Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Neurological Disorders and Stroke (NINDS)
Funding Opportunity Title	NINDS PHASE III Investigator-Initiated Multi-Site Clinical Trials (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	Reissue of PAR-10-198
Related Notices	July 22, 2013 - This PAR has been expired and reissued as PAR-13-278. March 25, 2013 - See Notice NOT-NS-13-023. Notice to Extend the Expiration Date. February 6, 2013 - See Notice NOT-NS-13-006; NINDS Policy for Submission of Applications Containing Clinical Trials. July 15, 2011 - See Notice NOT-NS-11-018 NINDS Policy for the Requirement of Authorization from the Food and Drug Administration (FDA) to use an Investigational Drug, Biologic Product or Device in a Clinical Trial Prior to Submission of an Application.
Funding Opportunity Announcement (FOA) Number	PAR-11-173
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.853
FOA Purpose	The purpose of this Funding Opportunity Announcement (FOA) is to provide a vehicle for submitting grant applications for investigator-initiated, multi-site, randomized, controlled Phase III clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS). The trials may address any research question related to the mission and goals of the NINDS. Information about the mission, strategic plan and research interests of the NINDS can be found at the NINDS website (http://www.ninds.nih.gov/).

Posted Date	March 22, 2011
Open Date (Earliest Submission Date)	May 5, 2011
Letter of Intent Due Date	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date(s)	Standard dates apply
Expiration Date	(Now Expired July 22, 2013 per issuance of PAR-13-278); (Extended to September 8, 2013 per NOT-NS-13-023), Originally May 8, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

Purpose:

The purpose of this Funding Opportunity Announcement (FOA) is to provide a vehicle for submitting grant applications for investigator initiated multi-site Phase III randomized, controlled clinical trials. The trials may address any research question related to the mission and goals of NINDS.

NIH defines a Phase III trial as a broadly based prospective Phase III clinical investigation to evaluate an experimental intervention in comparison with a standard or control intervention or to compare two or more existing treatments. The definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based intervention trials also are included.

Multi-site clinical trials are trials that recruit study subjects from two or more geographically distinct enrollment sites, or centers. The sites are usually distinct in other characteristics (e.g. demographic, socioeconomic, or clinical). Subject enrollment and study protocols are followed at these sites.

Background:

Phase III clinical trials are the most complex and challenging trials to design and implement. For completion within the funding period and budget awarded clinical trials need extensive planning and proactive oversight. Prior to beginning patient enrollment several steps need to be completed during a start up period, including creating a manual of procedures, finalizing case report forms, building the research database, contracting sites, obtaining IRB approval, training study personnel, etc. The time and effort required to complete these steps are often underestimated. In addition to lengthy study start-up, slow participant enrollment can cause trial delays and result in the need of additional funding in order to complete the planned trial. Preventing trial failure due to poor planning, enrollment and retention requires anticipatory and flexible management to ensure that the completion of the trial is feasible within the award made to the grantee. The purpose of this FOA is to provide a mechanism suitable for the submission and successful implementation of a large, complex phase III clinical trial, incorporating several stages to allow the investigators and NINDS to assess study progress and feasibility.

Objectives of the Program:

The proposed research must address a scientifically important question, must provide valuable information to the existing knowledge base, and must have public health applicability. Research topics should be based on the NINDS' strategic plan and research interests.

A phase III trial is conducted to provide a definitive answer regarding the safety and efficacy of an intervention. The main interest resides in falsifying the null hypothesis that the treatment is not effective. The trial design should therefore primarily ensure that high quality, complete data regarding the primary outcome will be collected in the most efficient manner in terms of time, resources and burden to participants. Secondary outcomes should be included only when they are anticipated to provide important supportive or explanatory evidence. This FOA should also be used for the submission of an adaptive trial designed with a seamless phase II/III transition where data from subjects participating in the Phase II portion of the trial are used in the evaluation of Phase III. If the trial is designed to require more than 5 years to complete (i.e., long-term endpoint, extended follow-up, adaptive design, etc.) the applicant must provide a description of the plans for the entire trial including plans for the submission of a type 2 application for the additional years beyond this 5 yr application and include the total estimated cost and duration of the trial within the research strategy section of this application. Proposed milestones (described in the next section) should be included for the entire trial. The inclusion of this information will be used for planning purposes and to support the rationale for the full trial. The impact/priority score assigned to this application will be based on the five year application submitted and will not guarantee the successful funding of the type 2 application.

