New NCCIH Funding Opportunities for Natural Product Clinical Trials Webinar Summary
May 9, 2017
2:00 p.m. to 3:30 p.m. ET
Purpose of the Webinar:
On Tuesday, May 9, 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 clinical trials of natural products
- Introduce the concept of “building blocks” in clinical research
- Give details about the various funding opportunities available from NCCIH
The webinar conveyed important information about changes in the policy for NCCIH acceptance of applications for clinical trials of natural products. It also provided details about the different Funding Opportunity Announcements (FOAs) for clinical trials, including new cooperative agreements (U awards) and phased awards, about the need for consultation with the U.S. Food and Drug Administration (FDA) regarding the need for an Investigational New Drug (IND) application for the proposed research, and about NCCIH’s Natural Product Integrity Policy.
- 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
- Craig Hopp, Ph.D., Deputy Director, Division of Extramural Research, NCCIH
- Ashlee Tipton, Ph.D., Scientific Review Officer, Division of Extramural Activities, 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 scope and mission, and factors to consider when designing clinical trials of natural products and selecting an appropriate FOA for a clinical trial application.
NCCIH’s Scope and Mission
NCCIH’s research portfolio includes both basic and clinical research on a variety of complementary health approaches, including both mind and body interventions and natural products. Today’s webinar focuses on clinical trials of natural products.
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.
Clinical Trials of Natural Products
NCCIH wants to support definitive multisite clinical trials of natural products. However, in most instances, additional preliminary data–or “building blocks”–need to be developed before definitive trials can be designed and performed.
NIH leadership recently addressed the quality of clinical trials in an article in the Journal of the American Medical Association, 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.
Why a New Approach to Clinical Trial Funding?
NCCIH has developed a new approach for funding clinical trials for several reasons.
- The new approach is part of the NIH-wide initiative to improve clinical trials.
- 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.
- NCCIH funds research that helps people manage important health issues, such as hard-to-manage symptoms, including pain, anxiety, and depression.
NCCIH has funded some large-scale clinical trials of natural products, most of which failed to demonstrate the hypothesized benefit. There are exceptions: For example, the trial of chelation therapy for preventing cardiovascular events in patients with a previous heart attack had some positive results, and the intervention is now being studied in a replication trial.
Common Limitations of Trials
Many clinical trials of natural products have had similar limitations. Often, trials have been conducted at a single site, which reduces the generalizability of their results. In instances when a trial failed to demonstrate the hypothesized benefit, the results have been difficult to interpret because there were many unanswered questions before the trial was conducted. Dosing studies may not have been performed and so there may be uncertainty whether the participants received a large enough dose of the natural product, whether the study used the correct frequency of dosing, whether the right product and formulation were selected, and whether an appropriate population was selected. Many of these limitations 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 needs to be collected. For natural products, this starts with fundamental preclinical knowledge and any historical use information that is available. The next step is product development and testing—to ensure that the product is of high quality and that its pharmacokinetics are understood. This is followed by optimization of the dose, investigation of the biological signature of the product, and optimization of trial methods. Only after this preliminary work is completed should a product be tested in a large-scale multisite efficacy trial.
In the past, it was often difficult for investigators to find funding for research to develop the building blocks to support a definitive clinical trial of a natural product. NCCIH’s new FOAs for clinical trials of natural products fill this gap. They provide pathways to support the developmental steps between basic science and high-impact clinical trials. They include funding opportunities for early stage clinical research (R61/R33 and R33), intermediate stage research (U01), and large multisite clinical trials (Collaborative UG3/UH3 for the trial’s Clinical Coordinating Center (CCC), accompanied by U24 for a Data Coordinating Center (DCC)). The R61/R33 and R33 FOAs for natural product research have expired, but NCCIH has issued notices that these FOAs will be re-issued this summer with receipt dates in October 2017 (NOT-AT-17-010 and NOT-AT-17-011).
What Has Changed?
