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High-Risk, High-Reward Research Programs

The High-Risk, High-Reward Research program welcomes any project relevant to the NIH mission, including clinical trials. Though technical and conceptual risks are expected in highly innovative projects, clinical research must also contend with potential risks to human subjects. Because awards are administered by the most topic-relevant NIH Institute or Center (IC), applicants proposing NIH-defined clinical trials should contact program staff at the appropriate IC to ensure their applications conform to NIH and IC-specific policies for clinical trials.

IC Specific Instructions Contact
NCATS The National Center for Advancing Translational Sciences (NCATS) strives to develop innovations in order to reduce, remove or bypass costly and time-consuming bottlenecks in the translational research pipeline to speed the delivery of new drugs, diagnostics and medical devices to patients. Translational science is the field of investigation focused on understanding the scientific and operational principles underlying each step of the translational process. Translating biomedical discoveries into clinical applications is essential to improving human health. It is also a complex process with high costs and substantial failure rates. NCATS is interested in supporting clinical trials that aim to improve this translational process. Some examples of research that could be supported through this FOA include but are not limited to
  • Testing of innovative technologies that demonstrably increase the efficiency and effectiveness of intervention testing.
  • Validation of innovative outcome measures or biomarkers that could increase the efficiency of clinical trials.
  • Testing innovative clinical trial designs, such as adaptive designs or other approaches, that would enhance clinical trials with small sample sizes.
  • Evaluation of novel endpoints that demonstrate applicability across multiple disease states.
  • Testing of innovative methodologies to speed development of therapeutics for those with rare diseases.
Valery Gordon, PhD, MPH
Phone: (240) 383-2087
NCCIH   Contact by research area

Lori Henderson, PhD
Phone: (240) 276-5930

NEI NEI will only accept “Mechanistic” or “Minimal Risk” clinical trials under this funding opportunity. A mechanistic trial is defined as "a study designed to understand a biological of behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention." "Minimal risk" means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. Donald Everett, MA
Phone: (301) 451-2020
NHGRI   Simona Volpi, PharmD, PhD
Phone: (301) 480-3480
NHLBI   Katherine Kavounis
Phone: (301) 594-1369
  1. Applications proposing to conduct non-pharmacological intervention research must define the stage of intervention development proposed as defined by the NIH Stage Model.
  2. Applications should adhere to NIA Guidance on Clinical Trials.
Contact the NIA Office of Clinical Research
NIAAA Policies and guidance established by the US Food and Drug Administration (FDA), NIH, and NIAAA should be reviewed by researchers prior to applying for support or initiating studies involving human subjects research or clinical trials. See NIAAA Human Subjects Research and Clinical Trials website for more information.  
NIAID   Gregory Deye, MD
Phone: (240) 292-4199
NIAMS   Contact by research area
NICHD NICHD Policies on Clinical Research and Related Issues Caroline Signore, MD, MPH
Phone: (301) 496-5577

The mission of the National Institute on Drug Abuse (NIDA) is to advance science on the causes and consequences of substance use and substance use disorders (SUD) and to apply that knowledge to improve individual and public health. In this regard, NIDA addresses the most fundamental and essential questions about substance use and SUD — from detecting and responding to emerging trends and understanding how substances work in the brain and body, to developing and testing new approaches to treatment and prevention. NIDA is interested in supporting mechanistic clinical trials* and Basic Experimental Studies with Humans (BESH) that aim to aid these processes through this FOA.

Some examples of research include but are not limited to:

  • Neuroimaging and behavioral studies investigating specific SUD-related neural circuits and/or cognitive constructs
  • Modulation of SUD-related circuits using pharmacological manipulation or non-invasive brain stimulation to investigate neural mechanisms underlying cognition, behavior, and clinical outcomes relevant to SUD
  • Testing of environmental, behavioral, or pharmacological manipulations as potential treatment or prevention targets for SUD, with emphasis on mechanisms of action
  • Leveraging AI/ML for integrating data; Natural Language Processing (NLP) for analysis and of data from disparate sources (medical records, policies, wearable devices, etc.)
  • AI-based image analysis
  • AI to monitor behavior
  • Multi-disciplinary collaborations

*A mechanistic clinical trial is designed to understand a biological or behavioral process, the pathophysiology of a disease, biomarkers for a disease or response to treatment, or the mechanism of action of an intervention. It is not designed to test the safety or demonstrate the efficacy/effectiveness of an intervention.

Katia Howlett, PhD, MPP, MBA
Phone: (301) 443-4877
Roger Little, PhD
Phone: (301) 435-1316
NIDCD The NIDCD Clinical Trials webpage contains information on NIDCD clinical trials policies, requirements, and guidance. Trinh Ly, MD
Phone: (301) 435-4085
NIDCR Lillian Shum, PhD
Phone: (301) 594-0618
NIDDK NIDDK accepts applications for low risk clinical trials in its mission. Please see NOT-DK-21-004 for further information. Barbara Linder, MD, PhD
Phone: (301) 594-0021
NIGMS NIGMS supports basic biomedical research that contributes to the understanding of fundamental cellular and physiological principles. General areas of interest include cell biology, biophysics, genetics, developmental biology, pharmacology, physiology, biological chemistry, biomedical technology, bioinformatics and computational biology. The Institute also supports research in certain clinical areas, primarily those that affect multiple organ systems. Additional information is available on the NIGMS website about research interests (including staff contact information) and clinical studies and trials.

Contact by research area

NIMH NOT-MH-19-006: NIMH Acceptance of Clinical Trial Applications under the Parent R01 and R21 Clinical Trial Required, or Basic Experimental Studies Involving Humans (BESH) Announcements is Limited to Mechanistic Clinical Trials Contact by research area
NINDS   Contact by research area


This page last reviewed on September 12, 2023