Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Heart, Lung, and Blood Institute (NHLBI) National Institute on Aging (NIA) National Institute on Deafness and Other Communication Disorders (NIDCD) National Institute on Drug Abuse (NIDA) National Institute of Nursing Research (NINR) National Center for Complementary and Alternative Medicine (NCCAM)
Funding Opportunity Title	Low-Cost, Pragmatic, Patient-Centered Randomized Controlled Intervention Trials (UH2/UH3)
Activity Code	UH2/UH3 Phase Innovation Awards Cooperative Agreement
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-HL-14-019
Companion Funding Opportunity	RFA-HL-14-020, R01Research Project
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.837, 93838, 93.839, 93.233, 93.213, 93.279, 93.866, 93.173, 93.361
Funding Opportunity Purpose	This NIH Funding Opportunity Announcement (FOA) invites applications to plan and conduct low-cost, pragmatic randomized controlled trials (RCTs). Pragmatic RCTs seek to determine the effectiveness of an intervention in a real world setting. Trials proposed under this FOA should answer questions that are high impact to patients or health care providers, and must leverage existing clinical practice settings and/or existing electronic resources such as registries for the conduct of clinical trials. Trials must include features such as randomization at the point of patient care; data collection integrated into or obtained from routine clinical records or similar existing electronic resources; minimal eligibility criteria, and interventions delivered as part of routine clinical care. Funds from the NIH will be made available through the UH2/UH3 cooperative agreement award mechanism. The initial one-year UH2 phase will support the refinement of electronic and other existing resources, further development of study partnerships, and finalization of the trial protocol and manual. UH3 awards will be made after administrative review of UH2 awards that have met agreed upon milestones. The four-year UH3 phase will support the conduct of the planned clinical trial.

Posted Date	November 7, 2013
Open Date (Earliest Submission Date)	December 23, 2013
Letter of Intent Due Date(s)	December 23, 2013
Application Due Date(s)	January 23, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June 2014
Advisory Council Review	August 2014
Earliest Start Date	September 2014
Expiration Date	January 24, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

Despite the rapid pace of discovery in health care, only a small part of routine medical therapy provided to individual patients is based on the highest level of evidence, the phase 3 patient-centered RCT. An even smaller amount of high-quality evidence supports systems of health care delivery. The underlying reasons for this include research studies with highly restrictive inclusion and exclusion criteria, limited testing of health care delivery strategies, and the high cost of RCTs as they are currently conducted. There is increasing demand for high-quality evidence to determine the most effective treatment, diagnostic strategy and health care delivery system. Comparative effectiveness studies are in high demand and new initiatives targeted at translating evidence-based practices into routine clinical care are being enacted. The Million Hearts, a collaboration across several federal agencies, is one such initiative with the goal of preventing one million heart attacks and strokes over five years by translating the evidence base in cardiovascular prevention (aspirin, blood pressure control, cholesterol management, and smoking cessation) to the greater population. To meet this increasing demand for high-quality evidence in the health care arena, efficient, low-cost strategies for the conduct of large-scale, high-impact RCTs are needed.

The advancing electronic resources of the health care delivery system, the development of private-sector high-quality mega-registries, and the increasingly integrated health care environment offer such an opportunity. The Federal Government’s mandate for physician practices to adopt electronic medical records, the use of patient registries, and the growth of personal health records has resulted in comprehensive data systems that could be utilized for the recruitment and conduct of RCTs. Health care payers are also embracing studies to increase the evidence base for models of care delivery (e.g., innovative teams or referral patterns), treatment models (e.g., intensive titration of therapy), and incentive strategies (e.g., pay for performance). Patient advocacy groups have initiated databases of volunteers willing to enroll in clinical studies. The development of inexpensive mobile and web technologies to collect data from individuals may also expand the opportunity for less expensive trials. The intersection of these movements has provided an opportune time to develop and implement more streamlined RCTs.

