Investigator-Initiated Clinical Trial U01 Implementation Awards Questions and Answers

Table of Contents

U01 General Information

Planning the Application

Writing the Application

Applying and After

U01 General Information

What is a clinical trial U01 implementation cooperative agreement?

The NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) is for principal investigators (PIs) implementing a high-risk clinical trial. Applications must include project milestones, and NIAID staff have substantial scientific involvement during the award.

The U01 is for projects that are high risk, which we define as follows:

  • The investigators plan to provide a non-routine intervention, i.e., an intervention that would not otherwise be provided for the study condition in the facility where the trial is being conducted.
  • The investigators plan to administer an unlicensed product or use a licensed product for an unapproved indication.

For studies that are not high-risk, applicants may apply for a R01 or R21 as described in the Investigator-Initiated Clinical Trial R01 and R21 Grants Questions and Answers.

If you apply for a R01 or R21 and for other reasons we determine that substantial staff involvement is necessary, we may ask you to apply for a U01.

What does NIAID consider to be implementation?

Implementation refers to activities related to the conduct of the clinical trial such as:

  • Training of study personnel
  • Enrollment and recruitment of study subjects
  • Data collection, management, and quality control
  • Laboratory work and data analyses
  • Study management and oversight
  • Establishment of committees to manage the complexity of the trial
  • Preparation of the final study report
  • Other related post-enrollment activities

Is there anything a U01 clinical trial implementation cooperative agreement cannot support?

Yes. It will not support planning activities for a clinical trial such as:

  • Development of study design, clinical protocol, and informed consent or assent documents
  • Identification of collaborators and enrollment sites
  • Development of the statistical analysis and data management plans
  • Development of the investigator's brochure or equivalent
  • Establishment of the research team
  • Development of a manual of operations including details, validation, and quality control for any non-standard clinical or laboratory/mechanistic testing that will be performed
  • Development of a plan for the acquisition and administration of study agents
  • Obtaining required Office of Human Research Protections assurances if not already in place
  • Development of the milestone plan
  • Determination of whether an application for an investigational new drug (IND) or investigational device exception (IDE) should be submitted to the FDA (or relevant regulatory agency outside the U.S.), and who will hold the IND or IDE
  • Development of a complete set of suitable documents for submission to the appropriate regulatory authorities
  • Development of a data and safety monitoring plan (i.e., DSMB, SMC, or ISM)
  • Development of a detailed budget for conduct and completion of the clinical trial including funding for preparation of a final study report
  • Development of training materials and training plans for study staff

Will my project need milestones?

Yes.  We define a milestone as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Read the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement for information about the milestone plan.

Your application must describe a series of milestones for completing the clinical trial and contingency plans should there be delays. Milestones will be peer reviewed, negotiated with NIAID, and become part of the terms of award. See How do I comply with requirements for human subjects? below.

How do I determine whether to apply for an R01, R21, U01, or U44 award?

If the clinical trial you propose is not high risk, apply for an R01 or R21. If the clinical trial is high risk, apply for a clinical trial implementation U01.

Is an R34 required before I submit an R01, U01, or U44 application?

No. However, you must have ready all the documentation you would have prepared during an R34 clinical trial planning grant.

What role will NIAID program staff play in administering my U01 implementation award?

NIAID staff will monitor progress toward meeting your milestones during your annual progress review. They will also oversee the management and reporting of adverse events and have regular communications with you and your study team.

Can I benefit from NIAID resources?

Yes. PIs will benefit from the involvement of NIAID staff. Also, NIAID program staff may be able to help you access Institute-funded resources, such as those in existing networks, facilities, and laboratories.

How do I qualify for a U01 implementation award?

Here are the points to consider:

  • You must be ready for an implementation U01, i.e., you must be able to include the following in the application, if applicable:
    • Complete clinical protocol
    • Informed consent forms and, if applicable, assent forms
    • Statistical analysis plan
    • Plan for acquisition and administration of study agents
    • Investigator's Brochure or equivalent for study products
    • Documentation of adequate cofunding, if necessary for completion of the trial
    • Plan for submission of regulatory documents to appropriate regulatory authorities, e.g., IND and IRB submissions
    • Listing that includes identification and qualifications of clinical trial sites, pharmacies, and laboratories
    • Table of Contents for the Manual of Operations
    • Comprehensive laboratory plan
    • Milestone plan
    • Data management plan
  • If you are not ready to begin the trial and require more time to prepare some of the items above, consider applying for an NIAID Clinical Trial Planning Grant (R34, Clinical Trial Not Allowed).
  • Apply for a U01 if the clinical trial you propose is high risk—see What is a clinical trial U01 implementation cooperative agreement?
  • Most institutions are eligible, whether academic, for-profit, non-profit, domestic or foreign.

