A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience
Issue link: https://innovationscns.epubxp.com/i/499434
Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] 24S needed. Multicenter trials are the mainstay in gaining FDA approval of a therapeutic for a psychiatric disorder indication, it does appear to add considerable variance to data collection and generation of results that may not be in keeping with ability of traditional designs to separate drug effects from placebo. By instituting neurobiologic primary endpoints with symptom rating scales as detailed in Case 3, the ability to decrease variance could be potentially accomplished, but methodology across all sites would still have to be standardized. It appears that more rigorous testing and planning at early stages using neuropharmacologic objective biomarkers could lead to better Phase III study design and dose selection which favors successful treatment trial outcomes. CONCLUDING REMARKS Changing the way in which individuals are classified and selected for enrollment into drug development initiatives, with use of endpoints that are objective, could provide great benefits to clinical trial programs (Figure 7). Spending more time categorizing target engagement with phenotypic relevance and employing biomarkers that are objective benchmarks for dose-selection and safety parameters could result in fewer negative and failed trials. A decrease in the overall cost of programs by shifting focus at an appropriate time dictated by results generated at the earlier stages of development is prudent. By doing so, post-hoc analysis may yield to detailing a more homogenous patient population by use of genetics and objective endpoints that could lead to less variance in positive outcome measures when re-testing the compound. Characterizing effective FIGURE 7. Evolutionary life cycle clinical design machine in p sychiatry. Schematic representation of machine gears which signify evolution of clinical trial design machines in psychiatry. Each gear face illustrates a progression in the steps of the clinical design strategy that begins at the noon p osition and extends clockwise back to the beginning, with the end point being a marketing indication (IND). Top gear details traditional design strategies that have largely been used in psychiatry. A target, often derived from serendipitous r esults of an existing treatment, will stimulate a rational chemical drug development initiative to a desired biochemical target of interest. This compound will then be tested in animal models of psychiatric illness that have p redictive validity. Once meeting the rigors of these preclinical processes, the drug goes through Phase I to Phase III clinical studies which hopefully leads to filing for treatment of a psychiatric indication. Left gear details applied design strategies that build off recently patented drugs with an approved marketed indication that have other potential patient populations in mind. This effort may lead to some preclinical testing, but largely progresses quickly to clinical trials and hopefully a second IND. Right gear details advanced design strategies for a potential patient population in mind that are largely not able to undergo traditional drug components of animal testing (such as device based treatments), with some animal modeling in preclinical stages that may be applicable. Genetics and functional neurobiologic markers may be used to stratify a patient population during the clinical trial design that can lead to an indication. Bottom gear details future design strategies that first evaluates human and animal data to objective neurobiologic findings as a potential target related to psychopathology that can be tested. No animal testing is necessarily required (other than possibly for safety parameters) and human studies can be undertaken with compounds that are in existence as active controls. Testing targets as primary outcome measures may require limited samples sizes to observe an effect and can lead to more reliable stop/go decisions. This strategy is one that can satisfy NIMH proposed RDoC initiatives, may be adopted by pharmaceutical companies to base treatments effects on objective neurobiological targets, and would require obtaining a marketed indication and sufficient demand from a patient population for return on investment following regulatory inputs and oversights.