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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

Read the questions and answers below or see the Table of Contents above.

What is a clinical trial U01 implementation cooperative agreement?

NIAID's investigator-initiated clinical trial implementation U01 is a cooperative agreement for 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 clinical trial implementation R01. For more information, read the Investigator-Initiated Clinical Trial R01 Implementation Grants questions and answers.

If 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 IND or 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)Guide 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 implementation grant or U01 implementation cooperative agreement?

If the clinical trial you propose is not high risk, apply for an R01. If the clinical trial is high risk, apply for a clinical trial implementation U01. For NIAID's definition of risk, see What is a clinical trial U01 implementation cooperative agreement?

Is an R34 required before I submit an R01 or U01 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, for example, 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:
    • 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 applicable and necessary for completion of the trial.
    • Plan for submission of regulatory documents to appropriate regulatory authorities, for example, 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.
    • Data management plan.
    • Site quality management plan.
  • If you are not ready to begin the trial, consider applying for an R34 clinical trial planning grant.
  • Apply for a U01 rather than a milestone-driven R01 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) Guide 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) Guide 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?

NIAID can hold the IND. Other arrangements are possible; please discuss them with the appropriate NIAID program staff.

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 as defined by NIH. The process would usually not be required for clinical studies that:
    • Evaluate a diagnostic test unless the results of the studies will be used to:
    • Evaluate subjects undergoing a procedure or receiving a vaccine, drug, or biologic as part of clinical care and involve collecting additional samples that do not pose more than minimal additional risk to the subject.

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

If my research will use samples from subjects receiving treatments outside the proposed study, can I apply for an investigator-initiated clinical trial?

Treatment or prophylaxis is not a clinical trial if subjects are receiving medical treatment or prophylaxis according to standard intervention or the best judgment of their treating physician. If you can obtain the samples you need with less than high risk to the subjects, an R01 application is appropriate.

Make sure your application clearly states that the treating physician is independent of the research proposal. For further advice, discuss your project with the NIAID point of contact listed in the NIAID Clinical Trial Implementation Cooperative Agreement (U01) Guide announcement.

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) Guide announcement.

If I am planning a study that is primarily basic research and one of the four 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) Guide 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) Guide 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) Guide announcement.

Planning the Application

Read the questions and answers below or see the Table of Contents above.

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

No. We do strongly encourage you to request a prior consultation with NIAID staff, though. 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?

Follow these steps:

  1. Prepare for a discussion.
  2. Call or email. 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) Guide announcement to discuss your research idea and get advice.
    • Allow enough time. We strongly recommend that you request prior consultation as soon as possible—it may take six weeks for us to respond.
  3. Prepare request. Within two weeks of your initial discussion (a minimum of eight weeks before the receipt date) do the following:

In your cover letter, you will identify the staff member who agreed to accept assignment of the application to NIAID and attach the prior consultation summary letter from the division director.

See Requesting Prior Consultation to Discuss Submission of a Clinical Trial Planning (R34) or Implementation (R01 or U01) Application and the questions below 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 signed by the NIAID division director that summarizes the prior consultation, which you will include with your U01 application.

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?

No.

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. 

Writing the Application

Read the questions and answers below or see the Table of Contents above.

Where can I find resources for writing my application?

Go to these NIAID resources:

Contact the appropriate NIAID point of contact in the  NIAID Clinical Trial Implementation Cooperative Agreement (U01) Guide announcement for division-specific procedures.

How do I prepare my U01 implementation cooperative agreement application?

Read the NIAID Clinical Trial Implementation Cooperative Agreement (U01) Guide 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 PDF file in the PHS 398 Cover Letter File of the grant application package.

What is the page limit for my Research Plan?

