
• Explain the choice of model(s) or assay(s), primary, secondary and exploratory endpoints, and why they are clinically relevant.
• Describe power analyses and associated assumptions for the determination of sample size, statistical handling of the data such as criteria for data inclusion or exclusion, and describe the procedures of how blinding and randomization were conducted.
• When interpreting the results, consider alternative interpretations of the experimental data, relevant literature in support of or in disagreement with the results, and include discussion of effect size in relation to potential clinical impact.
• Applicants should explain what key data, if any, have been replicated, by the applicants or by independent investigators.
• When showing figures, there should be associated text with information on the number of animals per group and how many times the experiments were repeated. Showing the most promising results of a series of tests is not acceptable.
• Include quantitative information on purity and selectivity of the agent in these experiments for adequate evaluation and interpretation of the in vivo data.

2. Agent(s)

• Describe what is known about your agent(s) on the structure/identity, selectivity, bioactivity, potency, stability, production, etc.
• Define what an optimized candidate would look like at the end of the Optimization Track. Include quantitative characteristics for structure/identity, in vitro activities and in vivo pharmacology, specificity, selectivity, stability, etc. Explain how the desired quantitative characteristics are consistent with the desired TPP. Introduce what parameters of the agent(s) will be modified during the funding period.

3. Assays

• Describe in vitro and in vivo assays that will be used to enable optimization of the agent(s) and/or to characterize the candidate. Provide data on how these assays work in the PD/PI or collaborator's laboratories using the agent(s) in the presence of appropriate controls, with sufficient information on dynamic range and variability. Demonstrate the assay's fit for the proposed use in the project (if these were described under the scientific rationale section, it can be referenced).

B. Approach

Detailed Plans for Research Strategy (Including Milestones and Timelines)

In this section applicants should elaborate on their research plans. Describe milestones to be used for measuring success in achieving each of the research plan key objectives. One or more milestone(s) should be used for each key objective. For each milestone provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and related rationale. Quantitative criteria should be robust and be consistent with the state-of-the-art in the field. The quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. Specify the timeline for each milestone. There should be at least one milestone each year. NINDS recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment. If the research contains parallel activities from an independently funded, ongoing study prior or during the funding period, it should be noted with appropriate milestones.

Plans could include but are not limited to:

• Describe how each parameter (such as potency, selectivity, stability etc.) will be optimized. If multiple parameters are to be optimized, explain whether this will be done sequentially, in parallel, or in an iterative process.
• Propose experiments such as demonstration of in vivo efficacy, target engagement with dose-response, bioavailability at the site of action (including brain penetration), and pharmacokinetic-pharmacodynamics relationships. For proposed critical experiments, include the following:
• The choice of models, assays, and clinically-relevant endpoints (primary, secondary, and exploratory when applicable) for these studies;
• Information on study design, power analyses and associated assumptions for sample size estimation (e.g., what is considered a minimal change predictive of clinically meaningful change, variance known as described in Supporting Data Section, false positive and false negative tolerance), and detail the procedures to reduce bias, such as how blinding and randomization will be done;
• Data handling rules such as criteria for inclusion and exclusion of data;
• Plans for data analysis and interpretation;
• How minimal and optimal doses will be determined;
• Whether and how the confirmation of the results will be performed;
• The minimal purity of the agent to be used for the experiments;
• Describe in addition how target engagement assays will be incorporated into the program to support therapy development.
• Describe replication of key data.
• Describe how the production and reproducibility of production of the candidate will be optimized or evaluated.

Note: Applicants are encouraged to discuss impediments that could require a revision to the research plan, milestones, or timeline, with a discussion of alternative approaches.

At the end of the Plans for Research Strategy section, summarize milestones and timelines; an example is available for applicants (CREATE Bio Milestone Summary and Timeline).

C. Team Management Plan

Therapy development is a complex and time consuming undertaking, and NINDS expects applicants to form multidisciplinary teams that consist of preclinical and clinical scientists, PK experts, CMC experts, regulatory experts, statisticians, project manager, and other academic/industry experts relevant to the therapeutic modality and disorder. This multidisciplinary team should establish a desired TPP (see details in Section IV-Research Strategy), define the attributes of a successful candidate for the intended clinical indication, identify gaps that need to be filled during this funding period, and design the details of the plans and experiments to execute the research strategy. Engaging a team that includes members experienced in the IND process will help identify issues, strategize solutions and options, plan details of studies and set a realistic timeline. Describe how the team, including consultants, has already been engaged and a plan as to how they will continue working together over the course of the project (e.g., recurring team meetings, review and report of data across disciplines, decision-making, participate in meetings with NINDS, communication, etc.). Letters of support should be included and should not be generic, but instead indicate what has been contributed so far and what they expect to provide during the project to allow an evaluation of team engagement (see below). Indicate the willingness of the PD/PI(s) and key personnel to operate under the cooperative agreement terms and conditions outlined in section VI.2. Of the FOA. Note: Multi-PI plans should not duplicate information from the multi-PI plan.

