NIH/NCATS – Clinical Trial Readiness for Rare Diseases, Disorders, and Syndromes (R03, R21 Clinical Trial Not Allowed)

Please read the individual FOAs carefully before applying to either.

The NIH supports translational and clinical research on a broad range of diseases that are defined as rare; that is, diseases affecting fewer than 200,000 individuals in the United States (per the Rare Diseases Act of 2002). Collectively, there are an estimated 7,000 rare diseases, which affect approximately 25-30 million people in the United States. Most are serious or life-threatening, leading to significant morbidity and mortality, and most affect children. Despite advances in our understanding of the causes and mechanisms of many rare diseases, effective treatments are available for fewer than 5%.

To address this significant public health concern, the NIH investment into discovery research has contributed to unprecedented opportunities to translate scientific advances into better treatments. Gene therapy and related approaches are an example of opportunities that have resulted from technological advances. However, to evaluate such potentially transformative treatments, researchers, biopharmaceutical companies, and regulators need high quality, natural history data, as well as biological and clinical outcome measures fit for the intended purpose. The absence of such information often represent a bottleneck in therapy development for many rare diseases.

This initiative aims to support studies that address these gaps in understanding of disease natural history and appropriate outcome measures. Given the large number of rare diseases and the limited funding available, this initiative will focus on studies for which it can be demonstrated that there are clinical development candidates for the indication, and for which there are unmet medical needs. The initiative will promote partnerships among academic investigators, industry, and patient groups, and will encourage interactions with the Food and Drug Administration (FDA). Use of existing data standards, tools, information technology platforms, and candidate clinical outcomes measures and biomarkers will also be encouraged, rather than the discovery or de novo development of such tools and resources.


This FOA describes a specialized type of clinical research that is intended to provide data necessary for the design of future clinical trials.

Clinical trial readiness is the state of having validated clinical research tools and knowledge of disease natural history necessary for the design of efficient clinical trials. Validated clinical research tools can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials. Knowledge of disease natural history necessary for clinical trial design can include characteristics for stratification or determining inclusion and exclusion criteria; the stage of disease progression that may be responsive to treatment; and data needed for determining sample size through power calculations.

This FOA uses terminology defined in the BEST (Biomarkers, EndpointS, and Other Tools) Resource, which was developed by the FDA-NIH Biomarker Working Group. Investigators are encouraged to use the terms below, where appropriate in their applications. Guidance to reviewers will include these definitions as a way to promote consistent evaluation of the applications. (See for reference to the BEST Resource’s glossary for the following definitions.)

Biomarker – A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. Categories of biomarkers include: Susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, safety.

Clinical outcome assessment (COA) – An assessment of an outcome that reflects how an individual feels, functions or survives. The four types of COAs are clinician-reported, observer-reported, patient-reported, and performance outcomes.

Context of Use (COU) – A statement that fully and clearly describes the way the medical product development tool is to be used and the medical product development-related purpose of the use.

Concept – In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture (or reflect).

Validation – A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose. For this FOA, the intended purpose should be the collection of data in a clinical trial that will be used to determine whether to move forward with the intervention being tested to a later stage trial or for regulatory approval. This FOA supports applications that focus on clinical validation. Biochemical and molecular biomarkers should have substantial data supporting analytical validation collected prior to submission of an application to this FOA.

  • Analytical Validation – A process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures).  This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness.
  • Clinical Validation – A process to establish that the test, tool, or instrument acceptably identifies, measures or predicts the concept of interest.
  • Construct Validity – A process to establish, using quantitative methods, the extent to which the relationships among items, domains, and concepts of a clinical outcome assessment conform to a priori hypotheses concerning logical relationships that should exist with other measures or characteristics of patients and patient groups.
  • Content Validity – A process to establish from qualitative research the extent to which the clinical outcome assessment instrument measures the concept of interest including evidence that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use.


To optimize clinical trial readiness, there needs to be sufficient understanding of the rare disease to permit design, conduct, and interpretation of rigorous clinical trials. FDA published Draft Guidance on common issues in drug development for rare diseases. This FOA is intended to support studies that address some of the issues presented in this guidance document, including the need for adequate understanding of the course of the disease and the need for sensitive and reliable biomarkers and outcome measures to be used during a clinical trial.

The R03 grant mechanism will support small research projects that can be carried out in a short period of time with limited resources. Projects must have a focus on clinical trial readiness. Projects could include:

  • Pilot or feasibility studies
  • Secondary analysis of existing data
  • Small, self-contained research projects
  • Development of research methodology
  • Development of research technology

Projects that are appropriate for the R21 FOA should focus on diseases that lack critical components of trial readiness and should have candidate therapeutics that will be ready for testing in clinical trials by the time the trial readiness study is completed. For the purpose of this initiative, clinical trial readiness can include two categories of projects:

1) Those that define the presentation and course of the rare disease (e.g., natural history studies including retrospective projects, and longitudinal or cross-sectional approaches), in ways that are essential for the design of upcoming clinical trials.

2) Those that utilize sensitive, reliable, valid, and responsive tools to identify or select appropriate participants for clinical trials, or to measure the effects of interventions. These tools include COA measures and biomarkers. Investigators are encouraged to use or modify existing resources, validate existing tools in specific rare disease populations, or add components to existing disease-specific tools (such as symptom scales).

Deadlines for both FOAs:  January 7, 2019, June 10, 2019, October 24, 2019, June 8, 2020, October 26, 2020, June 7, 2021, October 25, 2021 (letters of intent due 30 days prior to deadline)