Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (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

The purpose of this funding opportunity announcement (FOA) is to solicit applications for the clinical Hubs of the Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN). SIREN will provide a robust and readily accessible infrastructure for rapid implementation and high quality performance of clinical trials in a breadth of emergency indications related to neurology (e.g., status epilepticus, traumatic brain or spinal cord injury; not cerebrovascular because StrokeNet is the primary network for stroke clinical research), cardiovascular (e.g., cardiac arrest, decompensation of cardiac failure), respiratory (e.g., respiratory arrest, pulmonary embolus), hematology (e.g., exsanguination) and trauma. SIREN will consist of one Clinical Coordinating Center (CCC), one Data Coordinating Center (DCC) and up to 15 clinical centers with their satellite sites (Hub and Spoke clinical site model). The SIREN infrastructure should be sufficient for implementation of at least four simultaneous large (>1,000 patient), simple, pragmatic trials in the Emergency Department (ED) and pre-hospital (e.g., transportation, EMS) settings. The purpose of SIREN is to advance emergency medicine by efficiently enabling performance of rigorous comparative effectiveness studies and assessments of novel therapeutic interventions.

There is a clear public health imperative to stimulate and support research that improves care and clinical outcomes. According to the Centers for Disease Control and Prevention (CDC), unintentional injuries are the leading cause of death for Americans under the age of 45. In 2011, the most recent year with data published by the CDC, there were 136 million ED visits in the United States, accounting for about 4% of all health care spending. Of the 136 million visits, 12%, or some 16 million, resulted in a hospital admission. About half of the top 10 reasons for presentation at an ED (i.e. chest pain, headache, cough, back symptoms, shortness of breath) are neurologic or heart, lung, blood (HLB) conditions and together these make up about 17% of all ED visits.

Clinical emergency care research covers all stages of the provision of emergency care, from pre-hospital emergency medical services to hospital EDs, trauma systems and emergency operative interventions. The principles of emergency care making accurate and timely diagnoses and interventions are independent of the disease, organ system and venue. The ED is the common entry portal for more than half of all hospitalized patients. Although dysfunction may start in one organ system, in a critical situation other organs can become rapidly involved, so successful care must address multiple systems. These characteristics of emergency care justify establishment of SIREN as a single, adaptable network able to support clinical trials in the multiple indications of neurology, cardiology, respiratory, hematology and trauma.

SIREN will harness multidisciplinary emergency care expertise to provide scientific leadership and the infrastructure required to conduct large, simple, pragmatic clinical trials to advance knowledge of optimal patient management in the prehospital and ED setting. In addition, the network may be called upon to include other venues where post emergency care is provided (such as critical care units, the operating room or other hospital settings) when required by the needs of peer-reviewed, meritorious clinical trials.

The Hubs will contribute to these objectives by exemplary execution of clinical trials, including rapid start up and enrollment, protection of human subjects, and provision of accurate data in a timely fashion. To facilitate trial performance, the Hubs will select and provide oversight and leadership to satellite clinical sites ("Spokes").

SIREN is funded by NINDS, NHLBI and NCATS, with NINDS as the lead institute. The Office of Emergency Care Research (OERP) and the Combat Casualty Care Research Program (CCCRP) in the US Army Medical Research and Materiel Command (USAMRMC) contributed their expertise during planning. SIREN will consist of one clinical coordinating center (CCC), one data coordinating center (DCC) and up to 10 clinical center Hubs with their affiliated satellite clinical sites ( Spokes ), with the capability to coordinate clinical research in a large number of EDs across the United States.

The Clinical Coordinating Center (CCC) will provide scientific and organizational leadership to SIREN to achieve both efficiency and excellence in its implementation and performance of clinical trials. Responsibilities of the CCC will specifically include the SIREN central Institutional Review Board (IRB), master contract agreements with the clinical sites for trial performance, recruitment plans, enrollment tracking and quality improvement. The role and responsibilities of the CCC are described more fully in RFA-NS-16-014.

The Data Coordinating Center (DCC) will provide scientific and organizational leadership to SIREN in all aspects of data management, data quality, statistical design and statistical analysis. Responsibilities of the DCC particularly include management and support of the Data Safety Monitoring Board(s) (DSMB), and reporting to regulatory authorities (e.g., central IRB, FDA). The role and responsibilities of the DCC are described more fully in RFA-NS-16-015.

The Hubs will provide scientific leadership and conduct clinical trials in the ED and pre-hospital (e.g., ambulance, other transport) settings. A Hub is envisioned as a regional academic medical center or tertiary care facility which will enroll patients itself along with providing clinical and organizational leadership to its network of 2-10 satellite sites (Spokes). The Hub must be capable of providing physicians with expertise in emergency medicine, neurology, cardiology, pulmonology, hematology, general surgery, trauma surgery, neurosurgery, cardiovascular surgery or other subspecialties, as required. The roles and responsibilities of the Hubs and Spokes are described more fully below (see Hubs: Characteristics, Roles and Responsibilities).

The CCC, DCC, Hubs and Spokes are each integral components of the network. SIREN's success will require close, active cooperation and collaboration to assimilate these elements into a highly effective clinical research structure. Participants at all levels in SIREN are strongly encouraged to promote innovative methods to improve efficiency and quality in performance of emergency care clinical research.

