October 28, 2015
2:00 p.m. to 3:00 p.m. EST
Purpose of the Webinar:
On Wednesday, October 28, 2015, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) hosted a pre-application webinar for potential applicants to discuss two new Funding Opportunity Announcements (FOAs):
- Phased Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R61/R33)
- Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R33)
The webinar provided technical assistance and conveyed important information to prospective grant applicants, including an overview of the research grant submission process, an in-depth discussion of the funding opportunity announcements, and what to expect in the peer-review process. The webinar also provided the opportunity for potential applicants to virtually meet the Program Director overseeing the effort and featured a question-and-answer session.
Anita McRae-Williams, M.A., Outreach Program Manager, National Center for Complementary and Integrative Health (NCCIH) (Webinar Moderator)
Wen G. Chen, Ph.D., Program Director, Basic and Mechanistic Research in Complementary and Integrative Health, Division of Extramural Research, NCCIH
Additional NCCIH Staff Present:
Shelley Carow, Chief Grants Management Officer, NCCIH
Dale B. Dreer, Ph.D., Chief, Office of Scientific Review, NCCIH
John S. Williamson, Ph.D., Branch Chief, Basic and Mechanistic Research in Complementary and Integrative Health, Division of Extramural Research, NCCIH
This report summarizes information provided during the webinar about: (1) the general framework for NCCIH’s Mind and Body Intervention; (2) the purpose and scientific details of the R61/R33 Request for Applications (RFA) and the R33 RFA; (3) the budget, duration, and page limit of the RFAs; (4) key sections of the RFAs to which potential applicants should pay particular attention; and (5) answers to the questions posed by participants.
What is a “Mind and Body Intervention”?
- As described in NCCIH’s Strategic Plan, mind and body research encompass a wide variety of interventions which are based on physical procedures or techniques that are administered or taught to others by a trained practitioner or teacher.
- Some commonly used examples of such interventions include, but are not limited to, acupuncture, meditation, guided imagery, progressive relaxation, tai chi, yoga, spinal manipulation, massage therapy, hypnosis, and Qi gong. More information is available on the NCCIH website.
NCCIH Framework for Research on Developing and Testing Mind and Body Interventions
- Over the past decade or so, the NCCIH has developed a general conceptual framework for research on developing and testing mind and body interventions. The Institute categorizes research on mind and body interventions into three general stages:
- The exploratory/piloting stage of studies asks questions about whether the benefit of the interventions can be measured with a clinically meaningful signal, whether the interventions can be optimized for future studies, and whether the study is feasible with people adhering to protocol.
- The efficacy/effectiveness stage of studies focuses on efficacy (which refers to a clinically meaningful effect measured in an ideal design) or effectiveness/comparative effectiveness (which assess the effects in real-world settings).
- The third stage focuses on dissemination and implementation to assess whether the interventions can be widely used.
- Mechanistic studies of mind and body interventions are considered as part of the exploratory/pilot stage of studies. Such mechanistic studies may represent a sequential but iterative process among probing specific mechanistic measures, their associations with clinically meaningful signals, and the ability to optimize the interventions based on the mechanistic insights.
- Specifically, the first step of such research may be to measure the mechanistic changes affected by the intervention in association with a functional or clinical signal. The second step would then be to utilize the mechanistic insight to optimize the intervention.
- The sequential nature of intervention development and optimization consequently requires a phased research approach.
Overview of the R61/R33 and R33 RFAs
- The two newly published RFAs are intended to support a phased approach to mechanistic studies in human subjects, with the ultimate goal of optimizing the effects of the mind and body interventions.
- The first phase of such studies (the R61 phase) is designed to demonstrate that the fundamental mechanisms of mind and body interventions may be modifiable.
- The second phase (the R33 phase) is designed to optimize the intervention’s effects on the presumed mechanisms, build validated clinical research tools, and strengthen clinical impact of these interventions (e.g., by suggesting approaches to modifying the interventions, monitoring/enhancing its clinical effects, or identifying a suitable target population).
- Importantly, both phases of these mechanistic studies should be adequately powered for the effects on the proposed mechanistic measures. Neither phase is intended for randomized clinical trials with primary objective to determine efficacy or effectiveness of clinical outcomes.
- Should an applicant be funded for the R61 phase, the funding of the R33 phase is not guaranteed.
- An administrative review process will determine the transition from the R61 to the R33 phase. The results from the R61 phase and the availability of funds will both be important in determining the success of the transition.
Key Application Elements
- Applications for either of the two RFAs must clearly define and describe three key elements in both the Specific Aims page and in the Research Strategy section, as follows:
- The first element is Intervention. Which mind and body intervention is proposed to be studied in this proposal and why? Applicants should describe the delivery of the intervention with some details.
