Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute of Neurological Disorders and Stroke (NINDS), (http://www.ninds.nih.gov)

Title: Neurological Emergencies Treatment Trials (NETT) Network: Clinical Coordinating Center (U01)

Announcement Type
New

Request For Applications (RFA) Number: RFA-NS-06-002 

Catalog of Federal Domestic Assistance Number(s)
93.853

Key Dates
Release Date: November 1, 2005
Letters of Intent Receipt Date(s): December 12, 2005
Application Receipt Dates(s): January 12, 2006
Peer Review Date(s): April 2006
Council Review Date: May/June 2006
Earliest Anticipated Start Date: July 2006
Expiration Date: January 13, 2006

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

Section II. Award Information
  1. Mechanism(s) of Support
  2. Funds Available

Section III. Eligibility Information
  1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
  2.Cost Sharing or Matching
  3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
  1. Address to Request Application Information
  2. Content and Form of Application Submission
  3. Submission Dates and Times
    A. Receipt and Review and Anticipated Start Dates
      1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
  4. Intergovernmental Review
  5. Funding Restrictions
  6. Other Submission Requirements

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
  3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
    A. Cooperative Agreement Terms and Conditions of Award
      1. Principal Investigator Rights and Responsibilities
      2. NIH Responsibilities
      3. Collaborative Responsibilities
      4. Arbitration Process
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

BACKGROUND

Fifteen million adults and children are seen in U.S. emergency departments annually for acute neurological disorders that vary in seriousness from trivial to life threatening. Most patients are initially evaluated and treated by emergency medicine physicians, not by specialists in neurological diseases.  Optimal management during the first hours of neurological emergencies is often critical to recovery: a window of opportunity that cannot be reopened later due to the unique vulnerability of the CNS.

There is a lack of availability of office-based/operating room-based specialists in neurological diseases and emergency medicine physicians who care for neurological emergencies. This limits collaborative clinical research that underpins advances in the effective treatment of neurological emergencies. Considering the frequency and importance of neurologic emergencies, relatively little high-quality, treatment-oriented clinical research has been undertaken, in particular, research involving collaboration between specialists in neurological diseases and the emergency medicine physicians who typically deliver urgent care.

In order to improve outcomes for patients with neurological emergencies through research aimed at new therapies and their more effective implementation, the NINDS seeks to develop the Neurological Emergencies Treatment Trials (NETT) Network. The NETT Network is designed to facilitate high-quality clinical trials in multiple types of emergency neurological disorders afflicting adults or children, to encourage collaboration between emergency medicine physicians and specialists in neurological disease in trial design and execution, and to facilitate the implementation of new therapies into clinical practice. Once established, the NETT Network is intended to serve as a resource for investigator-initiated clinical research in acute neurological disorders. Following the initial trials funded through this initiative during the development phase, subsequent trials will be funded by research initiators through the traditional NINDS peer-review mechanisms.  

RESEARCH OBJECTIVES

Overall Goal: the goal of this RFA is to develop and widely implement efficacious treatments for patients with a broad spectrum of neurological emergencies, in order to decrease the burden of neurological disease.

Specific Objectives: 

1. To create a clinical research network of emergency medicine physicians, neurologists, and neurosurgeons who will work together to efficiently develop more and better treatments for patients with acute neurological disorders through NINDS-sponsored clinical trials.

2. To conduct two large, streamlined Phase III clinical trials involving neurological emergencies to demonstrate the capability of the Network, and to stimulate general interest in the NETT Network for future collaborations.  Responses to this RFA should include 2 protocols relevant to NETT and covering 2 different neurologic diseases, i.e. no more than one trial in epilepsy, stroke, or traumatic brain injury.   Funds to carry out the 2 trials should be included in the Clinical Coordinating Center (CCC) application, but not funds for the statistical center or sites, which will be in other RFAs to be announced later.  The budget for the CCC should include drugs, drug distribution, special procedures, medical devices or other equipment.

Description of clinical trials should include:  target disease, primary objective, secondary objectives, scientific rationale, design and intent of study, relevance and priority of the study to NETT, sample size, number of clinical centers, patient selection criteria, recruitment plan, informed consent process, administration of intervention including dose and duration, extent and type of blinding/masking, follow-up plan, endpoints and outcomes, statistical and clinical basis, statistical methods to analyze primary and secondary outcomes, interim monitoring plan, ethical and consent considerations, participating pharmaceutical or device manufacturing company and IND/IDE status or FDA exemption.

Applicants should propose plans and methods to accomplish the following aims:

NETT Network Organization

The basic structure of the NETT Network will consist of a Clincal Coordinating Center, responsible for overall coordination of NETT as described below and and the focus of this RFA.  In close sequence, additional RFAs will detail  a Statistical and Data Management Center, and 10-20 Clinical Site “Hubs”.  There will be  three key committees that will collaborate to develop the network and complete two clinical trials during the award period, and are detailed below. In order to demonstrate the interacting roles of each component, each will be developed in the following paragraphs.

