April 18, 2017
2:00 p.m. to 3:30 p.m. ET
Purpose of the Webinar:
On Tuesday, April 18, 2017, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) hosted an informational webinar to provide an overview of:
- The changes NCCIH is making in the way that we accept applications for investigator-initiated clinical trials
- Why these changes are being made
- How investigators can find more information about NCCIH’s new clinical trial Funding Opportunity Announcements (FOAs) and their requirements.
The webinar conveyed important information about NCCIH’s recently released series of clinical-trial–specific FOAs and how they provide a pathway of funding from early-phase trials to intermediate trials and finally to multisite clinical efficacy, effectiveness, or pragmatic trials. The webinar also provided the opportunity for potential applicants to ask questions of the webinar speakers.
- 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
- Emmeline Edwards, Ph.D., Director of the Division of Extramural Research, NCCIH
- Martina Schmidt, Ph.D., Chief, Office of Scientific Review, 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 (1) the rationale behind NCCIH’s new approach for funding clinical trials, (2) the need and opportunity for preliminary “building block” studies to precede efficacy trials, (3) the change from the parent R01 mechanism to NCCIH clinical trial specific FOAs include R grants and U awards (cooperative agreements), and (4) the requirement that efficacy trials be conducted at multiple sites and include an independent data coordinating center.
The Importance of Clinical Trials
- NCCIH’s overall research portfolio includes both basic and clinical research, but today’s webinar focuses on clinical trials. NCCIH wants to support definitive, multisite clinical trials whose results will impact health care delivery and provide evidence to support treatment guidelines. However, in most of the areas we study, there is a need for additional preliminary data or “building blocks” before a definite clinical trial can be conducted.
- Even when clinical practice guidelines recommend complementary approaches—as the American College of Physicians guidelines do for back pain—the evidence on which the recommendations are based may be of low to moderate quality.
- NIH as a whole is concerned about the quality of the clinical trials it supports. NIH seeks to ensure that trials investigate mission-relevant, high-priority topics and are likely to advance knowledge and improve health. With this in mind, NIH has launched a multifaceted initiative to improve clinical trials.
- One aspect of NIH’s initiative is a requirement that applications for clinical trials be submitted in response to specific FOAs designed for clinical trials. This webinar focuses on NCCIH’s new FOAs for clinical trials, which were created as part of this overall NIH effort.
- Why the focus on clinical trials? One reason is that research on human subjects makes up a large part of both NIH’s and NCCIH’s extramural research funding—40 percent and 64 percent, respectively.
The Role of Clinical Trials in NCCIH’s Mission
- NCCIH funds research that supports our overall mission and strategic plan, including research on both natural products and mind and body approaches.
- NCCIH’s mission is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative health interventions and their roles in improving health and health care. We want to support clinical trials that align with our mission.
- Two of the three scientific objectives in NCCIH’s current Strategic Plan (Objective 2: Improve Care for Hard-to-Manage Symptoms and Objective 3: Foster Health Promotion and Disease Prevention) directly relate to clinical trials.
Why a New Approach for Clinical Trials at NCCIH?
- NCCIH is participating in the NIH-wide initiative to strengthen the clinical trial research portfolio.
- Clinical trials are important to NCCIH because we study health interventions widely used by the American public—often with scarce evidence of their efficacy and inadequate understanding of potential safety concerns.
- NCCIH funds research, including clinical trials, to help people manage important health issues—such as nonpharmacologic approaches to pain.
- NCCIH’s new clinical trial FOAs require that definitive efficacy, effectiveness, or pragmatic trials be conducted at multiple sites. This requirement was put in place because many earlier clinical trials were conducted at single sites, and this reduced the generalizability of their findings. Often, it was unclear whether the intervention could be delivered with fidelity at other locations.
- After clinical trials have been completed—especially in instances where the trial failed to demonstrate the hypothesized benefit—the research community is often left with unanswered questions. For example: Was the intervention delivered correctly? Did the participants get a sufficient dose of the treatment? Were the duration and frequency of the intervention appropriate? Was the population appropriate, or was their condition too advanced for the intervention to be helpful? For natural products, was the correct product studied?
