Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required)

Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required) is sponsored by National Heart, Lung, and Blood Institute (NHLBI), NIH. Supports investigator-initiated single-site clinical trials in areas relevant to cardiovascular sciences.

PAR-27-011: Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required) Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Heart, Lung, and Blood Institute ( NHLBI ) Funding Opportunity Title Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required) R61 / R33 Exploratory/Developmental Phased Award Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) 93. 837, 93. 838, 93.

233, 93. 840, 93. 839 Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) supports applications to develop and conduct investigator-initiated single site clinical trials including efficacy, comparative effectiveness, pragmatic and/or dissemination and implementation science clinical trials.

Trials using innovative designs such as platform trials, adaptive, and Bayesian designs are encouraged. These trials may include ones that test different therapeutic, behavioral, dissemination and implementation science clinical trials and/or prevention strategies. Trials for which this NOFO applies must be relevant to the research mission of the NHLBI and meet the NIH definition of a clinical trial (see NOT-OD-15-015 ).

For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website . This NOFO will utilize a bi-phasic, milestone-driven mechanism of award. The objective of the application is to present the scientific rationale for the clinical trial and a comprehensive scientific and operational plan that describes it.

The application should address project management, participant recruitment and retention, performance milestones, scientific conduct of the trial, and dissemination of results. The multiple PD/PI model is strongly encouraged but not required. Applicants are encouraged to include a PD/PI with expertise in biostatistics, clinical trial design, and coordination.

The application should also describe its approaches to increase community engagement from conceptual design of the intervention through implementation and sustainability, close gaps in health outcomes within the US population, and increase health for all.

Funding Opportunity Goal(s) The Division of Cardiovascular Sciences supports research and training to foster heart and vascular research in the basic, translational, clinical and population sciences, and to foster training to build talented young investigators in these areas, funded through competitive research training grants.

The Division of Lung Diseases supports research and research training on the causes, diagnosis, prevention, and treatment of lung diseases and sleep disorders.

The Division of Blood Diseases and Resources supports and research and training to foster research and research training on the pathophysiology, diagnosis, treatment, and prevention of non-neoplastic blood diseases, including anemias, sickle cell disease, thalassemia; biology of red blood cells, white blood cells, and platelets, hematopoietic stem cells and the bone marrow niche, hemophilia and other abnormalities of hemostasis and thrombosis.

The Center for Translation Research and Implementation Science (CTRIS) plans, fosters, and supports late-stage research to identify promising approaches for ensuring successful integration of evidence and evidence-based interventions within clinical and public health settings, such as health centers, worksites, schools, and communities in the United States and abroad.

The National Center on Sleep Disorders Research (NCSDR) supports research and research training related to sleep disordered breathing, and the fundamental functions of sleep and circadian rhythms. Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due 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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Use Grants. gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of 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 Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description This NOFO supports applications to develop and conduct investigator-initiated single-site clinical trials. Clinical trials supported by this NOFO include Phase II and above clinical trials.

This NOFO is applicable to single-site clinical trials only, and will utilize a bi-phasic (R61/R33), milestone-driven mechanism consisting of a start-up phase of up to one year (R61), and a full enrollment and clinical trial execution phase of up to four years (R33). Proposed research may utilize a design anywhere along the continuum of efficacy, effectiveness, pragmatic and/or dissemination and implementation research clinical trials.

For this NOFO, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while efficacy trials do so under more idealized circumstances. Implementation trials test strategies to adopt and integrate evidence-based health interventions and change practice patterns within specific settings.

These implementation trials can include hybrid implementation/effectiveness studies. Innovative trial designs such as adaptive and Bayesian designs will be considered. The trial design should be appropriate for the study question.

Trials for which this NOFO applies are expected to contribute to the evidence base for important health matters of relevance to the research mission of NHLBI, close gaps in health outcomes within the US population, and increase health for all. For additional information about the mission, strategic vision, and research priorities of the NHLBI, applicants are encouraged to consult the NHLBI website .

A key characteristic of this NOFO 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 R33 phases of the project.

These clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. Applicants are strongly encouraged to employ project management principles as appropriate. Applications that address contingency plans to proactively confront potential delays or disturbances in meeting the 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 within a geographic area, those participants will receive an intervention or undergo outcome assessments under the direction and oversight of one research team at one investigational site.

