NIDDK High Risk Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34 Clinical Trial Optional)

NIDDK High Risk Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34 Clinical Trial Optional) is sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at NIH. Funding opportunity for planning cooperative agreements to implement high-risk multi-center clinical studies, potentially including studies related to schistosomiasis.

Expired PAR-25-090: NIDDK High Risk Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34 Clinical Trial Optional) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) Funding Opportunity Title NIDDK High Risk Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34 Clinical Trial Optional) U34 Planning Cooperative Agreement February 19, 2026 Notice of Change: Expiration of PAR-25-090 - NIDDK High Risk Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34 Clinical Trial Optional).

See Notice NOT-DK-26-102 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

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

Assistance Listing Number(s) Funding Opportunity Purpose NIDDK supports investigator-initiated, high-risk multi-center (more than one center) clinical studies through a two-part process that may include an implementation planning cooperative agreement (U34).

The U34 is designed to: 1) Permit early peer review of the rationale for the proposed clinical study; 2) Permit assessment of the design and protocol of the proposed study; 3) Provide support for the development of documents needed for the conduct of the study, including a manual of operations; and 4) Support the development of other essential elements required for the conduct of the clinical study.

The proposed clinical study should be hypothesis-driven and focus on a disease in the mission of NIDDK. Consultation with NIDDK scientific staff is strongly encouraged prior to the submission of the U34 application. 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. New Date February 19, 2026 per issuance of NOT-DK-26-102 .

(Original Expiration Date: June 11, 2027 ) 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.

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 NIDDK supports investigator-initiated, high-risk multi-center (more than one center) clinical studies through a two-part process that may include an implementation planning cooperative agreement (U34).

The U34 is designed to: 1) Permit early peer review of the rationale for the proposed clinical study; 2) Permit assessment of the design and protocol of the proposed study; 3) Provide support for the development of documents needed for the conduct of the study, including a manual of operations; and 4) Support the development of other essential elements required for the conduct of the clinical study.

The proposed clinical study should be hypothesis-driven and focus on a disease in the mission of NIDDK. Consultation with NIDDK scientific staff is strongly encouraged prior to the submission of the U34 application. As explained in NOT-DK-20-051 , the risk level of a study may be related to interventional and/or operational risk.

The examples below provide general guidelines for risk assessment and are not exhaustive. Potential applicants are strongly encouraged to contact NIDDK staff to discuss their proposed study and determine the most appropriate mechanism for submitting their application.

Examples of high-risk interventions include: An intervention that has an unknown safety profile or has substantial side effects (including all studies requiring an IND/IDE application).

This would include studies of a drug in a new population, or study of a licensed product for an unapproved indication; A complex or invasive intervention, including diagnostic procedures; A study involving complex assessment of multiple outcomes, including the ascertainment of outcomes using invasive research procedures; Pragmatic trials proposing significant changes to standard of care practices, or significant coordination with multiple care providers and healthcare data systems; A multi-center study involving more than minimal risk in vulnerable study populations (as defined in 45 CFR 46).

Studies that do not meet the above criteria will generally be considered to involve low-risk interventions. Low-risk multi-center studies usually include the administration/use of a licensed product for an approved indication, or the provision of a routine intervention that could be used in the setting in which it is being studied (e.g., a lifestyle intervention to promote weight loss).

Examples of multi-center studies with high operational risk include: An inexperienced investigator, defined by lack of experience in conducting clinical trials, coordinating research across multiple centers, or recruiting the population to be studied; A complex study design that involves standardization of research measures and outcomes collection and research data capture over multiple centers; A study that involves the establishment of agreements with third parties that intend to utilize research study data to support regulatory filings with the FDA.

Multi-center studies that do not meet the above criteria will generally be considered to have low operational risk. A multi-center study is classified as “high risk” if it utilizes either a high-risk intervention or has high operational risk, or both. Extensive administrative planning (e.g., manual of operations development) is required before participant recruitment can occur in a multi-center clinical study.

Investigators considering submission of an investigator-initiated research grant application for a high-risk multi-center clinical study will generally not have the resources to complete this rigorous planning and documentation process without support from NIDDK.

NIDDK believes that a two-part cooperative agreement process that separates administrative implementation from participant recruitment and study conduct will remedy these issues.

