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 Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Funding Opportunity Title

Exploratory Clinical Trial Grants in Arthritis and Musculoskeletal and Skin Diseases (R21)

Activity Code

R21 Exploratory/Developmental Research Grant  

Announcement Type

New

Related Notices

  • August 29, 2014 - See Notice NOT-AR-14-021. NIAMS Policy for Submission of Applications Containing Clinical Trials.
  • June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
  • May 1, 2014 - See Companions PAR-14-199, NIAMS Clinical Trial Planning Cooperative Agreement (U34) & PAR-14-200, NIAMS Clinical Trial Implementation Cooperative Agreement (U01).

Funding Opportunity Announcement (FOA) Number

PAR-14-192

Companion Funding Opportunity

 None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

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

93.846

Funding Opportunity Purpose

The goal of this FOA is to foster the development and implementation of interventional exploratory clinical trials aimed at providing clinically meaningful improvements in symptoms, function or disease course for patients with rheumatic, musculoskeletal or skin diseases.  The trials must address research questions related to the mission and goals of the NIAMS and may evaluate drugs, biologics, devices, or surgical, dietary, behavioral or rehabilitation therapies. This Exploratory Clinical Trials Grants Program is designed to facilitate the execution of creative, short-term interventional studies to obtain the experimental data needed to launch future clinical trials.  The proposed trials should strive to investigate new ideas and may use creative trial designs.  Proposed studies should focus on research questions that have the potential to contribute critical clinically-relevant data in support of a future, more robust clinical trial, or that can impact and benefit clinical decision making at the patient level.    

Key Dates
Posted Date
Open Date (Earliest Submission Date)

June 2, 2014

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

July 1, 2014; Nov 3, 2014, March 2, 2015, July 1, 2015; Nov 2, 2015, March 1, 2016, July 1, 2016, Nov 1, 2016, March 1, 2017, by 5:00 PM local time of applicant organization.

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)

Not Applicable

Scientific Merit Review

November/December 2014, March 2015, July 2015, November/December 2015, March 2016, July 2016, November/December 2016, March 2017, July 2017

Advisory Council Review

January 2015, May 2015, October 2015, January 2016,  May 2016, October 2016, January 2017, May 2017, October 2017

Earliest Start Date

April 2015

Expiration Date

March 2, 2017

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


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Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description


Purpose

The goal of this FOA is to foster the development and implementation of interventional exploratory clinical trials aimed at providing clinically-meaningful treatment improvements in symptoms, function or disease course for patients with rheumatic, musculoskeletal or skin diseases.  The trials must address research questions related to the mission and goals of the NIAMS and may evaluate drugs, biologics, devices, or surgical, dietary, behavioral or rehabilitation therapies.  This FOA encourages applications for exploratory clinical trials that provide some of the critical data required for a future trial whose aim is to establish efficacy or effectiveness (e.g., a future Phase 3 trial or a Pivotal device trial).  A wide range of trials at different stages of development are allowed and must aim to generate data that inform further clinical development of the proposed intervention.  Early-stage studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, efficacy, dosing).  Later-stage studies will generally include randomization and masking and should yield data that allow a clear go/no-go decision regarding whether the intervention should proceed to a larger trial to establish the safety and efficacy of the intervention. 

Research Objectives

This Exploratory Clinical Trials Grants Program is designed to facilitate the execution of creative, short-term interventional studies that may utilize emerging novel clinical trials designs to obtain the experimental data needed to launch future clinical trials.  The objectives may require a more flexible (i.e., adaptive) approach to design so that changes can be made in response to accumulating results, and the analysis may entail data exploration that is pre-specified in the protocol.  The rationale for the proposed exploratory study should be supported by strong preclinical data. Preliminary data specifically related to clinical effect of the proposed intervention in the targeted condition are not required for R21 applications; however, they may be included if available. The proposed trials should strive to investigate new ideas and/or clinical trial approaches designed to focus on research questions that have the potential to contribute critical, clinically-relevant data in support of a future, more robust clinical trial, or that can impact clinical decision making at the patient level. Ideally, these studies are expected to generate data of value to future clinical trials or patient care by gathering evidence of a clinically-meaningful improvement in the efficacy, tolerability, dose response, and/or toxicity of a new or available therapeutic intervention (or their combination) in a population relevant to the NIAMS mission.

Rare diseases research groups are especially encouraged to use this mechanism for pilot trials to be conducted at multiple Institutions necessary to obtain an adequate number of patients.  A high priority is the use of such studies to help stimulate the translation and implementation of promising research developments from laboratory, preclinical and early human testing into clinical practice. 

