Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3) - Clinical Trial Required

Released Date
Expiration Date
Activity Code
UG3/UH3
Full Announcement
PAR-18-407

New FOAs for Investigator-Initiated Phase II and Above Multi-site Clinical Trials - Frequently Asked Questions

The New FOAs for Multi-site Clinical Trials


Q1.  What is a “clinical trial” for the purpose of these FOAs?

A1.  The Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC) FOAs apply to clinical trials as defined by NIH (see below) that enroll participants at two or more independent recruitment sites. The FOAs are not intended to support single-site clinical trials, first-in-human/Phase I trials, or multi-site observational studies that do not fit the NIH definition of a clinical trial (NOT-OD-15-015).

The NIH definition of clinical trial is (NOT-OD-15-015):

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 “multi-site” (as opposed to a “single-site”) clinical trial for the purpose of this FOA? 

A2.  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.

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. 

Phase II and beyond single-site clinical trial research grant applications relevant to NHLBI’s mission should generally be submitted toPAR-18-406 (for additional information, see the FAQs for Investigator-Initiated Single-site Clinical Trials (Phase II and above).   

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 strongly 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 multi-site clinical trial funding under these FOAs?

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 helps determine the common short-term side effects and risks associated with the intervention. Phase II studies are typically well-controlled, closely monitored, 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 profile of an agent would be considered a Phase I (rather than a Phase II) and would not be the type of study intended to be funded under these multi-site clinical trial FOAs.

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 multi-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. You are encouraged to discuss your application with your program officer for further guidance.


Q5.  Why are changes being made at this time to the way NHLBI solicits multi-site clinical trials?

A5.  The new FOAs are intended to enhance the selection, conduct, and oversight of NHLBI multi-site clinical trials through the identification, inclusion, and application of well-defined performance milestones. This approach will enhance selection of trials that are operationally feasible and promote the ability of multi-site clinical trials in Phase II and above to complete on budget, on time, and according to the originally-planned objectives of the study. Performance milestones will be identified by the investigators and reviewed by NHLBI, thus establishing shared expectations regarding trial performance. NHLBI will use the performance milestones to monitor and oversee trial conduct and results dissemination.
 

Q6.  What notable requirements are in the NHLBI FOAs for multi-site clinical trials?

A6.  Some of the more notable requirements include: 

  • Requesting that a protocol synopsis be included as an attachment, which will be part of the application that reviewers will be required to assess.
  • Having applicants provide more detailed information up front 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.
  • Articulating in the FOA peer-review criteria that will ensure rigorous evaluation of both scientific impact and operational feasibility.
  • Having both the CCC and the DCC applicants submit project management plans that outline strategies to proactively manage the clinical trial activities, including continuing evaluation of potential barriers to scientific and clinical activities, 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/IDE meeting and FDA communications 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). 
  • 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.
  • Providing project support for five years with the potential for up to seven years if strongly justified.

For additional changes and more detail, please read the Funding Opportunity Announcements, available at:

Q7.  There seems to be much overlap in the application requirements for the CCC and the DCC. How distinct must the grant applications be?  

A7.  In many cases, the innovation and significance sections of the DCC and CCC applications may be similar. However, for example, the DCC might be implementing an innovative data management system that would be highlighted just in the DCC application. There may be other elements of innovation in trial design and conduct that are particular to either the DCC or CCC and would be reflected in the corresponding application. 

Q8.  May the DCC and CCC be at the same institution or location?

A8. Yes. 

Q9.  May I include in my application to the UG3/UH3 FOA a proposal for a pilot study to be conducted during the UG3 phase?

A9.  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-16-037 (R34).

Q10.  Should proposals for multi-site implementation clinical trials be submitted under this FOA?

A10.  Multi-site implementation clinical trials (i.e., a study examining barriers to, or strategies to promote, the broad implementation of a particular clinical therapy) may apply under this FOA, but there are other options. To the extent that there is an open FOA in which NHLBI is participating for particular types of trials, that FOA may still be used. 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.
 


Application Submission and Review Process


Q11.  Will the review criteria change from those used previously?

