Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Eye Institute (NEI)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute on Drug Abuse (NIDA)

National Center for Complementary and Integrative Health (NCCIH)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Research on Women's Health (ORWH)

Funding Opportunity Title
HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type

Reissue RFA-NS-19-010

Related Notices

None

Funding Opportunity Announcement (FOA) Number
RFA-NS-21-010
Companion Funding Opportunity

None

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

93.853; 93.273, 93.866, 93.213; 93.867; 93.273; 93.846; 93.865; 93.279; 93.121; 93.847; 93.313;

Funding Opportunity Purpose

The purpose of this funding opportunity announcement (FOA) is to support preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising small molecule and biologic hits/leads to Phase I clinical trials and readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) https://heal.nih.gov/research/clinical-research/eppic-net or other Phase II clinical studies. Applicants must have a promising biologic or small molecule hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, development of a pharmacodynamic/target engagement biomarker, assembly and filing of an Investigational New Drug (IND) application and Phase I clinical testing. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress.

Key Dates

Posted Date
September 16, 2020
Open Date (Earliest Submission Date)
October 18, 2020
Letter of Intent Due Date(s)

30 days prior to receipt date.

Application Due Date(s)

November 18, 2020, March 24, 2021, July 14, 2021, October 15, 2021, February 15, 2022, June 15, 2022, by 5:00PM local time of applicant organization.  All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review

February 2021, June 2021, October 2021, February 2022, June 2022, October 2022

Advisory Council Review

May 2021, October 2021, January 2022, May 2022, October 2022, January 2023

Earliest Start Date

June 2021, November 2021, February 2022, April 2022, November 2022, February 2023

Expiration Date
September 08, 2022
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose:

The purpose of this funding opportunity announcement (FOA) is to support preclinical optimization and development of safe, effective, and non-addictive analgesic small molecule and biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising small molecule and biologic hits/leads towards Phase I clinical trials and readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) https://heal.nih.gov/research/clinical-research/eppic-net or other Phase II clinical studies. Applicants must have a promising small molecule or biologic hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, pharmacodynamic or target engagement biomarker development, assembly of an Investigational New Drug (IND) application, and phase I clinical studies. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress.

Background:

This study is part of the NIH's Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across the NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an over reliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments. This program announcement is intended to create a foundation to initiate the optimization and development of pain therapeutics and catalyze the development of partnerships between the academic and industrial sectors so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

To facilitate the discovery and development of therapeutics for pain researchers have the opportunity to collaborate with NIH-funded consultants and contract research organizations (CROs) that specialize in medicinal chemistry and Good Manufacturing Practices (GMP) manufacturing, pharmacokinetics, PET ligand development, biomarker assay validation, pharmacodynamics and related biomarkers,toxicology, formulations development, and Phase I clinical studies. The NIH offers researchers funding for drug discovery and development activities that can be conducted in their own laboratories.

This Funding Opportunity Announcement (FOA) invites applications for new non-addictive pain therapeutic projects. The Program Director/Principal Investigator (PD/PI) will be responsible for conducting or leading all studies that involve disease- or target-specific assays, models, and other research tools such as target engagement or pharmacodynamic biomarkers. A PD/PI with, for example, medicinal chemistry expertise and resources, may request funding to conduct structure-activity relationship (SAR) studies in his or her own lab but collaborate with contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies. By contrast, a PD/PI with limited experience in drug discovery and development may opt to collaborate with NIH contractors for all activities not related to disease or target biology. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with NIH contractors on activities of their choice.

For each project funded under this FOA, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PD/PI and a NIH consultant and will include members of the PD/PI's team, additional subject matter expert consultants, and NIH staff. The LDT will establish an overall strategy for the project, including milestones proposals, plan studies to be conducted by NIH contractors, and coordinate activities across different research sites.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss how they may best utilize NIH contract resources and whether their application fits the mission of a particular NIH IC. See also Applicant Webinar information under Section IV.7 below ("Other Submission Requirements and Information").

