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Summary - Technical Assistance Webinar for RFA-AT-20-001, “Preclinical Screening for Natural Product Drug Interactions (Clinical Trial Not Allowed, R21)”


Purpose of the Webinar

On Thursday, October 3, 2019, the National Institutes of Health (NIH) National Center on Complementary and Integrative Health (NCCIH) hosted a preapplication webinar to provide information for applicants about the funding opportunity announcement (FOA) for “Preclinical Screening for Natural Product Drug Interactions (Clinical Trial Not Allowed, R21),” RFA-AT-20-001.

Webinar Speakers

  • D. Craig Hopp, Ph.D., Deputy Director, Division of Extramural Research, NCCIH
  • Anita McRae-Williams, M.A., Outreach Communications Program Manager, Division of Extramural Research, NCCIH (Webinar Moderator).

Background Basics

This is an R21 request for applications (RFA) focused on preclinical screening of natural product drug interactions. Each award will include up to $275,000 of direct costs over 2 years. Awardees can divide the budget up as they wish, as long as no more than $200,000 is used in any 1 year. NCCIH plans to make five to six awards total from this RFA.

The target applicant audience is teams that include pharmacologists, individuals knowledgeable in pharmacokinetics, and natural products chemists who can help isolate specific compounds and further elucidate their mechanisms of action for observed interactions.


The principal investigator (PI) can be from almost any U.S.-based institution—nonprofit, academic institution, small business, etc. The applicant cannot be from a foreign institution, but foreign collaborators are allowed. Specific justifications must be provided in these instances, such as why the foreign collaborator is needed and the unique expertise the foreign collaborator has that is not available within the United States. Institutions and individual PIs can submit more than one application, but the applications must be scientifically distinct from each other.

Major Objectives

The major objectives are listed within the RFA. This RFA is looking for preclinical screening to uncover interactions between a variety of natural products, especially those consumed in either food or dietary supplements, and different medications, both pharmaceutical prescription drugs and over-the-counter drugs. The RFA is specifically interested in pharmacokinetic interactions—those that are mediated by various Phase I and Phase II drug metabolizing enzymes and the associated transporters.

The RFA is also interested in either followup on preclinical screens or further elucidation of mechanisms of already-discovered interactions in an existing collection of natural products. For example, you may already have a complex mixture, and you want to identify the active perpetrator of a particular interaction. Or, you may already have an isolated natural product, and you want to further delve into the mechanisms of a particular interaction.


The interactions that are allowed for this RFA are limited to pharmacokinetic ones: interactions involving Phase I or Phase II metabolizing enzymes and transporters. For this RFA, it would not be appropriate to look at a pharmacodynamic interaction. For example, it would not be appropriate to study synergies or antagonisms of a natural product and a drug with similar mechanisms of action. NCCIH is certainly interested in these types of pharmacodynamic interaction studies, but applications would need to be submitted through other FOAs. Applications to this RFA that are based on pharmacodynamic interactions will be withdrawn and not reviewed.

Libraries and complex mixtures are not necessarily required for this RFA. For instance, performing a deeper dive on an identified individual natural product would be appropriate. NCCIH is particularly interested in (1) green tea and green tea catechins and their interaction with mycophenolic acid, and (2) goldenseal and its various alkaloid constituents and their interactions with metformin.

If animal models are proposed, you would need to provide a clear and well-justified case for why the animal model is relevant to and would accurately predict human metabolism. The position of the Food and Drug Administration (FDA) regarding drug interactions is that animal models are typically poor predictors of human metabolism.

Research Plan

Information about the research plan is found in Section IV of the RFA, under PHS 398 Research Plan. It is important to read this section carefully because it lists what needs to be included in your research plan, such as the types of research desired and the types of research descriptions required. The reviewers will be asked to assess how well you have addressed and incorporated these concerns and questions in your research plan.

Coordination With U54

This RFA is issued with a companion RFA, the larger RFA-AT-20-002, a renewal of the ongoing U54. R21 grantees will be expected to eventually work with the U54 grantee and to deposit their data in the U54-maintained data repository focused on drug interaction research. You will need to describe a general strategy for how that data will be structured to maximize (1) the ability of others to use the data, and (2) uploading and incorporating the data into the database. The strategy should include how you plan to coordinate and cooperate with the U54 grantee. You do not need to indicate any type of explicit agreement with the existing U54, as the current U54 grantee may not be the next U54 grantee.

Review Perspective

Completeness, Compliance, and Responsiveness

Scientific review officers (SROs) will assess the completeness and compliance of the application with the RFA. Applications that are incomplete (are missing required information), noncompliant (include information that they are not supposed to), or nonresponsive (delve into scientific areas that are not responsive to what the RFA is asking for) will not be accepted for review.

Review Criteria

There will be five scored review criteria, which are the standard ones for all FOAs: significance, investigators, innovation, approach, and environment. A separate 1 to 9 score will be given for each criterion. Additional review criteria could impact the scores and will be factored into the overall impact score.

