U01 Frequently Asked Questions

Some of the most common questions about the U01 are answered below.

Is the U01 Multi-Center High-Risk Clinical Study Cooperative Agreement limited to multi-center clinical trials?

No. The U01 Multi-Center High-Risk Study Cooperative Agreement will support all types of multi-center clinical studies including epidemiologic studies, observational studies, and interventional clinical trials.

What is the definition of a multi-center study?

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.

What is the definition of a high-risk study?

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 FOAs for clinical trials (PA-20-183 or PA-20-184 , or other appropriate FOAs 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 FOAs from NIDDK.

Does NIDDK require a U34 before they will fund a U01 Multi-Center High-Risk Clinical Study Cooperative Agreement?

No. NIDDK does not require a U34 if all the planning activities can be completed through some other 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. It is the experience of NIDDK that 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 conduct of the study. The U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement mechanism 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 recruitment to begin once the U01 is awarded.

What role will NIDDK play in U01 Multi-Center High-Risk Clinical Study Cooperative Agreement?

The U01 Multi-Center Clinical Study funding mechanism 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 directing and executing the proposed multi-center clinical study with NIH staff being substantially involved as a partner with the Principal Investigator, as described under Cooperative Agreement Terms and Conditions of Award in PAR-21-102 and PAR-21-103.

What should I do if I want to submit a U01 Cooperative Agreement?

Contact the appropriate NIDDK Program Director to discuss your proposed application, and do so as soon as possible, 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 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 designated in the PARs (PAR-21-102 and PAR 21-103) and you will be directed to the appropriate individual.

How far in advance of the U01 Cooperative Agreement application receipt date should I contact NIDDK?

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.

Please remember that the consultation process is distinct from the NIH requirement that investigators requesting $500,000 or greater direct costs in any year (exclusive of consortium F&A) are required to have pre-approval to submit the application at least 6 weeks prior to the receipt date. 

What information should be included in a letter requesting consultation about applying for a U01 Multi-Center High-Risk Cooperative Agreement?

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:

  • Date of proposed submission

  • Study title

  • Study PI, and other key investigators (attach biosketch(es)) 

  • 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

  • Proposed sample size including power calculation 

  • General statistical assumptions for the proposed study design and analysis 

  • Confirmed 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

  • Detailed budget by year

  • Evidence that the U34 planning components have been completed

Who should I contact for prior consultation?

You should contact the appropriate program director for the subject matter of the application. See 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 PARs (PAR-21-102 and PAR 21-103) and they will direct you to the appropriate individual.

If the U34 is appropriately productive (e.g., protocol finalization, manual of operations development), will a U01 application still require peer-review?

Yes. The U01 Multi-Center High-Risk Clinical Study Cooperative Agreement application will undergo NIH peer-review. Specific review criteria used to evaluate U01 applications may be found within PAR-21-102 and PAR 21-103 NIDDK Multi-Center Clinical Study Cooperative Agreement (U01).

Why will U01 applications undergo peer-review if the multi-center clinical study has already been peer-reviewed as a part of the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement?

The peer-review of the U01 Multi-Center High-Risk Clinical Study Cooperative Agreement will evaluate whether the proposed study remains scientifically important and feasible. During the multi-center clinical study planning of the U34 Multi-Center Clinical Study Implementation Planning Cooperative Agreement, changes in the study protocol may be necessary to accommodate advances in the scientific field. Furthermore, the rationale and/or significance of the proposed study may become obsolete. Therefore, peer-reviewers will be asked to re-evaluate the significance, innovation, approach, investigator and environment criteria as described above.