National Heart, Lung, and Blood Institute (NHLBI)
April 30, 2020 - Notice of Change in Application Due Date for RFA-HL-21-011. See Notice NOT-HL-20-783.
March 10, 2020 - Reminder: FORMS-F Grant Application Forms & Instructions Must be Used for Due Dates On or After May 25, 2020- New Grant Application Instructions Now Available. See Notice NOT-OD-20-077.January 10, 2020 - Notice of Technical Assistance Webinar for NHLBI RFA-HL-21-011. See Notice NOT-HL-20-748. July 26, 2019- Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128
August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137
93.840, 93.837, 93.838, 93.839, 93.233
This milestone-driven Funding Opportunity Announcement (FOA) invites applications for single-site, biphasic, late-stage implementation and translation (T4) research trials to identify and test pragmatic and sustainable implementation strategies that will increase the use of evidence-based practices (EBP), i.e., evidence-based guidelines or other well-accepted evidence-based interventions, for preventing and/or managing heart, lung, and blood diseases and/or sleep (HLBS) disorders. Clinical trials for this FOA must meet the NIH definition of a clinical trial (see NOT-OD-15-015). Applicants will be expected to address a planning phase (R61) of up to one year, and an implementation research phase (R33) of up to four years for the clinical trial. During the planning phase awardees will be expected to: finalize selection of the EBP; recruit participating organization(s); prepare the implementation protocol; develop milestones and a project timeline; and develop plans for data collection and management, and participant recruitment and retention. Robust plans for the implementation research clinical trial and the supporting implementation strategy dissemination package are required for the R33 phase of the application. Upon administrative review by the NHLBI, only meritorious R61 projects that meet the predetermined scientific milestones will be selected to transition to the R33 phase.
Investigators with expertise in T4 clinical trials and hybrid studies for heart, lung, blood, or sleep conditions are expected to be part of the research team. In addition, applications proposing collaborative investigative teams combining expertise in qualitative methods, administration of T4 implementation clinical trials as appropriate at various levels (e.g., individual, clinical practice, facility, etc.), quality improvement, health economics, implementation of skills development programs, and robust experience in the adaptation and implementation of other established EBP will be encouraged. Personnel involved in the proposed strategy, e.g., nurse practitioners, patient, family members, respiratory therapists, pharmacists, hospital intensivists, etc., should be meaningfully engaged in the conceptualization and the planned execution of the proposed project.
Applications proposing to establish a new EBP are not within the scope of this FOA.
November 19, 2019
April 1, 2020
New Date May 1, 2020; July 1, 2020
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
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.
New Date July 2, 2020 per issuance of NOT-HL-20-783. (Original Expiration Date: May 2, 2020)
It is critical that applicants follow the instructions in 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 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.
Despite the development of evidence-based practices (EBPs) for heart, lung, and blood diseases and/or sleep (HLBS) disorders and conditions, the anticipated public health impact of EBPs has not been realized. Efficient, sustained, broad-scale adoption of EBPs have lagged due to insufficient development and testing of actionable and semi-automated strategies for implementing the EBP which reflect pragmatic factors. These include assessment of the readiness of an organization and its personnel to adopt, adapt, and implement EBPs; identification and mitigation of barriers to implementation; workflow assessments; skills development needed to implement an intervention strategy, development of context-specific adaptations based on the community and cultural preferences; and solicitation of meaningful input from diverse personnel impacted by the implementation strategy for the EBP. Through these research projects, an important research gap will be addressed, the identification, testing, and reporting of specific methods and resources included in implementation strategies, in order to promote the systematic uptake of EBPs into routine practice.
