1. Why does NCCIH offer separate clinical trial funding opportunity announcements (FOAs) for mechanistic studies and clinical outcome studies?
NCCIH recognizes a difference between clinical trials that are designed to answer specific questions about the clinical effect(s) of interventions, and mechanistic studies that have the primary goal of understanding how an intervention works.
- A clinical outcome study is defined as one with the objective of determining the clinical safety, tolerability, feasibility, efficacy, and/or effectiveness of pharmacologic, nonpharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions.
- A mechanistic study is defined as one designed to understand the mechanism of action of an intervention, a biological or behavioral process, or the pathophysiology of a disease.
NCCIH has created a suite of separate clinical trial FOAs to support mechanistic research focused on understanding how a mind and body or natural product intervention works, and to support clinical research to develop and test the feasibility, efficacy and effectiveness of mind and body or natural product interventions for particular conditions. We have chosen to create separate FOAs for mechanistic questions and for clinical questions because it’s very difficult to conduct well-designed rigorous research that simultaneously address both sets of questions. We encourage investigators to choose which research question they wish to focus on first – “How Does an Intervention Work?” or “Does this Intervention Work for a Given Condition?”; investigators can then select an appropriate FOA.
2. What types of research do the NCCIH clinical trial FOAs support?
They fund investigator-initiated natural product studies and mind and body intervention studies, and are designed to support all phases of clinical intervention development and testing.
We support investigators working to establish “building blocks” that bridge the gap from basic research to high-impact clinical trials on complementary and integrative health interventions. Examples of building blocks include feasibility testing, assessment of outcome measures, and intervention fidelity testing. Since it’s often difficult for investigators to find research funding to establish these building blocks, we provide funding mechanisms for these foundational components.
3. What kinds of human subjects research will NCCIH still accept through the Parent R01?
The NIH now offers 3 options for the Parent R01 (see comparison of FOA types by clinical trial allowability):
- Parent R01 Clinical Trial Not Allowed (PA-19-056): NCCIH will continue to accept applications to this FOA for observational studies such as survey studies, cohort studies, or case-control studies, as well as secondary analyses of existing data sets or banked samples.
- Parent R01 Clinical Trial Required (PA-19-055): NCCIH will only accept applications that propose human mechanistic trials/studies; no applications will be accepted that include any specific aims that propose to assess efficacy or effectiveness of any intervention (see NOT-AT-19-011).
- Parent R01 Basic Experimental Studies with Humans Required (PA-19-091): NCCIH will accept applications that propose basic science experimental studies involving humans, referred to in NOT-OD-18-212 as “prospective basic science studies involving human participants.” These studies assess biomedical or behavioral outcomes in humans for the purpose of understanding the fundamental aspects of phenomena without specific application toward processes or products in mind.
4. What will happen to my application if I submit a clinical trial focused on clinical outcomes to the Parent R01 (Clinical Trial Required) and ask for it to be assigned to NCCIH?
NCCIH won’t accept your application (see NOT-AT-19-011). The Center for Scientific Review (CSR) might be able to find another Institute or Center (IC) at NIH to accept it, but if other ICs won’t accept it because it doesn’t align with their mission, the application will be withdrawn without review. To avoid this possibility, contact NCCIH program directors for advice prior to submission and use the NCCIH clinical trial–specific FOAs when appropriate.
5. What’s different about the NCCIH-issued clinical trial FOAs?
The NCCIH FOAs are specifically designed for investigator-initiated clinical trials on complementary and integrative approaches.
- Applicants using the FOAs must provide details about their proposed clinical studies in a standardized way via the “PHS Human Subjects and Clinical Trials Information” form in the application package.
- The NCCIH clinical trial FOAs also require additional attachments depending on each FOA. These attachments may include a Clinical Trial Experience Table, a Milestone Plan, and/or a Project Management Plan. See the Mind and Body FOAs and Natural Product FOAs for more details. Please check for “Related Notices” in the FOAs in case there are any changes to required elements.
