It is critical that applicants follow the Research (R) 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

This Funding Opportunity Announcement (FOA), RFA HG-17-008, invites applications from Clinical Groups (CGs) to participate in the Implementing Genomics in Practice (IGNITE) II: Pragmatic Clinical Trials Network, in collaboration with additional CGs with enhanced clinical diversity (RFA HG-17-009) and one Coordinating Center (CC, RFA HG-17-010). This network will conduct pragmatic clinical trials to measure the clinical utility and cost-effectiveness of genomic medicine interventions; assess approaches for real-world application of genomic medicine in diverse clinical settings; and produce generalizable knowledge on the types of genomic medicine interventions requiring randomized clinical trials and effective methods for conducting them. The term pragmatic clinical trials is used to mean trials designed to test real-world effectiveness in broad groups using flexible protocols to produce results that can be generalized to routine practice settings outside tertiary care.

Definitions. For the purposes of this FOA, the following definitions are used:

• "Clinical Groups" refers collectively to the multi-site awardees to be funded under this FOA and the companion RFA-HG-17-009 (Enhanced Diversity Clinical Groups), involving diverse settings and populations. These CGs will address the Objectives described below in the "Research Approach" and "Research Strategy" sections. Requirements specific to each Clinical Group FOA are noted within the respective FOA.
• Clinical Sites refers collectively to the diverse clinical practice settings comprising each Clinical Group.
• "Clinical utility" is defined broadly as the assessment that a genomic intervention will lead to an improved health outcome, including diagnosis, treatment, management, or disease prevention that will benefit a patient or his/her family members, as described in a position statement from the American College of Medical Genetics and Genomics (ACMG; http://www.ncbi.nlm.nih.gov/pubmed/25764213).
• "Healthcare settings" refers to the healthcare context in which medical care is provided (e.g., specialized medical centers, community clinics, primary practice).
• Diverse clinical settings refers to healthcare settings outside specialized medical centers such as community hospitals, family medicine clinics, and primary care practices.
• "Diversity" refers to the inclusion of patients who come from racial or ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes, and will be used in part to distinguish the expectations for patient recruitment and retention by applicants to this FOA compared to those applicants to RFA-HG-17-009 (Enhanced Diversity Clinical Groups).
• Minority refers to the inclusion of patients who come from the following minority racial/ethnic populations: African American or Black, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander (e.g., Guam, Tonga), or Latino or Hispanic. (https://www.nimhd.nih.gov/docs/2009-2013nih_health_disparities_strategic_plan_and_budget.pdf).
• "Underserved" refers to populations who are "medically underserved as defined by the Health Resources and Services Administration (HRSA) (http://www.hrsa.gov/shortage/mua/).
• "Evidence" refers to information generated in the course of IGNITE II, including, but not limited to: data, records, observations, outcomes, analyses, measures, publications, best practices, and recommendations.
• "Secondary findings refer to results unrelated to the reason for ordering the genomic test but which may be of medical value (http://www.ncbi.nlm.nih.gov/pubmed/23788249).
• Participants refers to patients enrolled in the selected PCTs, randomized to receive one or more interventions, and followed for outcomes. As these PCTs are intended to be directly relevant to clinical care, almost all study participants are expected to be patients in the Clinical Sites participating in the PCT, and the terms are largely used interchangeably for the purposes of this FOA.

NHGRI’s genomic medicine research programs have explored and tested appropriate uses of genomic information in clinical care through collaborative networks evaluating electronic health record (EHR)-driven phenotyping and return of genomic results, newborn and clinical genome sequencing, variant curation, and dissemination of genomic medicine approaches to diverse clinical settings outside specialized centers. Despite the positive impact of genomic medicine on improving health outcomes as demonstrated by these studies, it has become clear that a major barrier to large-scale genomic medicine implementation is the lack of compelling clinical evidence that would convince clinicians to adopt promising strategies and medical insurers to pay for them.

The need for rigorous evaluation of the validity and utility of genomic medicine interventions and the best approaches for incorporating them in medical practice was highlighted in a recent National Academy of Medicine report which noted, the gold standard of clinical utility is the evaluation of results from prospective trials that have randomized subjects to genetic testing or no genetic testing in an effort to compare different genetically informed treatments with usual care or from genetically stratified trials that compare treatment outcomes between different genetic groups (NAM, Evidence Framework for Genetic Testing, 2017). Prospective trials demonstrating positive impact on important patient outcomes are widely viewed as providing the strongest evidence supporting clinical adoption, but are often expensive, lengthy, and cannot be conducted for every intervention or every genetic variant. In addition, traditional randomized clinical trials (RCTs) often fail to inform routine practice because they are designed to demonstrate efficacy or treatment impact in carefully selected participants with highly experienced investigators under ideal conditions, putting them at risk of over-estimating benefits and under-estimating harms. RCTs infrequently produce results that are easily translated to the real world, with at times dramatic decreases in effectiveness of a treatment when translated to routine clinical practice.

Pragmatic clinical trials (PCTs), in contrast, provide a more practical approach that is better integrated with routine clinical care. PCTs are designed from the start with input from healthcare providers, patients, and systems to produce practical evidence on improving outcomes of greatest value to these stakeholders. PCTs are designed to improve practice and policy, and unlike most traditional RCTs, take place in settings where routine care occurs, such as community clinics, primary care practices, hospitals, and pharmacies. They include diverse, representative populations in multiple, heterogeneous clinical care settings and compare selected interventions to real-world alternatives (rather than to placebo or no treatment). Assessing multiple outcomes is important not only to patients but also to clinical decision- and policy-makers. They employ flexible protocols that allow for customization to the characteristics and demands of local settings, and recruit diverse populations with broadly inclusive selection criteria and few exclusions. Electronic health records (EHRs) are closely integrated in study design and execution, allowing efficient and cost-effective identification and recruitment of patients, data collection, monitoring, and outcome assessment. Recognizing that traditional and pragmatic trials exist on a continuum, PCTs for IGNITE II will be selected to emphasize assessment of effectiveness (in routine settings) rather than efficacy (in ideal settings) and to produce results that will directly inform decision-making of healthcare providers, patients, administrators, and policy-makers.

