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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

The goal of the NIAMS clinical trial program is to prevent or reduce symptoms and improve outcomes and function in patients with rheumatic, musculoskeletal or skin diseases. The purpose of the Exploratory Clinical Trials Grants Program is to foster clinical trials that will lead to clinically meaningful improvements in prevention, diagnosis, or treatment of these diseases.

Research Objectives

This Exploratory Clinical Trials Grants Program is designed to facilitate the execution of short-term, interventional studies. Such studies must meet the NIH definition of a clinical trial and be feasible within the time and budget constraints of this FOA. A high priority is the use of such studies to stimulate the translation of promising research developments from laboratory, preclinical, and early human testing into clinical practice.

The rationale for the proposed 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.

Examples of research areas of interest include, but are not limited to:

• Conducting early-stage safety/tolerability/dose/efficacy trials with drugs, biologics, devices, behavioral interventions, and/or physical therapy for treatment of arthritis, musculoskeletal, or skin disease.
• Clinical trials to provide data required to support a future, more robust clinical trial whose aim is to help establish the safety and efficacy or effectiveness of an intervention.
• Clinical trials in rare diseases where the number of potential study participants is limited.
• Clinical trials to determine the predictive value of a potential biomarker.

Applicants should take note of the following:

• Consultation with NIAMS: Applicants are encouraged to consult with NIAMS staff as plans for an application are being developed (see Section VII, Agency Contacts). This early contact will provide an opportunity to clarify NIAMS policies and guidelines as well as to discuss how to develop an appropriate project timeline and milestone plan, which is subject to peer review. Also, discussions regarding strategies for recruitment and inclusion of women and minorities are available.
• Efficacy/Effectiveness: This FOA is not intended to support the conduct of a large-scale clinical trial where the primary aim is to establish or confirm robust efficacy or effectiveness. Information for applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs or pivotal device trials) can be found at: http://www.niams.nih.gov/Funding/Clinical_Research/clinical_policy.asp.
• Rationale: The rationale for a trial should be based on: 1) unmet medical need(s); 2) plausible biological mechanism(s); and 3) compelling preclinical (in vivo, ex vivo and/or in vitro) data. If available, preliminary clinical data can be presented.
• Premise: There should be a discussion of the premise for the trial and how it supports the need to test the proposed hypothesis or intervention should be included; the premise should be well supported by preliminary data, information in the literature, and/or knowledge of biological mechanisms.

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.

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

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) 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.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other Attachments: The application must contain the following information, according to the instructions below, to provide evidence that the investigator(s) has planned a feasible clinical trial. The information provided here supports the Research Strategy. The following documents must be uploaded as separate pdf files with the names indicated below.

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 is expected to include the following information that supports the Clinical Trial Protocol Overview section in the Research Strategy:

• Brief and/or Official Protocol Title
• Intervention to be tested: A description of the intervention to be tested, and a brief description of the protocol to be followed in each arm of the trial.
• Intervention / dosage and frequency: If applicable provide a description of the dose frequency and type of administration of the intervention(s).
• Primary and important secondary endpoints: Specify the endpoints for the primary and, if applicable, important secondary endpoints.
• Study Population: A description of the study population, including the sample size, gender, age, demographic group, required health status, and geographic location.
• Inclusion/Exclusion Criteria
• Recruitment plans: A discussion of the availability of potential participants for the proposed study and the ability of participating sites to recruit and retain the proposed target number of participants.
• Retention plans: Approaches to be used for retention, cooperation and follow-up of those enrolled and to address any anticipated changes in the composition of the study population over the course of the trial.
• Group Assignment: Describe methods used to assign participants to study groups (treatment arms) and randomization.
• Subject Participation Duration: Time it will take for an individual participant to complete all study visits. When possible provide a brief snapshot of the protocol’s schedule of events capturing time points and planned activity at study visits. For example:
• Week 1 Screening/Baseline Visit (4 hours) - eligibility criteria, obtain informed consent, screening assessment(s), labs, etc.;
• Week 2,4,6,8, Study Visit(s) (3 hours) intervention(s), assessment(s), labs, scan(s) etc.;
• Week 12 and 18 Follow-up visits (3 hours) - assessment(s), labs, scan(s) etc.;
• Week 24 End of study visit (2 hours) - assessment(s), labs, scan(s) etc.
• Study Duration: Estimated time (in months) from when the study opens to enrollment until: (a) completion of data collection; and (b) final data analyses.
• Availability of Investigational Product (IP) and IND/IDE status: If applicable, provide a summary of the availability of IP and support for acquisition and administration. Please indicate the IND/IDE status of the IP, if applicable, and whether or not the investigators have had any interactions with the Food and Drug Administration (FDA). If the agent currently has an IND/IDE number, provide that information. Note that the NIH IC may request consultation with the FDA and the IND/IDE sponsor about the proposed clinical trial after peer review and prior to award.
• FDA info on early feasibility studies: If applicable, provide FDA info available on early feasibility studies.