A11.  Yes. The new FOAs articulate peer-review criteria that will promote rigorous evaluation of not only the study’s scientific impact but also its operational feasibility. For example, the reviewers will be asked to review the milestone plan and the information provided to support accrual goals.

Q12.  Under what conditions will an application advance from the UG3 to the UH3 phase?

A12.  Toward the end of the UG3 phase, NHLBI will conduct an administrative review of the extent to which peer-reviewed milestones (including enrollment milestones) are met in the UG3 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;
  • Institutional Review Board approval of the trial; and
  • All necessary regulatory approvals, as well as source(s) of the necessary drugs, devices, or other resources as needed.

Finally, enrollment into the clinical trial will begin in the UG3 phase to allow for an evaluation by the end of the UG3 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 UH3 phase award will be issued, subject to NHLBI funding availability.

Q13.  At what point in time during the UG3 award period will investigators know that the administrative review of that phase was successful and their UH3 phase will be awarded?

A13.  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. 

Q14.  Is the administrative review a competitive one? That is, will more UG3 awards be made than can be supported through the UH3 phase?

A14.  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. 

Q15.  Will this change the preapproval process for projects with a proposed direct cost budget of $500,000 or more? 

A15.  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 (at 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. 

Q16.  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?

A16.  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 preapproval 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.

Q17.  I am an investigator at an institution outside the United States. Am I eligible to apply for the CCC or DCC awards under these FOAs?

A17.  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 apply for a DCC or CCC award.

Q18.  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?

A18.  Yes, you do. In addition, we strongly encourage you to contact your NHLBI Program Officer to discuss the need for another consultation visit or call.
 

Currently Funded Trials


Q19.  NIH has issued a requirement that NIH-funded multi-site studies utilize a single IRB. How will that requirement be reflected in these FOAs?

A19.  The NIH requirement for a single IRB on studies it funds applies to all competing grant applications (new, renewal, revision, or resubmission) with receipt dates on or after January 25, 2018. Ongoing, non-competing awards will not be expected to comply with this policy until the grantee submits a competing renewal application. In the meantime, applicants may consider the use of a single IRB in advance of this policy’s effective date.

Q20.  I am interested in applying 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 FOAs (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 (Phase II and above) through a milestone-driven cooperative agreement (U24) award?

A20.  You will have to apply under the new FOAs 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.
 

Investigator Input


Q21.  Has the investigator community had input into these proposed changes?

A21.  Yes. In November 2015, NHLBI published a “Request for Information” on Optimizing the NHLBI Clinical Trials Enterprise: Performance Milestones and Metrics.  NHLBI received robust input from many diverse stakeholders through this process. NHLBI has also consulted its advisory council, which is composed of scientists and clinicians in academic, industry, and clinical care settings. Collectively, that input informed the development of the new FOAs. 

    

Content and Form of CCC and DCC Application


Q22.  In the Research Strategy, the CCC FOA describes what should be provided in a Recruitment and Retention Plan, including two tables showing enrollment goals and number of potential participants available at each site. Does this need to be two separate tables if the information can be fit into one table, and is there any other place the table(s) can be provided in the application besides the Research Strategy?

A22.  Description of the Recruitment and Retention plan is a key element to the FOAs, and applicants should address questions 1 -11 listed in the CCC FOA. The table showing the recruiting sites and site PDs/PIs and the table documenting enrollment goals and number of participants available at each site can be condensed into one table (see NOT-HL-16-338). Furthermore, the table may be provided in the Clinical Protocol Synopsis Attachment under Enrollment Sites but should be appropriately referenced in the Recruitment and Retention Plan. The 12 page limit for Clinical Protocol Synopsis may not be exceeded.      

Q23.  Should the Project Management Plans for CCC and DCC be identical?

A23.  No. The Project Management Plan for the CCC application should address the processes governing resource management, study deployment, and operations/execution that will be implemented to coordinate the clinical operations for the trial. The Project Management Plan for the DCC should address the processes governing resource management, study deployment, and operations/execution that will be implemented to coordinate study administration, data management, and biostatistical support. Both plans should address collaboratively how the CCC and DCC will proactively evaluate and prioritize issues that jeopardize study goals and develop corrective responses to resolve fiscal and logistical issues (risk planning) in a timely manner. 

    

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.