Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Neurological Disorders and Stroke (NINDS)
Funding Opportunity Title	Clinical Research Sites for the Network of Excellence in Neuroscience Clinical Trials (NEXT sites) (U10)
Activity Code	U10 Cooperative Clinical Research Cooperative Agreements
Announcement Type	New
Related Notices	June 30, 2017 - This RFA has been reissued as RFA-NS-17-024. June 9, 2011 - See RFA-NS-12-004 Spinal Muscular Atrophy (SMA) Biomarker Study (U01). April 8, 2011 - Notice of Intent to Publish a Request for Applications for a Spinal Muscular Atrophy (SMA) Biomarker Study (U01) and Convene a Related Workshop. See NOT-NS-11-012. December 7, 2010 - Pre-application Meeting for the Network of Excellence in Neuroscience Clinical Trials (NEXT). See Notice NOT-NS-11-005.
Funding Opportunity Announcement (FOA) Number	RFA-NS-11-008
Companion FOA	RFA-NS-11-009, U01 Research Project Cooperative Agreements RFA-NS-11-010, U01 Research Project Cooperative Agreements
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestics Assistance (CFDA) Number(s)	93.853
FOA Purpose	The purpose of this funding opportunity announcement (FOA), issued by NINDS, is to invite applications to participate as a Clinical Site in the Network for Excellence in Neuroscience Clinical Trials. This clinical research network will develop and conduct multiple, scientifically sound, possibly biomarker-informed exploratory clinical trials evaluating the most promising therapies, whether from academic, foundation or industry discoveries. Examples include Phase 2 clinical trials and clinical research studies aimed at validating biomarkers and clinical outcomes in preparation for clinical trials. The network will provide a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of protocols in neurological disorders affecting adult and/or pediatric populations. While the network will not be specific to one disease, it will have the capacity to coordinate a cadre of specialist investigators to implement studies efficiently in response to disease-specific opportunities. This FOA solicits applications for Clinical Sites. Separate FOAs solicit applications for the Clinical Coordinating Center and the Data Coordinating Center (RFA-NS-11-009 and RFA-NS-11-010).

Posted Date	December 7, 2010
Letter of Intent Due Date	February 11, 2011
Application Due Date(s)	March 11, 2011
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	May/June 2011
Advisory Council Review	August 2011
Earliest Start Date(s)	September 2011
Expiration Date	March 12, 2011
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.

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

PURPOSE

The purpose of this funding opportunity announcement (FOA), issued by NINDS, is to invite applications to participate as a Clinical Site in the Network for Excellence in Neuroscience Clinical Trials (NEXT). This clinical research network will develop and conduct multiple, scientifically sound, possibly biomarker-informed exploratory clinical trials evaluating the most promising therapies, whether from academic, foundation or industry discoveries. Examples include Phase 2 clinical trials and clinical research studies aimed at validating biomarkers and clinical outcomes in preparation for clinical trials.

The network will provide a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of protocols in neurological disorders affecting adult and/or pediatric populations. While the network will not be specific to one disease, it will have the capacity to coordinate a cadre of specialist investigators to implement studies efficiently in response to disease-specific opportunities.

The network will include multiple Clinical Sites, one Clinical Coordinating Center (CCC), and one Data Coordinating Center (DCC). The network is designed to increase the efficiency of clinical trials, to facilitate patient recruitment and retention, to increase the quality of neuroscience clinical trials, and to enable public-private partnerships.

BACKGROUND

To translate recent, high quality neuroscience discoveries into better treatments for people burdened by neurological disorders, efficient clinical trials are needed. These trials require cooperation and coordination among investigators, patients and industry partners. Clinical trial networks can increase the efficiency of research by providing infrastructure, centralized resources, and access to patients; however, with more than 400 neurological diseases falling under the auspices of NINDS, creating multiple specialized research networks would not be feasible.