Baseline funding for the CCC, DCC and Hubs will be through a series of three awards (RFA-NS-16-014, RFA-NS-16-015, RFA-NS-16-016). The FOAs will support cooperative agreements, under which the SIREN CCC, DCC, and Hubs will be expected to achieve agreed milestones and metrics, as described in each of the FOAs. The baseline funding is purposefully lean, as it is anticipated that SIREN will additionally be supported by the individual clinical trial awards. Ideally, SIREN should have 3 to 4 clinical trials on-going during the second year of its five year term. All participants in SIREN (CCC, DCC, Hubs) should actively stimulate and encourage the submission of clinical trial applications from the scientific community, including investigators within SIREN as well as others not affiliated with the network. Interested potential applicants are strongly encouraged to communicate with the Scientific/Research Contacts for this FOA regarding the processes and procedures for clinical trial applications at least three months prior to the planned submission date.

With concordance of the funding NIH Institutes, clinical trials from other NIH or federal agencies which are relevant to emergency medicine may be conducted in SIREN. Over the 5-year project period, SIREN is expected to implement at least four large (>1000 patients), simple, pragmatic clinical trials in the ED and pre-hospital (e.g., emergency medical services [EMS]) setting. The terms simple and pragmatic denote clinical trials which are consistent with and can be efficiently incorporated into standard emergency care. Typical features include brief, inclusive patient eligibility criteria, procedures which integrate easily into or with standard of care practices and limited, focused data collection. Appropriate trials may test novel devices, medications or procedures or may compare effectiveness of existing therapeutic approaches. Trials in SIREN will be hypothesis driven, not registries or descriptive observational studies.

The clinical trials to be conducted in SIREN will be funded individually by project-specific grants from the participating NIH Institutes (e.g., NINDS and NHLBI). SIREN is intended as a multidisciplinary network reflective of the spectrum of clinical challenges confronted in emergency care. Collaborative projects that include disorders relevant to the missions of more than one of the participating Institutes (i.e. NINDS, NHLBI, and NCATS) will be strongly encouraged. SIREN is not intended to be simply a neurology network or a cardiovascular network, and will conduct, in a fair and balanced manner, clinical research relevant to neurology and to heart/lung/blood.

Clinical trial applications may come from academic investigators (inside or outside of SIREN), investigators in military medical facilities, small business, industry, or other eligible institutions. SIREN may also be called upon to join or engage in other, on-going clinical trials in emergency medicine. SIREN should be prepared to work collaboratively with other programs or networks, as a lead, partner or participant, as appropriate.

A typical SIREN Hub is envisioned as a medical center with full multidisciplinary coverage (24/7) such as 1) a level 1 trauma center or 2) a major referral neurologic or cardiovascular academic medical center or 3) a tertiary care facility. If a Hub is not itself a Level 1 trauma center, it must either be co-located with one or have a committed Spoke which is a Level 1 trauma center. A Hub must function as an exemplary clinical research site itself, while concurrently providing leadership, organizational oversight and research support to its Spokes.

The Hub is expected to participate as a clinical site in every clinical trial performed in SIREN, whether the focus is neurological, heart/lung/blood or trauma. Each Hub must be able to:

1) execute clinical trials in the ED setting; 2) provide and coordinate the multiple medical and surgical specialties which may participate in the clinical trials, such as neurology, cardiology, pulmonary, neurosurgery, trauma surgery, cardiothoracic surgery, anesthesia and hospital intensivists; 3) demonstrate a strong working relationship with pre-hospital providers (e.g., EMS); 4) propose and oversee a network of Spokes.

Each Hub must have a flexible network of Spokes. The principal function of the Spokes is to provide access to a larger patient population for trial enrollment. Spokes also increase access to patients with a particular disease or injury, to patients from underserved communities, or complement the Hub by providing access to specific research or clinical expertise. For each clinical trial, the Hub would be expected to construct a network of 2-10 Spokes specifically tailored to the needs of that particular trial. Since the requirements of each clinical trial will be somewhat different, the identity and configuration of Spokes will be unique for each clinical trial. Therefore, a Hub should have relationships with a number of potential Spokes, and the ability to add Spokes as appropriate. To demonstrate the ability to attract Spokes, the applicant is requested to identify in the grant submission five Spokes committed to participation in at least one clinical trial. Since these five Spokes are unlikely to meet all possible clinical trial requirements, the Hub may need to have plans and mechanisms for recruiting and adding other Spokes, when needed.

The Hub and Spokes together must be able to 1) support recruitment of at least 100 subjects per year into the planned four concurrent trials; 2) provide physicians with expertise in cardiology, neurology, pulmonary, hematology, trauma surgery, thoracic surgery, neurosurgery, intensive care and anesthesia. Spokes may range from academic emergency centers to community hospitals, as appropriate to expand patient access and representation of minority, rural and other segments of the population. The Spokes may be geographically related partnering medical centers or geographically distant centers where productive collaboration has been well established. Spokes should be located in North America; if outside of the United States the applicant must explain how the Spoke will coordinate with the SIREN central IRB. Spokes may enroll and treat patients on-site or may identify patients to transfer to the Hub for enrollment. There is no ideal or preferred arrangement.

Active participation of the prehospital providers is also critical to achieving the recruitment of at least 100 subjects per year into the planned four concurrent trials. The configuration of providers is highly variable; the catchment area of the Hub ED might be served by one or several providers. As with Spokes, there is no a priori preferred arrangement; the applicant should propose the configuration optimal for their situation.

