The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising mind and body interventions. These mind and body approaches are widely used by the public, and they are increasingly recognized to provide a non-pharmacological approach to symptom management (e.g., chronic pain, mild depression, anxiety, etc.). These approaches can be utilized by individuals to help prevent, treat, or self-manage various conditions (e.g., chronic pain, headache, anxiety, promote wellness), as well as being complementary to treatment offered by conventional health care. For the purposes of the current funding opportunity announcement (FOA), mind and body interventions include various meditation approaches (e.g., mindfulness), hypnosis or guided imagery, meditative movement approaches (e.g., yoga, tai chi, qi-gong), body-based approaches (e.g., spinal manipulation, massage, mobilization, acupuncture), or a combination of these approaches (e.g., meditation and yoga, or mindfulness-based stress reduction MBSR).
There is a need for research to evaluate mind and body approaches as they are used and delivered to determine whether they are safe and efficacious/effective for given conditions/disorders. For clinical trials to address this need they must be well designed and test hypotheses that will guide decisions about the inclusion of these interventions/approaches into the delivery of health care for a given condition or disorder. It is typically necessary to conduct a series of early-phase clinical trials to gather the multiple types of preliminary data needed to design subsequent large and rigorous efficacy or effectiveness studies. Although the scientific literature may provide the rationale for conducting an efficacy or effectiveness trial, investigators often lack critical information about key elements needed to design and implement such a trial. Some key aspects that may need further investigation to plan the future trial could include intervention refinement, finalizing the intervention delivery method, the outcome(s), or recruitment strategy necessary to design and conduct an efficacy or effectiveness trial. Early phase clinical trials can fill this information gap, thereby improving study design and knowledge of trial feasibility. Later phase trials can go further by assessing whether the intervention can be delivered with fidelity across sites in preparation for a future multi-site trial; determining the optimal duration or frequency of the intervention to be used in the future multi-site trial; optimizing an intervention to have a greater impact on the potential mechanism of action; or exploring, developing, and testing adaptive interventions.
For more information about what NCCIH recommends for the multi-staged process for mind and body intervention development and testing, see the NCCIH website .
Considerations for Selection of Study Design
For mind and body interventions that either are or can be delivered in groups, investigators must have a strong rationale for the choice among trial design options. The selection of study design should be guided by decisions about how best to deliver the intervention and by concerns regarding contamination and logistics.
In traditional randomized clinical trials (RCTs), individual participants are randomized to receive an intervention that is delivered individually (e.g. spinal manipulation, acupuncture, or individually delivered hypnosis). When an intervention can be delivered in a group format there are several methods of randomizing participants to the intervention. The first option is an individually randomized group treatment trial (IRGTs), where individual participants are randomized to one of the interventions but the intervention is delivered in small groups (e.g. yoga, Mindfulness Based Stress Reduction, or tai chi classes). The second option is a group-randomized trial (GRTs), also called cluster-randomized trial (cRCTs), where groups of participants are randomized to study conditions, often defined by their workplace, school, primary care provider, or community. In cRCTs, the intervention provided to the randomized groups can be delivered individually, in small groups, or to the entire group.
Feasibility pilot studies can help investigators develop methods for successfully implementing IRGTs, GRTs or cRCTs. For example, the pilot study may help investigators determine whether they can recruit eligible participants within a specific time-frame to enable an IRGT design; acceptable timeframes for group meetings to which participants will adhere; procedures to limit group contamination; appropriate group sizes; and other methods related to implementing an IRGT, GRT or cRCT design.
The study team biostatistician will need to consider how the chosen study design will impact the proposed data analysis and sample size estimates for the larger efficacy study. The justification should include consideration of the positive intraclass correlation expected in data obtained from participants in the same groups, or clusters (IRGT, cRCT, or GRT). In general, these types of studies need to consider how the data analysis and sample size address the extra variation expected in the data and the degrees of freedom available to estimate that extra variation. Failure to account for this variable in the sample size calculation can result in underpowered studies.
Overview of NCCIH Mind and Body Clinical Trials Research Funding Opportunities
A clinical trial is defined by NIH 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.”
