April 24, 2017
2:00 p.m. to 3:00 p.m. ET
Purpose of the Webinar:
On Monday, April 24, 2017, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) hosted an informational webinar to provide an overview of
- NCCIH’s new approach to funding investigator-initiated clinical trials for mind and body interventions
- The “building blocks” concept and how it applies to clinical trial funding
- NCCIH’s new clinical trial Funding Opportunity Announcements (FOAs) for mind and body interventions.
The webinar conveyed important information about changes in the rules for submission of applications for clinical trials of mind and body interventions. It also provided details about the different FOAs for clinical trials, including new cooperative agreements (U awards) and phased awards.
- Wendy J. Weber, N.D., Ph.D., M.P.H., Branch Chief, Clinical Research in Complementary and Integrative Health Branch, Division of Extramural Research, NCCIH
- Robin Boineau, M.D., M.A., Medical Officer, Division of Extramural Research and Office of Clinical and Regulatory Affairs, NCCIH
- Slava Soldatenkov, Ph.D., Scientific Review Officer, Division of Extramural Affairs, NCCIH
- Wen Chen, Ph.D., Acting Branch Chief, Basic and Mechanistic Research in Complementary and Integrative Health Branch, Division of Extramural Research, NCCIH
- Lanay Mudd, Ph.D., Program Director, Division of Extramural Research, NCCIH
- Eve Reider, Ph.D., Program Director, Division of Extramural Research, NCCIH
- Anita McRae-Williams, M.A., Outreach Program Manager, Division of Extramural Research, NCCIH (Webinar Moderator)
This report summarizes information provided during the webinar about NIH and NCCIH initiatives to improve clinical trials, NCCIH’s mission and scientific priorities, changes in funding opportunities, and factors to consider when selecting an FOA for a clinical trial.
Clinical Trials and NCCIH’s Mission
NCCIH’s mission is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative interventions and their roles in improving health and health care. In line with this mission, NCCIH wants to support definitive multisite clinical trials whose results will impact health care delivery and provide evidence for treatment guidelines. However, in most areas of clinical inquiry, there is a need for additional preliminary data or “building blocks” before definitive clinical trials can be performed. This is reflected in clinical practice guidelines, such as the low-back pain treatment guidelines from the American College of Physicians, which recommend the use of certain complementary approaches while acknowledging that the evidence supporting them is of low-to-moderate quality.
An NIH-wide Focus on Improving Clinical Trials
NIH leadership has recently addressed the quality of clinical trials, stating that NIH must ensure that the trials it supports investigate high-priority, mission-relevant questions that are most likely to advance knowledge and improve health. NIH has launched a multifaceted effort to improve clinical trials. One part of this effort is a requirement that all clinical trial applications be submitted in response to clinical-trial–specific FOAs.
NCCIH has developed a new approach for funding clinical trials as part of this NIH-wide initiative. Clinical trials are important to NCCIH because we study health interventions that are widely used by the American public—often with scarce evidence of their efficacy and an inadequate understanding of potential safety concerns. Also, NCCIH funds research that helps people manage important health issues, such as the use of nonpharmacologic approaches to pain.
Common Limitations of Trials
Many clinical trials of complementary health approaches have been completed, and many of them have similar limitations. Often, trials have been conducted at a single site, which reduces their generalizability and makes it unclear whether the intervention can be delivered elsewhere with fidelity. In instances when a trial failed to demonstrate the hypothesized benefit, the reason for the negative results is often unclear. It may be uncertain whether the intervention was delivered correctly, whether the participants received enough of the treatment, whether the duration and frequency of the intervention were adequate, and whether the right population was selected (e.g., a condition may be too advanced in a given population for the intervention to be successful). Many of these limitations of clinical trials reflect insufficient preliminary research to develop the “building blocks” needed as a foundation for the design of a definitive trial.
The Building Block Concept
Before a definitive clinical trial can be performed, preliminary data need to be collected. For complementary mind and body interventions, this starts with fundamental knowledge and any historical use information that is available—in some instances, many centuries of it, as with yoga and acupuncture. Building on that base, the next step is studies in people to refine the intervention and test its feasibility. Then, studies are needed to optimize the intervention and the methods that would be used in a definitive trial. With these building blocks in place, it then becomes possible to conduct a multisite efficacy or effectiveness study, which may be followed by pragmatic trials to determine whether the intervention can be delivered effectively in health care systems.
NCCIH’s new FOAs provide investigators with funding options to establish each of the building blocks needed for clinical trials of mind and body approaches. In the past, investigators have reported that it is difficult to find funding to establish the building blocks. The new FOAs provide opportunities to conduct research all the way across the continuum between basic/mechanistic research and definitive efficacy trials.
