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 Data Coordinating Center (DCC) 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 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 DCC will contribute to this objective by performing clinical trial data management, data quality control, data monitoring and statistical analyses for SIREN. The DCC is responsible for the SIREN Data Safety Monitoring Board (DSMB) and preparing reports for external regulatory and oversight groups. The DCC is encouraged to be innovative in improving clinical trial efficiency and quality.

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 15 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 DSMB, and reporting to regulatory authorities (e.g., central IRB, FDA). The role and responsibilities of the DCC are described more fully below (see DCC: Roles and Responsibilities).

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 that 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 in RFA-NS-16-016.

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, and 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.

The DCC will provide scientific and organizational leadership, and will facilitate the conduct of clinical trials within SIREN. Its role includes data management, data quality, monitoring, statistical analysis, and provision of data summaries to external groups. The DCC is encouraged to be innovative and support SIREN goals of rapid implementation and high quality through techniques such as modular Case Report Form (CRF) design, risk based monitoring and web based data capture. It should strive to collect complete, accurate and precise data while minimizing the burden on the participating clinical sites. The DCC will need to address the challenges of working in pre-hospital settings (e.g., ambulance, helicopter), in regards to both randomization and data capture. The DCC has the primary responsibility for the Data and Safety Monitoring Board (DSMB), including meeting facilitation in addition to preparation of reports and provision of interim analyses. The DCC also has responsibility for reporting to external regulatory and oversight groups such as the central IRB, FDA and SIREN Federal Committee (defined under SIREN Governance Committees). The DCC will collaborate closely with the CCC (RFA-NS-16-014), the clinical research sites (RFA-NS-16-016), and the clinical trial Program Director/Principal Investigator (PD/PI)..

Significant responsibilities of the DCC include the following:

a) SIREN DSMB members will be selected and appointed by the participating Institutions through the SIREN Federal Committee (see SIREN Governance, below). There will be one central DSMB, with addition of ad hoc members to provide expertise required for oversight of each individual clinical trial. The DCC will work with the DSMB members in creating and finalizing the DSMB charter and analysis plans, and in provision of data and analyses for the open and closed portions of all DSMB meetings. The DCC will be called upon to facilitate the DSMB meetings, and to provide staff, including a dedicated statistician, to participate in both open and closed meetings. The DCC may be called upon to assist and support the DSMB in composing minutes and recommendations, and in verifying that these are conveyed appropriately to the SIREN Federal Committee and/or participating Institute Director. It is intended that routine DSMB meetings will take place in association with scheduled bi-annual SIREN Steering Committee meetings, although the DSMBs will have the ability to meet (by teleconference or in person) more often or at other times as they deem appropriate. The CCC may assist the DCC by providing some logistical support, such as travel arrangements or expense reimbursement.

b) Regulatory and other External Reporting The DCC is responsible for any and all reports required by external regulatory authorities because it holds the clinical trial data base; however, preparation of the reports should be performed collaboratively with the clinical trial PD/PI, CCC and Hub PDs/PIs. Anticipated reports include: 1) on-going expedited reporting of serious, unexpected, related adverse events to the FDA and central IRB; 2) periodic reporting of clinical trial status and safety events to the central IRB and SIREN Federal Committee; 3) reporting trial status and final results on clinicaltrials.gov; 4) annual IND update or IDE progress report, for trials conducted under IND or IDE. In addition, the DCC will respond in a timely manner to all requests for ad hoc status and/or safety event reports from appropriate authorities. If there are instances where the clinical trial PD/PI or site PDs/PIs are required to submit additional reports (e.g., ex-US regulatory authorities if multinational trial, institutional IRB), the DCC is responsible for supporting preparation of these reports and verifying that submission occurs in a timely manner. The DCC supports NIH-encouraged data sharing by preparing the final, limited personal health information or de-identified data set in an appropriate format and submitting this to a secure data repository after publication of the primary study results or after 18 months, whichever comes first. Inclusion of digital data such as ECG tracings, MRI images in the shared data set is encouraged.

c) Risk Based Monitoring (Oversight of Clinical Investigations -- a Risk-based approach to monitoring, FDA, 2013) entails determination of the most efficient means of monitoring and review required to ensure highest accuracy of pre-identified key data fields and acceptable levels of accuracy in remaining data fields. The plan should stipulate technical approaches, such as on-site monitoring and/or various levels of stringency in off-site monitoring. It is suggested that the DCC create a general template for SIREN Risk Based Monitoring in parallel with development of its data capture systems during Year 1 of the SIREN DCC award. This template should address anticipated approaches to data fields common to all clinical trials (e.g., demographics, patient disposition) and should serve as a basis for subsequent trial specific Risk Based Monitoring plans.

