Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Funding Opportunity Title	NIAMS Clinical Trial Implementation Cooperative Agreement (UM1)
Activity Code	UM1 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	July 14, 2011 - See Notice NOT-AR-11-020 Notice of Updated NIAMS Policy for Investigator-Initiated Clinical Trials. May 27, 2011 - See Companion PAR-11-219 NIAMS Clinical Trial Implementation Cooperative Agreement (U01). March 18, 2011 - See Notice NOT-AR-11-014 Notice of New NIAMS Policy for Investigator-Initiated Clinical Trials.
Funding Opportunity Announcement (FOA) Number	PAR-11-168
Companion FOA	PAR-11-169 (U34)
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.846
FOA Purpose	This Funding Opportunity Announcement (FOA) issued by the NIAMS invites cooperative agreement (UM1) applications for implementation of investigator-initiated interventional clinical trials (all phases). Applications for clinical trials submitted to the NIAMS are normally expected to go through a two-part process, which begins with a (U34) planning phase (Part 1) followed by an application for the (UM1) clinical trial implementation phase (Part 2). See PAR-11-169 for information about the NIAMS Clinical Trial Planning Cooperative Agreement (U34). Investigators who have completed all necessary pre-trial planning and preparation through other means may also apply for a NIAMS UM1. Consultation with NIAMS staff is strongly encouraged prior to the submission of the clinical trial implementation UM1 application. The NIAMS expects such trials to be hypothesis-driven, milestone-defined, related to the research mission of the NIAMS, and considered high priority by the Institute.

Posted Date	March 18, 2011
Letter of Intent Due Date	30 days after publication date, August 15, 2011, December 15, 2011, April 15, 2012, August 15, 2012, December 15, 2012, April 15, 2013, August 15, 2013, December 15, 2013
Application Due Date(s)	July 1, 2011, November 1, 2011, March 1, 2012, July 1, 2012, November 1, 2012, March 1, 2013, July 1, 2013, , November 1, 2013, March 1, 2014 , by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	October/November 2011, February/March 2012, June/July 2012, October/November 2012, February/March 2013, June/July 2013, , October/November 2013, February/March 2014, June/July 2014
Advisory Council Review	January 2012, May 2012, October 2012, January 2013, May 2013, October 2013, January 2014, May 2014, October 2014
Earliest Start Date(s)	April 1, 2012, July 1, 2012, December 1, 2012, April 1, 2013, July 1, 2013, December 1, 2013, April 1, 2014, July 1, 2014, December 1, 2014
Expiration Date	March 2, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 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. While some links are provided, 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.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH s Applying Electronically website.

Part 1. Overview Information
Part 2. Full Text of 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

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 prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. Behavioral human subjects research involving an intervention to modify behavior (diet, physical activity, cognitive therapy, etc.) fits this definition of a clinical trial. Human subjects research to develop or evaluate clinical laboratory tests (e.g., imaging or molecular diagnostic tests) might be considered to be a clinical trial if the test will be used for medical decision making for the subject or the test itself imposes more than minimal risk for subjects (SF424).

As announced in NOT-AR-11-014, published concurrently with this announcement,

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 trials involving greater numbers of subjects or of greater complexity or risk, investigators should apply for funding through a NIAMS Clinical Trial Implementation Cooperative Agreement (UM1). These larger and more complex trials require substantial planning and preparation prior to opening for recruitment, and investigators are expected to apply for a NIAMS Clinical Trial Planning Grant (U34) prior to submitting an application for the UM1 to implement the trial. The planning grant will allow an investigator to accomplish the planning activities (manual of operating procedures, FDA approvals, etc) which are often necessary for actually implementing a clinical trial; applicants for a Clinical Trial Implementation Cooperative Agreement are expected to be able to begin the trial without further planning activities when the UM1 is awarded. Investigators who have already completed planning activities either by a previously awarded NIAMS U34, R34, or other means may also submit a UM1 implementation grant application, but are strongly encouraged to consult with NIAMS staff in advance. Investigators considering applying to the NIAMS for a clinical trial grant should refer to the NIAMS Clinical Trials Policy web site.

