Innovations In Clinical Neuroscience

SEP-OCT 2014

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

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 1 , N U M B E R 9 – 1 0 , S E P T E M B E R – O C T O B E R 2 0 1 4 ] 64 patient occurs, the current structure of the FDA-CASA 2012 will not give clinicians any awareness of the change. FDA-CASA 2012 does not g ive clinicians enough information to review data in order to determine if a particular medication causes such a shift. Number of events versus time spent. The FDA 2012 Draft Guidance, through its use of the C–SSRS as a standard reference assessment instrument, focuses on the total number of times the behaviors occur. There is an implicit assumption that the number of events correlates with severity or seriousness or risk of suicidal behaviors. While this is an interesting idea, it has not been adequately tested, and we found in tracking over 31,000 events of suicidality in a single case over a year 1 4 that the evidence in support of this association is very weak. In contrast, we found that the evidence supporting the value of tracking time spent in suicidality was much more valuable for this purpose. 14 Suicidal ideation and behavior categories and definitions citation. At the top of Appendix A (line 466) 4 containing the FDA categories and definitions used in the FDA 2012 Draft Guidance is a reference to a 2007 document by Posner et al. This reference is inadequately sourced. The source is almost certainly the 2007 paper delineating the nine-category classification developed by Posner et al, 1 but the corresponding footnote (#10) only provides a website address for a Columbia University website for the 11-category C–SSRS, an instrument that is described in a 2011 paper by Posner et al. 2 The website in turn does not provide a link to the 2007 paper or to the 2011 paper by Posner et al 2 that describes the C–SSRS. We find this confusing since the FDA definitions contained in this appendix are central to the FDA 2012 Draft Guidance. The absence of a proper source citation makes it difficult to easily find the source and then to compare the FDA definitions in the FDA 2012 Draft Guidance with the source. And as it turns out, the categories and definitions in Appendix A do not match those in t he 2007 classification and, as we show elsewhere, 18 they are not always in precise alignment with the C–SSRS. CONCLUSION The results of our review suggest that the 2012 FDA Draft Guidance still needs work. In particular, the categories do not capture the full range of suicidal ideation and behavior (they are not exhaustive) in that they select and categorize only some combinations of relevant ideation and behavior while not capturing many others (26 not captured out of 32 total ideation combinations). Moreover, definitions are not clear enough to be unambiguous and all too often misalign with category names (titles above definitions). Users, whether they be raters, investigators, or sponsors, who consult the document as an aid in decision making on an item response on a scale are hampered by this kind of ambiguity. At best, end users will ask questions and make consistent decisions in a given interview. At worst, they will cherry pick, using the title to classify one patient and the definition or some part or phrase of the definition to classify another patient. This impacts comparability over time and between collections, especially when data is collected at multiple sites with hundreds of end users in a drug trial and can render data output flawed. For pharmaceutical company sponsors of studies, the problem is further compounded since the categories for the 2012 Draft Guidance do not match categories in previous 2010 Draft Guidance, making it difficult to pool data over time to properly detect trends for a particular drug or drug class. These problems need to be remedied because they pose potential threats to public health, to research on the safety of medications, and to the search for effective medication treatments for suicidality. REFERENCES 1. Posner K, Oquendo, MA, Gould, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035–1043. 2. Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–1277. 3. United States Food and Drug Administration, United States Department of Health and Human Services. Guidance for Industry: Suicidality: Prospective Assessment of Occurrence in Clinical Trials, Draft Guidance. September 2010. https://www.federalregister.gov/artic les/2010/09/09/2010-22404/draft- guidance-for-industry-on-suicidality- prospective-assessment-of- occurrence-in-clinical-trials. Accessed October 1, 2014. 4. United States Food and Drug Administration, United States Department of Health and Human Services. Guidance for Industry: Suicidality: Prospective Assessment of Occurrence in Clinical Trials, Draft Guidance. August 2012. Revision 1. http://www.fda.gov/downloads/Drug s/Guidances/UCM225130.pdf. Accessed October 1, 2014. 5. World Health Organization. World Suicide Prevention Day 10 September 2012. http://www.emro.who.int/media/ news/suicide-prevention- day2012.html. Accessed October 1, 2014. 6. United States Department of Health and Human Services. National Strategy for Suicide Prevention: Goals and Objectives for Action. A Report of the U.S. Surgeon General and of the

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