The IGNITE Network was funded in 2013 and 2014 (RFA-HG-12-006, RFA-HG-12-007, and RFA-HG-13-004), and has worked collaboratively to develop new methods for implementing genomic medicine in diverse clinical settings outside of specialized care and disseminated its findings to the genomic medicine community through its SPARK Toolbox and other means. In August 2016, NHGRI held the workshop entitled IGNITE and Beyond: The Future of Genome Medicine Implementation to identify optimal study designs for future genomic medicine implementation program(s). Key recommendations from this workshop include providing flexibility to follow-up single site study observations in genomic medicine implementation with expanded, large-scale studies to confirm findings and decrease bias; fostering collaboration between academic and community centers to increase access to genomic medicine in underrepresented and lower socioeconomic level populations; and partnering with stakeholders including payers and technology companies to get input on study design, conduct, and interpretation to provide the specific evidence needed for genomic medicine sustainability.

The objective of the IGNITE II program is to support a Network of multi-site Clinical Groups (CGs) involving diverse settings and populations and a CC to conduct PCTs of genomic medicine interventions previously demonstrated to be feasible and of potential value in clinical care. Proposed trials will also include assessments of approaches for real-world applications and provide generalizable knowledge about when, how, and in what circumstances PCTs should be used in genomic medicine. Results of each trial will be compared to existing evidence from non-interventional studies to identify potential biases affecting the generalization of observational data to clinical practice in genomic medicine.

During the five-year project period, the IGNITE II Network will conduct 2-4 network-wide PCTs chosen from the protocols proposed by the funded CGs. The IGNITE II Protocol Review Committee (described below) will evaluate the PCT protocols proposed by each funded CG. Two to four protocols will then be selected based on clinical importance, feasibility of implementation in the funded CGs, potential impact, and cost, and the Steering Committee (SC) will adapt and expand each protocol to be implemented Network-wide utilizing the patient populations and multiple Clinical Sites comprising the funded CGs. Protocols conducted during the project period may be one of those proposed by the funded CG investigators or may be a modified or combined version of one or more proposed protocols. Ideally, all CGs will be expected to participate in all protocols put forth by the SC for the project period, although not all the Clinical Sites of a CG are expected to participate in every protocol. Protocols will be selected to maximize involvement of diverse Clinical Sites within the CGs, and may be modified during the protocol implementation and adaptation process with this end in mind. Note that for the purposes of this FOA, protocols refers to the PCTs proposed by each CG and ultimately selected for network-wide implementation.

It is anticipated that each CG will have sufficient Clinical Sites, patient populations, and experience to enroll a minimum of 3,000 patients in all implemented protocols combined and to complete screening and enrollment for each implemented protocol within a 12-month period. For this FOA, at least 35% of enrolled patients should satisfy the above definition of "diversity," while at least 75% of patients who satisfy this definition of "diversity" will be required for the companion enhanced diversity FOA (RFA HG-17-009). For both FOAs, at least 50% of patients should be recruited from diverse clinical settings such as community hospitals, family medicine clinics, and primary care practices. All recruited patients should be receiving their care predominantly at U.S. clinical care settings. Each CG should have a broad range of expertise in and capabilities for genomic medicine implementation (such as genomics, clinical medicine, pediatrics, clinical informatics, pharmacology, bioethics) collectively across its Clinical Sites, though not all Clinical Sites need have all capabilities.

Each CG should propose one PCT protocol of a genomic medicine intervention that has been effective (shown improved clinical outcomes and/or decreased patient or provider costs) previously and that can be adapted for implementation across the entire IGNITE II network, and should describe ability and expertise to implement a wide range of genomic medicine protocols and participate in network-wide, collaborative analyses.

Protocols proposed for implementation in IGNITE II should address important clinical problems of public health significance and be viewed by key stakeholders as having an important impact on patient outcomes. They should propose an intervention with preliminary evidence of feasibility in routine care settings, improved health outcomes, and/or cost effectiveness. Protocols should have greater than 80% power to detect clinically meaningful outcomes in a sample size of 1,000 15,000 patients, including important subgroup analyses such as those defined by key demographic characteristics. Note that each CG is expected to enroll a minimum of 3,000 patients toward the sample size of the trials proposed but is not expected to enroll the entire sample needed for the proposed trial. For cost and logistical considerations, PCTs requiring smaller sample sizes for clinically meaningful questions and outcomes will be preferred. Primary outcomes on which the success of the trial will be judged should be achievable within 12 months of randomization. Proposed protocols should be easily implemented in the course of clinical care and be readily adaptable to a wide range of clinical settings, including resource-limited sites. Protocols should also be relevant to patients meeting the definition of diversity above and to resource-limited sites.