Letters of Support: Applicants should include letters of support from consultants, contractors, and collaborators.

• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should come from a high official within the private entity who has authority to speak on these issues.

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

• Investigators should include a brief one-paragraph description of how the final 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 patent protection is secured.

Appendix:

Do not use the Appendix to circumvent page limits. The instructions for the Appendix of the Research Plan are described in the SF424 (R&R) Application Guide.

Note that Phase I SBIR/STTR Appendix materials are not permitted.

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

Commercialization Plan

All applicants are expected to describe a realistic plan (extending beyond the U44 Phase II), which outlines how and when full commercialization can be accomplished. The full commercialization of the product/technology should be carried out with non-SBIR funds.

The following subsections with the headings should be included within the Commercialization Plan, in addition to the requirements listed in the SF424 Application Guide:

1) Statement of Need

Applicants must provide a concise Statement of Need . This statement is expected to provide answers to the questions listed below:

• What are the perceived barriers for the product/technology under development?
• To what extent would a possible award under this FOA advance the product or technology far enough to attract sufficient, independent third-party financing and/or strategic partnerships to carry out full commercialization?

2) SBIR Commercialization History

Applicants should provide an SBIR/STTR Commercialization History that addresses the questions listed below. The following questions should be addressed for all SBIR/STTR awards received from any Federal agency:

• Has the company gone through any name changes within the past five years? If so, then all previous company names should be listed in the application.
• Is the company a subsidiary or a spin-off? If so, then the name of the parent company should be provided.
• What percentage of the company’s revenue was derived from SBIR/STTR funding during each of the past 5 years, including both Phase I and Phase II awards? Applicants should report a percentage value for each year individually.
• What is the total number of SBIR/STTR Phase II awards that the company has received from the Federal government? For each award, companies should provide the award number, the award amount, project duration, and the name of the awarding agency.
• What are the total revenues that have been generated to date as a result of the commercialization of the SBIR/STTR projects funded within the past 5 years?

3) Intellectual property (IP) strategy

Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, if applicable.

Applicants should describe the IP landscape surrounding their therapy. Applicants should describe any known constraints that could impede their therapeutic discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address any questions of freedom to operate. Applicants should include a letter (see letter of support) from the entity who owns the IP indicating whether they will provide the agent(s), if there are any limitations on the studies that can be performed with that agent(s), agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.

If patents pertinent to the therapy being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. 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 IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), SBA Company Registry, eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and time. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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) SBIR/STTR 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) SBIR/STTR Application Instructions. 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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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.

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 (SAM). Additional information may be found in the SF424 (R&R) SBIR/STTR 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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy -.

• In addition, NINDS will accept regulatory meeting minutes and transcripts, patents, and late-breaking data.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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 therapy may be considered small compared to other markets. Provided these smaller markets are sustainable and provide some economic benefit to the applicant company, applications should not be penalized for their comparatively smaller market. NIH is supportive of research for both rare and high incidence disorders that fall under the mission of NIH.

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? Is there a strong scientific premise for the project? 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? Does the proposed project have commercial potential to lead to a marketable product, process or service? (In the case of Phase II, Fast-Track, and Phase II Competing Renewals, does the Commercialization Plan demonstrate a high probability of commercialization?)

Specific to this announcement:

Regarding the section on Clinical Impact and Feasibility:

If the project is successful in meeting its proposed Target Product Profile, how will it affect clinical practice with consideration to existing treatments and therapeutic development efforts underway in academia and industry, including all therapeutic classes?

Regarding the section on Supporting Data for Entry:

Scientific Premise: what is the robustness of the data provided in support of the target (can be molecular, cellular or system) for the intended disease? Does the agent(s) show efficacy and target engagement in relevant animal model(s) using sufficient experimental and statistical rigor? Were the efficacy endpoints used clinically relevant? For key experiments, did the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization were conducted? Have key data been replicated? If not, evaluate plans under Approach section.

