Summary - Preapplication Webinar for RFA-AT-20-002, Center of Excellence for Natural Product Drug Interaction Research (U54 Clinical Trial Required)

SUMMARY

Purpose of the Webinar

On Thursday, October 3, 2019, the National Institutes of Health (NIH) National Center for Complementary and Integrative Health (NCCIH) hosted a preapplication technical assistance webinar to provide information for applicants about the funding opportunity announcement (FOA) for the Center of Excellence for Natural Product Drug Interaction Research, RFA-AT-20-002.

Webinar Speakers

D. Craig Hopp, Ph.D., Deputy Director, Division of Extramural Research, NCCIH
Wendy Weber, N.D., Ph.D., M.P.H., Chief, Clinical Research Branch, Division of Extramural Research, NCCIH
Anastasia Solis, Program Analyst, Division of Extramural Research, NCCIH (webinar moderator

Background on the Funding Opportunity

This funding opportunity is a cooperative agreement using the U54 activity code. The cooperative agreement mechanism is used when NIH staff are going to have significant direct involvement above and beyond the normal oversight of grants. This RFA is a reissue of an earlier RFA. It is a continuation of an ongoing program.

The budget is $2.25 million in total costs annually, which equates to about $1.5 million in direct costs. Applicants must budget for attendance of key staff at an annual meeting. The target audience for this RFA is interdisciplinary teams of pharmacologists with expertise in pharmacokinetics; natural products chemists, particularly analytical chemists; and bioinformaticians to handle the data repository that is a major part of this project.

The major objectives are:

To establish the clinical relevance of pharmacokinetic interactions for three to five complex natural products. The interactions studied must be pharmacokinetic.
To provide guidance and leadership to the broader research community on how best to research metabolism-mediated drug interactions involving complex natural products. This goes beyond just giving a talk at a meeting or publishing a paper. More extensive involvement, such as organizing symposia at meetings or guest editing special journal issues, as well as actively seeking opportunities to interact with the research community, is expected.
To continue to develop and maintain the existing repository for the data and methodology resources generated by this project as well as data generated by other researchers, such as those conducting the companion R21 projects. The existing repository is structured in a way that makes it possible to transfer it to the new grantee.

Application Components

The organization of this U54 differs from that of a standard research project grant or program project grant. The application components consist of:

An overall component
An administrative core
A pharmacology core
An analytical core
An informatics core
Additional functions or activities proposed by the applicant, if any.

In the overall component, applicants need to describe their overarching approach for identifying and prioritizing natural products, how they will assess the impact of interactions from in vitro through clinical trials, and how the center structure will achieve synergy among the various components.

This RFA requires a clinical trial and potentially could include a clinical trial for each natural product studied. Pharmacokinetic human studies are considered clinical trials by the NIH definition. However, applicants should include only one Study Record for the first clinical trial to be conducted. Reviewers will look at how well this study is designed. Decisions about other clinical trials will be made by the grantee and NCCIH after the cooperative agreement begins. Because these other clinical trials are considered “delayed onset,” no Study Record is required.

The administrative core is responsible for:

Day-to-day operations
The organization and management of the steering committee
Leadership and guidance to relevant research communities (metrics of success must be included)
Development of annual milestones.

The application will include the milestones for the first year; later milestones will be negotiated with NIH staff. The grantee will be assessed and evaluated on how well the milestones were achieved.

The pharmacology core is responsible for:

Selection and prioritization of the three to five natural products to be studied
Conducting necessary in vitro work to quantify interactions (include criteria to justify advancing to a clinical trial)
Conducting a clinical trial if warranted
Data analysis and interpretation.

The analytical core is responsible for:

Establishing specifications for approved natural products (requirements the study material has to meet, key constituents, tolerances)
Sourcing natural products in sufficient quantity to execute all necessary work and subsequent quality control analysis.

The informatics core is responsible for:

The ongoing maintenance and development of the permanent data repository
Establishing a common data format to be used by external contributors (such as the R21 investigators).