Purpose and Objectives
This Funding Opportunity Announcement (FOA) is specifically designed to address the gap in translation by expediting the delivery of evidence-based HLBS interventions and supporting research that employs implementation frameworks to develop and test implementation strategies for EBP that are sustainable beyond the period of external research funding, and which are transferable to other end-use stakeholders. The FOA supports pragmatic milestone-driven, single-site, biphasic, late-stage (T4) translation and implementation research projects which propose to identify and test adaptable implementation strategies that will increase the scale-up and sustainable use of EBPs for preventing and/or managing HLBS disorders. For the purpose of this FOA, late-stage translation and implementation research is defined as research to identify strategies to achieve sustainable uptake of proven-effective interventions into routine clinical, or public health practice and/or community-based settings to improve health. The FOA also supports the development and dissemination of the implementation strategy plan which may include re-usable infrastructure such as national standards for data extraction and interoperability, e.g., NOT-OD-19-122, so that others may adapt the implementation strategy(ies) and replicate sustainable success.
Applications submitted in response to this FOA must meet the NIH definition of a clinical trial (see NOT-OD-15-015). The primary outcome metrics are implementation outcome measures, such as, acceptability, uptake and adoption, implementation costs, affordability analysis, fidelity, penetrance, sustainability, etc.. Clinical outcome measures may be used for baseline assessment of a? need for improvement in delivery of EBP and/or to demonstrate that the EBP has achieved desired improvement in outcomes.
Applicants considering health economic analyses are encouraged to review NOT-OD-16-025 for the NIH policy related to funding health economics research.
Applicants may wish to generate insights on behavioral, financial, and other factors that influence the implementation, adherence, dissemination, and adoption of EBP. Given the importance of understanding the implementation costs of an intervention strategy, applicants are encouraged to collect information on the costs to develop the implementation strategy in the planning (R33) phase and the costs to conduct the implementation strategy in the (R61) phase.
Applicants address the research objectives of both the planning (R33) and implementation (R61) research phases. A key element of this FOA is completion of core milestones. A core milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be performance-based to achieve completion of the trial on time and on budget, and must be established for both the R61 and the R33 phases of the project. Applicants are strongly encouraged to employ project management principles; applications that generate how these management strategies can be configured to assist others in replication of successful implementation strategies are encouraged. Applications that address proactive contingency plans to confront potential delays or disturbances in meeting milestones are strongly encouraged.
The definition of a single-site clinical trial is one in which the protocol is implemented by one investigational site that conducts and coordinates the protocol. While a single-site clinical trial may enroll participants from multiple locations/clinics, all participants will receive an intervention (or specific to this FOA, an implementation strategy) or undergo outcome assessments under the direction and oversight of one research team at one investigational site.
Investigator(s): NHLBI expects that the assembled investigative team will include implementation scientist(s), expertise in biostatistics, clinical trial, mixed-methods, experience in creating and deploying skills-development material needed to deploy the implementation strategy, as well as personnel with appropriate experience to enable development of partnerships with various stakeholders, anticipate challenges, resolve conflicts, and manage roles and responsibilities in a constructive and efficient fashion. If an assessment of cost of the implementation is planned, an expert in health economics should be engaged from the beginning.
Phases of Award
Applications submitted in response to this bi-phasic, milestone-driven FOA must address a planning phase (R61) of up to one year, and an implementation research phase (R33) of up to four years for the clinical trial and development and dissemination of an implementation package.
The R61 phase supports the selection of the EBP and implementation framework(s); assessment of organizational readiness for change;
The R33 phase supports updates to the procedures, documents, execution of, and analyses of the outcomes of the implementation clinical trial. In addition, R33 phase supports the development, refinement, and dissemination of a comprehensive implementation package, which would support sustained use of implementation strategy beyond funding period and/or others' ability to adapt the implementation strategy for their use.
Investigators and NHLBI will mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, prior to award. The overall planned enrollment will be agreed upon between the grantee organization (or recipient) and the NHLBI prior to an award. Enrollment of participants into the implementation strategy clinical trial is expected to begin before the end of the R61 phase to optimize the probability of successfully completing the trial on time and on budget. NHLBI will conduct an administrative review approximately 9 months into the R61 phase to determine if there has been adequate progress toward achievement of milestones included in the Notice of Award to transition to the R33 phase. Milestones and timelines for the R33 phase may be revised and finalized at the time of the R61/R33 transition.
