Innovations In Clinical Neuroscience

SEP-OCT 2014

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

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[ 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E R 9 – 1 0 , S E P T E M B E R – O C T O B E R 2 0 1 4 ] Innovations in CLINICAL NEUROSCIENCE 55 contained in the 2012 Draft Guidance does not capture the full range of suicidal ideation and behavior (type II error). Definitions, moreover, are f requently ambiguous (susceptible to multiple interpretations), and the potential for misclassification (type I and type II errors) is compounded by frequent mismatches in category titles and definitions. These issues have the potential to compromise data comparability within clinical trial sites, across sites, and over time. Conclusion: These problems need to be remedied because of the potential for flawed data output and consequent threats to public health, to research on the safety of medications, and to the search for effective medication treatments for suicidality. INTRODUCTION Guided by findings from meta- analyses that some drugs might be implicated in suicidal behavior, the United States Food and Drug Administration (FDA) began mandating the collection of retrospective narrative data on suicidal ideation and behavior in clinical trials falling under its authority as early as 2003. Subsequently, it began classifying suicide events using the Columbia Classification Algorithm for Suicide Assessment (C-CASA), a nine- category classification system developed at Columbia University. 1 Based on these data and later data from prospective trials using the Columbia–Suicide Severity Rating Scale (C–SSRS), 2 the FDA issued draft guidance on assessing suicidal ideation and behavior in drug trials in 2010. 3 This draft guidance was revised and updated in August of 2012 when the FDA released new official draft guidance 4 recommending the prospective capture of suicide information using 11 categories that appear to be based on the C–SSRS. The FDA Draft Guidance was released during a time of growing concern about suicide and suicide behavior globally and nationally. 5,6 With broad interest in detecting and preventing suicidality, the FDA's 2012 official endorsement of the C–SSRS helped cement the C–SSRS's use in a widening range of s ettings stretching from the pharmaceutical industry (for clinical trials) to the United States Centers for Disease Control and Prevention (CDC) to schools and correction systems in some states and even the United States Military. 7,8 As the C–SSRS diffuses into new settings and the FDA's 2012 classification system becomes increasingly set, as it were, in stone, it may be useful to step back and look at the extent to which the 11 categories the FDA has apparently adopted from the C-SSRS accurately capture the spectrum of suicidal ideation and behavior. Ideally, national data collection and classification efforts targeting suicide, whether for drug trials or other epidemiological uses, need to be able to consistently and reliably identify individuals who are suicidal and those who are not. In addition, to be useful beyond the borders of any one nation (an important concern for pharmaceutical companies who operate globally), data collection and classification efforts should meet international standards. Among other "essential components," according to recent United Nations guidance to national statistical agencies, data collection and classification efforts should contain "categories that are mutually exclusive and exhaustive," and "definitions that are clear and unambiguous, and which define the content of each category." Data collection and classification efforts should also be "robust enough to last for a period of time," "meet user needs," and "provide comparability over time and between collections." 9 Finally, as with any technical or scientific document, the assumptions that guide the text should be as explicit as possible. 10 This paper evaluates the FDA's 2012 classification system for suicidal ideation and behavior (we will call it the FDA-CASA 2012) in the context of these standards. METHODS A critical review was used to evaluate the suicidality classification system (FDA-CASA 2012) adopted b y the FDA in its 2012 Draft Guidance. In line with internationally accepted criteria for classification, we focused specifically on whether the FDA-CASA 2012 is comprehensive (covering all potential categories of suicidal ideation and behavior that could be seen in practice) and on whether the definitions that guide specific categories are unambiguous, mutually exclusive, and robust. We also examined the underlying assumptions that appear to guide the FDA 2012 Draft Guidance. These assumptions are important to uncover and highlight since, as Professor Agger of the University of Texas points out in relation to technical and scientific writing in general, the assumptions that guide a scientific text are all too often buried under heavy technical prose. As a result they can be "hidden from the community of science and thus protected from external challenges." Uncovering these assumptions and putting them out for debate can help identify blind spots, omissions, tensions, and contradictions, or what Agger calls the "internal fissures and fault lines" in a text. 10 We divided this article into three parts. In the first part, we examine general issues and problems relating to the FDA-CASA 2012 classification system. In the second part, we focus on specific categories highlighting individual issues within these categories. We conclude with a discussion of the implications of the review. GENERAL ISSUES AND PROBLEMS Missing combinations of suicidal ideation (type II error). An important component of any classification system is that the categories be complete (i.e., no categories be omitted). The FDA- CASA 2012, since it is now more closely aligned to the C-SSRS,

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