Innovations In Clinical Neuroscience

SEP-OCT 2014

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

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Page 19 of 201

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 ] 20 assessments (29.8%, 17/57); version control of SIB assessment instruments (28.1%, 16/57); and having to exclude/discontinue p atients if they report SIB (24.6%, 14/57). The majority of respondents (80.7%, 46/57) reported their company had experienced multiple challenges in implementing SIB assessments in clinical trials (range from 2 to >5 different types of challenges). DISCUSSION The results of this survey provide initial evidence supporting the view that prospective assessment of SIB has been widely incorporated in industry-sponsored clinical trials since the appearance of the FDA draft guidance in 2010. 1 Not surprisingly, the most common indications for which monitoring has been done include psychiatric and neurocognitive disorders, but monitoring has also been extended to a range of other neurologic and pain conditions, including studies in stroke victims and patients with neurodegenerative disorders such as amyotrophic lateral sclerosis and Parkinson's disease. The C-SSRS 5 ,6 was identified by the survey as the most commonly used instrument for prospective assessment of SIB in industry- sponsored clinical trials. This is in line with its endorsement as an acceptable scale in both the 2010 and 2012 FDA draft guidance. 1, 2 A significant number of respondents also reported using the S-STS and other scales; however, the survey did not elicit comparative information on sponsor experiences with the different scales, which would have been of interest. Most importantly, the results of this survey show that a broad range of time periods is being utilized for the assessment of SIB in subjects considered for clinical studies. This diversity may be related to the screening and baseline use of the SIB assessment. Specifically, it may relate to whether the assessment is used to include or exclude subjects from the study and/or whether it is being used to assign a current baseline SIB status to the subject for use in analysis of the study data for e mergence of new SIB. There appears to be little consistency in choice of past time periods for screening and baseline assessments; nor is it clear how look-back periods have been derived. The lack of consistency in assessment periods used by different companies suggests substantial uncertainty about what is the appropriate past time period for determining subject-level suicide risk at study entry. Some confusion may derive, in part, from the August 2012 FDA draft guidance that baseline SIB evaluation should include an assessment of lifetime SIB. 2 Use of a lifetime assessment for determining the baseline SIB status of a subject may be problematic, as SIB events of the distant past may not be relevant to current clinical states. Inclusion of remote events may also lead to inflation of reported baseline rates of SIB. Further research is needed to identify optimal look-back periods for use at screening to identify subjects at increased risk of suicide, who may require increased surveillance, and for use at baseline to assign current SIB status for detection of treatment emergent SIB. While the optimal look-back periods may vary across indications, standardization of assessment time periods at the screening and baseline visits would facilitate data aggregation across multiple studies within a development program to support meta-analysis of SIB data as well as across different programs from the same or different companies. The variability reported by survey respondents regarding the approach different companies have taken to summarize study-level SIB data also suggests there is confusion among sponsors regarding best practices for analyzing and reporting clinical trial SIB data. Implementation of prospective assessment of SIB in clinical trials was anticipated to make retrospective analysis of potential suicide-related adverse event data unnecessary. 1,2 However, the results of the current survey suggest that some companies may continue to u tilize both approaches to the analysis of their SIB data. Although cross-industry efforts have been undertaken to develop a consensus position regarding the best methods for analyzing and reporting study- level SIB data, the impact of these recommendations across the industry, to date, appears to be limited. 18 Numerous challenges for implementing SIB in clinical trials were identified. Interestingly, cross cultural differences in the acceptance of SIB assessments was the most commonly reported challenge by sponsors. This is in contrast to the earlier ISAW survey of study sites that did not identify this as a major issue. 3 Similar to findings from the previous survey, difficulty obtaining translations of SIB instruments into relevant languages was a challenge for a substantial proportion (35.1%) of respondents, despite the reported availability of a wide range of translations of the C-SSRS ( lations_cssrs.html). These findings could have implications for the quality of SIB data collected in global studies, which are conducted in many regions and different cultures across the world. Such concerns may require development of more culturally sensitive SIB assessment tools, as well as culturally specific rater training materials and methods. Availability of accurate translations of SIB tools is a necessary first step, but alone may not be sufficient to address cultural sensitivities and resistances around revelations of suicidal thoughts and behaviors. The second most common challenge identified by this survey was site difficulty in obtaining an adequate baseline SIB history. This issue was also reported as a major challenge by site investigators in the prior survey of clinical study sites. 3 Taken together, the results of these

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