Biological activity, pharmacodynamic response, or preliminary clinical efficacy should be evaluated in an appropriately designed phase I/II exploratory clinical trial. Such applicants should refer to the NINDS Exploratory Clinical Trials programs PAR-10-199.

Ancillary studies, defined as research activities undertaken to address a scientific question relevant to the parent study and that require access to data or records from the parent study and/or involve collection of additional data, specimens, or records from patients enrolled in the parent study, are not permitted within the phase III clinical trial application. Ancillary studies to this trial may be submitted separately using the Ancillary Studies in Clinical Trials of CNS/PNS Disorders NINDS Accelerated Awards Program (http://grants.nih.gov/grants/guide/pa-files/PAR-09-263.html).

NINDS requires the submission of separate applications for the Clinical Coordinating Center (CCC) and the Data Coordinating Center (DCC). Separate applications for core functions (e.g., imaging centers, quality of life/economic analyses) may be submitted, but are not required. For the purposes of peer review all of these applications will be considered as a cluster and will be reviewed together and receive the same impact/priority score and summary statement. When multiple applications are submitted as part of a cluster, then all the pre-submission requirements for applications requesting direct costs of $500,000 or more in any one year apply when the combined budgets of the clustered applications equal or exceed $500,000 (see section IV.6 for submission instructions).

The NINDS Phase III program is designed to structure the submission and facilitate the execution of a phase III trial. Applicants are strongly encouraged to consult with NINDS program staff as early as possible prior to the anticipated application submission date (see Agency Contacts, Section VIII). Applicants requesting direct costs of $500,000 or more for all components of the trial (e.g., CCC, DCC, etc.) in any one year (excluding consortium F&A costs) should also consult the NINDS Guidelines for submitting large/expensive clinical research projects in order to obtain Institute approval to submit the application http://www.ninds.nih.gov/research/clinical_research/policies/large_projects.htm.

Experimental Approach and Implementation:

The proposed experimental approach should include a randomized design and clear description of the study population, subject eligibility and inclusion/exclusion criteria; regulatory status (e.g. open IND or report on pre-IND meetings and IND status); recruitment and retention strategies; methods of randomization; methods of avoiding bias (e.g. blinding); primary and secondary endpoints and outcome measures; treatment and any follow-up procedures; and quality control procedures. Applicants should provide a plan for using Common Data Elements (CDE; see: http://www.commondataelements.ninds.nih.gov/) in their study case report forms and include a specific data sharing plan in the application. Statistical methods should be proposed that are appropriately matched to the study design and include sample size and power calculations, plans for analysis, planned interim analyses, and data management. Statisticians sometimes use computer simulations to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, taking into account the impact of such factors as noncompliance, dropout, missing data, and subject eligibility criteria (risk profile). If simulations were performed to aid in the design of this clinical trial, sufficient details about the simulations should be provided (possibly in an appendix to the trial protocol) to assure that the simulations were performed and analyzed in a valid manner. See the article, The design of simulation studies in medical statistics , by Burton et al., Statist. Med. 2006: 25:4279-4292 for guidance on how to document a simulation study. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations reveal. The application must include the status of regulatory approvals as necessary to conduct the proposed research (e.g., open IND/IDE, or report on pre-IND/IDE meetings and IND/IDE status, or exemption letter from FDA if applicable, and/or status of RAC approval, etc). IRB approval at the coordinating center is strongly preferred but not required at the time of submission. NINDS requires FDA and IRB approval at the coordinating center prior to award, and encourages investigators to seek regulatory and ethics approvals as early as possible prior to submission. The implementation of the clinical trial will be divided into three stages and is expected to include the following activities (described as milestones in the application as described above):

1. Planning and Start-up stage:

• Finalize protocol, study procedural manual, consent forms, and data management plan.
• Develop data management system and case report forms, based on NINDS common data elements whenever possible.
• Receive approval from the NINDS appointed Data and Safety Monitoring Board (DSMB).
• Initiate contracts, start-up and training of study personnel at the proposed performance sites (NINDS expects the initiation of all study sites to occur in the start-up stage or if a large number of sites are needed a plan that describes how additional sites will be started after the initiation of the trial.).
• Initiate process for including proposed international performance sites (if applicable).
• Register trial with www.clinicaltrials.gov/.

