Required Application Instructions

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

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

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

Background

Clinical research is a significant NIAMS investment aimed at answering critical questions about a particular disease or disease process. It is essential to support clinical studies to test promising new interventions with the potential to improve health practices and clinical care. Special attention must be paid to enabling these important studies to get through the administrative processes at a reasonable pace so that the conduct of the study, analysis of data, and dissemination of results are not delayed.

The NIAMS is committed to identifying effective approaches to address the burden of arthritis and musculoskeletal and skin diseases and disorders. Improving health through the generation of high quality data from well-designed and executed clinical trials is a high priority for the NIAMS.

A clinical trial is defined by NIH as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

The NIAMS has redesigned its clinical trials program in order to support the spectrum of such studies with funding mechanisms tailored to different levels of complexity. For clinical trials involving a relatively small number of subjects and short-term interventions, applications should be submitted to PAR-14-192, Exploratory Clinical Trial Grants in Arthritis and Musculoskeletal and Skin Diseases (R21). Clinical observational studies (studies that do not involve an intervention) that aim to obtain information necessary for designing future clinical trials and feed into the other components of the NIAMS overall program should be submitted to PAR-15-115, Clinical Observational (CO) Studies in Musculoskeletal, Rheumatic, and Skin Diseases (R01)." For trials involving greater numbers of subjects or of greater complexity or risk, investigators should apply for funding through this NIAMS Clinical Trial Implementation Cooperative Agreement (U01) for a single- or multi-site trial. These larger and more complex trials require substantial planning and preparation prior to opening for recruitment, and investigators are expected to be able to begin the trial without further planning activities when the U01 is awarded. In order to accomplish necessary planning with NIAMS support, investigators may apply for a NIAMS Clinical Trial Planning Grant (U34) prior to submitting an application for the U01 to implement the trial. The planning grant will allow an investigator to accomplish the planning activities (manual of operating procedures, FDA approvals, etc.) that are often necessary for actually implementing a clinical trial. Investigators who have already completed planning activities either by a previously awarded NIAMS U34, R34, or other means may also submit a U01 implementation application, but are strongly encouraged to consult with NIAMS staff in advance. Investigators considering applying to the NIAMS for a clinical trial award should refer to the NIAMS Clinical Trials Policy web site. Information about NIAMS Policies, Guidelines and Sample Templates for Clinical Trials at: http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp.

Overview of NIAMS Clinical Trials Policy

Clinical Trial Planning Phase (U34)

The first phase of the NIAMS clinical trials award process is the Clinical Trial Planning Cooperative Agreement (U34) which will provide the support for planning activities necessary for implementation of a clinical trial. The U34 is generally expected to precede the submission of a U01 Clinical Trial Implementation Cooperative Agreement application, although this is not a requirement Note that an application for the U01 may be submitted while activities other than those required for the elements requested in the Research Plan or Appendix continue in the U34-funded planning phase. However, the materials to be developed in the U34 planning phase should be completed by the time the U01 is to be awarded, and investigators are expected to be ready to implement the proposed trial at the time of the U01 award.

Clinical Trial Implementation Phase (U01)

Once appropriate planning and milestones have been completed, either through a U34 or some other means, investigators may apply for the U01 Clinical Trial Implementation Cooperative Agreement.

Each U01 clinical trial implementation application will include the clinical protocol, a Clinical Investigator's Brochure where appropriate, or other equivalent document(s) that contain(s) relevant non-clinical and preclinical data on study products, and a Manual of Procedures, and meet all applicable NIAMS, NIH, Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) policy requirements. Information about Institutional Review Board and Independent Ethics Committee (IRB/IEC) registration and assurances can be found at http://www.hhs.gov/ohrp. The NIAMS strongly encourages the use of a central IRB.

Information to guide Investigators for preparation of clinical trial implementation can be obtained from the NIAMS Scientific/Research staff. NIAMS clinical research policy and guidance information as well as NIAMS templates for the manual of operating procedures, and data and safety monitoring are available at the following website: http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp.

