New NCCIH Funding Opportunities for Natural Product Clinical Trials. May 9, 2017

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1 New NCCIH Funding Opportunities for Natural Product Clinical Trials May 9, 2017

2 The Webinar will start at 2:00 p.m. All participants have been placed on mute. We will take questions at the end of the presentation via . Please send your questions to:

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

4 New NCCIH Funding Opportunities for Natural Product Clinical Trials May 9, 2017

5 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.

6 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

7 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

8 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 ) All applications for clinical trials to be submitted in response to clinical trial specific Funding Opportunity Announcements (NOT-OD & NOT-OD ) Single IRB of record for NIH multisite studies (NOT-OD ) Clinical trial registration and summary results information reporting (NOT-OD )

9 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.

11 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

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

14 Framework for Human Subjects Research

15 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)

16 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) Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics (R33) NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) PAR PAR PAR 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. 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. 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) Natural Product Multisite Clinical Trial Data Coordinating Center (Collaborative U24) PAR PAR 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. Companion Data Coordinating Center for multisite clinical trials to ensure independence and objectivity of data collection and analysis.

17 Range of Research Questions

18 What has changed?

19 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 ). 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

20 Building Blocks of Natural Product Clinical Trials

21 Examples of Building Blocks of Natural Product Clinical Trials

22 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.

23 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

24 Why is a biological signature important? Natural Product Delivered - 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

25 Why is a biological signature important? Natural Product Delivered - 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 Want to minimize the increased risk of noninformative trials. Therefore, include biological signature whenever possible. Product has no effect or worsens clinical outcome Difficult to interpret results because no biological signature

26 + Why is a biological signature important? Reproducible Biological Signature Demonstrated + Clinical Outcome Improves Clinical Outcome No Change Product improves clinical outcome and biological signature may be mediator Product has no effect on clinical outcome and biological signature is not a useful target Natural Product Delivered - Reproducible Biological Signature Not Possible - + +/- +/- - Clinical Outcome Worse Clinical Outcome Improves Clinical Outcome No Change or Worse Product worsens clinical outcome Biological signature may be mediator of worsening outcome and is not a useful target Product improves clinical outcome and have no idea how it has this impact Including the biological signature Want to minimize the increased risk of noninformative trials. Therefore, include biological signature whenever possible. results in more informative trials Product has no effect or worsens clinical outcome Unable to interpret results because no biological signature

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

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

29 Exploratory Clinical Trials and Studies of Natural Products in NCCIH High Priority Research Topics R61/R33 and R33 (PAR and PAR ) See NCCIH Blog by Dr. Wendy Weber Building a Foundation for Clinical Trials of Natural Products, September 27, 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.

30 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

31 NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) (PAR ) 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.

32 NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01) (PAR ) 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.

33 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

34 NCCIH New Multisite Randomized Controlled Trial FOAs UG3/UH3 and U24 (PAR and PAR ) 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.

NCCIH New Multisite Randomized Controlled Trial FOAs UG3/UH3 and U24 (PAR-17-174 and PAR-17-172) Building blocks desired as preliminary data prior to multisite trial All the requirements of the U01

35 NCCIH New Multisite Randomized Controlled Trial FOAs UG3/UH3 and U24 (PAR and PAR ) 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.

36 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

37 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 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

38 Range of Research Questions

39 What Does NCCIH Fund?

40 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

41 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.

42 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: Ashlee Tipton, Ph.D.

43 Resources NCCIH new Web site for key information about clinical trial FOAs: FOA description, links to FOA, required application elements, and Program Director contact information NCCIH Clinical Trial FOA Frequently Asked Questions General questions about which FOA to use:

44 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

45 Range of Research Questions

Questions now? Email: 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 Craig Hopp, Ph.

46 Questions now? Wendy Weber, N.D., Ph.D., M.P.H. Branch Chief, Clinical Research in Complementary and Integrative Health Branch, DER, NCCIH Craig Hopp, Ph.D. Deputy Director DER, NCCIH Ashlee Tipton, Ph.D. Scientific Review Officer, DEA, NCCIH

47 Questions After the Webinar? Questions:

48 National Center for Complementary and Integrative Health Clearinghouse: Web site: nccih.nih.gov

New NCCIH Funding Opportunities for Mind and Body Clinical Trials. April 24, 2017

New NCCIH Funding Opportunities for Mind and Body Clinical Trials April 24, 2017 Introductions Wendy Weber, N.D., Ph.D., M.P.H. Branch Chief, Clinical Research in Complementary and Integrative Health Branch,