D) Quality Assurance In addition to oversight of data quality in clinical trials, the DCC should assess and strive to improve the quality of its own performance. The CCC has broader responsibility for quality assessment and improvement across SIREN. The CCC review will be performed at least annually and may include metrics such as start-up time, patient recruitment and retention, time from last patient, last visit to database lock, and number and aging of data queries. Quality reviews will be performed at least annually. The DCC is expected to cooperate with and provide support to the CCC for these quality reviews. The DCC is further encouraged to propose innovative approaches to quality assessment and improvement.

DCC Roles and Responsibilities in terms of leadership and SIREN organization include but are not limited to:

• Providing scientific leadership, particularly in relationship to data and statistical issues;
• Actively participating in all SIREN Steering Committee (SSC), SIREN Management Committee (SMC) and SIREN Operations Committee (SOC) activities (see SIREN Governance Committees);
• Promoting visibility and awareness of SIREN and encouraging and supporting submission of clinical trial applications;
• Organization and support of the SIREN DSMB (as detailed above);
• Developing SIREN Standard Operating Procedures (SOPs) which address all aspects of data management and statistical analysis;
• Assessing status of existing resources for emergency medicine clinical trials, such as NIH Common Data Elements and CRF forms, and creating and submitting new CDEs and CRFs if required;
• Supporting the CCC in creation of the SIREN website, if requested;
• Establishing web capabilities for trial randomization, trial data collection and DSMB communications and data storage (which may be independent or incorporated into the SIREN website);
• Developing a Risk Based Monitoring Plan (RBM) template for SIREN;
• Providing instruction and training to clinical sites regarding SIREN data management processes, procedures and metrics;
  • Clinical sites will include up to 10 Hubs that will participate in every clinical trial, 2-10 Spokes/Hub that will vary by trial, potential ad hoc non-network clinical sites, and prehospital providers (number will vary from trial to trial).
• Providing a mechanism (e.g., call in center, hot line, web chat) for promptly addressing data related questions from sites and prehospital providers, both for general SIREN processes and specific to each clinical trial.
• Providing leadership and guidance to clinical trial PD/PIs and to Hub, Spoke and other clinical site PDs/PIs and to pre-hospital providers on required regulatory reporting (e.g., annual central IRB safety reports, annual IND updates, clinicaltrials.gov reporting);
• Implementing procedures for backing up the program’s clinical and administrative data, including regular back-up of the database with storage at a remote facility;
• 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

The CCC and DCC, once selected for potential funding, will jointly submit to the NINDS and SIREN Federal Committee their SOPs for SIREN. These will be revised from the individual versions originally submitted as part of their applications, and will present a collaboratively developed plan. They will also submit a scope of work document that details the division of tasks and responsibilities. It is essential that the tasks required in planning and executing a complex, multi-center trial be clearly defined, and that the responsibilities of the collaborators (including CCC and DCC) be clearly delineated. It is therefore required that the joint DCC and CCC SOPs and scope of work document show excellent and seamless communication and coordination and reflect an in-depth understanding of the overall operational conduct of a complex, multi-center trial network.

The Responsibilities of the SIREN DCC in relation to clinical trials include, but are not limited to:

• Responsibility for all aspects of data management, including quality control, for at least four large (>1000 patients), simple, pragmatic multi-center clinical trials;
• Overseeing statistical conduct from final protocol design to analysis/publication for at least four large (>1000 patients), simple, pragmatic multi-center clinical trials.

More specific detail follows, broken down by activities relevant to the progressive stages of clinical trial execution.

Prior to clinical trial application submission, during the pre-application concept assessment phase of a clinical trial, the DCC is responsible for:

• Providing information and guidance to all potential investigators as they apply for NIH funding for a clinical trial to be performed in SIREN: (e.g., assess protocol synopsis and schedule of activities), particularly regarding statistical design;
• Performing a feasibility study of the proposed clinical trial, particularly in relation to any challenges in data management;
• Developing the components of the clinical trial budget that will be necessary to support DCC infrastructure and functions.