The purpose of this FOA is to encourage investigators to use existing resources to conduct low-cost pragmatic patient-centered randomized controlled trials of interventions targeted at patients, families healthcare providers, communities or health care systems through the integration of RCTs into existing clinical practice settings. While key features of high-quality clinical trials must be maintained (standardized inclusion and exclusion criteria, randomization, study protocol with standardization where appropriate, masking to treatment assignment to the degree possible, and objective assessment of outcomes), separate research infrastructure and staff should be minimized.

To be responsive to this FOA, applicants must:

• Utilize existing electronic resources such as electronic health records, personal health records, or patient registries for key aspects of the trial such as identification, recruitment and consent of eligible patients; monitoring compliance or obtaining interim study data when necessary; and ascertainment of study outcomes.
• Conduct the trial in a real-world setting that includes a broad representation of patients who would have the condition under study including those with multiple morbidities, at high risk, and vulnerable.
• Utilize trial endpoints that are relevant to patients and clinicians (e.g., morbidity, hospitalizations, clinical events, and quality of life). Surrogate (such as blood biomarkers) or intermediate outcomes are discouraged; they may be acceptable when the proposed measures are valid and adequate rationale is provided. Secondary endpoints may include analyses focused on decreasing or maintaining utilization while improving health outcomes.
• Minimize separate infrastructure utilized only for the clinical trial. Investigators should strive to conduct all aspects of the trial including administration of the intervention within existing clinical resources and describe evidence of sustainability of successful interventions after the conclusion of the trial.
• Exploration of low-cost methods to collect, store and utilize biological specimens as part of the pragmatic trial structure is encouraged.

Applications that do not propose to use existing electronic resources, conduct the trial in a real-world setting with minimal inclusion and exclusion criteria, utilize endpoints that are relevant to patients and clinicians, and minimize separate infrastructure will be considered non-responsive.

Applicants must plan for both a UH2 and a UH3 phase The UH2 section must include a description of the milestones that will be reached at the end of the UH2 phase. To successfully transition to the UH3 phase, the project must reach the following milestones in addition to any trial specific ones outlined in the application:

• Development and documentation of all collaboration and partnerships necessary for conduct of the clinical trial. These may include selection of clinical sites, selection of study champions in relevant delivery locations, and execution of data use agreements.
• Finalization of protocol, manual (s) of procedure, and data collection forms. These should have all necessary approvals including local Institutional Review Boards (IRB) and protocol review committees (if the funding IC requires). If data collection forms are to be integrated into an existing electronic record, demonstration of the integration must be provided. If data will be collected from existing electronic sources, demonstration of validated methods to collect such data should be provided.
• All necessary human subject protection approvals and procedures in place. This includes IRB approval, review and approval of final informed consent documents or waiver of informed consent, and selection of medical monitors/data safety monitoring boards. Applicants must comply with IC specific safety monitoring such as use of IC established DSMBs.
• Provide documentation of a potential study population adequate to meet the sample size of the trial. Demonstration of the ability to recruit potential participants to enroll in the clinical trial is highly desirable.

Each applicant should submit additional milestones that are specific to their proposed clinical trial. These should be quantifiable and the metrics to measure success fully explained in the application. Additional milestones may be negotiated after funding decisions have been made.

• Applicants must not propose work that duplicates efforts already underway. When possible, applicants should adopt or adapt resources of ongoing NIH supported efforts in informatics as well as other national efforts including but not limited to the many federal investments in the HMORN, the CTSAs, REDCap, PROMIS, NIH Toolbox, DEcIDE, eMERGE, other networks, CERTs, SHARP, Vaccine Safety Datalink, the Sentinel Initiative.
• Interventions that are not yet approved for use by the FDA or require significant interaction with research staff for safety monitoring would not be appropriate.
• Partnerships with health care organizations, payers, professional organizations, and/or patient advocacy groups are encouraged.
• Applicant must agree to work with and provide information to the Administrative/Evaluation Coordinating Center as needed during the UH2 and UH3 phase. A formal evaluation on the methods used and their efficiency and effectiveness will be conducted by the Administrative/Evaluation Coordinating Center at the conclusion of the UH2 and UH3 phases.