2. Feasibility stage:

• Complete contracts, initiation, and training of additional performance sites including any international sites if used.
• Achieve acceptable enrollment rate that ensures the trial can be completed as proposed in the application.

3. Completion stage:

• Complete enrollment and follow-up of all study participants.
• Minimize loss to follow up.
• Analyze data, submit primary outcome paper for publication, and register results in clinicaltrials.gov within one year of completion of all subject follow-up.
• Provide public access to complete data set within 2 years of publication of the primary outcome paper.

The information provided in the application should be organized in a manner that will facilitate peer review. The body of the application must present an overview of the state of the science, current status of therapeutics for the disease, and relevance of the trial for treatment of the disease. Also, in the body of the application, the methodological aspects of the protocol, and approach to data collection and analysis should be presented in summary only, with specific references to additional information and details provided in the protocol (submitted as appendix).

The award and continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies (see NINDS policy for continuation of phase III clinical trials; NOT-NS-10-009).

Institute Staff Involvement

Under this Cooperative Agreement (U01) mechanism, NINDS will have substantial continued staff involvement in the award and execution of this clinical trial award. NINDS staff will closely monitor progress during the award. This monitoring will include oversight of the IRB approved protocol by the NINDS Program Official, documentation of adequate serious adverse event management and reporting, and regular communications with the PD/PI and staff; additional involvement generally includes participation in meetings of the steering committee and other leadership committees.

The Terms and Conditions for an award for a clinical trial will include recruitment milestones expected to be met by the study as a whole at specific time periods, accrual goals for women and minorities (as appropriate), and any other identified requirements for completion of the approved research.

As with any award, continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NINDS will consider ending support and negotiating a phase-out of the award. The NINDS retains the option to obtain periodic external peer review of progress.

Due to the unique requirements of the NINDS Phase III Clinical Trials Program, applicants are strongly encouraged to consult with NINDS Program Staff early on during the planning for an application. This early contact will provide an opportunity to clarify the applicant's understanding of NINDS policies and guidelines, including the scope of projects within the NINDS and the requirement that trial objectives be milestone-driven. These discussions also provide important information and guidance on how to develop an appropriate timeline and milestone plan, which are subject to peer review under this program. Pre-application consultation includes an introductory call to discuss the scope and goals of the program (at least 3 months prior to submission), followed by a conference call or in-person meeting with NINDS staff.

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 SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period	The maximum request cannot exceed 5 years but the actual funded project period is dependent on reaching specific milestones as described in this FOA.

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)

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

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) 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
• Grants.gov
• 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 Program 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 SF 424 (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.

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 SF 424 (R&R) Application Guide.

Applicants may submit a renewal application. See also NINDS policy for continuation of phase III clinical trials (NOT-NS-10-009).

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, 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.

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

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

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

Resource Sharing Plan

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

• Investigators seeking $500,000 or more in direct costs in any year should address a Data Sharing Plan, or explain why data-sharing is not possible.
• NINDS expects the primary outcome paper of the trial to be submitted for publication within 1 year of the completion of the trial (i.e., when the last participant completes follow-up of the primary outcome. The complete dataset should be made available for sharing within 2 years of the publication of the primary outcome paper.
• Resource sharing policies for Sharing Model Organisms and GWAS Sharing Plan are not applicable for this FOA.

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, with the following modifications:

The study protocol (required and formatted using the NINDS protocol template: http://www.ninds.nih.gov/research/clinical_research/toolkit/protocol.htm), Clinical Investigator’s Brochure or equivalent, as well as any of the other items relevant to the protocol (e.g., the consent form, documentation to access the study population, etc.), are to be submitted as appendices. The study protocol should be inserted as the first item in the appendix.

