U34 Frequently Asked Questions

NIDDK will support investigator-initiated, high-risk, multi-center clinical studies through a two-part process: (1) an optional implementation planning cooperative agreement (U34) followed by (2) a cooperative agreement (U01) to conduct the study.

This policy applies to all high-risk clinical studies, interventional trials, as well as observational studies, conducted at more than one center.

A multi-center study is one which is conducted at more than one center. 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 study will not be considered to involve multiple centers if participant recruitment occurs at more than one site in a geographic area, but all interventions and/or outcomes assessments are performed by a single study team. A data coordinating center is not considered a clinical research center.

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.

Low-risk clinical trials within the mission of NIDDK may use the parent NIH NOFOs for clinical trials (PA-20-183 or PA-20-184, or other appropriate NOFOs from NIDDK.

Low-risk observational studies or other types of human subjects research that is not a clinical trial may use PA-20-185 or specific NOFOs from NIDDK.

Clinical studies require extensive administrative planning (e.g., protocol finalization, manual of operations development, case report form design, data management and study oversight, etc.) before participant recruitment may begin. These activities require significant resources and personnel; thus, the administrative planning process typically begins after the study has been peer-reviewed and funded, using valuable time that is needed for the actual conduct of the study. The U34 will provide sufficient time and funds to complete detailed clinical study activities/documents necessary to comply with NIDDK standards and regulatory requirements. This will allow participant recruitment to begin once the U01 is awarded.

After successfully completing the administrative implementation activities of the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement, investigators can apply for a U01 Multi-Center Clinical Study Cooperative Agreement and request up to 5 years to conduct the clinical study.

No. The U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement mechanism is designed to support the planning activities of all types of multi-center clinical studies including epidemiologic studies, observational studies, and interventional clinical trials.

Study-related activities conducted during the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement will depend on the type of clinical study (e.g., epidemiologic study, drug trial, behavior intervention). The U34 may support activities such as, but not limited to, the development/completion of the following items:

• Final study protocol. Please note that a proposed protocol must be included in the U34 application, as an appendix. The U34 period may be used to modify and/or finalize the protocol, if necessary, based on comments received during the review process, logistical issues or new scientific progress during the U34 period

• Informed consent form(s) and, if applicable, assent form(s)

• Investigator’s brochure or equivalent

• Manual of operations including details, validation, and quality control for any non-standard clinical or laboratory/mechanistic testing which will be performed

• Data monitoring and management plan

• A plan for the acquisition and administration of study agent(s) or device(s)

• Required Office of Human Research Protections assurances if not already in place

• Complete set of suitable documents for submission to the appropriate regulatory authorities

• Safety oversight plan

• Detailed budget for conduct and completion of the clinical trial including funding for preparation of a final study report

• Identification of clinical study site(s)

• Training materials and training/certification plans for study staff

• Initial IRB approval

• Applicable regulatory elements of the Food and Drug Administration if an IND/IDE is needed for implementation of the research plan

• Agreements with industry, as needed, to provide drugs, devices, or other resources

• In the event of an award, the NIDDK and the Principal Investigator will agree on a list of milestones to be completed during the U34 project period

No, the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement 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 must include the study protocol. The proposed study design and protocol will be key elements in the peer-review of all U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement applications.

For clinical trials, NIDDK supports pilot and feasibility trials through PAS-23-086.

No. The U34 Multi-Center Clinical Study Implementation Planning Cooperative agreement is not designed for this purpose. The U34 application must include details of the proposed study design and a proposed protocol, which will be critically evaluated during the peer-review process.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. The total project period for an application submitted in response to the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement funding opportunity may not exceed two years. Applicants may request up to $225,000 in direct costs per year (excluding consortium Facilities and Administrative [F&A] costs). The funds requested are expected to vary based on the number of clinical sites involved in the study and the complexity of the study.

No. U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement applications are not required to request two years of funding. Applicants may request less than 2 years of funding if, in the applicant’s judgment, the planning process will require less than 2 years of funding support.

No. Renewal applications will not be accepted for the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement. The U34 mechanism will provide up to a maximum of 2 years of funding to support the planning activities required of new projects.

The U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under Section VI. 2. Administrative Requirements, Cooperative Agreement Terms and Conditions of Award in PAR-24-094.

Contact the appropriate NIDDK Program Director to discuss the proposed application for a U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement and do so as soon as possible, preferably at least 12 weeks before the submission date. Program staff will help the investigator understand whether the proposed full clinical study addresses a high priority research area and meets programmatic needs including balance across research areas, whether it is appropriate to conduct using this mechanism, and whether funds might be available for the subsequent, full clinical study. See the Research Programs & Contacts to identify the correct program director for your application. If you are not sure of the appropriate program director, contact one of the program directors in the PAR (PAR-24-094) and you will be directed to the appropriate individual.

