NIH – Bench Testing Therapeutic/Indication Pairing Strategies (UG3/UH3)

The purpose of this FOA is to support pre-clinical studies to evaluate a therapeutic/indication pair for drug repurposing. The repurposing hypothesis should be generated using a developed method that is publicly available. Examples include independent crowdsourcing strategies [e.g., http://www.ncats.nih.gov/ntu/assets/currenthttp://openinnovation.astrazeneca.com/, or any website that lists experimental therapies (drugs or biologics)], or use of computational algorithms. Supported projects will demonstrate usefulness of the method to improve data usability for future repurposing studies. The initial UG3 award will support the execution of rigorous, pre-clinical target engagement and/or efficacy studies.

Once UG3 pre-clinical milestones have been met, the UH3 award may be made to support clinical trial planning. The purpose of the clinical trial planning phase is to allow time and support for the complete planning, design, and preparation of all the documents necessary to enhance the probability of being able to achieve enrollment goals and determine a definitive outcome for Phase I and Phase II clinical trials for a new therapeutic use. It is intended that results obtained from this FOA could lead to subsequent investigator initiated clinical trials.  It is expected that all assets investigated will have started a Phase I trial by the time an award is made. This initiative will support a planning period for a new hypothesis-driven and milestone-defined Phase I (if necessary) and/or planning for a Phase II clinical trial for a new therapeutic use.

Background

Discoveries that clarify the molecular basis of disease provide unprecedented opportunities to translate research findings into new medicines. However, developing a new medicine takes an enormous amount of time, money and effort, mainly due to bottlenecks in the therapeutic development process. Delays and barriers mean that translation of a promising experimental therapy into an approved drug often takes a decade or more.  NCATS intends to support strategies that reduce delays, decrease costs and improve success rates.

Drug repurposing/repositioning is one such strategy. Many existing experimental drugs, FDA approved drugs, and biologics already have been tested in humans, and detailed information is available about their pharmacology, formulation, and potential toxicity. By building upon previous research and development efforts, new uses for existing drugs or biologics can be advanced to testing in clinical trials more quickly than starting from scratch. If a new therapy receives regulatory approval, it can be efficiently integrated into clinical practice.

NCATS’ approach is generally disease agnostic and does not favor applications in any disease area over another. It focuses not on specific diseases, but what is common among them and the translational science process. NCATS mission is focused on process improvements (new technologies/approaches to accelerate the process of getting more treatments to patients) by developing and deploying solutions that can be used by all translational science researchers. NCATS complements other NIH ICs that also support translational research in disease specific areas.

NCATS is interested in pre-clinical studies that demonstrate utility of an approach for identifying new therapeutic/indication pairs. The strategy should be applicable to other diseases, so that successful use of the method can improve the efficiency of predicting new indications for existing therapeutics.

For pre-clinical studies that meet milestones and go/no-go criteria, NCATS is interested in working with investigators to ensure that clinical trial plans are adequately resourced and properly budgeted before applications are submitted for Phase I and Phase II clinical trials for a new therapeutic use.

Research Objectives and Scope

This initiative will support studies that test the pre-clinical efficacy of an existing therapeutic for a new indication (therapeutic/indication pair), as identified with a published and/or publicly available computational algorithm, or published and/or publicly available independent crowdsourcing strategy.

For this FOA NCATS will use the following definitions:

  • Crowdsourcing: Crowdsourcing occurs when an investigational drug is publicly posted for investigators to propose ideas for new therapeutic uses. Generally, crowdsourcing is an approach used for investigational therapeutics, not therapeutics approved by the FDA, since approved drugs already are known to the public.
  • Computational algorithm: A computational algorithm is the business end of bioinformatics. A computational algorithm will mine existing data and, in this case, identify therapeutic/indication pairs for experimental investigation.
  • Published or publicly available method: A published method is generally one that is in a peer-reviewed publication. A publicly available method could be available via a website or could be a commercially available product. The publicly available strategy does not need to be free, but it should be available to investigators who would like to use it.

Studies of interest to NCATS include:

  • Projects that demonstrate the value of computational algorithms for repurposing due to the potential uptake of successful approaches by the broader research community to subsequently identify additional therapeutic/indication pairs.
  • Projects that repurpose a drug or biologic, originally developed or approved for a completely different indication.  (For example, a computational prediction that a drug, which was originally developed to treat melanoma and may be effective in treating rheumatoid arthritis, would be of greater interest than if that same drug was predicted to be effective in a different solid tumor cancer).
  • Pre-clinical studies that demonstrate the utility of an already published or publicly available method (computational strategy/independent crowdsourcing) for identifying a novel therapeutic/indication pair.
  • Projects testing a drug or biologic combination therapy that meets the other requirements of this initiative.  Awards made under this FOA can only be used for proof of concept testing and not all required preclinical testing to ascertain toxicity as a combination therapy.

Pre-clinical funds (UG3) may support some or all the following:

  • Pre-clinical studies that are a use case for testing an automated strategy for identifying the new therapeutic/indication pair.
  • Testing multiple therapies, working through the same mechanism of action or pathway, to identify the therapy with the greatest efficacy.
  • Experiments with clear go/no-go decisions that will provide data needed to determine if a subsequent clinical trial planning period is needed.
  • Studies that might include testing efficacy of a drug or biologic in an animal model; testing in a physiologically disease-relevant ex vivo human system, when disease-relevant animal models do not exist; or conducting studies to verify target engagement in a model system. However, because investigational therapies explored under this FOA will already have been through a Phase l clinical trial for a different indication, it is expected that IND-enabling pre-clinical toxicity will already be complete.

