Investigator-Initiated Clinical Trial R01 and R21 Grants Questions and Answers

Table of Contents

General Information

The following investigator-initiated clinical trial grants are research project grants that include milestones for meeting recruitment and other targets:

In their applications, applicants must describe each stage of the clinical trial, provide criteria for completing it, and give contingency plans if they do not meet the timeline.

R01 and R21 grants do not have the substantial scientific involvement by NIAID staff that the clinical trial U01 cooperative agreement has because they are not high risk, which we define as follows:

  • The investigators plan to provide a routine intervention, i.e., an intervention that would normally be provided for the study condition in the facility where the trial is being conducted.
  • The investigators plan to administer a licensed product for an approved indication.

For studies that are high risk, applicants may apply for a NIAID Clinical Trial Implementation Cooperative Agreement (U01, Clinical Trial Required). If for other reasons we determine that substantial staff involvement is necessary, we may ask you to apply for a U01.

For more information, read the Investigator-Initiated Clinical Trial U01 Implementation Awards Questions and Answers.

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

  • Developing study design, clinical protocol, and informed consent documents
  • Identifying collaborators and enrollment sites
  • Developing the statistical analysis and data management plans
  • Developing the investigator's brochure or equivalent
  • Establishing the research team
  • Developing a Manual of Operations including details, validation, and quality control for any nonstandard clinical or laboratory/mechanistic testing that will be performed
  • Developing a plan for acquiring and administering study agents
  • Obtaining required Office of Human Research Protections assurances if not already in place
  • Developing the milestone plan
  • Determining whether an application for an investigational new drug (IND) or investigational device exemption (IDE) should be submitted to the FDA (or relevant regulatory agency outside the U.S.), and who will hold the IND or IDE
  • Developing a complete set of suitable documents for submitting to the appropriate regulatory authorities
  • Developing a data and safety monitoring plan (i.e., DSMB, SMC, or ISM)
  • Developing a detailed budget for conducting and completing the clinical trial including funding for preparing a final study report
  • Developing training materials and training plans for study staff

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.

Regardless of risk level, the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement (U44, Clinical Trial Required) is an option for small businesses only.

No. However, you must have ready all the documentation you would have prepared during an NIAID Clinical Trial Planning Grant (R34, Clinical Trial Not Allowed) grant.

Yes. NIAID staff will monitor progress toward meeting your study’s timeline 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.

Yes. NIAID program staff may be able to help you access Institute-funded resources, such as those in existing networks, facilities, and laboratories.

Here are the points to consider:

  • You must be ready for a clinical trial grant. In other words, you must be able to include the following in the application, if applicable:
    • Clinical protocol synopsis
    • Informed consent and assent forms
    • Statistical analysis plan
    • 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
  • If you are not ready to begin the trial and require more time to prepare some of the items above, consider applying for an R34 clinical trial planning grant.
  • Most institutions are eligible, whether academic, for-profit, nonprofit, domestic, or foreign. Read more in your chosen opportunity announcement.

Follow the instructions in the SF 424 (R&R) – General Application Guide for NIH and Other PHS Agencies. 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.

Yes. NIAID Clinical Terms of Award will be part of the terms and conditions of award.

Typically, no. However, 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.

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.

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

Yes, in one of these three situations:

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

In any case, you should speak to the NIAID point of contact listed in the FOA to confirm.

Although we will fund most successful applications for non-high-risk trials as R01s, we may convert some R01s or R21s to U01 or UH3 cooperative agreements on a case-by-case basis.

Possibly. To figure out whether your sample collection is considered a clinical trial, answer the questions on NIH’s decision wizard, Does your human subjects research study meet the NIH Definition of a clinical trial?

For further advice, discuss your project with the NIAID point of contact listed in the R01 or R21 FOA.

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 further advice, discuss your project with the NIAID point of contact listed in the R01 or R21 FOA.

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 R01 or R21 FOA.

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

Discuss your project with the NIAID point of contact listed in the R01 or R21 FOA.

