Investigator-Initiated Single-site Clinical Trials - Frequently Asked Questions

Investigator-Initiated Single-site Clinical Trials (PAR-22-189)

[For questions regarding NIH policy on clinical trials, please refer to the NIH Office of Extramural Research page on Clinical Trial Requirements for Grants and Contracts]

Scope of this NOFO

Q1. What is a “clinical trial” for the purpose of this FOA?

A1. A clinical trial is defined by NIH (NOT-OD-15-015) as:

A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

Q2. What kinds of applications are accepted for the single-site clinical trials NOFO (PAR-22-189)?

A2. PAR-22-189 supports applications to develop and implement investigator-initiated single-site clinical trials. Clinical trials supported by this NOFO include Phase II and above clinical trials. This NOFO is applicable to single-site clinical trials only. Proposed research may utilize a design anywhere along the continuum of efficacy, comparative effectiveness, pragmatic and/or implementation research clinical trials.

Q3: What kinds of applications are NOT accepted for PAR-22-189?

A3. The following types of clinical trials are not intended to be supported by this NOFO:

  • Phase I (first-in-human) trials
  • Observational studies that do not meet the NIH definition of a clinical trial
  • Multi-site trials
  • Drug or device safety trials
  • Mechanistic or Basic Experimental Studies in Humans (BESH)

Q4: What is a “single-site” (as opposed to a “multi-site”) clinical trial for the purpose of this NOFO?

A4. A single-site clinical trial utilizes one investigational site to conduct and coordinate the protocol. While a single-site clinical trial may enroll participants from multiple locations/clinic within a geographic area, participants will receive an intervention and/or undergo outcome assessments under the direction and oversight of one research team located at one investigational site. There may be cases where the application meets the definition of a single-site trial but the trial requires coordination using a DCC. Contact program staff to consult on your specific situation.

A multi-site clinical trial involves the implementation of the same clinical protocol at two or more independent investigational sites where participants are seen for an intervention and/or outcomes assessment. In a multi-site trial, investigational sites are typically administratively or corporately distinct from each other.

Multi-site clinical trial research grant applications relevant to NHLBI’s mission must be submitted to PAR-22-192 and PAR-22-193.

Illustrative examples of single-site and multi-site clinical trials are provided in the Appendix below. Investigators with questions about whether the clinical trial that they are proposing is a single-site or multi-site clinical trial (and the NOFOs that may be appropriate for their trial) are encouraged to discuss their application with an NHLBI program officer for further guidance.

Q5. What other funding opportunities can I consider if my trial does not seem to fit the single-site PAR-22-189 requirements?

A5. Consider the NOFOs listed below by type of clinical trial application:

1. Pilot Studies

  • NHLBI will accept applications for pilot studies that collect data that are critical to finalize the design of a future full-scale clinical trial, in response to PAR-21-079 NHLBI Clinical Trial Pilot Studies (R34 Clinical Trial Optional) and its reissues.
  • Trials potentially eligible for the NHLBI R34 may test the feasibility of novel and efficient (pragmatic) trial designs, as well as determine the feasibility of an intervention, intervention parameters, subject availability, or other information essential to complete the design of a trial.

2. Mechanistic Clinical Trials

  • In response to PA-20-183 NIH Research Project Grant (Parent R01 Clinical Trial Required) and its reissues, NHLBI will accept under that NOFO only applications for mechanistic studies that meet the NIH definition of a clinical trial (see NOT-HL-19- 690 and NHLBI Mechanistic Clinical Trials FAQs).
  • For the purposes of this NHLBI policy, a mechanistic clinical trial is defined as a study designed to understand a biological or behavioral process, the pathophysiology of a disease/condition, or the mechanism of action of an intervention.
  • NHLBI recognizes that some of the aims of applications that propose a mechanistic clinical trial may also include exploration of fundamental mechanisms that are a major precursor to, or an iterative element of, a clinical study where the latter design or conduct is predicated at least in part on the results of these basic and early translational research aims. As such, NHLBI recognizes that applications can be "hybrid" meaning that they may include as their aims not only a mechanistic clinical trial but also fundamental basic science research aims. NHLBI will accept such hybrid applications as well as applications solely proposing mechanistic trials in response to PA-20-183 and its reissues.
  • While mechanistic clinical trials must address the safety of human subjects and may include assessments of clinical outcomes, the purpose of such trials is not the evaluation of safety, clinical efficacy, and/or clinical management.