Are the agent(s) sufficiently profiled so that all the parameters needed to be optimized to achieve the desired candidate profile specified? Are the parameters to be optimized of high importance so that at the end of the project funding period a candidate consistent with the TPP will be generated?

Are essential assays (in vitro and in vivo) that will be used to optimize the agent(s) well characterized (e.g., the dynamic range, variability) and available in the applicant's or collaborator's laboratory and suitable for the proposed use?

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?

Specific to this announcement:

Has a multidisciplinary team been engaged, including expertise in preclinical, clinical, PK, CMC, regulatory, statistics, and any other experts relevant to the therapeutic modality and disorder? Is there any expertise lacking? Based on the team management plan and letters of support descriptions of how the members have already contributed to the design and proposed implementation of the project and how they will continue working together over the course of the project, does the team seem capable and sufficiently engaged to successfully complete the activities needed to obtain an optimized therapeutic candidate?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? For a Phase I application, are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this announcement:

Regarding the Section on Detailed Plans for Research Strategy

(Including Milestones and Timelines):

Are plans with all necessary steps to optimize the agent(s) in order to obtain a candidate clearly spelled out? Can all the proposed parameters be optimized within 4-5 years of funding support?

Are there sound rationales for the choice of model(s), and advancement criteria?

How rigorous are the experimental design and methodological approaches? For key critical experiments (such an in vivo demonstration of efficacy and target engagement with a dose response), does the application have the following:

• A primary, secondary, exploratory endpoint (when applicable), and an explanation as to why they were chosen
• Appropriate controls
• An explanation of assumptions and reference to supporting data for power analyses
• A description of planned data analyses and data handling rules such as criteria for data inclusion or exclusion
• A detailed description of the procedures of how blinding and randomization will be implemented
• Minimal requirement of the purity of the reagents
• Plan for replication if not already done

If applicable, is the plan to validate the target engagement assays at the site of action relevant to the proposed therapy development?

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?

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 arrangement?

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 and Timelines

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions? If a criterion is not to be used for go/no-go decisions, is it justifiable?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps?

Are there any gaps in the proposed milestone?

Would achieving all milestones in the application allow the project to achieve the end goals outlined below?

• Optimization is finished, and the final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality- specific characteristics, is complete.
• For a candidate with sufficient purity, have its minimal effective dose, optimal effective dose, and
• time and duration of treatment, been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and in vivo target engagement assays? [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. The in vivo study results should also include assessment of pharmacokinetics, bioavailability at the relevant site of action, and the pharmacokinetics-pharmacodynamics relationship. In particular for CNS disorders, there needs to be rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS) and available at an effective dose or evidence that the agent can act in the periphery. Key studies should be sufficiently powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with sufficient information available about study design, execution, analysis, and interpretation.
• Feasibility for production and reproducible production of the candidate.

Market, Customer, and Competition

How compelling is the value proposition, and to what extent does the application demonstrate a substantial market-pull for the technology under development?

How well has the applicant described the market niche(s) for the product/ technology, and how urgent is the unmet need(s) being addressed?

To what extent has the applicant identified realistic, market-based milestones that can be achieved over the next five years?

How well has the applicant demonstrated an understanding of the competitive environment in which they plan to sell their product?

To what extent has the applicant identified their customers and demonstrated a clear understanding of their needs?

How well has the company addressed potential hurdles that may delay or prevent acceptance of their product?

How reasonable are the applicant's plans for generating a revenue stream, and how realistic are the revenue projections?

Company

How well can the applicant SBC sustain itself and grow as a business?

To what extent do the prior experience and qualifications of the project team members lend confidence that the team will be successful in commercializing the proposed product/technology? For example, how successful have the PD(s)/PI(s) been in commercializing other SBIR/STTR supported technologies and discoveries in the past?

To what extent will the applicant's business alliances and/or corporate partnerships help in facilitating commercialization? For example, will third-party investors play an active role in facilitating the commercialization of the product/technology, and if so to what extent?

If the SBC has received previous SBIR/STTR funding from ANY Federal agency, then how successful is the company’s track record in commercializing prior SBIR/STTR projects?

Intellectual Property (IP)

How strong is the applicant's intellectual property (IP) portfolio/position (pertinent to the proposed project), and to what extent does the company have a reasonable strategy to protect its IP going forward?

Are potential issues regarding the IP landscape for the therapeutic being developed and the freedom to operate addressed?

Do the IP Strategy and related letters of support address potential concerns?

Are there any known constraints that could impede the development of the therapeutic?