After approval and award of a clinical trial, during the Planning Phase of approved clinical trials, the DCC is responsible for:

• Working with the clinical trial PD/PI (and trial statistician if included in the clinical trial grant award) to finalize data management aspects of the protocol;
• Working with the clinical trial PD/PI (and trial statistician if included in the clinical trial grant award) to finalize the trial sample size and the Statistical Analysis Plan;
• Working with the clinical trial PD/PI and CCC to create a database for each clinical trial in a timely manner;
• Promptly developing Case Report Forms (CRFs).
• Creating and implementing a web based or equally/more user-friendly randomization scheme and process;
• Developing a clinical trial specific data quality assurance plan;
• Developing a clinical trial Risk Based Monitoring plan.

During the Enrollment and Data Collection Phase of approved clinical trials, the DCC is responsible for:

• Supporting all data management aspects of each clinical trial conducted in SIREN;
• Establishing a web-based, user-friendly database for each trial;
• Verifying that data base meets required criteria for security features, such as
  • secure, password protected database access, and audit trails, consistent with the guidelines of the U.S. DHHS;
  • patient confidentiality features consistent with HIPAA and other regulations;
• Providing web-based or other user-friendly, rapid mode of central randomization;
• Performing central and on-site monitoring consistent with the Risk Based Monitoring Plan;
• Generating and promptly resolving data queries;
• Establishing and implementing quality assurance procedures for data quality and completeness;
• Providing data to the CCC to support drug supply and distribution;
• Working with the CCC, Hubs, Spokes, ad hoc clinical sites and prehospital providers to report and track trial status in terms of enrollment, retention, protocol deviations, CRF completion, data query aging and other metrics;
• Providing in a timely manner true copies of data files and supporting documentation for each SIREN clinical trial;
• Providing a statistician to participate in open and closed portions of DSMB meetings;
• Providing data analyses for and conducting DSMB meetings;
• Performing required regulatory reporting.

During the Analysis and Publication Phase of each clinical trial, the DCC is responsible for:

• In collaboration with the clinical trial PD/PI (and trial statistician if included in the clinical trial grant award) overseeing or performing final study analyses per protocol;
• In collaboration with the clinical trial PD/PI (and trial statistician if included in the clinical trial grant award) overseeing or performing preparation of presentations and publications;
• In collaboration with the clinical trial PD/PI (and trial statistician if included in the clinical trial grant award) and the CCC, compiling and presenting final study reports to central IRB, DSMB, FDA, SIREN Federal Committee and other regulatory bodies.
• Supporting data sharing via the NIH data repositories and clinicaltrials.gov.

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 submission.

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 data sharing policies; 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 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 PDs/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 PDs/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 Institutes funding the SIREN program of RFA-NS-16-014, RFA-NS-16-015, RFA-NS-16-016 (e.g., NINDS, NHLBI and NCATS). 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 respective 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 not 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.

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

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

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 CCC and a DCC will not be made to the same PI or institution to ensure that data analyses and data acquisition are performed independently.

Investigators at the DCC institution may apply for a Hub award (RFA-NS-16-016). A DCC and a Hub at the same institution should be led by separate PI's to ensure that the PIs have appropriate expertise and that the DCC activities and the Hub activities each receive 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: conwitr@ninds.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

For this specific FOA, the Research Strategy section is limited to 30 pages.

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:

Facilities and Other Resources:

• Resources include not only equipment (e.g. computers, software), but also people and knowledge resources, such as, general support (e.g., administrative staff); colleagues or organizations with research and/or clinical trial expertise.

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

The PD/PI for the SIREN Data Coordinating Center will be an experienced statistician and expert in data management and analysis for clinical trials. The applicant should present evidence to demonstrate the following experience:

• Successfully implementing and coordinating data management in multi-center clinical trials;
• Successfully implementing and coordinating statistical analyses in multi-center clinical trials;
• Successfully managing projects conducted in a highly collaborative setting;
• Supporting and facilitating DSMBs.
• Designing clinical trials;
• Introducing innovative methods to rapidly implement clinical trials, minimize burden of data collection on sites, rapidly achieve data base lock, implement risk based monitoring, and increase trial data quality.
• Experience maybe particularly relevant when: 1) the trial was performed in the emergency department setting; 2) the trial was performed in a prehospital setting; 3) the trial was in a disorder related to neurology, cardiology, pulmonary, hematology or general trauma.