The most important change in NCCIH’s clinical trial funding is that NCCIH is no longer accepting most clinical trial applications through the Parent R01 FOA (NOT-AT-17-006). After May 8, 2017, you must submit most clinical trial applications in response to NCCIH’s 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 for assignment to NCCIH. 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).
More Details on Building Blocks
The building blocks for natural product clinical trials can be broken down into more specific elements.
- At the stage of product development and testing, key areas of research include pharmacokinetics, identification of a reproducible biological signature, selection of an appropriate population and an appropriate outcome measure, and gathering of information about the quality of the product.
- At the stage of optimization of dose and trial methods, key areas of research include formulation and dose optimization of the product’s impact on a biological signature, as well as development of efficient methods for recruitment and retention of study participants, and effective data collection and management methods.
What Is a Biological Signature and Why Is It Important?
A biological signature of a natural product is a measure of the postulated mechanism of action by which the product may modify the condition or symptom of interest. It may be an objective single measure or a proxy, correlate, or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.
Having a biological signature is important because it results in more informative clinical trials. In the absence of a biological signature, trials may not be informative. With a biological signature, trial results are meaningful regardless of the clinical outcome. If the clinical outcome improves, the biological signature may be a mediator of the effect and a target for the potential development of a new treatment. If there is no effect, then the biological signature is not a useful target. If the clinical condition worsens, the biological signature is not a useful target and may be a mediator of the worsening outcome.
For some conditions, it may be impossible or impractical to directly measure the biological impact of a natural product. In those situations, the applicant should
- Have a clear rationale for why a biological signature cannot be studied in human participants;
- Consider proposing other objective, reproducible measures that may be proxy to or indicative of a biological or behavioral effect of the product; and
- Have strong, compelling preliminary data to warrant further clinical study of the product.
In situations where investigators cannot measure the biological signature of a natural product, they should contact an NCCIH Program Director (email@example.com) to determine which FOA is best for their proposed research.
FOAs for Early Stage Research
If you are planning an early stage trial, the R61/R33 or direct R33 funding opportunities are most appropriate. The R61/R33 is a phased award, in which the first (R61) phase involves determining whether the natural product can impact a biological signature in humans and establishing its short-term pharmacokinetics and bioavailability. The subsequent R33 award (or a direct R33, if pilot data are already available) is suitable for studies to reproduce the impact of the natural product on the biological signature, possibly optimize the dose of the product to enhance its impact on the biological signature, and assess the correlation between the biological signature and clinical outcomes.
Placebos are allowed and may be needed in early stage clinical studies of natural products. They can help investigators demonstrate that the changes seen are due to the product and not regression to the mean or the natural course of a disease.
The R61/R33 or direct R33 mechanisms will not support multisite efficacy or effectiveness trials, clinical trials designed solely to estimate intervention effect sizes, applications that do not propose to give the natural product to human participants and measure the impact on a biological signature, observational studies. These types of studies should use other FOAs instead of the R61/R33 or R33. Applications for studies that focus on the treatment or prevention of cancer should be directed to the National Cancer Institute.
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, it wouldn’t make sense to attempt to replicate a biological signature if one had not been established.) Only one application and one peer review process are required for both phases. A crucial part of the application is defining measurable 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.
Funding for Intermediate Stage Clinical Research on Natural Products
NCCIH has established a U01 natural product Phase II cooperative agreement for intermediate stage research. This mechanism supports:
- Dosing and formulation optimization of the product’s biological signature
- Studies to determine which patient phenotypes are likely responders vs. nonresponders
- Other final building blocks to prepare for a multisite efficacy trial, such as establishing efficient methods to
- Recruit and retain participants
- Achieve adherence to the study protocol
- Complete collection of follow-up data
This mechanism will not support multisite efficacy or effectiveness trials, first-in-human trials, observational studies, or studies of interventions for the prevention or treatment of cancer.