In the traditional model, a consortium of clinical sites is created for each new multi-center trial. This causes redundancy and delays because infrastructure is duplicated. Protracted contract negotiations and approvals at multiple Institutional Review Boards (IRBs) often cause further delays. In addition, there may be loss of expertise as experienced research coordinators move to other fields after a trial is completed. The objective of the network is to increase the efficiency of clinical research through shared infrastructure for NINDS clinical trials.

RESEARCH OBJECTIVES

The network aims to share expertise and infrastructure across diseases, to leverage research resources at clinical sites, and to flexibly take advantage of clinical research opportunities as they arise in different disease areas. Finite resources and especially for rare diseases a small pool of potential participants limit the number of large, confirmatory efficacy (Phase 3) trials that can be conducted at any given time. Therefore, NINDS aims through the network to support exploratory trials that can provide more rapid preliminary testing of new treatments.

The objective of the network is to streamline the implementation of clinical research by using standardized master trial agreements and infrastructure that utilizes a central IRB of record.

While NINDS has historically funded trials to test drugs already approved for other indications, the network is designed to assure the broadest access to any new therapies for patients by carrying out trials coming from partnerships between NINDS and industry, foundations, or academia. These trials will be utilizing a variety of the NIH agreement mechanisms (e.g., Cooperative Research and Development Agreements [CRADAs]) that maximize industry participation and support.

It is envisioned that the network will not be "idle" at any time. During the start-up period, as well as during periods of time when new network projects will not take up the entire capacity, the Clinical Site coordinators and Clinical Site principal investigators will improve the quality and facilitate the implementation of clinical trials at their sites, by offering their support to ongoing NINDS-funded trials and enhancing patient recruitment and retention. The CCC will track site performance as it relates to ongoing NINDS-funded trials.

RESEARCH APPROACHES

Shared Network Infrastructure

This FOA solicits applications for funding of infrastructure for clinical sites. The additional project-specific funds to support the implementation of network protocols will be part of future awards. These funds will be distributed to the Clinical Sites via the CCC on a per-patient basis, according to protocol budgets approved by the network Steering Committee (SC) and via master trial agreements with the Clinical Sites. The Clinical Sites must be willing to follow this funding arrangement for each protocol they choose to participate in.

The network will give preference to clinical sites agreeing to use a central IRB of record, to accelerate IRB approval in multi-center trials. To that effect, the network will use a federated" IRB model. This model gives participating institutions the option to choose one of three tiers of IRB review:

• Tier 1 indicates the reliance on a central IRB as IRB of record;
  
  
• Tier 2 indicates an option to designate a central IRB as IRB of record in addition to a local IRB;
  
  
• Tier 3 indicates the reliance on local review.

Applicants and their institutions should indicate their willingness to participate in a federated IRB model with the option to designate one central IRB as IRB of record, as an efficient alternative to the currently prevalent local review of the initial protocol and progress reports and adverse events. The CCC will have to coordinate a central IRB of record and manage all required IRB communication and documentation including but not limited to tracking approval, maintaining regulatory documents, communicating with the local IRBs, and handling adverse event reporting and notifications.

Clinical Sites will be offered network-approved fee-for-service reimbursement for the per-patient cost from the CCC to implement protocols, according to budgets approved by the SC and NINDS for each protocol. Sites will have the option not to participate, but will not be able to negotiate the direct costs as funded by NINDS for a given trial, and as approved by the network SC.

Network Projects

Over the 7-year project period, the network will conduct approximately 5-7 clinical research projects, and will promote the implementation of ongoing NINDS-funded clinical trials. The exact number of protocols supported in the 7-year program will depend on the nature and extent of the investigations proposed and the availability of funds.

This RFA is soliciting applications from centers that have access to patient populations with a variety of neurological disorders.