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (R&R) Application Guide. Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(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.

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 Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NINDS Referral Office by email at nindsreview.nih.gov@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants requesting $500,000 or more in direct costs for the entire cluster of components for the trial (e.g., CCC, DCC, etc.) for 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 SF 424 (R&R) Application Guide.

The Manual of Study Procedures (MOP) is not required under this program announcement and should not be included in the application.

The following sections must be included in the application:

Specific Aims: The hypotheses and specific aims of the trial must be clearly and concisely stated. The primary and secondary endpoints to be measured must be clearly defined. The inclusion of secondary endpoints should be justified by stating the need for the supportive or explanatory data they are likely to yield.

Research Strategy:

Significance and Biological Relevance: The significance and biological relevance of the proposed clinical trial must be clearly stated. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed and how results of the trial (positive or negative) may be explained based on the biological action of the proposed intervention. The application should state why the proposed study is necessary with an emphasis on the public health relevance or significance of the question and how the results will advance our knowledge or clinical practice in this disease area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

Preliminary Studies: The major findings of the pre-clinical and clinical studies that led to the proposed clinical trial should be presented. Data from pre-clinical and pilot studies demonstrating the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the completion of the trial and the potential impact of the results.

Approach: A concise summary of the proposed research plan should include-

• a randomized design including the rationale for the particular design chosen
• a description of the study population including the characteristics of this population and why it is an appropriate group to answer the question posed
• a list of subject eligibility and inclusion/exclusion criteria; or of group eligibility criteria for group-randomized trials
• recruitment and retention plans, including a discussion of the availability of subjects for the proposed study and the ability of enrollment centers to recruit and retain the proposed number of subjects. Data supporting recruitment estimates and when applicable retention estimates should be included.
• methods of randomization
• description of the intervention to be tested
• descriptions of all clinical, laboratory, physiological, behavioral, or other outcome assessments addressing the primary and secondary research questions
• potential biases or challenges in the research protocol proposed and how they will be addressed
• Statistical Methods: The statistical section should describe sample size and power calculations, linking the calculations to the primary and secondary endpoints, the hypotheses to be tested, methods of data preparation and presentation, plan for interim analyses and main analysis plans, randomization methods, and methods to handle missing data, and plans for interim analyses or pre-specified adaptive features.
• details of the data management, quality control and statistical methods should be included in the DCC application (include methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy. Data collection forms should incorporate data elements from the NINDS Common Data Elements Project (see: http://www.commondataelements.ninds.nih.gov/).
• Overall Plan for Study Milestones: Applications must include proposed yearly milestones, which will be subject to peer review. The milestones must include achievable goals for the study start-up stage, enrollment feasibility stage, and completion stage as described below. Investigators should strongly consider including an interim analysis for futility in their milestone plan. Adaptive designs, allowed under this mechanism, should include a pre-specified adaptation plan and allow for clear go/no-go decisions. During the execution of the project, NINDS staff will assess progress toward and achievement of milestones. Achievement of these milestones will be evaluated by NINDS prior to releasing funding for each year of the award and failure to achieve these milestones may lead to study termination.

Study Organization and Administration:

• The application must include a description of the organization of the study and how the trial will be managed.
• A description of the role of any internal or external advisory committees, including the role of the medical safety monitor must be included. The oversight, responsibilities, and coordination of any centers or cores proposed must be discussed.
• The application must describe any sub-contracts or service agreements for personnel or facilities and include in the application documentation of their commitment, co-signed by a business official and the scientific director at the participating center.
• A timetable for completion of the various stages of the trial must be included.

Investigators:

The overall clinical trial must be directed by an investigator with experience in the conduct of clinical trials and expertise in the content area of the trial. Such experience must be documented. Biographical sketches for all key investigators must be provided. Most clinical trial designs will require a multidisciplinary team.