Scope:

This program announcement is specifically focused on the preclinical translational development necessary to advance small molecule and biologic non-addictive therapeutics for pain to Phase I clinical testing. The program supports preclinical optimization and development of small molecules and biologics leading to the assembly and submission of an IND application and the implementation of phase I clinical studies. The scope of this program excludes basic research, and studies of disease mechanism or mechanistic/mechanism of action studies of the intended therapeutic. Further, development of animal models, diagnostics, rehabilitation strategies, or therapeutic devices is out of scope.

General Entry Criteria:

Projects must enter at the UG3 phase of the program. Projects may enter the program at the Discovery or Development stage. For entry at the Discovery Stage, projects must have a promising small molecule or biologic starting point for optimization, a rigorous biological rationale for the intended approach, and scientifically sound assays to test the agent. Applications for entry into the Development stage must have identified the candidate therapeutic. In addition, a strong package of data linking the putative therapeutic target to the proposed disease indication and supporting the hypothesis that altering the target activity will produce desirable outcomes for the disease is required. Finally, the proposed therapeutic must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use.

For the UG3 phase, this FOA encourages projects proposing the following optimization activities:

  • Optimization using potency and efficacy screens
  • Preliminary efficacy and toxicology testing in appropriate animal models for pain
  • Characterization and testing for ADME (absorption, distribution, metabolism, and excretion)
  • Initial development of pharmacodynamic/target engagement biomarkers associated with the therapeutic target or pathway

It is expected that by the end of the UG3 phase, awardees will have characterized and selected a lead candidate that is ready for in vivo efficacy testing, though additional optimization may be necessary.

For advancement to the UH3 phase, the following development activities are in scope:

  • Any further optimization activities as listed above, if needed
  • Non-GLP toxicology studies (e.g. dose range finding toxicology)
  • Pharmacokinetics (PK)
  • Pharmacodynamic (PD) and related target engagement biomarker studies
  • Formulation and stability studies
  • Cell bank development and testing
  • Gene expression level
  • Biodistribution, tumorigenicity, and immunogenicity
  • Process development
  • Manufacturing of candidate therapeutics for IND
  • IND-enabling safety pharmacology, genotoxicity, hERG and toxicology studies

 Activities considered Nonresponsive of this Announcement

The following activities are considered nonresponsive:

  • Screening to identify hit compounds
  • Basic research and studies of disease mechanism
  • Animal model development
  • Development of diagnostics and diagnostic devices
  • Studies directed beyond Phase I clinical testing
  • Opioid sparing projects and projects targeting mu-opioid

Additional Resources

To support these projects, additional existing NIH resources may be made available to the applicant outside of this grant budget. Applicants are strongly encouraged to contact NIH staff to discuss these options. These resources include, but are not limited to the following:

NINDS

NINDS has established contract support for Medicinal chemistry (including synthesis/SAR, computational chemistry and in vitro ADMET), pharmacokinetic studies, toxicology (GLP and non-GLP) and safety testing, drug formulation and manufacture, and phase I clinical studies and can provide access to experts in therapeutics development through a consulting service. . Applicants must contact NINDS staff (contacts provided below) in order to utilize these resources and determine how to best leverage these as part of the application. As appropriate, applicants are encouraged to make use of the NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default).

NCATS

Applicants are also strongly encouraged to utilize the state-of-the-art capabilities at the NIH National Center for Advancing Translational Sciences (NIH/NCATS).Depending on the nature of the proposed collaboration, NCATS will make available its comprehensive capabilities in support of HEAL initiatives.The capabilities include, but are not limited to, screening and scalable production of relevant stem cells; biofabrication of 3D functional tissues for drug testing; using quantitative high-throughput screening to identify promising compounds to be optimized by medicinal chemists; and implementing IND-enabling studies. A more detailed description of the capabilities can be found at: https://ncats.nih.gov/heal/intramural-capabilities* and https://ncats.nih.gov/alliances/forms.

Milestones:

Because therapeutics optimization and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Go/No-Go milestones will be established by a team consisting of the PD/PI and NIH program staff at the start of each project and updated as needed. These milestones will be based upon a template outline of achievements necessary to progress through the stages of therapeutic development, but will be tailored to the specific therapeutic and its intended disease indication.