Building blocks that are needed prior to a U01 trial include:
- Pharmacokinetic data on the specific natural product and formulation to be studied
- Demonstration that the product can produce a clinically meaningful change in a biological signature (if possible)
- Evidence of a correlation between the biological signature and a clinical outcome
- Evidence that the product does not produce frequent or severe adverse effects in pilot trials
- Completion of final data collection from pilot studies
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.
Funding for Efficacy Research on Natural Products
NCCIH will fund efficacy trials of natural products through companion UG3/UH3 and U24 FOAs. Every efficacy trial needs to be multisite, and investigators must submit a UG3/UH3 application (for the Clinical Coordinating Center (CCC)) and a U24 application (for an independent Data Coordinating Center (DCC)) at the same time. This mechanism will support efficacy or effectiveness trials. Most efficacy trials will have budgets (for the CCC and DCC combined) that exceed $500,000 in direct costs/year. Therefore, per NIH policy, investigators need NCCIH permission to apply. Building blocks needed prior to a multisite efficacy trial include all those required for the U01 funding opportunity plus
- Evidence that a multisite trial is feasible and that the research team has experience doing multisite trials
- Preliminary data on the specific natural product in the same patient population
- Data to demonstrate that the selected doses are likely to have the greatest impact on the biological signature and minimize the risk of adverse events
- Complete final data collection from any pilot studies
NCCIH requires that trials at this stage be conducted at multiple sites to increase rigor, reduce bias, and provide the most informative results. Conducting trials at multiple sites increases the generalizability of the results, increases the diversity of the population studied, and enhances the ability to meet recruitment requirements in a reasonable amount of time. Having an independent DCC keeps 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 CCC and DCC 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/UH3 phased award.
Consulting With the FDA
Investigators who wish to conduct NCCIH-funded clinical trials of natural products must contact the FDA before submitting an application to NCCIH to determine whether they need an Investigational New Drug (IND) application. The FDA determines whether an IND is necessary or whether a waiver can be granted. Waivers must be granted in writing, and NCCIH needs a written copy. Applications must include a “Regulatory Communication Plan” as a required attachment. Nearly all NCCIH-funded natural product studies in human participants have required INDs.
NCCIH’s Product Integrity Policy
Because botanical products have some well-documented quality concerns, NCCIH has implemented a Product Integrity Policy to ensure that the products used in the studies we fund are well characterized. Investigators must develop quality control protocols prior to funding, and independent confirmation of supplier quality documentation is required. Information on product quality will be requested in the Just in Time letter prior to funding. More information is available on the NCCIH website.
The Review Process
Applications submitted using the natural product 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 allow applicants to provide study details (such as a protocol synopsis and Regulatory Communication Plan) in a standardized way. Review panels will take the information in the attachments into account when evaluating applications. It’s important to make sure that all the required elements, including attachments, are included in your application. If your application is incomplete, it will not be reviewed.
Summary of Questions and Answers
With all of these different mechanisms, how do I decide which funding opportunity to apply for?
We have a wide variety of FOAs available to applicants now. For clinical trials, we have natural-product–specific FOAs and FOAs specific to mind and body interventions; make sure you’re choosing from the right set for your proposed research. Then, within that set, choose the FOA that most closely matches the stage of research that your project represents. In each set, there are FOAs for early phase trials, intermediate trials, and full-scale efficacy, effectiveness, or pragmatic trials. Each of the FOAs describes what preliminary data are needed for that stage of research. Consider what level of preliminary data you have and what type of study you want to conduct, and then read the FOAs carefully to decide which one is right for you. Please contact our Program Directors at firstname.lastname@example.org for further guidance.
Who will review applications submitted in response to the clinical trial FOAs?
NCCIH special review panels with expertise in both clinical trials and complementary health approaches will review the applications. The panels will include experts familiar with the challenges faced by this research community. Applications for clinical trials of natural products will go to panels who are knowledgeable about both natural products and clinical research. The panel should be able to provide valuable advice and constructive feedback to investigators.