Are IP filing plans described?

If multiple institutions are involved, is IP sharing addressed?

For Phase II Applications, how well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

For Phase I/Phase II Fast-Track Applications, reviewers will consider the following:

1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

2. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/STTR funding sources that would enhance the likelihood for commercialization?

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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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 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 Data Sharing Plan.

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 NINDS, 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 committee 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. Following initial peer review, recommended applications will receive a second level of review by the NINDS Advisory Council. 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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The Office of Inspector General Hotline accepts tips from all sources about potential fraud, waste, abuse and mismanagement in Department of Health & Human Services programs. The reporting individual should indicate that the fraud, waste and/or abuse concerns an SBIR/STTR grant or contract, if relevant. Report Fraud.

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 Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the U44 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 purpose of the NIH 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 primary responsibility for:

• The PD(s)/PI(s) will have primary responsibility for defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Awardees are responsible for developing and proposing rigorous milestones that will be achieved during the project period.
• Awardees will retain custody of and have all rights to the data and therapy developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Awardees are responsible for pursuing patent protection. Patents should include a reference to NIH funding support by including the grant/cooperative agreement number in the patent.
• Awardees are responsible for providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NINDS Research/Scientific staff request raw data, awardees agree to provide the data.
• Awardees agree to allow NINDS staff to join multi-disciplinary project team meetings
• Awardees agree to participate at least once a year in progress meetings (teleconferences) that are organized by NINDS staff.
• Regarding meetings and interactions with regulatory agencies, awardees agree to communicate meeting dates and agenda to the NINDS Research/Scientific staff and invite their participation.
• Awardees agree to communicate study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with regulatory agencies, and other authorities, if applicable.

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

• Each project will have the support of one or more Project Scientists from NINDS Research/Scientific staff who are assigned an administrative role for the neurological disorder being studied and have expertise in the implementation of the NINDS CREATE Bio Program in Translational Research.
• The NINDS Project Scientists will have substantial scientific/programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• NINDS Project Scientist(s) provides input on the milestones and makes decisions regarding their finalization.
• NINDS Project Scientist(s) will be responsible for assessing the progress of the projects toward the specified milestones, and for recommending if further funds should be released to the project.
• NINDS Project Scientist(s), in consultation with the PD/PIs, may add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.
• NINDS Program Scientist(s) participates in meetings together with PD/PIs with regulatory agencies related to the funded project.
• NINDS Program Scientist(s) may join in multi-disciplinary project team meetings
• An important part of the NINDS CREATE Bio program is the coordination of research efforts across different funding mechanisms and research capabilities, and the coordination among efforts aimed at different neurological disorders. NINDS Project Scientists will have the primary responsibility for this overall coordination.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as an NIH Project Scientist.
• NINDS leadership will make decisions on project continuation based on Research/Scientific staff recommendations, programmatic prioritizations and budget considerations. NINDS Research/Scientific staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.
• NINDS reserves the right to consult subject matter experts to evaluate the program and advise program staff.

Areas of Joint Responsibility include:

Clarifying, negotiating and finalizing the milestones and timelines.

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 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. Final decisions made by NINDS regarding a discontinuation are not appealable.

NIH requires that SBIR/STTR grantees submit the following reports within 120 days of the end of the grant budget period unless the grantee is under an extension. 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.

• Final RPPR (requirements have recently changed - please see the NOT-OD-12-152)
• Final Invention Statement and Certification (HHS 568)
• Annual Invention Utilization Reports
• Federal Financial Report (FFR) replaced the Final Cash Transaction Report (PSC 272)
• Phase II Data Collection Requirement for Government Tech-Net Database

Failure to submit timely final reports may affect future funding to the organization or awards with the same PD/PI.

For details about each specific required report, see Part III. Section 5, "SBIR/STTR Award Guidelines, Reporting Requirements, and Other Considerations, in the Supplement Grant Applications For All Competing Applications and Progress Reports.

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 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

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)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

SBA Company Registry (Questions regarding required registration at the SBA Company Registry and for technical questions or issues)
Website to Email: http://sbir.gov/feedback?type=reg

Chris Boshoff, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.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.

The SBIR Program is mandated by the Small Business Innovation Development Act of 1982 (P.L. 97-219), reauthorizing legislation (P.L. 99-443) P.L. 102-564, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), and as reauthorized and extended under P.L. 114-328, Section 1834. The basic design of the NIH SBIR Program is in accordance with the Small Business Administration (SBA) SBIR Policy Directive.