The R61 phase will support finalization of the protocol and the informed consent/assent document; the development of the manual of operations and procedures, case report forms and other resources necessary to the performance of the trial; further development of study partnerships; establishment of a Data and Safety Monitoring Board (DSMB) and review and approval of the protocol by the DSMB; and Institutional Review Board approval of the trial.

For trials using an FDA regulated product and requiring an IND or IDE application to administer the product to humans, investigators must (1) secure IND authorization or IDE approval and (2) provide documentation of this authorization or approval to NHLBI before a funding decision will be made.

Necessary drugs, devices, or other resources must be obtained by the end of the R61 award to allow for the successful launch and execution of the proposed clinical trial in the R33 phase. Investigators and NHLBI will review and mutually agree upon final revised milestones that will be included in the Terms and Conditions of the grant, if awarded.

Transition from the R61 to the R33 phase is predicated on the successful completion of all milestones proposed and peer-review for the R61 phase of the application. The core milestones must be met during the R61 phase to allow for successful launch of the full trial in the R33 phase. The overall planned enrollment will be agreed upon between the recipient and the NHLBI prior to an award.

Enrollment of participants into the 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 progress toward achievement of milestones included in the Notice of Award.

Milestones and timelines for the R33 phase may be revised and finalized at the time of the R61/R33 transition. Less than satisfactory progress in the R33 phase may lead to closing out the award. R33 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 facilitates 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 R61 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 closing out 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 Supplement to the NIH Policy for Data Management and Sharing .

This NOFO encourages investigators experienced in the conduct of clinical research to apply. Early Stage Investigators with clinical research experience are strongly encouraged to apply, provided they will receive scientific support from senior investigators (e.g., as Co-Investigators).

Clinical Trials Not Supported by and Non-Responsive to this NOFO The following types of clinical trials are not intended to be supported by this NOFO and will be considered non-responsive: Phase I (first-in-human) trials Observational studies that do not meet the NIH definition of a clinical trial (see NOT-HL-18-611 ) Drug or device safety trials Mechanistic or Basic Experimental Studies in Humans (BESH) ( NOT-HL-19-690 ) Prior to submitting to this NOFO, all applicants are strongly encouraged to consult with the Scientific/Research contacts for the area of science for which they are planning to develop an application.

Early contact (at least 12 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. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Required: Only accepting applications that propose clinical trial(s). Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the requested project award period. The maximum project period of the combined R61 and R33 phases is 5 years, with up to 1 year for the R61 phase and up to 4 years for the R33 phase.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions - Includes all types Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) Foreign Organizations/International Collaborations Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts.

All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. This new requirement was effective, May 1, 2025. Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding.

This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components , funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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.

Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2. 3. 9.

2 Electronically Submitted Applications for additional information. System for Award Management (SAM) – 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. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.

gov registration process. The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.

gov registrations; all registrations must be in place by time of submission. 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 SAM registration in order to complete the Grants. gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account.

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

Eligible Individuals (Program Director/Principal Investigator) 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 their organization to develop an application for 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 How to Apply-Application Guide. ESI applicants can be the PI/PD of an application providing they can show support of senior investigators (e.g., Co-I, Multi-PI (MPI)) with appropriate clinical trials experience.

ESIs are strongly encouraged to be part of the study team and they should be budgeted for support at a level appropriate for the role on the project. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package 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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice , or other notice from NIH Guide for Grants and Contracts ). 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

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 clinical trial, including project management tools that will be used. If applicable, discuss any community participatory agreements and/or stakeholder agreements to support the protocol.

Other Attachments: The following attachments marked as “Required" must be provided, or the application will not proceed to peer-review: 1. Single-site Justification Plan (Required): 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 (Required): 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 performed, including directly supporting the needs of scientific study leadership to identify barriers, making timely responses, and optimizing the allocation of limited resources to meet pre-defined study objectives.

This description should include: A description of the project management team and levels of effort. A risk assessment and management plan that addresses contingencies in the event that there is inadequate progress toward achieving the R61 and/or R33 core milestones. The plan should identify a range of contingencies that could threaten study progress or feasibility, and propose solutions using study resources.

Key methodology and standard operating procedures governing resource management, study deployment, operations/execution, and study closure. How the clinical trial management team will resolve fiscal and logistical issues in a timely manner including plans to proactively evaluate and prioritize study risks and issue corrective responses.