3. Phase I (Early Phase) Clinical Trials

  • Investigators planning a phase I (early phase) clinical trial (up to but not including phase II), must submit an application to the following NHLBI NOFOs specifically designed for early phase clinical trials:
    • PAR-21-119 Diagnostics and Therapeutics Early Phase Clinical Trials (R61/R33-Clinical Trial Required), or its reissues
    • PAR-21-118 Diagnostics and Therapeutics Early Phase Clinical Trials (R33-Clinical Trial Required), or its reissues
    • Applications with early phase clinical trials will only be accepted by NHLBI via PAR-21-119 and PAR-21-118 or their reissues. The purpose of the early phase trial is to evaluate safety, side effects, best dose, timing, and/or best route of administration for a new treatment or therapy.

4. Phase II and Beyond Multi-site Clinical Trials

  • An investigator submitting a Phase II and beyond clinical trial using multiple recruitment sites must apply to PAR-22-192 and PAR-22-193 or their reissues. See NHLBI Policy Regarding Submission of Clinical Trial Applications (NOT-HL-18-611) for additional information. There may be cases where the application meets the definition of a single-site trial, but the trial requires coordination using a DCC. Contact program staff to consult on your specific situation.

Q6. I am submitting an application for research that includes both a clinical trial and a number of basic research aims. Under what circumstances would this type of project with mixed clinical and basic science research aims be appropriate for this NOFO as opposed to other possible funding opportunities?

A6. This NOFO is for applications for single-site studies that include Phase II and above clinical trials. Proposed research may utilize a design anywhere along the continuum of efficacy, comparative effectiveness, pragmatic and/or implementation research clinical trials. Associated research questions closely related to the aims of the clinical trial, such as understanding the intervention’s effects or the varied response of the participants to the intervention, are permitted as secondary aims.

However, if the study includes a clinical trial (1) as a method to explore fundamental mechanisms of normal biology or pathobiology, or (2) as a major precursor to, or iterative element of, a clinical study (whose design or conduct is predicated at least in part on the basic science study), then it may be more appropriate to apply for funding under the NIH parent R01 or the NHLBI P01 (see Q5 for more detail). You are encouraged to discuss your application with your program officer for further guidance.

Characteristics and Requirements of the Single-site Clinical Trials NOFO

Q7. Why does NHLBI solicit applications for single-site clinical trials in Phase II and above through this NOFO (and not through a parent NIH NOFO)?

A7. As part of an overall strategy to optimize its clinical trials enterprise, NHLBI first modified in 2015 its NOFOs for clinical trials to enhance the identification, inclusion, and application of well-defined performance milestones (as well as a phased approach). This will enhance the selection of trials that are operationally feasible and promote the ability of the study team to achieve their planned objectives of the clinical trial within the 5 year timeframe and budget at a single site. Performance milestones are to be identified by the investigators to establish expectations regarding trial performance and will be peer-reviewed. Milestones must be performance-based to achieve completion of the trial on time and on budget, and must be established for both the R61 and R33 phases of the project.

Q8. What funding mechanism is being used to support trials under this NOFO?

A8. Applications awarded under this NOFO will be funded through a biphasic investigator-initiated award. The first phase will be an R61 (Phase 1 Exploratory/Developmental Grant), which is used to prepare for initiation of the trial. That award is for one year. The second phase, conditional on a positive evaluation through an administrative review of the first phase (as described in Question 14), will be an R33 (Exploratory/Developmental Grants Phase II), which will provide support for the conduct of the clinical trial. The R33 phase award can be for up to 4 years.

Q9. Why are detailed milestones and metrics important for single-site trials?

A9. Although single-site clinical trials are, in general, operationally less complex than multi-site clinical trials, they still benefit from careful planning, including the identification of milestones and metrics that promote the successful conduct of the trial. NHLBI’s conduct in monitoring milestones in R61/R33 phase, may include, as appropriate, use of a CAP and award phase-out in certain cases.

Q10. What are the required attachments for single-site trial applications submitted in response to PAR-22-189: Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required)?

A10. Five attachments must be provided or the application will not be reviewed:

  1. Single-site Justification Plan
  2. Trial Management Plan
  3. Clinical Trials Research Experience
  4. Plan for Enhancing Diverse Perspectives (PEDP)
  5. Community-Engagement Plan (CEP)

Q11. What notable characteristics are in the NHLBI NOFO for single-site clinical trials?

