NIH – Clinical Trial Planning: Therapeutic/Indication Pairing Strategies (U34) (Clinical Trial Not Allowed)

December 18, 2017 by School of Medicine Webmaster

The purpose of this NCATS FOA is to support clinical trial planning for studies that will 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.,, or any website that lists experimental therapies (drugs or biologics)], or use of computational algorithms.

The clinical trial planning phase is to allow time and support for the complete planning, design, and preparation of all the documents and development of other essential elements 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 implementation of clinical trials.  It is expected that all assets investigated will have completed a Phase I trial by the time an award is made under this FOA. 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. Funds provided by NCATS may only be used to support planning of phase III clinical trial activities, but not the phase III trial itself except in the case of a rare disease or condition that meets certain criteria.


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 licensed 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.

Research Objectives

The intent is for NCATS to work with investigators to ensure that clinical trials are adequately resourced and properly budgeted before applications that request support for implementation of clinical trials are submitted for Phase I and Phase II clinical trials for a new therapeutic use.

This FOA intends to support clinical trial planning for innovative ideas for the discovery of new therapeutic uses of existing drugs/biologics in previously unexplored diseases. The project may plan clinical trials for the use of an existing marketed or investigational drug or biologic as: 1) a stand-alone intervention; or 2) an adjunctive intervention with existing standard of care (if there is no evidence of drug-drug interactions with the proposed standard of care treatment).  In either case, this initiative will support clinical trial planning on a therapeutic/indication pair, which was identified with a published or publicly available computational algorithm, or publicly available independent crowdsourcing strategy to identify a new therapeutic/indication. The method should already be published or publicly available, so it can be disseminated to improve data usability for future repurposing studies.

Phase II clinical trials may be planned for a common disease. If needed, Phase I clinical trials may also be planned for the new indication for a common disease.  Rare disease trial plans should follow Draft FDA Guidance: “Rare Diseases: Common Issues in Drug Development Guidance for Industry”. Specifically, one or more adequate and well-controlled clinical trial(s) may be planned in a rare disease population.

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 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 a commercially available product. The publicly available strategy does not need to be free, but it should be available to investigators that would like to use it.
  • Phase I clinical studies are planned for the target patient population to evaluate safety, determine a safe dose range, and identify side effects prior to conducting a Phase II clinical trial.
  • Phase II clinical trials are planned for a larger patient population, typically 150 subjects or less for trials in adults. The purpose of the Phase II clinical study is to eventually test for a preliminary signal of efficacy.
  • Rare Disease: A disease or condition that affects fewer than 200,000 people in the U.S.
  • Common Disease: Any disease or condition that is not a rare disease.
  • Clinical trials for Rare Disease: Due to small numbers of available patients, the terms Phase I, II and III clinical trials may not always be appropriate.  Therefore, well-controlled studies in a rare disease population may be planned to demonstrate substantial evidence of efficacy in treating or preventing the condition and to establish evidence of safety for that use. Evidence of efficacy for a rare disease may be established in one or more adequate and well-controlled clinical trials in the identified population. See Rare Disease: Common Issues in Drug Development Guidance for Industry for more information.

Planned clinical trials should use the selected therapeutic in its existing formulation/route of administration. The only exception is for pediatric indications, which may need to be formulated for a pediatric population. Examples include formulation as a solution/suspension for oral administration (ages 6 to 11) or a small tablet/capsule (ages 12 to 18). Palatability issues also may have to be addressed for pediatric administration.

Organizations involved in the research project should be identified at the time of application. To help ensure rapid transition to future Phase II clinical trials, the therapeutic must have completed Phase I clinical testing in humans for a different indication by the time a clinical trial planning award is made.

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, and/or review inclusion/exclusion criteria for feasibility.