- Questions like these often reflect the fact that an efficacy trial was conducted without sufficient prior research to develop the “building blocks” to design it most appropriately.
“Building Blocks” and the Research Continuum
- The building blocks that are needed before a well-designed multisite efficacy trial can be conducted include
- Fundamental preclinical knowledge and any information that can be gleaned from historical use of the intervention
- Product development and testing (for natural products) or intervention refinement and feasibility testing (for mind and body interventions)
- Optimization of the dose/intervention and trial methods.
- NCCIH’s new clinical trial FOAs are specifically designed to provide opportunities to develop the building blocks needed for a successful multisite efficacy trial. In the past, it was often difficult for investigators to find research funding for studies to establish these foundational components.
- Each of NCCIH’s new clinical trial FOAs is targeted for studies at different stages in the continuum, from the earliest preliminary studies to full-scale multisite efficacy, effectiveness, or pragmatic trials.
- Although this webinar focuses on clinical trials, NCCIH is still interested in funding research across the continuum, from basic and mechanistic studies all the way through pragmatic trials.
Clinical Trial FOAs for Mind and Body Interventions and Natural Products
NCCIH has issued two separate series of FOAs—one for clinical trials on mind and body interventions and one for clinical trials on natural products.
Mind and Body
- A detailed webinar on the mind-and-body clinical trial FOAs will be held on April 24 at 2 p.m.
- Full information on the mind-and-body clinical trial FOAs is available on the NCCIH Web site at nccih.nih.gov/grants/funding/clinicaltrials.
- There are six FOAs for mind and body clinical trials, ranging from an R34 for early phase and feasibility trials, through R61/R33 and R33 opportunities for investigations of mechanistic effects and optimization of the intervention, to a U01 designed to allow researchers to collect the final building blocks to plan for a multisite clinical trial, and finally, companion announcements for a UG3/UH3 award for the clinical coordinating center and U24 award for the independent data coordinating center for a fully powered multisite clinical trial.
- A detailed webinar on the natural products clinical trial FOAs will be held on May 9 at 2 p.m.
- Full information on the natural products clinical trial FOAs is available on the NCCIH Web site at nccih.nih.gov/grants/funding/clinicaltrials.
- There are five FOAs for natural products clinical trials. The first two, an R61/R33 and an R33, are designed for studies that measure the impact of the product, replicate the findings, optimize the dose, and establish the biologic signature. These are followed by a U01 for mid-stage studies and companion FOAs for the clinical coordinating center (UG3/UH3) and independent data coordinating center (U24) for a fully powered multisite clinical trial.
What Has Changed?
- After May 8, NCCIH will no longer accept most clinical trial applications through the Parent R01 FOA (NOT-AT-17-006). Instead, researchers must use the more specific FOAs for clinical trials, if you want them to be assigned to NCCIH.
- The new FOAs will allow researchers to incorporate more relevant information in their grant applications.
- The new FOAs must be used for all stages of clinical outcome trials.
- The Parent R01 can still be used for certain types of human subjects research including: observational studies (cohort, case-control, or survey), secondary data analyses, and mechanistic-focused studies (those with no aims to examine clinical outcomes).
The U Mechanism
- The new FOAs do not include the R01 mechanism. Instead, the advanced stages of clinical research will be funded using U mechanisms—U01, UG3/UH3, and U24.
- U mechanisms are cooperative agreement awards. They are used for investigator-initiated applications. They are designed for use 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:
- One will be a Program Director, who will be responsible for administration of the award, review of progress reports, etc.
- The other will be a Project Scientist, who will work directly with the investigators as part of the team and participate in trial planning and oversight.
- At the time of funding, NCCIH will assign two staff members to work with the investigators:
Why Multisite Efficacy Trials?
- NCCIH is requiring that all efficacy, effectiveness, or pragmatic trials be conducted at multiple sites because this increases the likelihood that results can be generalized, increases the diversity of the population to meet NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research, and demonstrates that the intervention can be delivered with fidelity at more than one location.
- Multisite trials will be required to have independent data coordination (funded by the companion U24 award) to provide methods for consistent data collection at different sites and to assure independent data quality and analysis.
