Margaret C. Grabb’s research while affiliated with National Institute of Mental Health, National Institutes of Health and other places

Biomarkers are critically important in the development of drugs, biologics, medical devices, and psychosocial interventions for psychiatric disorders. As the lead federal agency charged with setting and supporting the national agenda for mental health research, the National Institute of Mental Health (NIMH) funds a broad portfolio of basic, translational, and clinical research focused on identifying, developing, and validating biomarkers for serious mental illnesses and neurodevelopmental conditions. In psychiatric research over the past 10 years, there has been an intensive effort to identify biomarkers as potential tools to improve treatment options for individuals with mental health concerns and increase success in the development of novel interventions. This chapter highlights examples of biomarker technologies that have been utilized to advance understanding of the pathophysiology of psychiatric disorders and the development of novel therapeutics.

Purpose/background: Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue. Methods/procedures: This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder. Recent and current biomarker studies in Fragile X syndrome occurring subsequent to the clinical studies are reviewed to see if they might address any chain of evidence gaps. Findings/results: Despite the strong preclinical basis for targeting molecular mechanisms, the lack of efficacy seen in clinical studies remains uninterpretable, with regard to ruling in or out the utility of targeting the mechanism in a clinical population, given the absence of studies, which address whether doses of administered drug impacted the targeted brain mechanism. Implications/conclusions: The value of pursuing clinical studies of compounds targeted to novel mechanisms in the absence of clinical pharmacological evidence of some anticipated mediating pharmacokinetic/pharmacodynamic signals is questionable. One or more biomarkers of a drug effect on brain function are needed to establish dose dependent CNS effects that allow one to interpret clinical results as ruling in or out a mechanism and providing a firm basis for continuing or not, as well as informing dose selection in any clinical efficacy trials. Initiatives to address this general need in pediatric psychopharmacology are highlighted.

In 2012, the US National Institute of Mental Health launched three clinical trial contracts under a new FAST initiative. The overall goal for these contracts (Fast-Fail Trials) was to focus early-stage trials, testing novel pharmacologic agents that target the central nervous system, on pharmacologic-based designs to objectively identify doses that produce central nervous system effects. The three contracts targeted different psychiatric populations: psychotic (FAST-PS), mood and anxiety (FAST-MAS), and autism spectrum disorders (FAST-AS). The FAST initiative was a first attempt for the National Institute of Mental Health to adapt an experimental medicine approach to its clinical trial portfolio. As the Fast-Fail trials implemented this new approach for the field, we present the rationale for each trial, design considerations, results, and how each one contributed new knowledge to the field of psychopharmacology; important lessons for pharma and biotech. Under the FAST initiative, the National Institute of Mental Health assembled research teams with a broad range of expertise, who developed and validated the outcome measures and study protocol, and conducted multi-site clinical trials, testing candidate compounds. In the FAST-PS contract, the team validated an imaging-based pharmacodynamic biomarker of the effect of ketamine in the brain that could be utilized in subsequent clinical trials. The initial FAST-AS study was an important first step in the design of early-stage target-engagement trials in autism spectrum disorder, suggesting that a resting electroencephalogram can be used as a pharmacodynamic measure in future studies. The FAST-MAS study showed that blocking the kappa-opioid receptor significantly affects functional magnetic resonance imaging ventral striatal activation in the monetary incentive delay task in anticipation of gain. Together, the outcomes of the FAST-FAIL trials demonstrated the importance of rigorously designed and informative central nervous system trials, including the value of pharmacodynamic measures in early-stage trials. Use of these measures furthered our knowledge about the relationship between specific molecular mechanisms, brain effects, and therapeutic effects in patients with mental illnesses.

Many psychiatric and behavioral disorders manifest in childhood (attention deficit hyperactivity disorder, obsessive compulsive disorder, anxiety, depression, schizophrenia, autism spectrum disorder, etc.) and the opportunity for intervening early may attenuate full development of the disorder and lessen long term disability. Yet, pediatric drug approvals for CNS indications are limited, and pediatric testing generally occurs only after establishing adult efficacy, more as an afterthought rather than with the initial goal of developing the medication for a pediatric CNS indication. With pharmaceutical companies decreasing funding of their neuroscience research divisions overall, the prospects for moving promising investigational drugs forward into pediatrics will only decline. The goal of this review is to highlight important challenges around pediatric drug development for psychiatric disorders, specifically during clinical development, and to present opportunities for filling these gaps, using new strategies for de-risking investigational drugs in new clinical trial designs/models. We will first present the current trends in pediatric drug efficacy testing in academic research and in industry trials, we will then discuss the regulatory landscape of pediatric drug testing, including policies intended to support and encourage more testing. Obstacles that remain will then be presented, followed by new designs, funding opportunities and considerations for testing investigational drugs safely.

Background: Pharmacological clinical trials in autism spectrum disorder(ASD) have yielded mixed results in efficacy. One challenge that may contribute to this situation is the heterogeneity in study participants, lack of biological targets associated with deficits in the core domains of ASD dysfunction, and the lack of objective biological measures of treatment response. Objectives: The goal of this presentation is to discuss the promise of biomarkers in stratifying subjects to enrich for the specific deficit being tested in the trial, and to highlight outcome measures that may inform whether a treatment is working. Methods: NIMH has created a program, called the “Fast Fail Trials” which is designed to develop and test ASD biomarkers in clinical trials of investigational compounds. Before initiating the first trial, we formed an advisory committee to establish compound selection criteria, identify compounds to test and then help inform the biomarker selection. Results: There is a wide range of biomarkers that are being tested in ASD but much fewer being incorporated into trial designs. Examples of potential biomarkers include brain activity measures such as fMRI and EEG/MEG, peripheral measures that correlate with sympathetic nervous system activity, eye tracking, various cognitive assessments, actigraphy, sleep measures and peripheral blood measures. This presentation will provide an overview of different biomarkers being studied in ASD that could be used in stratifying subjects and/or assessing treatment response. The significant effort needed to incorporate biomarkers in ASD trials will be emphasized. To illustrate how this can be done, the presentation will provide 1-2 case examples on the application of biomarkers into an ASD trial, based on NIMH’s recent efforts in the Fast Fail Program Conclusions: Different methodologies are becoming available to test how biomarkers can be used to stratify or enrich for subjects with specific phenotypes (deficits in a core domain of function) in ASD clinical trials. However, many studies have used small numbers of subjects and broad inclusion criteria and therefore the measures have not been tested or validated for their ability to define subgroups with ASD that may benefit most from the intervention. Challenges remain as to the feasibility, specificity (developmental age, level of function, core symptom), reproducibility, sensitivity of measures to change over time, etc. Especially in early treatment trials, the ability to correlate a brain activity measure such as EEG or fMRI with cognitive outcomes may be more informative than reliance on behavioral measures or patient reported outcome measures. The timing is right to begin incorporating quantitative biological measures into trials to test novel hypotheses for therapeutic interventions.