Research on biological markers of disease process and treatment response were highlighted at the 48th annual New Clinical Drug Evaluation Unit meeting, “New Research Approaches for Mental Health Interventions,” convened by the NIMH, May 27-30 in Phoenix.

In a workshop on biomarkers, pharmacogenetics, and pharmacogenomics, Michael Henry, MD, of Caritas St Elizabeth’s Medical Center in Boston, indicated that technological improvements in scanner design, along with increasing understanding of neuropathophysiology, “offer an unprecedented opportunity for utilizing brain imaging techniques to improve the precision of clinical trials.”

Henry foresees the application of technologies such as MRI, PET, and single photon emission CT to reduce diagnostic variability in study populations, measure drug penetration of target sites, and establish biomarkers of therapeutic efficacy. Although imaging in clinical trials is most common in cardiology and oncology, Henry noted its recent use in trials of agents for dementia, depression, and psychosis.

Andrew Leon, PhD, of Weill Medical College of Cornell University, New York, agreed with the described potential of biomarkers to serve as primary end points in clinical trials but reminded conferees that the current status is either as secondary end points or “hypothesized moderators of outcome.” To go forward, he asserted, clinical trials will need to include validity testing of putative biomarkers.

An example of a promising biomarker suggested by animal research ,1 Leon offered, is the presence of the brain-derived neurotrophic factor single-nucleotide polymorphism, Val66Met, which could be associated with decreased response to SSRI antidepressants. Leon suggested that a longitudinal data analytic strategy, such as a mixed-effects model, could reduce the statistical impact of study population attrition on evaluating association of this and other biological measures with treatment response.

A view from the pharmaceutical industry on establishing clinical trial designs to assess or apply biomarkers was provided in the workshop by William Potter, MD, PhD, of Merck Research Laboratories. He noted that the industry has recently committed to the principle of using available, validated biomarkers to select doses for clinical efficacy trials and, thereby, reduce the time to establish dosing and exposure to subtherapeutic or excessive doses. Potter pointed to sleep polysomnography as having a particularly long history in this application. In addition, Potter indicated, PET studies have been applied to guide dosage for several classes of compounds, including atypical antipsychotics, SSRI antidepressants, substance P antagonists, and cannabinoid type 1 receptor antagonists.

“In the case of many targets for which no appropriate PET ligand exists, a number of pharmacodynamic downstream measures of drug activity are being explored, from awake EEG to exploratory proteomics of CSF, pre- and postdrug,” Potter indicated.

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