NCCIH has designed its Mind and Body Clinical Trials Program to support a range of investigator-initiated studies with funding mechanisms tailored to address different scientific questions and levels of study complexity from early stage discovery research through large scale efficacy or effectiveness trials. This pipeline of research is supported under funding opportunities that include the following options:
- Pre-clinical/animal studies (which may use Parent R21 or R01 FOAs);
- Mechanistic studies focused on the fundamental science of mind and body approaches (which may use NCCIH Clinical Trial Optional R21 or R01 FOAs);
- Human mechanistic studies to determine and verify the biological mechanisms or social behavioral process of a given mind and body approach and optimize the impact of the intervention (phased innovation awards using R61/R33);
- Human feasibility studies to ascertain preliminary data on ability to recruit/randomize and accrue participants; fidelity of delivering the intervention; participant adherence; determining appropriate outcomes and follow-up; and retention of participants (the current R34);
- Clinical trials to determine or optimize “dosing;” develop and test adaptive intervention strategies; demonstrate fidelity of the intervention across sites and/or further ascertain clinical effects of the intervention in a given patient population with a given condition (U01);
- Multi-site clinical trials to determine efficacy/effectiveness (UG3/UH3 with companion U24).
Fundamental Science (R01, PA-18-323; R21, PA-18-322)
Fundamental research on mind and body approaches can address three key aspects. The first is the approach itself: What components impact the biological system or subjective experience? The second is the biological system potentially targeted by the approach: What cellular systems or hormonal, genetic, or neural mediators, for example, are influenced by the intervention? The third is the mechanisms: What are the key processes (i.e., biological and/or behavioral) by which the approach exerts its effects? Applications to these FOAs should propose fundamental science research projects that address at least one of these three aspects. These FOAs may support clinical trials of mind and body interventions in which the primary outcomes are mechanistic. However, they should not be used for clinical trials of mind and body approaches in which the primary outcomes are clinical endpoints (e.g., clinical pain assessments), although clinical endpoints may be measured as secondary outcomes. Applications submitted should not include any specific aims that propose to measure efficacy or effectiveness of any intervention. Investigators who wish to conduct studies with clinical endpoints as the primary outcomes should consider other NCCIH-issued FOAs described here.
Clinical Trial Planning Phase – Exploratory Clinical Trials (current FOA)
To maximize the impact of Mind and Body clinical trials, it is necessary to first refine the intervention to enhance its clinical benefit, improve adherence, and/or verify feasibility of the trial. Research supported under the R34 should generally precede submission of a fully powered efficacy, effectiveness or pragmatic trial, although this is not a requirement if such data are available or can be obtained through other means. Although the scientific literature may provide the rationale for conducting a clinical trial, investigators often lack critical information about the intervention, the outcome, or recruitment strategy necessary to design an efficacy or effectiveness trial. The R34 provides a funding opportunity to elucidate the optimal research strategy by conducting studies to adapt the intervention to a specific patient population; refine the intervention to determine the appropriate duration or frequency of treatment; and/or determine the appropriate outcome measure(s). The R34-funded study should have collected the preliminary data that would enhance the probability of reaching more definitive outcomes in a subsequent larger trial. This developmental work could include refining the assessment protocol, experimental intervention protocol, as well as the comparison intervention protocol and randomization procedures (if appropriate); examining the feasibility of recruiting and retaining participants into the study conditions (including the experimental condition and the comparison condition, if relevant); and developing supportive materials and resources.
Determining Biopsychosocial Mechanisms (R61/R33, PAR-18-114)
A key phase in developing a mind and body intervention can be determining and validating its biological signature or psychological process for the condition(s) of interest in a given human population. Research supported under the R61/R33 may precede submission of a fully powered efficacy, effectiveness, or pragmatic trial, although this is not a requirement if such data is already available or can be obtained in other ways. The Phased Innovation Award for Mechanistic Studies to Optimize Mind and Body Interventions in NCCIH High Priority Research Topics (R61/R33) supports two-phased research applications to: (1) discover the underlying biological, neurological, physiological, and/or behavioral mechanisms or processes relevant to mind and body interventions and then, (2) to utilize the results from the initial phase to improve, refine, enhance, or strengthen the identified mechanisms or processes through either rigorous validation and refinement of the intervention, or using combined approaches that, together, will modulate the underlying mechanism or process. This second phase should also be able to provide preliminary evidence that the mechanism or process modulated by the intervention is associated with a functional outcome or clinical benefit for a specific clinical condition or disorder.
The data collection in the R34 or R61/R33 should be finished and the data analysis completed before a U01 or UG3/UH3 is submitted. If these research funding mechanisms are used, it is expected that the information obtained will guide activities proposed under the U01 or UG3/UH3 grant application.