Processes required for orderly project closure including how the study will comply with the NIH Data Management and Sharing Policy, and biorepository plans if specimens will be stored after planned study testing and analyses are complete.

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 Research Experience (CRE) (Required): The following attachment must be provided, or the application will not proceed to peer-review.

Applicants must provide a detailed table listing the characteristics of clinical studies that demonstrate relevant experience in clinical research coordination. The table must be provided as an attachment called "Clinical 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) 4.

Community-Engagement Plan (CEP) (Required): A description of how the proposed trial addresses the quality and consistency of community engagement from conceptual design of the intervention through implementation and sustainability (as applicable) must be provided as an attachment using the filename "Community-Engagement Plan. pdf" and may not exceed 1 page .

An approach that emphasizes collaboration with community partners, leaders, and knowledge holders, leveraging community resources and local service delivery and/or settings to address the needs of multiple interested collaborators is encouraged. Additionally, approaches based on models and or principles such as those used in conducting Community-Based Participatory Research (CBPR) are encouraged whenever feasible and appropriate.

Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, under-resourced, community-based) is strongly encouraged. As appropriate, plans may include a Community and Scientific Advisory Board that targets community representation and scientists not directly involved in the project.

Describe how the efforts discussed in the CEP are expected to meaningfully contribute to innovation. Consideration of how members of the community advisory board and scientific board will be recruited, retained, engaged in and acknowledged is encouraged. SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed.

All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether they are budgeted. Describe the experience of key scientific personnel in the conduct of clinical trial coordination and management, including success in meeting milestones and timelines, expertise in the content area of the proposed clinical trial, and expertise in biostatistics and clinical trial design.

The experience of each PD/PI and all Key Personnel must be carefully documented and roles and responsibilities must be well-defined. In addition, the respective responsibilities and authority of each PD/PI must be specified.

Include biosketches for a multidisciplinary team of appropriate personnel (clinician, statistician, data manager, study coordinator(s), etc.) to facilitate the implementation of all aspects of the clinical trial, including recruitment of subjects, design/implementation of the trial protocol, and coordination of roles/responsibilities.

Describe the expertise of the project manager and other significant contributors to the project relevant to successful execution of the trial. All instructions in the How to Apply- Application Guide must be followed. 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). Include costs associated with community engagement activities (e.g., community advisory board(s), infrastructure needs), as applicable. 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. All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions: Research Strategy: The Research Strategy should present an overview of the state of the science and relevance of the trial, a detailed discussion of the specific protocol, and the approach to data collection, analysis, and dissemination.

In the overview, address the study research objectives and the overall conduct of the clinical trial, including the prioritization of this proposed clinical trial in the context of other overlapping clinical research. The following criteria should be addressed: Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated.

It is particularly important to provide a discussion of the evidence supporting equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance science. Include a description of how results will impact health or clinical care.

A discussion of the risk, cost, and benefits of the study should be included for evaluation of the trial's significance. Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms. Approach: The research approach section should include detailed descriptions of the supporting data and the experimental approach.

Supporting Data: Describe the formative clinical studies (including any pilot/feasibility studies) that provide the basis for the proposed clinical trial. Include other research as appropriate to demonstrate that the chosen approach chosen is justified.

If the clinical trial is Phase III, 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: Include critical features of conducting the clinical trial that are not already submitted as part of the PHS Human Subjects and Clinical Trials Information Form .

Applications must include, but are not limited to, the following experimental approach items: A detailed description and rationale for the research hypothesis(es) The rationale for the specific design chosen (e.g., pragmatic, explanatory, cluster-randomized) Evidence supporting that: 1) equipoise exists between the arms of the trial; and 2) the intervention(s) or control arms tested are not know to be inferior to the range of practice (or usual care) at the site, in the community, and described in relevant standards of care A detailed rationale explaining why the proposed study population is the most appropriate group to answer the research question(s) Justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions.

Use of patient reported outcomes as well as other or non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) Plans to implement the laboratory evaluations (as appropriate) and monitor Good Clinical Practices (GCP) (see NOT-OD-16-148 ) A description of Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate A discussion of major challenges in implementing the study and how they will be addressed A discussion of event rates and contingency plans if the effect size or event rate is underestimated 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