Investigators are strongly encouraged to contact their Program Officer prior to submitting applications for a U34 clinical trial planning grant or UM1 clinical trial implementation grant. Applicants are also strongly encouraged to submit a Letter of Intent (LOI) to the NIAMS before submission of an application for either a U34 or a UM1, including new and resubmission applications. Applicants are encouraged to allow enough time before the planned receipt date, particularly if there has been no prior consultation with the NIAMS about the application. LOI should be submitted to the Scientific/Research contacts listed in the FOA who will share the request with the appropriate Program Officer. This program announcement, NIAMS CLINICAL TRIAL IMPLEMENTATION COOPERATIVE AGREEMENT (UM1), addresses the implementation phase; a companion FOA addressing the design and planning of the trial (U34) is also available (PAR-11-169).

Overview of the NIAMS policy for investigator-initiated clinical trials

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 intervention 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 has determined that investigator-initiated, interventional clinical trials requesting NIAMS support should undergo a rigorous planning, design, and documentation phase before a decision is made to implement a study with a substantial fiscal and human investment. The implementation of a clinical trial requires extensive administrative planning (e.g., protocol finalization, manual of operations development, establishing collaborations and estimating recruitment potential) before participant recruitment can occur. The NIAMS is offering this two-part process that separates planning from subject recruitment and study implementation to provide adequate support and facilitate the timely implementation of the studies important to the mission of the institute. In addition, use of the cooperative agreement mechanism will allow NIAMS programmatic input during the early planning stages and throughout the conduct of the actual clinical trial.

Part 1: Clinical Trial Planning Phase (U34)

The first phase (Part 1) of the NIAMS clinical trials grant process is the Clinical Trial Planning Cooperative Agreement (U34) which is expected to precede the submission of a clinical trial cooperative agreement (UM1) application. The NIAMS will support clinical trial planning grants (U34) for complete planning, design and documentation of investigator-initiated Phase I, II, III, or IV clinical trials. The U34 grant will provide up to two years of support for clinical trial planning, though many planning grants will only require one year. Applicants are strongly encouraged to consult with NIAMS staff prior to submission of a U34. The use of a Letter of Intent is also encouraged. U34 applications will be peer-reviewed by a standing clinical trials review committee managed by the NIAMS Scientific Review Branch. U34 awardees who have met specified milestones, as defined in their U34 application and agreed upon by NIAMS in consultation with the investigator(s) prior to the award of their U34, may submit a cooperative agreement application (UM1) for clinical trial implementation (details are presented in this FOA). Note that once these milestones are met, the application for the UM1 may be submitted while other activites continue in the U34-funded planning phase. However, the materials to be developed in the U34 planning phase should have been completed by the time the UM1 is to be awarded, and investigators are expected to be ready to implement the proposed trial at the time of the UM1 award.

If the investigators conclude that a clinical trial is not warranted, the reasons for not proceeding with the UM1 implementation application should be documented in a final report to the NIAMS that summarizes the U34 award activity.

Part 2: Clinical Trial Implementation Phase (UM1)

Once appropriate planning and milestones have been completed, either through a U34 or some other means such that the clinical trial would be ready to implement by the time the UM1 is awarded , investigators may apply for a the Clinical Trial Implementation Cooperative Agreement (UM1). The investigators must be ready to implement the proposed trial by the time the UM1 is to be awarded.

Each clinical trial implementation application will use the PHS398 application and include the clinical protocol, Clinical Investigator's Brochure where appropriate, or other equivalent document(s) that contain(s) relevant non-clinical and preclinical data on study products, a Manual of Procedures, and meet all applicable NIAMS, NIH, Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) policy requirements. Planning grant awardees must prepare their protocols, Clinical Investigators' Brochures, and Manuals of Procedures to meet this guidance (see http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_guidelines.asp for the NIAMS’s Clinical Protocol and Manual of Procedures guidelines). Information about Institutional Review Board and Independent Ethics Committee (IRB/IEC) registration and assurances is found at http://www.hhs.gov/ohrp/.

A clinical trial implementation cooperative agreement application should describe all necessary components to successfully conduct a clinical trial. Implementation support is defined as support for activities related to the conduct of the clinical trial, including, but not limited to:

• training of study personnel;
• enrollment and recruitment of study subjects;
• data collection, management and quality control;
• laboratory work and data analyses;
• study management and oversight;
• establishment of committees to manage the complexity of the trial;
• preparation of the final study report; and
• other related post-enrollment activities.

