Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Neurological Disorders and Stroke (NINDS)
Funding Opportunity Title	Spinal Muscular Atrophy (SMA) Biomarker Study (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	RFA-NS-11-009, RFA-NS-11-010, RFA-NS-11-008
Funding Opportunity Announcement (FOA) Number	RFA-NS-12-004
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.853
FOA Purpose	The purpose of this funding opportunity announcement (FOA), issued by NINDS, is to invite applications for a study of candidate biomarkers in Spinal Muscular Atrophy (SMA). The study will be done using the NeuroNEXT infrastructure (as established in response to RFA-NS-11-009, RFA-NS-11-010, RFA-NS-11-008) along with ad hoc clinical sites as appropriate. This is a milestone-driven cooperative agreement program involving participation of NIH staff in the development of the project plan and monitoring of research progress.

Posted Date	June 9, 2011
Open Date (Earliest Submission Date)	August 1, 2011
Letter of Intent Due Date	August 1, 2011
Application Due Date(s)	September 1, 2011, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	November/December 2011
Advisory Council Review	January 2012
Earliest Start Date(s)	April 1, 2012
Expiration Date	September 2, 2011
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

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

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

Background

Spinal Muscular Atrophy (SMA), associated with a mutation in chromosome 5, is thought to be the second most common autosomal recessive disease in the US affecting 1/6000 live births. The disease is caused by loss of the survival of motor neuron 1 gene (SMN1) which codes for full-length protein. SMA Type 1 is one of the most common genetic causes of infantile death. Although the disease can be readily diagnosed, there are no approved treatments for SMA.

Advances in preclinical research have uncovered potential drug targets, however clinical development of treatments for SMA has been hampered by multiple factors including: 1) the paucity of natural history studies, 2) the absence of qualified identifiers of biological activity of potential interventions, 3) the need for qualified markers of disease progression and/or markers of disease amelioration.

Goals for this SMA biomarker validation study:

• Evaluate biomarkers and clinical outcomes longitudinally across a spectrum of SMA cases. Investigators are encouraged to incorporate controls, as appropriate;
• Establish a clinical outcomes and biomarker database;
• Contribute samples to the NINDS biorepository at Coriell to capture and share methods and pre-competitive data.

Experimental Approach and Implementation:

Biomarkers are defined as cellular, biochemical, and molecular (including genetic and epigenetic) characteristics measurable in biological materials by which normal and/or abnormal processes can be recognized and/or monitored. Biomarkers have multiple potential applications, including but not limited to, the ability to measure disease progression, the ability to demonstrate effects of investigational agents, the ability to demonstrate response to an investigational agent, and the ability to predict response or potential adverse events to a given intervention and/or surrogates showing therapeutic response. This FOA is encouraging applications for studies of candidate biomarkers in SMA that have potential for usefulness in the evaluation of new treatments. A short-term intervention to evaluate a pharmacodynamic biomarker may be included.

This FOA does not solicit studies of candidate biomarkers for SMA diagnosis.

Study requirements

In co-sponsorship with the Food and Drug Administration (FDA), the National Institute of Neurological Disorders and Stroke (NINDS) organized a workshop in May of 2011 to discuss the current state of biomarker development in SMA. Those discussions should inform but not limit the choice of biomarkers proposed (http://www.ninds.nih.gov/news_and_events/proceedings/sma_workshop.htm). Applicants are strongly encouraged to visit the link after mid-June 2011 to review the workshop summary.

The study will need to include persons with SMN1 mutation associated SMA Type I, II or III as well as controls as appropriate, potentially including SMA carriers. Enrollment is to be completed within 6 months. Each study participant should be followed for a minimum of 12 months.

In patients with SMA Type I, recent natural history data in addition to biomarkers is of particular importance. Since the number of incident SMA I cases at any given site is expected to be small, the NINDS intends to use the current opportunity to collect data on SMA I patients at the participating sites. This will be done through an NINDS-provided protocol which will describe specific data of interest and utilize standardized case report forms. The successful applicants will be invited to provide input into the protocol before it is finalized. The data to be collected under this protocol will include information about clinical events such as time to requirement for ventilator and/or nutritional support and other clinical data. The study investigators and their staff are expected to support this data collection.

In December 2010, FOAs (RFA-NS-11-009, RFA-NS-11-010, RFA-NS-11-008) were released for a Clinical Coordinating Center (CCC), a Data Coordinating Center (DCC) and a group of clinical sites, which combined will form the Neurology Network of Excellence in Clinical Trials (NeuroNEXT). The study selected in response to this FOA will be conducted through the NeuroNEXT infrastructure using the NeuroNEXT core clinical sites as well as ad hoc clinical sites as appropriate.