Follow the instructions in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement. Don't put anything in the Appendix that belongs in the Research Strategy to circumvent the page limits.

Will NIAID's Clinical Terms of Award apply to my U01 implementation cooperative agreement?

Yes. NIAID Clinical Terms of Award will be part of the terms and conditions of award. See the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement for additional terms and conditions of award, which will be modified for each cooperative agreement.

Does my clinical trial need to include a randomized design?

No. Randomization is required only if it is an appropriate element of trial design.

Who will hold the IND for my clinical trial?

If the trial requires an IND, NIAID can hold it. Other arrangements are possible; discuss them with the appropriate NIAID program staff. The final decision whether NIAID will hold the IND is NIAID's to make.

When does a diagnostic test evaluation need to come under the investigator-initiated clinical trial process?

A study of unapproved diagnostic tests in which the results of the test are reported back to either the treating physician, the subject, and/or public health authority, will need to come back under the investigator-initiated clinical trial process.

Are there circumstances where the investigator-initiated clinical trial process is not required or appropriate?

Yes, in one of these situations:

  1. Your research might fit better into our existing clinical trial infrastructure.
  2. Your research is more appropriate for a different funding opportunity: a request for applications, a program announcement, or a solicitation.
  3. Your research might not qualify as a clinical trial under the NIH Definition of Clinical Trial.

In all cases, you must speak to the NIAID point of contact listed on the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement to confirm.

If my research involves studies of samples from subjects enrolled in a separate clinical trial, can I submit my proposal as a U01?

Yes, as long as providing samples for your studies represents minimal additional risk to the clinical trial subjects. You should explicitly state that you are not requesting support for the clinical trial. You will need to provide documentation that the clinical trial sponsor is aware of your proposal and will provide necessary access to the samples.

For additional advice, discuss your project with the NIAID point of contact listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

If I am planning a study that is primarily basic research and one of the aims involves a clinical trial, can I submit the study as a U01?

Each application has unique circumstances, so we will decide on a case-by-case basis. For help, call the NIAID point of contact listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

You may also wish to read Are there circumstances where the investigator-initiated clinical trials process is not required or appropriate?

If my research involves human subjects but is not covered by the examples in this document, can I submit my proposal as a U01?

Discuss your project with the NIAID point of contact listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

Where can I find more information about clinical trial planning and implementation awards?

Go to the Investigator-Initiated Clinical Trial Resources main page for resources, and contact staff listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

Planning the Application

Must I have permission to submit a U01 implementation cooperative agreement application?

No, unless the budget requested exceeds $500,000 in direct costs in any given year. We do strongly encourage you to request a prior consultation with NIAID staff regardless of your requested budget. Learn more in the Investigator-Initiated Clinical Trial Planning and Implementation Awards SOP.

How do I start the process for a U01 implementation cooperative agreement application?

At least 10 weeks before the application due date, call or email the program officer listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement to discuss your research idea and get advice. See Requesting Prior Consultation: Clinical Trial Applications and Planning Grants for details.

Is there a page limit for the prior consultation package?

Yes, the limit is five pages.

How do I get documentation of my prior consultation for a U01 implementation cooperative agreement?

A program officer will send you a letter summarizing the prior consultation and signed by a NIAID division director. Include this letter in your application as an Other Attachment.

What is the timeframe for NIAID's prior consultation process for my U01 application?

NIAID will provide a prior consultation summary letter within six weeks after the consultation.

Must I prepare a letter of intent?

It is not required; however, it is highly encouraged.

Is there a limit to the number of U01 applications I can submit?

No, you may submit more than one application provided each is scientifically distinct.

Can I propose more than one clinical trial in my application?

No, each U01 application will support the implementation of one clinical trial.

How much time and money can I request for a U01 implementation cooperative agreement?