Therefore, NIDDK will support investigator-initiated, high-risk multi-center clinical studies being conducted at more than one center through a two-part process:1) An implementation planning phase, followed by 2) A multi-center cooperative agreement (U01) to conduct the study.

This NOFO PAR-25-090 , NIDDK Multi-Center Clinical Study Implementation Planning Cooperative Agreements (U34), addresses a U34 application to support the planning phase; companion NOFOs (for clinical trials PA-25-147 and for observational studies PAR-25-089 ) address the second part of the application process. NOT-DK-20-051 Discusses the process and explains high-risk versus low-risk studies.

The U34 is a cooperative agreement award mechanism, with the NIH staff being substantially involved as a partner with the Principal Investigator/Program Director. The U34 is designed to provide early peer review of the rationale and design of the proposed clinical study and to support all administrative study group activities that are required in order to begin recruitment of participants.

These activities include, but are not limited to: establishing the research team, developing the tools for data management and oversight of the research, defining the recruitment strategies, finalizing the protocol and investigators brochure, writing the Manual of Operations, establishing a data and safety monitoring plan, and initiating the IRB approval process.

The U34 is not designed for the collection of preliminary data, for the conduct of pilot studies to support the rationale for a clinical study, or for the design of the study. The U34 application will include the proposed study design and the protocol. NIDDK has an expectation that recruitment for clinical trials and studies will reflect the population in the U.S. that is at risk for/has the disease or condition being studied.

NIDDK is committed to conducting clinical studies that have been developed in partnership with patients, community members, families, healthcare providers, organizations, and other relevant partners who are affected by or have a direct interest in the research.

Active and meaningful engagement should involve these individuals and/or organizations in the development, design, and execution of the study, as well as in dissemination of findings. Meaningful engagement must entail more than focus groups, surveys or other activities where people are only involved as participants or respondents.

Rather, engagement approaches must involve bidirectional and sustained communication and interactions that result in informed decision-making about high-priority research needs and issues that are important to affected individuals, community members, and/or organizations, especially populations who disproportionately experience NIDDK mission diseases.

Engagement activities that bring to bear the expertise and lived experience of affected individuals and communities may yield interventional, recruitment and retention approaches that are more likely to be acceptable and effective.

Engagement that involves trust building and appropriate research approaches (i.e., identifying the health problem, design, and materials) is an important method to enhance and assess research outcomes including recruitment and retention goals, specific health outcomes, and sustainability of efficacious interventions.

Ideally, affected individuals, groups, and organizations are not only engaged, but integrated into the research team which includes appropriate orientation and on boarding support to the team, and compensation. This NOFO will only support research within the mission of NIDDK.

Research applications in areas that are primarily within the missions of other NIH Institutes and Centers are not appropriate for this NOFO and will not be supported. NIDDK has many diseases within its mission , but all research related to relevant diseases may not be appropriate for NIDDK.

Applicants to this NOFO are strongly encouraged to contact NIDDK staff as soon as possible in the development of the application, and at least 12 weeks prior to the target submission deadline, so that NIDDK staff can help the applicant understand whether the proposed clinical study is within the goals and mission of the Institute and is appropriate for this NOFO.

You should contact the Program Director responsible for your area of research . If you are not certain whom to contact, you should reach out to the Program Director representing the appropriate scientific division, listed in Section VII (Agency Contacts), and you will be directed to the correct Program Director.

For the purpose of this NOFO, a clinical research center may encompass one or more physical locations where the clinical study is being conducted -- i.e., where study participants are recruited, and/or are intervened upon and/or have outcomes assessed under a single protocol – as long as all locations are under the overall direction of a single investigator. A data coordinating center is not considered a clinical research center.

The activities required in the U34 will depend on the type of study (e.g., epidemiologic study, drug/device/biologics trial, behavior intervention).

Because the purpose of the U34 is primarily for the conduct of administrative tasks needed to prepare for participant recruitment, activities involving human subjects will generally not be conducted during the U34 phase; however, brief activities involving interactions with individuals similar to those expected to participate in the full study during the U01 award may be allowed in order to aid in development of study procedures or operations (e.g., assessing usability of a form, device calibration, workflow optimization).

As noted above, the U34 period may also include engagement activities. Activities supported by the U34 include, but are not limited to: Finalize the study protocol. Develop consent form(s) and, if applicable, assent form(s).