Applications that lack the Clinical Protocol Synopsis are considered incomplete and will not be reviewed. 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. The statistical analysis plan should be matched to the type of trial being proposed.

• A concise description of the overall strategy, methodology, and analyses to be used to accomplish the goals and specific aims of the trial;
• A description of the proposed study design and rationale for its selection with respect to the translation of the clinical question into a statistical hypothesis;
• A description of the statistical methods that are appropriate for the study design, including sample size, duration of the trial; power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested should also be described. Provide justification for the primary and secondary outcome variable(s) and data to be collected, and the relevance to the clinical and statistical hypothesis being tested;
• A description of the methods for randomization, masking, and selection of control groups, and specific analytic techniques and plans for handling dropouts, missed visits, and losses to follow-up.
• Computer simulations: If computer simulations were performed to aid in the design of the trial, sufficient details about the simulations should be provided as part of the Statistical Analysis Plan. See the article, The design of simulation studies in medical statistics , by Burton et al., Statist. Med. 2006: 25:4279-4292 for guidance on how to document a simulation study. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

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 considered incomplete and will not be reviewed.

3. Milestone Plan: A Milestone Plan must use the filename "Milestone Plan.pdf."

The Milestone Plan provides detailed project performance and timeline objectives and must include a timeline for the following general milestones, as applicable:

• Finalization of clinical protocol (with program agreement, if applicable);
• Registration of clinical trial in ClinicalTrials.gov;
• Completion of regulatory approvals;
• Enrollment of the first subject;
• Enrollment and randomization, if applicable of 25%, 50%, 75% and 100% of the projected study population, including women, minorities and children (as appropriate);
• Completion of data collection time period;
• Completion of primary endpoint and secondary endpoint data analyses;
• Completion of final study report;
• Reporting of results in ClinicalTrials.gov;
• Other protocol-specific performance milestones and timeline; these milestones will be negotiated at the time of the award, if appropriate.

Applications that lack the Milestone Plan will be considered incomplete and will not be reviewed.

4. Clinical and Data Monitoring Plan: The Clinical and Data Monitoring Plan is a required attachment and must use the filename "Clinical and Data Monitoring Plan.pdf." The plan should reflect the size, complexity, and risk of the trial proposed.

Each Clinical and Data Monitoring Plan includes two parts: (A) The Clinical Monitoring Plan for the quality assurance of the proposed clinical trial through clinical monitoring activities, and (B) the Data Monitoring Plan for the quality controls proposed through data monitoring activities.

The NIH requirements for monitoring clinical trials as described below are in addition to the application's Data and Safety Monitoring Plan (DSMP) attachment on the PHS 398 Research Plan form which describes how patient safety in the trial will be monitored, and the regulatory requirement in 45 CFR 46 for on-going review and approval of all non-exempt human subjects research by the IRB of record.

• Part A: The purpose of the Clinical Monitoring Plan is to verify that the clinical trial is being conducted, and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Describe the persons/entity responsible for conducting the monitoring (e.g., contracted Clinical Research Associate, Data Coordinating Center, Independent study monitor from the Clinical Coordinating Center)

Describe the frequency of planned monitoring activities (e.g., Study Initiation, Interim Visits, Study Close Out), locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center) and what data will be reviewed.

Provide an overall description of the monitoring plan to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study intervention and system to record and manage exceptions and deviations. If applicable, describe monitoring of participating facilities such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Include a description to assure that the investigational product(s) accountability and reconciliation are performed adequately during and at the end of the trial per applicable regulatory requirements.

Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies the appropriate reporting to relevant authorities, including but not limited to the IRB of record, DSMB if one is assigned, FDA if applicable, institutional officials and the NIH.

• Part B: The purpose of the Data Monitoring Plan is to ensure that validated systems and controls are in place to assure the integrity of the clinical research data being collected for the proposed study:

Describe methods and systems for data collection (e.g., Case Report Forms/CRFs), data entry, data verification and data validation. Describe the data query process and frequencies and any planned mitigation strategies in the event of noncompliance.

Describe methods and systems to ensure data confidentiality and subject privacy.

Describe process for locking the final trial datasets and the planned procedures on data access and sharing, as appropriate.

Applications that lack the Clinical and Data Monitoring Plan will be considered incomplete and will not be reviewed.

5. Intervention Documents: The Intervention Documents attachment is required and must use the filename "Intervention Documents.pdf." The Intervention Documents should include one of the following documents according to the type of intervention(s) to be used in the proposed clinical trial:

Investigator's Brochure and Description: (provide for trials in which the interventions are other than behavioral or social). A compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects.