Request resources and time appropriate to complete the clinical trial. You may request up to five years of support.

Do I need to follow requirements for a big grant application?

If you are requesting a budget over $500,000 in direct costs in any one year, include a section for approval of a big grant application in your request for prior consultation.

Although a large budget requires approval, we will handle both requests together. Read the Investigator-Initiated Clinical Trial Planning and Implementation Awards SOP for details.

Can the application have more than one principal investigator?

Yes, if you follow procedures for a multiple PI application. Read more at Multiple Principal Investigators.

Writing the Application

Where can I find resources for writing my application?

Go to these NIAID resources:

Reach out to the appropriate NIAID point of contact in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement for division-specific procedures.

How do I prepare my U01 implementation cooperative agreement application?

Read the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement for instructions.

What are the key elements of my application?

Here is an overview of the key elements of what you include in a U01 application:

  • Time-sensitive, hypothesis- and milestone-driven clinical trial
    • Criteria for completing the stages and contingency plans for each stage
    • Anticipated impediments that could require a revision in the timeline with alternative approaches
  • Clear primary and secondary endpoints
  • Description of the study population, reason it is an appropriate group to study, subject eligibility, inclusion and exclusion criteria, and a recruitment and enrollment plan
  • Statistical methods matched to the study design
  • Plans for data monitoring and safety
  • Overview of the state of the science, current status and relevance of the trial, and a synopsis of the clinical protocol

How do I include the prior consultation letter in my U01 application?

Attach a copy in the SF 424 (R&R) Cover Letter Attachment form of the grant application package following the instructions in the SF 424 (R&R) Application Guide.

What is the page limit for my Research Plan?

Your Research Plan is limited to one page for the Specific Aims and 12 pages for the Research Strategy.

What should I address in the Research Strategy?

The following three sections comprise the Research Strategy: Significance, Innovation, and Approach. In addition, the Research Strategy may not exceed 12 pages and must include:

  • An overview of the state of the science, a discussion of the significance of the clinical and mechanistic (if applicable) problems being studied, the need for the trial, and the potential impact of the results of the trial, as well as how the trial will test the hypotheses proposed
  • Clear primary and secondary endpoints
  • A concise description of the overall strategy, methodology, and analyses to be used to accomplish the goals and specific aims of the trial
  • A discussion of potential biases or challenges in the protocol and how they will be addressed
  • Statistical methods that are appropriate for the study design, including sample size and power calculations (this is in addition to what is in the Statistical Analysis Plan)
  • A discussion of studies that led to the proposed clinical trial and information or data from preliminary studies which address the need for and the feasibility of the trial
  • A description of the study organization and administration, including a description of committee structures needed to manage the complexity of the trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any sub-contractors or service providers for personnel or facilities
  • A description of the plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP), as appropriate
  • The appropriate oversight over the conduct of the trial, including at a minimum the appropriate clinical monitoring, safety monitoring, regulatory submissions, and quality management (this is in addition to what is in the Data Safety Monitoring Plan)
  • Explanation why the study population is an appropriate group to study the research questions posed, subject eligibility, and a feasible recruitment and enrollment plan; plans for recruitment and ensuring availability of study participants, including plans for recruitment and retention of children, women, and minorities; plans for recruitment outreach and follow-up procedures
  • The process to be used for obtaining informed consent and assent
  • Plans for acquisition and handling of study agents
  • Demonstrated consideration of ethical issues involving the disease or condition under study
  • Any anticipated impediments that could require a revision in the timeline and accompanying discussion of alternative approaches

What do I have to include in my application to ensure it's complete?

You must complete all information and attachments requested in the PHS Human Subjects and Clinical Trials Information section of the SF 424 (R&R) Application Guide

If your application omits any of these items, it will be considered incomplete and will not be reviewed. Read the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) for full instructions.

How do I comply with requirements for human subjects?

Closely follow the instructions in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement. 

Do I need resource sharing plans?

Yes, as applicable:

  • Data Sharing Plan: Include a one-paragraph description of how you will share the final research data or explain why this is not possible. 
  • Sharing Model Organisms: If you expect to develop a unique model organism, include a plan for sharing and distributing the organisms and related resources or explain why this is not possible.
  • Genome-Wide Association Studies: If you are conducting a genome-wide association study, include a plan for submitting the data to the GWAS data repository or explain why this is not possible. 