Milestones must address timing of overall recruitment/enrollment and retention goals, including accrual goals for women, minorities, and individuals of all ages including children and older adults. It is expected that performance of core milestones, such as planned enrollment goals, will be shared on a regular basis through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI. Subject to NHLBI funding availability and scientific priorities, R33 awards will be made after administrative review with specific attention to the extent to which all agreed-upon milestones have been met. If the R33 is funded, NHLBI will review the progress of the clinical trial on a regular basis. Slower than anticipated progress towards meeting milestones will result in a re-evaluation of the award by NHLBI including whether the objectives of the trial can be met on time and on budget. If milestones have not been satisfactorily met, subsequent funding years may not be approved and may lead to phasing out of the award.
NHLBI policies regarding milestones and relevant clinical research/studies policies are described in the following: NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies, and NHLBI Data Sharing Policy.
Collaborative investigative teams are encouraged to combine expertise in: implementation research; adaptive trial design for EBP; selecting and providing skills development for successful use of the implementation strategies; administration of late-stage implementation clinical and hybrid trials at appropriate unit of administration (e.g., clinic, shift, person, group, etc.); and, experience in designing sustainable EBP implementation protocols and workflows. It is highly recommended that representatives of each role of personnel impacted by the workflow of the implementation strategy, e.g., nurse practitioner, patient, family members, respiratory therapist, pharmacist, hospital intensivists, data analyst, etc., be consistently engaged in order to provide feedback during the planning, implementation, and refinement phases of the research project.
The following types of Clinical Trials, if proposed, will be considered non-responsive to this FOA
Clinical Trials that propose:
Prior to Submission
Prior to submitting an application to this FOA, applicants are strongly encouraged to participate in the to-be-scheduled Technical Assistance Webinar, confer with the Frequently Asked Questions, as available, and to consult with the Program Officer (PO) for this FOA. Early contact with the PO (at least 10 weeks prior to submission) is encouraged. This period of time provides an opportunity for NHLBI staff to discuss the scope and goals, and to provide information and guidance to the applicants. Applicants w?ill be responsible for recording the completion of milestones through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI. ?
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
The NHLBI intends to commit up to $3,750,000 per year in total costs for new awards in Fiscal Years 2021.
The NHLBI intends to fund up to five new awards in Fiscal Year 2021. The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets may request up to $485,000 direct costs per year in FY 2021 through FY 2025. Investigators are encouraged to request what is well-justified for their research program.
The maximum project period is five years. The scope of the proposed project should determine the project period.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
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.
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.
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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.
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:
The letter of intent should be sent to:
Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Facilities and Other Resources:
Describe how the available infrastructure at the single performance site will be leveraged to facilitate the efficient operation of the proposed implementation clinical trial, including project management tools that will be used.
Other Attachments: The attachments listed below must be completed and attached or the application will not be peer reviewed.
1. Single-site Justification Plan: A Single-site Justification Plan must be provided as an attachment using the filename "Single-site Justification Plan.pdf" and may not exceed 2 pages. This plan should describe how all participants for the trial will be enrolled at a single institution and in the allotted timeline.
2. Trial Management Plan: A description of how the proposed trial will be managed must be provided as an attachment using the filename "Trial Management.pdf" and may not exceed 5 pages. Describe the strategy that will be used throughout the project to ensure that management activities of the clinical trial are met including directly supporting the needs of scientific study leadership to identify barriers, make timely responses to challenges, and optimize the allocation of limited resources to meet pre-defined study objectives. The trial management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks. This plan is expected to include:
In summary, the trial management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time and to successfully manage and mitigate risks.
3. Clinical Trial Research Experience: A detailed table listing the characteristics of trials that demonstrate experience in trial coordination in the last 5 years must be provided as an attachment called "Clinical Trial Research Experience.pdf " and may not exceed 3 pages.
