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New NCCIH Funding Opportunities for Natural Product Clinical TrialsMay 9, 2017

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Introductions

During the Q&A my colleagues from the Division of Extramural Research and the Office of Scientific Review will assist me in answering your questions.

E-mail questions to: NCCIHwebinarQ@mail.nih.gov

Wendy Weber, N.D., Ph.D., M.P.H.Branch Chief, Clinical Research in Complementary and Integrative Health Branch, DER, NCCIH

New NCCIH Funding Opportunities for Natural Product Clinical TrialsMay 9, 2017

The NCCIH Mission

Define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative interventions and their roles in improving health and health care.

NCCIH wants to support definitive multisite clinical trials of natural products.

In most areas of clinical inquiry, there is a need for additional preliminary data or building blocks to design these definitive clinical trials.

“NIH must ensure that supported trials investigate a mission-relevant question that is of high priority, do not needlessly duplicate previously conducted trials (in contrast to providing needed replication), and have the highest likelihood to advance knowledge and improve health. To achieve this goal, a number of challenges in the design, efficiency, and reporting of clinical trials need to be addressed.”

“NIH has launched a multifaceted effort to improve the quality and efficiency of clinical trials”

“Specifically, these changes are aimed at enhancing the application and award processes, increasing NIH’s ability to assess the merits and feasibility of clinical trial applications; improving over-sight and transparency; and increasing the sharing of clinical trial results.”• Good Clinical Practice (GCP) training for investigators and

NIH staff responsible for conducting or overseeing clinical trials (NOT-OD-16-148)

• All applications for clinical trials to be submitted in response to clinical trial specific Funding Opportunity Announcements (NOT-OD-16-147 & NOT-OD-17-043)

• Single IRB of record for NIH multisite studies (NOT-OD-16-094)

• Clinical trial registration and summary results information reporting (NOT-OD-16-149)

Why a New Approach for Clinical Trials?• NCCIH is participating in the NIH-wide initiative to

strengthen the clinical trial research portfolio.• Clinical trials are important to us because we study

health interventions widely used by the American public – interventions often used with scarce evidence of efficacy and inadequate understanding of potential safety concerns.

• NCCIH funds research that helps people manage important health issues, such as research that focuses on hard-to-manage symptoms.

Common Limitations of Trials Single-site studies reduce generalizability of the results

When the study fails to demonstrate the hypothesized benefit… Did the participants get a high enough dose of the natural

product? Did the study use the correct frequency of dosing? Was the right population selected? Were they too progressed in

condition or symptoms? Or was the condition not progressed enough?

Was the right product or formulation selected?

Often lack key building blocks for designing the efficacy trial

New FOAs provide investigators with funding options to establish the building blocks along the research continuum

Framework for Human Subjects Research

Research Continuum In the past, it was often difficult for investigators to find

research funding to establish these building blocks.

The new FOAs provide pathways to support the developmental steps for relevant clinical trials on complementary and integrative health approaches. Each FOA is targeted for studies at different stages of

the research continuum: early-phase trials intermediate trials full-scale multisite efficacy trials

Investigator-Initiated Natural Product Clinical Trial FOAs

Title FOA Number Purpose

Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics (R61/R33)

PAR-16-418

Early stage testing to establish the impact of the natural product on a biological signature. In the second phase, replicate the impact on the biological signature and assess correlation between change in biological signature and clinical outcomes. Additionally, can assess pharmacokinetics and impact of varying doses on the biological signature.

Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics (R33)

PAR-16-419

Replicate the impact of a natural product on the biological signature and assess correlation between change in biological signature and clinical outcomes. Additionally, can assess pharmacokinetics and impact of varying doses on the biological signature.

NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) PAR-17-216

Midstage intervention testing to refine recruitment and retention methods, improve fidelity of intervention delivery, and improve data collection quality across multiple sites. Additionally, can assess which dose has greatest impact on biological signature with low risk of adverse events.

Clinical Coordinating Center for NCCIH Multisite Investigator-Initiated Clinical Trials of Natural Products (Collaborative UG3/UH3)

PAR-17-174

Clinical coordination of a multisite efficacy, effectiveness, or pragmatic trial. Trial should be fully powered to measure clinical outcomes and use multiple sites to enhance generalizability of study outcomes.

