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Investigator-Initiated Clinical Trial R01 Implementation Grants

Questions and Answers

Table of Contents

R01 General Information

Planning the Application

Writing the Application

Applying and After

R01 General Information

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

What is a milestone-driven R01 clinical trial implementation grant?

NIAID's investigator-initiated clinical trial implementation R01 is a research project grant that includes 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 milestones.

The R01 does not have the substantial scientific involvement by NIAID staff that the clinical trial U01 implementation cooperative agreement has because the R01 is for clinical trials that 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 clinical trial implementation U01 cooperative agreement. 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.

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.
  • Enrolling and recruiting study subjects.
  • Data collecting, managing, and quality control.
  • Laboratory work and data analyses.
  • Study management and oversight.
  • Establishing committees to manage the complexity of the trial.
  • Preparing the final study report.
  • Other related post-enrollment activities.

Is there anything an R01 clinical trial implementation grant cannot support?

Yes. It will not support planning activities for a clinical trial such as:
  • Development of study design, clinical protocol, and informed consent 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 nonstandard clinical or laboratory/mechanistic testing that will be performed.
  • Development of a plan for acquiring and administering 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 submitting 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 conducting and completing the clinical trial including funding for preparing a final study report.
  • Development of training materials and training plans for study staff.

What is a milestone?

We define a milestone as a scheduled event in the project timeline, signifying the completion of a major project stage or activity.

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 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 milestone-driven R01 clinical trial implementation grant?

Is an R34 required before I may 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.

Do NIAID staff have any roles for my R01 implementation grant?

Yes. 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. 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 an R01 implementation grant?

Here are the points to consider:

  • You must be ready for an implementation R01, i.e., you must be able to include the following in the application:
    • Complete clinical protocol.
    • Informed consent and, if applicable, 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.
    • 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 milestone-driven R01 rather than a U01 if the clinical trial you propose is not high risk—see What is a milestone-driven R01 clinical trial implementation grant?
  • Most institutions are eligible, whether academic, for-profit, nonprofit, domestic, or foreign. Read more in the NIAID Clinical Trial Implementation Grant (R01) Guide notice.

Follow the instructions in the SF 424 Application Guide and NIAID Clinical Trial Implementation Grant (R01) Guide notice. 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.

Will NIAID's clinical terms of award apply to my R01 implementation grant?

Yes. NIAID Clinical Terms of Award will be part of the terms and conditions of award. See the NIAID Clinical Trial Implementation Grant (R01) Guide notice for sample terms and conditions of award, which will be modified for each cooperative agreement.

Will there be an IND for my clinical trial?

Not likely.

Does my clinical trial need to include a randomized design?

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

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

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: 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 any case, you should speak to the NIAID point of contact listed in the NIAID Clinical Trial Implementation Grant (R01) Guide notice to confirm.

Are there circumstances where my R01 would be converted to a U01?

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

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 Grant (R01) Guide notice.

If my research involves studies of samples from subjects enrolled in a separate clinical trial, can I submit my proposal as an R01?

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 Grant (R01) Guide notice.

If I am planning a study that is primarily basic research and one of the four aims involves a clinical trial, can I still submit the study as an R01?

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 Grant (R01) Guide notice.

You may also wish to read Are there circumstances where the investigator-initiated clinical trial 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 an R01?

Discuss your project with the NIAID point of contact listed in the NIAID Clinical Trial Implementation Grant (R01) Guide notice.

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

Go to Investigator-Initiated Clinical Trial Resources main page for resources, and contact staff listed in the NIAID Clinical Trial Implementation Grant (R01) Guide notice.

Planning the Application

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

Must I have permission to submit an R01 implementation grant application?

No. However, we do strongly encourage you to request a prior consultation with NIAID staff. Learn more in the Investigator-Initiated Clinical Trial Planning and Implementation Awards SOP.

How do I start the process for an R01 implementation grant application?

We recommend that you 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 relevant NIAID program officer to discuss your research idea and get advice.
    • Allow enough time. We strongly recommend that you request prior consultation with NIAID staff 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:

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 an R01 implementation grant?

A program officer will send you a letter summarizing the prior consultation and signed by the NIAID division director to include with your R01 application.

What is the timeframe for NIAID's prior consultation process for my R01 application?

We expect to respond to you within six weeks of receiving your formal written request.

Must I submit a letter of intent?

No.

Is there a limit to the number of R01 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 R01 application will support the implementation of one clinical trial.

How much time and money can I request for an R01 implementation grant?

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.  

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 Grant (R01) Guide notice for division-specific procedures.

How do I prepare my R01 implementation grant application?

Prepare your application using the SF 424 Grant Application Package. Read the NIAID Clinical Trial Implementation Grant (R01) Guide notice for details.

What are the key elements of my application?

Here is an overview of the key elements for an R01 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 summary letter in my R01 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, Statistics Analysis Plan, Data Safety and Monitoring Plan, Milestone Plan and Complete Clinical Protocol, and informed consent. If applicable, also include assent forms, comprehensive laboratory plan, and Table of Contents for the Manual of Operations.

If you omit any of these components, your application will be considered nonresponsive and will not be reviewed. Read the NIAID Clinical Trial Implementation Grant (R01) Guide notice for full instructions.

How do I comply with requirements for human subjects?

Closely follow the instructions in the Part II Supplemental Instructions for Preparing the Protection of Human Subjects Section of the Research Plan and in the NIAID Clinical Trial Implementation Grant (R01) Guide notice.

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 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?

What should I include in the Appendix?

Include the following documents in the Appendix material: 
  • Informed consent forms and, if applicable, assent forms.
  • Statistical analysis plan.
  • Identification and qualifications of clinical trial sites, pharmacies and laboratories.
  • Copies of data collection forms, questionnaires, or other relevant materials.

Follow the instructions in the SF 424 Application Guide and NIAID Clinical Trial Implementation Grant (R01) Guide notice. 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.

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.  

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 Grant Application Guide for further instructions.

Can the application have more than one principal investigator?

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

Applying and After

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

How do I submit my R01 implementation grant application?

Apply electronically using the SF 424 Grant Application Package. Learn more in the NIAID Clinical Trial Implementation Grant (R01) Guide notice.

Find general information about electronic application in our Applying for a Grant questions and answers.

When can I submit my R01 application?

For both AIDS and non-AIDS applications, you may submit in September, January, and May. See the NIAID Clinical Trial Implementation Grant (R01) Guide notice for details.

Who will peer review my R01 application?

An NIAID special emphasis panel will peer review it.

Does the R01 implementation grant 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 mechanistic studies are proposed, how do they contribute to the understanding of the disease or treatment?

Investigator(s). Is there adequate expertise and ability of the investigator and the clinical trial team to organize, manage, and execute the proposed trial? Does the investigative team include statisticians, data managers and study coordinators? 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 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, power calculation.
    • duration of the trial.
    • inclusion and exclusion criteria.
    • ancillary therapies.
  • 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?
  • Does the application adequately address potential ethical issues?
  • 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 standardization/quality control of, and adherence to, the clinical protocol and data collection or distribution guidelines?

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?

Can I resubmit my R01 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. To resubmit, follow the suggested format in the grant application package.

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 the clinical trial within the performance period of my R01, can I apply for an extension?

You may be able to apply for an extension. To learn more, read the NIAID Policy for Extension of Investigator-Initiated Clinical Trials Guide notice.

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 grant?

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