Develop an investigators brochure or equivalent. Develop a manual of operations including details, validation, and quality control for any non-standard clinical or laboratory/mechanistic testing which will be performed. Develop the data monitoring and management plan.

Develop a plan for the acquisition and administration of study agent(s) or device(s). Obtain required Office of Human Research Protections assurances if not already in place. Develop a complete set of suitable documents for submission to the appropriate regulatory authorities.

Develop a safety oversight plan. During the U34 award, NIDDK may appoint a Data and Safety Monitoring Board (DSMB) for clinical trials or an Observational Study Monitoring Board (OSMB) for epidemiological studies. Finalize a detailed budget for conduct and completion of the clinical study, including funding for preparation of a final study report.

Identify clinical study site(s) and laboratory/service cores. Develop training materials and training/certification plans for study staff. Initiate the single IRB approval and site reliance agreement process.

Satisfy all regulatory elements of the Food and Drug Administration if an IND/IDE application is needed for implementation of the research plan. Negotiate agreements with industry, as needed, to provide drugs, devices, or other resources. Negotiate other agreements (e.g., DUA, MTA) that are needed to conduct the study and collect participant data.

Hold discussions regarding archiving of data, samples and other project-generated resources in the NIDDK Central Repository or other NIDDK-approved repository. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The investigator(s) should be prepared to transfer data and samples to the Repository.

This NOFO is not designed for the collection of preliminary data to support the rationale for or the design of the proposed clinical study. The application must include the proposed study design and a full protocol. The overall goal of the U34 funding period is to complete all administrative tasks required before recruitment of participants can begin.

In the event of an award, the NIDDK and the PD/PI will agree on a list of milestones to be completed during the U34 project period. Successful completion of the U34 will generally result in an application to conduct the clinical study.

It is expected that receipt of a U34 will lead to the timely submission of a U01 application for support of the full-scale study, incorporating the elements developed under the planning cooperative agreement. During the U34 award, NIDDK may appoint an external monitoring board to review the study design and make recommendations to NIDDK concerning the proposed study, including the study design.

Discussions about whether the study should be conducted will include consideration of the following factors: attainment of pre-specified milestones, the external board recommendations, scientific landscape, study costs, opportunity cost, and availability of funds. Award of a U34 does not guarantee acceptance or funding of a U01 application.

Further information regarding the U34/U01 process supported by these companion NOFOs, including a set of frequently asked questions (FAQs) can be found at: https://www. niddk. nih.

gov/research-funding/human-subjects-research . Applications Not Responsive to the NOFO Research applications in areas that are primarily within the missions of other NIH Institutes and Centers are not responsive to this NOFO. Further information about the NIDDK mission, including areas not covered by NIDDK, is available here .

Low-risk clinical study applications (see NOT-DK-20-051 ) are not responsive to this NOFO. Low-risk clinical trial applications may be submitted to PA-25-305 or PA-25-303 . Applications for low-risk observational studies may be submitted to the PA-25-301 .

Applications involving animal or in vitro studies are not responsive to this NOFO. Recruitment of participants exclusively from foreign sites is not allowed under this NOFO. Foreign components may provide scientific input (e.g., special data analyses or laboratory assays).

Non-responsive applications will not be reviewed and will be withdrawn from consideration. Applicants are reminded of the NIH policy on the use of a single Institutional Review Board for multi-site research ( https://grants. nih.

gov/grants/guide/notice-files/NOT-OD-17-076. html ), as well as the NIH policy on the registration and reporting of the results of clinical trials ( http://grants. nih.

gov/grants/guide/notice-files/NOT-OD-16-149. html ). Applicants are also encouraged to review NIDDK policies for clinical research and cooperative agreements here: https://www.

niddk. nih. gov/research-funding/human-subjects-research/policies-clinical-researchers.

Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions : Investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator.

Such studies may propose a parallel group- or cluster-randomized trial, an individually randomized group-treatment trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions.

Additional information is available at https://researchmethodsresources. nih. gov/ .

See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement for this NOFO. Application Types Allowed Resubmission - from PAR-24-094 and this NOFO.

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. Optional: Accepting applications that either propose or do not 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. Budgets for direct costs of up to $225,000 per year are allowed.