To ensure that the network is efficiently using resources from its inception, a short-term clinical research project will begin soon after the network has been established. It is anticipated that this first project will be a biomarker validation study for spinal muscular atrophy (SMA). A separate future FOA will solicit applications for this SMA protocol. Additional trials will be selected from project proposals from industry and academic investigators submitted in response to a second, future FOA that will solicit applications for Phase 2 clinical trials to be implemented through the network. It is anticipated that at least one of the total trials conducted will be targeted to children.

Following a second level of review by the NINDS advisory council, NINDS will select protocols to be fully developed by a protocol lead team consisting of the Project Director/Principal Investigator (PD/PI), disease-experts as co-investigators, and the network representatives.

The final protocol will be approved after technical review by a Protocol Review Committee. A subset or all of the Clinical Sites will then be invited to participate in a given project and will have the option to accept or decline, depending on their capacity, interest, and patient population relevant to the specific protocol. It is also possible that non-network sites may be added ad-hoc for a specific project, for their expertise and patient population to complement the network sites.

RESEARCH TOPICS

Each Clinical Site's Scope of Work includes, but is not limited to:

• Identifying an experienced clinical trials expert with a track record in successfully conducting clinical research as a PD/PI.
  
  
• Reaching out to the local medical community and to potential referring physicians and identifying potential co-investigators with disease-specific clinical research expertise interested in working with the PD/PI. The investigators may be from either the same institution or different affiliated institutions.
  
  
• Identifying an experienced coordinator to work full-time with the investigators on network projects, and participate in network-wide communications, training, protocol review, and patient recruitment and retention. The coordinator’s primary responsibilities will be to the network trials. However, the coordinator will also be expected to assist with other NINDS-funded clinical trials at their site when network activities are not demanding their full-time effort and thus, the network will not "idle" at any time.
  
  
• Participating in a minimum of four network clinical research projects or trials during the funding period. A Clinical Site PD/PI and any of the potential disease expert co-investigators may submit trial applications for peer-review in response of the future network Phase 2 PAR, and if successful may assume responsibility for being the lead Clinical Site on a given peer-reviewed, network-approved research project, which would entail providing continued leadership in protocol development and implementation in collaboration with the network.
  
  
• Implementing shared protocols involving, but not limited to: 1) assembling a local research team, 2) establishing contractual agreements, 3) obtaining IRB approval & informed consent, 4) recruiting, treating, and following patients according to the study protocols, and 5) collecting and entering accurate, high quality data into the central web-based data management system. To increase the efficiency and reduce start-up time, sites are required to work through standardized master trial agreements agreed to by the network.
  
  
• Accurately identifying and recruiting all eligible subjects for network- and other NINDS-supported clinical research projects, and retaining participants throughout the follow-up period as required by protocol. Reaching out to patients for potential trial participation. Ensuring human subjects' protections and adequate gender and minority representation among subjects enrolled at network Clinical Sites, and ensuring protocol adherence.
  
  
• Tracking and reporting trial and performance data to the CCC and/or NINDS on a regular and frequent basis, including recruitment, retention, and adverse events, as required per protocol and by the IRB and regulatory bodies.
  
  
• Working with the DCC to ensure complete, accurate, and timely data entry, as well as rapid and complete resolution of any data queries, and to maintain a high level of data quality and completeness. Clinical Site PDs/PIs are also expected to cooperate with monitoring visits and to assist the DCC with the development and implementation of: 1) common data elements, 2) data entry forms, and 3) public dissemination of project results, as needed.
  
  
• Helping new clinical investigators develop skills and experience to progress to more senior or experienced status, when appropriate.
  
  
• Participating in all network Steering Committee (SC) meetings and maintaining cooperative interactions with all other Clinical Sites, the CCC, and the DCC in all aspects of the network.
  
  
• Assisting the network SC by serving on SC working groups developed on an as-needed basis, and charged with the planning and implementation of protocols, as well as with recommendations on issues such as publications guidelines, quality control, etc.
  