The table columns should include:
Column A: clinical study title
Column B: applicant's role in the study
Column C: a brief description of the study design
Column D: planned enrollment
Column E: actual enrollment
Column F: whether the studies completed on schedule or not
Column G: publication reference(s)
All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. Describe the experience of key scientific personnel in project planning and implementation, including the following:
The experience and authority of each PD/PI and all Key Personnel must be carefully documented. Roles and responsibilities, including coordination of the responsibilities of other project team members, must be well defined. Include biosketches for a multidisciplinary team of appropriate personnel (implementation and dissemination research specialist, clinician(s), skills development expert, data manager, study coordinator(s), personnel responsible for the implementation strategy such as patient navigator, etc.) to facilitate the accomplishment of all aspects of the implementation trial, including recruitment of subjects, design of the implementation strategy, implementation of the trial protocol, development and dissemination of the actionable implementation strategy.
All instructions in the SF424 (R&R) Application Guide must be followed.
While co-funding is not required, given the FOA's emphasis on sustainability of implementation strategy, applicants are encouraged to consider if co-funding in-kind or otherwise, would be desirable and feasible.
Provide detailed, annual budgets that will enable the trial to meet its milestones. In the budget justification, provide the detailed budget needs (per year and total) and an implementation and cost management plan (e.g., capitation).
If partial funding is to be provided by sources other than NHLBI, these contributions should be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Term and Condition of Award. If the Third Party support ceases and the trial is no longer tenable without the Third Party support, a close-out plan may be requested.
Include budget support, if needed, for any personnel to attend steering committee/executive committee meetings.
Budgets should request only the costs that will be required for the activities to be performed in a given year. Generally, the NHLBI expects the requested costs in year 1 to be lower than in the following years, depending on recruitment targets.
If applicable, budgets should include all costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing reports for the DSMB, assessing DSMB member conflict of interest, meeting reimbursement for DSMB members, and support for at least one DSMB meeting per year.
Research Strategy: The research strategy should present an overview of the state of the science for the EBP and the relevance of the implementation trial for the HLBS condition(s) that will be addressed. Include a detailed discussion of the scientific protocol and the ways in which the research sites population shares the researchers' conviction that improvement is needed, as well as how the proposed clinical trial of the implementation strategy for the EBP is expected to generate sustainable improvement in health outcomes. The research strategy is not expected to generate findings which are nationally generalizable, but must demonstrate that there is an appropriate end-use stakeholder population to whom the anticipated findings are applicable and can be disseminated. Applications that include plans to specify and test mechanisms of change, leverage existing data resources, utilize vigorous reporting requirements, foster sustainability, including re-use of information, and provide information to enable others to adapt successful implementation strategies are strongly encouraged. NIH encourages researchers to explore the use of Fast Healthcare Interoperability Resources (FHIR(®)) standard to capture, integrate, and exchange clinical data for research purposes (NOT-OD-19-122).
The following criteria should be addressed:
Describe the proposed implementation research framework(s) (e.g., such as Consolidated Framework for Implementation Research (CFIR); Behavior Change Wheel; Promoting Action on Research Implementation in Health Services (PARiHS); Pragmatic-explanatory continuum indicator summary (PRECIS); Reach Effectiveness Adoption Implementation Maintenance (RE-AIM); PRECEDE-PROCEED, K2A, etc.) and how the framework will be tailored to the study population, the EBP, and the implementation strategy that will be employed. Discuss the validated organizational and other outcome measures that will be used to assess readiness for and impact of the EBP (e.g., acceptability, adoption, appropriateness, feasibility, implementation costs, penetration, and sustainability in the selected context beyond the project period).
Significance: The significance of the need to improve compliance with the EBP at the study site(s) must be clearly stated. Describe evidence supporting the need for and timeliness of the study, with emphasis on how the anticipated results will address an evidence gap and therefore advance science.
A plan for estimating the costs for the adaptation of the strategy and costs for on-going implementation are encouraged. Describe plans for , evaluating the impact of the implementation strategy on clinical outcomes. Include a description of how results will be configured and disseminated to facilitate adaptation of the strategy by other groups and/or sites.
