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NIMH Support for Clinical Trials Research

NAMHC Concept Clearance

Presenter:

Mi Hillefors, M.D., Ph.D.
Division of Translational Research

Goal:

This effort aims to continue the manner in which NIMH solicits and conducts clinical trials research, emphasizing the experimental therapeutic approach to the treatment and prevention of mental illnesses across the lifespan. NIMH’s series of clinical trials Funding Opportunity Announcements (FOAs) covers the intervention development pipeline, from first-in-human, early testing of new interventions, confirmatory efficacy trials, to effectiveness trials.

Rationale:

Traditionally, clinical trials in mental health involve participants selected on the basis of heterogeneous clinical indications and outcomes focused on symptom reduction. Such trials, whether positive or not with respect to symptom change, deliver little information about how the intervention might work or the underlying cause of the disorder and therefore provide little guidance for further treatment development or refinement. In 2014, NIMH implemented an experimental therapeutic approach in which initial intervention development is conducted in milestone-driven steps. The first step is to demonstrate that the intervention exerts a measurable effect on a hypothesized “target” or mechanism of action rather than focusing on demonstrating a change in clinical symptom(s). Following the initial demonstration of target engagement, the next step of novel intervention development involves replicating target engagement and evaluating whether intervention-induced changes in the target is associated with clinical benefit. In subsequent steps of intervention refinement and testing (e.g., confirmatory efficacy studies, effectiveness trials), target engagement is confirmed and replicated to advance understanding of disease/intervention mechanisms, facilitate interpretation of trial results, and inform efforts to refine and optimize interventions.

NIMH requires objective, quantifiable, and reproducible measures of both target engagement and the intervention’s clinical effects. NIMH is also interested in the development of novel interventions that focus on operationally defined, empirically supported functional domain(s) or symptom(s) of mental disorders in which not all subjects may share the same underlying disease process. For example, NIMH Research Domain Criteria (RDoC) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures, and clinical subjects.

Overall, the NIMH series of clinical trials FOAs aims to continue NIMH’s efforts to support clinical trials research with an emphasis on strengthening target identification and validation to improve treatments. NIMH also emphasizes the need for increased efficiency, transparency, and data sharing.