Clinical Trial Cooperative Agreement (U01, PAR-18-118)
The NCCIH Mind and Body Clinical Trial Cooperative Agreement (U01) award is for investigators who have typically completed either a relevant R34 or R61/R33 study, or have obtained analogous data by other means. The objective of the NCCIH U01 FOA is to increase the evidence base on which high priority mind and body clinical trials are based. The U01 will support non-efficacy/effectiveness clinical trials assessing key aspects of a clinical trial that could include but are not limited to the following: develop and test adaptive interventions using sequential, multiple assignment, randomized trials (SMARTs) design to determine the treatment options at decision points, possible tailoring variables, or a sequence of decision rules; optimize the intervention by evaluating which elements of a complex intervention are impactful using a multiphase optimization strategy (MOST) design; assess the relative fidelity of an intervention across sites for a future multi-site, randomized, clinical trial; or large scale, “dosing studies” for definitive determination of optimal “dose” which could include studying the frequency and duration for an intervention, among other variables, to be used in a future multi-site, randomized clinical trial.
Multi-Site Investigator-Initiated Clinical Trials Cooperative Agreement (UG3/UH3, PAR-17-175; with companion U24, PAR-17-173)
The UG3/UH3 FOA will support applications to implement a multi-site clinical trial of a mind and body intervention (Phase III and beyond). Under this phased award the UG3 phase supports the planning and development of resources necessary to perform the trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the clinical trial. The UG3/UH3 award is used to implement a Clinical Coordinating Center (CCC) for an investigator-initiated multi-site clinical trial of mind and body interventions (efficacy, effectiveness, and pragmatic trials). In addition, multi-site clinical trials require a companion Data Coordinating Center (DCC) application (U24) be submitted with, and linked to the CCC application. Both applications undergo peer review simultaneously. Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Multiple sites are necessary to increase generalizability of findings and enhance recruitment efficiency as well as representativeness of the participants. Multi-Site clinical trials are expected to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. The Clinical Coordinating Center for Multi-Site Trials FOA runs in parallel with a companion FOA that solicits applications for the companion DCC. Multi-site trials will be expected to achieve the required phase III trial requirements of NIH (see:https://humansubjects.nih.gov/glossary and http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
The objective of this FOA is to develop the building blocks with which to design high priority mind and body clinical trials to enhance the probability of reaching more definitive outcomes. Important building blocks include working out the details of the experimental protocols, including the assessment protocol, the experimental intervention protocol, as well as the comparison intervention protocol and randomization procedures (if appropriate); examining the feasibility of recruiting and retaining participants into the study conditions (including the experimental condition and the comparison condition, if relevant); and developing supportive materials and resources. Investigators should keep in mind the future planned trial and then design the R34 to provide the necessary preliminary data for a future efficacy, effectiveness, or pragmatic trial; or controlled cohort or case-control study.
Accordingly, collection of preliminary data regarding feasibility, acceptability, safety, and target outcomes is appropriate. Given the limited sample sizes that can be supported under this exploratory R34 grant mechanism, proposing the use of a comparison group for conducting fully powered tests of outcomes (i.e., efficacy), underpowered test of outcomes (i.e., “preliminary efficacy”) or attempting to utilize the highly variable point estimate of an effect size for power calculations would not be appropriate. Power calculations for subsequent larger studies should be based on an achievable, clinically meaningful improvement due to the intervention in the research population. A comparison group could be proposed for some aspects of the exploratory study, such as for determining the acceptability and feasibility of group assignment. Investigators should consult the NCCIH website (https://nccih.nih.gov/grants/whatnccihfunds/pilot_studies) for more information on the uses and misuses of pilot studies.
The following are examples of the types of clinical trials appropriate for this FOA:
- Mind and body intervention refinement to assess acceptability and adherence to dose, frequency and/or duration for testing in a future clinical trial.
- Iterative intervention refinement to address challenges with intervention fidelity, participant adherence, or participant retention.
- Development and feasibility testing of the integration of a mind and body approach into a health care system or delivery, to inform design of future pragmatic trials.
- Assess acceptability or feasibility of randomization or other aspects of trial design.
- Develop an appropriate control/comparison intervention for a future larger study.
Information to guide investigators for preparation of clinical trial implementation can be obtained from the NCCIH Scientific/Research staff. NCCIH clinical research policy and guidance information as well as NCCIH templates for the manual of operating procedures, and data and safety monitoring are available at the following website: https://nccih.nih.gov/grants/toolbox.
Preliminary Data Requirements
Preliminary data are not required for this FOA. However, there should be a clear and compelling rationale for the selected intervention’s proposed impact on the outcome of interest. This FOA is not appropriate for de novo intervention development.