Specific examples of research areas of interest include, but are not limited to those listed below:

Applicants should take note of the following:

Exploratory Investigational New Drug (IND)/Early Feasibility studies: The proposed project may be an exploratory IND study with very limited human exposure as defined by the FDA. See the following Section for the necessary IND/IDE documentation: Section IV. Application and Submission Information, 2. Content and Form of Application Submission, SF424 (R&R) Other Project Information, Other Attachments, FDA Documentation.The following web addresses provide additional useful FDA guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf) or early feasibility studies of devices as defined by the FDA, and http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103.pdf.

PDs/PIs who are seeking support only for drug development and do not have access to medicinal chemistry and drug development expertise are encouraged to consider other programs for those areas which are available through individual NIH Institutes. Note that the Bridging Interventional Development Gaps (BrIDGs) (http://www.ncats.nih.gov/research/rare-diseases/bridgs/bridgs.html), previously the NIH Rapid Access to Interventional Development (NIH-RAID) Program (www.nihroadmap.nih.gov/raid), offers investigators access to IND-directed services on a competitive basis, and investigators who are seeking support for such studies are encouraged to apply there.  

Section II. Award Information
Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Direct costs are limited to $400,000 over the three-year period (exclusive of consortium/subcontractual Facilities and Administrative (F&A) costs).  A detailed (non-modular) budget must be used for applications requesting greater than $250,000 direct cost in any single year.

Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is three years.

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

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

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.

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

Section IV. Application and Submission Information


1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

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

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

Page Limitations

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

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

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.  

Other Attachments:

1. Clinical Protocol Synopsis

The filename "Clinical Protocol Synopsis.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The clinical protocol synopsis must include the following information:

Applications that lack the Clinical Protocol Synopsis are incomplete.  The NIAMS may require a complete clinical protocol prior to award.

2. Statistical Analysis Plan

The filename "Statistical Analysis Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

This plan is critical to knowing whether applicants have selected the correct cohort size based on proper power calculations and/or are using the most appropriate methods to analyze the resulting data and make correct conclusions at the end of the study.

Applications that lack the Statistical Analysis Plan are incomplete. 

3. Organizational Structure

The filename "Organizational Structure.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Descriptions of the organization of the study and how the trial will be managed; the role of any internal and external committees (e.g., executive committee, endpoint adjudication committee), and the responsibilities and oversight of any central laboratories/reading centers or resource centers (e.g., drug distribution center).

Applications that lack the Organizational Structure are incomplete.  

4. Data and Safety Monitoring (DSM) Plan

The filename "Data and Safety Monitoring Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The DSM plan should be commensurate with the risk level of the proposed clinical research and must be included for all clinical trials (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board (IRB)), the Office of Biotechnology Activities (as appropriate), the Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board (if one is used).

The DSM Plan must address the following areas:

For exploratory clinical trials it generally will be acceptable for the data and safety monitoring to be conducted by an investigator-appointed Study Monitoring Committee (SMC), an Independent Medical Monitor (IMM), or, for single-site trials involving low risk, the Program Director/Principal Investigator and his/her IRB.  However, NIAMS may decide to establish an independent Data and Safety Monitoring Board (DSMB) depending on the risk of the trial to participants.  Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) as well as the NIAMS Guidelines for Data and Safety Monitoring (http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp#2).

Applications that lack the DSM Plan are incomplete.

5. FDA Documentation

The filename "FDA Documentation.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

At the time of grant submission, if the intervention is a drug, biologic, or device, applicants must provide proper documentation with respect to the FDA IND/IDE submission and provide information on one of the following four scenarios:

(a) The protocol has been submitted to the FDA under an open IND/IDE and the IND/IDE is not under full or partial clinical hold.  Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.

(b) The protocol has been submitted to the FDA under an IND/IDE and is on full or partial hold.  Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations.

(c) The protocol is exempt from an IND/IDE.  Under this scenario applicants must provide a copy of the exemption letter (e.g. 21 CFR 312.2) from the FDA or, if a nonsignificant risk device, the applicant must provide proper justificationin accordance with: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046164.

(d) Evidence of, 1) pre-IND/IDE meetings with the FDA that are planned or have been held, and 2) a timeline for IND/IDE submission.

Applications that lack the FDA Documentation are incomplete.  Prior to grant award, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NIAMS, especially if the trial has been placed under full or partial clinical hold.

6. Timeline

The filename "Timeline.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers. 

 Applicants should include a proposed timeline for reaching important study milestones such as: (a) obtaining regulatory approval of the final protocol; (b) establishing agreements with participating industry partners, if indicated; (c) obtaining adequate supply of the investigational agent; (d) finalizing the study procedures and training participating clinical site staff; (e) enrolling 25%, 50%, 75% and 100% of the sample size; and (f) completing all subject follow-up and data collection activities.

