Investigator-Initiated Multi-Site Clinical Trials - Frequently Asked Questions

Investigator-Initiated Multi-Site Clinical Trials (PAR-22-192 and PAR-22-193)

[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 multi-site clinical trials NOFOs (PAR-22-192 & PAR-22-193)?

A2. PAR-22-192 and PAR-22-193 support applications to develop and implement investigator-initiated multi-site clinical trials. Clinical trials supported by these NOFOs 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.

Q3: What kinds of applications are NOT accepted for PAR-22-192 and PAR-22-193?

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

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

Q4. What is a “multi-site” (as opposed to a “single-site”) clinical trial for the purpose of these NOFOs?

A4. 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.

A single-site clinical trial, on the other hand, utilizes one investigational site to conduct and coordinate the protocol. While a single-site clinical trial may enroll participants from multiple locations, those participants will receive an intervention and/or undergo outcome assessments under the direction and oversight of one research team located at one investigational site.

Single-site clinical trial research grant applications relevant to NHLBI’s mission should generally be submitted to PAR-22-189.

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 strongly 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 multi-site PAR-22-192 and PAR-22-193 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 primary 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 FOAs 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 Single-site Clinical Trials

An investigator submitting a Phase II and beyond clinical trial using a single recruitment site must apply to PAR-22-189 or its 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. These NOFOs are for applications for multi-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 that are closely related to the primary aim 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 whose primary aim is (1) to explore fundamental mechanisms of normal biology or pathobiology, or (2) is done 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 Multi-site Clinical Trials NOFOs

Q7. What are the required attachments for multi-site trial applications submitted in response to PAR-22-192: Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3 Clinical Trial Required)?

A7. Four attachments must be provided or the application will not be reviewed:

Trial Management Plan
Clinical Trials Research Experience
Plan for Enhancing Diverse Perspectives (PEDP)
Community-Engagement Plan (CEP)

Q8. What notable characteristics are in the NHLBI NOFOs for multi-site clinical trials?

A8. Some of the more notable characteristics include:

A protocol synopsis that is a part of the application that peer-reviewers will evaluate;
Applicants provide detailed information on integrated (CCC & DCC) timelines and processes for reaching core milestones, including accrual targets;
Recruitment and retention plans with data to support accrual projections;
A network description, if the clinical trial proposes to use a network CCC and/or DCC;
Awards that include milestone-driven and performance-based expectations;
Clinical coordinating center (CCC) and data coordinating center (DCC) awards made under distinct mechanisms, but that are coordinated and synchronized;
NOFO peer-review criteria that will ensure rigorous evaluation of scientific impact, operational feasibility, community engagement and diverse perspectives on the study team;
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 UG3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase; and
Providing project support for five years with the potential for up to seven years if strongly justified;
Emphasizing the importance of providing evidence of equipoise in trial design including in the letters of support from the clinical sites;
Underscoring core milestones as critical control points integral to successful conduct of trial;
Requiring integration throughout the application of project management principles and procedures (including a timeline) as a key strategy in risk management;
For Network trials, requiring description of how trials will leverage Network infrastructure and access patient populations; and
Emphasizing NHLBI’s monitoring of milestones in UH3/R33 phase, and, as appropriate, use of a Corrective Action Plan (CAP) and award phase-out;
Having a completed draft protocol available upon request for Program Staff before funding.

Major differences from PAR-19-329 & PAR-19-330 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 Acknowledging NIH’s Interest in diversity and required plans to meet these objectives;
Requires inclusion of Plan for Enhancing Diverse Perspectives (PEDP) and 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:

Q9. There seems to be some overlap between the CCC and the DCC applications. How distinct must the grant applications be?

A9. In many cases, innovation and significance sections are contingent on the trial proposed in the CCC application. However, many aspects of the trial operations will be specific to the DCC application. Core Milestones and the Study Timeline should be identical. On the study timeline indicate which specific tasks will be conducted by the CCC and which will be conducted by the DCC. There may be other elements of innovation in areas such as trial design and conduct that are particular to either the DCC or CCC and would be reflected in the corresponding application.

Q10. Which application is required to describe the statistical analysis and power calculation, the CCC or the DCC?