What Has Changed?
The most important change is that NCCIH is no longer accepting most clinical trial applications through the Parent R01 FOA (NOT-AT-17-006). After May 8, 2017, most clinical trial applications must be submitted in response to clinical-trial–specific FOAs if you want your application assigned to NCCIH. The clinical-trial–specific FOAs allow researchers to incorporate more relevant information in their grant applications. Investigators must use these FOAs for applications submitted to NCCIH for all stages of trials with clinical outcomes.
Applications for some types of studies involving human subjects can still be submitted via the Parent R01 FOA. These include observational human studies (cohort, case-control, survey), secondary data analyses (datasets or biorepositories), and mechanistic-focused trials (with no aims to examine clinical outcomes).
If you’re planning a June application, please contact the NCCIH Division of Extramural Research at email@example.com, so that we can make sure you are using the right FOA for your proposed study.
Selecting the Right FOA
Selecting the correct FOA for your proposed clinical trial of a mind and body intervention depends on the research question you wish to address.
- If you want to determine how the mind and body intervention works, and you are planning to do fundamental science, the Parent R01, Parent R21, Parent R15, or various FOAs in which NCCIH has signed on along with other institutes and centers (ICs) may be right for your study.
- If you want to optimize the impact of your intervention based on how it works, the new R61/R33 or R33 FOAs for mind and body interventions may be appropriate.
The R61/R33 is a phased innovation award. The first phase (R61) supports research to establish whether an intervention can modulate a biological mechanism or psychological process in humans and to demonstrate that the intervention and control conditions can be delivered consistently. The second phase (R33) supports research to optimize the impact on the mechanism or process by modifying the delivery of the intervention, combining the intervention with other effective interventions, or selecting for a more mechanism-relevant population.
Investigators who already have the type of data that would be developed under an R61 award can apply for an R33 directly.
Dr. Wen Chen is the contact person at NCCIH for all awards related to studying the mechanism or process of mind and body interventions. She can be reached at firstname.lastname@example.org.
What Is a Phased Award?
The R61/R33 is an example of a phased award. Phased awards are used when the supported research has two distinct phases with separate aims, and the transition to the second phase is dependent on the success of the first. (For example, if the first phase failed to demonstrate that the intervention had the expected effect on a biological mechanism or psychological process, it wouldn’t make sense to go on to a second phase that was intended to optimize the intervention.)
Only one application and one peer review process are required for both phases. A crucial part of the application is defining the go/no-go criteria and milestones to explain when you would vs. would not proceed to the second phase. If the negotiated milestones of the first phase are met, the transition from the first to the second phase of funding requires only administrative review.
Selecting the Right FOA for Clinical Outcome Research on a Mind and Body Intervention
If your research question to be addressed is whether the intervention works for a clinical condition, there are multiple FOAs to choose from, depending on the type and stage of the research that is being proposed.
- If you are planning an observational study, the Parent R01, Parent R21, Parent R15, or various FOAs in which NCCIH has signed on along with other ICs may be right for your study.
- If you are planning an intervention study, you need to use the new clinical-trial–specific FOAs.
Which FOA is appropriate depends on where you are in the process of developing building blocks.
Examples of early stage research include refining your intervention and testing its feasibility (which may involve studies of frequency and duration, measurement and populations, or adherence and fidelity, or development of an intervention manual). Optimizing the study methods may involve demonstrating that the study team can efficiently recruit and retain participants and consistently collect and manage data, as well as demonstrate the intervention is capable of reproducible measures of the mechanism (encouraged but not required) or intervention optimization based on the mechanism (encouraged but not required).
The R34 mechanism, which NCCIH has used for a while, supports early phase clinical trials of mind and body approaches to collect data critical for the planning and design of a subsequent definitive trial. This mechanism will not support tests of efficacy or effectiveness, or studies to validate biomarkers of mind and body approaches. No building blocks are required as preliminary data prior to an R34 trial, but the application should provide a rationale for why the intervention has promise of a clinical benefit for the condition proposed for study.
The person to contact at NCCIH about the R34 funding mechanism is Dr. Lanay Mudd (email@example.com).
Studies designed to collect the final building blocks of information prior to a definitive clinical trial on a mind and body intervention are funded under a U01 cooperative agreement. This mechanism supports a variety of studies—including studies to optimize interventions by identifying critical elements, to assess multisite fidelity and feasibility, or to determine the optimal duration and frequency of an intervention (“dosing” studies). This mechanism will not support multisite or single-site efficacy or effectiveness trials (use the UG3/UH3 described below). It also will not support trials on interventions for the treatment or prevention of cancer. Applications related to cancer should be submitted to the National Cancer Institute (NCI).