Applications that lack the Timeline are incomplete.

7. Plans for Future Development

The filename "Plans for Future Development.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

All applications must outline specific plans for future development in the event of promising results.  For early stage trials, such as first-in-humans or limited human exposure to establish dosing, safety and tolerance, as well as proof of mechanism or proof of concept clinical trials, applicants should clearly detail the clinical development plan (CDP) for the intervention. For a later stage clinical trial of a drug, biologic or device, specific plans for the next steps of the therapy's development (such as a future efficacy trial) must be succinctly stated.

Applications that lack the Plans for Future Development are incomplete.

SF424(R&R) Senior/Key Person Profile

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

At least one individual listed as a key person should have experience in the conduct of clinical trials and one key person should have expertise in the disease area. Such experience should be documented, including timely submission of primary publications from previous trials or studies.  Both key persons must devote adequate time and effort to the study. The application also should indicate the prior experience of study team members in clinical trial design and implementation.

Most clinical trials will require a multidisciplinary team (clinician, statistician, data manager, study coordinator, etc.) and the application should reflect their hands-on involvement in the design and implementation of the study protocol.

R&R or Modular 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:

Specific Aims: The specific aims of the exploratory clinical trial must be clearly and concisely presented.  The primary and major secondary hypotheses to be evaluated must be clearly stated.

Research Strategy:

Clinical Significance and Biological Relevance: The significance and, when applicable, the biological relevance of the proposed clinical trial must be clearly stated.  It is particularly important that there be discussion of how the trial will test the primary hypothesis and how the results of the trial (positive or negative) will advance the field.  The application should explain why the proposed trial is necessary to plan for subsequent studies.

Prior Studies and Rationale for Development: The major findings of the preclinical and/or clinical studies that led to the proposed clinical trial should be described accordingly to support the rationale for the trial.  Pilot studies that show the need for and the feasibility of the trial should also be discussed.  Study conceptualization and planning must be at a stage sufficient to allow for an assessment of the likelihood of trial success.

Applications should address the reasons for consideration of the intervention.  This may include preclinical in-vitro and in-vivo data.  Animal efficacy data should be included in the rationale only when the model and read-out are considered sufficiently associated with the human condition.  Other considerations are toxicology data (e.g., whether the FDA has found the toxicology data to be acceptable to proceed with the proposed trial); medicinal chemistry/pharmacology data (e.g., whether the formulation is feasible and the pharmacokinetics acceptable for use as intended in the trial); regulatory considerations (e.g., details on FDA, European Medicines Agency (EMA), and other agencies’ evaluations; discussion of the likelihood of regulatory approval based on acceptability of endpoints, orphan drug status, etc.); public health impact if subsequent efficacy trials are conducted and positive; ethical dimensions; and patient perspectives on acceptability of the proposed intervention. Characteristics of any preliminary research results provided in support of the proposed project, whether conducted by the applicant or others, should be described in the application so that peer review may evaluate the strength of the supporting evidence.  If preclinical data (e.g., animal studies) supporting evidence for the trial are not conclusive, the applicant should discuss the limitations of those data. In addition, all applications must outline specific plans for future development in the event of promising results.

Study Design: A discussion of the trial protocol must be presented and must include the items listed below: 

Inclusion of Minorities and Women: NIH policy requires that women and minorities be included in clinical trials, unless it is not scientifically justifiable.  Applicants must include a plan to enroll women and minorities, unless it is not scientifically justifiable.  Factors that may contribute to successful recruitment of minorities and women include: appropriate site selection, patient or community engagement for the major elements of the project, and the use of focus groups to address barriers to inclusion.  Applicants should include a discussion of how the gender and minority findings will be reported to the NIAMS.

Letters of Support: Applicants are encouraged to include letters from patient organizations or other supporting documentation to show that patients were included as partners in the concept development and design of the trial.

Applicants are also encouraged to include documentation of the commitment of any subcontractors, companies providing study agents or other resources for the trial,  and consultants as well as service agreements for personnel or facilities.  Letters of commitment must be co-signed by the business official of the collaborating center.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

A data sharing plan is strongly encouraged.

NIAMS expects the primary outcome paper of the trial to be submitted for publication within twelve to eighteen months of completion of subject follow-up.

Appendix:  Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.      

NIAMS expects that the following additional documents will be included in the Appendix material of the application in the order listed below:

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

3. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

Documentation of regulatory approvals (e.g., Institutional Review Board, Recombinant DNA Advisory Committee) must be provided to NIH prior to funding.   