  
• Leveraging local research resources. Applications from institutions that have a General Clinical Research Center (GCRC) or Clinical and Translational Science Award (CTSA) funded by the NIH National Center for Research Resources should identify the resources that could be available to support the proposed network Clinical Site, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. In such a case, a description of the GCRC or CTSA and how the applicant proposes interacting with it should be included, as well as letter of agreement from either the GCRC/CTSA Program Director or PI. Having a GCRC or CTSA at the institution is not a requirement for application.

Network Structure and Management

The NINDS Network of Excellence in Neuroscience Trials will include: one Data Coordinating Center (DCC), one Clinical Coordinating Center (CCC), and up to 25 Clinical Sites. A network Clinical Site should be able to conduct trials in adult populations, pediatric populations, or both. Special consideration will be given to children's hospitals. Investigators at the NIH Clinical Center may also function as an additional clinical site.

• The NINDS will be responsible for organizing and providing overall support for the network. The NINDS Office of Clinical Research staff and the NINDS Office of Grants Management will be responsible for the overall management of the network. In addition to regular grant stewardship, an NINDS Project Scientist will be involved substantially with the awardees as a NINDS partner, consistent with the Cooperative Agreement mechanism. The NINDS will appoint the Data and Safety Monitoring Board (DSMB) and the Scientific Advisory Board (SAB).
  
  
• A Steering Committee (SC) composed of three principal investigators representing the Clinical Sites, the DCC PD/PI, the CCC PD/PI, the PDs/PIs of active network projects, and the NINDS Project Scientist will be the main governing body of the network. The NINDS will appoint an SC Chair who may or may not be independent of the Clinical Sites, the CCC and the DCC, to preside over SC meetings and serve as the SC representative to the SAB. The SAB is an external group of experts who will review the network program and advise the network investigators and the NINDS.
  
  
  • All major scientific decisions will be determined by majority vote of the SC;
    
    
  • Each SC member will have one vote; the SC Chair will cast a vote in case of a tie;
    
    
  • The protocol lead PDs/PIs of approved network protocols will become SC members for the duration of the project they are leading;
    
    
  • The initial three Clinical Site representatives will be appointed by NINDS to the SC for a 2 to 3-year term;
    
    
  • The second slate of SC investigator-members will consist of the highest overall enrolling investigator and two investigators elected by their peer investigators to a 2-year term. For continuity, one of the three initial SC investigator members will serve on the committee for 2 years, and two will serve for 3 years so that not all tenures expire at the same time;
    
    
  • It is anticipated that the SC will meet two times per month by telephone conference call and at least three times per year by in-person meetings;
    
    
  • The SC will have primary responsibility for network governance. SC working groups will be established by the SC to perform specific functions, such as, for example:
    
    
    • Protocol planning and development;
    • Publications;
    • Per-patient budget approval;
    • Quality control assurance;
    • Conflict of interest.
      
      
  • Awardees will be required to accept and implement policies including standardized master trial agreements approved by the SC.
    
    
• The Data Coordinating Center (DCC) will support protocol data management, data quality control (including data monitoring), and statistical design and analysis. The DCC will also initiate and coordinate activities to promote standardization of data elements using the NINDS common data elements when available, or help develop common data elements and standardized protocols. See RFA-NS-11-010 for more details describing the responsibilities of the network DCC.
  
  
• The Clinical Coordinating Center (CCC) provides overall study coordination, working closely with the DCC and the Clinical Sites. The CCC will coordinate the activities of the SC, develop and implement investigator and staff training programs and meetings, oversee drug acquisition and distribution as needed, work closely with the project-specific lead protocol teams, support project investigators in IND submission and reporting to the Food and Drug Administration (FDA), establish and maintain standardized master trial agreements with the network sites and distribute funding for network trial projects, maintain regulatory documents and coordinate the central IRB process, support outreach to patients and inclusion of patients in protocol and recruitment plan development, editorial and meeting coordination for manuscript preparation, and development of operational and publication guidelines within the framework outlined by the network CCC RFA. See RFA-NS-11-009 for more details describing the responsibilities of the network CCC.
  