Clinical trial planning funds cover time and support to complete all clinical trial planning activities, including, but not limited to all elements that enable the applicant to develop a complete application for subsequent implementation of a Phase I and/ or Phase II clinical trial for the new therapeutic use, or a rare disease clinical trial for a new therapeutic use:

  • 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.
  • Collect small but statistically meaningful feasibility data that can be extrapolated to a larger population. This may be used to determine how fast or slow enrollment will occur, to identify appropriate inclusion and exclusion criteria, and to determine feasibility for the enrollment goals to be achieved at the geographical sites represented. Studies such as evaluations of databases, interviews, surveys, and focus groups are allowable. These studies should be well designed and rigorous so that they answer the questions of whether a population of sufficient size can be identified and whether that population would have interest in participating in the study.
  • 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.
  • During the clinical trial planning period, the applicant will plan to demonstrate the capacity to obtain access to the drug product in the dosage form that will be administered to patients, if a subsequent clinical trial is conducted. The drug product must meet critical quality attributes for pharmaceutical development. Learn more:
  • Availability of the Investigational Product and Investigational New Drug status (Required): Obtain documentation of access to the selected therapeutic that is manufactured according to U.S. Food and Drug Administration chemistry, manufacturing, and controls standards and Good Manufacturing Practices, and access to any data (e.g., Investigator’s Brochure, study reports, ability to cross reference the Drug Master File) needed for obtaining regulatory approval, and for conducting the proposed clinical trials. A letter of support from a pharmaceutical partner, who will provide drug, may be provided with a contingency that the drug will be provided (pending NIH funding).
  • Regulatory status: 1) Indicate whether an FDA-approved therapeutic is available for purchase; 2) whether a new IND is not needed as documented through communication with FDA; 3) for studies where asset is provided by a pharmaceutical partner a letter should be provided indicating that a Collaborative Research Agreement or equivalent will be executed, and the PD/PI has the right to cross-reference specific sections of the pharmaceutical company partner’s IND/Drug Master File, etc.
  • A Resource Access Plan for obtaining the drug product should address any additional complexities associated with materials and data obtained from foreign sources, if applicable.
  • If the drug or biologic to be tested is not marketed, and evidence that a Phase I trial for a different indication has been conducted on the drug or biologic (publication, registration number, etc.) is not available, include documentation from the therapeutic provider that clearly states that a Phase I trial for a different indication has been completed and indicates by whom the trial was conducted.
  • Prepare the following documents 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).
  • 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.
  • Develop a manual of operations with quality control/assurance procedures. A data quality management plan should be developed for all sites to ensure the quality of the data collected.
  • Identify collaborators, enrollment sites, and clinical site(s), which may include negotiating sub-contracts.
  • Adapt and test existing survey instruments or protocols for a new population. For example, determine if the enrollment goals can be achieved, determine if the patients are interested in the therapy, and determine if patients would be interested in participating in the protocol.
  • Prepare a data sharing plan, as appropriate and consistent with achieving the goals of the program 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.
  • Develop a budget for site assessment and protocol training.
  • Plan for centralized site monitoring (when appropriate) if multiple sites are involved. Learn more:
  • Develop a plan to access the new therapy, so that a resource access plan for the applicant may demonstrate capacity to access drug product

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

  • Projects that meet the NIH definition of a clinical trial,
  • Projects that involve prospective enrollment of patients, are designed to administer therapies to human subjects, or are designed to randomize human subjects.
  • Projects that propose to obtain efficacy measures in human subjects, or
  • Projects that involve subject recruitment (other than focus groups, interview, or surveys) for a clinical trial will not be funded under this FOA.
  • Projects designed to validate patient reported outcomes in survey instruments.
  • Support for pre-clinical studies.
  • Applications that propose clinical trial planning for projects that are solely the result of traditional experimental methods.
  • Applications for support of clinical trial planning for drug development projects 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 are not truly a new use of an existing therapy (e.g., 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.
  • Applications that propose planning a clinical trial for a drug or biologic that has not completed a Phase I clinical trial for a different indication.
  • Applications that propose to plan a clinical trial for a formulation of a drug/biologic that is different from what has been tested in phase I studies previously. The only exception is for pediatric indications, which may need to be formulated for administration in a pediatric population.
  • Projects that plan to test the efficacy of a dietary supplement alone or in combination with other treatments.
  • Applications that plan phase III clinical trial activities for a common disease or condition.

Deadlines:  Standard dates apply


Filed Under: Funding Opportunities