NIH program staff and leadership will conduct an annual administrative review. At the end of the UG3 phase, NIH program staff and leadership will determine if the project will advance to the UH3 phase. If needed, additional meetings to administratively review progress may take place. If justified, future year milestones may be revised based on data and information obtained during the previous project period. The reviews will be based on:

  • Successful achievement of milestones
  • The overall feasibility of project advancement, considering data that may not have been captured in milestones
  • Competitive landscape for the disease indication and drug target
  • HEAL Programmatic priorities
  • Availability of funds

Intellectual Property:

Since the ultimate goal of this program is to bring new pain therapeutics to the market, the creation and protection of appropriate intellectual property are significant considerations in designing research strategies and prioritizing projects for funding. Each applicant is expected to address intellectual property issues related to the proposed therapeutics, with input from the institution's technology transfer officials, if applicable. Peer reviewers will be instructed to comment on the intellectual property landscape for each application. The project milestone plan may include commercialization milestones to protect and leverage intellectual property. Recipients of awards are encouraged to identify potential licensing and commercialization partners early in the therapy development process. The PD(s)/PI(s) is encouraged to work closely with technology transfer officials at his or her institution, if applicable, to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. See Section IV.2.Other Project Information for details.

Implementation:

 The program provides funding through the UG3/UH3 cooperative agreement mechanism. As a cooperative agreement, implementation will involve participation of NIH program staff in the planning and execution of the therapy-directed projects. This program is envisioned as a two stage UG3 and UH3 program. The UG3 portion of the award is designed to support optimization research for the first two years. Our goal is to fund ~5 projects in each of FY21, FY22, FY23 appropriations permitting with projects having a limited budget for the first two years during the UG3 phase. Based on the progress to milestones, only a limited number of projects will proceed to the UH3 phase for the remainder of the award period which will include final optimization and development leading to IND-enabling studies, either through the grant budget or through contract resources outlined above.

IC-Specific Areas of Interest

NCCIH

The National Center for Complementary and Integrative Health (NCCIH) will support research on optimization and development of safe and non-addictive therapies for acute or chronic pain conditions, including chronic low back pain, that are treated with complementary and integrative health approaches. Examples of complementary and integrative health approaches relevant to this FOA include, but are not restricted to, herbal products, dietary supplements, special diets, microbial metabolites, probiotics, microbial based therapies, or a combination of any of these therapies with each other or with conventional pharmacological therapies.

NIAAA

NIAAA is interested in developing novel non-addictive small molecules/biologicals to treat alcoholic neuropathic pain as well as treatment options for coexisting chronic pain and excessive alcohol use/AUD subjects.

NICHD

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is interested in supporting research aimed at developing novel, non-addictive pharmacotherapies for (1) more effective and safer treatment of pain in pediatric or obstetric populations; (2) the treatment of chronic gynecologic pain syndromes, including vulvodynia/vestibulodynia, chronic pelvic pain, and dysmenorrhea, and post-operative gynecologic pain; (3) the management of persistent pain associated with multiple chronic conditions in individuals with physical impairments. Investigators are strongly encouraged to discuss their research plans with NICHD Scientific/Research contact prior to submitting their application.

NIDCR

The National Institute of Dental and Craniofacial Research (NIDCR) is interested in preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

NIDDK

 

The NIDDK encourages applications for research to develop therapies and technologies for pain conditions within the mission of NIDDK. Topics of special interest include, but are not limited to the pain associated with diabetic neuropathy; urologic chronic pelvic pain syndromes such as Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome; urinary stone disease and post-ureteroscopy stent-associated pain; functional gastrointestinal and motility disorders such as gastroparesis and irritable bowel syndrome; inflammatory bowel disease; hepatobiliary diseases such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and biliary dyskinesia; and exocrine pancreatic diseases such chronic pancreatitis.

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?
Optional: Accepting applications that either propose or do not propose clinical trial(s)

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NIH intends to fund an estimated 5 awards for fiscal year 2021. Future awards will depend on annual appropriations.

Award Budget

Application budgets must reflect the actual needs of the proposed project but should not include the costs of NIH contract resources requested.

Award Project Period

The total duration may not exceed 5 years. 