If a natural product has already been shown to be safe and efficacious in vitro, in animals, and in humans for treating one disease, can those data be used to support a planned clinical trial for a different disease application?
Broadly speaking—without regard to the specific indication or the specific product—yes, you can use previous animal or in vitro research on potential mechanisms that may be beneficial for different disease conditions. That evidence may provide a rationale for moving into a new area of research. But if the specific product has never been studied in the specific patient population that you now want to study in clinical trials, your first application would likely need to be an R61/R33 to demonstrate that the product has a specific biological impact in that patient population.
How should data from a successful but unpublished case study be presented in an application?
We encourage all of our investigators to publish their research. Published peer-reviewed research is viewed differently from unpublished data in an application. However, reviewers will look at unpublished data and will evaluate its quality. You can describe the data and cite it as unpublished research.
How can I find a reliable and interested physician to run the part of the trial that involves patients?
One possibility is to look at the NIH Reporter and ClinicalTrials.gov websites to see who’s running clinical trials in your area in the patient population that is relevant to your area of research. In general, you want to find a clinical trialist who has experience doing studies in the specific patient population because they know how to recruit and retain those types of participants and often have clinical training in the actual disease condition. Asking around your institution about who’s doing research in that area can also be helpful.
Will NCCIH consider funding studies of a natural product containing multiple ingredients?
Yes. However, for all natural products, we require a rigorous product integrity review, and as the number of ingredients in the product increases, the complexity and level of effort required to confirm the product’s integrity increase accordingly. The reviewers of an application involving a complex natural product might also consider the need to correlate specific ingredients with specific outcomes, and the more complex the product becomes, the more difficult it becomes to make this justification.
How does NCCIH define “natural product”?
Something that comes from nature—an organism or a mineral. Synthetic versions of natural products are still natural products as far as NCCIH is concerned, but derivatives of natural products are not. We typically do not support clinical studies on derivative, especially if the studies are undertaken to optimize clinical outcomes. In general, we consider botanicals, dietary supplements, and pre or probiotics to be natural products.
Must natural products have an industry sponsor (and thus a pathway to FDA approval)?
NCCIH does not require products to have an industry sponsor. You do need a supplier who is willing to provide enough information about the product and how it’s made to meet the requirements for your IND application, if the FDA requires one. Therefore, the supplier’s cooperation is essential. Whether to submit a New Drug Application for the product to get FDA approval for a specific indication is up to the supplier. It is not something we require at any stage of our application process. NCCIH would not be the IND holder. It would be the principal investigator.
If the principal investigator plans to position the natural product as a nutraceutical that would be sold over the counter, what evidence would NCCIH require toward the goal of applying for a Qualified Health Claim for the product? Does NCCIH have any guidance on this topic?
Decisions about Qualified Health Claims are within the FDA’s purview, not NCCIH’s. NCCIH typically does not get involved in the regulatory aspects of how a product would be marketed. The need for an IND is dictated by the design of the study, so if you’re measuring specific clinical outcomes, as you would be by the U01 stage, you may need an IND—although the FDA would make that determination. The FDA has required INDs for most of the natural products studied in NCCIH-funded clinical trials. The FDA has extensive guidance on their website about the IND process for botanicals.
If a natural product has been shown to be efficacious and to have minimal adverse effects in adults, would NCCIH be interested in supporting clinical trials of the product in children and adolescents? There are no preliminary data in the younger population.
We would need to talk with you about any preliminary data you have in children. Children are considered a vulnerable population, and the FDA may make different decisions about what information they require before you can do studies in children than they would for adults. In general, NCCIH supports pediatric research and studies in adolescents. The key issue is whether you have adequate information on the safety and toxicity of the product. In some instances, the FDA might require further studies in adults before you move into pediatric trials.
Do you fund trials related to HIV and the use of natural products for HIV patients?