NHLBI

Examples of studies that would be of interest to NHLBI include, but are not limited to, the following:

• Randomized controlled trial of referral models that promote appropriate utilization of technology (e.g., implantable cardioverter-defibrillator placement).
• Randomized controlled trial of models that incentivize treatment of patients to mitigate the risk of acute episodic care (e.g., stepped care for asthma to reduce emergency room visits).
• Randomized controlled trial to test the effect of providing technologies for disease self-management in chronic obstructive pulmonary disease and congestive heart failure.
• Randomized controlled trial of strategies to increase both patient and provider adherence to proven therapies (e.g., automated checklists or prompts for guideline-based therapeutic decision-making, co-location of pharmacy services, and community settings for medication reconciliation).
• Cluster-randomized clinical trial to evaluate a physician and nurse-led educational outreach intervention to enhance transfusion practices.
• Randomized trial to determine the efficacy of prevention therapies such as aspirin or statins in reducing cardiovascular disease in all individuals over the age of 80 compared to targeted use of those therapies in those over the age of 80 who have had a previous CVD event.
• In patients with high blood pressure, an RCT trial comparing the strategy of home blood pressure measurements for therapy changes to achieving target blood pressure compared to clinic measurements on clinical outcomes such as cardiovascular disease.
• A randomized controlled trial testing blood transfusion policy to maintain a hemoglobin greater than 10 mg/dl compared to one that maintains the hemoglobin at 8 mg/dl in patients hospitalized for cardiovascular surgery on the outcome of length of stay.
• An randomized controlled trial comparing a strategy of prophylactic platelet transfusion versus therapeutic-only platelet transfusion strategy in hospitalized patients with a low platelet count to improve clinical outcomes.

NIA

Examples of research topic areas that may be relevant to this FOA include, but are not limited to:

• Development and validation of effective electronic strategies to reconcile medication type and dose across care transitions (hospital to home, home to hospital including intermediate care such as between inpatient units, rehabilitation facilities and nursing homes).
• A randomized controlled trial to determine the most effective therapeutic agent(s) and target level of blood pressure (systolic and diastolic) for isolated systolic hypertension in older patients.
• Effectiveness of incorporating an automated notification system in an electronic inpatient pharmacy ordering system that alerts providers to the potential for drug-drug interactions or adverse drug effects in individual patients meeting specific age-associated clinical parameters (e.g., creatinine clearance:body surface area).
• Effectiveness of incorporating an automated electronic health record notification system that identifies older patients at increased risk of major bleeding based on hematologic/coagulation factors, concurrent medications, renal function, anthropomorphic changes, and/or other variables.
• Clinical trials comparing age-based dosing regimens (loading and maintenance) for warfarin in older patients taking commonly prescribed medications and/or with multiple chronic conditions across the spectrum of care facilities (hospital, subacute care, long-term care, home, anticoagulation clinics, office settings).
• Randomized controlled trial to evaluate the effectiveness of incorporating geriatric assessment (i.e., systematic assessment of functional, cognitive, medical, and other parameters) in older adults referred for invasive or surgical procedures.
• Randomized controlled trial assessing the effectiveness of anticoagulation strategies for non-valvular atrial fibrillation in patients older than 80 years, including those with multiple chronic conditions or renal dysfunction.
• Trials incorporating specific palliative care services (e.g., symptom management, establishment of care goals consistent with patient and family preferences, discontinuation of potentially unnecessary treatments) in older adults within and across care settings.
• A pragmatic trial, with broad inclusion and few exclusionary criteria, which addresses a question important for the management of persons with multiple chronic health conditions, testing an intervention, or coordinating several interventions with the broad goal of determining whether the intervention (s) improves health outcomes.
• A trial to compare beneficial and adverse outcomes from differing management strategies for specific combinations or multiple chronic conditions prosing management challenges, such as congestive heart failure with osteoarthritis and chronic conditions that contraindicate use of beta blockers and/or ACE inhibitors.
• Pragmatic trials of alternative incentive-based approaches to encouraging individuals to adopt healthy behavioral changes. Such approaches might include offering financial incentives for weight loss, commitment contracts for exercise, or lottery-based schemes to enhance adherence to medications, among others.
• Pragmatic trials of low- or zero-cost alternative defaults (altering the choice architecture) which could shape individual health behavior; these could include switching high-risk individuals from active-choice enrollment to automatic enrollment in health awareness counseling, engineering reports of lipid panel results to include estimates of increased cardiovascular risk, automatic calendaring of vaccination appointments in large organizations, or other innovative approaches at the organizational level which might encourage behavioral change.
• Pragmatic trials of alternative approaches to managing care for dementia sufferers with other medical conditions which involve repeated hospitalizations which are often followed by skilled nursing facility visits.
• Pragmatic trials of computerized interventions to remediate cognitive decline, which can now be delivered over the web at very low marginal cost, but which have not been carefully tested for efficacy.
• Pragmatic trials to shape physician behavior through electronic medical records based approaches (e.g., to require additional justification for inappropriate prescriptions or failing to prescribe based on reported lab test results).