Additionally, as the intent of IGNITE II is to inform clinical care and help create a new treatment paradigm that is readily translated to routine care, it is anticipated that protocols will be easily implemented in the course of patient care. Similarly, IGNITE II encourages interoperability of processes, standards, best practices, and data across sites and with external healthcare systems as feasible. As common opportunities or best practices that apply across diseases and healthcare settings are identified, these opportunities will in turn contribute to broader efforts to build a shared evidence base for clinical decision-making, such as through the ClinGen Program (https://www.clinicalgenome.org/), which aims to build an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research, or the NIH All of Us Research Program (https://allofus.nih.gov/) which leverages advances in genomics, emerging methods for managing and analyzing large data sets while protecting privacy, and health information technology to accelerate biomedical discoveries.

An independent Data and Safety Monitoring Board (DSMB), established by the NHGRI in accordance with NIH policies, will conduct interim reviews of trial data to monitor patient safety, and review study performance and overall progress.

Research Examples

NHGRI intends to support PCT protocols that are feasible as a trial across a large and diverse number of Clinical Sites, address issues of public health significance, and have a high potential to inform future clinical practice. Applications that propose protocols of genomic interventions relevant to diverse populations and that can be implemented in diverse clinical settings are strongly encouraged.

Examples of research topics include, but are not limited to, the following:

Pharmacogenomics-based drug selection and dosing

Risk reduction in genetically-defined high-risk individuals

Early diagnosis in critically-ill newborns or other groups at high risk of undetected genetic disease

Because of significant research already in progress on implementing genomics in the care of cancer patients, trials evaluating tumor sequencing will be considered non-responsive under this FOA. Trials evaluating germline cancer susceptibility may be acceptable if cancer is one of several conditions evaluated for susceptibility, especially if cancer will clearly be a minority of conditions and patients evaluated. Trials evaluating germline cancer susceptibility as a major component will be considered a low priority for NHGRI funding. Applicants are strongly encouraged to contact NHGRI to discuss their proposed trial and patient population well in advance of the submission date.

Applicants are not limited to the topics listed and are strongly encouraged to contact NHGRI to discuss their proposed topic to ensure that it is pertinent to the objectives of this FOA.

ELSI Research

In addition to the 2-4 network-wide PCTs, IGNITE II may also include a network-wide study of Ethical, Legal and Social Implications (ELSI) research relevant to the diverse populations and healthcare settings represented in IGNITE II. To ensure that the network-wide ELSI research study is relevant to the PCTs selected for implementation, the ELSI research study will be solicited separately, funding permitting, through asupplement. The ELSI research study will be collaboratively developed by the CGs after award and should not be proposed in this application. For planning purposes only, general topics for the future ELSI research study could include: population differences or similarities in perceptions of the risks and benefits of genomic medicine; recognizing and addressing barriers, interests and viewpoints to participation in genomic medicine; and the perceived utility of genomic medicine interventions, including patient-centered measures of satisfaction.

Genomic Medicine Research

IGNITE II is also expected to include other research and associated activities related to dissemination and implementation of genomic medicine, such as meetings and workshops. Such activities may be supported through a supplement , but are not being solicited at this time. For planning purposes only, topics for such activities could include, but are not limited to, effectiveness of specific educational or implementation approaches, impact of interventions on healthcare provider organizations, and development of policies to facilitate implementation.

IGNITE II will be a cooperative network of CGs, a CC, and the NHGRI.

Coordinating Center (CC)

The CC will play a major research role in the development of the clinical protocols, analyses of data, protocol finalization and execution, development and statistical modeling, analyses of clinical and cost-effectiveness outcomes, and subgroup effect analyses. During the execution of the protocols, the CC will collect data on recruitment and enrollment and report trial progress to the SC, Data Safety and Monitoring Board (DSMB), and/or NHGRI as needed. These data will be used to inform SC evaluation and recommendation of protocol modifications for successful execution of the protocols and the overall success of the Network.

The CC will perform traditional network coordination and support activities such as, but not limited to: coordination of activities of the PRC, DSMB, SC, and subcommittees, including teleconferences and in-person meetings 3 times/year, coordination of the activities of the DSMB including a teleconference once/year and an in-person meeting with the IGNITE II SC once/year, editorial coordination for manuscript preparation as needed, and overall study coordination and quality assurance. The CC will also initiate and coordinate activities to promote standardization of terminologies and methodologies used in IGNITE. See RFA-HG-17-010 for more details on the responsibilities of the IGNITE II CC.

Clinical Groups (CGs)

CGs are responsible for conducting the research (subject recruitment and implementation of all study procedures) and disseminating research findings. CGs will be responsible for the planning and collection of clinical and genomic test results that will permit the analysis of effects of interventions on patient outcomes and natural history. In conjunction with the CC and NHGRI, CGs will be responsible for finalizing and prioritizing protocols, developing common definitions and standardization across protocols, and analyzing and interpreting research results. Each CG will be required to participate in a cooperative and interactive manner with all other CGs and the CC in all aspects of the network, including developing Network procedures and subcommittees, finalizing PCT protocols and costs, developing a collaborative IRB process for submission to a single, shared IRB, and writing template informed consents. NHGRI’s decision to fund a particular CG will not commit IGNITE II to conduct that applicant’s proposed protocol. It is encouraged that the investigators participating in the CGs come from diverse backgrounds, such as racial and ethnic minority populations, to ensure a diversity of experience and perspectives. See RFA-HG-17-009 for more details on the enhanced diversity IGNITE II CGs.