  
• An independent DSMB, established by the NINDS in accordance with NIH policies and with input from the SC, will monitor patient safety, and review study performance.

Funding Instrument	This FOA will use the NIH Cooperative Agreement award mechanism (U10). In the cooperative agreement mechanism, the PD(s)/PI(s) retain(s) the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the PD(s)/PI(s), as described under the Section VI.2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The total amount of funding that NINDS expects to award through this announcement is up to $52.5 Million. The anticipated number of awards is up to 25. Although the financial plans of the IC provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds.
Award Budget	The expected direct cost amount for individual awards is up to $200,000 annually for 7 years. Facilities and Administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004. 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.
Award Project Period	This is a one-time solicitation to fund the network for 7 years. Plans beyond the current funding period are undetermined.

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 not 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.

The Principal Investigator for a Clinical Site will be a clinical trials expert with a track record in successfully implementing clinical trials.

• Institutions will be required to document commitment to the PD/PI by providing departmental and institutional support letters, and are encouraged to demonstrate support via other means (e.g., additional protected time, departmental research leadership position, facilities, space, or resources for the PD/PI and/or Clinical Site).
  
  
• Applicants are strongly encouraged to list, in addition to the PD/PI, several co-investigators with disease-specific clinical research expertise and access to a clinic population who are interested in working with the PD/PI. At an institution with pediatric and adult patients, the disciplines appropriate for clinical site investigators and co-investigators include pediatric and adult neurologists, neurosurgeons, neuropsychologists, neuroradiologists or other related specialists with a strong interest in clinical research and a wide range of disease interests such as behavioral neurology, neuromuscular disorders, movement disorders, vascular neurology, neuroimmunology, or general neurology. These experts may be from the same institution or different institutions.

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

Only one Clinical Site application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed.

Awards for a CCC and a Clinical Site may be made to the same institution. However, it is preferable that the CCC and the Clinical Site grant at a given institution be awarded to two investigators, to ensure that the CCC activities as well as the local Clinical Site activities receive full attention.

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 are not permitted in response to this FOA.

Renewal applications are not permitted in response to this FOA.

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.

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/PI
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Petra Kaufmann, MD
National Institute of Neurological Disorders and Stroke
National Institutes of Health
6001 Executive Blvd., Room 2116
Bethesda, MD 20892-9520 (Express/Courier: Rockville, MD 20852)
Telephone: (301) 496-9135
Email: NEXT@ninds.nih.gov

Pre-Application Meeting: The NINDS anticipates holding a technical assistance meeting in January 2011 (now December 17, 2010 per NOT-NS-11-005), through a teleconference to which all interested prospective applicants are invited. Program and review staff will make presentations that explain their goals and objectives for the NEXT Initiative and answer questions from the attendees. Prospective applicants are urged to monitor the NIH Guide for Grants and Contracts regarding a Notice for the date and time of the meeting (http://grants.nih.gov/grants/guide/index.html).

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:

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Room 3201, MSC 9529
6001 Executive Boulevard
Bethesda, MD 20892-9529 (Rockville, MD 20852 for express/courier service)
Telephone: (301) 496-9223
Fax: (301) 402-0182
E-mail: nindsreview.nih.gov@mail.nih.gov

All page limitations described in the PHS398 Application Guide must be followed, with the following exceptions or additional requirements:

• Research Strategy section is limited to 30 pages. Applications received that exceed these page limitations will not be reviewed.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

Applications should include the following information in the relevant subsections:

1) Leadership Plan

The PD/PI should describe, in the Approach section of the Research Strategy, how clinical trials and research at the Clinical Site will be strategically supported by the network Clinical Site PD/PI and coordinator.