The design and requirements will be unique for each meritorious clinical trial, therefore SIREN must be flexible. Hubs should be resourceful and innovative in approaching the challenges of each study. Examples of some variations which might occur include, but are not limited to:

• SIREN is intended for adult clinical trials, but some clinical trials might include some children or adolescents, if appropriate for the disease under study;
• requirement of patients with a relatively infrequent condition, such as spinal cord injury or acute pulmonary edema secondary to decompensated heart failure;
• management which continues from the ED into subsequent care settings such as the intensive care unit, operating room or hospital floor;
• outcome measures collected well beyond the ED encounter, i.e., 30 days, 90 days or longer after the intervention;
• complex diagnostic or therapeutic interventions with aggressive time goals (e.g., MRI potentially including nonstandard acquisitions, interventional cardiology);
• complex pre-hospital capabilities, such as telemedicine or air transport (e.g., helicopter, plane);
• conduct of more than four concurrent clinical trials.

Milestones will be determined at the time of award. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement (see Cooperative Agreement Terms and Conditions of Award).

a) Master Contracts and Payments will be used to speed implementation of clinical trials in SIREN. The CCC will negotiate and maintain a master contract with each Hub and each Spoke RFA-NS-16-014. Payments will be on a per-patient basis, according to clinical trial budgets and the master trial agreement, and will be directly distributed by the CCC to each Hub and Spoke. All clinical centers, both Hubs and Spokes, are expected to work cooperatively with the CCC and to accept the master contract and payment system. Applicants are encouraged to consult with their institutions regarding acceptability of master contracts. Applicants who cannot accept master contracts and payments will need to justify this in the application..

b) Central Institutional Review Board (IRB). The CCC will implement and manage a central IRB for SIREN RFA-NS-16-014 and will create reliance agreements with each Hub and Spoke (unless the Spoke uses the Hub’s IRB). It is expected that clinical centers will use the central IRB for standard clinical trials. Potentially one or more of the clinical trials conducted within SIREN will require Exception from Informed Consent (EFIC) with requirements for community consultation, opt out options and public disclosure (see Exception from Informed Consent Requirements for Emergency Research, FDA, 2013 and 21 CFR 50.24 ). It is preferred that clinical centers use the central IRB for EFIC studies, though fulfillment of community based requirements may entail collaboration with local IRBs, local community liaisons, local community representatives or other means. Applicants are strongly encouraged to consult with their institution, potentially including their institutional IRB, regarding: 1) acceptability of a central IRB for emergency care clinical trials that are not EFIC, 2) acceptable approaches to EFIC trials under a central IRB. Applicants who do not accept the central IRB should provide an alternative which preserves efficient study initiation, along with a justification for this choice.

Any clinical trials supported by DoD funds are reviewed and approved by the U.S. Army Medical Research and Materiel Command Office of Research Protections, Human Research Protection Office of Research Protections, Human Research Protection Office to ensure DoD-specific regulations, including 10 USC 980 and DoDI 3216.02, are appropriately addressed. Additional information about these requirements is located at (https://mrmc.amedd.army.mil/index.cfm?pageid=Research_Protections.hrpo). Applicants are strongly encouraged to consult with their institution, potentially including their institutional IRB, regarding institutional compliance with DoD specific human subjects protections.

c) Patient Enrollment The Hub is responsible, in cooperation with the CCC, for creating and executing clinical trial-specific patient recruitment plans for itself and its Spokes. Achievement of recruitment goals for diverse and underserved populations (i.e., ethnic groups, racial groups, gender, rural populations) is particularly important. If recruitment is not meeting expectation, the Hub, in cooperation with the CCC and clinical trial PD/PI, must create and execute a corrective action plan(s).

d) Quality Assurance The Hub is responsible for quality control and improvement for itself and its group of Spokes and prehospital providers. The CCC has broader responsibility for creation and monitoring of specific, quantifiable performance metrics for SIREN, which will likely include start-up time, patient recruitment and retention, time from last patient last visit to data base lock, and number and aging of data queries. Quality reviews will be performed at least annually. Hubs and Spokes are expected to cooperate with the CCC in quality reviews and are further encouraged to propose innovative approaches to quality assessment and improvement.

e) Clinical Trial Grant Submissions The scientific value of SIREN will be realized through clinical trials conducted in the network. Additionally, clinical trial grants will provide significant contributions to financial support of the infrastructure (i.e. CCC, DCC and Hubs) during Years 2 - 5 of SIREN. Therefore, it is important that Hub research personnel encourage and support submission of high quality, impactful clinical trial grant applications from colleagues at their institution or elsewhere within the emergency medicine community. Hubs PDs/PIs and team members are also encouraged to themselves initiate or contribute to clinical trial applications.

f) SIREN Governance Committees. The Hub PD/PI or designee is expected to actively participate on the SIREN Steering Committee (SSC) and to serve on a rotating basis on the SIREN Management Committee and SIREN Operations Committee. The governance committees and anticipated meeting frequency are described at the end of this section.