A11. Some of the more notable characteristics include:

  • A protocol synopsis that is a part of the application that peer-reviewers will evaluate;
  • Detailed information on timelines and processes for reaching core milestones, including accrual targets;
  • Recruitment and retention plans with data to support accrual projections;
  • Underscoring core milestones as critical control points integral to the successful conduct of the trial;
  • Specifying milestone-driven and performance-based expectations in the application and notice of award. The core milestones must be met during the R61 phase to allow for successful launch of the full trial in the R33 phase of the clinical trial.
  • In addition to the evaluation of scientific impact the peer review criteria include rigorous evaluation for operational feasibility;
  • For trials using an FDA regulated product and requiring an IND or IDE application to administer the product to humans, (1) IND authorization or IDE approval and (2) documentation of this authorization or approval to NHLBI before a funding decision will be made. Necessary drugs, devices, or other resources must be obtained by the end of the R61 award to allow for the successful launch and execution of the proposed clinical trial in the R33 phase;
  • Emphasizing the importance of providing evidence of equipoise in trial design and the letters of support;
  • Requiring integration throughout the application of project management principles and procedures (including a timeline) as a key strategy in risk management.

Major differences from PAR-19-328 include (this applies to new and resubmission applications):

  • Acknowledging the diversity of clinical trial types and appropriateness of platform trials, adaptive, and Bayesian designs;
  • Acknowledging NIH’s interest in diversity;
  • Requiring inclusion of a Plan for Enhancing Diverse Perspectives (PEDP) and a Community Engagement Plan (CEP) to describe approaches for increasing community engagement and diversity as well as reducing health inequities and disparities.

For more detail, please read the Funding Opportunities, available at: PAR-22-189: Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required)

Q12. What information is needed in the Single-Site Justification Plan?

A12. This Single-Site Justification Plan should describe how all participants for the trial will be enrolled at a single institution and in the allotted timeline. It may not exceed 2 pages.

Q13. What information is required in the Trial Management Plan attachment?

A13. The Trial Management Plan should focus on the plans to assess risks to the study and manage those risks, providing contingency plans that are specific to the clinical trial activities. This will include plans to achieve core milestones and pro-actively evaluate and prioritize study risks and issue corrective responses. It may not exceed 5 pages.

Q14. What personnel experience should be included in the Clinical Trial Research Experience attachment?

A14. Information should be provided on all key personnel with relevant experience in the past 5 years, including but not limited to the PD/PI, MPI or co-investigators. It may not exceed 3 pages.

Q15. What information is required for the Plan for Enhancing Diverse Perspectives (PEDP) attachment?

A 15. PEDP can include, but is not limited to:

  • Description of any planned partnerships that may enhance geographic and regional diversity.
  • Plan to enhance recruiting of women and individuals from groups traditionally under-represented in the biomedical, behavioral, and clinical research workforce.
  • Proposed monitoring activities to identify and measure PEDP progress benchmarks.
  • Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
  • Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
  • Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
  • Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.
  • May not exceed 1 page.

Q16. What information is required for the Community Engagement Plan (CEP) attachment?

A16. The Community Engagement Plan should emphasize collaboration with community partners, leaders, and knowledge holders, leveraging community resources and local service delivery and/or settings to address the needs of multiple stakeholders is encouraged. As appropriate, plans may include Community-Based Participatory Research (CBPR) models, as well as a Community and Scientific Advisory Board that targets community representation and scientists not directly involved in the project. It may not exceed 1 page.

Q17. I am an investigator at an institution outside the United States. Am I eligible to apply for awards under this NOFO?

A17. Yes. Institutions outside the United States are eligible to apply for these awards, as are applications with foreign components. Potential foreign applicants are strongly encouraged to discuss their application with NHLBI Program Staff before they apply.

Q18. How are single-site clinical trial R61/R33 applications peer reviewed?

A18. The R61/R33 applications are reviewed by the NHLBI Single-Site and Pilot Clinical Trials Study Section (SSPT). The standing committee meets three times per year for January, May, and October councils, respectively.

Pre-Application and Post-Award Administrative Review and Transition Process

Q19. What is evaluated during the R61 administrative review and when is it evaluated?

A19. The administrative review includes evaluation of R61 milestone completion and will typically occur at about 9 months of the R61 award. It is anticipated that the review will be completed, and investigators will be notified whether the R33 phase will be awarded before the R61 award ends. In general, awards will not be adjusted to include any new recruitment sites.

Q20. Under what conditions will an application advance from the R61 to the R33 phase?

A20: At 9 months into the R61 phase, NHLBI will administratively review progress and extent to which peer-reviewed milestones are met in the R61 phase, including:

  • Finalized protocol and informed consent documents
  • DSMB review and approval of final protocol, template consent(s) and/or assent(s), and data and safety monitoring plan
  • IRB approval of final protocol and consent and/or assent
  • Enrollment of the first participant during the R61 phase

In addition, all necessary drugs, devices, or other resources as needed are to be obtained during this period. The extent to which the milestones have been met and the trial is poised to be conducted successfully will determine whether the R33 phase award will be issued, subject to NHLBI funding availability.

Q21. Is the administrative review a competitive one? That is, will more R61 awards be made than can be supported through the R33 phase?