Data and Safety Monitoring Board (DSMB)

An independent DSMB, established by the NHGRI in accordance with NIH policies, will conduct interim reviews of trial data to monitor patient safety and review performance and overall progress of the IGNITE II PCTs. The DSMB will also monitor the need to modify protocols. The DSMB will consist of experts in clinical trials, genomic medicine, bioethics, biostatistics, and PCT design and coordination. An NHGRI scientist will serve as the Executive Secretary to the DSMB. The DSMB will meet semi-annually (one conference call and one in-person meeting) in the Bethesda, MD area. The DSMB will review serious adverse event reports on an ongoing basis. Following each meeting, the DSMB will submit recommendations to NHGRI regarding the continuation of each PCT. The NHGRI will address the recommendations and prepare a report for PD(s)/PI(s) that can be provided to their IRBs.

NHGRI

NHGRI is responsible for organizing and providing overall support for IGNITE II. The NHGRI Program Office and Office of Grants Management are responsible for the overall management of IGNITE II. In addition to regular grant stewardship, the NHGRI Project Scientist(s) will be involved substantially with the awardees, consistent with the Cooperative Agreement mechanism. The NHGRI will be a voting part of the SC and will appoint the DSMB.

Protocol Review Committee (PRC)

An independent PRC, established by the NHGRI, will provide review and input for all proposed PCT protocols. The PRC will consist of a chairperson, scientists with expertise in genomic medicine, clinical trial design, biostatistics, outcome measures, and other areas of expertise as needed, and relevant stakeholders. Relevant stakeholders include professional societies, hospital systems, payers, regulatory agencies, and patient groups. An NHGRI scientist will serve as the executive secretary for the PRC. Because the PRC serves as an independent group providing guidance to the NHGRI, IGNITE II investigators will not communicate with PRC members regarding study issues, except as authorized by the PRC’s Executive Secretary. The PRC will review full protocol proposals for scientific merit, feasibility, and appropriateness of budget and will make recommendations regarding priority directly to the NHGRI on the scientific merit and priority of the protocol. The PRC will provide a written critique of each proposal and a final prioritization to the NHGRI. Once protocols are selected to move forward in IGNITE II, the SC will adapt prioritized protocols for implementation across the IGNITE II Network.

Steering Committee (SC)

A SC comprising the Program Director(s)/Principal Investigator(s) [PD(s)/PI(s)] of the CGs and the CC, and the NHGRI Project Scientist, will constitute the main governing body of IGNITE II. All major scientific decisions will be determined by majority vote of the SC. It is anticipated that the SC will meet at least twice per month by conference call and three times per year in the Bethesda, MD area for in-person meetings. The SC will have primary responsibility for the general organization of IGNITE II, finalizing clinical protocols and cost estimates, facilitating the conduct and monitoring of the trials, reporting trial results in a timely manner, and working with NHGRI to disseminate the findings. The SC will be responsible for creating a plan for clinical and genomic data sharing, according to NHGRI policies, during the first year of the program. Subcommittees of the SC will be established to address specific activities, such as publications and presentations, genomic testing, clinical decision support, and quality control and assurance. Awardees will be required to accept and implement policies approved by the SC.

Program Formation and Governance

Awards made under this FOA will be cooperative agreements (see Section VI.2., Cooperative Agreement Terms and Conditions of Award). Close interaction among awardees and the NIH will be required to develop appropriate strategies and tools to carry out this program. A Consortium will be organized with all of the Principal Investigators and key personnel funded under this FOA and the companion IGNITE II FOAs.

The IGNITE PRC will evaluate the proposed PCTs as described above. The exact number of PCTs supported will depend in part on the nature and complexity of the protocols and the availability of funding. PCTs to be conducted in IGNITE II will be selected from the trials proposed by successful applicants in response to this FOA, but a decision to fund a particular CG will not commit the IGNITE II network to conduct that applicant’s proposed protocol.

Soon after funding, the IGNITE II SC will meet to set IGNITE II-wide goals for the project period. The SC is expected to establish subcommittees and Working Groups to facilitate collaborative work and standardize approaches. PDs/PIs or Working Groups may propose new research collaborations with non-network investigators and organizations, as long as the activities are conducted in accordance with the policies and practices of the Network. Key collaborators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, will be eligible to attend SC meetings in addition to the PD(s)/PI(s).

Data Sharing and Clinical Trial Registration

Consistent with achieving the goals of the program, NIH expects that the project datasets (phenotypic, environmental, covariate, process, outcome measures and other relevant data) and associated genomic data from IGNITE II will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/). Resources such as study protocols, informed consent form templates, results report templates, and bioinformatic tools are expected to be made available through an open access section of a database such as dbGaP, ClinVar, public web sites such as the SPARK Toolbox, and/or publication in the scientific literature. In addition to traditional databases, the NHGRI expects datasets and informatic tools selected as part of this FOA to be made available through NHGRI approved cloud based platforms for sharing to the larger scientific community. Also, to assist in improving data sustainability and utility, applicants are encouraged to align the development of their data sets using the Findable, Accessible, Interoperable, Reproducible (FAIR) Guiding Principles https://www.nature.com/articles/sdata201618.

Consistent with the International Committee of Medical Journal Editors requirements (http://jamanetwork.com/journals/jama/fullarticle/2630773?amp;utm_source=JAMAPublishAheadofPrint&utm_campaign=06-06-2017), it is expected that all PCTs that go forward in the Network be registered in clinical trials.gov and include a data sharing plan in the trial’s registration that includes the following: whether individual de-identified participant data (including data dictionaries) will be shared; what data in particular will be shared; whether additional, related documents will be available (e.g. study protocol, statistical analysis plan); when the data will become available and for how long; and by what access criteria data will be shared (including with whom, for what types of analyses, and by what mechanism).

After the initial review, NHGRI program staff will conduct an additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee. The final negotiated version of the data sharing plan will become a term and condition of the award of the cooperative agreement.