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Other

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

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

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

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

Required Registrations

Applicant organizations

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

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) – 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.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

 

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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

   

For applicants with interest in small molecules, the letter of intent should be sent to:

Charles Cywin, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: Charles.Cywin@nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

The following additional instructions apply:

 

Other Attachments:

Applications must include an Intellectual property (IP) strategy (2 pages maximum).

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

For Discovery stage projects, applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

For Development stage projects, applicants should describe their efforts to confirm that there are unlikely to be IP or other legal constraints that could block or impede development or commercialization of the proposed compounds. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

 

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

 Budget Justification: All for-profit applicants must document the matching (non-Federal) component and the federal (non-matching) component in the total project budget. That is, the requested budget plus the cost-matching budget must be detailed in tabular format to document the cost-matching (non-Federal) component and the federal (non-cost matching) component. The amount of matching is subject to adjustment based on total allowable costs incurred.  All costs and contributions used to satisfy the matching requirement must be documented by the recipient, including how the value for in-kind contributions was determined, and are subject to audit. The cost matching requirement is not negotiable for for-profit organizations.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specify whether the application is proposed for entry at the Discovery or Development stage. Clearly indicate within a table which activities will be conducted by PD/PI and associated personnel (i.e. funded by the UG3/UH3 award) and which activities will be conducted by NIH contract research organizations and/or consultants. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by NIH contractors need not be described in detail in the application since these will be planned after the award by the LDT. An overview of the goals, rather than a detailed plan, should be provided in the application.

Specific Aims: The Specific Aims section should include Aims delineated for the UG3 and UH3 phases.

Research Strategy:

The Research Strategy section should include the following subsections:

  • Clinical Impact (Significance)
  • Biological Rationale (Significance)
  • Testing strategy (Approach)
  • Team management (Approach)
  • Innovation
  • Table of proposed activities that provides the following information: Activity (optimization effort, assays, PK, etc.), throughput (e.g. samples per month), source (PD/PI lab, sub awardee, NIH Contractor), advancement criteria.

Clinical Impact (Significance):

Each application generally should focus on one or more specific pain condition(s). The target patient population and intended use guide the design of the drug and of the preclinical studies, such as toxicology and formulation.

For the specific pain condition(s) proposed, briefly describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed condition indication.

  • Briefly discuss available treatments, including all treatment modalities, and their limitations.
  • Discuss how the proposed project relates to therapeutics development efforts underway in academia and industry.
  • Provide a Target Product Profile (TPP), a table based on an FDA template that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy (see guidance and example at http://neuroscienceblueprint.nih.gov/resources/target-product-profile.htm). Explain why the minimally acceptable and ideal parameters offer advantages over currently available treatments and how they relate to other therapeutics under development.
  • Briefly comment on the feasibility of conducting clinical trials toward the goals in the TPP (e.g., availability of patients for clinical trials).
  • Describe the clinical expertise used to determine the goals of the drug development program and the clinical trial.

Biological Rationale (Significance):

  • Describe the intended biological target/pathway and pathophysiology. Indicate whether evidence from multiple groups supports this is a compelling target for the condition.
  • Provide the evidence that links this target to the particular pain condition proposed.
  • Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed pain condition.
  • Describe what is known about your agent(s) i.e., structure, function, identity, selectivity, bioactivity, potency, stability, production, etc.
  • Define desired characteristics of an optimized candidate including but limited to quantitative characteristics for structure/identity, in vitro testing 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.

Testing Strategy (Approach):

In this section applicants should elaborate on their research plans to achieve the ultimate goal of assembling an IND application and beginning a Phase I Clinical Trial by the end of the project. This can include a table indicating acceptable and ideal characteristics of the eventual lead therapeutic and a diagram of in vitro and in vivo screening funnels.

Include details on efforts to ensure the experimental design is rigorous. This includes, but is not limited to justification for model systems, endpoints, minimal requirements for agent purity, route and timing of delivery, adequacy of controls and sample sizes, description of statistical analyses, inclusions of measures to reduce bias, and plans for replication, if applicable.

Propose 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.
  • 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.
  • NIH 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.
  • Specify and provide details on what other NIH resources may be utilized in the project.

