New FOA for Investigator-Initiated Phase II and Beyond Single-site Clinical Trials - Frequently Asked Questions
[For changes in NIH policy regarding clinical trials, please refer to the NIH Office of Extramural Research page on Clinical Trial Requirements for Grants and Contracts]
Applicability of the FOA for Single-Site Clinical Trials in Phase II and Beyond
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 is a “single-site” (as opposed to a “multi-site”) clinical trial for the purpose of this FOA?
A2. 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, 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.
A multi-site clinical trial, on the other hand, 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.
Illustrative examples of single-site and multi-site clinical trials are provided in the Appendix to these FAQs. 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.
Q3. How is “Phase II” defined for the purpose of applying for clinical trial funding under this FOA?
A3. Phase II clinical trials are those being conducted to obtain preliminary data on the efficacy of a drug, device, biologic, or other clinical intervention. This phase of testing also provides further data on the common short-term side effects and risks associated with the intervention in a larger population than a Phase I study. Phase II studies are typically controlled trials and may enroll up to several hundred participants with the target condition. In contrast, a trial introducing an agent into a human for the first time, or for a new indication, that is aimed primarily at understanding the safety and/or dosage profile of an agent would be considered a Phase I and would not be the type of study intended for funding under this clinical trial FOA.
See NHLBI “Clarification of NHLBI Policy Regarding Submission of Phase II and Beyond Clinical Trials Applications“ (NOT-HL-17-519) for additional information.
Q4. 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?
A4. This FOA is for applications for single-site studies that have a clinical trial in Phase II or beyond as their central aim. 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 Q7 for more detail). You are encouraged to discuss your application with your program officer for further guidance.
Q5. Should proposals for single-site implementation clinical trials be submitted under this FOA?
A5. Single-site implementation clinical trials (i.e., a study examining barriers to, or strategies to promote, the broad implementation of a particular clinical therapy) can apply under this FOA, but there are other options. If there is an open FOA in which NHLBI is participating for particular types of trials, that FOA may be used. At present, there is an open FOA (PAR-16-238) specific to dissemination and implementation research. Therefore, an application for funding an implementation research study may be submitted under the FOA specific to dissemination and implementation clinical trials as long as the FOA is open, or otherwise under the new FOA for Investigator-Initiated Phase II and Beyond Single-site Clinical Trials provided that the proposed research is being implemented by a single site.
Q6. Are there types of Phase II and beyond single-site clinical trials that are not meant to be solicited under this FOA?
A6. This FOA is not meant for applications that propose the following types of research, for which there are other more appropriate FOAs. This includes applications for:
- Multi-site clinical trials in Phase II and beyond. Applications for funding these trials should be submitted under PAR-18-407 (UG3/UH3) for the Clinical Coordinating Center and PAR-18-410 (U24) for the Data Coordinating Center.
- Clinical trials that have as their primary intent to explore fundamental mechanisms of normal biology or pathobiology; refer to Notice 17-519 Early phase (Phase 0 or I) clinical trials including “first in human” and “safety” clinical trials, which can also continue to be submitted under the NIH parent R01 or other appropriate FOA.
- Clinical trial pilot studies that are appropriate for NHLBI’s R34 Clinical Trial Pilot Studies FOA (PAR-16-037).
- Studies supported by an SBIR/STTR grant.
- Clinical trials proposed as part of a Research Career Development (“K”) award.
Impetus for and Purpose of the New Single-site Clinical Trials FOA
Q7. Why are changes being made at this time to the way NHLBI solicits applications for single-site clinical trials?
A7. As part of an overall strategy to optimize its clinical trials enterprise, NHLBI is modifying its FOAs for clinical trials to enhance the identification, inclusion, and application of well-defined performance milestones. This approach, first taken with multi-site trials in Phase II and beyond, is now being applied to funding applications for single-site trials in Phase II and beyond. This will enhance the selection of trials that are operationally feasible and promote the ability of single-site and multi-site clinical trials in Phase II and beyond to achieve their planned objectives within the proposed timeframe and budget. Performance milestones will be identified by the investigators to establish expectations regarding trial performance and will be peer-reviewed.
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 in Phase II and beyond are, in general, operationally less complex than multi-site clinical trials in Phase II and beyond, they still benefit from careful planning, including the identification of milestones and metrics that promote the successful conduct of the trial.
Q9. What notable requirements are in the NHLBI FOA for single-site clinical trials in Phase II and beyond?
A9. Some of the more notable requirements include:
- Having applicants prepare a single-site justification plan; this plan should describe how all participants for the trial will be enrolled at a single institution and in the allotted timeline.
- Requiring that a protocol synopsis be included as an attachment, which will be part of the application that peer-reviewers will evaluate.
- Having applicants provide detailed information on:
- timelines and processes for reaching key milestones, including accrual targets,
- data to support accrual projection, and
- the proposed team’s expertise in clinical trial conduct.
- Having applicants submit project management plans that outline strategies to proactively manage clinical trials. Plans should include such elements as the sequence of the tasks proposed and the critical path for their completion, continuing evaluation of potential barriers to implementation, upfront development of contingency plans, and timely implementation of solutions, as needed.
- For trials using an FDA regulated product, requiring that the results of the pre-IND or IDE meeting, or other evidence of communication with the FDA regarding the proposed use of an FDA-regulated product in a trial, be provided in the application, as well as requiring that applicants obtain all necessary regulatory approvals—including IND authorization or IDE approval, as applicable—prior to award (more information about this requirement can be found in a May 9, 2018 Notice).
- Including peer-review criteria in the FOA that will ensure rigorous evaluation of both scientific impact and operational feasibility.
- Specifying milestone-driven and performance-based expectations in the application and notice of award.
Q10. What funding mechanism is being used to support trials under this FOA?
A10. 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
Q11. Will the review criteria change from those used previously?
A11. Yes. The peer-review criteria for applications submitted under the new FOA will promote rigorous evaluation of not only the study’s scientific impact but also its operational feasibility. For example, the peer-reviewers will be asked to review the milestone plan and the information provided to support accrual goals.
Q12. Will the process for requesting a ≥500K budget be the same for this PAR?
Q13. Under what conditions will an application advance from the R61 to the R33 phase?
A13. Toward the end of the R61 phase, NHLBI will conduct an administrative review of the extent to which peer-reviewed milestones (including enrollment milestones) are met in the R61 phase, including:
- finalization of the protocol and the informed consent/assent document;
- the development of the manual of operations, case report forms, and other resources necessary to implement the protocol;
- further development of study partnerships;
- establishment of a Data and Safety Monitoring Board and review of the protocol; and
- Institutional Review Board approval of the trial.
In addition, all necessary regulatory approvals, as well as source(s) of the necessary drugs, devices, or other resources as needed are obtained during this period. Finally, enrollment into the clinical trial will begin in the R61 phase to allow for an evaluation by the end of the R61 phase of early enrollment and the probability of successfully completing the trial on time and on budget. 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.
Q14. 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?
A14. 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.
Q15. Is the administrative review a competitive one? That is, will more R61 awards be made than can be supported through the R33 phase?
A15. No, this is not NHLBI’s intent. To the extent that NHLBI has awarded an R61, the Institute will be poised to fund the R33 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 R61 phase.
Q16. I am an investigator at an institution outside the United States. Am I eligible to apply for awards under this FOA?
A16. 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
Q17. 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?
A17. If you believe that unanticipated events necessitate changing your milestones after you are funded, 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.
Q18. Are there any circumstances under which a single site trial funded under this FOA may add performance sites?
A18. 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 all of 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.
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.