See Section VIII. Other Information for award authorities and regulations.

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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.

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

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).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) 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:

Ebony Madden
Telephone: 301-503-5620
Fax: 301-480-277-
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.

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. CG budgets must reflect support for base level personnel and infrastructure costs to design and implement the proposed PCT exclusive of all costs specific to participant recruitment, intervention, follow-up, and analysis of any specific trial. The base level CG budget must include the effort required for network participation, including participating in regular teleconferences for discussion of protocols and other network committees including regular SC conferences, Network meetings, and activities related to IRB approval and updates, manuscript preparation, and travel costs for in-person meetings. Costs may include a travel budget for attendance of 4-5 CG investigators at three SC meetings (2 days, 1-2 nights) per year.

CGs should request base level funds that include personnel and infrastructure required for initial activities of the network, support for the ongoing infrastructure, and daily administrative and personnel needs exclusive of needs for the proposed PCT.

CG budgets should also include estimated total direct costs of participant recruitment, intervention, follow-up and analysis for the CG s share of the total number of participants needed for its proposed PCT. The proposed budget should include patient-related costs or clinical costs that are not part of usual care such as tests, sample and data collection, supplies, and drugs. Note that all 4-6 CGs will be enrolling for the network-wide protocol PCTs that will be implemented. For budgeting purposes, each CG should assume it will be recruiting one-fifth of the total number needed for its proposed PCT. The budget should also include costs of genomic testing and any equipment that may be unique to the proposed protocol. The CG budget should not include costs such as preparation of manuals of operation, data collection software, or training materials as these will be supported by the Coordinating Center. The budget pages as well as the budget justification should clearly identify which line items are for infrastructure (up to $250,000 direct cost) and which are for the CG’s share of the proposed PCT. Proposed PCTs should have an estimated total direct cost across all IGNITE CGs of no more than $5.1M (in addition to base CG and CC support) over the 2- to 4-year course of their conduct.

Supplemental funds will be provided to support additional personnel, genotyping, equipment, supplies, etc. needed to carry out the 2-4 network-wide pragmatic clinical trials, the network-wide ELSI research study, and/or any additional research activities performed by the Network.

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

A. Clinical Group Overview and Capabilities

In this narrative subsection, discuss the settings and populations of the Clinical Sites that make up the applicant’s Clinical Group (CG) and the plans for implementing the genomic medicine PCTs agreed upon by the network. In addition, the Overview subsection should address the following areas:

Qualifications and Experience: Without duplicating information in the Biosketches, applicants should describe the PD(s)/PI(s) experience in designing, implementing, analyzing and disseminating research on genomic medicine interventions. Senior/key personnel with expertise in clinical implementation, pragmatic clinical trials, genomic testing, integration of genomic variants into electronic health records, informed consent, genetic counseling, assessment of clinical and psychosocial outcomes, ELSI, cost-effectiveness, and healthcare utilization should be included. Past experience with genomic medicine implementation in diverse clinical settings should be highlighted, including experience with developing and implementing reporting formats, identifying primary or secondary findings, and disclosing genomic results in clinical care. Applicants should detail prior experience with assessing clinical utility, setting up systems for data integration, and conducting pragmatic clinical trials and health disparities research. Prior experience(s) working in multi-site research networks to meet individual study and collaborative goals should also be highlighted. Describe plans to leverage the experience and expertise of the CG team to achieve collaborative conduct of multi-site PCTs of genomic medicine interventions. CGs must have an established research program in the scientific areas of interest, appropriate expertise, ability to carry out PCT protocols, an infrastructure that supports multi-site trials, a track record of successful collaborative research, and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. Include a description of abilities and experience required to:

• Collect and report highly detailed clinical data to answer the primary and secondary outcomes of the IGNITE II Network trials
• Successfully complete participant recruitment and retention
• Conduct genomic testing in a CLIA-compliant manner
• Integrate genomic results and harmonize CDS into patients EHRs

Collaboration: Applicants should describe plans to support collaborative research and interaction with other CGs, the CC, and the NHGRI in all aspects of the IGNITE II Network. Include a plan to maintain close cooperation and effective communication among the Clinical Sites in the applicant’s CG, and evidence of the capability of the applicant’s CG to participate and interact effectively in cooperative, multi-site research. Discuss capability to participate in a distributed data entry system to transmit and edit data from the CG. Describe how unique strengths (e.g. PCT designs, genomics, clinical informatics, cost-effectiveness, multi-disciplinary team leadership, patient recruitment, retention and adherence strategies, and ELSI research such as ethics, behavioral and social sciences, and engaging with diverse populations) will be integrated and leveraged to contribute to the collaborative effort. Include descriptions of supervision, data handling, quality assurance, cost effective management, and communication in management plans.

Population and recruitment: Applicants should provide a narrative describing the CG’s ability to enroll 3,000 patients with 35% enrollment of patients satisfying the definition of "diversity" during a 12-month enrollment period, with objective sources of data on the size of the available population(s) and demonstration of past experience in the successful recruitment and retention of diverse patients in clinical research studies. A discussion must be included on the ability to enroll specific patient populations from diverse clinical settings which are both relevant to the proposed PCT as well as to other trials that may be implemented network-wide.

Clinical Sites: Applicants should provide a table of the Clinical Sites within your Clinical Group listing the clinical setting (e.g. academic institution, community hospital, primary care practice, etc.) and the site s characteristics including: EHR type; number of patients available for recruitment; demographic information including race/ethnicities of the proposed patient population (% White, Black or African American, Hispanic, Native American, Asian, etc.), and age (median and range); number of studies previously conducted at the Clinical Site; number of patients enrolled in previous studies and percent enrolled of those invited (% yield); and race/ethnic composition, % underserved, and median age of patients enrolled in studies.