It is important to read the review criteria carefully; they’re in Section V. Application Review Information in the RFA. Reviewers will be assessing whether the listed criteria are addressed in your application. In addition to the standard review language noted in the RFA, there is language added to each criterion for this specific FOA, and it is important to address those points as well.

Letter of Intent

A letter of intent is requested to be submitted 30 days prior to the RFA receipt date. The letter of intent receipt due date was October 1. The letter of intent, however, is requested but not required. You can submit an application without sending a letter of intent. You can also submit the letter of intent now. If you submit a letter of intent, include only the title of the application, PI’s name, institution, and key personnel and their institutions, and send it to the Chief of the Office of Scientific Review, Martina Schmidt, Ph.D., at You are encouraged to send a copy to Dr. Hopp ( and contact him prior to submitting your letter of intent or application so that he can advise you on the fit of your specific aims with the RFA’s objectives.

Review Panel

Applications will be reviewed by an NCCIH-organized special emphasis panel (SEP). (This means that you do not need to indicate to which study section you think your application should be directed.) NCCIH’s Office of Scientific Review will recruit reviewers with the specific expertise needed to review the applications received. NCCIH expects to have the appropriate expertise needed to review all applications. In a cover letter submitted with your application, you can indicate the type of expertise you think is needed on the panel to adequately and accurately review your application, whether it be mass spectrometry or Caco-2 cell permeability assays, for example. Reviewers will be asked to assess how well your submission addresses the standard review criteria and the additional specific FOA review criteria and to determine how impactful the application will be in addressing the goals of the RFA.

Questions and Answers

Q: Is there a designated study section for this R21? If not, do you recommend a particular study section?
A: There is no need to request a study section. A special emphasis panel will be organized by NCCIH’s Office of Scientific Review, and the review staff will recruit the appropriate expertise to review your application.

Q: Do I need to be affiliated with the U54 in order to submit an R21 application?
A: No, there is no requirement that you have an existing relationship or collaboration with the U54 group. We do, however, want the awarded grantees to interact with the U54 group. Ultimately, we want to expand the availability of the research to the broader research community.

Q: If we can’t make the deadline, will this RFA be reissued at a future date?
A: There are currently no plans to reissue this RFA for additional future receipt dates. If you cannot make the November 1 deadline, you can still submit through the parent or other R21 mechanisms. Also, we will not be accepting any late applications, even in cases of continuous submission privileges with the Center for Scientific Review (CSR)—those privileges do not apply to RFAs.

Q: Does the library of compounds have to be a specific natural product or can it be a class of compounds inspired by other natural products? How should we focus—natural products scaffold versus actual natural product target molecules?
A: The library should be overwhelmingly natural products. We are not interested in libraries of semisynthesized or derivatized natural products. For the purposes of this RFA, we are trying to understand what people might be consuming that could perpetrate interactions with medications, so the library should be largely representative of things that people are or could be consuming. A library of synthetic compounds would not be appropriate for this RFA. Libraries of pharmaceuticals and drug-drug interactions also would not be appropriate.

Q: Although the RFA is designated as preclinical, may existing clinical specimens be used to generate data or validate a new method?
A: You cannot conduct a clinical trial, but you can use biospecimens, especially if they are deidentified samples. If, for example, you have plasma samples, urine samples, tissue biopsies, etc., and you want to use them in some context to help further the research, that would be allowed.

Q: Should the screening assays to evaluate library botanicals be novel?
A: The screening assays can be novel, but the assays should yield data that will help to advance natural products for further clinical study. The assays should reflect the most likely scenarios. You would still want to use Phase I and Phase II metabolizing enzymes, for instance. We don’t want to necessarily be discovering some new obscure enzyme that might facilitate some sort of transformation.

Q: I’m a potential PI who works at a nonprofit academic institution. Is it all right to include a collaborator from industry who has expertise in pharmacokinetic-based drug drug, herb drug interactions?
A: Yes, industry collaboration is allowed through this RFA as long as the industry collaborator is fine with engaging in academic research.

Q: Would it be appropriate to have an application studying to what extent inhibition of a specific CYP by a natural product influences the therapeutic index of a drug?
A: This touches on the interface between pharmacodynamic and pharmacokinetic interactions. If, for example, the pharmacokinetic interaction changes the IC-50 curve of a particular natural product or pharmaceutical by inhibiting an efflux pump, and you could increase the efficacy or lower the IC-50 of a drug, then that would be allowed. If you’re looking at the impact of the pharmacokinetic interaction as a change in the therapeutic index, making it either more effective or less dangerous, that would also be allowed through this RFA.