It is important that the PD/PI be available to attend and actively contribute to all required SIREN governance committee meetings (see SIREN Governance Committees in Part 2. Section I. of this FOA).

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 DCC research team are determined by the applicant, but typically would include:

• An experienced data management team including an experienced programmer and project manager;
• Experienced clinical monitor(s), particularly for execution of on-site monitoring;
• At least one experienced statistician, with a documented track record in supporting large pragmatic RCTs (experience with emergency medicine trials ad with adaptive or innovative statistical methodology are desirable);
• The DCC must be able to support at least four concurrent large clinical trials, including providing unblinded data for DSMBs and regulatory reporting while not endangering blinding of staff conducting the trials.

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

• The budget submitted for this FOA should reflect baseline costs needed to initiate, organize and maintain the DCC in a state capable of performing timely pre-application concept assessment and ready for rapid implementation of clinical trials
• Salary support for the PI and research team members should only include time spent on SIREN activities, which may include organizational/administrative tasks, support of individual clinical trials, and participation in SIREN governance and committee activities;
• The budget should also include travel costs for at least two DCC team members to attend in person DSMB meetings.
• The budget should not include costs for tasks specific to each 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 I.

A) Background and Experience

The applicant should include a description of current and up to 10 recently completed multicenter clinical trials where the applicant held significant responsibility for data management and/or statistical analysis. The most informative and relevant examples would be clinical trials involving emergency care and/or performed in the ED or prehospital setting. Trials involving neurology, cardiology, respiratory, hematology, or trauma are also relevant. The summary may however include clinical trials on any disease in any clinical setting, if judged informative by the applicant. The following metrics should be presented in tabular form for each clinical trial:

• Identification information: title, funding source, PD/PI, disease or disorder
• CRF: time required from start of CRF production until data collection system operational at first clinical site;
• Randomization scheme: time required from start of designs until system operational at first clinical site;
• Time from finalization of clinical trial protocol to finalization of Statistical Analysis Plan (SAP);
• Number of DSMB interim analyses performed and for each 1) data included (eg safety only, interim efficacy analysis) 2) time from date of last included patient visit until data provided to DSMB;
• Time from last patient's visit to database lock;
• Time from database lock to final analysis of primary outcome;
• Time for query resolution, number/percentage >30 days, >60 days, >90 days, >120 days (for final locked data base);
• Number and percentage of missing data cells (in final locked data base)

Published manuscripts that highlight recently coordinated trials should be referenced in the application in the Bibliography and References Cited section of the application.

The applicant should summarize experience with 1) preparing and submitting data to NIH or other shared data repositories; 2) performing analyses and posting results to clinicaltrials.gov.

B) Leadership

Demonstration of leadership capability is required for the DCC PI(s) and should cover the specific points outlined in the Senior/Key Person Profile.

• Leadership derives not only from the DCC PD/PI, but also from members of the DCC research team. A brief leadership plan should be presented which identifies and describes the roles of DCC personnel, along with how they will contribute to the success of SIREN. A brief leadership plan should be 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 describe how the DCC plans to stimulate and foster 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 comment on any special expertise or unique strengths they can offer for leadership or collaboration within SIREN.

C) Organization and Project Management

• The PD/PI should describe the a duties of the proposed DCC research staff.
  • 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.
• The organization of the research team for performance of day to day administration and operation of the DCC should be described.
  • See DCC: Roles and Responsibilities regarding specific tasks.
• Applicants should describe the standard operating procedure (SOPs) they have in place and the processes they currently apply when implementing multi-center clinical trials.
  • Applicants are encouraged to provide examples of SOPs used for implementation of multi-center clinical trials, including, but not limited to SOPs describing database access, data quality control, data queries with audit trails, etc., as an appendix in the application.
  • Applicants should discuss how they will accommodate variability in site identity and number from trial to trial.

