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NIMH’s New Focus in Clinical Trials

Concept Clearance

Presenter

Thomas Insel, M.D.
Director
National Institute of Mental Health

Goal

The goal of this effort is to transform the manner in which NIMH solicits and conducts clinical trial research, and to focus applications towards an emphasis on the experimental therapeutics approach to the treatment and prevention of mental disorders in adults and children.

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. As a result, NIMH is shifting to an experimental therapeutic paradigm in which interventions are evaluated in stages The first stage is to demonstrate that the intervention exerts some measurable effect on a hypothesized “target” or mechanism of action; the intervention is used as a manipulation with the immediate goal of determining whether the intervention affects a target rather than attempting to demonstrate a clinical treatment effect. “Target engagement” refers to verification that the intervention has had the predicted effect on the target. Targets may be molecular, cellular, circuit, behavioral, or interpersonal, commensurate with the intervention. Once target engagement is demonstrated, measures of target engagement are then related to clinical outcomes to test the hypothesis that the target is relevant to the clinical problem under study.

NIMH aims to support clinical trials that posit an intervention’s “target” or mechanism of action by which the intervention might ultimately modify the functional domain or symptom(s) of interest. Objective, quantifiable, and reproducible measures of both target engagement and the intervention’s clinical effects are included in the refocused clinical trial effort at NIMH. In addition, NIMH is particularly interested in the development of novel interventions that focus on operationally defined, empirically supported functional domains or symptom(s) of mental disorders, as opposed to broad diagnostic categories, 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 (see the RDoC webpage for more details).

Overall, this initiative aims to refocus the NIMH’s efforts to support clinical trials research, with an emphasis on strengthening target identification and validation to improve treatments. NIMH is also emphasizing the need for increased efficiency, transparency, and data sharing.

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