2) Collaboration Plan

In the relevant sections of the Biosketch, Resources/Facilities, the Research Strategy or, where applicable, in the Multiple PD/PI Leadership Plan, applicants should state their general support of collaborative research and their willingness to participate in a collaborative and interactive manner with other Clinical Sites, the Data Coordinating Center, and the NINDS and its partners in all aspects of the network program. Applicants are encouraged to describe any special expertise or unique strengths they can offer to the collaborative effort (e.g., team leadership and training, protocol adherence strategies, dissemination activities, recruitment strategies). Applicants should describe the potential pool of co-investigators at the site and their area of expertise. The applicant should indicate how co-investigators will be identified, motivated, and integrated into the network, and how the network team will support the co-investigators. A detailed plan must be included in the Research Strategy section of the application on outreach and collaboration with other clinical investigators at the Clinical Site, because the success of the network at the Clinical Site will depend on collaboration with co-investigators with disease-specific clinical research expertise and a clinic population who are interested in working with the PD/PI.

In the Budget Justification section, applicants should indicate their willingness to attend all network investigator meetings, which will include conference calls at least two times a month and in-person meetings at least three times a year.

In the Approach section of the Research Strategy, applicants should discuss their willingness, and that of the institutions involved, to establish standardized master trial agreements with the Clinical Coordinating Center to reduce trial start-up time. Agreeing on master trial agreement templates for recurring issues (e.g., publications) will expedite trials initiated under these standardized master trial agreements.

In the Resources/Facilities section, applicants should discuss their capability to participate in a distributed data entry system, since Clinical Sites should be able to interact with the Data Coordinating Center to transmit and edit data.

3) Recruitment and Outreach Plan

This section should be briefly summarized in the 30 page Research Strategy, and additional detail including a table (see below) should be provided either in the Research Strategy or in the Human Subjects section of the application. Applicants should demonstrate (with reference to specific, objective sources of data on the size of the available population) access to a sufficient number of patients to participate in a wide range of neuroscience clinical trials. This is best demonstrated by showing a table that lists by disease the potential co-investigators and their qualifications, track record and interest, as well as the patient population, e.g., total number of patients with the disease seen annually, number of patients currently participating in trials, number of new patients per year for the last full calendar year. SMA should be specifically included among the diseases listed, but a site does not have to have access to SMA patients to be eligible to apply. The applicant should also indicate how outreach into the community, to referring physicians and to patients will take place, what actions and materials will be used to support recruitment of patients, and how patients will be included in the conception, planning and implementation of trials so that a strong partnership between investigators and patients can serve as a foundation for successful trial recruitment and retention.

Patient access may be accomplished by establishing links with other groups (e.g., other health care providers in the community, such as neurology practices, primary care practitioners, pediatricians, local hospitals, rehabilitation centers, patient support groups, and health maintenance organizations) in addition to the applicant’s institution. If links with other groups are anticipated, the application should include a plan in the Approach section of the Research Strategy with appropriate letters of support (appended in the Letters of Support section of the application) describing (1) how the applicant Clinical Site will link to and operate with the other groups, and (2) how the Clinical Site will monitor the quality of the other group s performance (screening, and, if applicable, patient recruitment and data collection).

The application should include a brief description of anticipated problems with recruitment and plans for addressing these problems. Note that proposed solutions to recruitment problems may not include requesting additional funds under this FOA.

4) Leveraging Local Clinical Research Resources Plan

The applicant should describe in the Resources/Facilities section how local clinical research resources such as equipment, space and research staff will relate to the network, and, if applicable, how the network will integrate CTSA resources.

5) Plan to Increase the Efficiency of the Clinical Research Enterprise at the Clinical Site

For new trials, plans to reduce start up time by increasing the efficiency of contracting and IRB review through use of standardized master trial agreements and federated IRB models and, for ongoing NINDS funded trials (whether network trials or other), means to monitor and track performance and to increase recruitment and retention should also be described in the Research Strategy.

6) Performance Monitoring and Potential Interventions Plan

In the Research Strategy section, the application should include a plan for how the PD/PI will monitor performance and collect data on start up, recruitment and retention for new and potentially also for ongoing NINDS-funded clinical trials at the Clinical Site.