D) Communication Plan

• Administration of SIREN and implementation of clinical trials will require close collaboration between the CCC and DCC. Applicants should describe their communications plan for the DCC, and any experience they have previously had working in a CCC/DCC structure.
• Successful implementation of clinical trials will require close collaboration between the DCC and the clinical sites, including pre-hospital providers. Applicants should describe the communication plan, including 1) general site training on SIREN processes; 2) clinical trial specific training; 3) aspects of instruction and training and the mechanism for answering questions from sites; 4) mechanism(s) (e.g., call in center, hot line, web chat) for promptly addressing questions from sites. Prior experience with specific mechanisms, such as call in centers or hot lines, should be provided.
• Applicants should describe the communication plan with the clinical trial PD/PI. Some projects may include a trial-specific statistician, independent of the DCC. The plan for delineating roles and responsibilities and for collaboration with a trial-specific statistician should be included.
• Applicants are encouraged to describe any special expertise or unique strengths they can offer to enhance communication and collaboration (e.g., established database tools, hardware, software, quality control tools, monitoring expertise, team leadership and training, communications platforms, website design and management).

E) Data Management and Data Quality Assurance

Based on the tasks outlined in "DCC: Roles and Responsibilities", the applicant should describe plans for data management and data quality assurance. It is suggested that the presentation be organized using the clinical trial stages used in "DCC: Roles and Responsibilities." The plan should build on existing strengths and capabilities, which should be clearly described. The applicant is encouraged to address the following desirable attributes:

• User-friendly interface directed at the experience and knowledge of users such as EMS personnel or nurses (rather than that of programmers, data managers or statisticians);
• Convenience for the location of the users (i.e. ambulances, helicopters, busy ED);
• Ability to directly import digital data from electronic sources (e.g., laboratory, ECG, imaging data, electronic health records) into the trial database;
• Minimal burden of data collection on clinical personnel and sites;
• Seamless integration of data from disparate sources into a single central database, which facilitates reporting, and eventual data sharing and dissemination;
• Data validation performed as thoroughly as possible on collection and/or entry and completed promptly on an ongoing basis;
• Rapid and convenient generation and resolution of queries with minimal burden on clinical personnel;
• Support and integration with a risk based monitoring approach to early recognition of signals for problems at specific clinical sites or across the clinical trial;
• Easy and prompt dissemination of data to statisticians and other analysts, in a variety of tab delimited formats;
• Easy and prompt production of regular and ad hoc reports on trial status, progress, safety and, when needed, outcomes;
• Graduated, role-based security, which permits varying degrees of access to data based on an individual’s role in the study;
• Protection for personal health information (PHI) consistent with applicable federal regulations;
• Log of all authorized access.

F) Risk Based Monitoring

The applicant should summarize experience with and plans for use of Risk Based Monitoring (RBM) for data quality assessment and for clinical trial or program quality improvement. The plan may include, but is not limited to the following: 1) likely criteria to be included in a SIREN program RBM and clinical trial RBMs, 2) balance between central and on-site monitoring, 3) background and training of staff performing central and on-site monitoring, 4) whether or how to include clinical or medical reviews as an RBM component, 5) algorithms for identification of quality issues by RBM, 6) communication of identified issues, 7) triggers for on-site monitoring, 8) creation and implementation of quality improvement plans for identified deficiencies.

G) Statistical Support Plan

• Some clinical trials will ask the DCC to provide statistical support. In other cases, the clinical trial grant may include an independent, non-DCC statistician. The application should clearly address statistical support in each of these two situations.
• Based on the tasks outlined in "DCC: Roles and Responsibilities", the applicant should describe plans for statistical support and analysis. It is suggested that the presentation be organized using the clinical trial stages used in "DCC: Roles and Responsibilities." The plan should build on existing strengths and capabilities, which should be clearly described.
• The applicant should outline the expertise of the DCC in clinical trial design including simple, pragmatic trial designs, comparative effectiveness designs, and adaptive trial designs.
• The DCC may be called upon to provide rapid analyses in response to inquiries from the SIREN Federal Committee or regulatory authorities. Experience and plans for rapid provision of accurate analyses should be described. Examples should provide specific descriptive detail, for example the number of days from request to analysis available, or the number of tables and figures provided.

H) DSMB and Regulatory Reporting

The applicant should describe the experience of the DCC with support and facilitation of DSMBs, including but not limited to experience in:

• serving on and facilitating DSMBs;
• rapid collection of data for interim analyses;
• preferred formats for reports on study status (e.g., enrollment, disposition), protocol deviation (include detection as well as reporting), safety data;
• design, conduct and interpretation of futility analyses for effectiveness or enrollment;
• maintaining study blinding while providing unblinded data to the DSMB (failures should be included as well as successes);
• provision, distribution and collection of data for DSMB meetings, particularly including retrieving unblinded data from DSMB members;
• rapid provision of requested additional analyses.