The responsibilities of the SIREN Hub include but are not limited to:

• Accepting and implementing policies and procedures approved by the SIREN Steering Committee (see SIREN Governance Committees);
• Participating in all clinical trials conducted in SIREN;
• Identifying and recruiting Spokes, including altering or adapting its Spoke network to the particular needs of each clinical trial;
• Providing the Spokes with clinical leadership, research support, guidance and oversight for SIREN processes and procedures and regular communication regarding status of SIREN and individual clinical trials;
• Creating a research alliance with local pre-hospital providers (e.g., EMS) within the Hub and Spokes;
• Providing required data for feasibility assessments of clinical trial applications (e.g., enrollment estimates, budget estimates) to the CCC;
• Implementing awarded clinical trials at the Hub and Spoke sites, involving, but not limited to: 1) assembling local research team(s), 2) training the Spokes and pre-hospital providers on SIREN and clinical trial procedures, 3) assuring protocol adherence, 4) recruiting, treating, and following patients according to the study protocols, and 5) collecting and entering accurate, high quality data into the central data management system.
• Accurately identifying and recruiting eligible subjects for clinical trials, with attention to adequate gender and minority representation;
• Retaining participants throughout the follow-up period as required by protocol;
• Ensuring adequacy of human subjects' protections;
• Tracking and reporting trial and performance data to the CCC and/or DCC on a regular and frequent basis, including recruitment, retention, and adverse events, as required per protocol and by the IRB;
• Providing complete, accurate, and timely data entry, as well as rapid and complete resolution of any data queries, and a high level of data quality and completeness to the DCC.
• Cooperating with monitoring visits;
• Providing data to the DCC in a timely fashion for DSMB meetings;
• Actively participating in quality assessment and improvement;
• Actively participating in all SIREN Steering Committee (SSC), and, as appropriate, SSC subcommittees, SIREN Executive Committee (SMC) or SIREN Operations Committee (SOC) meetings and activities (see SIREN Governance Committees);
  • Specifically, Hub PD/PI’s or designees are expected to provide clinical scientific viewpoints and expertise on the breadth of issues discussed in the above venues.
• Participating in authorship of manuscripts and public dissemination of project results, as appropriate;
• Proposing innovative methods and leveraging existing local research resources to enhance programmatic efficiency;
  • Applicants are specifically encouraged to interact with the Clinical and Translational Science Award (CTSA), if present at their institution, to identify resources. This may include access to or assistance from Recruitment (RIC) and Trial (TIC) liaisons at the CTSA.
• Promoting visibility and awareness of SIREN within the Institution and the larger emergency medicine community;
• Actively encouraging and supporting submission of clinical trial applications;
• Increasing and disseminating knowledge about emergency medicine research at the Hub and Spokes to medical students, residents, fellows and allied health professionals, such as EMS technicians and nurses, when feasible. Helping new clinical investigators develop skills and experience to progress to more senior or experienced status, when appropriate.

The success of SIREN requires collaboration and cooperation among its component parts and members. Therefore, participation in the SIREN governance committees is an important responsibility. The final governance structure will be determined with the participants after awards are made for the CCC, DCC and Hubs. The following proposed structure, based on that of other clinical trial networks, is provided as a guide for applicants to use in composing the research plan and budget of their application.

The SIREN Steering Committee (SSC) will be the main governing body. The responsibilities of the SSC include to: 1) provide scientific leadership in SIREN; 2) promote awareness of SIREN throughout the emergency community; 3) encourage and support development of clinical trial concepts and proposals for SIREN; 4) systematically assess clinical needs and goals for emergency care research. Membership and meeting frequency are outlined in the table entitled "SIREN Governance Committees". SSC meetings may include other ad hoc participants, such as research team members from the CCC, DCC, Hubs, Spokes, or clinical trials.

The SSC may establish SSC working groups or SSC subcommittees on an as-needed basis for specific functions, such as: 1) Support of CCC or DCC functions (e.g., developing per-patient budgets; assuring quality control; monitoring conflicts of interest; developing and standardizing per-patient budgets); 2) Development of core competencies and technologies (e.g., imaging, ECG data analysis); 3) Subject area working groups (e.g., neurology, cardiac, pulmonary, trauma) with attention to encouraging and developing clinical trial grants; 4) Working groups for allied health professionals (e.g., EMS, study coordinators); 5) Advisory committees (e.g., patients and advocates, external experts); 6) Special topics ( publication plans, training/education materials).

The SIREN Management Committee (SMC) and the SIREN Operations Committee (SOC) oversee the day to day administration and operations of SIREN. The first is more oriented towards strategic and administrative functions, the second towards operational and executional functions. Each clinical trial will have a Trial Committee, responsible for conduct of that particular trial; thus there are anticipated to be four Trial Committees.

Table: SIREN Governance Committees

Committee	Membership	Meetings
SIREN Steering Committee	CCC PD/PI (chair), DCC PD/PI, PD/PI or designee from each Hub	Monthly by phone or webinar, adjusted by SIREN activity and needs Biannual face to face meetings in Washington DC metro area
SIREN Management Committee	CCC PD/PI (chair), DCC PD/PI, selected Hub PIs*	Weekly or biweekly by phone or webinar
SIREN Operations Committee	CCC PD/PI (chair), DCC PD/PI, selected CCC and/or DCC research team members, selected Hub PIs*	Weekly or biweekly by phone or webinar
Trial Committee	Clinical trial PD/PI (chair), CCC and DCC research team members (one of which should be either the CCC PD/PI or DCC PD/PI)	Monthly by phone or webinar, adjusted by activity and needs of trial
* Hub PD/PIs or designees will serve on a rotating basis, with attention to balance across specialties (e.g., neurology, cardiology)

Federal oversight will be provided by the SIREN Federal Committee, which will consist of representatives from the participating institutions funding the SIREN program of RFA-NS-16-014, RFA-NS-16-015, RFA-NS-16-016 (e.g., NINDS, NHLBI and NCATS) along with expert consultation from the Office of Emergency Clinical Research (OECR) . NINDS is the lead institute for grants and funding for the SIREN infrastructure of CCC, DCC, and clinical Hubs. Each of the institutions on the SIREN Federal Committee will provide one member to participate on the SSC, SMC and SOC. Independent of the governance above, the NIH Directors retain oversight for all funded research from individual institutes or programs. The Directors authority overrides all SSC, SMC and SOC decisions.