- The second element is Mechanism. The proposed or hypothesized mechanism should be precisely defined, preferably by the exact assessments or measures to be used to determine the mechanistic process. A general category should not be used as the hypothesized mechanism.
- For example, if an applicant would like to determine the neural mechanism, he or she should define precisely the brain regions or networks to be tested in the study as the proposed mechanism.
- Similarly, if an applicant wants to test molecular mechanisms, the mechanism should be defined by the hypothesized molecules or protein complexes or pathways as the mechanism rather than a general term called “the molecular mechanism.” A rationale should be provided explaining why such a mechanism may be a reasonable direction to study for the proposed intervention or the outcome. How novel is the proposed mechanism? Is it novel from the intervention perspective or the outcome perspective?
- The third element is Outcome. Similar to mechanism, the outcome (whether functional or clinical) should be quantifiable. The outcome may be studied in either a healthy population or a clinical population, depending on the applicant’s hypothesis.
Choosing Between the R61/R33 Combination RFA and the R33 Stand-Alone RFA
- The decision to submit to the R61/R33 combination RFA versus the stand-alone R33 RFA should be based on the current scientific knowledge of the applicant’s intended intervention.
- It may be helpful for applicants to conduct a literature search to determine whether their proposed intervention and mechanism have already been studied in an interventional design. In other words, is the intervention shown to impact the proposed mechanism in comparison to another intervention or at least usual care in a prospective study?
- If not, then applicants may want to propose to test this idea first in the R61 phase, followed by work on optimizing the intervention in the R33 phase (if this is the case, applicants should apply for the R61/R33 combination RFA).
- If so, then applicants may want to start developing strategies to optimize the intervention based on the known mechanistic insights in the R33 phase (and therefore should apply for the R33 stand-alone RFA).
- For applications submitted to either the R61/R33 combination RFA or the stand-alone R33 RFA, investigators must clearly spell out the design, optimization strategies, and three key elements (intervention, mechanism, and outcome) of the R33 phase.
R61/R33 Combination RFA
- For those applicants who elect to pursue the R61/R33 combination RFA, the primary goal in the R61 phase is to determine whether the intervention can specifically increase or decrease the quantifiable measures of the mechanism. In this phase, the primary focus should be the mechanism—the sample size and calculations should be based on generating potentially statistically significant changes for the mechanism.
- Investigators may also add another outcome measure in the R61 that should be relevant to the proposed mechanism.
- Such an outcome measure could be either a functional measure in a healthy population or a clinical outcome measure in a clinical population.
- The point of adding such outcome measures in the R61 phase is to determine whether the intervention’s effect on the mechanism correlates to changes in the outcome. It is not expected that the study should be powered for changes in outcome C.
- Given the exploratory nature of the R61, study designs in this phase may vary. Applicants should determine whether there is any literature demonstrating the correlation between the intervention and their proposed mechanism in an observational design.
- If so, applicants may consider proposing an interventional study to probe the relationship between the intervention and the mechanism.
- If not, applicants may propose both an observational study to assess the correlation between the intervention and mechanism as well as an interventional study to assess whether the intervention can in fact modify the mechanism.
R33 Stand-Alone RFA
- With the R33, investigators will build on prior mechanistic studies about the modifiable relationship between the intervention and mechanism as well as develop strategies to enhance the effect of the intervention on the mechanism. In this phase, the studies should be powered for the statistical effects on the mechanism.
- Investigators should also include relevant clinical outcome measures if possible.
- It is highly recommended that the R33 studies should utilize an interventional design.
- The choice of control groups should be determined by the specific mechanism to be tested.
- Investigators should also try to blind the subjects and the raters whenever possible.
- NCCIH Office of Clinical and Regulatory Affairs Director Dr. Catherine Meyers recently published a blog specifically discussing issues related to planning for effective blinding. Investigators are highly recommended to read this blog while planning for the R33 phase application.
R33 Optimization Strategies
- Investigators are encouraged to think creatively and innovatively regarding their strategies for optimizing mind and body interventions in the R33 phase.
- Such optimization strategies may include:
- Those focused on modifying the intervention by selecting and amplifying its active components—the idea being that the modified intervention will result in stronger effects on the proposed mechanism and consequently a stronger clinical outcome.
- Those focused on directly modifying the mechanism by adding a device or combining with another therapy that has been shown to modulate the same mechanism. By adding another therapy (such as a device, natural product, or a pharmacological treatment) that may also modulate the same mechanism, there may be synergy between the mind and body intervention and the added therapy to augment the mechanistic impact, thus leading to an enhanced effect on the clinical outcome(s).