The NETT Network Clincial Coordinating Center (CCC) for which applications are solicited in the RFA, will provide overall leadership for the project, including coordinating the activities of the 10-20 NETT Clinical Site Hubs, particularly recruitment, follow-up, and data quality. It will initiate investigator training and certification, supervise quality control measures, organize limited on-site monitoring, coordinate meetings and teleconferences as appropriate between all study investigators. The Coordinating Center will develop and manage the trial protocols, assure compliance with regulations and monitor the informed consent process, supervise and encourage recruitment, prepare blinded reports on adverse events, monitor study execution at study sites, and arrange the supply of study medication for the trials. Methods for monitoring eligibility of participants should be proposed and initiated for later implementation. The Coordinating Center will be responsible for quarterly progress reports to the NINDS, the NINDS-appointed NETT Advisory Group (NETT-AG), and one or more DSMBs.

Collaborating with the NETT Network Statistical and Data Management Center, the Coordinating Center will develop and implement data management procedures, including templates for common database elements to facilitate database and data form sharing across trials, develop data forms, and manuals of operations.  Forms will be compatible with standard emergency department forms used for registration and billing, for ease of data extraction.  In addition, there will be uniform testing on patients to include the Rankin scale, quality of life scales, and neuro-cognitive testing, so that comparisons across neurologic diseases can be made.

The Coordinating Center staff will be required to travel to meetings with the members of the Statistical and Data Management Center and the NINDS Program Director, as well as to Clinical Site Hubs.  Training workshops and annual investigator meetings may be proposed. Travel and meeting arrangements should be described, justified, and included in the budget proposal.

During the initial development phase of the network, funding will be awarded to the NETT Network Coordinating Center as part of this RFA contract to carry out two large, streamlined Phase III clinical trials. High visibility, high interest clinical trials will be important in order to stimulate initial interest in the NETT Network and engender enthusiastic participation by emergency medicine physicians.

The NETT Network Statistical and Data Management Coordinating Center (SCC) will implement data entry systems, develop study forms in collaboration with the Coordinating Center as described above, receive data from the Clinical Site Hubs, perform data checks/queries, undertake interim monitoring and analyses for the Coordinating Center, NINDS, and DSMBs.  Biostatistical analysis and trial reporting for the two trials will be done through collaboration with the Steering Committee.

The 10-20 regional Clinical Site Hubs will coordinate activities at 2-10 emergency departments (or “spokes” in a “hub and spoke” model) involving 18-25 emergency medicine physicians, neurologists, neurointensivists, and neurosurgeons or others, depending on local circumstances. Typical Hubs are envisioned as regional academic medical centers or tertiary care facilities capable of providing research support for the Spokes. Spokes will vary in institutional format from academic emergency centers to community hospitals, with the latter serving to expand patient access, to allow assessment of the intervention in a “real world” practice setting, and to facilitate dissemination of the research results. Depending on the specific trial design, the Spokes could either enroll patients on-site, using the Hub for research support, or identify participants for transfer to the Hub for specialty care. The Hub would provide clinical leadership and local neurological expertise, coordinate IRB activities and human subject protections, data entry, and manage subcontracts. Involvement of nonacademic-affiliated hospitals, non-urban hospitals, and hospitals serving minority populations will be considered in Hub selection. Funding for Hubs will be closely linked to research productivity (e.g. recruitment, data quality); the costs of maintaining the infrastructure will be minimized. Representatives of Clinical Site Hubs will selectively participate on the Steering Committee.  During the trial, Hubs may be added, deactivated, or placed in a follow-up mode with budget reduction, depending on performance and recruitment requirements, and requirements for protecting human subjects.

NETT Network Committees

1. NETT Advisory Group (NETT-AG) will perform a concept review before formal scientific review which will be carried out by a subset of the clinical trials review group NSD-K.  It will be organized by NINDS and be composed of advisors in Emergency Medicine and Neurology, including external advisors, and will include experts in clinical trials of neurological emergencies. It will serve as an oversight committee, giving initial approval to the trial protocols, modifications to the protocols, the overall budget, and plans for analysis, and will forward reports and recommendations to NINDS. 

2. NETT Network Steering Committee will consist of the principal investigator of the Coordinating Center (who will serve as the chair), a co-P.I., if designated, a principal investigator of the Statistical and Data Management Center, the NINDS Scientific Program Director, and selected members from the Clinical Site Hubs.  The specific membership and charter of the Steering Committee will be proposed by the Coordinating Center and approved by the NETT-AG.  The Steering Committee will approve the final protocols, supervise overall execution of the trial, generate and approve study policies, consider modifications of the protocol and operations, and plan and draft study-related publications.