The treatment and prevention of HIV are under the purview of the National Institute of Allergy and Infectious Diseases (NIAID). Applications for natural products to treat or prevent HIV would need to go to NIAID. If you’re talking about managing symptoms such as fatigue or side effects of drug treatment for HIV, then NCCIH might be interested in your application. You would need to follow our usual process of starting with early stage studies and then moving on to intermediate stage and larger trials.
Is an IND required before submitting an application?
No. You do not need to hold the IND prior to submitting your application. However, by the time that we’re close to funding an award, most investigators have submitted their IND application. You will not be able to start any clinical research until the IND is in place or you have received a waiver from the FDA.
Is testing the behavioral effects of a natural product on a nonclinical population, such as college undergraduates, in preparation for a test with a clinical population considered a clinical trial or a preliminary investigation? How should an application for such a study be submitted?
It depends on what outcomes you’re measuring. NIH’s definition of a clinical trial is quite broad, with three elements. Are you enrolling human participants? Are you giving them an intervention? (It sounds as though you would be in this case.) And what outcomes are you measuring? NIH defines clinical outcomes quite broadly to include any psychological outcome or any clinical measure of disease. If your proposed study meets that definition, you would need to use our new FOAs. Please talk to us about which outcomes you’re looking at so we can help you choose an FOA, but in general, it looks as though the R61/R33 would be an appropriate choice, with the R61 work done in your nonclinical population and the R33 moving into a clinical population.
Can you give us an idea of what the cutoffs (percent of grants funded) are for various types of applications?
We don’t publish paylines and we don’t provide specific success rates for different funding opportunities. You can get some information about success rates from NIH Reporter for different mechanisms. But remember that most of the clinical trial FOAs are still very new.
For basic and mechanistic studies funded under the R01 or R21 mechanisms, are there specific study sections for natural products research?
No. Most study sections are organized the way most of the Institutes and Centers (ICs) at NIH are organized, that is, around a disease, organ system, or body part. There are no standing study sections within the Center for Scientific Review (CSR) that focus on natural products. Occasionally, NCCIH will issue a specific Request for Applications (RFA) focused on natural products, and in those cases, our staff would organize a special review panel.
We submitted an application to the Parent R01 in June 2016. How will resubmittal be handled post June 2017?
You cannot use the Parent R01 for a resubmitted application for a trial with clinical outcomes if you want it to be assigned to NCCIH for funding consideration. If you did use the Parent R01, the application would not be assigned to NCCIH because we no longer accept applications for clinical trials through the Parent R01. If an investigator submits an application for a clinical trial using the Parent R01, the Center for Scientific Review (CSR) will try to find another Institute or Center to accept it, but if this effort is unsuccessful, the application will not be reviewed and will have to be withdrawn. To avoid this possibility, we encourage you to contact an NCCIH Program Director (email@example.com) for advice on how to apply under the new clinical trial FOAs. You will need to redesign your application to fit the requirements of one of the clinical-trial–specific funding opportunities based on the amount of preliminary data that you have.
Are pilot data needed for R61s? Is an application considered stronger if pilot data are included? Also, is it possible to propose a study of responders vs. nonresponders as a mechanistic study for R61? Or is such a design suitable only for a U01?
Technically, the R61 does not need pilot data, although you need a very strong rationale and justification for why you’re proposing to study a particular product for a particular condition. Some applications for the R61 have historical data, preclinical data, or animal or in vitro research. You do not necessarily need human subjects data to submit an R61 application. The review criteria specifically indicate that this type of data is not necessary, so reviewers will not be anticipating that pilot data will be included in all R61 applications. However, if you’re applying for the R33, reviewers will expect that you have human data on the specific product and patient population because you’ll need to replicate the effect of the product on the biological signature.
You certainly could propose to look at responders and nonresponders in an R61, but the study probably would not be powered to evaluate the differences between the two groups. The R61 phase is only 2 years, and the R33 is for up to 3 years. The U01 allows up to 5 years of funding and a larger budget, so it might be more appropriately powered to look at responders and nonresponders.