The NeuroNEXT Clinical Coordinating Center (CCC) will work with the Investigators to implement the proposed study efficiently. The NeuroNEXT Data Coordinating Center (DCC) will provide data management support. Data and biospecimens generated will be used to create a publicly available resource for SMA biomarker validation and discovery, and must be accessible to qualified investigators within and outside NeuroNEXT. Biospecimens may be include but are not limited to bodily fluids, DNA, and fibroblasts as well as evaluations of motor, imaging, and electrophysiological studies; the number and type of biospecimens to be collected is up to the applicant. The NINDS biorepository at Coriell will be utilized for biospecimen banking.

The implementation of the clinical study will be divided into two stages and is expected to include the following activities:

1. Planning and Start-up stage:

• Submit a Letter of Intent to the FDA Biomarker Qualification Review team regarding the study to receive specific consultation and advice pertaining to context-of-use in SMA (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf),
• Finalize protocol, study procedural manual, and consent forms.
• Working with the NeuroNEXT DCC, develop data management and quality control system.
• Working with the NeuroNEXT DCC, develop study case report forms (in conjunction with the CDE initiative http://www.commondataelements.ninds.nih.gov).
• Using the NeuroNEXT CCC, initiate contracts, start-up and training of study personnel at the proposed performance sites.
• Document quality assurance/control in bio-specimen handling/transport at all performance sites (Domestic and Foreign). Foreign Organizations will need to document compatibility of their data collection methods with US data collection.
• Achieve acceptable enrollment rate that ensures the study can be completed as proposed in the application. The core NeuroNEXT clinical sites will determine the potential number of enrollees at their respective sites and will provide those numbers to the PI of the funded study in order to allow for planning and rapid enrollment at study initiation.

2. Completion stage:

• Complete enrollment and follow-up of all study participants.
• Minimize loss to follow up.
• Submit samples to NINDS biorepository at Coriell.
• Analyze data and submit study results paper for publication, within one year of completion of all subject follow-up.
• Provide public access to complete data set(s) within 18 months of study follow-up completion or after publication of the main study results paper, whichever comes first.
• Upon publication of the study results, the PD/PI will be expected to contact the FDA to discuss further steps needed, if any, for use of study-identified biomarkers in future clinical trials of Spinal Muscular Atrophy designed for regulatory approval purposes.

If investigators choose to incorporate patient reported outcomes in the study, NINDS suggests that they review the following FDA guidance to assist in their planning: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

IRB approval at the coordinating center is strongly preferred but not required at the time of submission.  If the study will involve use of an investigational agent for proof of principle, an active IND is required prior to award. NINDS requires FDA and IRB approvals prior to award, and encourages investigators to seek regulatory and ethics approvals as early as possible prior to submission. 

The award and continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies.

Webinar

NINDS will hold an informational webinar to discuss this FOA at 11 am on July 11th, 2011; call-in number is 800-857-9635, passcode 13878. Applicant attendance at the webinar is optional. A link with the call-in number as well as the hyperlink for viewing of the projected slides will be provided at www.ninds.nih.gov/NeuroNEXT. To preserve anonymity, interested parties may send questions directly to Dr. Elizabeth McNeil ([email protected]) for discussion during the webinar and/or publication on the NINDS/OCR webpage.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIH intends to fund a single award, corresponding to a total of $1,750,000 for fiscal year 2012. Future year amounts will depend on annual appropriations.
Award Budget	Application budgets need to reflect actual needs of the proposed project, including provision of per patient cost estimates.
Award Project Period	Up to 3 years.

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

Higher Education Institutions:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• 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 eligible to apply, but will have to work with the U.S.-based NeuroNEXT infrastructure.

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

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

It is not necessary to be part of NeuroNEXT in order to be eligible to respond to this FOA.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

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

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

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(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The letter of intent should be emailed to:

D. Elizabeth McNeil, MD MSc
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd Room 2115
Bethesda MD 20892
Telephone: (301) 496-9135
Fax: 301-502-1501
Email: [email protected]

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy

The following information should be included in the Research Strategy section of the application:

Applicants should describe the significance, background, rationale, preliminary data, study design, and approaches for the candidate biomarkers selected for evaluation. Applicants should focus on studies that are likely to yield significant results within 2 years and which will allow a go or no go decision for further study.