B. Pragmatic Clinical Trial

Describe the PCT proposed by the CG for network-wide adoption, including the scientific question to be addressed, its clinical and scientific importance, its potential for implementation across diverse clinical settings including resource-limited sites, and how its results (whether positive or negative) are expected to change clinical practice. Describe key design features, estimated sample size and power, timeline, and strategies for integration of the PCT protocol into the clinical workflow that minimize burden on providers and patients. Describe plans for conducting genomic testing in a CLIA-compliant manner and outline approaches to maximize cost efficiency

Describe the patient population targeted, with minimal but precise inclusion and exclusion criteria, and primary and any secondary clinical and cost-effectiveness outcome measures achievable within a 12-month follow-up period. Note that timeframes for collecting outcomes can be shorter than 12 months, and shorter timeframes may be logistically and fiscally desirable. Describe an analysis plan for proposed outcomes and any anticipated analysis of pre-defined subgroup effects. Describe relevant follow-up beyond 12 months to determine long-term outcomes of secondary interest, if appropriate.

Include preliminary data of evidence of the genomic medicine intervention changing clinical management, improving outcomes, and/or lowering treatment costs compared to standard of care.

Describe the proposed genomic medicine intervention, including the genetic variants to be tested, if any, the sequencing or genotyping assays to be used, and equipment needed. Describe the proposed study population and expected frequency of clinical characteristics, genotypes, exposures, etc. relevant to the proposed PCT, and an estimate of the expected distribution of female and minority patients, and children. Provide a power analysis for the entire proposed sample size for the trial. Indicate how many patients are available in the applicant’s Clinical Sites for the proposed PCT and how many will be required from the entire IGNITE II network to conduct the PCT. In addition, a brief description of anticipated problems with recruitment and plans for addressing these problems with minimal additional costs should be included. Note that proposed solutions may not include requests for additional funds. Describe experience of the group as a whole in recruitment and retention of diverse patients in longitudinal studies or clinical trials with longitudinal follow-up. Describe experience of the group as a whole with recruitment in diverse healthcare settings, including resource-limited settings.

Include a plan for comparing results of the PCT to observational study data to identify potential biases affecting the generalization of observational data to clinical practice. The observational studies currently proposed for use in the comparison should be named and the results of these studies described, recognizing that additional studies may accrue and should be included when these comparisons are ultimately conducted.

Due to regulatory requirements for using research results in clinical care, a Food and Drug Administration (FDA) Investigational Device Exemption (IDE) may be needed for new genomic methods used in clinical care, separate from the requirement for the test to have been conducted within a CLIA-certified environment. Investigators must be prepared to discuss the possible need for an IDE with their current IRB and document the outcome of those discussions, and to subsequently engage in pre-submission discussions with the FDA if the IRB determines they are needed. These typically involve submission of actual study protocols, including the entire genomic testing pipeline from sample preparation to return of results. Applicants may wish to consult the following Points to Consider in Assessing When an Investigational Device Exemption (IDE) Might be Needed : http://www.genome.gov/27561291.

Protection of Human Subjects: In this section, describe the strategies and protections that should be in place to minimize harm due to involvement in the proposed PCT. It is expected that the IGNITE II Network will use a single IRB (sIRB) for ethical review of the PCTs. Applicants should describe their experience with a single IRB and whether they propose serving as the sIRB for a PCT. Applicants should indicate their willingness to participate in a network that uses a sIRB.

Letters of Support: Letters of institutional and departmental support for participation in IGNITE II should be included in the application. The letters of support should demonstrate willingness to participate in IGNITE II PCTs, and a single IRB for multi-site research.

Letters of support should be included from the applicant institutions for the CGs documenting commitment from institution and department leadership to participate fully in IGNITE II and are encouraged to demonstrate appropriate commitment and resources such as protected time, departmental research leadership position, facilities, space, or resources for the CG.

Letters of support should also be included from each Clinical Site that will participate in the CG. Clinical Sites should document commitment from site leadership to participate fully in IGNITE II and are encouraged to demonstrate appropriate commitment and resources such as protected time, facilities, space, or resources for the Clinical Site; describe their experience in enrolling patients in clinical research studies; and provide a one-page summary, which can be in template form, of the following:

• Site name and location
• Site PI and relevant experience
• Clinical setting (academic center, community hospital, private practice, etc.)
• Number of past and current research studies performed
• Proportion of women, minorities and underserved populations enrolled into these research studies in the past year
• Percent yield of enrollment (number ultimately enrolled divided by number approached) into these studies in the past year
• Size and demographics of patient population gender, race/ethnicity, age
• Percentage of patients with key inclusion and exclusion criteria for the proposed PCT
• Type of EHR system(s) in use at site
• Plans for switching EHR systems in the next 5 years
• Equipment relevant to the proposed PCT available on site
• Access to CLIA-certified laboratory
• Whether the site has an IRB
• Average time between IRB submission and approval
• Whether the site is open to using a single, shared IRB

If the application plans to address any anticipated problems with recruitment by utilizing additional Clinical Sites not included in the initial application, letters of support from those reserve sites should be included.

In addition, letters of support should be included from key stakeholders (clinicians, patients, representatives from health insurance companies, etc.) that indicate that results of the proposed trial could possibly change their practice.