Team management:

Team building is an essential step in the development of the overall plan for therapeutics development. Because translational research is intrinsically interdisciplinary, the plan will often involve cooperation among basic researchers, experts in preclinical development, and clinicians, and may include the participation of private-sector companies and voluntary organizations.

  • Any collaborators, consultants, or subcontractors should be identified, no matter when during the conduct of the research activity the proposed interaction occurs.
  • 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 NIH, communication, etc.).
  • Explain how other NIH resources are or are not applicable to the project as appropriate.
  • Explain the plan for collaboration to develop pharmacodynamic or target engagement biomarkers.
  • Letters of support mustbe 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.

Innovation:

Explain how the project offers a novel approach to treating the proposed disease indication.

  • If therapeutics that target the same molecule, pathway, or cellular process have been tested in clinical trials for the proposed disease indication, explain why the proposed approach would be expected to provide a benefit over those therapeutics.
  • If drugs with similar structures have been tested in clinical trials for the proposed disease indication, explain why the proposed drug would be expected to give significantly better clinical outcomes.
  • Comment on the novelty of proposed approach, target, pathway, assays or models.

Letters of Support:

Applicants mustinclude letters of support from consultants, contractors, and collaborators not provided through NIH.

If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.

  • 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) will be needed and in place once the project is funded. This letter should come from a high official within the private entity who has authority to speak on these issues.
  • For-profit applicants must include a letter(s) of support confirming that the required secured cost matching (cash; in-kind commitments such as salary, consultant costs, equipment) is available and confirm that the essential personnel have the authority within the organization to allocate resources.

 

 

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

The following modifications also apply:

Investigators must follow the HEAL Public Access and Data Sharing policy https://heal.nih.gov/about/public-access-data.

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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) 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 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

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

Foreign Institutions

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

3. Unique Entity Identifier and System for Award Management (SAM)

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), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. 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) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Webinar

In order to learn more about this FOA and to have the opportunity to ask questions, a pre-application informational webinar will be held on September 15th from 3:00-4:00 pm EDT (12:00 -1:00pm PDT). Information on how to join the webinar is provided below:

RFA Webinar: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)

To join the web presentation, at least 10 minutes before the starting time:

1. Go tohttps://nih.webex.com/nih/onstage/g.php?MTID=e7de6b5b17d137af425ad083e5b7f9e69

2. Click "Join Now"

For audio you can follow the prompts on your monitor, or:

Call-in toll number (US/Canada): 1-650-479-3208
Access code: 126 784 1069


For assistance contact Tim Lyden at: timothy.lyden@nih.gov

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The NIH is encouraging applications for translational research that may involve standard methodologies applied toward novel therapeutic approaches. Therefore, a project that does not necessarily employ novel methodologies may still be essential to advance the field.

 

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

 

Evaluation of the approach should emphasize the biological rationale, the potential for identifying a candidate with suitable properties, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI. Any additional resources (e.g., contracts or consultants) provided by NIH should be presumed to be industry standard.

 

In addition, for applications involving clinical trials: A proposed Clinical Trial application should include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact

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).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the starting agent(s) robust and plans for optimization needed to achieve the desired candidate profile specified? Will the parameters proposed for optimization result in a candidate consistent with the requirements stated in the TPP? Is there evidence of clinical feasibility?

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?

Specific to this FOA:

 

If the project is successful in meeting its proposed Target Product Profile, will it result in the the development of safe, effective, and non-addictive small molecule and biologic therapies to treat pain as proposed in the application? Will there be significant hurdles the applicants are not considering? 

 

Scientific Premise: what is the robustness of the preliminary data provided in support of the target/intervention (can be molecular, cellular or system) for the intended pain condition? Were the unpublished and published data used in support of the application from rigorously designed experiments and are they 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 starting agent(s) robust and plans for optimization needed to achieve the desired candidate profile specified? Will the parameters proposed for optimization result in a candidate consistent with the requirements stated in the TPP? Is there evidence of clinical feasibility?

 

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?

 

 

In addition, for applications involving clinical trials

 

 Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?i

Investigator(s)

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?