The applicant should describe the plan for DSMB support for SIREN, including though not limited to the points above.

The DCC will be responsible for data compilation, analysis, report preparation and report submission to other regulatory oversight bodies, such as the central IRB, FDA or SIREN Federal Committee. These responsibilities include expedited safety reports, periodic annual reports, final reports and ad hoc reports. Applicants should discuss their prior experience with each of these types of reports.

• If there is experience with expedited safety reporting, indicate the number of reports filed and the proportion that were successfully filed within required regulatory timeframes.
  • Explain how narrative composition and medical review were incorporated;
• If there is experience with annual reports, include specific metrics such as the number completed, recipient (e.g., FDA, institutional IRB), method used for planning and tracking, data base preparation including determination of stop date, interval from last data base entry to analysis available, interval from last data base entry to report ready, proportion filed within regulatory timeframe.
• Indicate what materials have been developed, particularly if available for use in SIREN. Relevant materials include SOPs, tracking data bases, templates, and standard report formats.
  • Examples of existing SOPs or templates may be included in an appendix.
• How were interactions with clinical trial PDs/PIs and clinical sites incorporated to support preparation of each of the above types of reports.
  • The applicant should provide a plan which addresses preparation, tracking and filing of each of the above types of reports for clinical trials in SIREN. The points mentioned above should be addressed in the plan.

I) Data Standardization

• The PD/PI should describe how standardization of data collection and data collection instruments will be promoted, including the use of existing or creation of new NIH common data elements.
• The applicant should mention experience and plans for performing additional analyses for and posting data on clinicaltrials.gov.

J) Quality Assurance

A specific plan for quality assurance and improvement should be provided for the DCC, including metrics, responsible personnel, and mechanisms for collecting data and for implementing improvement plans. Focus on actions undertaken at the DCC and indicate how these will be integrated with the CCC quality effort. Results of any prior audits conducted should be provided, along with any executed responsive improvement plan.

Letter of Support: A statement of commitment from each participating institution or organization must be provided. At least one letter of support from the applicant's institution must be included in the application. This letter should address how the general 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 DCC director, assignment of specialized research space, cost sharing of resources, and/or other ways proposed by the applicant institution. There may be multiple letters of support from the institution or its components, particularly if the institution is providing support of collaboration for specific DCC responsibilities. At least one letter confirming institutional support should come from a high-level institution official(s) (e.g., Dean of the School of Medicine, Hospital President, and Vice President for Research).

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:

The DCC is responsible for facilitating data sharing for clinical trials conducted in SIREN. The PD/PI should describe the plan and procedures for submission of datasets of completed trials to an NIH and/or another federal repository, using data exchange standards.

• Describe de-identification and protection of privacy;

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.

The following items are recommended for inclusion in the Appendix:

• Sample documents that illustrate the DCC's expertise, such as CRFs, data dictionaries, user manuals, database training instruments etc.
• Sample study data quality plan describing the DMC's database access, data quality control, data queries with audit trails, etc.
• Sample Risk Based Monitoring Plan;
• Sample SOPs.

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 DCC contribute to the advancement of clinical research, particularly data and statistical components, 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 and research team have the appropriate experience to successfully lead, design and implement the data management and statistical components of multicenter clinical trials to be performed in SIREN? Is there evidence to suggest that the PD/PI and research team have appropriate experience to prepare them to facilitate and manage the SIREN DSMB(s)? For regulatory reporting?

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?

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 DCC?

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 the application present evidence to indicate that the PD/PI or other proposed DCC team members have a history of creating and/or applying innovative methods to statistical and data management related aspects of clinical trials?

Does the application contain innovative proposals for addressing some of the particular challenges facing the DCC, such as randomization and data collection in the prehospital setting or busy ED, or collecting accurate, high quality data in a manner that minimizes burden on the clinical research team?

Does the application contain innovative proposals for incorporating complex digitized data (e.g., ECG monitor data, CT or MRI images) into the shared data repository?