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:

A plan for sharing project datasets (phenotypic, environmental, covariate, process data, and outcome measures) and associated genomic data should be provided. Awardees are expected to comply with the NIH Genomic Data Sharing Policy (https://gds.nih.gov/). The plan should also describe how informed consent will be designed and obtained to allow broad data sharing of project datasets for General Research Use or Health/Medical/Biomedical Research as defined by NIH at https://osp.od.nih.gov/wp-content/uploads/standard_data_use_limitations.pdf. Broad data sharing for general research use is strongly encouraged for the IGNITE II pragmatic clinical trial datasets. A plan to share resources such as study protocols, informed consent form templates, results report templates, and bioinformatic tools should also be provided.

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 PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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 NHGRI, 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 the policy.

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? Does the proposed trial address important clinical problems of public health significance?? Will completion of the proposed trial improve future clinical trial design and personalized clinical management? Is there the possibility for significant improvement in outcomes and reduction in disease progression for such patients? Are letters of support from key stakeholders provided that indicate that outcomes from the trial have the potential to change their practice?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?Are there demonstrated experience and success in collaborative research projects involving investigators within and outside of their institution? Is there sufficient involvement of investigators from racial and minority ethnic populations in the Clinical Sites? Do the investigators have experience in the recruitment of racial and ethnic minority populations as well as recruitment of patients from diverse clinical settings?

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 proposed trial address important treatment questions that have not been addressed before? Are novel PCT designs and analyses proposed?

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?

Has the applicant documented the ability to enroll at least 3,000 patients of whom 50% are from diverse clinical settings (community hospital, family medicine clinics, primary care practices, etc.) and 35% from racial and ethnic minority populations, underserved populations, or populations who experience poorer medical outcomes? Is there evidence of the Clinical Sites ability to enroll patients with specific clinical characteristics relevant to the proposed PCT, as well as patients more broadly relevant to a variety of potential genomic medicine PCTs, within 12 months of the initiation of a given PCT protocol? Does the proposed study have at least 80% power to detect clinically meaningful outcomes at the sample size proposed, taking into account the expected frequency of the relevant clinical characteristics and demographic subgroups?

Are the methods proposed efficient, cost-effective, practical, and are they likely to inform novel designs for future clinical trials and translate into clinical use? Is preliminary data provided of evidence of the genomic medicine intervention changing clinical management, improving outcomes, and/or lowering treatment costs compared to standard of care?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Is there evidence of the applicants access to genetic testing in a CLIA-compliant manner?

Is there a diversity of Clinical Sites within the proposed CG with regard to populations relevant to a variety of genomic medicine PCTs?

Are strong letters of institutional support included? Is the willingness to participate in a single shared IRB indicated clearly?

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

For Renewals, the committee will consider the progress made in the last funding period.

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 NHGRI, 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 Council for Human Geome Research. 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.

• Complementarity to and synergy with other funded projects.
• Programmatic balance among conditions to be studied, healthcare settings, and approaches to be implemented.
• Ability of investigative group to work effectively in large collaborative efforts or consortia.
• Public health importance of conditions to be studied.
• Diversity of study patients, particularly with respect to inclusion of minority or underserved populations in the U.S., and relevance of proposed research questions related to diversity and health disparities.
• Ability to recruit and study large sample sizes efficiently and cost-effectively.
• Applicability of the proposed approach to other healthcare settings

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.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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, 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:

• Determining, designing, and adapting protocols, setting project milestones, and conducting the Network PCTs.
• Participating in group activities, including a study-wide Steering Committee.
• Implementing Steering Committee recommendations for trial implementation, data collection, and standardization at the Clinical Sites involved in the relevant protocols.
• Obtaining the necessary consent or re-consent and IRB approval for participation in the clinical trials and return of results, according to the proposed trial protocols.
• Ensuring all genomic tests to be used in clinical care are generated in a CLIA-compliant environment.
• Developing and implementing appropriate educational resources for patients and clinicians.
• Evaluating the impact of the genomic medicine intervention on clinical, patient, and cost-related outcomes.
• Identifying concerns unique to minority and underserved populations, and to diverse healthcare settings.
• Providing protocols, reports and data to the CC in a timely fashion as agreed upon by the Steering Committee.
• Cooperating with other awardees in the timely publication and dissemination of the results of the PCTs and the eventual release to the scientific community of methods, tools, and results, and other resources.
• Abiding by common definitions, protocols, procedures, etc. as chosen by majority vote of the Steering Committee.
• Sharing results according to the NIH Genomic Data Sharing Policy, and any other data sharing policy agreed to between the NIH and the applicant.
• Adhering to policies regarding data access, publication, and intellectual property established by NIH and the Steering Committee for this program.
• Not disclosing confidential information obtained from other members of the program.
• Notifying the Project Scientist(s) of all major interactions with another member of the Steering Committee related to IGNITE II.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee and External Scientific Panel.
• Attending and participating in Steering Committee meetings and accepting and implementing clinical trial protocols, as appropriate.
• Abiding by relevant policies, including, but not limited to:
• NIH Genomic Data Sharing policy (https://gds.nih.gov/)
• Notice for Use of Cloud Computing Services for Storage and Analysis of Controlled-Access Data Subject to the NIH Genomic Data Sharing (GDS) Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-086.html)
• Notice on Clarifying NIH Priorities for Health Economics Research (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-025.html)
• Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-094.html)
• FDA policy on Investigational Device Exemptions (IDE): http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/default.htm
• 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 Project Scientist(s) are scientists of the NHGRI who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist(s) will participate as a member of the Steering Committee and will have one vote. He/she and/or other NHGRI scientists may serve on additional committees, when appropriate. The NHGRI Project Scientist (and other NHGRI program staff) may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees (e.g. recruitment, intervention, follow-up, quality control, adherence to protocol, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, and preparation of publications). NHGRI Program staff, on behalf of the NHGRI, will have the same access, privileges, and responsibilities regarding the collaborative data as the other members of the Steering Committee.