A21. No. The Institute intent to fund the R33 phase provided that the administrative review indicates successful completion of the first phase (R61). That determination would be made independently of how other trials fared in the administrative review of their R61 phase; however, NHLBI can always decide not to award the R33 phase.

Q22. Will the process for requesting a ≥500K budget be the same for this PAR?

A22. Yes. The NHLBI policy for applications for >500K applies to application submitted to PAR-22-189 (or its reissues). Please refer the instructions on the NHLBI >500K website (

Q23. What if unanticipated events occur after I am funded that necessitate changing the timing or nature of my clinical trial milestones? Is that allowed? If so, what do I do?

A23. In general, NHLBI does not expect there will be changes to Core Milestones. It is expected that the peer-reviewed milestones will be completed as planned. However, if an unanticipated event necessitates changing any of your milestones or impacts the study timeline, then you should contact the NHLBI program official as soon as possible to discuss this development. The program official will work with you to determine whether changes are warranted and, if so, how they may be implemented.

Q24. Are there any circumstances under which a single site trial funded under this NOFO may add performance sites?

A24. Yes, but these are expected to be extremely rare and limited circumstances. These situations must be discussed with your program official. You may be able to add a performance site if:

  • The additional site is part of the same corporate organization as the originally funded site; for example, a hospital may wish to add to the trial a satellite clinic in another city that is nonetheless part of the same health system as the hospital;
  • The additional site can be added without a change to the trial budget;
  • Study staff for the additional site will be trained and supervised by the original site;
  • The additional site will use the identical protocol;
  • The additional site will use the same IRB as the original site; and
  • Trial coordination, as well as aggregation and analysis of data, can be accomplished by the originally funded site.

If these criteria are not met, you will not be able to add a performance site. If adding an additional site is not appropriate, your program official will evaluate whether the best course of action is to (1) complete the study as originally designed, or (2) if the original research aims cannot be achieved, have you reapply under the NHLBI NOFO for multi-site clinical trials. If an additional site is deemed appropriate under the current award, this modification will have to be formally approved by NHLBI and reflected in a revised Notice of Grant Award.

Q25. Are there changes to the application resulting from the change to FORMS-H?

A25. Yes, please see for further information on FORMS-H changes.


Illustrative Examples of Single-site and Multi-site Clinical Trial Proposals

Examples of Single-site Clinical Trial Proposals

  • An investigator at Medical School A proposes to use functional electrical stimulation as an intervention to prevent cardiovascular declines in acute spinal cord injury. The intervention will be conducted at Medical School A. Participants are recruited from Medical School A only.
  • An investigator at University A proposes a community-based intervention to test the value of aspirin in the primary prevention of cardiovascular disease. The University will recruit participants from 12 counties in one state for the active arm. Participants will come to University A for physical exams and to provide blood samples. Control data will be collected from medical records from individuals with appropriate medical histories in the same counties. University A will compile the data and carry out all analyses.
  • An investigator at Public Health School A is proposing to test vitamin supplementation in school age children as an intervention to prevent asthma. Healthy children between the ages of 8 and 12 are being recruited and enrolled at schools in City B, where childhood asthma is a common public health problem. The intervention is being planned and coordinated by the investigator at Public Health School A and will be overseen by local public health officials in City B. The investigator will travel periodically to City B to conduct follow-up testing and data collection.
  • A team of investigators within a unified health system that serves multiple locations (clinics) runs a trial to implement a EHR-based recruitment plan at hospitals within the health system.

Examples of Multi-site Clinical Trial Proposals

  • An investigator has developed a drug for the treatment of asthma and, under IND, proposes to conduct a Phase II trial at two medical schools. The investigator submitting the application is at Medical School A and proposes to collaborate with an investigator at Medical School B. Each investigator will recruit trial participants from the patient populations at the hospitals affiliated with their respective schools, administer the drug to participants at each hospital, and conduct trial follow-up and data collection independently. The investigators will collaborate on data analysis and publication.
  • An investigator at University A proposes to conduct a physical activity intervention under controlled conditions with the aim of improving cardiovascular function in elderly patients. Trial participants will be recruited from five university-based and independent cardiology practices in the city where the university is located. The physical activity intervention will be conducted at three physical therapy practices under the supervision of three investigators (including the lead investigator). Each investigator will monitor patients and conduct follow-up testing and data collection independently. The investigator at University A will then pool and analyze the data.
  • An investigator at Medical School A proposes to utilize a cooling device to limit the damage from acute myocardial infarction. The cooling intervention will be conducted at nine independent investigational sites (university and community hospitals). Participants will be recruited from all of the investigational sites. Medical School A will coordinate the protocol, as well as collect and analyze the data originating from all nine sites.