Has an appropriate multidisciplinary team been engaged? Is 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 of successfully completing the activities needed to obtain an optimized therapeutic candidate? Are they appropriately leveraging NIH resources in a complementary fashion?

 
 

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA:

 

Would the proposed drug be expected to give significantly better clinical outcomes than have been observed in previous efforts focused on the same target? Will it offer a safer, effective, and non-addictive small molecule or biologic therapy to treat pain?
 

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

The NIH is committed to promoting rigorous and transparent research in all areas of science (see https://grants.nih.gov/policy/reproducibility/guidance.htm).

 

Specific to this FOA:

  • Are plans with all necessary steps to optimize the small molecule or biologic in order to obtain a candidate clearly spelled out?
  • Are proposed milestones appropriate?
  • Is the overall plan for therapy development through IND de novo submission practical, achievable, and of high quality? Can it be accomplished within the funding period?
  • Are there plans to develop a pharmacodynamic or target engagement biomarker that can be used in Phase I or II?
  • Are there adequate plans for optimization of the therapeutics, as appropriate?
  •  
  • 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

 

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable:

Phase I Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

 

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Specific to this FOA:

 

Are there any intellectual property constraints that potentially could impede the development of the therapeutic and/or commercialization and achievement of the goals of the program?

Study Timeline

Specific to applications involving Phase I clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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.

Vertebrate Animals

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.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Specific to this FOA:

 

Does the project appropriately leverage any existing NIH resources?

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by 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 will receive a written critique.

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

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke 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.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to 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.

 

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and SafetyMonitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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.

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.

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.

Cooperative Agreement Terms and Conditions of Award

The PD(s)/PI(s) will have the primary responsibility for:

  • Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this UG3/UH3.
  • Serving as co-chair of the project Lead Development Team (LDT).
  • With the LDT, assisting in the development of a project milestone plan at the outset of the project.
  • Hosting a face-to-face meeting at the outset of the project and working with NIH staff to assist in the development of a project milestone plan.
  • Presenting project updates (including raw data, when requested) in regular conference calls or other intermittent face-to-face meetings.
  • Coordinating and participating with NIH staff in all aspects of scientific and technical management of the project.
  • Collaborating and communicating effectively with NIH service contractors to achieve project goals.
  • Implementing all scientific and policy decisions approved by NIH staff or an oversight committee.
  • Submitting periodic milestone progress reports in a standard format, as agreed upon at the initiation.
  • Preparing for annual administrative site visits by NIH Program staff.
  • Ensuring that primary and secondary screening data and assay protocols developed as a part of this project are deposited in a centralized relational database a (NIH provided access) according to the timeline agreed upon by the LDT and the NIH Program Official and according to program policies.
  • Awardees agree to participate in the overall coordination of NIH research efforts in translational research in pain. This participation may include collaboration and consultation with other translational research awardees, and the sharing of information, data, and research materials.
  • Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
  • Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. Awardees are responsible for pursuing patent protection.
  • Submission of the IND application and scheduling meetings with the FDA.
  • Ensuring NIH staff and consultants on the LDT are included in all meetings with the FDA.
  • Providing protocol, supporting clinical documents and regulatory documents required for administrative review prior to clinical trial.

NIH staff has 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 NIH program staff who are assigned an administrative role for the target or pain condition being studied and have expertise in the implementation of NINDS cooperative agreement programs.
  • The NIH 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.
  • Providing the LDT with NIH consultants who can provide strategic and technical guidance.
  • NIH Project Scientists will coordinate and participate in LDT meetings to discuss project status, planning, and implementation
  • NIH Project Scientists will facilitate collaboration and data exchange among the awardee, NIH-contracted consultants, and service providers.
  • NIH Project Scientists will enhance the project progress by providing access to various NIH resources when appropriate.
  • NIH Project Scientists will assist in the development of a finalized project milestone plan at the outset of the project and approve the final milestone language for incorporation into the award notice.
  • NIH Project Scientists will be responsible for assessing the progress of the projects toward the accomplishment of specified milestones, and for recommending if further funds should be released to the project.
  • The NIH Project scientists will serve as scientific liaisons among the awardee and other NIH program staff and report periodically on the progress of the project to NIH leadership.
  • NIH Project Scientists will facilitate the establishment of contacts and collaborations between awardees and other persons or organizations whose participation will assist with the accomplishment of project goals. These persons or organizations may include the FDA, disease voluntary organizations, pharmaceutical companies, or research organizations that can provide essential services on contract.
  • An important part of the NIH HEAL Initiative is the coordination of research efforts across different funding mechanisms and research structures, and coordination among efforts aimed at different pain conditions. NIH Project Scientists will have the primary responsibility for this overall coordination and provide a perspective on the priorities of the HEAL Initiative and other NIH translational programs.
  • 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.