The NHGRI reserves the right to phase out an IGNITE II trial (or an individual award) in the event of (1) failure to develop or implement mutually agreed upon collaborative protocol; (2) substantial shortfall in participant recruitment, follow-up, data reporting, or quality control; (3) major breach of a protocol or substantive changes in the agreed-upon protocol with which NHGRI cannot concur; (4) attaining of a major study endpoint before schedule with persuasive statistical significance; or (5) human subject ethical issues that may dictate an early phase out of a trial or the program.

Annual continuation and level of funding for the CG will be based on NHGRI review of actual recruitment and overall performance, determined as part of the NHGRI review of the annual non-competing continuation grant progress reports submitted by awardees.

The NHGRI reserves the right to modify or phase out the IGNITE II network based on feasibility of achieving network goals as determined by recommendations, generated during the periodic reviews, from external experts and NHGRI staff.

In the event of an early phase out of a trial or program, IGNITE II awardees should transfer all project datasets (phenotypic, environmental, covariate, process data, and outcome measures), associated genomic data, and resources (study protocols, informed consent form templates, results report templates, bioinformatic tools, etc.) collected or developed before the trial and/or program was stopped as directed by NHGRI.

The Project Scientist(s) will have the following substantial involvement:

• Serving as Executive Secretary of the Protocol Review Committee in the group process of prioritization of PCT protocols proposed by the funded Clinical Groups.
• Participating with the other Steering Committee members in the group process of setting research priorities, and contributing to the adaptation of research protocols to be implemented Network-wide. The Project Scientist will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities among and for the awardees and as an information resource for the awardees about genome research activities. The Project Scientist(s) will also coordinate the efforts of the program with other groups conducting similar studies.
• Attending all Steering Committee meetings as a voting member and assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action.
• Reporting periodically on the progress of the program to the Director of NHGRI, as appropriate, and to the National Advisory Council for Human Genome Research, as appropriate.
• Retaining the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Serving on subcommittees of the Steering Committee, as appropriate.
• Serving as a liaison between the Steering Committee and the Data Safety and Monitoring Board (DSMB), serving as the Executive Secretary of the DSMB, and arranging for timely preparation and distribution of minutes from the closed session.
• Serving as a liaison between the Steering Committee and other federal agencies such as the Food and Drug Administration (FDA) or the Centers for Medicaid and Medicare Services (CMS).
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.
• Other NHGRI staff may assist the awardees, as designated by the Program Official.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as an NIH Project Scientist.

In addition to the above responsibilities, the NHGRI Project Scientist may also serve as Program Official, and be responsible to the normal program stewardship, consistent with the provisions of the Cooperative Agreement mechanism.

Areas of Joint Responsibility include:

• The Steering Committee will serve as the main scientific body of the program. The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one NHGRI Project Scientist, one Project Scientist from component NIH Institute/Centers (ICs) funding an award, and the PD/PI from each awarded cooperative agreement from this and accompanying IGNITE II FOAs. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired. It is anticipated that additional coordination mechanisms may be set up with other U.S. and international groups that may collaborate with the program.
• Awardees agree to the governance of the trials through a SC. The lead investigator(s) from each CG and the CC and an NHGRI representative will comprise the SC. All major scientific decisions will be determined by majority vote of the SC. Each CG, the CC, and the NHGRI Program Office will have one vote. Note that each CG and the CC will have one vote, even if there are multiple PD(s)/PI(s). If the CGs or CC choose to utilize the multi-PD/PI mechanism, all the PDs/PIs are expected to participate in all SC meetings and teleconferences; however, each CG has one vote. It is anticipated that SC meetings will be held up to twice a month by conference call and 3 times a year in person. The first year, during network establishment and initial protocol selection, may require more frequent contact.
• An independent Data and Safety Monitoring Board (DSMB) will be appointed by the Director, NHGRI, to provide overall monitoring of study performance, interim data, and safety issues. An NHGRI scientist will serve as Executive Secretary to the DSMB.
• Members of the SC will be required to accept and implement policies approved by the SC.
• To address particular issues, the Steering Committee may establish Working Groups as needed, which will include representatives from the program and the NIH and possibly other experts.

Data Safety and Monitoring Board

A Data Safety and Monitoring Board (DSMB) will evaluate the progress and safety the clinical trials of the IGNITE II Network, providing recommendations to the network about the progress, data integrity, and safety of all components of the Network.

The DSMB will be composed of senior scientists with expertise relevant to the PCTs implemented in IGNITE II. The IGNITE II DSMB will meet at least twice per year, once per year in person and once by telephone conference. At least once per year, there will be a joint meeting with the Steering Committee to allow the members of the DSMB and the Steering Committee to interact directly. Twice per year the DSMB will assess the progress, data integrity, and safety of the network PCTs and make recommendations to the network about changes, if any, which may be necessary.

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 RPPR, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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 Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Ebony Madden
National Human Genome Research Institute (NHGRI)
Telephone: 301-503-5620
Email: [email protected]

Alexander Katz
National Human Genome Research Institute (NHGRI)
Telephone: 914-462-1745
Email: [email protected]

Ken Nakamura
National Human Genome Research Institute (NHBRI)
Telephone: 301-402-8823
Email: [email protected]

Deanna Ingersoll
National Human Genome Research Institute (NHGRI)
Telephone: 301-435-7858
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.