Eligibility

The principal investigator can be from almost any U.S.-based institution (universities, nonprofits, small businesses, etc.). Applications from foreign institutions are not allowed. Foreign components/collaborators are not allowed. Institutions may submit more than one application, but they must be scientifically distinct—they can’t be variations on the same thing.

Clinical Trial Requirements

Applications must include a clinical trial. If the application does not include one, it will be withdrawn and not reviewed. One Study Record that describes the first pharmacokinetic trial to be performed must be included. In the application, there is a set of four questions that determines whether the planned work includes a clinical trial. Applicants must answer “yes” to all four questions.

The new human subjects/clinical trial form in the application consolidates all the clinical trial information into a single place in the application. It’s not a simple set of checkboxes. It requires many attachments and much additional information. It’s important to allow enough time to complete it.

Applicants often ask which information should be included in the clinical trial form and which information should be included in the Research Strategy. The two sections should not duplicate each other, but the Research Strategy should still discuss the overall strategy, methods, and analyses of the proposed pharmacokinetic study.

The current Appendix policy does not permit applicants to attach a protocol to the application. If a protocol is included, the application cannot be reviewed.
NIH has a set of annotated forms and a video tour of the clinical trial form. These are very helpful resources. Go to https://grants.nih.gov/policy/clinical-trials/new-human-subject-clinical-trial-info-form.htm for further information.

Review Perspective

The completeness, compliance, and responsiveness of applications are crucial because applications that don’t meet these criteria will not be accepted for review. Completeness means that all the necessary pieces of information (like the Study Record) are included. Compliance means that the application doesn’t violate any rules (for example, including a protocol or exceeding a page limit). Responsiveness means that the proposed science is in line with what the RFA asks for.

Some factors that determine compliance for this RFA include letters of support, the presence of all the required components (overall component and cores), and page limitations (6 pages for each component).

Each of the cores will be reviewed separately and assigned a criteria score. After the cores are evaluated, the overall component will be evaluated and an overall score will be determined. The score-driving review criteria include both the standard NIH criteria (significance, investigators, innovation, approach, and environment) and additional review criteria specified in the RFA. Separate scores on a 1 to 9 scale will be determined for each of the scored criteria, and the additional review criteria will also be factored into the overall impact score.

It is crucial to read the review criteria carefully. In addition to the standard review criteria, language has been added to this specific FOA telling the reviewers what to look for. This language also tells applicants what to include in their applications.

The cores will not receive individual numerical scores. Instead, they will receive merit descriptors (outstanding, acceptable, or unacceptable). Cores do not have standard review criteria. Instead, they have specific review criteria that should be addressed in the application.

Letters of intent are requested but not required. They should include only the title, principal investigator’s name, institution, and key personnel. They should be sent to Martina Schmidt, Ph.D., at schmidma@mail.nih.gov, and applicants may send a copy to Dr. Hopp. NCCIH asks that letters be submitted by October 22, 2019, which is 30 days before the application due date, but letters submitted after that date will be accepted.

Applicants are encouraged to discuss their proposed applications with Dr. Hopp before submitting letters of intent and especially before submitting applications.

Composition of the Review Panel

All applications submitted in response to this RFA will be reviewed by a Special Emphasis Panel (SEP). Reviewers will be selected based on their specific areas of expertise related to the science proposed in the applications. Applicants do not need to indicate in a cover letter which study section their applications will go to; they will all go to the SEP. The reviewers will be oriented to use the review criteria for this specific RFA.

Take Home Messages

It’s critical to read the entire RFA carefully to ensure that your application is complete, compliant, and responsive.
This U54 has multiple components, and there are different review criteria for each component. There are also specific review criteria for this RFA in addition to the standard review criteria.
Applications will be reviewed in a SEP.
Contact Dr. Hopp at hoppdc@mail.nih.gov to discuss your application. NCCIH wants to fund the best science related to the Center’s interests. By discussing your application with Dr. Hopp, you can determine whether it fits the broad criteria of this RFA, while still allowing you flexibility to do the science you propose.