Leadership of the Institute/Center funding the project will make decisions on project continuation with input from NIH staff and/or any established oversight committee, based on:

  • Successful achievement of milestones
  • The overall feasibility of project advancement, considering data that may not have been captured in milestones
  • Based on emerging and published literature on competition for the disease indication and drug target
  • Program priorities
  • Availability of funds

Areas of Joint Responsibility include:

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 cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

 

 

Project Lead Development Team (LDT): The LDT typically will be co-chaired by the PD/PI and an NIH-contracted drug development consultant and will include additional members from the PI's group, consultants and NIH staff. This team will collaboratively set strategic direction and guide the workflow for the project on an ongoing basis. The LDT will meet approximately every two weeks via teleconference to analyze and interpret data from the PD/PI and contracted laboratories and to formulate the subsequent experimental plan. The LDT will propose milestones and produce progress reports for evaluation by an External Oversight Committee and program staff as needed.

The members of this collaborative effort are all made aware of the requirement for confidentiality due to the intent of the awardee to pursue commercialization of any qualified outcomes. Contractors and consultants of NIH will be made aware of the confidential nature of work done under this collaborative effort. The handling and disposition of this confidential data and business privileged information may be covered by the Trade Secrets Act, 18 U.S.C. Section 1905.

Dispute Resolution:

 

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

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.

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and 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)

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

Michael Oshinsky, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email:
michael.oshinsky@nih.gov

Charles Cywin, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email:
charles.cywin@nih.gov

Ann-Marie Broome, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779 
Email: 
Ann-Marie.broome@nih.gov

Hye-Sook Kim, Ph.D.

National Center for Complementary and Integrative Health (NCCIH)

Telephone: (301) 827 - 6910

E-mail: hye-sook.kim@mail.nih.gov

Mark Egli, Ph.D.

National Institute on Alcohol Abuse and Alcoholism

Phone: 301-594-6382
Email: Mark.Egli@nih.gov

Houmam Araj, PhD.

National Eye Institute (NEI)

Phone: 301-451-2020

Email: arajh@nei.nih.gov

Charles Washabaugh, PhD

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Telephone: 301.496.9568

E-mail: washabac@mail.nih.gov

Sam Ananthan, Ph.D.

National Institute on Drug Abuse (NIDA)

Email: 301-443-1887

Telephone: sam.ananthan@nih.gov

Zhaoxia Ren, MD, PhD

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Telephone: 301-402-9340

Email: zren@mail.nih.gov

Yolanda F. Vallejo, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4655
Email: yolanda.vallejo@nih.gov

Teresa L.Z. Jones, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301.435.2996
teresa.jones@nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

 

Shelley Carow

National Center for Complementary and Integrative Health (NCCIH)

carows@mail.nih.gov

301.594.3788

Karen Robinson-Smith
National Eye Institute (NEI)
Phone: 301-451-2020
Email: Karen.Robinson.Smith@nei.nih.gov

Judy Fox

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Telephone: 301-443-4704

Email: jfox@mail.nih.gov

 

Erik Edgerton

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Telephone: 301-594-7760

Email: edgertont@mail.nih.gov

 

Bryan S. Clark, M.B.A.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Telephone: 301-435-6975

Email: clarkb1@mail.nih.gov

 

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email: 
pfleming@mail.nih.gov

Diana Rutberg, MBA
National Institute for Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email:
rutbergd@mail.nih.gov

Eunica Haynes
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-827-4018
Email: haynese@mail.nih.gov

 

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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