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

Investigator-Initiated Single-site Clinical Trials (PAR-19-328)

[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 FOA

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 FOA (PAR-19-328)?

A2. PAR-19-328 supports applications to develop and implement investigator-initiated single-site clinical trials. Clinical trials supported by this FOA include Phase II and above clinical trials. This FOA 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-19-328?

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

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 FOA?

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, participants will receive an intervention and/or undergo outcome assessments under the direction and oversight of one research team located at one investigational site.

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-19-329 and PAR-19-330.

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 FOAs 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-19-328 requirements?

A5. Consider the FOAs 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-19-155 NHLBI Clinical Trial Pilot Studies (R34 Clinical Trial Optional) and its reissues.
Studies 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-19-055 NIH Research Project Grant (Parent R01 Clinical Trial Required) and its reissues, NHLBI will accept under that FOA only applications for mechanistic studies that meet the NIH definition of a clinical trial (see NOT-HL-19-690).
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-19-055 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 FOAs specifically designed for early phase clinical trials:

PAR-18-683 Diagnostics and Therapeutics Early Phase Clinical Trials (R61/R33-Clinical Trial Required), or its reissues
PAR-18-684 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-18-683 and PAR-18-684 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-19-329 and PAR-19-330 or their reissues.
See NHLBI Policy Regarding Submission of Clinical Trial Applications (NOT-HL-18-611) for additional information.

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 FOA as opposed to other possible funding opportunities?

A6. This FOA 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 FOA

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

A7. As part of an overall strategy to optimize its clinical trials enterprise, NHLBI first modified in 2015 its FOAs for clinical trials to enhance the identification, inclusion, and application of well-defined performance milestones. 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. Why are detailed milestones and metrics important for single-site trials, which are typically less complex and easier to manage than multi-site clinical trials?

A8. 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.

Q9. What notable characteristics are in the NHLBI FOA for single-site clinical trials?

A9. Some of the more notable characteristicss include:

Having applicants submit as an attachment required for peer review a Trial Management Plan that outlines strategies to proactively manage the clinical trial. Plans should include such elements as the sequence of the tasks with focus on risk identification and mitigation (i.e., development of contingency plans), and timely implementation of solutions, as needed;
Having applicants submit a Clinical Trials Research Experience attachment that is required for peer review;
A protocol synopsis that is a part of the application that peer-reviewers will evaluate;
Having applicants provide detailed information on timelines and processes for reaching core milestones, including accrual targets;
Recruitment and retention plans with data to support accrual projections;
Having applicants submit a Single-Site Justification Plan as an attachment that is required for peer review;
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;
Including peer-review criteria in the FOA that will ensure rigorous evaluation of both scientific impact and operational feasibility;
FOA peer-review criteria that will ensure rigorous evaluation of both scientific impact and operational feasibility;
Specific review criteria that pertain to the protocol synopsis, recruitment and retention plans, timelines and milestones, trial management plans, and key investigator’s research experience; and
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.

Q10. What are the major differences in this reissue (PAR-19-328) of the FOA as compared to the earlier issuance (PAR-18-406)?

A10. Major differences include:

Acknowledging the diversity of clinical trial types;
Emphasizing the importance of providing evidence of equipoise in trial design;
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; and
Emphasizing NHLBI’s monitoring of milestones in R61/R33 phase, and, as appropriate, use of a CAP and award phase-out.

Q11. What personnel experience should be included in the Clinical Trial Research Experience attachment?

A11. 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.

Q12. What funding mechanism is being used to support trials under this FOA?

A12. Applications awarded under this FOA 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 up to one year. The second phase, conditional on a positive evaluation through an administrative review of the first phase, 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.

Application and Review Process

Q13. Will the process for requesting a ≥500K budget be the same for this PAR?

A13. Yes. The NHLBI policy for applications for >500K apply to application submitted to PAR-19-328 (or its reissues). Please refer the instructions on the NHLBI >500K website (hyperlink)

Q14. Under what conditions will an application advance from the R61 to the R33 phase?

A14. 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:

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 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. The awardee will be able to share milestone completion progress through eConnect, an NHLBI platform that will facilitate transfer of electronic information to NHLBI

Q15. At what point in time during the R61 award period will investigators know that the administrative review of that phase was successful and their R33 phase will be awarded?

A15. The administrative review will typically occur at about 9 months into the 12-month R61 award. It is anticipated that the review will be completed, and investigators will be notified whether the R33 phase will be awarded at about 10 or 11 months into the R61 award.

Q16. Is the administrative review a competitive one? That is, will more R61 awards be made than can be supported through the R33 phase?

A16. No, this is not NHLBI’s intent. The Institute will 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.

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

A17. Yes. Institutions outside the United States are eligible to apply for these awards, as are applications with foreign components.

After the Clinical Trial is Funded

Q18. 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?

A18. 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.

Q19. Are there any circumstances under which a single site trial funded under this FOA may add performance sites?

A19. Yes, but these are limited and should 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 FOA 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.

Q20. Are there changes to the CCC or DCC applications resulting from the change to FORMS-F?

A20: Yes, in the Human Studies & Clinical Trials Information of the CCC -- Section 4: Protocol Synopsis -- no longer requires a “Brief Summary”. Due to this change the numbering of all subsection changed slightly and in the Study Design of both the CCC and DCC, the “Narrative Study Description” has been replaced by the “Detailed Description” (4.1.a). All instructions in the FOAs apply.

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.

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.