The information provided in the application should be organized in a manner that will facilitate peer review. The body of the application should present an overview of the state of the science, and relevance of the study for biomarkers in SMA.  The methodological aspects of the protocol, and approach to data collection and analysis should be summarized, with specific references to additional information and details provided in the protocol. 

While final milestones will be determined at the time of grant award, the applicant should propose for consideration by the reviewers clear milestones that provide objective, quantitative outcomes that will justify continuing the project.

Approach

A concise research plan should include:

• A description of the study population
• A list of subject eligibility and inclusion/exclusion criteria
• Description of the observed or hypothesized clinical significance of the biomarkers to be evaluated 
• Description of the intervention to be tested (if applicable)
• The PD/PI’s should assume that the NeuroNEXT sites will have the capacity to conduct a SMA biomarker study. Once a proposal has been selected for funding, NINDS will determine, with the NeuroNEXT steering committee, whether the NeuroNEXT clinical sites alone can enroll sufficient patients or whether ad hoc sites need to be added, possibly from the list provided by the applicant. The applicant should provide a description of recruitment and retention plans.
• Statistical Methods:  The statistical section should describe sample size and power calculations, methods of data preparation and presentation and methods to handle missing data.

Study Organization and Administration:

The application must include a description of the organization and management of the study. Applicants must document their ability to recruit patients, to collect clinical data and to collect, process, track, ship and store specimens.

While it is not necessary to have previous specimens available in order to respond to this FOA, Applicants should describe in detail any ongoing prospective specimen collections proposed for inclusion in this study. The description should include information on the types of patients and controls accrued, clinical information to be collected, and types of specimens to be collected. If the applicants already have specimen repositories that they are willing to make available, they should describe the purpose of the study(s) from which samples are being made available, the extent of the clinical information collected and the quality control/assurance methods used in relation to those biospecimens. Sites with adequate existing case-control repositories should furnish a list of SMA types and number of specimens by type as well as providing information on the availability of follow-up data.

Applicants should describe procedures for quality assurance and laboratory quality control. The procedures and the documentation should include confirmation of laboratory reports and inter-laboratory comparisons of test results and procedures. The applicants must discuss their experience with quality control issues and other considerations that may arise in multi-institutional studies. While all performance sites (Domestic and Foreign) will need to document quality assurance/control in bio-specimen handling/transport, Foreign Organizations will need to document compatibility of their data collection methods with U.S. data collection.

The following information should be included in the Facilities and Other Resources section of the application:

• The applicant should provide detailed information, with possible details from past studies, on all sites ability to recruit and retain subjects, including a discussion of the availability of SMA patients at the PD/PI’s site as well as at any proposed ad hoc sites. This information may be provided in tabular format.
• Description of On-site sample preparation facilities considering proposed biospecimens.

Protection of Human Subjects

Data and Safety Monitoring Plan

Applicants must include a Data and Safety Monitoring (DSM) Plan for all clinical studies that is commensurate with the risk level of the proposed clinical research. All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the NINDS/NIH, the Office of Biotechnology Activities, Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board (if one is used). Therefore, the DSM Plan must address the following areas:

• Who will manage and conduct the monitoring;
• What will be monitored;
• Proposed monitoring time points;
• Where the monitoring will occur;
• How the reportable events will be managed and reported;
• How sites/centers, and participating facilities (labs, pharmacies) will be monitored.

Clinical Protocol

• The clinical protocol should be uploaded as an "other attachment" (item 12 of 4.4 'Other Project Information Component')
• A chart of expected enrollment timelines must be included.
• A timeline of study evaluations must be included.
• Informed consent documents must be included.
• Applicant may also provide non-referenced or non-published, non-standardized clinical assessments and data collection tools

Resource Sharing Plan

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

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix

Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide

Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide. Foreign applicants must incorporate use of the NeuroNEXT clinical sites as well as the NeuroNEXT Data Coordinating Center and Clinical Coordinating Center in their study proposal. Foreign applicants should budget for at least two trips annually to the USA so that they can participate in steering committee and investigator meetings.

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

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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

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

This initiative is not subject to intergovernmental review.

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

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

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness to the FOA by the NINDS. Applications that are incomplete and/or nonresponsive will not be reviewed.

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

Qualifications and experience

It is expected that the most competitive applicants will have a thorough proficiency in both clinical and scientific issues related to SMA. Therefore, applicants should emphasize in their submission, including in the personal statement of the biosketch, any expertise they have in SMA genetics, neurophysiology, clinical research, or any other area that might be considered an asset for SMA biomarker development efforts.

