11th Annual Working Group Dinner Session Descriptions
Assessment of Abuse Liability in Drug Dependent Subjects
Chairs: Marta Sokolowska; Beatrice Setnik; Michael Klein
The FDA Draft Guidance on Assessment of Abuse Potential of Drugs (January 2010) specifies that participants in human abuse potential studies should be healthy volunteers and have a recent or current history of using drugs recreationally. Recreational use refers to the intermittent use of drugs for reasons other than medical purposes (such as to experiment, to relax, to feel good or to get high). However, a separate vulnerable population that is less well-understood is the population of drug-dependent individuals. First and foremost, these may be the group of drug users who are most likely to seek out and abuse new medications. In addition, these individuals have a large wealth of drug-taking experience and expertise with drug induced subjective effects. This workshop will present an overview of critical scientific and methodological issues associated with studying drug-dependent abusers. Such topics include participant recruitment, environment of study (inpatient versus outpatient), immediate detoxification prior to the study versus maintenance throughout the study, outcome measures employed in the trials, and more broadly, a review of the literature and future directions suggested therein.
Addressing Methodological Challenges in International CNS Clinical Trials
Chairs: Richard Keefe, Amir Kalali
Overall objective: Generate a consensus document addressing methodological challenges of international CNS clinical trials.
CNS drug development has become internationally driven and implemented. As a result, new scientific, regulatory, cultural, and operational complexities need to be considered for successful outcomes. In our initial meetings, we gathered input from attendees regarding their greatest concerns for international clinical trials, and decided to focus on the processes for translation and cultural adaptation and harmonization of outcome measures for global clinical trials. The specific stated objective of the group is to establish best practice guidelines on the translation and cultural adaptation of Clinician Reported Outcomes with the ultimate goal of minimizing the impact of culture in clinical trials. We have produced an outline of a manuscript devoted to this topic, generated and distributed a reading list to working group participants, and developed a survey for collecting information from key stakeholders about their current practices of translating and culturally adapting Clinician Reported Outcomes (ClinROs). We will discuss the results of the survey at our upcoming meeting in February. These results will help us to determine the gaps between current practices on translation processes for ClinROs and those recommended in guidance documents.
Algorithms/Flags to Identify Clinical Inconsistency in the Use of Rating Scales in CNS RCTs
Chairs: Jonathan Rabinowitz, Nina R. Schooler
The algorithm/flags working group has been renamed “algorithms/flags” reflecting the group’s view that rules exceeds the mandate of review of clinical assessments. At the Winter meeting the group will: review and approve general ( all scale) principles for review and flagging); provide final review of flags identified for the PANSS at the last meeting; develop a plan for dissemination of PANSS results and choose the next scale to work on.
Behavioral and Psychiatric Symptoms in Dementia
Chair: Larry Ereshefsky, David Miller, Luca Pani
This working group is being convened to focus on the methodological challenges facing the development of treatments for the Behavioral and Psychiatric Symptoms of Dementia (BPSD). This group is in part stimulated by the recent EMA Alzheimer’s Disease Workshop which highlighted the methodological challenges and serves as a robust starting point to define our Working Group’s scope. Some of the issues we may discuss are: Understanding how evolving AD diagnostic and biomarker approaches affect development of treatments for BPSD (pre dementia, early, late categorizations with various diagnosis and staging structures (DSM V, NIA-AA, IWG)); Address pseudospecificity concerns, recommending approaches to evaluate a treatment that appears to improve behavioral symptom domains as well as cognition/function; Proposing innovative trials designs and regulatory acceptance; Managing intrinsic variability of symptoms and evaluating strengths and limitations of various behavior rating scales; Distinguishing and evaluating treatment of existing symptoms or delays/prevention of likely to occur symptoms of BPSD; Regulatory perspectives and review and lessons learned from ongoing and prior clinical trials for BPSD.
