Synergy in Action


Publication Guidelines

Innovative Approaches for Slowing Disease Progression in Parkinson’s Disease: Takeaways from the 14th Annual International Society for Central Nervous System Clinical Trials and Methodology Scientific Meeting

Monica Javidnia, PhD, Mark Frasier, PhD; Ira Shoulson, MD; Ibrahim Turkoz, PhD; and Kumar Budur, MD, MS
Innov Clin Neurosci. 2020;17(14–19) (open access)
The International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) partnered with the Michael J. Fox Foundation for Parkinson’s Research to hold a joint session on innovation in Parkinson’s disease research at the ISCTM 14th Annual Scientific Meeting held February 20 to 22, 2018 in Washington, D.C. The session focused on (1) biomarkers and outcomes measures in Parkinson’s disease clinical trials; 2) clinical trial designs, outcomes, and statistical approaches; and 3) the path forward. This paper aims to summarize key takeaways from the session presenters, panelists, and audience members.

Issues and Perspectives in Designing Clinical Trials for Negative Symptoms in Schizophrenia: Consensus Statements

Stephen R Marder, MD, Michael Davidson, MD, Silvia Zaragoza, PhD, Alan Kott, MUDr, Anzalee Khan, PhD, Xingmei Wang, MS, Dawn I Velligan, PhD, Daniel Umbricht, PhD, Remy Luthringer, PhD, David Daniel, MD
Schizophrenia Bulletin Open, Volume 1, Issue 1, January 2020 (open access)
Individuals from academia, the pharmaceutical industry, and regulators reevaluated earlier recommendations for the design of clinical trials for negative symptoms based on data from recent large trials. A session in February, 2018 at the International Society of CNS Clinical Trails and Methodology (ISCTM) annual meeting reviewed results from selected trials that reported findings between 2013 and 2018. The group reached a consensus on prior recommendations that should be reconsidered in future trials which included: (1) How can placebo effects be minimized? (2) Should global measures of negative symptoms be included? (3) Should a new drug targeting negative symptoms be tested in a monotherapy design or in an add-on design? (4) Can new information from negative symptom trials inform the selection of clinical outcome assessments (COA’s) for future trials? For each of these issues new data was evaluated, discussed by the group, and in some cases the earlier recommendations were revised.

Consistency checks to improve measurement with the Montgomery-Asberg Depression Rating Scale (MADRS)

Jonathan Rabinowitz, Nina R. Schooler, Brianne Brown, Mads Dalsgaard, Nina Engelhardt, Gretchen Friedberger, Bruce J. Kinon, Daniel Lee, Felice Ockun, Atul Mahableshwarkar, Joyce Tsai, Janet B.W. Williams, Colin Sauder, Christian Yavorsky, ISCTM ALGORITHMS/FLAGS TO IDENTIFY CLINICAL INCONSISTENCY IN THE USE OF RATING SCALES IN CNS RCTs working group members
Journal of Affective Disorders article/S0165032718332105 (open access)
International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Montgomery-Asberg Depression Rating Scale (MADRS). Twenty-two flags were identified. Seven flags are believed to be strong flags that suggest that a thorough review of rating is warranted. The flags were applied to assessments derived from the NEWMEDS data repository. Almost 65% of ratings had at least one inconsistency flag raised and 22% had two or more. Application of flags to clinical ratings may improve reliability of ratings and validity of trials.

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting

Phillip Chappell, MD, MBA , Michelle Stewart, PhD; Larry Alphs, MD, PhD; Franco DiCesare, MD; Sarah DuBrava, MS; Jill Harkavy-Friedman, PhD; Pilar Lim, PhD; Sian Ratcliffe, PhD; Morton M. Silverman, MD; Steven D. Targum, MD; and Stephen R. Marder, MD
J Clin Psychiatry 2017;78(6):e638–e647 (Open Access)
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.

Consistency checks to improve measurement with the Positive and Negative Syndrome Scale (PANSS)

Jonathan Rabinowitz, Nina R Schooler, Ariana Anderson, Lindsay Ayearst, David Daniel, Michael Davidson, Anzalee Khan, Bruce Kinon, Francois Menard, Lewis Opler, Mark Opler, Joanne B Severe, David Williamson, Christian Yavorsky, Jun Zhao, ISCTM ALGORITHMS/FLAGS TO IDENTIFY CLINICAL INCONSISTENCY IN THE USE OF RATING SCALES IN CNS RCTs working group members
Schizophrenia Research article/S0920-9964(17)30141 (Open Access)
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.

Performance-based and Observational Assessments in Clinical Trials Across the Alzheimer’s Disease Spectrum

Philip D. Harvey, PhD, Stephanie Cosentino, PhD; Rosie Curiel, PhD; Terry E. Goldberg, PhD; Jeffrey Kaye, MD; David Loewenstein, PhD; Daniel Marson, PhD, JD; David Salmon, PhD; Keith Wesnes, PhD; and Holly Posner, MD
Innov Clin Neurosci. 2017;14(1–2):30–39
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.

Outcomes Assessment in Clinical Trials of Alzheimer’s Disease and its Precursors: Readying for Short-term and Long-term Clinical Trial Needs

Holly Posner, MD, MS, Rosie Curiel, PsyD; Chris Edgar, PhD; Suzanne Hendrix, PhD; Enchi Liu, PhD; David A. Loewenstein, PhD; Glenn Morrison, MSc, PhD; Leslie Shinobu, PhD; Keith Wesnes, BSc, PhD, FSS, CPsychol, FBPsS; and Philip D. Harvey, PhD
Innov Clin Neurosci. 2017;14(1–2):22–29
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.

Mitigating the Effects of Nonadherence in Clinical Trials (open access)

Thomas M. Shiovitz,MD, Earle E. Bain,MD, David J. McCann, PhD, Phil Skolnick, PhD, Thomas Laughren,MD, Adam Hanina,MBA, and Daniel Burch,MD
The Journal of Clinical Pharmacology 2016, 56(9) 1151–1164 C 2016, The American College of Clinical Pharmacology DOI: 10.1002/jcph.689
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.

Sleep, Sleep Disorders, and Mild Traumatic Brain Injury. What We Know and What We Need to Know: Findings from a National Working Group

Emerson M. Wickwire, Scott G. Williams, Thomas Roth, Vincent F. Capaldi, Michael Jaffe, Margaret Moline, Gholam K. Motamedi, Gregory W. Morgan, Vincent Mysliwiec, Anne Germain, Renee M. Pazdan, Reuven Ferziger, Thomas J. Balkin, Margaret E. MacDonald, Thomas A. Macek, Michael R. Yochelson, Steven M. Scharf, Christopher J. Lettieri
Neurotherapeutics April 2016, Volume 13, Issue 2, pp 403-417
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.

Biomarkers for drug development in early psychosis: Current issues and promising directions

Goff DC, , Romero K, Paul J, Perez-Rodriguez M, Crandall D, Potkin SG
European Neuropsychopharmacology 2016.01.009 (Public Access permission obtained)
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.