- NCCIH special review panels will use the information in PHS Human Subjects and Clinical Trials Information form and the additional attachments to assess key elements of the clinical study, investigator experience, and how regulatory issues will be addressed
6. How do I decide if NCCIH is the best fit for my proposal vs. other NIH ICs?
We strongly encourage you to review the NCCIH Strategic Plan, including the top scientific priority areas listed in the plan, to see if your research interests might be in line with the Center’s. You may also review the Center’s active funding announcements and read any FOAs of interest. If NCCIH is one of several NIH components that has signed on to an FOA, pay attention to statements about our Center’s research interests. Also, look for NIH Guide notices listed in the FOA itself.
We encourage you to contact the appropriate NCCIH program director to discuss your potential application. It may facilitate the conversation if you send a short summary of the specific aims of your study.
7. How do I decide which FOA to apply for?
NCCIH has developed separate independent clinical trial FOAs for (1) natural product studies and (2) mind and body interventions, so be sure you’re looking at the series best suited for your area of research.
Then, within that series, choose the FOA that most closely matches the stage of research that your project represents. Each series includes FOAs for early phase trials, intermediate trials, and full-scale efficacy, effectiveness, or pragmatic trials. Each FOA describes what type of preliminary data is needed for the stage of research that the FOA supports.
8. Who will review applications submitted in response to NCCIH clinical trial FOAs?
Applications submitted to the Fundamental Science Research on Mend and Body Approaches R01 and R21 FOAs (PA-18-322 and PA-18-323) are reviewed by standing study sections in the NIH Center of Scientific Review. Applications to all the other NCCIH clinical trial FOAs will be reviewed by NCCIH special review panels with expertise in both clinical trials and complementary health approaches. The panels will include experts familiar with the challenges faced by this research community. They should be able to provide valuable advice to NCCIH and constructive feedback to investigators.
Natural product trial applications will go to a special review panel with expertise in clinical trials and natural products. Mind and body intervention trial applications will go to a different special review panel with expertise in clinical trials and mind and body interventions.
9. Are there additional review criteria that will affect my proposal’s scores and prospects for funding?
Yes. Applicants need to pay close attention to the review criteria in the FOA. Investigators must include all requested information and address the specific review criteria listed in the FOAs. Review criteria will impact the scoring of the application.
10. I’ve heard that applications may be returned without review if they don’t contain the required elements or aren’t compliant with the FOA instructions. Is this true, and how can I be sure that my application is complete and compliant?
Yes. It’s standard procedure at NIH to review applications for completeness. The NCCIH clinical trial FOAs describe attachments and information that must be included for your application to be considered responsive and complete. If your application does not include these required elements, it will be returned to the submitting institution. See the Mind and Body FOAs and Natural Product FOAs for more details. Please check for “Related Notices” in the FOAs in case there are any changes to required elements.
In addition, the FOAs indicate what stage of research will be supported by each FOA. If your proposed trial is not appropriate for the FOA (for example, if you submit an application for an efficacy trial to an early phase clinical research FOA), your application will be reviewed, but NCCIH will not fund it.
11. Are multisite trials allowed?
Yes, the UG3/UH3 FOAs encourage the submission of multisite trials to assess efficacy and effectiveness of complementary health approaches, and the U01 FOAs also allow multisite studies, but please discuss your proposed trial with the appropriate NCCIH program director before submitting your application.
All UG3/UH3 clinical trial proposals require the submission of a companion data coordinating center application (U24).
12. Are multisite trials expected to have a single Institutional Review Board (IRB)? Who will organize a single IRB?
NIH issued a policy in 2016 that establishes the expectation that a single IRB of record will be used for multisite research. You can find an introduction to this policy on NCCIH’s Research Blog and the full policy on NIH’s Web site.
13. Will NCCIH be taking a more active role as a collaborator in my research?
For the cooperative agreement mechanisms (i.e., U awards), once an award has been made, an NCCIH staff member will be assigned as a program scientist and participate in the steering committee for it. This person will serve as a resource for the study team.