Questions and Answers

Q: What relationship is expected between the U54 and the R21 group?
A: This U54 has a companion RFA, using the R21 mechanism, that is soliciting smaller scale preclinical research projects on natural product drug interactions. At the application stage, no a priori relationship between the U54 and R21 researchers is expected. In fact, such a relationship is not possible because the R21 grants haven’t been awarded yet. However, the U54 grantee must be willing and able to coordinate and cooperate with the R21 groups and other researchers to get their data into the data repository. It’s essential for data from the R21s to get into the repository managed by the U54.

Q: Does NCCIH have any suggestions for high-priority natural products?
A: NCCIH is interested in complex natural products, such as a whole plant extract or mixture, rather than single chemical entities from natural sources (e.g., resveratrol from grapes). One of the goals of this project is to better understand how to do interaction research on complex products and how to guide the public on their use. The evaluation of interactions of single chemical entities is already well understood.

The complex natural products studied should be those that the public could at least theoretically be consuming, such as botanicals or herbals, dietary supplements that consist of complex mixtures, or perhaps even probiotics (if there’s reason to think they may have pharmacokinetic interactions with drugs).

The speakers clarified that the interactions studied must be pharmacokinetic. Other types of interactions are of interest to NCCIH, but proposals for research on those interactions must be submitted in response to other FOAs.

Q: What is the level of preliminary data expected for selection of a botanical to be studied for potential of interaction?
A: There should be a strong rationale for selecting and prioritizing the products, but it need not be based on the applicant’s own data. Data from the literature, case reports from the U.S. Food and Drug Administration, or other threads of information that suggest that a particular complex natural product might be responsible for interactions with medications can be used. The RFA asks you to include the rationale for selection and prioritization of the natural products in your submission, and reviewers will be looking for this information.

The products should be selected to help fill gaps in knowledge, not to address topics that are already known and reported. For example, it would be hard to justify studying St. John’s wort because its pharmacokinetic-based interactions are so well understood. On the other hand, it would also be hard to justify studying natural products that have no evidence of any potential for pharmacokinetic-based interactions, even if they have interesting biological activities. It would be acceptable to study natural products that may only cause interactions in certain groups of people, e.g., those with a specific genetic profile or members of a specific cultural group, as well as products that may have interactions that could affect wider populations.

Q: To establish the botanical specifications in the analytical core, do we have to assess quality of plant material in crude extracts and formulations on the market in order to set limits on quality for each botanical?
A: Yes, but it’s not necessary to have done this before submitting your application. In the course of the project, the analytical core would be required to look at the plants and determine what key constituents should be present. And if you’re choosing a particular formulation, what are its components? The application should describe the strategy for doing this, but explicit data do not have to be provided at the time of application.

Q: If the natural product studied is manufactured outside the United States, will that count as foreign involvement in the grant?
A: No, as long as no significant contributions from foreign scientists are involved. It would be necessary to follow all laws and regulations that govern importing dietary supplements into the United States, as well as NCCIH’s natural product integrity policy.

Q: To ensure compatibility going forward, what is the format or database program in use by the existing U54?
A: Information about the current repository is available at napdicenter.org. That page has an icon for “Data Repository” that will take you to the repository. Applicants would have to contact the current group directly (contact information is available in NIH RePORTER or can be obtained from Dr. Hopp) to get information about how the repository was constructed.

However, it is not expected that applicants will collaborate with the group responsible for the current repository. It was a requirement in the prior RFA that the repository be designed to be portable. It can be picked up and dropped onto another server. Applicants are expected to be able to maintain the current repository going forward but not to collaborate extensively with the current grantee.

Q: What key tests for performance of dosage forms do you expect in the analytical core?
A: It depends on the dosage form. For example, if the dosage form is a capsule, does the dissolution profile indicate that the important components are released into the matrix? If it’s a tea, does brewing yield a consistent composition in the cup of tea? The type of dosage form will define what the important performance metrics are for that dosage form.

Conclusion
Everyone who registered for this webinar will receive a summary of the webinar and a copy of the slides by email. Potential applicants who have additional questions about the RFA should contact Dr. Hopp at hoppdc@mail.nih.gov.