The Review Process
- Applications submitted under the new FOAs will be reviewed by special review panels familiar with both NCCIH’s research priorities and the goals of the new FOAs.
- The applications must include special required attachments (described in the FOAs) that allow applicants to provide more details about their proposed studies and the team’s experience. Using the information provided in the attachments, the review panels will have the opportunity to assess important aspects of the proposed trials such as rigor, feasibility, and potential impact.
- For information about NCCIH’s clinical trial FOAs, visit this Web site: https://nccih.nih.gov/grants/funding/clinicaltrials
- For frequently asked questions about the FOAs, visit https://nccih.nih.gov/grants/funding/clinicaltrials/faq
- For general questions about which FOA to use, contact the NCCIH Division of Extramural Research at firstname.lastname@example.org
- For answers to specific questions, please follow up with the program/scientific contacts listed on the individual FOAs.
Summary of Questions and Answers
What kinds of human subjects research will NCCIH still accept through the Parent R01?
Observational studies, secondary data analysis, and clinical trials that have only mechanistic outcomes, not clinical outcomes. Animal- and cell-based studies are also acceptable. If you are planning a June submission, please contact us to make sure you are using the appropriate FOA for your proposed study if you want to have it assigned to NCCIH.
Who will review applications submitted in response to the new clinical trial FOAs?
Applications will be reviewed by NCCIH special review panels that have expertise on the science proposed in the applications. The review panels will have expertise in clinical trials research and complementary health approaches and will be familiar with the challenges faced by the research community.
It is planned that applications for natural products studies will go to a review panel with specific expertise in natural products and clinical trials, and applications for mind and body studies will go to a review panel with specific expertise in mind and body interventions and clinical trials.
How do I decide which FOA to apply for?
First, choose the appropriate series of applications for the topic you plan to study. There are two. One is intended for natural products studies and the other is intended for mind and body intervention studies.
Second, within that series, choose the FOA that most closely matches the stage of research your project represents—early phase, intermediate, or full-scale efficacy, effectiveness, or pragmatic trials. Each FOA fully describes the preliminary data you need to have so that you can apply.
If you’re not sure which FOA to choose, contact NCCIH extramural program staff.
We have an R01 application written for a two-site efficacy clinical trial to be submitted for the June 5 deadline. This has already been through internal review and is ready to submit. What do we need to do to make this fit with the new funding mechanism?
You cannot use the parent R01 if you want your application assigned to NCCIH. If you’re planning a fully powered efficacy trial, you will need to use the new UG3/UH3 and U24 funding mechanisms. We recognize that this is a challenge for investigators who have already been working on applications for the June deadline. If you’re planning an earlier stage trial to determine whether your intervention can be conducted across multiple sites with fidelity, you could use the U01 mechanism. However, the U01 mechanisms would not be appropriate if the trial has the primary aim of measuring efficacy.
It is very difficult to implement a multisite trial and stay within the funding limit of $500K per year. Is a higher limit being considered?
Yes. We recognize that rigorous multisite efficacy trials are expensive and often require more than $500K a year in direct costs. In the UG3/UH3 FOAs, investigators are encouraged to contact NCCIH several months in advance to seek permission from NIH to submit an application with a budget that exceeds the $500K annual limit for the coordinating center and data center combined. Please reach out to an NCCIH program director to get the information you need. The timeline is tight for the June receipt date, but we will work with you to get documented approval for permission to apply for a grant above $500k. For more information, see NCCIH Policy: Applications for Large Budget Clinical Trials Over $500,000 in Direct Costs in Any Year.
Where do mind and body interventions conducted through secure live video fit in? Are multiple sites still required for these trials, which can recruit geographically diverse patients from across the United States?
Regardless of the design of the trial, we would want to see many of the same key elements in demonstrating good adherence to your intervention. We developed the FOAs to fit as many scenarios as we could anticipate. We will work with individual investigators to determine whether there is a need for multiple recruitment sites for interventions with recruitment through the Internet. This specific case is best discussed one-on-one with Dr. Robin Boineau, the scientific contact for the multisite efficacy trial FOA.