Examples of studies that might be supported by this FOA include, but are not limited to:

• Clinical trials focusing on the prevention or treatment of a rheumatic, musculoskeletal or skin disease or disorder;
• Clinical trials to investigate safety, efficacy, or effectiveness of novel therapeutic approaches for one or more of these conditions;
• Clinical trials testing methods to increase preventive health behaviors for one or more of these
• conditions.

Each NIAMS U01 Clinical Trial Implementation Cooperative Agreement award will support the implementation of a single clinical trial.

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).

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

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

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

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

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

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

The letter of intent should be sent to:

Shahnaz Khan, MPH
Telephone: 301-594-2463
Fax: 301-402-7478
Email: khanshah@mail.nih.gov

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:

Milestone Plan:

A Milestone Plan must be included in Other Attachments. Applications that lack the Milestone Plan will be considered incomplete and will not be reviewed.

Applicants are required to provide detailed project performance and timeline objectives in a section entitled Milestone Plan and must include a timeline for the following general milestones, as applicable:

• Completion of regulatory approvals
• Enrollment of the first subject
• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment time period for all study subjects, including women, minorities and children (as appropriate)
• Completion of data collection time period
• Completion of primary endpoint and secondary endpoint data analyses time period
• Completion of final study report
• Detailed protocol-specific performance milestones and timeline; these milestones will be negotiated at the time of the award, if appropriate.

Clinical Protocol Synopsis:

A Clinical Protocol Synopsis must be included in Other Attachments. Applications that lack any of the Clinical Protocol Synopsis elements listed below will be considered incomplete and will not be reviewed.

• A description of the study population, including subject eligibility and inclusion/exclusion criteria;
• Sampling, recruitment and enrollment plans, including a discussion of the availability of subjects for the proposed study and the ability of enrollment center(s) to recruit and retain the proposed number of subjects;
• The process to be used for obtaining informed consent and, if applicable, assent;
• Approaches to be used for retention, cooperation and follow-up of subjects and to address any anticipated changes in the composition of the study population over the course of the trial;
• If appropriate to the study, a description and justification for the selection of the dose, frequency and administration of the intervention(s);
• A description of each enrollment site and how data from the site(s) will be obtained, managed, and protected. Describe plans to address the possibility of adding or dropping enrollment centers.
• Describe the appropriateness of the organizational structure, particularly the administrative, data coordinating, enrollment and laboratory/testing centers, for the single- or multi-site trial proposed;
• Provide evidence of the ability of the individual center(s) to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure;
• Descriptions of all clinical, laboratory, physiological, and/or behavioral tests to enable the research questions to be answered;
• A description of the data management and quality control plan, including methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; and data confidentiality and subject privacy;
• Identification and qualifications of clinical trial site(s), pharmacies and laboratories;
• A comprehensive Laboratory Plan;
• Documentation of availability of study agents and support for acquisition and administration of study agent(s); and
• The Site Quality Management Plan.

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 goals of the trial and the expected outcome(s) should be concisely stated in the Specific Aims section. The specific objectives of the trial must be clearly and concisely presented, including a specification of the primary and major secondary endpoints to be measured. There should be a clear explanation of the importance of various endpoints.

Research Strategy: The Research Strategy should include:

• A discussion of the significance of the problem being studied and how the trial will test the hypothesis(es) proposed; discuss whether this clinical trial is necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy;
• A description of the need for a clinical trial to test the proposed hypothesis or intervention. The premise for the trial should be well supported by preliminary data, information in the literature or knowledge of biological mechanisms;
• 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 rationale for the proposed study design and its adequacy. Describe the translation of the clinical question into a statistical hypothesis;
• A description of the intervention to be tested and the protocol to be followed in each arm of the trial, including a discussion of potential biases or challenges in the protocol and how they will be addressed;
• A description of the statistical methods that are appropriate for the study design, including sample size, duration of the trial, and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested. 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;
• A description of the study organization and administration, including, but not limited to: a description of committee structures needed to manage the complexity of the trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any subcontractors or service providers for personnel or facilities, and the impact of the organizational structure on the scientific goals of the project; and
• If a Phase III trial, describe how the potential findings are likely to be generalizable. Describe any ethical issues surrounding the trial and the disease/condition under study. Provide 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).

