Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

Issue link: http://innovationscns.epubxp.com/i/499434

Contents of this Issue

Navigation

Page 26 of 41

[ 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 ] Innovations in CLINICAL NEUROSCIENCE 27S This article is based on proceedings from the "Taking Personalized Medicine Seriously—Biomarker Approaches in Phase IIb/III Studies in M ajor Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014. INTRODUCTION In 2005, it was well recognized that drug candidates fail in development for one of four major reasons: 1) the compound is given to the wrong subjects; 2) the compound is given at the wrong dose or schedule; 3) the favorable effects of the compound are not detected; or 4) the compound has a significant effect in animal models in laboratory species, but not in humans. 1 Almost a decade later, the same issues of patient selection and target engagement were dominant themes in a review of the failures in drug development at Astra Zeneca between 2005 and 2010. 2 One area, which received considerable interest in the meantime for the solution of these problems, is the exploration of individualized medicine by utilizing biomarkers. There is, however, the perception that there are principal obstacles to the development and use of biomarkers. The lack of a generally accepted biological theory of psychiatric diseases (i.e., a clear understanding of the connection between biological changes and disturbed behavior and perception) is a fundamental problem. There is the notion of a principal gap between biological and psychological phenomena. A recent survey in practicing psychiatrists in the United States 3 found a clear indication for the persistence of brain-mind dualism in psychiatric reasoning. Biomarker assessments may help to bridge this gap. More practical concerns come from the notion that biomarkers are in principal difficult to assess and expensive. Furthermore, there is a lack of clarity about regulatory implications of the use of biomarkers. We will see that these concerns may arise from a lack of clarity about different types of biomarkers and their differing practical value, in particular predictive b iomarker versus surrogate marker (Table 1). 5–8 Here, the development of technologies and methodologies in personalized medicine (biomarkers) focusing on improving patient selection and detecting target engagement to enhance the success rate of later stage clinical trials and to deliver significantly improved clinical outcomes from new medications are considered. This article is based on proceedings from the "Taking Personalized Medicine Seriously—Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014. REGULATORY ISSUES: THE USE OF BIOMARKERS IN PHASE IIB/III STUDIES IN DEPRESSION AND SCHIZOPHRENIA (T. Laughren) The fundamental problem facing psychiatric drug development is that the clinical targets are imprecise. There remains a profound lack of understanding of the underlying neurobiology of psychiatric disorders. This is hardly surprising given the complexity of the human brain, and the fact that we understand little about its normal functions, let alone malfunctions. The long-awaited Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) was released in May of 2013 with considerable controversy. For all the fanfare and anticipation, DSM 5 serves no better than the previous editions to define psychiatric pathophysiology in a manner that can inform development of treatment interventions. It could be said that, ironically, even though many clinicians and investigators may not find the DSM 5 optimal, the entire field remains heavily reliant on it. Currently the major challenge facing the field is finding better, more biologically based approaches to carving up the psychiatric illness space (i.e., moving beyond DSM). This will require q uantum leaps in our fundamental understanding of human brain neurophysiology and pathophysiology: a true challenge for 21st century neuroscientists. 9 Beyond DSM for psychiatric drug development, there has been increasing interest in targeting phenomenological domains, albeit without neurobiological understanding, within accepted DSM diagnostic entities (e.g., cognitive impairment associated with schizophrenia [CIAS]) as well as across DSM diagnostic entities (e.g., agitation, impulsivity, specific cognitive deficits). There has also been interest in biological subgroups, defined by various biomarkers, even without clinical understanding of what these classifications might represent. These types of biological subgroups could be based on any of the many different types of biomarkers that have been proposed to date. As with phenomenological domains, these could be applied within or across DSM diagnostic entities. One might consider the research domain criteria (RDoC) as way of combining biology and phenomenology, but it remains to be seen whether or not these will serve as useful targets for drug development. Definition of biomarkers. The United States Food and Drug Administration (FDA) defines biomarkers as measureable characteristics that reflect physiological, pharmacological, or disease processes in animals or humans. As such, biomarkers have many applications in drug development. The focus of the current discussion is primarily on finding biomarkers that can predict efficacy or risk associated with drug treatment (i.e., an approach to subgrouping the larger population into responsive vs. nonresponsive or at risk vs. not at risk). Examples include imaging measures, serum assays, genetic assays, physiological measures, histopathologic findings, psychological

Articles in this issue

Archives of this issue

view archives of Innovations In Clinical Neuroscience - ISCTM Supplement 2015