7) Training Plan

The network presents a rich environment for young investigators to be exposed to and develop additional research skills and to assist them in progressing to more senior status. The applicant should describe in the Approach section of the Research Strategy, the plans to reach out to young investigators.

In addition, the application should include the following:

• A table listing potential co-investigators at the Clinical Site, along with their disease-specific clinical research expertise and the approximate number of patients they see in their clinic population, by disease of interest. While key personnel should be separately listed in the application, the above table should be included in the Research Strategy section.
  
  
• A table listing the current and the five most recent multi-center trials that the site has participated in should be included in the Preliminary Data section of the Research Strategy, consisting of the following:
  
  
  • The complete name of the trial;
  • The funding source;
  • The name of the site PD/PI;
  • The start-up time from award to IRB approval;
  • The time from initiation of contract negotiation with lead site to contract executed;
  • The time from award to first patient screened;
  • The time from award to first patient enrolled;
  • The enrollment rate;
  • The total number of patients enrolled at the site;
  • The proportion of patients lost to follow-up;
  • The number of protocol violations at the site.
    
    
• Letters of support from potential co-investigators at the Clinical Site, affirming an interest in collaborating with the potential local network site PD/PI and with the network as such, describing their expertise, track record, interest, and access to patient populations. These should be included in the separate Letters of Support section of the application.
  
  
• An institutional letter of support from the applicant's departmental and/or institutional leadership should be included in the Letters of Support section of the application.

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.

It is expected that the network research resources such as Manual of Operations, study manuals, case-report forms, phenotype ascertainment instruments, and newly developed common data elements will be made available to the public after publication of study findings (e.g., through NINDS Common Data Elements [CDEs], see http://www.commondataelements.ninds.nih.gov/, or the National Technical Information Service, see http://www.ntis.gov/index.aspx).

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.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Qualifications and Experience

Applicants should describe qualifications and experience in the Biosketches and in the appropriate narrative sections of the application (Background/Preliminary Data section of the Research Strategy). It is anticipated that participation in the network will be a complex and time-consuming undertaking and applicants for Clinical Sites must have the necessary experience and expertise to oversee or support clinical trials in pediatric and/or adult patients with neurological disorders.

Links with NIH Resource Centers

• Applications from institutions that have a General Clinical research Center (GCRC) or Clinical and Translational Science Award (CTSA) funded by the NIH National Center for Research Resources should identify the resources that could be available to support the proposed network Clinical Site, commenting particularly on those aspects that will enhance their programmatic and scientific efficiency. In such a case, a description of the GCRC or CTSA and how the applicant proposes interacting with it should be included in the Resources/Facilities section, as well as letter of agreement from either the GCRC/CTSA Program Director or PI in the Letters of Support section of the application. Having a GCRC or CTSA at the institution is not a requirement for application.

Budget

A detailed budget for the Clinical Sites should be presented.

The budget does not need to include Data Coordinating Center or Clinical Coordinating Center costs nor costs for training, investigator meetings, or patient enrollment, treatment or follow-up.

Clinical Site applicants should consider the following issues regarding Clinical Site core budgets. It is expected that the individual Clinical Site will require a minimum level of effort to sustain the organizational aspects of the network. This includes an expected minimum of 2.4 - 3 person months total effort for the leadership (PD/PI); a full-time professional clinical research coordinator over the course of the project period (keeping in mind that protocol funds will include time for study personnel on a per-patient/service basis required to execute protocols over and above personnel proposed in the Clinical Site core budget); and travel costs for approximately three trips each year for two team members to attend SC meetings in Bethesda, MD, and other travel or meetings related to network operations.

The total should not exceed $200,000 direct costs per year in years 1-7 (all of which will be 12-month project years). The release of funds will be milestone-driven, according to milestones to be specified in the Notice of Award. Clinical Sites who will not meet the milestones would be replaced, if necessary. Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation (see NOT-OD-05-004). All costs in the proposed budget should include appropriate justification.