Go to Investigator-Initiated Clinical Trial Resources for resources or contact staff listed in the R01 or R21 FOA.

Planning the 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.

At least 10 weeks before the application due date (12 weeks for an extended trial), call or email the relevant NIAID program officer to discuss your research idea and get advice. Learn more in Requesting Prior Consultation: Clinical Trial Applications and Planning Grants.

Yes, the limit is five pages.

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.

We expect to respond to you within six weeks of receiving the formal written request you send after your prior consultation.

No. It is not required, however, it is highly encouraged.

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

No, each R01 application will support only one clinical trial.

Request enough time to complete the clinical trial.

You may request up to five years of support for an R01, six or seven years of support for an extended R01, and up to two years of support for an R21.

Request resources appropriate to complete the clinical trial.

For an R01, your budget is not limited. For an R21, your budget limit is $275,000 in direct costs with a $200,000 maximum in any one year.

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.

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

Writing the Application

Go to these NIAID resources:

Contact the appropriate NIAID point of contact in the R01 or R21 FOA for division-specific procedures.

Prepare your application using the SF 424 grant application package. Read the R01 or R21 FOA for details.

Here is an overview of the key elements:

  • Time-sensitive, hypothesis-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

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.

For an R01, your Research Plan is limited to one page for the Specific Aims and 12 pages for the Research Strategy.

For an R21, your Research Plan is limited to one page for the Specific Aims and 6 pages for the Research Strategy.

The following three sections comprise the Research Strategy: Significance, Innovation, and Approach. In addition, the Research Strategy must include the following information:

  • 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 and have 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 should not duplicate the specific topics discussed 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, Good Laboratory Practices, and Good Manufacturing Practices, 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 of why the study population is an appropriate group to study the research questions posed, subject eligibility, inclusion and exclusion criteria, 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, if these are included in the study; indicate 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, if applicable
  • Demonstrated consideration of ethical issues involving the disease or condition under study
  • Any anticipated impediments that could require a revision in the timeline must be identified and accompanied by a discussion of alternative approaches

Closely follow the instructions in the PHS Human Subjects and Clinical Trials Information section of the SF 424 (R&R) Application Guide. Read the R01 or R21 FOA for further instructions.

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.

Prepare a modular budget if you are applying from a single domestic institution and the budget is less than $250,000 in direct costs in any year.

Prepare a detailed budget if your budget is more than $250,000 in direct costs in any year, you are applying from a foreign institution, or your application involves multiple institutions—see How do I prepare an application that involves multiple institutions?

Follow the instructions in the SF 424 Application Guide and any appendix instructions in Section IV. Application and Submission Information of your chosen FOA. 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.

As described in Section IV of PAR-20-139, Investigator Initiated Extended Clinical Trial (R01 Clinical Trial Required), applications in response to PAR-20-139 must include a complete clinical protocol in the Appendix.

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.

For a detailed budget (over $250,000 in direct costs in any year), the prime institution submits the Research & Related Budget component. Attach the individual budgets for the subawards separately to the Research & Related Subaward Budget Attachment Form. This does not apply to R21 applications.

For a modular budget (less than $250,000 in direct costs in all years), the prime institution submits the PHS 398 Modular Budget component only. Provide information on the subaward's budget in the budget justification; do not provide separate budgets for subawards.

Follow the instructions in the R01 or R21 FOA.

Yes, if you follow procedures for a multiple-PI application.

Applying and After

Apply electronically using the SF 424 Grant Application Package. Learn more in the R01 or R21 FOA.

Find general information about electronic application in our Applying for a Grant section.

Standard receipt dates apply. See the R01 or R21 FOA.

An applicable Center for Scientific Review study section.

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?

Investigators

With regard to the proposed leadership for the project, do the principal investigators 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/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

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?

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 hypothesis, 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 dosages, 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/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?

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 center 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?

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 multiple sites or centers are proposed, 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?

All review criteria are listed in Section V. Application Review Information in the R01 or R21 FOA.

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. To resubmit, follow the suggested format in the grant application package.

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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