Objective: To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials.

Participants: Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17–18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting.

Evidence: Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting.

Consensus Process: Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded.

Conclusions: All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions.

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials.

Assessment of the earlier stages of Alzheimer’s disease requires different strategies than those previously developed for fully syndromal Alzheimer’s disease . This challenge is further magnified in very early stages, where symptomatology may be minimal and functional deficits very subtle to absent. This paper reviews strategies for performance-based assessment of the early stages of Alzheimer’s disease , including assessments of cognition, functional capacity, and social cognition. Meetings with an International Society for CNS Clinical Trials and Methodology working group served as the basis for this paper and its companion. The current state of the art of detection and staging-oriented assessments is presented, and information is provided regarding the practicality and validity of these approaches, with a special focus on their usefulness in clinical trials for new medication development.

An evolving paradigm shift in the diagnostic conceptualization of Alzheimer’s disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer’s Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer’s disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment.
With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer’s disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer’s disease clinical trials.

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study.Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM)Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.

Disturbed sleep is one of the most common complaints following traumatic brain injury (TBI) and worsens morbidity and long-term sequelae. Further, sleep and TBI share neurophysiologic underpinnings with direct relevance to recovery from TBI. As such, disturbed sleep and clinical sleep disorders represent modifiable treatment targets to improve outcomes in TBI. This paper presents key findings from a national working group on sleep and TBI, with a specific focus on the testing and development of sleep-related therapeutic interventions for mild TBI (mTBI). First, mTBI and sleep physiology are briefly reviewed. Next, essential empirical and clinical questions and knowledge gaps are addressed. Finally, actionable recommendations are offered to guide active and efficient collaboration between academic, industry, and governmental stakeholders.

A major goal of current research in schizophrenia is to understand the biology underlying onset and early progression and to develop interventions that modify these processes. Biomarkers can play a critical role in identifying disease state, factors contributing to underlying progression, as well as predicting and monitoring response to treatment. Once biomarker-based therapeutics are established, biomarkers can guide treatment selection. It is increasingly clear that a wide range of potential biomarkers should be examined in schizophrenia, given the large number of genetic and environmental factors that have been identified as risk factors. New models for analysis of biomarkers are needed that represent the central nervous system as a highly complex, dynamic, and interactive system. Many tools are available with which to study relevant brain chemistry, but most are indirect measures and represent only a small fraction of the potential etiologic factors contributing to the molecular, structural and functional components of schizophrenia. This review represents the work of the International Society for CNS Clinical Trials and Methodology (ISCTM) Biomarkers Working Group. It discusses advantages and disadvantages of different categories of biomarkers and provides a summary of evidence that biomarkers representing inflammation, oxidative stress, endocannabinoids, glucocorticoid, and biogenic amines systems are dysregulated and potentially interactive in early phase schizophrenia. As has been recently demonstrated in several neurodevelopmental and neurodegenerative disorders, a multi-modal, longitudinal strategy involving a diverse array of biomarkers and new approaches to statistical modeling are needed to improve early interventions based on the fuller understanding.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

Abstract
Objective: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. Design: An internet-based survey. Setting: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. Participants: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. Measurements: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. Results: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). Conclusion: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.

Last week at a meeting on clinical trials for central nervous system treatments, researchers convened to grapple with what they see as a serious and underrecognized problem in drug development: the fact that many people in clinical trials stop taking their experimental medications or don't take them as prescribed. These nonadherent participants can diminish the apparent effects of a drug compared with placebo and can potentially mask a drug's side effects or safety risks. As researchers recognize the effect of the problem on their trial data, some are taking greater pains to measure adherence through blood tests or electronic monitoring, and some are considering ways to design more adherence-friendly trials.
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