Q: Any guidance for how large the library of test samples needs to be? If large, is the focus on high throughput methods?
A: We’d like to see high throughput as much as possible for the screening aspects. Not all academic institutions are equally set up for high throughput. If you do high throughput, you have to have a large library. There’s no limit on the size of the library or how high the throughput is. There’s also no limit on the lower end of it, either—you can be studying one or two natural products. The aim is to increase the knowledge base around what natural products might produce potential interactions with pharmaceuticals. If you’re using large libraries, this will give you a better likelihood of finding something that might produce that interaction and give us more signals of what we might want to focus on going forward.

Q: It seems the screening approach is quite standard. How will novelty be evaluated?
A: Innovative assay methodologies would be appropriate if you are looking at specific interactions where there’s opportunity for novelty of discovery—novel natural products that weren’t previously known to produce interactions, for example. But innovation is not of primary importance. That is partially why we issued this as an RFA rather than through the parent R21, which is supposed to be much more high risk/high reward. Innovation is not as high priority with this R21 as it is with other, more typical R21 solicitations.

Q: Will resubmissions will be accepted?
A: If you already submitted an application through the parent R21 and it didn’t get funded, you could submit that to this RFA, but you could not submit it as a resubmission. It would need to be a new application because this RFA has different activity codes and a different funding mechanism than whatever you submitted to previously. Once you submit your application to this RFA, you will not able to resubmit it back to this RFA. If you are unsuccessful with this RFA, then you would need to return to the parent R21.

Q: Could the library of natural products be composed of only edible plant extracts?
A: Yes.

Q: Could preclinical prediction of botanical drug interactions in cells using omics approaches (combination of metabolomics, proteomics, and genomics) be acceptable?
A: Yes, that is acceptable as long as the omics approaches are focused on pharmacokinetic interactions. Any high throughput, high-content omic-based research to uncover interactions should be driven by the search for and focus on pharmacokinetic interactions. It should not be an untargeted look for interactions followed by seeing if they’re based on pharmacokinetics.

Q: How important is it to have a pharmacokinetic expert collaborator as part of the team?
A: You don’t necessarily have to have a card-carrying pharmacologist or pharmacokinetics person on your team. You need to demonstrate that you have the appropriate expertise to carry out the experiments that you’re proposing to do. That is, someone on your team needs to have sufficient expertise in the techniques and assays that you are proposing. The review criteria don’t require an expert in pharmacokinetics, but you need to have enough expertise to convince the reviewers that you can execute the research proposed.

Q: I can make or access families of natural products that have not been tested for any activity but are present in various foods. Do the natural products have to have some known or specific behavior to be considered as part of the RFA?
A: No. If you have natural products that are present in either the food supply or supplements or have the potential to be consumed by people, they would be appropriate. Natural products unlikely to be consumed by people, for example those present in aquatic or marine sediments, might not be appropriate for this RFA.

Q: Please clarify whether the page limit is 6 or 12 pages.
A: This RFA follows the standard page limits for R21s, which is 6 pages. If 12 pages is listed somewhere, that was an error.

Q: Does the application need to address drug drug interaction on drug-metabolizing enzymes and drug transporters, or can we focus on one of them for in-depth study?
A: It’s fine to focus on a single transporter or enzyme if you have reasons for thinking there is high potential for natural products to interact with that particular transporter or enzyme. It is also fine to focus on a small subset.

Q: I want to study how a natural product potentiates a vaccine. Is that allowed?
A: No, that is an example of a pharmacodynamic interaction. That type of research—trying to study synergies that produce extra benefit or mitigate toxicity—is not appropriate for this RFA. This RFA requires pharmacokinetic-based interactions.

Q: Will only data be transferred to the U54 site or will there will be an expectation to participate in U54 meetings?
A; The data, at minimum, will be expected. The U54 has a required annual meeting. The R21 does not explicitly require these grantees to attend the U54 annual meeting. However, there could be scenarios where meetings or workshops are organized that include both U54 and R21 grantees.

Q: re there classes of natural products that are of specific interest to NCCIH?
A: Yes, we are interested in compounds that have the potential to be consumed by the public—compounds in the diet or supplements. Well-known examples are St. John’s wort and grapefruit juice. We are trying to determine whether there are other items that are cause for concern, and the purpose is to understand the potential for herb drug interactions.

Q: Could studies for interactions using cancer cell lines be acceptable to predict botanical anticancer drug interactions?
A: Yes, they could be if they are pharmacokinetic based. Typically, pharmacokinetic interactions are studied using human liver microsomes or other types of well-known systems. If you want to propose studying cancer cell lines, that would be acceptable, but you would need to make the case for how they would help to predict or inform interactions in humans.

Q: Are studies of the effects of drugs on metabolism of natural products responsive to the FOA?
A: This might be allowed. However, you would need to make the case for why that interaction could be relevant to a significant natural product drug interaction in humans such that it would be of concern for consumers or health care practitioners.

If you have additional questions or would like to discuss your application in detail, please contact Dr. Hopp by email at