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 in 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 the performance metrics from past clinical trials (see Research Plan, A) suggest that the applicant is an exemplary DCC? Does the evidence support the ability to carry out key tasks (see DCC: Roles and Responsibilities) in a timely manner? To preserve the integrity of trial data and provide an accurate data base and high quality analyses?

Does the application support that the proposed DCC will provide exemplary oversight and support to the SIREN DSMB(s), including meeting facilitation, data compilation and report generation?

Does the application demonstrate that the proposed DCC will be capable of providing unblinded data for closed DSMB sessions without jeopardizing blinding of other clinical trial personnel?

Does the application suggest that external reporting obligations, including to the central IRB, FDA, SIREN Federal Committee, and clinicaltrials.gov will be performed reliably and accurately? In what ways does the proposed plan lend assurance that all regulatory reporting will be performed in timely manner with thorough, accurate and readily comprehendible reports suited to the requirements of the recipient?

In what ways does the proposed data management system achieve the characteristics of a desirable system as described in Research Plan, Item C? How well does the plan achieve the goals of making a user friendly system that minimizes burden on clinical trial sites (e.g., can digital data be imported from laboratory data bases and/or machines)? How robust are the data validation and query systems?

Does the application provide evidence that the proposed DCC will provide exemplary statistical support and consultation, including contributions to clinical trial design, creating statistical analysis plans and performance of analyses? Does the application provide evidence that trial-specific statisticians (when included in a clinical trial grant award) will be fully integrated with the DCC?

Does the application demonstrate that Risk Based Monitoring will be used to optimize generation of clean accurate, high quality clinical trial data while minimizing monitoring time, particularly on-site monitoring time? Does the application propose approaches for the particular needs or challenges of clinical trials conducted in the ED and prehospital settings?

Does the application demonstrate that the DCC has the required knowledge, experience and an appropriate plan for submitting de-identified, widely useable data bases to the data repository in a timely fashion at the conclusion of each clinical trial?

In what ways does the communication plan promote collaboration and information sharing: 1) with the CCC; 2) with clinical sites (Hubs, Spokes, ad hoc sites, pre-hospital providers); 3) with clinical trial PDs/PIs? In what ways does the communication plan provide assurance that the DCC will provide sufficient procedural training and will provide rapid, accurate resolution of questions/issues?

How does the application provide assurance that the planned administration and organization of the DCC itself, and the DCC quality assurance program will lead to exemplary DCC performance and contribute to the success of 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)?

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.

Additional DCC Responsibilities

Does the application provide evidence that the PD/PI and/or DCC research staff will encourage and/or contribute to submission of meritorious clinical trial grant proposals to SIREN?

Does the application demonstrate that the DCC will be able to work with NIH to create new common data elements for emergency care research?

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.
• 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:

• Coordinating all aspects of clinical trial data management, data quality control, and data monitoring for SIREN. In collaboration with the clinical trial PD/PI and their specific project statistician (if included in the clinical trial grant), the DCC is responsible for clinical trial statistics from finalization of the Statistical Analysis Plan through performance of the final analyses. The DCC provides support for the Data and Safety Monitoring Boards (DSMBs), particularly including preparation and provision on interim analyses. The DCC is responsible for data provision and reporting to regulatory agencies such as the central IRB and FDA.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• The NIH staff in collaboration with the SIREN Federal Committee will work with the SIREN investigators to develop performance milestones for the DCC. 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 SIREN Governance Committees)

Terms and Conditions of Award

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

• Completion of SIREN SOPs, including 1) plans to ensure data quality; 2) plans for data analysis and manuscript submission for publication within one year of trial completion; 3) data sharing.
• Creation of SIREN website for data capture;
• Completion of DSMB charter;
• Completion of template Risk Based Management plan.

In subsequent years, milestones will likely be more reflective of clinical trial support activities.

If the DCC does not meet agreed milestones for the first or any subsequent year of the grant term, funding may be terminated, if necessary. In addition, the award may be restricted if the DCC is unable to achieve acceptable ratings on quality metrics for its responsibilities to SIREN clinical trials, or is unsupportive of broader SIREN functions (e.g., failure to participate in SIREN governance committees).

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: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Robin Conwit, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: conwitr@ninds.nih.gov

George Sopko, MD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0504
Email: sopkog@nhlbi.nih.gov

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

Tijuanna DeCoster, PhD, MBA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.