Human Subjects:

NIH policy requires education on the protection of human research participants for all key personnel submitting applications for grants or proposals for contracts or receiving new or non-competing awards for projects involving human research participants. Certification of this requirement will be requested during the Just-in-Time process.

Applicants should refer to Part II of the PHS398 Application Instructions Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan.

Assurances of the protection of human participants and the biohazard safety of employees (if applicable) must be provided both for the overall study and for individual clinical sites. The applicant must discuss any issues which might lead to concern for the welfare of participants. Master templates of the forms to be used to obtain informed consent at each site must be included in an appendix. At a minimum, the human subjects sections of data coordinating center applications must address data security measures and confidentiality.

Data and Safety Monitoring Plan

Applicants must include a Data and Safety Monitoring (DSM) Plan for all clinical trials that is commensurate with the risk level of the proposed clinical research. 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 NINDS/NIH, the Office of Biotechnology Activities, Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board (if one is used) Therefore, 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

NIH requires the establishment of Data and Safety Monitoring Boards (DSMBs) for multi-site clinical trials involving interventions that entail potential risk to participants (http://grants.nih.gov/grants/guide/notice-files/not98-084.html). The purpose of this board is to provide independent advice to NINDS concerning scientific issues pertaining to subject safety, data quality, study conduct and study continuation. In monitoring safety in the trial, the board also may recommend termination in the event of early significance of findings or futility, or the determination of unacceptable adverse effects. The DSMB is appointed by the NINDS and consists of individuals who are not associated with the institutions participating in the trial (http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm). Potential members of this board should NOT be named in the application, although the areas of expertise needed for the board should be indicated.

Special Instructions for Submitting Applications as Part of a Cluster

• Multiple applications submitted as part of a Phase lll clinical trial will be considered as a cluster for the purposes of peer review and funding.
• All applications submitted as part of a cluster will be reviewed together, and will receive the same impact/priority score and summary statement.
• When multiple applications are submitted as part of a cluster, then all the requirements for applications of $500,000 or more apply when the combined budgets of the clustered applications equal or exceed $500,000. Thus the direct costs of the combined budgets are the unique trigger for applying the $500,000 policy requirements.
• Each application in the cluster must be prepared in response to this Funding Opportunity Announcement and be submitted using the SF424 (R&R) Application Guide and instructions.
• It is important that applicants who wish to submit linked applications announce their intentions clearly and early. Linked applications must mention the linkage in three separate areas of the application: the cover letter included with the application, the title of the application, and the abstract.

Title

• Each application in the cluster must use the Title field to denote clustering using a common base title plus a tag denoting the linkage. The tag identifier should be placed at the end of the title. Commonly used tags for Phase III multi site clinical trials include Clinical Coordinating Center (or CCC ), Data Coordinating Center (or DCC ), Economics and QOL Core, Imaging Core, etc.
• The Clinical Coordinating Center or the Data Coordinating Center may be designated as the lead application if applicable, but designating a lead application is not required. If either is considered the lead application, it should be indicated at the end of the tag, and in the abstract.
• The system truncates any title that exceeds the maximum character limit, so titles need to be succinct (i.e., no more than 80 characters).
• Trials with very long titles (i.e., more than 80 characters with tag) should use only an acronym plus the appropriate tag, and the full title should be spelled out in the abstract.

Cover Letter

• A PHS398 cover letter is required for each application and must include a list of all applications included in the cluster, including for each the name of the PD/PI; the unique Title (including the Tag); and the Applicant Institution.

Budget

• All applications must provide detailed scientific and operational plans as well as funding needs for the entire trial and data analysis period. The review of the application will consider the entire project. The NINDS commitment will be mindful of this total project need although the award period may be for less time.
• Investigators must submit a complete, justified, individual budget for each application and each year of support requested.
• Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core, if multiple centers or cores are proposed.
• If parts of the costs of the trial are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification along with supporting letters signed by individuals who have the authority to commit the institution. These outsource costs do not constitute cost sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.
• Further information concerning budget preparation may be obtained from the Office of Grants Management contact listed below.