NIDA

Examples of studies that would be of interest to NIDA include, but are not limited to, the following:

• Randomized controlled trials of different models, strategies, including innovative e-health technologies and social networks, for implementing evidence-based treatment practices in real world service delivery settings (for example rural primary care settings) and health care systems.
• Randomized controlled trials in medical office and community clinic settings of medications and behavioral interventions (including e-health interventions) that have been shown to be effective for patients with Substance Use Disorders.

NIDCD

Examples of research topic areas that may be relevant to this FOA include, but are not limited to:

• Evaluation and management of communication disorders of hearing (including tinnitus), balance, taste, smell, voice, speech and language, including addressing special biomedical and behavioral problems associated with people who have these communication impairments or disorders; and supporting efforts to create devices which substitute for lost and impaired sensory and communication function.

NINR

NINR solicits applications designed to enhance the evidence base for care of individual patients, families, and communities to increase knowledge of the most effective methods for health care delivery and to advance self-management and health promotion and integrate these more rapidly, and cost effectively into practice.

Examples of research topic areas that may be relevant to this FOA include, but are not limited to:

• Methodological research in clinical or public health practice.
• Research on current practices affecting availability and use of existing health care resources.
• Determination and removing barriers to implementation and dissemination technologies and methodologies into health care delivery systems.
• Test and evaluate health promotion interventions conducted in settings providing health promotion/disease prevention services to promote healht and symptom and self-management to include community participatory involvement and interdisciplinary team science.
• Facilitate clinical effectiveness and outcomes research using improved implementation science and technological methods as well as consistent measures, taxonomies, and data bases.

NCCAM

Examples of studies that would be of interest to NCCAM include, but are not limited to, the following:

• Pragmatic trials studying the incorporation of complementary health approaches into comprehensive pain management programs in patients with sleep disturbances.
• Cluster randomized trials introducing mindfulness-based approaches into comprehensive insomnia treatment programs.
• Pragmatic trials to study the impact of incorporating mindful-movement techniques (e.g., yoga, tai chi, or qi gong) into cardiac or pulmonary rehabilitation programs.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The following NIH components intend to commit the following amounts (total cost) in FY 2014: National Heart, Lung, and Blood Institute, $3,000,000, 6 awards National Institute on Aging, $1,000,000, 2 awards National Institute on Deafness and Other Communication Disorders, $500,000, 1 award National Institute on Drug Abuse, $500,000, 1 award National Institute of Nursing Research, $500,000, 1 award National Center for Complementary and Alternative Medicine, $500,000, 1 award
Award Budget	Application budgets are limited to $350,000 in direct costs for the UH2 phase and $500,000 in direct costs for each year of the UH3 phase
Award Project Period	The UH2 phase will be one year in length and the UH3 phase may be up to 4 years.

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

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

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

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:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214
Bethesda, MD 20892-7924 (Express Mail Zip: 20817)
Telephone: 301-435-0270
Fax: 301-480-0730
Email: nhlbichiefreviewbranch@nhlbi.nih.gov

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

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

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.