Should I prepare a detailed or modular budget?

Prepare a detailed budget. If your application involves multiple institutions, see How do I prepare an application that involves multiple institutions?

Should I include Clinical Trial Insurance information in my application?

No. Specifically, you should not list Clinical Trial Insurance costs in your application’s budget section. 

How should I format the Table of Contents for the Manual of Operations?

Simply list the applicable parts and sub-parts of the Manual of Operations. You do not need to include page numbers.

Make sure your Table of Contents has enough details to show that you have completed your study design and worked out operational issues.

What should I include in the Appendix?

Include a complete protocol and follow further Appendix instructions in Section IV. Application and Submission Information of the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement. 

Do not use the Appendix to circumvent the page limits. Applications that do not comply with page limits may face a delay in peer review. 

How do I prepare an application that involves multiple institutions?

If you propose research at multiple institutions, designate one institution as the prime institution and the other as a subcontract (subaward) to be administered by the prime institution.

Since you are preparing a detailed budget, the prime institution submits the Research and Related Budget Component forms. Attach the individual budgets for the subawards separately. Follow the instructions in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

Applying and After

How do I submit my U01 implementation cooperative agreement application?

Submit your application electronically using the SF 424 (R&R) – General Application Guide for NIH and Other PHS Agencies. For instructions, see the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

When can I submit my U01 application?

For both AIDS and non-AIDS applications, you may submit in September, January, and May. See the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trail Required) program announcement for details.

Who will peer review my U01 application?

An NIAID special emphasis panel will peer review it.

Does the U01 implementation cooperative agreement have specific review criteria?

Yes. In addition to the standard review criteria, reviewers will assess the following factors:

Significance

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy, or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors, or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding? Is the project plan realistic to allow for completion of the study and obtaining scientifically and clinically relevant final report within the period of the award?

Investigators

With regard to the proposed leadership for the project, do the PIs and key personnel have the expertise, experience, and ability to organize, manage, and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management, and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the design or research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Does the application adequately address the following, if applicable:

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variables and endpoints that will be clear, informative, and relevant to the hypothesis being tested? Is the scientific rationale or premise of the study based on previously well-designed preclinical or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research questions, test the proposed hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms or dosage, and duration of the trial appropriate and well justified? 

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization, masking, controls, and inclusion and exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex, gender, race, and ethnicity? 

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agents? Does the application propose to use existing available resources, as applicable? Does the application adequately address GCP, GLP, and GMP compliance if applicable? Does the application adequately address compliance with regulatory requirements? Are the consent and data collection forms, sites, pharmacies, labs, brochures, and Manuals of Operations appropriate?

Data Management and Statistical Analysis 

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical sites or at laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award? 

If the project involves human subjects or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion or exclusion of individuals on the basis of sex, gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

If proposed, are the administrative, data coordinating, enrollment, and laboratory/testing centers appropriate for the trial proposed? 

Does the application adequately address the capability and ability to conduct the trial at the proposed sites or centers? Are the plans to add or drop enrollment centers, as needed, appropriate? 

If international sites are proposed, does the application adequately address the complexity of executing the clinical trial?

If there are multiple sites or centers, is there evidence of the ability of each individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and (4) operate within the proposed organizational structure?

Be aware that your application will also be reviewed for protection of human subjects and other considerations listed under Section V. Application Review Information in the NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required) program announcement.

Can I resubmit my U01 application?

Yes, one time. Before resubmitting a revised application, we strongly suggest that you repeat the prior consultation process with the appropriate NIAID program official.

Use the results from the previous review to strengthen your project.

If I can't complete a clinical trial within the performance period of my U01, can I apply for an extension?

You may be able to apply for an extension. You can also take a no-cost extension—read more in the No-Cost Extension SOP.

Also see our Investigator-Initiated Clinical Trial Administrative Extension SOP and Extension of Investigator-Initiated Clinical Trials Question and Answers.

What if my question wasn't answered here, or I'd like to suggest a question?

Use the contacts listed above for questions about your specific situation. If you have a general question or a suggestion to improve this page, email the Office of Knowledge and Educational Resources at deaweb@niaid.nih.gov.

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