Natural Product Multisite Clinical Trial Data Coordinating Center (Collaborative U24) PAR-17-172

Companion Data Coordinating Center for multisite clinical trials to ensure independence and objectivity of data collection and analysis.

Range of Research Questions

What has changed?

Changes in How To Submit Clinical Trial Applications to NCCIH NCCIH is no longer accepting most clinical trial applications

through the Parent R01 FOA (NOT-AT-17-006). Applications after May 8, 2017 use new FOAs We have developed more specific funding opportunities that will

allow researchers to incorporate more relevant information in their grant applications

Use the new FOAs for all stages of clinical outcome trials

What human subjects applications will NCCIH accept via the Parent R01 FOA? Observational human studies – cohort, case control, survey Secondary data analysis – datasets or biorepositories Mechanistic-focused human studies (no aims to examine clinical

outcomes)

Contact a Program Director if you have questions!nccihderinquiries@mail.nih.gov

Building Blocks of Natural Product Clinical Trials

Examples of Building Blocks of Natural Product Clinical Trials

What Is a Biological Signature? A biological signature may be a measure of the postulated

mechanism of action by which the natural product may ultimately modify the clinical condition or symptom(s) of interest.

Biological signatures may be an objective single measure, proxy, correlate, or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.

What if There Is No Way To Measure Biological Signature? NCCIH acknowledges that for some conditions, it may be impossible or

impractical to directly measure the biological impact of a natural product.

In these circumstances the applicant should: 1. have a clear rationale for why studying a biological signature in

human participants is impossible or impractical; 2. consider proposing other objective, reproducible measures that

may be proxy to or indicative of a biological or behavioral effect for the natural product; AND

3. have strong, compelling preliminary data to warrant further study of the natural product in clinical studies.

In these situations, investigators are encouraged to contact a Program Director to determine which FOA is best for the proposed research

Why is a biological signature important?

NaturalProductDelivered

Reproducible Biological Signature Not Possible

-

Clinical Outcome Improves

+

Clinical Outcome No Change or Worse

+/--

Product improves clinical outcome, yet have no idea how it has this impact

Product has no effect or worsens clinical outcome

Difficult to interpret results because no biological signature

Why is a biological signature important?

NaturalProductDelivered

Reproducible Biological Signature Not Possible

-

Clinical Outcome Improves

+

Clinical Outcome No Change or Worse

+/--

Product improves clinical outcome, yet have no idea how it has this impact

Product has no effect or worsens clinical outcome

Difficult to interpret results because no biological signature

Want to minimize the increased risk of noninformative trials.Therefore, include biological signature whenever possible.

Why is a biological signature important?

NaturalProductDelivered

Reproducible Biological Signature Demonstrated

Product improves clinical outcome and biological signature may be mediator

Reproducible Biological Signature Not Possible

+

-

Clinical Outcome Improves+

Clinical Outcome Improves

+

Clinical Outcome No Change

+/-

Clinical Outcome Worse-

Clinical Outcome No Change or Worse

+/--

Product has no effect on clinical outcome and biological signature is not a useful target

Product worsens clinical outcome Biological signature may be mediator of worsening outcome and is not a useful targetProduct improves clinical outcome and have no idea how it has this impact

Product has no effect or worsens clinical outcome

Unable to interpret results because no biological signature

Want to minimize the increased risk of noninformative trials.Therefore, include biological signature whenever possible.

Including the biological signature results in more informative trials

Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics R61/R33 and R33 (PAR-16-418 and PAR-16-419) R61 Phase

Establish whether the natural product can impact a biological signature in humans. Predefined metrics of impact.

Establish short-term pharmacokinetics and bioavailability. R33 Phase of R61/R33 or Direct R33

Reproduce impact of the natural product on the biological signature. Desired to optimize the dose of the product to enhance the

impact on the biological signature. Assess the correlation between biological signature and clinical

outcomes.

Wendy Weber, N.D., Ph.D., M.P.H.

Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics R61/R33 and R33 (PAR-16-418 and PAR-16-419)

This mechanism will NOT support Multisite efficacy or effectiveness trials Clinical trials 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 Applications proposing to test natural products for the treatment

or prevention of cancer

Wendy Weber, N.D., Ph.D., M.P.H.

Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics R61/R33 and R33 (PAR-16-418 and PAR-16-419)

See NCCIH Blog by Dr. Wendy Weber “Building a Foundation for Clinical Trials of Natural Products,” September 27, 2016. https://nccih.nih.gov/research/blog/natural-products-clinical-trials

Placebos are allowed and may be needed to demonstrate that the changes seen are due to the natural product and not regression to the mean or natural course of disease.

Wendy Weber, N.D., Ph.D., M.P.H.

What Is a Phased Award? Used when the supported research has two distinct phases (e.g.,

R61/R33) with separate aims Transition to the second phase is dependent on whether the first phase

achieves the negotiated milestones Examples include: recruiting and retaining participants on time;

demonstrating a priori defined metrics of impact on a biological signature

If milestones are met, transition to the second phase of funding occurs after administrative review

One application and peer review process to evaluate both phases Measurable go/no-go criteria and milestones to describe when you

would vs. would not proceed to second phase will be evaluated by reviewers

NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) (PAR-17-216) This mechanism supports

Dosing and formulation optimization of the natural product's impact on the biological signature

Determining which patient phenotypes will be likely responders versus nonresponders

Final building blocks to prepare for multisite efficacy trial Establish efficient methods to recruit/accrue participants,

achieve adherence to the study protocol, retain participants during study, and complete collection of followup data

This mechanism will NOT support Multisite efficacy or effectiveness trials First in human trials Observational studies Interventions for the treatment or prevention of cancer

Wendy Weber, N.D., Ph.D., M.P.H.

NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) (PAR-17-216) Building blocks desired as preliminary data prior to U01 trial

Pharmacokinetic data on the specific natural product and formulation to justify the dosing frequency

Demonstration that the natural product can produce a clinically meaningful change in a measurable biological signature (e.g., mechanism of action) in the human population of interest. Data supporting the change in biological signature has been

replicated in a separate human study Exception if measuring biological signature is impossible or

impractical. Contact Program Director for more information Evidence there is a correlation between the impact on the biological

signature and changes in the clinical outcome Evidence that the natural product does not produce frequent or

severe adverse events in human pilot trials Completion of final data collection from any pilot studies

Wendy Weber, N.D., Ph.D., M.P.H.

What Is a U Mechanism? U mechanisms – U01, UG3/UH3, and U24

Cooperative agreement awards Used for investigator-initiated applications Used by the Federal Government when the funding agency

anticipates Federal staff will have involvement in the activities of the award

At the time of funding, NCCIH will assign two staff members to work with investigators:

1. Program Director, who is responsible for the administration of the award, review of progress reports, etc.

2. Project Scientist, who works directly with the investigators as part of the team and participates in trial planning and oversight during the trial

NCCIH New Multisite Randomized Controlled Trial FOAs UG3/UH3 and U24 (PAR-17-174 and PAR-17-172) Companion FOAs

Clinical Coordinating Center (CCC) UG3/UH3 Independent Data Coordinating Center (DCC) U24 ALL multisite trials must submit BOTH applications at same time

This mechanism will support multisite clinical trials Efficacy trials Effectiveness trials

Most will exceed budgets of $500,000 direct costs/year Per NIH policy, need NCCIH permission to apply

Wendy Weber, N.D., Ph.D., M.P.H.

Building blocks desired as preliminary data prior to multisite trial

All the requirements of the U01 funding opportunity AND Multisite clinical trial is feasible and experience of the team doing

multisite trials

Preliminary data are 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

Wendy Weber, N.D., Ph.D., M.P.H.