Biomarkers in Schizophrenia
Chairs: Steven Potkin, Don Goff
At the last ISCTM biomarkers dinner, there was a detailed discussion on the challenges in developing and evaluating biomarkers. The lack of using the same biomarkers in the same study or study population limits meaningful comparisons. There was consensus that a prospective study with a design that specifically included simultaneous measurements of a variety of blood, genomic, cognitive, and brain imaging measures is needed. Publication of another 200 or so biomarkers by itself is unlikely to advance the field. Alzheimer’s disease provides a model in ADNI in which a range of blood, imaging, cognitive, and genetic samples were collected on the same subjects and used for comparative purposes, allowing the construction of biomarker curves related to stage of illness. These curves and data also allow calculation of effect size and sample size needed to consider their use in clinical trials. The following curve from Cliff Jack is an example. LINK TO TABLE
These points will be explored in a draft manuscript on biomarkers in schizophrenia (working title: Schizophrenia Biomarkers Initiative), which will be distributed for comment prior to the February meeting. The draft will include both imaging and non-imaging biomarkers. The manuscript will be discussed in detail during the workshop and a consensus reached on issues of research design, subject inclusion, strategy for biomarker comparison, discussion of financing options to conduct such a study, as well as guidelines for data sharing.
Cognitive Assessment in AD and Its Precursors
Holly Posner, Phil Harvey
This edition of the working group will continue to refine our discussions of the importance and strategies for assessment of cognition in Alzheimer’s disease. For the Winter 2015 meeting, we will focus on three related topics. These include assessment of cognitive impairments in the earliest stages of AD, including in at risk populations. Further, we will examine social cognition across the course of the AD continuum, including in at risk populations, and we will consider the functional importance of social cognitive deficits as well as their contributions to other symptoms such as psychosis and agitation. We will also focus our attention on behavioral disturbances in AD, examining their measurement, relationship to other features of the illness such as social cognition and cognitive deficits, and will address treatment considerations. We will have a brief presentation on each of these topics and, as usual, extensive discussion and working group participation.
Identifying/Reducing the Effects of Non-Adherence in Clinical Trials
Chairs: Thomas Shiovitz, Earle Bain
The structure and outline of the White Paper on Nonadherence in Clinical Trials has been completed and opening sections (Background, Professional Subjects, Statistical Effects of Nonadherence, Methods to Detect Nonadherence) are in draft form. Now the fun begins. Discussions on where, when and how to act to identify and mitigate the effects of nonadherence at various stages of a clinical trial (prescreen, screen, post-randomization, post-Hoc analysis) will continue. Novel ways to define a modified ITT and regulatory issues will be explored. We welcome diverse voices at the workshop as specific recommendations of the Working Group begin to coalesce.
Implementing Innovations in CNS Trials
Chairs: Gary Sachs, Michael Detke
The goal of this working group is to improve the ability of our members and others to implement innovation in CNS trials (and perhaps beyond). We have reviewed examples from within CNS and other therapeutic areas of drug development, and from very different industries and disciplines (e.g., engineering, information technology, decision science, Lean Start-Up, Innovator’s Dilemma). We have met monthly by teleconference and biannually at the ISCTM meetings. Our initial deliverable is a publication reviewing the above, targeted for submission soon after the February 2015 meeting. Our next goal will be to decide whether to persist in this direction further, or pivot to a somewhat different goal in future meetings.
Suicidal Ideation and Behavior Assessment
Michelle Stewart, Phil Chappell, Larry Alphs
The Suicidal Ideation and Behavior Working Group has been reconstituted. Its goal will be to summarize the state of knowledge and the knowledge/practice gaps related to suicide ideation and behavior and how they might be addressed. Ideas will be evaluated for feasibility and prioritized. These will be presented to the ISCTM Executive Committee for further action through an ISCTM-sponsored consensus meeting and/or establishment of a follow-on ISCTM SIB working group. At the February session we will summarize the 2 previous WG surveys (sponsor and site), brainstorm and prioritize items. The development work will continue via telecons through April with a target of submitting a model/agenda for next steps to the ISCTM EC in May.