Innovation: The selection of an extant EBP is a pre-requisite of the FOA. Explain how this project is likely to advance dissemination and implementation research to enable sustainable improvement in clinical practice paradigms, and/or otherwise advance the field of late-stage implementation and dissemination research.
Approach: Explain how the elements of the implementation strategy will be selected and prioritized based on theoretical or empirically-derived change mechanisms, workflow, and personnel available. Describe how missing data will be handled and how drivers of uncertainty of estimates will be reported and explained. Explain how the sustainability objective will be integrated into the implementation strategy developed and tested. It is particularly important to provide a discussion of how this research will seek to generate and disseminate findings, including National standards for coding and data integration, which promote re-use and minimize reinvention of the implementation strategy.
Supporting Data: Briefly describe the EBP formative clinical studies (including any pilot/feasibility studies) that provide the basis for the proposed implementation clinical trial. Include other research as appropriate to demonstrate that the chosen approach is justified. If the implementation clinical trial is a hybrid or Phase III trial, include relevant data used to determine that the proposed trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial.
Experimental Approach: Critical features of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information form must include, but are not limited to, the following:
Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound. Milestones must address timing of overall recruitment/enrollment and retention goals. The milestones must address accrual goals for women, minorities, and individuals of all ages including children and older adults.
Describe the milestones that will be met in the R33 phase to address the specific aims, and ensure the successful completion of the clinical trial and dissemination of its results.
Core milestones of particular interest include but are not limited to:
Core R61 Trial Milestones
Core R33 Trial Milestones
Letters of Support: Letters of support which are necessary for the successful conduct of the trial should be provided. If partial funding is to be provided by sources other than NHLBI, provide Letter(s) of Support signed by an authorized organization representative (AOR).
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.
The following modifications also apply:
The following modifications also apply:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Section 2 - Study Population Characteristics
2.2 Eligibility Criteria
If applicable, include the required characteristics of the study sites and the required health status of study participants.
2.5 Recruitment and Retention Plan
The Recruitment and Retention Plan should address: 1) the expertise of the individual(s) responsible for screening, approaching and consenting potential participants; 2) engagement of relevant advocacy groups; 3) the process for identification and screening of study participants; 4) primary and back-up recruitment strategies (e.g., use of electronic health records); 5) participant retention and adherence strategies; 6) possible competition from other trials for study participants; 7) engagement of the clinical community(ies) that will play a critical role in the recruitment and retention; 8) recruitment of groups (e.g., for stepped-wise regression, adaptation trials, or for cluster-randomized trials).
2.7 Study Timeline
Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt Chart) of core milestones and key project management activities. A narrative is not expected in this section.
The study timeline should include core milestones that need to be met throughout the lifecycle of the clinical trial (to include both the R61 and R33 phases) to ensure its success, and the subtasks that will be used to reach the milestones. The period of time for the study duration is expected to be displayed in months and must include, but is not limited to, the following:
(a) when the qualitative and quantitative assessment of barriers, facilitators, preferences and workflow factors has been initially and periodically determined
(b) when the target end-use stakeholders have been identified
(c) when the initial and updated implementation strategies have been determined
(d) when the initial skills development plan has been finalized
(e) when the skills development plan begins
(d) when the study opens to enrollment
(e) when core milestones are met
(f) when subtasks needed to reach the core milestones are achieved
(g) when the analysis of the study data will occur
(h) when the submission of the primary study manuscript for publication is expected
(i) when the dissemination of the implementation strategy is expected
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
Describe the process that will be utilized to identify unanticipated problems and describe procedures for intervention discontinuation and stopping guidelines.
3.5 Overall Structure of the Study Team
Include a description of the following:
Section 4 - Protocol Synopsis
4.1 Brief Summary
Include protocol title.
4.2.a Narrative Study Description
Describe the protocol to be followed in each arm of the trial. Include a brief description of how the investigators will standardize and optimize adherence to the protocol. Specify concomitant interventions, if applicable. Describe the proposed experimental design including a discussion of the rationale for the particular design chosen (pragmatic, stepped-wedge, cluster-randomized, adaptive, etc.).