- Those focused on modifying the outcome by, for example, selecting a clinical outcome or a target population more relevant to the presumed mechanism. This strategy may be particularly useful if the R61 phase of the mechanistic study is performed in a healthy subject population (with the R33 then testing the same mechanistic impact in a clinical population). Although the mechanistic impact of the intervention in a healthy population may be small for a given functional outcome, when a suitable clinical population is chosen, the mechanistic impact may be much higher, likely due to a lower baseline of the mechanistic measure pre-intervention. Consequently, the benefit to a related clinical outcome may also be amplified.
Criteria for Transition from R61 to R33
- Every R61/R33 application must address and develop “go/no-go criteria” for the proposed transition from the R61 phase to the R33 phase.
- Examples of potential “go/no-go criteria” applicants may want to consider include:
- The ability to reliably and validly measure the proposed mechanisms in the R61 phase, provided with rationale and specifics
- The ability to complete the subject recruitment and assessments of baseline, mechanistic, and outcome measures in the R61 phase, provided with rationale and specifics
- Demonstration of the impact of the intervention on the proposed mechanisms with statistical significance;
- Preparatory work for the R33 phase, such as draft protocol, data safety monitoring plan, and additional preliminary data and other regulatory approvals required for the R33 phase.
- Applicants may have multiple potential mechanisms and/or multiple related outcomes in mind for a specific mind and body intervention.
- Investigators are encouraged to pick the most reasonable potential mechanism to focus on as the primary mechanism for both the R61 and R33 studies. The other potential mechanisms may be described and planned as secondary, alternative, or back-up plans.
- In such cases, investigators should also clearly describe how to determine which mechanism and outcome the R33 phase will be continued in the “go/no-go criteria.”
- The research/optimization strategy in the R33 should also reflect the plans for both the primary and secondary/alternative/backup mechanisms and outcomes to maximize the potential for successfully transitioning from the R61 to the R33 phase.
Award Duration, Funding, and Application Submission Information
- For the R61/R33 combination RFA:
- The first phase (R61) will support 1-2 years of research. Each R61’s budget should not exceed $275,000/year in direct costs. For FY 2016, the NCCIH intends to fund 5-10 awards (depending on the number of meritorious applications submitted and their budgets).
- The R33 phase will be supported for up to an additional 3 years at a level of no more than $500,000/year in direct costs.
- The total page limit for the R61/R33 application is 12 pages, excluding human subject protection description, other required documents, and appendices.
- Letters of Intent are due by December 15, 2015 Letters of Intent should be e-mailed to Dr. Dale Dreer and include a descriptive title of the proposal, names of phone numbers of the Principal Investigators (PIs) and other key personnel, participating institutions, and the name and title of the RFA to be cited.
- Applications are due on January 15, 2016. R61 phase applications are expected to be awarded in July-September 2016.
- Once funded, R61 investigators may submit a request for R33 transition in April-May time of 2017 or 2018 (investigators must also submit required materials illustrating the completion of the “go/no-go criteria.”)
- After administrative review by NCCIH program and scientific staff, the funding of the R33 phase may be awarded in July-September of the same year that the transition request is submitted.
- For the R33 stand-alone RFA:
- The NCCIH intends to fund 2-3 awards in FY 2016. The R33 RFA supports up to 3 years of research and the budget should not exceed $500, 000/year in direct costs.
- The total page limit for the R33 RFA application is also 12 pages.
- Letters of Intent are due by December 15, 2015 Letters of Intent should be e-mailed to Dr. Dale Dreer and include a descriptive title of the proposal, names of phone numbers of the PIs and other key personnel, participating institutions, and the name and title of the RFA to be cited.
- Applications are due on January 15, 2016.
- In contrast to the R61/R33 combination RFA, investigators who are successful in obtaining an R33 are expected to complete the proposed studies in 3 years and there will be no administrative review beforehand.
- It is strongly suggested that applicants read the entire RFAs carefully to gain a better understanding of both.
- In particular, applicants should pay close attention to the following sections of Part 2. Full Text of Announcement:
- Section I, Funding Opportunity Description.
- Section IV, Application and Submission Information – Part 2. Content and Form of Application Submission. The “Other Project Information” section provides important information about additional required materials that must be submitted as other attachments. The “Research Plan” section includes detailed guidance on how to write up the research strategy section of the proposal.
- Section V, Application Review Information. This section describes the review criteria.
- Scientific questions related to these RFAs should be submitted to Wen G. Chen, Ph.D. (phone: 301-451-3989; e-mail: email@example.com).
- Letters of Intent (due December 15, 2015) should be submitted to Dale B. Dreer, Ph.D. (phone: 301-480-9483; e-mail: firstname.lastname@example.org).
- Phased Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R61/R33): RFA-AT-16-005
- Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R33): RFA-AT-16-006.