A10. The DCC is the application that should be used to describe this section in detail. The CCC application should ensure that this section describes how the number of expected subjects, the expected effect size, the power, and the statistical methods (with respect to each outcome measure) have been adequately addressed. In addition, the CCC should indicate that the Statistical Design and Power attachment is provided in its entirety as a part of the collaborating DCC application.

Q11. I am interested in applying for funding for a clinical trial that I would like to conduct in collaboration with or through a Network. How can I apply? Must I apply under both NOFOs (the one for the CCC and the DCC) even though the Network already has a DCC in place? If so, will the DCC application be evaluated against all the criteria specified for investigator-initiated multi-site clinical trials through milestone-driven cooperative agreement (U24) award?

A11. You will have to apply under the multi-site Clinical trial NOFOs with both a CCC and a DCC application. The latter will be coming from the Network DCC. The DCC application for a U24 award will be evaluated against the applicable criteria described in the Data Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative U24) NOFO.

Q12. What information should I provide if my application will leverage a network?

A12. If a clinical trial will be conducted using the infrastructure of an existing Network, a 6-page Network Description Plan should be provided. The Network Description Plan should include:

Name of Network
Number of years and funding remaining to support the Network infrastructure and any information on the continuance of the Network
Plans to assess site performance
Infrastructure capacity and availability of patient populations considering current ongoing trials within the Network
Plans to incorporate the current Network infrastructure into the proposed trial, including participant recruitment, trial implementation, and central coordination through the CCC and data management, data analysis, or statistical analysis through the DCC
Plans to utilize master clinical trial agreements and a single IRB

Note: If both the CCC and the DCC applications intend to leverage the infrastructure of an existing network, the DCC application must also include this information.

Q13. May the DCC and CCC be at the same institution or location?

A13. Yes.

Q14. What information is required in the Trial Management Plan attachment?

A14. 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 CCC and the DCC activities. This will include plans to achieve core milestones and pro-actively evaluate and prioritize study risks and issue corrective responses. May not exceed 5 pages.

Q15. What personnel experience should be included in the Clinical Trial Research Experience attachment?

A15. Information can be provided within 3 pages on all key personnel with relevant experience; including but not limited to the PD/PI, MPI, or co-investigators.

Q16. What information is expected in the Plan for Enhancing Diverse Perspectives (PEDP) attachment?

A16. PEDP may include, but are 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.

Q17. What information is expected in the Community Engagement Plans (CEP) attachment?

A17. 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. May not exceed 1 page.

Q18. What information must be covered in site letters of support?

A18. Letters of support should be provided from all sites and must be signed by clinicians or clinical department chairs. The letter of support for any randomized trial should explain why the site views the trial as being in equipoise and arm that the intervention(s) or control arm(s) being tested are not known to be inferior to the range of practice (or usual care) at the site, in their community, and described in relevant standards of care.

Q19. May I include in my application to the UG3/UH3 NOFO a proposal for a pilot study to be conducted during the UG3 phase?

A19. The UG3/UH3 mechanism is not intended to support pilot studies to establish the feasibility of the clinical trial. However, the UG3 phase may be used to refine study procedures, such as imaging, clinical assessments, and laboratory tests, in support of a well-justified study design that is already based on appropriate pilot data. Investigators interested in conducting a pilot study can submit their application to PAR-21-079 (R34).

Q20. Should proposals for multi-site implementation clinical trials be submitted under these NOFOs?

A20. Yes. Multi-site implementation clinical trials (i.e., a study examining barriers to, or strategies to promote, the broad implementation of a clinical therapy) may apply under these NOFOs.

Q21. I am an investigator at an institution outside the United States. Am I eligible to apply for the CCC or DCC awards under these NOFOs?

A21. Yes. Institutions outside the United States are eligible to apply for the CCC or the DCC award. It is also acceptable for a non-US component of a US institution to be a part of a DCC or CCC award. Potential foreign applicants are strongly encouraged to discuss their application with NHLBI Program Staff before they apply.

Q22. If I revise my application with a revised budget that is at or above $500,000 in any one year and submit it as a new application or as an A1 (resubmission) application, do I need to submit another letter of approval from NHLBI?