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?

• How will the proposed clinical site contribute to the advancement of clinical research and clinical trials within the framework of the network?

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?

• Does the PD/PI have a track record of working collaboratively?
  
  
• Does the PD/PI have a track record in successfully implementing clinical trials?
  
  
• Is there evidence of experience in and willingness to participate appropriately in a collaborative program as described in this RFA?

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 interactions/communications between investigators at the site and the community (e.g., referring physicians and patient populations) clearly described and creatively optimized?
  
  
• Does the investigator have adequate plans to recruit patients with a variety of neurological disorders and with diverse gender/minority representation, as well as plans for human subjects' protection, good clinical practices (GCP)?
  
  
• Is the investigator willing and likely sufficiently available to participate in network-wide meetings, teleconferences, and SC working groups?
  
  
• Is the timeline for IRB approvals and contract negotiations sufficient?
  
  
• Is the institution able to utilize a central IRB of record that can accept standard network standardized master trial agreements for per-patient cost of clinical programs?

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 there adequate evidence of institutional and departmental commitment to the PD/PI (e.g., additional protected time, departmental research leadership position, facilities, space, or resources for the PD/PI and/or CS)?
  
  
• Based on data provided from the current and five most recently completed clinical trials at the site:
  
  
  • What is the institution's track record with regards to trial start-up time?
  • What is the institution's track record with regards to IRB review time?
  • What is the institution's track record with regards to contract negotiation?

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.

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

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/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 NINDS Scientific Review Branch (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 will:

• 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.
  
  
• 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 National Advisory Neurological Disorders and Stroke 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;
• Clinical trial expertise, track record, and resources;
• Track record and willingness to collaborate with other clinical researchers at the applicant’s institution, breadth of expertise among potential co-investigators;
• Willingness, and evidence of potential, to participate in all aspects of the network program, including protocol development and other SC working groups, and participation in teleconferences and in person meetings;
• Willingness to work collaboratively and strong track record of successful collaboration and participation in large, multi-center research teams;
• Recent and current NINDS-funded projects in the clinical neurosciences at the applicant’s institution;
• Ability to begin operations immediately;Agreement to accept the Cooperative Agreement Terms and Conditions of Award delineated in this FOA (see Section VI.2.A);
• Geographic balance of Clinical Center awardees;
• Access to pediatric and/or adult patient populations with a wide range of neurological disorders;
• Diversity of study populations among Clinical Center awardees, as well as balance between pediatric and adult populations, and access to minority populations.

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:

• Trial participant safety, implementation of network protocols in accordance with GCP and other regulatory requirements, participant recruitment and retention, reporting to the NINDS, CCC, DCC, and DSMB.
  
  
• 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:

• The NINDS staff working with the network investigators will develop performance milestones for clinical sites. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement.
  
  
• An NINDS Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.
  
  
• 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:

• A SC composed of three Clinical Site principal investigators representing the Clinical Sites, the Data Coordinating Center principal investigator, the Clinical Coordinating Center principal investigator, the PDs/PIs of active network projects, and the NINDS Project Scientist will be the main governing body of the network. The NINDS will appoint a SC Chair who may or may not be independent of the Clinical Sites, the CCC and the DCC to preside over SC meetings and serve as the SC representative.
  
  
• The Clinical Site PD/PI and coordinator are expected to participate in all network teleconferences and investigator meetings. They are also expected to assist the network SC in deciding how peer-reviewed research and trial proposals will be selected and prioritized for implementation through the network.
  
  
• Clinical Site PDs/PIs will also be expected to serve on SC working groups established on an as-needed basis and charged with tasks such as the planning and development of protocols, publication guidelines, quality assurance monitoring, etc.

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

Dr. Petra Kaufmann
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: NEXT@ninds.nih.gov

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

Tijuanna DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
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.