Protection of Human Subjects: A Data and Safety Monitoring (DSM) Plan that is commensurate with the risk level of the proposed clinical research must be included for all clinical trials (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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. 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 NIAMS/NIH, 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:

• Who will manage and conduct the monitoring?
• What will be monitored?
• Proposed monitoring time points
• Where the monitoring will occur
• How the reportable events will be managed and reported
• How site (s)/center (s), and participating facilities (labs, pharmacies) will be monitored

Inclusion of Minorities and Women in Clinical Trials: 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. 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. As well, applicants should include a discussion of how the gender and minority findings will be reported to the NIAMS.

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.
• Applications should describe plans to ensure that the data and biospecimens are collected in a manner that will promote appropriate data sharing and integration into larger databases (e.g., use of common data elements, see http://cde.nih.gov/), consistent with achieving the goals of this program. Applications should address strategies to ensure that data collected in a manner that could allow other researchers to analyze the data, including conducting meta-analyses, and provisions to support rapid sharing of trial data, as appropriate.

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.

The following additional documents must be included in the Appendix material. Applications that lack the documents listed below will be considered incomplete and will not be reviewed.

• Complete Clinical Protocol
• Informed consent form(s) and, if applicable, assent form(s)
• Copies of data collection forms, questionnaires or other relevant materials
• Investigator’s Brochure or equivalent for the study products(s)
• Table of Contents of the Manual of Procedures

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 10 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide. Applicants should go to the NIAMS website for information about what to include in their Letter of Request http://www.niams.nih.gov/Funding/Clinical_Research/clinical_letter_request.asp.

Prior consultation with the NIAMS at least 10 weeks prior to the application due date is strongly encouraged for submission of the NIAMS U01 Clinical Trial Implementation application, including new and resubmission applications. NIAMS staff will consider whether the proposed clinical trial meets the goals and mission of the Institute and whether it is appropriate to conduct it as an investigator-initiated clinical trial, but will not evaluate the technical and scientific merit of the proposed trial. Technical and scientific merit will be determined during peer review. In the presubmission consultation phase, if the proposed trial does not meet the goals and mission of the NIAMS, applicants will be so informed. If the NIAMS ascertains that substantial additional planning may be necessary, the investigator(s) will be encouraged to submit an application for the Clinical Trial Planning Grant Cooperative Agreement (U34) FOA, and delay the submission of the U01.

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

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

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

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

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

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the application present a clear rationale for the proposed hypothesis or intervention? Is the premise for the proposed intervention well supported by preliminary data, information in the literature or knowledge of biological mechanisms? Would the results of the proposed trial change clinical practice, community behaviors or health care policy? If a Phase III trial, are the potential findings likely to be generalizable? Are there ethical issues surrounding the trial and the disease/condition under study? If a Phase III trial, is the status of evidence showing whether or not clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected addressed (see Inclusion of Women and Minorities in Clinical Research)?

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? What are the qualifications of the trial statistician and data center staff to implement and monitor the study, analyze and report study results? What are the plans to address the possibility of adding or dropping enrollment centers? Is the organizational structure, particularly the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the single- or multi-site trial proposed?

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

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?

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?

Is the required study population available? Is the experimental design adequate and does it address the translation of the clinical question into a statistical hypothesis? Are the general statistical approach and specific analytic techniques as well as plans for handling dropouts, missed visits, and losses to follow-up appropriate? Are the sample size and duration of the trial appropriate? Are the primary and secondary outcome variable(s) and data to be collected clear, and are they relevant to the clinical and statistical hypothesis being tested? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed?