A22. Yes, you do. Contact your NHLBI Program Officer to discuss the next steps to seek approval under the >500K Policy.

Q23. How are multi-site clinical trial UG3/U24 applications peer reviewed?

A23. The UG3/U24 applications are reviewed by NHLBI Clinical Trials Review Study Section (CLTR). The standing committee meets three times per year for January, May, and October councils, respectively.

Post-Award Administrative Review and Transition Process

Q24. What is evaluated during the UG3 administrative review and when is it evaluated?

A24. The administrative review will typically occur at about 9 months into the 12-month UG3 award. It is anticipated that the review will be completed, and investigators will be notified whether the UH3 phase will be awarded at about 10 or 11 months into the UG3 award.

Q25. Under what conditions will an application advance from the UG3 to the UH3 phase?

A25. Toward the end of the UG3 phase (about 9 months), NHLBI will conduct an administrative review of the extent to which peer-reviewed core milestones are met in the UG3 phase. Core UG3 milestones include but are not limited to:

Complete 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 UG3 phase
25% of sites activated

The extent to which the core milestones have been met and the trial is poised to be conducted successfully will determine whether the UH3 phase award will be issued, subject to NHLBI funding availability. If the administrative review determines the trial should transition to the UH3 phase, Core UH3 milestones include but are not limited to the following:

Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and individuals of all ages, including children and older adults (as appropriate)
Study closure and completion plans
Collection of data related to primary and secondary endpoints and database lock
Submission of primary manuscript to peer-reviewed scientific journal(s), dissemination of results, and data sharing

Q26. Who is responsible for communicating completion of the core milestones to NHLBI?

A26. It is expected that, if funded, both the CCC and DCC will be responsible for milestone completion but that only one party, the CCC or the DCC, will be responsible for recording the completion of both CCC and DCC milestones through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI.

Q27. Is the administrative review a competitive one? That is, will more UG3 awards be made than can be supported through the UH3 phase?

A27. No, this is not NHLBI’s intent. To the extent that NHLBI has awarded an UG3, the Institute will be poised to fund the UH3 phase provided that the administrative review indicates successful completion of the first phase. That determination would be made independently of how other trials fared in the administrative review of their UG3 phase.

Q28. Will this change the pre-approval process for projects with a proposed direct cost budget of $500,000 or more?

A28. No. If the combined direct costs of the DCC and CCC applications equal or exceed $500,000 in any one year, the investigator still must contact program staff to obtain documented approval in the form of a letter from the Institute stating that it will accept the application for initial peer review (http://www.nhlbi.nih.gov/funding/policies/500kweb.htm). Program staff will continue to have consultations (staff visits) with the investigators at least 8 weeks ahead of the desired receipt date and involve any other relevant NHLBI staff . Investigators should submit a letter of request to the relevant Division Director, and if the project is approved, append the corresponding letter of approval to the cover letter of the CCC and DCC applications. The letter of approval needs to be submitted with the applications.

Even if the combined direct cost budget being proposed does not meet the $500,000 direct cost threshold, NHLBI nonetheless strongly encourages investigators to discuss their applications with NHLBI program staff.

If the application is of potential interest to several ICs, NHLBI Program Staff will coordinate with representatives from the other ICs to discuss their interest in the clinical trial and include them in the staff consultation.

Q29. Will this change the NHLBI process for CCC and DCC applications with a proposed combined budget with direct costs of $1,515,000 or more in any one year?

A29. No, it will not. Applications that involve CCC and DCC requested budgets that together exceed $1.515 million (combined) in direct costs in any given year need to go to the Large Application Panel (LAP), undergo the pre-approval process for applications with budgets of $500,000 or more in direct costs in any one year, and may still only be submitted twice a year. The letter of request must be submitted following the staff visit no later than November 15 or May 15, as applicable. This applies even if part of the costs are being shared with another IC, other organization, or company.

Q30. Are there changes to the CCC or DCC applications resulting from the change to FORMS-H?

A30. Yes, please see https://grants.nih.gov/grants/guide/notice-files/not-od-22-195.html for further information on FORMS-H changes.

Appendix

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 in the United States 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 the investigational sites. Medical School A will coordinate the protocol, as well as collect and analyze the data originating from all nine sites.