Information Required for the Enrollment of Subjects into the Clinical Trial

As required by the NINDS Guidelines for the enrollment of subjects into trial submitted to Institute (see http://grants.nih.gov/grants/guide/notice-files/NOT-NS-05-010.html), the clinical trial application must include relevant information that addresses the feasibility of recruiting subjects who are eligible for the clinical trial. Specifically, applicants must provide evidence that each recruiting center in the trial has access to a sufficient number of study participants who meet the eligibility criteria as defined in the submitted protocol. For multi-site applications, information must be provided for each site participating in the trial. This information should only be included in the research plan of the primary application for the Clinical Coordinating Center.

Information for the Use of NINDS Common Data Elements

The NINDS expects that applications submitted as an Investigator Initiated Phase III trial will use the NINDS Common Data Elements resource when constructing data collection forms. The Common Data Element website (see: http://www.commondataelements.ninds.nih.gov/) serves as a repository and dissemination tool for all NINDS CDEs for Investigators to utilize.

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 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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the preliminary data or the literature support the need for a clinical trial to test the proposed hypothesis or intervention? Is there adequate biologic and/or public health rationale for the study? Is the study ethically justified?

Investigator(s)

Are the PD/PIs, 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?

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 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 clinical research, 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? Are NINDS common data elements used?

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? Does the information provided support achievement of the goal that the study population can be enrolled in the time-frame of the proposed trial? Have necessary agreements with participating industry partners, if any, been established? Is there documentation of the commitment of any subcontractor and consultants, and of service agreements for personnel and facilities? Is there evidence that the study drug or device will be available in sufficient quantities?

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/priority score, but will not give separate scores for these items.

• Is the clinical trial likely to be completed within the project period?
• If an IND or IDE is needed to conduct the trial, is there evidence that study investigators have received an IND/IDE, have submitted an IND/IDE application, or have had pre-IND meetings with the FDA?
• Are the proposed project milestones adequate and feasible?
• Does the data collection process incorporate the NINDS Common Data Element project?
• Does the proposal make appropriate use of NINDS resources including partnership with existing research networks?

Clinical Trial Documentation (Study protocol, Clinical Investigator's Brochure or equivalent, etc):

• 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 the clinical trial documents compliant with GCP?

Plans for Patient Recruitment/Retention: Does the application document the following:

• Availability of the requisite eligible subject pool in proposed clinical center(s);
• 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);
• Plans for recruitment outreach and, as appropriate, follow-up procedures to ensure collection of data at stated intervals;
• Retention plans and practices.

Protections for Human Subjects

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

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

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) 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 NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments 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/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. Applications will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. 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.

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:

• The Principal Investigator will have the primary responsibility to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusion of their studies and for providing overall scientific and administrative leadership for the Research Project.
• The PI will oversee all aspects of the organization and execution of the studies outlined in the application and approved by NINDS after peer review.
• Awardees have primary and lead responsibilities for the project as a whole, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the primary leadership committee.
• 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 HHS, PHS, and NIH policies.

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

• An NIH Project Scientist will have substantial programmatic involvement during conduct of the phase III clinical trial, through technical assistance, advice, and/or other coordination that is above and beyond the normal stewardship role in awards, as described below.
• The Project Scientific Officer will function as one of several co-investigators, collaborating and interacting as necessary with the Principal Investigators in accomplishing the overall goals of the Research Program.
• 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. This individual will provide normal program stewardship as carried out for grants and she will serve on the clinical trial committees as deemed appropriate.
• A third NINDS Program Official, from the Office of Clinical Research, will serve as the NINDS liaison to the Data and Safety Monitoring Board.

Areas of Joint Responsibility include:

• The NINDS Project Scientific Officer will serve on the primary leadership committee. In addition, the Program Scientific Officer, or other NINDS Program Officials, may serve on other study committees regarding recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. The NINDS Project Scientific Officer will have voting membership on the primary leadership committee and its subcommittees.
• 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.

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.

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

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

Scott Janis, PhD
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: (301) 496-9135
Email: janiss@ninds.nih.gov

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

Ms. Tijuanna DeCoster, MPA
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: (301) 496-9531
Email: decostert@ninds.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.