Contact the appropriate Program Director at least 12 weeks before the desired receipt date. Since this is a cooperative agreement, NIDDK will ultimately have substantive scientific involvement with the proposed project. NIDDK will need sufficient time to thoroughly consider the proposed study. It is the Institute’s experience that applications for multi-center clinical studies may be scientifically meritorious but often need further work before they are ready for submission. Allowing as much time as possible for the consultation process will allow time for revisions, should they need to be made.

The details included in your letter may vary depending on the type of study planned (e.g., epidemiology study, drug trial, behavior intervention). Generally, the letter should include all of the following items:

• Date of Proposed Submission

• Study title

• Study PI (including biosketch)

• Primary institution

• Specific Aims

• Significance

• Summary of study protocol, including flow diagram depicting study

• Summary of safety/risk issues

• Proposed start date, duration, and timeline of the clinical trial or clinical study

• Estimated sample size including brief power calculation

• General statistical assumptions for the proposed study design and analysis

• Potential collaborating sites, including the demographics and availability of the study population at those sites. Include identification and a brief description of the Data Coordinating Center

• Discussion of product/intervention to be evaluated and how it will be obtained, if applicable, including industry partner(s) and regulatory issues that have/need to be resolved

• Total cost for the U34 phase

• Total cost estimate of the clinical study, not the planning grant, by year

• Milestones to be accomplished during the U34

You should contact the appropriate program director for the subject matter of the application. See the Research Programs & Contacts to identify the correct program director for your application.  If you are not sure of the appropriate program director, you can contact one of the program directors designated as contacts for information in the PAR and you will be directed to the appropriate individual (PAR-24-094).

A U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement is not required by NIDDK before a multi-center clinical study is funded by a U01 mechanism. If you believe you have accomplished all the necessary planning required to conduct the clinical study, you may apply for the U01. However, the U01 application requires that you document that all necessary planning has been completed before you submit the U01 application. The recruitment of participants should be ready to begin as soon as a U01 award is made. No planning activities are allowed under the U01.

No. Prospective applicants should note that obtaining a U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement award does not guarantee or imply funding for a subsequent U01 Multi-Center Clinical Study Cooperative Agreement application. If the planning phase is not successful, the NIDDK may decide not to allow a U01 Multi-Center Clinical Study Cooperative Agreement application. All U01 Multi-Center Clinical Study Cooperative Agreement applications will be peer-reviewed, and NIDDK will consider the results of the peer-review process when deciding whether to support the U01 Multi-Center Clinical Study Cooperative Agreement. Applicants should also remember that NIH requires that pre-approval be obtained for all applications requesting $500,000 or greater in direct costs (excluding consortium F&A) in any year.

U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement applications will be peer reviewed by special emphasis panels set up by the NIDDK Review Branch. Specific review criteria used to evaluate U34 applications can be found in PAR-24-094.

October 9, 2024, June 10, 2025, February 11, 2026, October 8, 2026, and  June 10, 2027

NIDDK will only support the planning phase of a multi-center clinical study if the proposed clinical study is worthy of support. Therefore, the review of the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement will include the rationale and design of the proposed clinical study, as well as a proposed protocol. If the clinical study is not significant, innovative and/or likely to answer the proposed research question, NIDDK may decide that the proposed clinical study does not meet the criteria for support of the planning phase of the study.

Reviewers will be asked to evaluate the innovation of the proposed study based on the rationale and design of the multi-center clinical study to be conducted after the planning phase of the U34. Reviewers may be asked to address questions such as:

• Is the multi-center clinical study to be conducted after the U34 planning phase original and innovative?

• Does the project challenge existing paradigms or clinical practice?

• Will the study address an innovative hypothesis or critical barrier to progress in the field?

• Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Both the approach of the U34 planning activities and of the proposed multi-center clinical study will be evaluated during peer-review of the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement. Peer-reviewers will be asked to evaluate the following questions:

• Will the study concept and design, methods, and analyses, including preliminary statistical analyses, successfully accomplish the aim(s) of the proposed clinical study?

• Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well-reasoned, and appropriate to the aims of the project?

• Are the activities proposed for the planning period adequate? Will the activities proposed be sufficient to allow for timely and successful study implementation?

• Does the applicant acknowledge potential problem areas and consider alternative tactics?

• Will the proposed planning activities address all major barriers that may confront the U01 clinical study, if accepted?

• For applications designating multiple PDs/PIs, does the Leadership Plan ensure that there will be sufficient coordination and communication among the PDs/PIs?

• Are the administrative plans for the management of the research project appropriate, including plans for resolving conflicts?

Yes. However, investigators are strongly encouraged to discuss the resubmission with their Program Director. NIDDK will consider the comments of the peer-reviewers in discussing a resubmission application with the investigator.

October 9, 2024, June 10, 2025, February 11, 2026, October 8, 2026, and June 10, 2027