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
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) 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 SF424 (R&R) Application Guide.

It is preferable that only 1-2 PD/PIs be identified on each Hub application

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

Only one Hub application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed. A Hub application will be from a single institution, which may include geographically or organizationally linked partners or sites (e.g., multiple hospitals within an academic institution and/or affiliations of private and community hospitals), though this is not required.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Awards for a Hub and a CCC may be made to the same institution. There should be different investigators leading the Hub and the CCC to ensure that each activity receives full attention.

Applicants must obtain 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, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

The letter of intent should be sent to:

Robin Conwit MD
Telephone: 301-451-5939
Fax: 301-480-1080
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

The PD/PI for the Hub will be a clinical trials expert with a track record of successfully implementing clinical trials. As support, applicants should provide evidence to demonstrate experience in:

• Conducting clinical trials in the ED and prehospital settings;
  • Experience in neurology, cardiovascular, respiratory, hematology or trauma clinical trials, whether or not in the emergency setting, is also relevant.
• Contributing to leadership of a multicenter clinical trial;
• Establishing and/or contributing to leadership of or a network of satellite or affiliated clinical centers;
• Collaborating with pre-hospital providers in clinical trials;
• Encouraging and implementing innovative methods to reduce clinical trial duration and cost and to increase trial quality at their site;
• Contributing to Steering Committees or comparable governance committees;
• Working in a highly collaborative setting.

Applicants are strongly encouraged to name an experienced research team. The applicants are encouraged to assemble a diverse team that includes women and minorities. The applicants are also encouraged to include young investigators or junior faculty, if appropriate. Members of the research team are determined by the applicant, but often may include:

• Experienced study coordinator (s) and/or study nurses(s). At least one of these individuals should be sufficiently experienced to serve as a resource and guide for the Spokes and pre-hospital providers;
• Other research physicians;
• Experienced recruitment coordinator or specialist;
• Experienced data management coordinator or specialist.

If the applicant or other Key/Senior Personnel have successfully been awarded a clinical trial grant or have served as a PD/PI on a clinical trial in the past, this should be included in the biographical sketch

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

Budget requests may include the following allowable items:

• The budget submitted for this FOA should reflect baseline costs needed to initiate, organize and maintain the Hub in readiness for rapid implementation of clinical trials.
• Partial support for the PI(s) salary but ONLY for time spent on site organizational/administrative tasks or SIREN governance activities;
• Salary support for full or part-time research nurses, administrative personnel, and study assistants;
• Travel directly related to SIREN (e.g., SIREN Steering Committee meetings, Spoke site visits).

The following items are NOT allowed in the budget requests:

• Costs of clinical care provided to patients (e.g., for patient care reimbursement, transportation costs);
• Clinical and Data Coordinating Center costs; and
• Any physician, nurse or personnel compensation beyond that described above.Funds for tasks specific to conduct of a specific clinical trial, since these will be awarded separately in the grant for that individual clinical trial.

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

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

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

Research Strategy: The Research Strategy must consist of the following Sections A F. Information should be presented in a manner which clearly delineates experience and capabilities for the Hub itself and the Hub with its proposed Spoke network.

A. Background and Experience

The applicant should include a description of current and up to 10 recently completed multicenter clinical trials involving the clinical site. The most informative and relevant examples would be clinical trials involving emergency medicine and/or performed in the ED or prehospital setting. Trials involving neurology, cardiology, respiratory, hematology, or trauma are also relevant. EFIC studies, particularly ones performed in the ED and/or pre-hospital setting, are highly relevant. The summary may however include clinical trials on any disease from any funding source, if judged informative by the applicant. The following metrics should be presented in tabular form for each clinical trial:

• Identification information: title, funding source, PI, disease or disorder, intervention
• Enrollment: total number, enrollment over time, demographic breakdown and relative ranking or contribution in the context of other participating sites ;
• Time from IRB approval to first patient enrolled;
• Number and percent of patients lost to follow up;
• Number and percent of patients who successfully completed the clinical trial;
• Protocol deviations: number, type
• Time for query resolution, number/percentage >30 days, >60 days, >90 days, >120 days (for final locked data base).

The role of the Hub and proposed research team should be clear. Published manuscripts that highlight recently coordinated trials should be referenced in the application in the in the Bibliography and References Cited section of the application.

B. Leadership

Demonstration of leadership capability is required for the Hub PI(s), and should cover the specific points outlined in the Senior/Key Person Profile. It is also expected that, in order to successfully lead a group of Spokes and pre-hospital providers, the PI already plays a leadership role in some capacity to the emergency medicine community or local medical community, which should also be described in the application.

• Leadership derives not only from the CCC PD/PI, but also from members of the Hub research team. A brief leadership plan should be presented which identifies and describes the roles of Hub personnel, along with how they will contribute to the success of.A brief leadership plan should presented, including a succession plan with identification of a substitute/back-up PD/PI candidate, if possible, to assure programmatic continuity.
• Applicants should indicate their capability and willingness to attend and contribute to SIREN governance committees (see SIREN Governance Committee section) and provide examples of leadership and/or substantial contributions in comparable venues.
• Applicants should state their general support of collaborative research and their willingness to participate in a collaborative and interactive manner in all aspects of SIREN.
• Applicants should comment on any special expertise or unique strengths they can offer to the collaborative effort.