6. 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 Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The goal of this initiative is to foster the development and implementation of interventional clinical trials aimed at providing clinically-meaningful treatment improvements in symptoms, function or disease course for patients with rheumatic, musculoskeletal or skin diseases.  This Exploratory Clinical Trials Grants Program is designed to facilitate the execution of creative, short-term interventional studies and obtain the experimental data needed to launch future clinical trials.  The objectives may require a more flexible approach to design so that changes can be made in response to accumulating results, and the analysis may entail data exploration. Evaluation of the applications will  include the scientific rationale/premise of the study and the study design as outlined in detail under Approach.  Where applicable, preclinical data used to support the rationale for the study will be evaluated for scientific rigor of the experimental design, for the strategies used to minimize bias, for the robustness and reproducibility of the reported results, and for consideration of alternative interpretations.  The scientific review also will focus on the overall impact of the study and will include the evaluation of the experimental design and all of the review criteria described below. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our clinical knowledge or understanding. Appropriate justification for the proposed work can be provided through rigorous literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data specifically related to clinical effect of the proposed intervention in the targeted condition are not required for R21 applications; however, they may be included if available.

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? 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?

Is completion of this exploratory project likely to enhance the design and/or conduct of future trials? 

Have the investigators provided evidence of a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale/premise?

Is it clear why the proposed exploratory trial is essential to inform the design and implementation of subsequent steps in the evaluation of the intervention?

Is the proposed project likely to yield clear answers needed to proceed to the next step of the therapeutic development of the intervention as proposed in this application?

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? 

Is there at least one individual listed as a key person who has experience in the conduct of clinical trials and at least one key person who has expertise in the disease area? Is such experience documented, including submission of primary publications from previous trials or studies?

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? 

Does the proposed trial have the potential to advance the field (e.g., by elucidating critical aspects of the pathogenesis of the disease or by breaking ground for future trials in this area) even if (a) the proposed study design, methods, and intervention are not innovative, and/or (b) the results of the trial indicate that further clinical development of the intervention is unwarranted?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

Are the outcome measures, dose/duration of study, appropriateness of inclusion/exclusion criteria, sample size, power calculations, clearly justified and explained in the application? 

Are there adequate plans for management and quality control of data collected at clinical sites or measured at central laboratories and reading centers?

Is the proposed design feasible and adequate to provide interpretable results?

Is there adequate consultation with patients and other stakeholders in study design (e.g., inclusion of a patient representative on the Steering Committee)?

Does the information provided in the application give reasonable assurance that the target sample size can be enrolled in the timeframe proposed?

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

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? 

Have necessary agreements with participating industry partners, if necessary, been established?

Is there documentation of the commitment of any subcontractors and consultants as well as service agreements for personnel and facilities?

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.

General Considerations

Is there evidence that all necessary regulatory approvals have been obtained or are being

sought?

Are the proposed project milestones (particularly regarding participant accrual goals) and timeline feasible and appropriate for the timely completion of the study?

If an IND or IDE is needed to conduct the trial, is there evidence that the study investigators have received an IND/IDE, have submitted an IND/IDE application, or have had pre-IND/IDE meetings with the FDA?

Plans for Patient Recruitment/Retention

Does the application document the following:

Availability of the requisite eligible subject pool in proposed clinical center(s);

Status of evidence showing whether or not clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected (see Inclusion of Women and Minorities in

Clinical Research below);

Appropriate plans and adequate site selection for the inclusion of minorities, women and children (unless exclusion is scientifically justified);

Plans for recruitment outreach and, as appropriate, follow-up procedures to ensure collection of data at stated intervals; and retention plans and practices? 

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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

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.

Clinical Trial Documentation

Are the clinical trial documentation materials sufficient to allow adequate training of study staff and recruitment of study subjects?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIAMS, 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:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information


1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: commons@od.nih.gov

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Rheumatic Diseases:

James Witter, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-1963
Email: witterj@mail.nih.gov 

Osteoarthritis and Diagnostic Imaging:

Gayle Lester, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-3511
Email: lester1@mail.nih.gov

Muscle Diseases:

Glen Nuckolls, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-4974
Email: nuckollg@mail.nih.gov

Orthopaedics:

James Panagis, M.D., M.P.H.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-3513
Email: panagisj@mail.nih.gov

Bone Diseases:

Faye H. Chen, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-9997
Email: chenf1@mail.nih.gov

Skin Diseases:

Ricardo Cibotti, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-5888
Email: ricardo.cibotti@nih.gov

Peer Review Contact(s)

Chuck Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-496-9568
Email: washabac@mail.nih.gov

Financial/Grants Management Contact(s)

Mark Langer
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-8216
Email: langerm@mail.nih.gov  

Section VIII. Other Information

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

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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