3. Data Safety Monitoring Boards (DSMBs) will be appointed by NINDS to monitor safety and performance and to review interim analyses performed by the SCC in the NETT clinical trials. Depending on the specific trials selected, one or more DSMB may be required.

NINDS will name an NINDS Scientific Program Director whose function will be to expedite the activities outlined under “Terms and Conditions” (below) and to represent NINDS on the Steering Committee.  The NINDS Scientific Program Director will not be responsible for scientific administration of the cooperative agreement, which will be done by a second NINDS program official, the NINDS Administrative Program Director.  In addition, a clinical research project manager from the NINDS Clinical Trials Cluster will set up the DSMB and will help with DSMB clinical research tasks.

Two randomized clinical trials will be selected from the RFA proposals, and if approved by the NETT-AG and Scientific Review, will be conducted in the Network.  Trial design should be simple (i.e. streamlined) making it amenable to execution at community emergency centers. Selection of trials will consider both high prevalence neurological disorders and lower prevalence disorders with high morbidity. The public health importance, economic impact of the disease, scientific merit, feasibility for completion within the time frame of the RFA, protocol quality and completeness, and budget will be considered in trial selection. A detailed recruitment plan, and plans for quality monitoring/control should be included. The estimated time required to enroll a participant, to complete the data forms, and to conduct patient follow -up, categorized by the type of investigator (e.g. emergency medicine physician, neurologist, neurosurgeon, etc.) should be described for each trial proposal. Pilot studies may be warranted prior to initiation of the main trials. For the development phase of the NETT Network, it is important to establish a model of large, streamlined trials of clear clinical relevance and substantial interest to neuro-clinicians and emergency medicine physicians, in order to demonstrate what the Network is capable of accomplishing.  Proposals for at least two trials must be included with the application, however if the studies proposed by the chosen CCC are not selected by the NETT-AG, the CCC must still agree to cooperate with the design and conduct of the alternative trials.

PROPOSED NETT TIMELINE

Year 1: First 6 months

- Award of grants for the Clinical Coordinating Center (CCC)
- Organize the emergency medicine community and educate about NETT goals
- Initial trial protocol development and manual of operation (MOP) for two trials
- Preliminary review of the two trial protocols by the NETT Advisory Group (NETT-AG)

Year 1: Second 6 months

- Award of grants to the Statistical and Data Management Center (SCC)
- Award of grants to 10-20 Hubs
- Continued development and finalization of trial protocols and MOP
- Scientific review of trial protocols
- Data entry systems developed and implemented by Statistical and Data Management Center, including site personnel training
- Begin IRB approval process of trial protocols
- Training of Hubs and Spokes in good clinical practices (if appropriate) and trial-specific aspects
- Initial DSMB(s) meet

Year 2: 

- Patient accrual to begin

Years 3-4:  Patient accrual and follow-up in the manner of a large simple trial.  Start of additional non-overlapping trials approved by NETT-AG and NINDS peer review.

Year 5: Trial close-out, data analysis, and preparation of papers for publication.

Note: Alternatives to this proposed timeline will be considered if appropriately justified.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the cooperative agreement (U01) award mechanism.

As an applicant, you will be solely  responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions. A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH U01 is a cooperative agreement award mechanism.  In the cooperative agreement mechanism, the Principal Investigator retains 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 Principal Investigator, as described under Section VI. 2. Administrative Requirements, “Cooperative Agreement Terms and Conditions of Award.”  Plans for continuation of this program beyond this current funding opportunity are not definite. 

This RFA is a one-time solicitation.  The anticipated award date is 2006. 

2. Funds Available

NINDS intends to commit approximately $1,000,000 in direct costs in FY 2006 to fund one new grant in response to this RFA. This funding will reflect the cost of starting a clinical trial and additional duties for the clinical coordinating center in the first year.  In subsequent years,  an applicant may request  $1,000,000 per year for a project period of up to 5 years, with a budget for total direct costs of up to $5,000,000.    

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.  

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation; see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

1.B. Eligible Individuals
Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs

2. Cost Sharing or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria
Not applicable

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo: Telephone (301) 435-0714, Email, GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: December 12, 2005
Application Receipt Date(s): January 12, 2006
Peer Review Date(s): April 2006
Council Review Date: May/June 2006
Earliest Anticipated Start Date: July 2006

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Robin Conwit, M.D.
Clinical Trials Group
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd.
Neuroscience Center, Rm 2181
Bethesda, MD 20892
Telephone: (301) 496-9135
FAX: (301) 480-1080
Email: conwitr@ninds.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 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)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

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

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Room 3201, MSC 9529
6001 Executive Blvd.
Bethesda, MD  20892-9529 (Rockville, MD 20852 for express/courier service)

Telephone: (301) 496-9223
FAX: (301) 402-0182
Email: nindsreview.nih.gov@mail.nih.gov

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NINDS. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk, and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

6. Other Submission Requirements

Plan for Sharing Research Data
 
The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources, addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria
Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NINDS in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

REVIEW CRITERIA FOR THE NETT NETWORK COORDINATING CENTER

1. Specific proposals for the coordination and management of the NETT Network, including leadership of the Clinical Site Hubs, IRB issues, investigator training/certification procedures, drug handling and accountability, trial monitoring, ability to coordinate with or provide a central repository for biological samples (if required by specific research projects), and publications’ policies.