C. Research Program

• The applicant should present their concept for a Hub and Spoke network, and discuss its capabilities and merits, along with attaining the flexibility and scalability for the range of clinical trial challenges presented in Hubs: Characteristics, Roles and Responsibilities.
• The applicant should describe how the Hub PD(s)/PI(s) will identify, recruit and manage Spokes. The application should include: 1) identity of 5 Spokes committed to participation in at least one clinical trial; 2) approaches to optimizing the Spoke network for individual trials; 3) plans for identifying, recruiting and selecting additional Spokes, as needed; 4) procedures for adding a Spoke. The applicant should discuss how they plan to make the Spoke network flexible and scalable to meet potential challenges.
• The applicant should describe how the Hub PD/PI will identify, recruit and manage prehospital providers. The application should include: 1) identity of at least one prehospital provider committed to participate in SIREN; 2) plans for identifying, recruiting and selecting additional prehospital providers, as needed; 3) procedures for adding a prehospital provider.
• The applicant should present data demonstrating the capability of the Hub, Spoke and pre-hospital provider network to achieve the minimum enrollment commitment of 100 patients per year (assuming four on-going studies). Inclusion of detailed descriptions of the catchment area and population served are required.
  • Applicants are encouraged to be specific, identifying cities, towns, counties or zip codes from which patients will be drawn.
  • Particular attention should be paid to underserved and diverse populations, including rural populations.
  • Quantitative data on ED visits and patient population should be provided, in total and broken down by gender, racial and ethnic composition.
  • Data concerning frequency or types of neurology, cardiovascular and traumatic disorders seen in the ED is desirable.
  • Contribution and coverage areas of different pre-hospital providers servicing the ED catchment area;
  • Catchment area, population data and prior trial experience may be presented using tables and/or maps.
• The applicant should identify a committed group of multidisciplinary professionals at the Hub and committed Spokes appropriate for performance of large, simple, pragmatic clinical trials in disorders of interest to SIREN.
  • A core clinical research team should include emergency medicine physicians and allied health staff such as ED nurses and prehospital providers (e.g., EMS). Plans for expansion, if required, during clinical trial conduct should be included.
  • Specific clinical trials may require participation of other disease experts and/or subspecialists, including but not limited to neurologists, cardiologists, pulmonologists, anesthesiologists, neurosurgeons, trauma surgeons, cardiothoracic surgeons or intensivists. Applicants should describe 1) the potential pool of disease experts and subspecialists; 2) plans for outreach, recruitment, collaboration and integration of disease experts/subspecialists; 3) plans to motivate disease experts to support recruitment, if needed.
• The applicant should describe how the Hub plans to promote awareness of SIREN, and stimulate submission of grant applications for clinical trials. Applicants should discuss specific actions and how these will be accomplished within the first 1 3 years of the planned 5 year funding cycle. Applicants should discuss specific actions and how these will be accomplished within the first 1 3 years of the planned 5 year funding cycle. This may include whether they themselves would initiate or contribute to clinical trial concept or grant.
• The application should include any particular experience with or proposals for innovative methods to reduce clinical trial duration and cost, and to increase trial quality. Proposals for utilization of novel methods in SIREN are encouraged.

D. Organization and Operations.

• The duties of proposed personnel responsible for day to day administration and operations at the Hub, committed Spokes and prehospital providers should be described.
  • If there is prior experience operating as a team, this should be described.
  • See Senior/Key Person Profile, for additional descriptions of the research team.
• SIREN intends to use master contracts, centralized trial budget estimation and payment on a per-patient basis. Institutional acceptability and experience with these approaches should be addressed for the Hub and committed Spokes.
  • Responsible personnel and procedures for negotiation and maintenance of master contracts should be identified.
• SIREN plans to establish a central IRB at the CCC, and prefers Hubs and Spokes to use this central IRB to facilitate clinical trial initiation. Institutional acceptability and experience with central IRBs should be addressed for the Hub, committed Spokes and prehospital provider, particularly in regards to EFIC studies and DoD human subjects requirements.
  • Responsible personnel and procedures for negotiation and maintenance of reliance agreements should be identified.
  • If required, a plan for local performance of specific EFIC requirements, such as community consultation, should be included.
• Since the Hub will participate in all clinical trials conducted in SIREN, the application should delineate the organization and operations of the Hub itself as a clinical center. The applicant should be specific. Examples of relevant information include though are not limited to:
  • standard operating procedures for clinical trial activation and conduct;
  • personnel responsible for and data resources used for enrollment feasibility estimates and patient recruitment (e.g., hospital or clinic charts, specialized registry or data base).
  • personnel responsible for and methods/mechanisms used for specific tasks during conduct of a clinical trial, such as: 1) management of investigational drug/device supply; 2) minimization of protocol deviations due to enrollment of inappropriate subjects; 3) patient retention; 4) actual data entry into patient records and study forms; 5) verification of accuracy of entered data; 6) timely resolution of data queries;
  • ability to perform and experience with data transfer, particularly including direct transfers of electronic data from ECG, clinical laboratories (e.g., hematology, chemistry), imaging (e.g., X-ray, MRI) and/or electronic health records into clinical trial data bases.
  • plan for extending clinical trial performance beyond the ED to other clinical venues (e.g., intensive care unit, outpatient clinic) if required by a specific clinical trial
• The application should present the organization and operations of the Hub/Spoke complex. Examples of topics include: 1) communication with the Spoke PDs/PIs and research staff; 2) training Spoke PDs/PIs and research staff on SIREN processes; 3) harmonizing or qualifying standard operating procedures; 4) motivation and incentives for participation and enrollment; 5) mechanisms for oversight of Spoke performance; 6) mechanisms for improving Spoke performance, if needed.
• The application should describe incorporation of prehospital providers into the organizational structure and operations. Will this be centralized at the Hub or delegated to the Spokes? Examples of topics include: 1) incorporation into master contracts; 2) incorporation into centralized trial budgeting; 3) incorporation into central IRB; 4) training on good clinical practices (GCP), informed consent and EFIC; 5) training for specific clinical trials; 6) communication challenges with dispersed workforce; 7) incentives for clinical trial participation and accrual; 8) tracking of performance during clinical trials; 9) oversight of performance quality. Specifics should be provided for the committed pre-hospital provider included in the submission.