Do multiple clinics under the umbrella of a single institution count as multisite, or must multiple educational institutions participate?
Because efficacy studies are best done with a geographically diverse population to increase their generalizability, we encourage you to partner beyond your own institution even if you could obtain an adequate sample size at your own site. You need to recruit a sample with characteristics and diversity similar to those of the overall U.S. population with the condition you are studying. In almost all cases, we would want to see a broad geographic distribution, but you are welcome to follow up with a more direct question to us.
What is the role of the R21 developmental/investigatory research grant in the new FOA process? Can we still submit under this mechanism?
For several years, NCCIH has not accepted applications for clinical trials through the R21 mechanism. If an application is submitted, NCCIH tries to find another Institute or Center (IC) that might be willing to take the application. If no IC will accept it, the application is returned to the Center for Scientific Review, which may make further efforts to find an IC to accept it. If this is not successful, the application is returned to the applicant.
The reason why NCCIH does not accept applications for clinical trials under the R21 mechanism is that the R21 does not allow for enough time and money to complete a rigorous clinical trial. There have been instances when investigators funded by R21s were unable to complete recruitment in time or did not have a sufficient budget to conduct a reasonable study. The new FOAs include opportunities for studies that represent the same stage of research as an R21, but they allow for enough time and money for the study to be completed successfully. Please contact NCCIH to determine which funding opportunity is most appropriate for you.
Will reviewers of applications submitted under the new U01, UG3/UH3, and U24 FOAs be told not to focus on mechanisms of action? If the study of clinical outcomes is the goal, then not identifying a mechanism of action should not be a barrier to a fair review and funding.
The later stage clinical trials that will be funded under these FOAs are focused on clinical outcomes rather than mechanistic ones, and review criteria will focus on the appropriate aspects. However, as part of the review criteria, the reviewers are asked to evaluate the quality of the preliminary data, the justification for the proposed work, and whether there’s enough evidence to support doing the research proposed in the application. We recommend reading the full FOA carefully, particularly Section IV and the review criteria.
Are these funding opportunities targeted primarily to mind and body interventions or can they be targeted to natural products for various diseases, such as chronic obstructive lung disease?
NCCIH’s mission is to conduct rigorous research on complementary health approaches; our mission is not disease specific. We support both natural product and mind and body studies, and our focus is not on treating disease but on managing symptoms.
We have two series of clinical trial FOAs, one for mind and body interventions and one for natural products. We recommend that you register for the May 9 webinar, where we will go into more detail about the FOAs for natural product studies.
Can you elaborate on the funding limits, especially for multisite and pragmatic trials?
The budget for UG3/UH3 and its U24 companion is based on the cost to do the trial including the need to power the trial appropriately to establish efficacy. Applicants must include their proposed budget when they request permission to apply. We will look closely at the cost per participant and other factors that help us to determine whether the budget is appropriate.
Can small businesses apply for the new FOAs, with or without an academic partner?
Yes, small businesses are eligible, with or without a partner. However, we would also encourage you to talk with us about funding opportunities that are only available to small businesses. We are often looking for high-quality research studies that can be funded through the small business FOAs.
Even if you apply under the special FOAs for small businesses, we encourage you to use a framework for designing your clinical research similar to the one we’ve described in this webinar because this is how we believe that clinical research should be conducted. The concept of developing building blocks before moving on to definitive clinical trials applies regardless of the funding mechanism you’re using. You could certainly design your Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) application in a way that allows you to perform phased research on your intervention.
Will the FOAs for natural products be intended for U.S Food and Drug Administration (FDA)-approved prescription drugs rather than over-the-counter medicinal foods?
Almost all of the natural product studies in humans that we support are performed under an Investigational New Drug (IND) application with the FDA. The FDA determines whether an IND is necessary. Whether a company takes the results of the trial forward to the formal New Drug Application (NDA) process is up to them. The IND sponsor or manufacturer are the ones who decide whether they want to market the product for a specific indication and seek FDA approval. Our goal, especially with small business funding, is to fund research that will result in a marketable product—which may be an over-the-counter supplement or a natural product that becomes marketed as a drug for an FDA-approved indication. Further questions should be directed to Dr. Wendy Weber.