Resources that may be available to support clinical trials during clinical trial implementation can be obtained from the NIAMS program staff. NIAMS clinical research policy and guidance information as well as NIAMS templates are available at the following website: http://www.niams.nih.gov/Funding/Clinical_Research/NIAMS_sample_documents.asp

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

• Clinical trials to investigate safety, efficacy, or effectiveness of novel therapeutic approaches;
• Clinical trials focusing on the prevention or treatment of rheumatic diseases, orthopaedic or bone disorders;
• Clinical trials testing new therapeutics or management strategies for muscle disorders or skin diseases; and
• Clinical trials testing methods to increase preventive health behaviors

Each NIAMS Clinical Trial Implementation (UM1) award will support the implementation of a single clinical trial. Applications that include more than one clinical trial will not be reviewed.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities..
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The maximum amount of time requested for a clinical trial implementation cooperative agreement may not exceed five years.

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

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

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 Organizations) are not eligible to apply.

Foreign (non-U.S.) components of U.S. Organizations are allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) 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 PHS398 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. It is expected that each application will be for a clinical trial for which investigators will have completed all necessary pre-trial planning and preparation either through a NIAMS clinical trial planning cooperative agreement (U34) or by other means such that the trial will be ready to be implemented when the UM1 is awarded.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the PHS398 Application Guide.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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.

Applicants are strongly encouraged to submit a Letter of Intent to the NIAMS before submission of the NIAMS Clinical Trial Implementation Cooperative Agreement (UM1) application, including new and resubmission applications. Applicants are encouraged to allow at least 10 weeks before the planned receipt date, particularly if there has been no prior consultation with the NIAMS about the application.

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 research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The letter of intent should be sent to:

Shahnaz Khan, MPH
Division of Extramural Research Activities
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Democracy One, Room 810, MSC 4872
Bethesda, MD 20892 (use 20817 for overnight courier delivery)
Telephone: 301-594-2463
Email: khanshah@mail.nih.gov

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and all copies of the appendix files must be sent to:

Charles Rafferty, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Democracy One, Room 818, MSC 4872
6701 Democracy Blvd.
Bethesda, MD 20892 (use 20817 for overnight courier)
Telephone: 301-594-5019
Email: raffertycn@mail.nih.gov

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed with the following requirement:

• Research Strategy section is limited to 30 pages.

All instructions in the PHS398 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, which is limited to one (1) page. The specific objectives of the trial must be clearly and concisely presented, including a specification of the primary and major secondary endpoints to be mesured. There should be a clear explanation of the importance of various endpoints.

Research Strategy

The following three sections comprise the Research Strategy: Significance, Innovation, and Approach. In addition, the Research Strategy may not exceed 30 pages and must include:

• A discussion of the significance of the problem being studied, the need for the trial, and the potential for the results of the trial outcomes to affect health care, policy or practice, as well as how the trial will test the hypothesis(es) 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 rationale for the proposed study design;
• 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;
• Statistical methods that are appropriate for the study design, including sample size and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested;
• A discussion of studies that led to the proposed clinical trial and information or data from preliminary studies which address the need for and the feasibility of the trial; and
• 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.
• Statistical Analysis Plan

Milestone Plan

A Milestone Plan must be included in the research strategy. Applications that lack the Milestone Plan will be considered incomplete and will be returned without review.

Applicants are required to provide detailed project performance and timeline objectives in a section entitled Milestone Plan. It is recommended that this section not exceed three (3) pages 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.

Instructions in the PHS398 Part II Supplemental Instructions for Preparing the Protection of Human Subjects Section of the Research Plan should be closely followed.

The clinical protocol synopsis should be included at the end of the Human Subjects section. Applications that lack the Clinical Protocol Synopsis will not be peer reviewed. It is recommended that the clinical protocol synopsis not exceed five (5) pages and must include the following information:

• 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;
• Methods of assignment of subjects to study groups and of randomization;
• 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;
• Descriptions of all clinical, laboratory, physiological, and/or behavioral tests to enable the research questions to be answered; and
• 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)
• the Site Quality Management Plan

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 sites/centers, and participating facilities (labs, pharmacies) will be monitored

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS) as provided in the PHS398 Application Guide, with the following modifications:

• 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 (please note all format requirements) as described in the PHS398 Application Guide, with the following modifications:

The following additional documents should be included in the Appendix material:

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

Not Applicable.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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 received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review , NIH. Applications that are incomplete will not be reviewed.