Applicants should budget for travel to an annual investigators meeting to be held in the Washington, DC area.

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:

Specific Aims: Applicants should include separate specific aims for each phase of the application (UH2 and UH3), but must not exceed the designated page limit.

Research Strategy: UH2 and UH3 research strategies must both be described. The UH2 is a one-year planning period. Planning period work may include protocol development and development of collaborations. Applicants may conduct small pilot studies testing recruitment strategies, outcomes ascertainment and integration of forms into existing electronic resources during the UH2 phase. The UH3 should be devoted to the conduct of the clinical trial.

Milestones and UH2/UH3 transition

Applicants must include their research strategy for both the UH2 and the UH3 phase. The UH2 section must include a description of the milestones that will be reached at the end of the UH2 phase. To successfully transition to the UH3 phase, the project must achieve the following milestones in addition to any trial-specific ones outlined in the application:

Develop and document all collaboration and partnerships necessary for conduct of the clinical trial. These may include selection of clinical sites, selection of study champions in relevant delivery locations, and execution of data use agreements.

Finalize protocol, manual (s) of procedure, and data collection forms. If data collection forms are to be integrated into an existing electronic record, demonstrate the integration. If data will be collected from existing electronic sources, demonstrate validated methods to collect such data.

Obtain all necessary human subject protection approvals and procedures including IRB approval, review and approval of final informed consent documents or waiver of informed consent, and selection of medical monitors/data safety monitoring boards. Applicants must comply with IC specific safety monitoring such as use of IC established DSMBs.

Document a potential study population adequate to meet the sample size of the trial. Demonstrate ability to recruit potential participants to enroll in the clinical trials.

Each applicant must submit additional milestones that are specific to their proposed clinical trial. These should be quantifiable and the metrics to measure success fully explained in the application. Additional milestones may be negotiated after funding decisions have been made.

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

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

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

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

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

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

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is the proposed pragmatic trial addressing a major public health issue? Will the completion of the proposed pragmatic trial change the concepts, methods and technologies used in large scale community-based clinical research?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do the PD(s)/PI(s) and key personnel have the necessary expertise in design and implementation of a large-scale pragmatic trial such as using electronic health records for recruitment and outcomes assessment? Do the PD(s)/PI(s) have extensive experience in performing proposed Planning Phase activities, and do they have a track record of successful investigative collaborations or partnerships with (within) health delivery organizations proposed in the application?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Does the application challenge and seek to impact current conventional approaches to clinical trials by utilizing novel approaches or methodologies for a pragmatic trial? Is a refinement, improvement or new strategy of approaches proposed? Does the application include mechanisms for leveraging novel collaboration and study oversight strategies? Is the research novel or innovative in its methods or approach, in the population being studied or in the intervention being evaluated, in ways that make it likely to improve care?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Is the proposed trial utilizing existing electronic resources for study activities such as identification of study participants, ascertainment of outcomes and monitoring of study conduct? Will the trial be conducted in a real-world setting with broad inclusion and exclusion criteria? Are the study outcomes meaningful to patients and clinicians? Is infrastructure developed solely for the purpose of the conduct of the trial minimized? Is the study intervention being delivered in the context of routine clinical care? Will proposed planning activities (including plans for identifying a sufficiently large target patient population), and proposed milestones, allow for implementing the clinical trial?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Are there sufficient infrastructure and expertise (e.g., clinical investigators, informaticists) to implement the proposed pragmatic trial within the proposed setting?

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.

Milestones

Are the steps and milestones clearly defined? Are the milestones feasible, well developed and quantifiable with regard to specific goals and accomplishments? Are adequate criteria provided for the UH2 phase that will be utilized in determining milestone completion before proceeding to the next phase of the project?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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 on the basis of established PHS referral guidelines 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 the assigned institute. 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.