NCCIH New Multisite Randomized Controlled Trial FOAs UG3/UH3 and U24 (PAR-17-174 and PAR-17-172)

Why Multisite Efficacy Trials? To meet evidence guidelines for rigor and reduce bias, efficacy trials

are most informative if they:

1. Are conducted as multisite trials Increases likelihood of generalizability of the results Increases diversity of the population to meet NIH policy and

guidelines on the inclusion of women and minorities as subjects in clinical research

Enhances ability to meet recruitment requirements for a fully powered study in a reasonable timeline

2. Have independent data coordination (companion U24) Provides methods for consistent data collection from sites Assures independent data quality confirmation and analysis

Why Use a Phased Award (UG3/UH3) for Multisite Clinical Trials? Planning phase (UG3) and implementation phase (UH3) Transition to the second phase is dependent on whether the

negotiated milestones are met for both the CCC and DCC. Examples: Finalize and get NCCIH and Data Safety and

Monitoring Board (DSMB) approval for protocol and study documents; get Institutional Review Board (IRB) approvals at all sites; negotiate contracts for sites; develop study database and data management plan; create site training materials

https://nccih.nih.gov/grants/toolbox#milestone

One application and peer review process to evaluate both phases

Planning phase demonstrates team’s ability to meet deadlines and prepare for the launch of the trial

Range of Research Questions

What Does NCCIH Fund?

https://nccih.nih.gov/about/strategic-plans/2016

Consulting With the FDA About the Proposed Clinical Trial

Investigators must contact the U.S. Food and Drug Administration (FDA) prior to submitting an application to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research

Clinical trials must be done in accordance with FDA regulations when applicable; the FDA makes determination

If an exception/waiver is granted by the FDA, it must be granted in writing and provided to NCCIH

Applications must include a “Regulatory Communication Plan” as a required attachment

Nearly all of the NCCIH-funded natural product studies in human participants are conducted under IND

NCCIH Product Integrity Process

Botanical products have some well-documented quality concerns

Implemented a Product Integrity Policy to ensure products used in NCCIH-funded studies are well characterized There is no “one” method for botanical characterization. Investigators must develop quality control protocols prior to

funding. Independent confirmation of supplier quality documentation is

required.

Information will be requested in the Just In Time letter prior to funding.

Craig Hopp, Ph.D.https://nccih.nih.gov/research/policies/naturalproduct.htm

Review Process Applications submitted to our new clinical trial FOAs will be reviewed

by special review panels familiar with NCCIH’s research priorities and the goals of the new FOAs.

Applications must include special attachments (described in the FOA) that will allow applicants to provide study details in a standardized way.

Examples – protocol synopsis, clinical trial experience table, regulatory communication plan.

Review panels will be able to use this additional information for their assessment of important aspects such as rigor, feasibility, and potential impact of the trial.

CAREFULLY READ THE FOA!!Be sure your application is complete:https://nccih.nih.gov/grants/funding/clinicaltrials/natural

Ashlee Tipton, Ph.D.

Resources NCCIH new Web site for key information about clinical trial FOAs:

https://nccih.nih.gov/clinicaltrials-funding FOA description, links to FOA, required application elements,

and Program Director contact information

NCCIH Clinical Trial FOA Frequently Asked Questions https://nccih.nih.gov/grants/funding/clinicaltrials/faq

General questions about which FOA to use: nccihderinquiries@mail.nih.gov

NCCIH wants to support definitive multisite clinical trials of natural products.

In most areas of clinical inquiry, there is a need for additional preliminary data or building blocks to design these definitive clinical trials.

Use the New NCCIH Clinical Trial FOAs!!

Contact a Program Director if you have questions!nccihderinquiries@mail.nih.gov

Range of Research Questions

Questions now?Email: NCCIHwebinarQ@mail.nih.gov

Ashlee Tipton, Ph.D.Scientific Review Officer, DEA, NCCIH

Craig Hopp, Ph.D. Deputy Director DER, NCCIH

Wendy Weber, N.D., Ph.D., M.P.H.Branch Chief, Clinical Research in Complementary and Integrative Health Branch, DER, NCCIH

Questions After the Webinar?E-mail Questions:nccihderinquiries@mail.nih.gov

National Center for Complementary and Integrative HealthClearinghouse: 1-888-644-6226Web site: nccih.nih.govTwitter: @NIH_NCCIH