What are the best NCCIH funding opportunities to support mechanistic studies?
If your study will involve human subjects and will also look at clinical outcomes such as weight or depression symptoms, then the new FOAs are most appropriate. If you are just doing fundamental science, with no clinical outcomes (for example, looking at the effect of meditation in the brain), you can use the parent R01. There are also other FOAs that may be appropriate, for example, there are several FOAs on the mechanisms of pain that involve multiple NIH ICs, including NCCIH. All such funding opportunities are listed on the general funding opportunities part of our Web site. If you want to look at the mechanism of a mind and body intervention and optimize it, the R61/R33 FOA would be a good one to consider.
Can the U01 FOA be used for single-site studies that are not fully powered for efficacy?
Yes, the U01 can be used for either single-site or multisite trials. It depends on what additional data you need before you can perform a multisite efficacy trial. For example, if you already have data showing that your intervention can be delivered with fidelity across multiple sites and you need to focus on determining the optimal dose, you may be able to get the data you need from a single-site study. The U01 can be used in a variety of ways. For more information, please join the specific natural products or mind and body FOA webinars to be held in the coming weeks.
Some mechanistic trials may involve measuring clinical parameters that could be construed as patient outcomes, although the study is not designed as an effectiveness trial. How does this affect the choice of funding opportunity?
We are well aware that the NIH definition of a clinical trial is quite broad and includes some studies that the investigator community would call mechanistic studies. NCCIH wants to support this kind of work. For mechanistic studies of mind and body interventions, it would be best to talk to Dr. Wen Chen at NCCIH, who is the contact for mind and body mechanistic research, to see whether the parent R01 or other FOAs would be most suitable for your proposed study.
Can an NCCIH-funded clinical trial have international investigators as co-principal investigators? I mean investigators from outside the United States.
The answer depends on whether you plan to conduct part of the clinical trial outside the United States. If you will not be enrolling participants from other countries, and if the foreign investigator is being brought on board simply for scientific expertise, that’s fine. However, NCCIH has made the decision that we won’t support international clinical trials—that is, trials that include participants from multiple countries—because of the added oversight burden they involve. The only exception is that we do fund research in Canada because the regulations are similar to those in the United States.
What is your advice on the best mechanism to gather effect size data for future efficacy trials?
On this topic, we often refer people to the great body of work by Dr. Helena Kraemer on the appropriate use of pilot studies. Based on Dr. Kraemer’s recommendation, effect sizes should be determined by how much you know about the clinical condition, what improvement is clinically meaningful, and what sample size is needed to detect that amount of change. We are developing content for our Web site on how to establish effect sizes. Effect sizes should not be based on small studies with unreliable effect size estimates. [See Pilot Studies: Common Uses and Misuses]
Will any of the grants fund formulation development? We are interested in developing a pharmaceutical-grade sustained-release formulation of a natural product for depression, anxiety, and fibromyalgia.
We don’t fund much work of this type because it is not hypothesis driven. We would be more likely to fund a study that compared formulations with one another, perhaps in terms of their effects on pharmacokinetics or a biological signature. One exception might be small business applications. If you plan to apply under one of the small business mechanisms, please contact NCCIH to discuss your proposed study in more detail.
Is it true that applications may be returned without review if they don’t contain required elements or are not compliant with FOA instructions? How can applicants make sure that their application is complete and compliant?
Yes, it is true. It’s important to follow the FOA instructions carefully. For example, if a required attachment exceeds the allowed page limit, the application is not compliant and will be returned.
Completeness refers to inclusion of all the required elements specified in the FOA. We suggest that in addition to reading the FOA carefully, you do a text search for words like “must” and “require” to make sure that you haven’t missed anything. On our Web page for the new FOAs, each FOA description has a link you can click on to see the required application elements for that funding opportunity.
Do the funding mechanism changes reflect a de facto change away from investigator-initiated research?
No. Investigator-initiated proposals have always been the “bread and butter” of NIH, and we continue to welcome them. The new clinical trial FOAs provide the framework for your investigator-initiated application.