The funds requested are expected to vary based on the number of clinical centers involved in the study and the complexity of the study. The maximum project period is 2 years. 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 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) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. 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. 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. 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.

Milestone Plan: The filename "Milestone Plan. pdf" must be used for this attachment. Applicants are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed clinical trial(s), as applicable.

Milestones should be easily measurable and realistic. Below is a list of potentially useful milestones; please tailor this list to each of your clinical trial/study aims and provide approximate dates or project year and quarters (e.g., Yr01/Q1, Yr01/Q2, Yr01/Q3, etc.) when each will be conducted/completed: Completion of all required regulatory approvals (e.g., IND/IDE from the FDA or agencies in other countries).

Finalize contracts/third party agreements. Finalize clinical protocol(s). Finalize recruitment materials, surveys and data collection tools.

Finalize data entry forms/system. Finalize training manuals and manuals of operations. Good Clinical Practice (GCP) and other relevant technical training of study staff.

Training of staff on study protocol and procedures. Registration of clinical trial in ClinicalTrials. gov. Enrollment of the first participant Enrollment of 25% of the target sample size Enrollment of 50% of the target sample size Enrollment of 75% of the target sample size Enrollment of 100% of the target sample size Posting of consent forms on ClinicalTrials.

gov. Completion of intervention (i.e., date of last intervention visit). Completion of data collection (i.e., date of last study visit). Completion of primary endpoint and secondary endpoint data analyses.

Completion of primary outcome paper. Closeout plans/communication of results to participants. Reporting of results in ClinicalTrials.

gov. These milestones will be negotiated at the time of the award, as appropriate. Future year support is contingent on satisfactory achievement of performance milestones. If milestones are not achieved fully, NIDDK may request development of a remedial plan and more frequent monitoring of progress, or take other remedial actions.

The Milestone plan is a separate document from the Study Timeline. Applications that lack the Milestone Plan are considered incomplete and will not be peer reviewed. Organization Plan: The filename "Organization Plan.

pdf" should be used. The application must describe how the study will be organized and managed, both for the planning period and for the full study. This should include information on the leadership of the study, the proposed clinical sites and the ability of the PD/PI to bring together the necessary study network.

Describe the process for identification and selection of additional collaborators that will be added during the U34 period, if applicable. The PD/PI should discuss in detail whether he/she, as well as other key members of the team, have experience in the conduct and administration of complex studies, including delineation of the success of those studies in terms of recruitment, retention and publications.

Provide a description of the study organization and administration, including, but not limited to: a description of committee structures needed to manage the complexity of the study, including plans to assure fidelity to the protocol and integrity of the data; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed.

If an advisory committee is planned, applicants should not contact or name potential advisory committee members. A succession plan should be included to address a circumstance in which the PI/PD or one of the MPI are no longer available. Applications that lack the Organization Plan are considered incomplete and will not be peer reviewed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. 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: Specific Aims : This section must delineate the aims for both the U34 planning period and for the full study. The primary and major secondary endpoints for the proposed full study should be specified.

Research Strategy : This section must address both the planning period and the full study. The investigator must describe how the planning period will be used and what activities will be conducted.

The applicant must clearly articulate the significance of the proposed study including why the clinical study is needed and what evidence gap the study will address, including a discussion of how the results will impact clinical care or public health. Preliminary data addressing the need for and supporting the feasibility of the study must be discussed.

The discussion of supporting data that provide the basis for the study's design must address the adequacy and quality of previous studies. The application must include a detailed description for the study design, addressing the scientific rationale for the design chosen, the population to be studied and the outcomes being assessed.

Sufficient details of the study design must be provided to permit assessment of the scientific importance of the study, the validity of the design and the feasibility of the study. Critical elements include overall design, primary objective, inclusion and exclusion criteria, proposed study population, and sample size. The primary endpoint and key secondary outcomes should be delineated.

The proposed timeline for recruitment, follow-up and study close-out should be documented. The statistical methods, including the assumptions made for power calculations for the full study, must be described. The sample size and statistical power calculations must contain enough detail so that a reviewer can readily duplicate the analysis.

The power analysis should include a discussion of the anticipated level of adherence to the intervention, if applicable, and rates of follow-up