Clinical trial planning funds (UH3) cover time and support to complete all clinical trial planning activities, including but not limited to:

  • Establish the clinical research team.
  • Develop clearly defined clinical research hypotheses and outcome measures.
  • Assess potential trial design strategies to capture the optimal intervention, dose, and target population.
  • Identify inclusion and exclusion criteria.
  • Obtain appropriate letters of support, including any letters necessary to demonstrate the support of consortium/site participants, cores, laboratories, pharmacies and other collaborators, including cost-sharing by NIH resources, in the case of intramural collaborators.
  • Prepare the following documents during the UH3 award period in preparation for potential future clinical trials:
  • Statistical analysis plan.
  • Recruitment and retention plan. Model the feasibility of an outcome or intervention in the field. Estimate available populations, attrition rate, or response rate. Determine if adequate adherence to treatment is achievable.
  • Develop a plan to address potential delays, and alternatives for conducting the study in the face of adverse outcomes or problems. In addition, this plan should inform the likelihood of accomplishing the trial in the time proposed for a subsequent application for funding of the Phase I and Phase II clinical trial.
  • Develop informed consent(s), and/or assent (if applicable).
  • Develop a manual of operations with quality control/assurance procedures.
  • Write the clinical trial protocol, including a data management plan, data safety and monitoring plan and a plan for collecting adverse events and reporting these events to regulatory authorities and NIH.
  • Identify collaborators, enrollment sites, and clinical site(s), which may include negotiating sub-contracts.
  • Adaptations and tests of existing survey instruments or protocols for a new population.
  • Prepare a data sharing plan.
  • If warranted, request a pre-IND meeting to obtain guidance for designing the clinical trial and obtaining approval of the IND.  The NCATS program official should be copied on any communication with FDA, if an application for clinical trial support from NCATS is anticipated.
  • Prepare FDA and regulatory documents for an IND package submission.
  • Obtain Office of Human Research Protection (OHRP) assurances (if not already in place), and initiate IRB approval using a single IRB.
  • Develop a detailed project timeline and appropriately resourced budget for conducting and completing the clinical trial, including funding for orderly close-out of clinical sites, and preparation of a final study report.
  • Budget plan for site assessment and protocol training that are required prior to initiation of a clinical trial.

NCATS strongly encourages applicants to involve patients or their representatives in the planning of the trial, as appropriate. For example, patient groups could be asked to help review screening instruments, develop clinical trial endpoints that are meaningful to patients, review inclusion/exclusion criteria for feasibility.

Projects that can be rapidly translated to the clinic (pharmacokinetics, pharmacodynamics, safety, and toxicology data are already available) are the priority for funding. Proposed projects are expected to use drugs or biologics that will have started a Phase I clinical trial for another indication by the time an award is made. Most of the IND enabling work will already be complete by the time a new therapeutic use trial begins. The following types of projects are not expected to improve the efficiency of accelerating new therapies to patients and are not a high priority for funding.

  • Projects that require reformulation: Funding will not be provided for reformulation. The only exception is for pediatric indications, which may need to be formulated as a solution/suspension for oral administration (ages 6 to 11) or a small tablet/capsule (ages 12 to 18). Palatability issues may also have to be addressed for pediatric administration.
  • Projects that require a changed route of administration: these studies are not anticipated to be able to enter clinical testing rapidly without added pre-clinical pharmacology/toxicology experiments (more time/expense).

The following will not be considered for support under this FOA:

  • Applications that propose repurposing projects that are solely the result of traditional experimental methods.
  • Applications for drug development that are the next logical step in an existing project.
  • Projects that are the result of a standard literature search or database search with no improved efficiency.
  • Projects that follow a previously demonstrated pathway.
  • Projects that are not truly a new use of an existing therapy (e.g., clinicaltrials.gov lists other trials for the therapeutic/indication).
  • Repurposing ideas that result solely from physically screening a library of drugs to identify the therapeutic/indication pair.

The following will not be funded during any phase of awards made under this FOA:

Projects that meet the NIH definition of a clinical trial, projects that propose testing the effectiveness of a dietary supplement, projects designed to pilot test ideas in human subjects, or projects that involve subject screening/recruitment will not be funded during any phase of awards (UG3 or UH3) made under this FOA.

UG3/UH3 Phased Innovation Awards

Applicants must plan for both a UG3 and UH3 phase in their application. The UG3 phase must include milestone-driven pre-clinical work to determine if a clinical trial planning period is justified. Projects should have clear, testable hypotheses and the research plan should use quantifiable measures for making a go/no-go decision to progress to clinical trials.  These studies might include testing efficacy of a drug or biologic in an animal model; testing in a physiologically disease-relevant ex vivo human system, when disease-relevant animal models do not exist; or conducting studies to verify target engagement in a model system.

Funding of the UG3 phase does not guarantee funds for the support of the clinical trial planning phase (UH3 phase). Funding of the UH3 award will be determined by successful completion of UG3 scientific milestones as determined by the NIH.

It is expected that elements completed during the clinical trial planning will be incorporated into a subsequent application for support of Phase I and Phase II clinical trials for a new therapeutic use.

Deadlines:  October 30, 2017, February 28, 2018, June 26, 2018, October 30, 2018, February 27, 2019, June 26, 2019, October 30, 2019,February 27, 2020, June 26, 2020.  Letters of intent are due 30 days prior to the corresponding deadline.

URL:  https://grants.nih.gov/grants/guide/pa-files/PAR-17-465.html