4.2.c Interventions - Description
Describe the rationale for the choice of the EBP selected and configuration of the implementation research strategy including such specific information as form, duration, and agent of the implementation strategy, and key characteristics of other forms of proposed approaches such as diagnostic tests and behavioral interventions.
4.4 Statistical Design and Power
Provide a justification for the proposed sample size based on appropriate study assumptions. Explain how the outcome(s) will address the hypothesis(es) being tested. Describe plans for interim and final analyses; methods of bias control; and methods for handling missing data (as applicable). The description should be detailed enough to allow replication of the analysis by an independent statistician.
For Phase III clinical trials, include plans for evaluation of the clinical and all primary outcome(s) by race/ethnicity, sex and gender, and include all relevant data to assess whether or not the trial includes adequate numbers for valid analyses of subgroups. In addition, justify adequacy of power to analyze subgroups of participants. Adaptive designs should include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.
Include a description of the approach to data management and validation, including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy; adjudication of events (as needed); and data reports.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?
Specific to this FOA
To what extent has the identification of significant referent end-use stakeholder population been demonstrated at a national or subnational population level?
For the purposes of this FOA, 'intervention' refers to the 'implementation strategy' and 'the safety, efficacy or effectiveness of an intervention (implementation strategy)' refers to 'the affordability, acceptability, and sustainability of the strategy'.
Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
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?
Specific to this FOA
To what extent does the investigative team have experience meaningfully engaging diversified personnel involved in the implementation strategy and demonstrating adeptness to design and test an implementation strategy which reflects the preferences and variation in resources, barriers, cultural context, organizational culture of the research sites and anticipated end-use stakeholders?
To what extent is there strong evidence that an appropriate research team has been identified at the investigational site for the purpose of managing the implementation strategy and conducting clinical outcome assessment, if participants are enrolled from multiple locations/clinic?
With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
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?
Specific to this FOA
To what extent has the research plan adequately addressed the distinctive FOA requirement to design, test, disseminate implementation strategy(ies) findings so that the implementation strategy could be sustained beyond the funded research project period, or replicated elsewhere in a streamlined fashion? To what extent has the application provided a compelling approach to leverage existing resources and promote reuse of critical aspects of the implementation strategy generated to enable others to have streamlined means of adapting the implementation strategy?
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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?
Specific to this FOA
To what extent do the implementation research objectives justify the proposed implementation framework and analytical plan, provide plans for interim and final analyses, provide methods of bias control and handling missing data, and enable characterization of the uncertainty of estimates and the drivers of that uncertainty? To what extent does the application adequately discuss how success will be determined?
If applicable, do the plans for adaptive designs for the implementation strategy include a pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified outcome measures for success?
Does the application adequately address the following, if applicable
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
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?
Specific to this FOA
How adequately does the application describe the physical resources, system functionality (e.g., electronic healthcare record (EHR) ) and clinical and community environments so that these aspects of the implementation strategy can be translatable or adaptable to other settings?
To what extent are adequate plans and resources available to coordinate the clinical trial at a single site?
How strong is the Single-site Justification Plan attachment and how well does it describe how participants for the trial will be enrolled at a single institution and in the allotted timeline? Is there evidence of the ability of the individual center to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Are the listed milestones for each phase appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound?
Data and Safety Monitoring
Is the proposed Data and Safety Monitoring Plan (DSMP) appropriate for the proposed clinical trial? What is the quality of the DSMP to monitor the site and participating facilities?
Is the study timeline described in detail, taking into account planning phase, meaningful engagement of stake holders, the anticipated rate of enrollment, and planned follow-up assessment, the preparation and dissemination of meaningful reporting of the findings? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)
For research that involves human subjects but does not involve one of the 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 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 individuals of all ages (including children and older adults) 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.
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 NHLBI, 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.
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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
Information regarding the disposition of applications is available 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.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety
Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
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.
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.
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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.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.
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.
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Rebecca A. Roper, MS, MPH
National Heart, Lung and Blood Institute (NHLBI)
Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
National Heart Lung and Blood Institute (NHLBI)
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