Intervention Monitoring Manual(s): (provide for trials in which the interventions are behavioral or social). A document that describes in detail the content and delivery of the intervention, the intervention manual should describe how to conduct the intervention, how to train the interventionists, how to monitor fidelity in delivering the intervention, and the rationale for the specified intervention.

Applications that lack the Intervention Documents will be considered incomplete and will not be reviewed.

6. FDA Documentation (if applicable)

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 justification in 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.

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.

Applications that lack the FDA Documentation (if applicable) will be considered incomplete and will not be reviewed.

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

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

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

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

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, if applicable, why the proposed trial is necessary to plan subsequent studies.

Premise: A discussion of the premise for the trial and how it supports the need to test the proposed hypothesis or intervention; the premise should be well supported by preliminary data, information in the literature or knowledge of biological mechanisms.

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; 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, applications should outline specific plans for future development, if applicable, in the event of promising results.

Study Design: A discussion of the trial protocol, which augments but does not repeat information from the clinical protocol synopsis, must be presented and must include the items listed below:

• A description of the study design (e.g., dose-escalation, open-label, crossover, factorial) and the rationale for this choice.
• A description of the target population, and why it is an appropriate group to address the hypotheses.
• A description of the intervention to be tested, how it will be administered, and how participants will be randomized. Relevant information that addresses the feasibility of supporting recruitment and retention estimates must be provided, including evidence that each recruiting center in the trial has access to a sufficient number of study participants who are likely to meet the eligibility criteria as defined in the submitted protocol. Evidence should be provided to support sufficient equipoise among the relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups), who consider the question to be important and the study acceptable.
• A discussion of the potential biases in the study and how they will be addressed.
• A summary of statistical methods including a discussion of the sample size and power calculations; study outcome measures; plans and rationale for interim analyses; plans for final analyses; methods of bias control; and methods for handling missing data.
• Biomarkers: Whenever possible, applicants are encouraged to include evaluation of early signals of activity utilizing biomarkers or surrogate endpoints that mechanistically test the activity of an intervention in terms of its presumed target. The use of early signals as primary outcomes is allowed, if sufficient solid rationale exists for its selection and the information is appropriately documented in the application.

Applicants planning Phase 2 clinical trials that require investigational new drug (IND) or investigational device exemption (IDE) applications should provide elements that are consistent with the requirements of the Food and Drug Administration (FDA) IND or IDE. The use of a protocol template for such studies is encouraged and can be found on the NIAMS Clinical Research Page.

Data and Safety Monitoring Plan: Do not duplicate information already covered in Other Attachment 4, Clinical and Data Monitoring Plan. Note that if an application is awarded, the NIAMS will organize an independent Data Safety and Monitoring Board or appoint a Safety Officer based on the risk and complexity of the trial.

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. This evidence may be supported by letters from stakeholders (e.g., professional organizations or patient groups).

Applicants are also encouraged to include documentation of the commitment of any subcontractors, companies providing study agents or other resources for the trial, 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 as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

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

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

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.

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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

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 clinical trials aimed at providing meaningful improvements in symptoms or function for patients with rheumatic, musculoskeletal or skin diseases. 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. 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.

The scientific review will include the evaluation of the experimental design and all of the review criteria described below. Reviewers will emphasize the overall impact of the study, including the conceptual framework, the level of innovation, and the potential to significantly advance our clinical knowledge or understanding.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA:

Have the investigators provided evidence of a sufficient body of preclinical or clinical research of high scientific rigor, preliminary data, or information in the literature or knowledge of biological mechanisms to support the study rationale/premise? Given the different types of clinical trials that can be submitted in response to this FOA, will this study answer the question that it is designed to address? Will the results of the proposed study be generalizable to other patients with the same condition(s)? Will this study, or a subsequent study informed by the data generated in this study, change the clinical outcome for patients with this condition(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?

Specific to this FOA:

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? Do these investigators have, or have access to, sufficient expertise in statistical analyses?

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

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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?

Specific to this FOA:

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 there adequate consultation with patients and other stakeholders in study design? Does the information provided in the application give reasonable assurance that the target sample size can be enrolled in the timeframe proposed?

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

Specific to this FOA:

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?

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

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

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

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

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

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

Not Applicable

Not Applicable

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.

Not Applicable

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

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

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

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

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

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

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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

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

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

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

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

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

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

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

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

Rheumatic Diseases:

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

Muscle Diseases:

Thomas Cheever, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: Thomas.Cheever@nih.gov

Orthopaedics:

Charles Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: Charles.Washabaugh@nih.gov

Bone Diseases:

Faye H. Chen, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-9997
Email: Faye.Chen1@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

Kathy Salaita, Sc.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5033
Email: Kathy.Salaita@nih.gov

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

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

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