- Director Dr. Catherine Meyers’ recently published a blog on issues related to planning for effective blinding: nccih.nih.gov/research/blog/effective-blinding-plan
- NCCIH home page: nccih.nih.gov
Summary of Questions and Answers
- Can I still apply to either of these opportunities if I have started my pilot study before your submission deadline? If the study needs to start after submission or approval, then may I address the phased innovation award stipulations and repeat the pilot?
- Without having additional information on the pilot, it is difficult to provide guidance on these questions. It depends on what the investigator means by “pilot study.” Investigators need to determine whether this pilot work would lead up to the equivalent of the R61 RFA type of work. If the investigator has not yet generated any data, he or she could consider applying to the R61/R33 RFA.
- I am a professor in Canada and heard that while R01s can be applied for internationally, the priority topics are only available to domestic PIs. Could you comment on this issue and whether the opportunities are likely to open up to international PIs?
- These RFAs are not initially open to international applicants. Should the program be successful, we are likely to turn this into a standing program, in which case investigators and components of foreign institutions may be added.
- Is an RCT desired for phase 1? Does the RCT need to be completed with the clinical population?
- For phase 1, the more rigorously designed the trial is, the better it will be. It depends on where the science is for a particular intervention and the hypothesized mechanism. If there is no correlation data to begin with, the investigator may want to begin there. But it may be useful to have an intervention in a trial that is close to an RCT design. The phase 1 work only needs to be powered for mechanism, which means that it generally will require a small sample size to get a meaningful effect.
- Are preliminary data needed for the R61 phase?
- The R61 is designed to begin with an idea, so preliminary data are not required.
- The RFA indicates that high-priority areas include mental health as it presents in primary care (e.g., mild/moderate depression/anxiety). Is PTSD a priority area only if patients come from primary care, or could they come from mental health clinics too?
- This question relates to the clinical outcomes and clinical populations for the RFA studies. The RFAs are intended to focus on the mechanisms of interventions. The high-priority outcomes were selected and highlighted in the RFAs because they are the outcomes for which many mind-body conventions have been utilized.
- Can you confirm total funding amounts? Is that $550,000 for a 2-year R61? It says no more than $275,000 per year at the R61 level, but just wanted to confirm.
- For the R61 phase, which can last for up to 2 years, the budget should not be more than $275,000 in direct costs per year.
- The RFA describes a preference for a randomized trial in the R61 phase. This would suggest some ability to test optimization of an intervention strategy in the R61 phase. Namely, determining whether an optimized intervention versus a regular intervention changes the mechanism. Please comment.
- This work is not being sought through the R61 phase. If this is the type of work that an investigator wants to do, he or she should probably go straight to the R33 phase. We do not encourage optimization in the R61 phase.
- Are multi-site studies allowed under these RFAs?
- If they can fit within the budget and time constraints, there is no restriction in terms of multi-site versus single-site applications.
- Can I send my specific aims page to Dr. Chen and get feedback?
- Applicants are welcome to send this information to Dr. Chen, but there is no guarantee that she will be able to provide any feedback. Any applicants who want to send this information to Dr. Chen are encouraged to do so as soon as possible.
- Will the study section review be conducted within an NCCIH special study section or added onto/routed through to a standing NIH study section?
- These applications will be reviewed by a panel convened by NCCIH.
- In the example that you discussed of utilizing brain stimulation to add to meditation in an R33 phase – the mechanisms of brain stimulation and the mechanisms of meditation may be worked out, but the combination of the two interventions has not been done (in this example). If the two mechanisms may be worked out, but the combination has never been done, is the R33 still OK, or does the R61 need to be done to combine the two combined mechanisms?
- If the mechanism has been done separately for the two interventions (meditation and brain stimulation), then the applicant should go straight to the R33 to test the combined effect.
- Is there only one shot for a successful application? In other words, can we revise the application based on the reviewers’ comments like other traditional NIH grants?
- The RFA is a one-shot process. However, because we are attempting to convert this into a standing program, if an applicant is not funded through the RFAs at this time, he or she is welcome to resubmit when the standing program opens. Applicants can also resubmit as an R01, but that may be challenging because of the special designs required of these RFAs.
- Does the R61/R33 research plan include 12 pages for the R61 phase only or both phases of a study?
- The 12-page limit applies to both phases of the study. Investigators must propose both phases for the R61/R33 research plan, not just the R61. Investigators cannot include only a brief description of the R33—the R33 is an important part of the review criteria.
- The R33 phase could test the optimized intervention versus standard intervention, or the optimized intervention versus a control condition (or optimized versus both a standard and control intervention in a three-arm or factorial design RCT). Please comment on preference.
- NCCIH does not have a preference; it should be driven by the specific hypothesis of the R33 phase.
- What is and is not included in the 12 page limit for the proposal?
- The details for the page limitation are outlined in the application instruction form and there are links to this information in the FOA. There is no page limit on the citations or the human subjects content.