It is important that clinical trials have a realistic timeline that explicitly addresses how long it will take from time of award to first participant accrual. NCCIH has an oversight process in place for clinical trials that may require revising and submitting a detailed study protocol, data and safety monitoring plan, case report forms, and accrual plan for NCCIH and IRB approvals, a site initiation visit by NCCIH to verify that the site is ready to begin participant recruitment and any subsequent remediation efforts. Investigators are encouraged to review the NCCIH Study Accrual and Retention Policy (https://nccih.nih.gov/grants/policies/SARP).
NCCIH Priorities for Clinical Trials of Mind and Body Interventions
As NCCIH’s mind and body clinical research portfolio matures, NCCIH has identified targeted areas of investigation. For this funding opportunity, applications will be considered of high programmatic priority if they meet the following two criteria:
- Includes one or more of the following high priority mind and body or integrated approaches: spinal manipulation, mobilization, massage, tai chi, qi gong, yoga, acupuncture*, hypnosis, guided imagery, progressive relaxation, meditation, biofeedback, mindfulness techniques, or complex approaches like music and art-based therapies. To be considered an integrated approach to care for this FOA, the intervention must combine one or more of these complementary health approaches added to standard care or other interventions such as a natural product, pharmacological approach, and/or another conventional behavioral approach (e.g. health coaching, physical activity or nutritional recommendations).
- Proposes to study a mind and body or integrated approach for one of the following high priority topic areas: symptom management – particularly for chronic pain syndromes; reduction of prescription drug (opioid) use or abuse in patients with chronic pain; enhancement of medication adherence; treatment or prevention of post-traumatic stress (disorder), traumatic brain injury, sleep disorders or disturbances, anxiety, depression, obesity, and smoking; promotion of psychological resilience or wellbeing; and promotion of healthy eating and physical activity.
*Applicants proposing acupuncture as an intervention should consult the NCCIH website (http://nccih.nih.gov/grants/acupuncture/priorities) to determine whether the proposed study is aligned with NCCIH’s updated priorities for acupuncture research.
NCCIH encourages applications to this FOA that meet the above criteria and also address health disparities; symptom management in patients with HIV/AIDS; or utilize special populations such as older adults, children, under-represented minorities, individuals in the military, or veterans.
Applications proposing research topics not identified above as high programmatic priority can be submitted, but will be considered of lesser or low programmatic priority.
Types of Clinical Trials Not Supported by this FOA
The following types of clinical trials will not be supported by this FOA and applications proposing such clinical trials will not be considered for funding:
- Studies proposing small trials with the sole purpose of estimating an effect size for a future trial.
- Mechanistic studies on the fundamental science of mind and body approaches (such studies should use R01 FOA, PAR-18-323; or R21 FOA, PAR-18-322)
- Studies to determine biological signature or psychological process (mechanism) of a mind and body approach (such studies should use R61/R33 FOA, PAR-17-149)
- Multi-site, phase III trials of efficacy/effectiveness (such studies should use UG3/UH3 FOA, PAR-17- 175 and companion U24 FOA, PAR-17-173)
- Natural product or pharmacological clinical trials that do not include a mind and body element to the intervention or comparison group (such studies should use NCCIH FOAs for natural products: https://nccih.nih.gov/grants/funding/clinicaltrials#natural)
- Single or multi-site observational studies that do not meet the NIH definition of a clinical trial (such studies should use the Parent R21 or R01 FOAs)
- Trials that propose to test mind and body approaches for the treatment or prevention of cancer (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute)
Optional Administrative Period
In view of the preliminary work required to initiate research activity for exploratory clinical testing of mind and body interventions, this FOA can provide support for an early administrative period of the award, prior to implementation of the preliminary clinical trial. This early administrative period of the award can be up to 12 months in length and could include support for, but is not limited to, developing tools for data management and clinical safety oversight (including the Data and Safety Monitoring Plan [DSMP]), finalizing the clinical protocol and informed consent documents, developing the manual of operations/procedures, and obtaining appropriate regulatory approvals (e.g., IRB, FDA). Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://nccih.nih.gov/grants/toolbox) to learn more about NCCAM’s requirements for clinical trials. Successful achievement during the early administrative period will be a requirement for initiating clinical testing and continued support of the project. The optional administrative period is included within the budget and project period limits specified in Section II. No human subjects activities are allowed during the administrative period.
Specific Areas of Research Interest
Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submitting to this FOA. Early contact (12 weeks prior to submission is strongly encouraged) provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance.
Deadlines: Standard dates and standard AIDS dates apply
Filed Under: Funding Opportunities