U01 applications require preliminary data on some of the building blocks, including the establishment of safety of the intervention, the demonstration that the proposed trial is feasible, and completion of final data collection from any pilot studies. Although not required, it is highly desirable to have evidence that the intervention can reliably produce a meaningful impact on a biological mechanism or psychological process.
If you anticipate that your U01 will require more than $500,000 direct costs in any given year, you will need permission from NCCIH before you can submit your application.
The person to contact at NCCIH regarding all aspects of the U01 FOA for mind and body interventions is Dr. Lanay Mudd (firstname.lastname@example.org).
What Is a U Mechanism?
The U01 is an example of a U mechanism—a cooperative agreement award. U awards are used for investigator-initiated applications when the funding agency anticipates that Federal staff will be involved in the activities of the award.
At the time of funding, NCCIH will assign two staff members to work with the investigators: a Program Director, who is responsible for the administration of the award; and a Project Scientist, who works with the investigators and is part of the research team for trial planning and oversight.
New Multisite Randomized Controlled Trial FOAs
The final opportunity for mind and body clinical trials is the UG3/UH3 cooperative agreement with a companion U24. This funding opportunity is designed to support multisite randomized controlled trials—including efficacy trials, effectiveness trials, pragmatic trials, and dissemination and implementation trials. Applications must be submitted for both a clinical coordinating center (UG3/UH3) and an independent data coordinating center (U24). Investigators must submit companion applications for both centers at the same time.
Most trials submitted under these FOAs will exceed budgets of $500,000 direct costs per year. Therefore, per NIH policy, investigators need to contact NCCIH to seek permission to apply.
Before conducting a multisite randomized controlled trial, investigators must have the following building blocks:
- Evidence that the clinical trial is feasible
- The specific intervention can be adhered to by the patient population.
- The investigators can recruit, retain, and randomize participants.
- The investigators can follow protocol and complete data collection.
- The intervention can be delivered with fidelity at multiple sites.
- Data to justify the intervention delivery (duration, frequency, timeline)
- No significant safety concerns from previous studies
In addition, the following evidence is not required but is highly desirable:
- Evidence that the intervention can reliably produce a meaningful impact on a biological mechanism or psychological process
- Evidence that the intervention has been optimized to enhance this impact.
Why Multisite Trials?
NCCIH requires multisite trials to meet guidelines to enhance rigor and reduce bias. Conducting trials at multiple sites increases the likelihood that the results will be generalizable, increases the diversity of the population, and demonstrates that the intervention can be delivered with fidelity at more than one location. Having an independent data coordinating center helps to keep methods of data collection consistent from site to site and ensures independent data quality analysis.
The UG3/UH3 Is a Phased Award
The UG3/UH3 is a phased award that includes a planning phase (UG3) and an implementation phase (UH3). The transition to the second phase depends on whether both the clinical and data coordinating centers meet the negotiated milestones. The planning phase demonstrates the team’s ability to meet deadlines and prepare for the launch of the trial. Only one application and peer review process are needed for the UG3 and UH3 awards.
In closing, the speakers emphasized that NCCIH has funding opportunities across the continuum of basic, mechanistic, and clinical research on both natural products and mind and body interventions. We have particular interests in pain, difficult-to-manage symptoms, promotion of healthy behaviors, and promotion of psychological resilience.
All applications submitted under the new clinical trial FOAs will be reviewed by special review panels familiar with both NCCIH’s research priorities and the goals of the new FOAs. Applications must include special attachments (described in the FOAs) that provide study details in a standardized way. The review panels will use this information to assess important aspects of the proposed trial.
A webinar on NCCIH funding opportunities for natural product clinical trials will be held on May 9 at 2:00 p.m., Eastern Time, and a webinar on an additional funding opportunity for pragmatic trials through the NIH Health Care Systems Research Collaboratory will be held on April 25 at 2:30 p.m., Eastern Time.
For more information on the clinical trial FOAs, visit https://nccih.nih.gov/clinicaltrials-funding. If you have specific questions, contact an NCCIH Program Director at email@example.com.
Summary of Questions and Answers
You said that the U01 should not be used for applications related to cancer. Can you fully explain what falls under cancer-related research? For instance, would studies on changing behaviors related to cancer (such as smoking and alcohol use) be excluded?
NCCIH will not fund research that is specifically focused on the prevention or treatment of cancer. NCI is the IC that funds studies in that area. However, mind and body interventions to change cancer-related behaviors such as smoking, weight loss, or increased physical activity can often be generalized to include other conditions besides cancer. NCCIH would be interested in funding studies on topics like these.