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

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

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

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the study including those outlined under "NIH Responsibilities".
• Awardees will participate in annual meetings of the awardees and will support any committees, task forces, and advisory panels as needed.
• Upon implementation of the protocol, each field center, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, and data collection.
• Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIH support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur with the concurrence by NIH Program Officer to ensure objectivity of research.
• Obtaining prior written approval of the NIH Grants Management Specialist in consultation with the NIH Program Officer for a change in any of the key personnel identified in the Notice of Award.
• Award recipients will own the rights in any tangible work products created under the terms of the cooperative agreement. Work products may include such things as research reports, papers, research, findings, training curricula, data sets, books, patient tools, and other materials. All such products shall be made accessible to the public and are subject to Government rights of access, as appropriate, in accordance with NIH’s legal directives and authorities.

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

• The NIH Project Scientist will have access to the data and work with the PD(s)/PI(s) to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist.
• The NIH reserves the right to phase out or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting. If the application is assigned to NHLBI, NHLBI support of this study is contingent upon adequate participant recruitment based on the Grantee’s Milestone Accrual Plan submitted at the time of funding. The Grantee is expected to demonstrate best effort compliance in accord with the NHLBI Milestone Accrual Policy (http://www.nhlbi.nih.gov/studies/index.htm ). Failure to achieve minimally acceptable milestone recruitment levels may result in the withholding future support and or negotiating an orderly close-out of this study.
• NIH staff will act as a resource and facilitator for activities of the awardee with non-HCS researchers and other NIH, DHHS, or other federally-sponsored research networks that may be relevant to this effort.
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the clinical trial by participating in the design of the activities, advising in the selection of sources or resources, advising in management and technical performance, or participating in the preparation of publications.
• Participate in the monitoring of issues relating to recruitment, retention and follow-up of study participants, and monitoring of data integrity and quality control through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting as needed to the administration and evaluation core.
• Assist in the development and modification of study protocols.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his staff, periodic site visits for discussion with the awardees research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship matters.
• Reporting periodically on progress of the program to the interested IC Directors.
• 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.

Areas of Joint Responsibility include:

• The PD(s)/PI(s) provide, in concert with the NIH staff, support necessary to ensure that sites and investigators, and NIH and other research partners fully comply with federal regulatory requirements, including but not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• Awardees and NIH will jointly develop appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health care provider organization patients, health care providers and other institutions.
• All awardees and NIH will cooperate to ensure the timely and broad dissemination of lessons learned, to inform researchers and health care systems engaged in research in health care settings.

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 investigator chosen without NIH staff voting from among the PI of the FOA, 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Phone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Denise Bonds, MD, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone:301-435-0379
Email: bondsde@nhlbi.nih.gov

Sergei Romashkan, MD, PhD
National Institute of Aging (NIA)
Telephone: 301-435-3047
Email: romashks@nia.nih.gov

Gordon B. Hughes, MD
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-4085
Email: hughesg@nidcd.nih.gov

Sarah Q. Duffy, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-6504
Email: duffys@nida.nih.gov

Karen Huss, PhD, RN, ANP-BC, FAAN, FAAAAI, FAHA
National Institute of Nursing Research (NINR)
Telephone: 301-594-5970
Email: hussk@mail.nih.gov

Partap S. Khalsa, DC, PhD, DABCO
National Center for Complementary and Alternative Medicine (NCCAM)
Telephone: 301-594-3462
Email: partap.khalsa@nih.gov

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: chiefreviewbranch@nhlbi.nih.gov

Tammi Simpson
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0166
Email: simpsontl@nhlbi.nih.gov

Deborah Stauffer
National Institute of Aging (NIA)
Telephone: 301-496-1472
Email: stauffed@nia.nih.gov

Christopher Myers
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-0713
Email: myersc@mail.nih.gov

Edith Davis
National Institute on Drug Abuse (NIDA)
Telephone: 410-360-4734
Email: edavis1@nida.nih.gov

George Tucker, MBA
National Center for Complementary and Alternative Medicine (NCCAM)
Telephone: 301-594-9102
Email: gt35v@nih.gov

Lawrence Haller
National Institute of Nursing Research (NINR)
Telephone: 301-402-1878
Email: HALLERL@mail.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.