NCCIH staff know of the challenges presented by complementary and integrative health research and are available to help grantees address these challenges. The NCCIH Clinical Research Toolbox is an example of one resource that we have developed to assist investigators.
14. Is it necessary to register all clinical trials with clinicaltrials.gov?
Yes. For more details, review the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information.
15. Is data sharing encouraged?
Yes. Please contact an NCCIH program director for details.
16. Is a recruitment plan required? Will NCCIH monitor progress of the trial? Are there consequences for failing to meet the recruitment milestones?
Yes, yes, and yes. Please consult NCCIH’s policy on Study Accrual and Retention for Human Subject Research for details. This policy provides transparency on how NCCIH will carry out its oversight responsibilities.
17. I want to apply for funding to further analyze an existing clinical trial database to address questions that are beyond those addressed in the planned primary analyses of the trial. Could I use the parent R01 FOA? Which one?
Yes. Because you do not plan to enroll new participants and will not be recontacting study participants, you could use the parent R01Clinical Trial Not Allowed FOA (PA-19-056).
18. I want to apply for funding to conduct a prospective observational study of patients being treated in real-life practice settings. Could I use the parent R01 FOA? Which one?
Yes. Because the participants are not assigned to a treatment as part of this observational study, you could use the parent R01Clinical Trial Not Allowed FOA (PA-19-056).
19. I currently have a human subjects R01 from NCCIH. How do I submit a competitive renewal for my R01 (type 2)?
As stated in NOT-AT-19-011, NCCIH no longer accepts most clinical trial applications via the Parent R01 Clinical Trial Required FOA (PA-19-055). If your R01 was funded under the Parent R01 FOA, NCCIH will not accept your renewal application via this FOA if it contains a clinical trial. The CSR might be able to find another IC at NIH to accept it, but if other ICs won’t accept it because it doesn’t align with their missions, the application will be withdrawn without review.
To avoid this possibility, contact NCCIH program directors for advice and use the new NCCIH clinical trial-specific FOAs when appropriate.
20. What is a Data Safety and Monitoring Plan?
A complete description can be found on the NCCIH Web site: Data and Safety Monitoring of NCCIH-Funded Clinical Research. The Web site includes sample templates that applicants may use.
21. How does an applicant decide whether a Data and Safety Monitoring Board (DSMB) is required?
NCCIH requires independent monitoring of all human subjects research. A DSMB is required for all Phase III trials and should be considered for other clinical trials with associated safety risks.
You can learn more from the documents in NCCIH’s Clinical Research Toolbox and from NCCIH’s policy on Data and Safety Monitoring of NCCIH-Funded Clinical Research.
22. What materials can be included in an appendix of an NCCIH clinical trial application?
Nearly all of NCCIH’s clinical trial FOAs require additional attachments including, an additional 3 pages for a table of all study investigators’ experience conducting clinical trials. Additional items are required for multisite trials. Please see the instruction section of the FOA you plan to use for further details.
- Per NIH policy (NOT-OD-18-126), clinical trial-related materials will be specified in the PHS Human Subjects and Clinical Trials Information Form and no longer allowed in the Appendix unless specifically stated as required in the FOA. Allowable appendix materials include: Blank data collection forms (surveys, questionnaires)
- Blank informed consent/assent forms
- Other items only if they are specified in the FOA as allowable.
23. What is the difference between an RFA (Request for Applications – Grants) and PA/PAR/PAS (Program Announcement/Program Announcement Reviewed in an Institute)?
A PA/PAR/PAS is an ongoing solicitation, usually with multiple receipt dates. A PAR is a PA with special receipt, referral, and/or review considerations. A PAS is a PA that includes specific set-aside funds. RFAs are solicitations in a well-defined scientific area to accomplish specific program objectives. RFAs usually have a single receipt date, are reviewed by a review group convened only for that RFA, and have set-aside funds for awarding grants.
Please contact the appropriate NCCIH program director to ensure your proposed study is within NCCIH priorities before preparing an application.