F. Quality Assurance

• A specific plan for quality assurance and improvement should be provided for the Hub, including metrics, responsible personnel, and mechanisms for collecting data and for implementing improvement plans.
• Describe how the Spokes and pre-hospital providers will be integrated into quality assurance.
• The applicant should discuss results of prior site audits at the Hub or committed Spokes, if available, and implementation of any responsive improvement plan. Relevant audits relate to clinical research and may have been conducted by NIH, FDA or industry

Letters of Support: A statement of commitment from each participating institution or organization must be provided. In addition, an institutional letter of support from the applicant's departmental and/or institutional leadership must be included in the application. It should address how the institutional commitment will be established and sustained, how the institution will maintain accountability for promoting scientific excellence, and how the SIREN effort will be given a high priority within the institution (relative to other research efforts and non-NIH supported programs.) The institutional commitment may be in the form of support for recruitment of scientific talent, provision of discretionary resources to the network site director, assignment of specialized research space, cost sharing of resources, and/or other ways proposed by the applicant institution. Letters from a high-level institution official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice President for Research) should be included confirming this commitment.

A statement of commitment to participate in SIREN should be provided from at least five Spoke sites, and from at least one pre-hospital provider (e.g., EMS). ). In environments where multiple pre-hospital providers serve the Hub and committed Spokes, letters from more than one provider would be appropriate. These letters should include description of particular resources to be committed, relevant prior experience, planned organizational and/or administrative structure in conjunction with the Hub, and willingness to participate collaboratively in the broader SIREN structure (e.g., central IRB, master contracts). The letter from the prehospital provider should also include willingness of the medical director to support research and willingness of the provider to make time available for training.

For those institutions with a Clinical Translational Science Award (CTSA), the applicants are encouraged to include documentation from the CTSA principal investigator regarding any support which will be provided to the Hub. This may include access to or assistance from Recruitment (RIC) and Trial (TIC) liaisons at the CTSA.

Additional letters of support may be included from key personnel, such as disease experts and physician subspecialists.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans 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.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to 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. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date 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 SF424 (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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(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. See Section III of this FOA for information on registration requirements.

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 System for Award Management. 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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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 Hub contribute to the advancement of clinical research and clinical trials within the framework of SIREN?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application indicate that the PD/PI has the appropriate experience to prepare him/her for leading and performing clinical trials in the ED and prehospital setting? What components of the PD/PI's experience prepare him/her for performing clinical trials in each of the disease areas included in SIREN (i.e., neurology, cardiovascular, respiratory, hematology, and trauma)?

Does the application indicate that the PD/PI has prior or existing leadership roles in the emergency medicine community and/or local medical community which will contribute to the success of SIREN?

How do the PD/PI's past experiences prepare him/her for establishing and/or leading a network of affiliated clinical sites?

In what ways does the application suggest that the PD/PI can contribute substantially to the SIREN governance committees (e.g., SIREN Steering Committee and subcommittees, SIREN Management committee, SIREN Operations committee)? Does the application demonstrate that the PD/PI will have time to attend the meetings and teleconferences?

Is there evidence to suggest that the applicant will be effective and successful in promoting and encouraging submission of meritorious clinical trial grants for SIREN? Is there evidence to suggest that the PI or other members of the Hub/Spokes research team might initiate or contribute to a clinical trial concept or proposal?

In what way does the PD/PI's experience prepare him/her for leading and working in highly collaborative settings?

Is there assurance that the proposed research team and administrative personnel are qualified, capable and experienced? In what ways will they increase the likelihood that performance will be exemplary at the proposed Hub? Spokes?

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?

Does this application demonstrate that the proposed Hub will participate in master contracts, centralized trial budgeting and per patient payments, as planned in SIREN? Does this application demonstrate that the proposed Spokes will participate in master contracts, centralized trial budgeting and per patient payments, as planned in SIREN?

Does this application demonstrate that the proposed Hub/Spokes will perform clinical trials (at least those that are not EFIC) under approval by a central IRB, as planned for SIREN? For EFIC studies, does the application evince willingness to either perform these clinical trials under a central IRB or to work with the central IRB on special requirements such as community consultation?

Does the application describe how the pre-hospital provider will be integrated into master contracts, centralized budgets and the central IRB? Does the application provide evidence to suggest that the PD/PI or other members of the proposed research team could institute novel and innovative procedures that would increase efficiency and/or quality of clinical trial conduct at the Hub and/or its affiliated Spokes and pre-hospital providers? Does the application provide evidence to suggest that the PD/PI, through participation in SIREN governance committees, could provide innovative ideas to increase efficiency and/or quality of clinical trial conduct throughout SIREN?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

To what extent do data in the application (e.g., prior clinical trial performance; catchment area) support the ability of this Hub/Spoke/ prehospital provider group to achieve the required minimum enrollment of 100 patients/ year? To contribute to enrollment goals for minorities, gender, or other underserved groups (e.g., rural patients)? Does this application lend assurance that the proposed Hub/Spoke group will be able to contribute to clinical trials in the planned range of disorders and diseases (i.e. neurology, cardiovascular, pulmonary, trauma)? Does it provide evidence for participation and interest from both ED physicians and disease experts (e.g., neurologists, cardiologists, pulmonologists, trauma surgeons, thoracic surgeons, neurosurgeons)? Are there letters of support and commitment?