Your Research Plan is limited to one page for the Specific Aims, 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:

  • Discussion of the significance of the problem being studied, need for the trial, and potential impact of the results, as well as how the trial will test the hypotheses proposed.
  • Concise description of the overall strategy, methodology, and analyses to be used to accomplish the goals and Specific Aims of the trial.
  • Description of and rationale for the proposed study design.
  • Description of the intervention to be tested and the protocol to be followed in each arm of the trial, including 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 and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis being tested.
  • Discussion of studies that led to the proposed clinical trial and information or data from preliminary studies that address the need for and the feasibility of the trial.
  • Description of the study organization and administration, including at least the following: 
    • Committee structures needed to manage the complexity of the trial.
    • Role of any internal or external advisory committees.
    • Oversight, responsibilities, and coordination of any sites or cores proposed.
    • Role of any subcontractors or service providers for personnel or facilities.

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

You must include an appropriate Clinical Protocol Synopsis, Statistical Analysis Plan, Data Safety and Monitoring Plan, Milestone Plan, and Complete Clinical Protocol.

If your application omits any of these components in the SF 424 Application Other Project Information Form under the section entitled "Other Attachments," it will be considered nonresponsive and will not be reviewed. Read the NIAID Clinical Trial Implementation Cooperative Agreement (U01) for full instructions.

How do I comply with requirements for human subjects?

Closely follow the instructions in the PHS 398 Part II Supplemental Instructions for Preparing the Protection of Human Subjects Section of the Research Plan and the NIAID Clinical Trial Implementation Cooperative Agreement (U01) Guide announcement.  

Clinical Protocol Synopsis

The Clinical Protocol Synopsis should be included at the end of the Human Subjects section. Applications that lack the Clinical Protocol Synopsis will not be peer reviewed. The Clinical Protocol Synopsis may not exceed three pages and must include the following information:

  • Description of the study population, including subject eligibility and inclusion and exclusion criteria.
  • Sampling, recruitment, and enrollment plans, including a discussion of the availability of subjects for the proposed study and the ability of enrollment centers to recruit and retain the proposed number of subjects.
  • Process to be used for obtaining informed consent and, if applicable, assent.
  • Approaches to be used for retention, cooperation and follow-up of subjects and to address any anticipated changes in the composition of the study population over the course of the trial.
  • Method of assigning subjects to study groups.
  • Method of randomization, if an element of trial design.
  • If appropriate to the study, a description and justification for the selection of the dose, frequency, and administration of the interventions.
  • Description of each enrollment site and how data from the sites will be obtained, managed, and protected.
  • Descriptions of all clinical, laboratory, physiological, and behavioral tests to enable the research questions to be answered.
  • Description of the data management and quality control plan, including methods for monitoring the quality and consistency of the interventions and data collection; policies and methods for ensuring blinding of study results; and data confidentiality and subject privacy.

Data and Safety Monitoring Plan

A Data and Safety Monitoring (DSM) Plan that is commensurate with the risk level of the proposed clinical research must be included for all clinical trials—see the NIH Policies and IC Guidance for Data and Safety Monitoring of Clinical Trials portal.

All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing, and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies, e.g., institutional review board, NIAID, NIH Office of Biotechnology Activities (if appropriate), Office of Human Research Protections, FDA, and any data and safety monitoring board.  

The DSM Plan must address the following areas:

  • Who will manage and conduct the monitoring.
  • What will be monitored.
  • Proposed monitoring time points.
  • Where the monitoring will occur.
  • How the reportable events will be managed and reported.
  • How sites or centers, and participating facilities (labs, pharmacies) will be monitored.

Milestone Plan and Complete Clinical Protocol 

A Milestone Plan and Complete Clinical Protocol must be included as a single PDF attachment to the Other Project Information component of the SF 424 application. 

Complete clinical protocol documents will not count toward the page limit for the Research Plan. Applications that lack the Milestone Plan or complete clinical protocol will not be reviewed.

Milestone Plan

Applicants must provide detailed project performance and timeline objectives in a section called Milestone Plan. This section may not exceed three pages and must include:

  • Detailed protocol-specific performance milestones, which will be negotiated at the time of the award.
  • Timelines for the following general milestones, as applicable:
    • Completion of regulatory approvals.
    • Enrollment of the first subject.
    • Enrollment of 25 percent, 50 percent, 75 percent, and 100 percent, of the projected recruitment time period for all study subjects, including women, minorities, and children as appropriate.
    • Completion of data collection time period.
    • Completion of primary endpoint and secondary endpoint data analyses time period.
    • Completion of final study report.