Do R34 feasibility studies need to be conducted at multiple sites, or could they be conducted with a certain population at one site?
R34 feasibility studies do not need to be conducted at multiple sites. In fact, the R34 funding mechanism is not well suited for multisite research. The R34 only allows for 3 years of funding and a relatively limited budget. It is better to use an R34 to refine your intervention and test feasibility at one site and then move on to a multisite feasibility study funded by a U01.
The R34 looks like it expires after the June 2017 deadline. Do you expect a renewal? And if so, when?
We cannot discuss FOAs that are not yet published. However, NCCIH remains committed to having a way to fund feasibility work.
Can you explain whether continuing renewal of R01s is still an option, or whether another mechanism should be pursued?
It depends on the type of research you’re doing under your R01. If it’s a clinical trial with clinical outcomes, you can’t use the R01 anymore. You need to use one of the new FOAs, and it would be considered a new application. But if you’re doing mechanistic research, you could use the Parent R01 for renewal.
For R01 applications, you cannot measure clinical outcomes as the primary aim, but you can collect data about them. They just can’t be the primary outcomes of the study.
If your R01 needs to be renewed, consider whether you are ready to move on to an efficacy study, in which case the U mechanisms might be suitable for you. We recommend talking to a Program Director to help you determine which FOA may be best for you. Contact us at firstname.lastname@example.org.
Which mechanism would be suitable for a dismantling study? In other words, if you have a mind body intervention, and you want to set up a study to discern the critical factors of the intervention that lead to a clinical effect, which mechanism would you recommend applying for?
This would likely fall under the U01 mechanism, which includes studies of adaptive or factorial designs to identify the components of a multicomponent intervention that have the greatest effect. However, if you’re not looking at clinical outcomes, a different mechanism might be better. It would be helpful to contact an NCCIH Program Director to discuss your proposed project before applying.
Will proposals submitted through the new FOAs go through the same two levels of review as other NIH grant applications?
The usual NIH rules apply, and the applications will go through two rounds of review.
One advantage of the new funding mechanisms is that applications will be reviewed by NCCIH-convened special review panels with specific expertise in mind and body interventions and clinical trials.
For the multisite U grant, do you need preliminary studies at each site, or is it enough to have preliminary results at the lead site?
We would not require all the sites to have experience with the particular intervention under study, but it is important that you do have experience with this intervention at multiple sites, so that the review panels will know that it is possible to implement it at multiple sites.
Are letters of intent needed for the U grant?
They are not required but are encouraged for all U applications. Also, if you will be asking for more than $500,000 in direct costs in any year, you don’t just need a letter of intent, you need permission to submit your application. That process takes many weeks and requires a lot of information. Because NCCIH is a small Center, committing to a large grant represents a significant portion of our budget. We evaluate proposals for large-budget studies carefully to ensure that they are consistent with our priorities. Please contact us if you have more questions.
Do the new FOAs indicate that NCCIH will focus more on clinical research rather than basic or mechanistic research?
No. NCCIH is still interested in funding research at all stages of the research continuum, from basic and mechanistic studies through definitive clinical trials.
I want to apply for funding to conduct a prospective observational study of patients being treated in real practice settings. Should I use the Parent R01?
Yes. Because the participants are not assigned to treatments, you should use the Parent R01.
Are multisite trials allowed?
Yes. In fact, the UG3/UH3 FOAs, with companion U24s, require the use of multiple sites.
Do principal investigators try to identify a project scientist for U grants or will that person be assigned?
If an award is made, a project scientist will be assigned. NCCIH will identify the most appropriate person on our staff; that person must not have conflicts that would make involvement in the study inappropriate. Principal investigators should not suggest names. If you put the name of an NCCIH scientist on your application, that creates a conflict and prevents the person you named from being assigned to work with you.
With the R34 expiring after the next round, can applications that receive a borderline score have a chance to resubmit?
We can’t talk about FOAs that have not been published. But you can certainly be assured that we intend to have funding opportunities that would allow resubmission of previous applications for this type of early exploratory research.
What will happen to an application for an efficacy clinical trial submitted to the Parent R01 after May 8?
NCCIH will not accept it. The Center for Scientific Review will try to find another IC to accept it, but if this effort is unsuccessful, the application will be withdrawn. If you’re thinking about submitting an application in June, make sure you use the right FOA so that it can be assigned to NCCIH if that’s where you want it to be. Please contact us. We can help you find the right funding opportunity.
I’m interested in applying for the R34 due in June. Is Dr. Mudd the right person to contact?
Yes. But you may be assigned to another Program Director. We take into account the research interests of our staff when making assignments. However, Dr. Mudd would be your initial contact.