Applicants should describe qualifications and experience to act as PD/PI for a multi-center study in the Biosketches and in the appropriate narrative sections of the application (Background/Preliminary Data section of the Research Strategy). This description should be provided in a brief narrative form; submission of a CV alone is insufficient.

Collaborations

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

Budget

A detailed budget should be presented including proposed per-patient costs for all candidate biomarkers to be evaluated. The budget should account for 12 months of follow-up per study participant. The budget should reflect expected costs for the applicant s center as well as any sites proposed by the applicant.

The applicant’s budget should be largely planned on a fee-for-service basis. The planning should include per-patient cost for the biomarker study proposed by the applicants and a small fee for chart review for the SMA type I natural history study protocol. A site-start up fee for the SMA team at each proposed site may be included. PD/PI time, Study coordinator time, clinical coordination time, and data management time are provided by NeuroNEXT infrastructure funding for all NeuroNEXT sites so the applicant’s budget submission does not need to reflect costs at the NeuroNEXT clinical sites.

The biospecimens collected during this study will be sent to the NINDS biorespository at Coriell. The shipping and storage associated costs have been budgeted for by NINDS and do not need to be included in the applicant’s budget submission.

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 biomarkers advance clinical research in SMA?

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? Is there appropriate integration of the NeuroNEXT components within the proposal based upon the information available in the NeuroNEXT FOAs? (RFA-NS-11-009, RFA-NS-11-010, RFA-NS-11-008)

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? Is the proposed plan and experience relating to subject recruitment and retention, staff training, data collection, and multi-site management adequate? Are the clinical outcomes methods well described with regard to training and reproducibility? Are the chosen clinical outcomes ones which would be considered clinically meaningful ? Are the methods to collect, process, store, and ship samples adequate and explained in a manner that would allow them to be standardized across multiple sites? Is there an appropriate approach to plans for future sharing of data and biospecimens? Has the applicant proposed clear milestones that provide objective, quantitative outcomes that will justify continuing the project.

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?

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 ApplicableNot 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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources. While all performance sites (Domestic and Foreign) will need to document quality assurance/control in bio-specimen handling/transport, Foreign Organizations will also need to document compatibility of their data collection methods with U.S. data collection.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review), will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke (NANDS) 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.
• Applicability of the proposed biomarkers for use in future clinical trials, including those which may have potential regulatory use.

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Supervision of the clinical study with consistent emphasis on collaborative interactions between investigators, advisory and steering committees, and NINDS representatives.
• Interaction with the NeuroNEXT Clinical Coordinating Center and the NeuroNEXT Data Coordinating Center as well as any ad hoc sites.
• Submission of a Letter of Intent to the FDA Biomarker Qualification Review team regarding the approved study to receive specific consultation and advice pertaining to future regulatory qualification for context-of-use in SMA.
• Acquisition of an IND from the FDA if an investigational agent is to be used to measure potential effects on candidate biomarkers.
• Upon publication of the study results, the PD/PI will be expected to contact the FDA to discuss further steps needed, if any, for qualification of study-identified biomarkers for context-of-use in future clinical trials of Spinal Muscular Atrophy designed for regulatory approval purposes.
• The PD/PI will be expected to act as a member of the NEXT steering committee for the duration of the study with possible participation in steering groups for planning, quality control, capitation, publications etc.
• Awardees will retain custody of and have primary rights to data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards:

• The NINDS staff (Project Scientist) working with the network investigators will develop milestones for the study. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement. The NINDS retains the option to obtain periodic external peer review of progress.
• 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.
• The NIH program staff will receive copies of any consultative advice received from the FDA Biomarker Qualification team related to this NIH-funded study.
• If the proposed trial should require that FDA issue an IND, the NINDS scientific and/or administrative program director(s) will be present at any meetings held with the FDA related to this NIH-funded protocol.

Areas of Joint Responsibility include:

• In collaboration with the NINDS Project Director, the PD/PI will be responsible for outreach to researchers and organizations to promote and enhance data sharing.

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 the expenditure data portion of the Federal Financial Report are required for closeout of an award as described in the NIH Grants Policy Statement.

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

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: [email protected]

D. Elizabeth McNeil, MD MSc
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9135
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone:  (301) 496-9223
E-mail: [email protected] .

Tijuanna DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9231
Email: [email protected]

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.