2. Ability to provide leadership to physicians involved in emergency medicine, neurology, neurosurgery, and neurointensive care.

3. Previous experience in management of multi-center Phase I-III clinical trials.

4. Trial protocols for two clinical trials appropriate for the NETT Network (see above).

5. Shared data elements and database features.

6. Ability to develop and/or interface with innovative telemedicine methods to enhance involvement of off-site neuro-clinicians in emergency department research and care, and to facilitate technological advances with Hubs. 

7. Budget proposal

8.  Description of clinical trials should include:  target disease, primary objective, secondary objectives, scientific rationale, design and intent of study, relevance and priority of the study to NETT, sample size, number of clinical centers, patient selection criteria, recruitment plan, informed consent process, administration of intervention including dose and duration, extent and type of blinding/masking, follow-up plan, endpoints and outcomes, statistical and clinical basis, statistical methods to analyze primary and secondary outcomes, interim monitoring plan, ethical and consent considerations, participating pharmaceutical or device manufacturing company and IND/IDE status or FDA exemption.  Page limit:  25 pages

For this award, 50% of the application rating will be based on ability to successfully lead the network and 50% on the specific clinical trial proposals (including budget).

The following will be considered in making funding decisions:

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

 Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

Program staff will be responsible for the administrative review of the plan for sharing research data.

2.D. Sharing Research Resources

 NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates
Not Applicable

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the Notice of Award. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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 (U01), 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 above.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for:

The Principal Investigator (PI) has primary authority and responsibility to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of the 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 or by action of the Steering Committee, NETT-AG, and the DSMB. 

The awardee will manage and conduct the proposed clinical trial in compliance with all established DHHS, NIH and NINDS policies and procedures.  The awardee will be responsible for protecting patient safety and obtaining adequate patient recruitment to complete the study. It is the grantee institution’s responsibility (1) to ensure that all sites engaged in research involving human subjects have an appropriate OHRP-approved Assurance and an IRB approval of the research consistent with 45 CFR Part 46 and (2) to retain documentation of compliance with the requirements of 45 CFR Part 46.

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.

2.A.2. NIH Responsibilities

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The NINDS Program Scientific Officer will serve on the Steering 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 Program Scientific Officer will have voting membership on the Steering Committee and its subcommittees.

The NINDS reserves the right to terminate or curtail the study (or an individual award) in the event of: (a) failure to develop or implement a mutually agreeable collaborative protocol; (b) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or major breach of the protocol; (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance; or (d) human subject or ethical issues that may dictate a premature termination.

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

2.A.3. Collaborative Responsibilities

The Steering Committee is responsible for overseeing all aspects of the clinical trial, including implementation of the study protocol, oversight of recruitment retention and enrollment, review of reports from the trial committees, and preparing and publishing scientific reports. 

The Steering Committee will develop the collaborative protocol and approve any modifications to the study design and ancillary protocols.  This Committee will define rules regarding access to data and will formulate the publication policy for the project.

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

2.A.4. Arbitration Process

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 arbitration. An Arbitration 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 arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Robin Conwit, M.D.
Clinical Trials Group
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2181
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9135
FAX: (301) 480-1080
Email: conwitr@ninds.nih.gov

2. Peer Review Contacts:

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Room 3201, MSC 9529
6001 Executive Blvd.
Bethesda, MD  20892-9529 (Rockville, MD 20852 for express/courier service)

Telephone: (301) 496-9223
FAX: (301) 402-0182
Email: nindsreview.nih.gov@mail.nih.gov

3. Financial or Grants Management Contacts:

Mr. Gavin Wilkom
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3254
6001 Executive Blvd.
Bethesda, MD 20892

Telephone: (301) 496-9231
Email: wilkomg@ninds.nih.gov

Section VIII. Other Information

Required Federal Citations

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time, the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding, or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://www.nih.gov/about/publicaccess/ and view the Policy or other Resources and Tools including the Authors' Manual (http://www.nih.gov/about/publicaccess/publicaccess_Manual.htm).
 
Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372, or Health Systems Agency review. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/. 


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NIH Funding Opportunities and Notices


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