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

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

Organizational Plan

Is the proposed organizational structure for the single-site or multi-site trial appropriate? What impact does the organizational structure have on the scientific goals of the project? Is there evidence of the ability of the individual center(s) to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure?

Data Management

Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed?

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

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

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

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

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

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

For Renewals, the committee will consider the progress made in the last funding period.

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

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

Clinical Trial Documentation

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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 submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Arthritis and Musculoskeletal and Skin Diseases 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.

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

All aspects of the study, including any modification of study design, conduct of the study quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators, including setting up and convening any external advisory or steering committees. The awardee agrees to accept close coordination, cooperation, and participation of NIAMS staff in those aspects of scientific and technical management of the study as stated in these terms and conditions:

• Meeting NIAMS policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. (http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp). Upon implementation of the protocol, each site , whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, data collection, and quality control;
• Managing involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by the NIAMS;
• Making all study materials and procedure manuals available in the public domain. Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIAMS/NIH; and
• Awardees who do not accomplish the negotiated milestones shall submit a milestone report which will include a discussion of why the milestones were not met in the agreed upon timeframe, and propose a corrective recruitment action plan. The corrective recruitment action plan shall include: amended milestones, plans to achieve the amended milestones and any additional items required by NIAMS staff. The plan shall be provided to NIAMS staff no later than 2 months following the missed milestone;
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

The NIAMS Project Collaborator will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAMS staff, including the Project Collaborator, may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies;

• Provide guidance and support in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational drugs, to the Food and Drug Administration;
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), provision of research resources and reagents available from the NIAMS grantees and contractors, advising in management and technical performance, or participating in the preparation of publications;
• Review the progress of the study, and of each participating facility, through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting;
• Oversee the adequacy of adverse event management and reporting, and have regular communications with the PD/PI and study team, which may include attendance at the safety monitoring (or DSMB) and related external advisory committee meetings or steering committee meetings;
• Monitor progress of study milestones. At each scheduled interim review, compare actual enrollment to the benchmarks and criteria identified in the application and negotiated prior to award;
• Studies in which recruitment milestones are not met as per criteria established pre-award, or for which regulatory approval has not been met within one year, and are deemed unlikely to improve sufficiently to bring the study to completion within an acceptable budget or time frame, may be closed for lack of progress following review and consideration by NIAMS staff (including the Project Collaborator):
  • If a study is finally determined to lack feasibility and will no longer accrue subjects, awardees are required to submit a close-out plan to NIAMS staff (including the Project Collaborator) within three months of a decision either by NIAMS Project Collaborator or the grantee that an awarded study is no longer feasible. The plan must be approved and signed by the Institutional Official and the PI/PD(s) listed on the award prior to submission;
  • The NIAMS may terminate or curtail the study (or an individual award) in the event of (a) failure to implement the study protocol, (b) a substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which the NIAMS does not concur, (d) reaching a major study objective substantially before schedule with persuasive statistical evidence, or (e) human subject ethical issues that may dictate a premature termination;

In addition, an agency program official or IC program director may be responsible for the normal scientific and programmatic stewardship of the award and may be named in the award notice.

Areas of Joint Responsibility include:

Data Safety and Monitoring Board: An independent Data and Safety Monitoring Board will be established by the NIAMS. The Data and Safety Monitoring Board will review interim results

periodically as established in the data and safety monitoring plan and report to the NIAMS Project Collaborator. The NIAMS Project Collaborator will report in writing to the PD/PIs on the recommendations of the DSMB and the NIAMS concurrence/non-concurrence of the DSMB recommendations. The PD/PIswill assume responsibility for reporting of the DSMB and the NIAMS recommendations to their respective Institutional Review Boards.

Dispute Resolution:

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

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

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

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

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
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)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Shahnaz Khan, MPH
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-2463
Email: Khanshah@mail.nih.gov

Anna Nicholson, MSHS
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-2463
Email: nicholsona@mail.nih.gov

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

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