Complete Clinical Protocol

A Complete Clinical Protocol must be included immediately after the Milestone Plan. Please see the Trans NIAID Clinical Research Toolkit for clinical protocol guidance and templates. We urge you to be succinct.

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?

What should I include in the Appendix?

Include the following documents in the Appendix material: 

  • Informed consent form and, if applicable, assent forms.
  • Statistical analysis plan.
  • Investigator's Brochure or equivalent for the study products.
  • Identification and qualifications of clinical trial sites, pharmacies, and laboratories.
  • Table of contents of the Manual of Procedures.
  • Comprehensive Laboratory Plan.
  • Documentation of availability of study agents and support for acquisition and handling of study agents.
  • Data Management Plan.
  • Internal site Quality Management Plan.
  • Copies of data collection forms, questionnaires, or other relevant materials.

Be sure to provide appendix material on CDs.

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

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 .

Applying and After

Read the questions and answers below or see the Table of Contents above.

How do I submit my U01 implementation cooperative agreement application?

Submit your application electronically using the SF 424 Application Guide. For instructions, see the NIAID Clinical Trial Implementation Cooperative Agreement (U01) Guide 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) Guide 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 special review criteria?

Yes, below are the factors added to the standard review criteria. Be aware that your application will also be reviewed for protection of human subjects.

Significance. If proposed, do the mechanistic studies contribute to the understanding of the disease or treatment? Are the study objectives and hypotheses adequately defined?

Investigator(s). Do the PD/PIs and key personnel have the necessary expertise in statistics, data management and study coordination to implement the proposed clinical trial and meet milestones and timelines? Are committee structures appropriate to the complexity of the trial?

For multicenter trials, does the application identify a core of potential center investigators and staffing for a coordinating center? Is the organizational structure of the multicenter trial appropriate?

Innovation. Nothing added.

Approach

  • Does the application adequately address the following:
    • intervention, study agents, and mode of delivery
    • availability of eligible patient population
    • informed consent or assent form
    • statistical hypothesis and analysis
    • endpoints and data to be collected
    • sample size and power calculation
    • duration of the trial
    • randomization, masking, inclusion and exclusion criteria
    • ancillary therapies
    • plans to standardize and monitor adherence to the clinical protocol
    • methods for standardization of procedures for data, site, and quality management
  • Does the application provide adequate milestones?
  • Is the plan for acquisition and handling of study agents appropriate?
  • Does the application adequately address differences in the intervention effect due to sex/gender and race/ethnicity?
  • Does the application clearly describe plans for patient recruitment outreach, enrollment, and retention?
  • Is the plan for regulatory approval likely to be successful?
  • Does the application adequately address potential ethical issues?
  • Does the application adequately address the clinical trial documentation (e.g., the investigator's brochure or equivalent)?
  • Does the application adequately address Good Clinical Practices, Good Laboratory Practices, and Good Manufacturing Practices compliance?
  • For multi-center trials, does the application adequately address the standardization/quality control of, and adherence to, the clinical protocol and data collection and/or distribution guidelines, and the use of a data coordinating center?

Environment.  -- Does the application adequately address plans to add or drop enrollment centers; the availability of the requisite eligible patient pool; the availability of children, women and minority individuals as trial participants and specific recruitment and retention plans for their inclusion; plans for recruitment outreach and, as appropriate, follow-up procedures to ensure collection of data at stated intervals?

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

Innovation. No additional criteria.

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 NIAID determines that my application is nonresponsive, can I send it to NIH as an investigator-initiated application?

NIAID will not peer review or fund any investigator-initiated clinical trial application that is nonresponsive. We encourage you to contact other NIH institutes to see if they might accept your application.

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 Extensions SOP and Investigator-Initiated Clinical Trial Administrative Extensions questions and answers.

Will I be able to renew my award?

No.

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

Email deaweb@niaid.nih.gov with the title of this page or its URL and your question or comment. We answer questions by email and post them here. Thanks for helping us clarify and expand our knowledge base.

Last Updated September 16, 2014

Last Reviewed September 16, 2014