Prior Consultation. Prior consultation with the NIAMS is strongly encouraged for submission of the NIAMS Clinical Trial Implementation (UM1) Grant 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 informed that the proposed trial does not meet the goals and mission of the NIAMS. If the NIAMS ascertains that substantial additional planning may be necessary, submission of the application may be considered under the Clinical Trial Planning Grant (U34) Cooperative Agreement FOA (insert link to companion FOA). The NIAMS reserves the right to determine that support for clinical trials may be directed through other available mechanisms supported by the NIAMS.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 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 PHS398 Application Guide. Applicants should go to the NIAMS website for information about what to include in their Letter of Request.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

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/priority score to reflect their assessment of the likelihood for the triall 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 triall 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 triall that by its nature is not innovative may be essential to advance a field.

Significance

Does the triall address an important problem or a critical barrier to progress in the field? If the aims of the triall are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is there preliminary data or literature or biological mechanisms supporting the need for a clinical trial to test the proposed hypothesis or intervention? Is there potential of the outcome to 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?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers well suited to the triali? 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 plans are there to address the possibility of adding or dropping enrollment centers? If a multicenter trial, is the proposed organizational structure, particularly the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate?

Innovation

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

Approach

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

Are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion 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 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?

Environment

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

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

Organizational Plan (Multi-site Clinical Trials). Is the proposed organizational structure appropriate? What impact does the organizational structure have on the scientific goals of the project? Is there evidence of the ability of the individual centers 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 procedure for data management to assess the effect of the intervention and quality control been addressed? Are the general statistical approach and specific analytic techniques and plans for handling dropouts, missed visits, and losses to follow-up appropriate?

Clinical Trial Documentation (Clinical protocol synopsis, Clinical Investigator s Brochure or equivalent, and MOP or equivalent). Are the materials complete, appropriate, and adequate to allow training of study staff and recruitment of study subjects if a cooperative agreement award is made? Are all of the clinical trial documents compliant with Good Clinical Practice (GCP) guidelines?

Plans for Patient Recruitment/Retention. Does the application document the availability of the requisite eligible subject pool in the proposed clinical centers? 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 (see Inclusion of Women and Minorities in Clinical Research below) addressed? Are plans for recruitment outreach, and as appropriate, follow-up procedures to ensure collection of data at stated intervals adequate? Are the plans for retention and criteria for withdrawal clear?

Adequacy of Data and Safety Monitoring Plan: Is the safety monitoring plan adequate? Does it address the risks involved and ethical aspects of expected risks? Does it discuss risk-benefit balance? Does it address informed consent procedures, a safety monitoring plan, and provisions for early termination? Are there plans for a Data and Safety Monitoring Board (required if a study is multi-site, blinded, and using a high risk intervention or population)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

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

Revisions

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 for recommended 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 trial 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/priority score.

Applications from Foreign Organizations

Not applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIAMS.(assignments will be shown in the eRA Commons), in accordance with NIH peer review policy and procedures, using the stated review criteria.

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/priority 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 and 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 NAMS Advisory Council . The following will be considered in making funding decisions:

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

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

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 business official.

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

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

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

Have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAMS staff 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 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.

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 within three months of a decision either by NIAMS staff 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.

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

Areas of Joint Responsibility include:

1. Steering Committee

For multi-center trials, a Steering Committee organized by the NIAMS Program Director will be the main oversight body of the study. The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols, approve the common protocols, facilitate the conduct of participant follow-up, monitor completeness of data collection and timely transmission of data to the DCC, and report various study results. It will also be responsible for establishing study policies in such areas as access to patient data, publications and presentations, and performance standards. Major scientific decisions regarding the core data will be determined by the Steering Committee.

The Steering Committee will be composed of all PD/PIs (data coordinating center and clinical centers), the NIAMS Project Scientist and others from the DCC, the clinical sites and the NIAMS as deemed necessary; however, only the principal investigators and the NIAMS Project Scientist or designee will be voting members.

A Chairperson for the steering committee will be selected by the NIAMS Program Director from among the PD/PIs. The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2. 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 Program Director. The NIAMS Program Director will report in writing to the Steering Committee on the recommendations of the DSMB and the NIAMS concurrence/non-concurrence of the DSMB recommendations. The PD/PIs will 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 Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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.

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

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

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

Charles Rafferty, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5019
Email: Raffertycn@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 Parts 74 and 92.