For research on HIV, it’s problematic to propose studies of natural products to NIAID. If one is trying to fund a study about treating an infectious disease using a natural product, is NIAID the only route, or are such studies of interest to NCCIH?
For HIV specifically, NIAID is the appropriate IC. For other types of infectious diseases, NIAID is the lead, but you could contact us to talk about your specific application.
Will any of these funding mechanisms support normal volunteer studies to examine basic pharmacokinetics and pharmacodynamics of natural products?
That kind of work would be done in the R61 phase, but you also need to apply for the R33 so that you can move your work into a clinical population in the R33 phase. The R61 could be done in normal, healthy participants, but the R33 cannot be. If you’re doing purely mechanistic research on the biological signature, the Parent R01 and Parent R21 are still options as well. We encourage you to contact an NCCIH Program Director (firstname.lastname@example.org) for advice on whether your application can be submitted under the Parent FOAs.
Do the new clinical trial FOAs indicate that NCCIH will be focusing more on funding clinical research rather than basic and mechanistic research?
No. NCCIH will still support foundational preclinical natural product research. We are definitely still interested in using preclinical models to better understand the biological signatures of natural products. A substantial portion of the research we fund is still basic, mechanistic, or preclinical in nature.
Are there new review criteria that may affect my proposal’s scores and prospects for funding?
Yes. Applicants should pay close attention to the information about review criteria provided in each FOA. There are specific review criteria that should be addressed and specific attachments that must be included so that the application will be considered complete. If these attachments are not included, the application will be considered incomplete and therefore will not go through review.
Are pharmacokinetic and bioavailability data from animal studies adequate, or do we need human data?
Because pharmacokinetics can differ between animals and humans, you will need to obtain human pharmacokinetic data. The R61 is appropriate for studies of pharmacokinetics and bioavailability in humans. We don’t specifically require human data for toxicity, but you will need to discuss this topic with the FDA if your application moves forward toward funding.
What if you’ve done an NCCIH-funded Phase III trial already, but you don’t have the complete biological signature of the product yet, and you want to study this biological signature, such as pharmacokinetics? What FOA fits this situation?
This depends on whether the Phase III trial was successful. That determines whether it would make sense to go back and do early phase work on the biological signature. If the product does not work, it may not make sense to collect additional data. It would help if we talked with you one-on-one about that. The R61 is the funding mechanism intended for research on pharmacokinetics and pharmacodynamics to establish a biological signature, but you must also submit an R33 application with it. You cannot submit an R61 alone. Your application would not be considered complete, and it would not be reviewed. Alternatively, if you already have some data on the biological signature, you can submit the R33 alone to replicate it.
I was told last year that you do not support natural products research for diabetes and that applications in that area should be submitted to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). But NIDDK says they’re not interested in natural products; they suggested that I contact NCCIH. What do you suggest?
It can be difficult for investigators to find a home for natural products research. Please send an email to email@example.com to provide more information about where you are in the stages of testing the product. It’s important to recognize that NCCIH is one of the smallest ICs in terms of budget at NIH. We cannot fund a lot of large-scale trials. Before we move into large-scale trials, we want to make sure that there are very strong preliminary data. We do sometimes partner with other ICs for studies. One example is the current chelation study, which is cofunded with several other ICs. If you have all the types of data necessary to lead up to a multisite efficacy study, NIDDK might be interested in eventually partnering with us on a large-scale trial. In general, NIDDK is the appropriate place for diabetes research. But we might be able to see whether an R61/R33 would be possible to develop the preliminary data that would make NIDDK more interested in your area of research.
What if our R61 shows effects that are not the ones we anticipated, and therefore we didn’t meet the milestones that we proposed, but we have data showing that the product has an effect on other mechanisms? Could we move ahead to the R33 phase?
No. You could not transition from the R61 to the R33 because you would not have met your milestones. However, you could use those data as pilot data for a new R33 application, which would be submitted for scientific peer review. When you submit an R61/R33 application, you have to set very clear criteria for when you would or would not move forward to the R33 phase.