To what extent does the resultant Hub/committed Spoke network fulfill the characteristics outlined in "Hubs: Characteristics, Roles and Responsibilities"?

Does the application provide evidence that the pre-hospital providers will be fully integrated in the organization? To what extent does the application indicate awareness of and suggest solutions to particular challenges of including prehospital providers and personnel in clinical trials?

In what ways does the application lend assurance that the applicant can tailor Spokes and prehospital providers to the needs of each trial, which include (1) execute clinical trials in the ED setting; 2) provide and coordinate the multiple medical and surgical specialties which may participate in the clinical trials; 3) demonstrate a strong working relationship with pre-hospital providers; 4) propose and oversee a network of Spokes. (see examples above in "Hubs: Characteristics, Roles and Responsibilities")? In what ways does the organization plan promote communication and collaboration: 1) among research personnel at the Hub; 2) with disease experts; 3) between the Hub and Spokes: 4) with pre-hospital providers?

Does the application support that the operational procedures and quality assurance program will lead to exemplary clinical trial execution? To what extent does the evidence in the application demonstrate that the Hub and committed Spokes can and will consistently deliver high quality clinical trial performance? Were findings from prior audits (if any) appropriately resolved?

Does the application provide evidence that the proposed Hub (PD/PI, research team) will encourage, promote, stimulate and/or contribute to submission of meritorious clinical trial grants to SIREN?

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?

In the letters of support and commitment, what level and extent of commitment does the institution demonstrate for the PD/PI (may be expressed as additional protected time, departmental research leadership position, facilities, space, or resources)?

Does the institution(s) provide evidence of willingness to accept SIREN procedures specifically including: 1) standardized master trial agreements; 2) per-patient payments: 3) centralized trial budgeting; 4) central IRB? To what extent does the institution appear willing to work with a central IRB on EFIC clinical trials?

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

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 Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

Not Applicable

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 score.

Not Applicable

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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. Assignment to a Scientific Review Group 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 score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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 Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Clinical trial expertise, track record, and resources.
• Strong track record of successful collaboration and participation in large, multi-center research teams and willingness to work collaboratively, including with other components of SIREN .
• Willingness and evidence of ability to participate in all aspects of the SIREN program, including the SSC, SMC, SOC, Trial Committees, SSC working groups, and participation in teleconferences and in person meetings.
• Current and/or successfully completed NINDS or NHLBI- funded clinical emergency care projects at the applicant’s institution.
• Ability to begin operations in February 2017;
• Agreement to accept the Cooperative Agreement Terms and Conditions of Award delineated in this FOA (see Section VI.2.A).

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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’s 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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Part 75 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

• Trial participant safety, implementation of network protocols in accordance with GCP and other regulatory requirements, participant recruitment and retention, reporting to the CCC, DCC, central IRB and DSMB.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The NIH staff in collaboration with the SIREN Federal Committee will work with the SIREN investigators to develop performance milestones for the Hubs. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement.
• An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards:
  • Cooperation or coordination with, or assistance to, awardees in performing project activities, e.g., development of research protocols; data collection, analyses, and interpretations; re-establishment of objectives during the course of a project;
  • Providing for an option to halt a project activity if technical performance requirements are not met or if program objectives have already been met;
  • Assistance with the selection of contractors or sub-awardees and in the selection of key project personnel other than PD/PI;
  • Technical monitoring to permit specific direction of the project, including recommending approval of changes in technical approaches;
  • Participation on committees as a voting member or in other functions responsible for helping to guide the course of SIREN; and
  • Participation in the presentation of research results, including publications from the project.
• In addition to the Project Scientist, an NIH Program Official will be responsible for the normal programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• SIREN committees, specifically the SIREN Steering Committee (SSC), and its working groups and subcommittees, SIREN Management Committee (SMC), the SIREN Operations Committee and Trial Committees (see section on SIREN Governance Committees).

Terms and Conditions of Award

The release of funds will be milestone-driven. Milestones will be determined jointly by the awardee, NINDS and the SIREN Federal Committee after the grant has been awarded and will be specified in the Notice of Award. The following are illustrative potential milestones for the first year of the award:

• Formation of a network of Spokes;
• Formation of a research collaboration with pre-hospital providers;
• Completion of reliance agreements for central IRB;
• Completion of master contracts.

When clinical trials are being conducted in SIREN, milestones will be reflective of enrollment and timely provision of high quality trial data.

The Hubs must achieve their agreed milestones during the first year in order to be eligible for future years of funding. Hubs that do not meet agreed milestones for any year of the grant term may be terminated, if necessary. In addition, awards may be restricted at sites unable to successfully participate in SIREN clinical trials (e.g., inadequate patient enrollment, unacceptable ratings on quality metrics) or unsupportive of broader SIREN functions (e.g., failure to participate in governance, failure to promote clinical trial grant submissions).

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 Research Performance Progress Report (RPPR) 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.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

Robin Conwit, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: [email protected]

George Sopko, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0504
Email: [email protected]

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

Tijuanna DeCoster, PhD, MBA
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 Part 75.