Chair: Gary Sachs, MD

This new ISCTM Working Group on Innovation grows out of the Strategic Thinking session held last February. The task of the group at this initial meeting will be to review the summary of the Strategic Thinking session around Innovation and discuss options for a specific focus that the Group should take initially and map out some early steps to accomplish these goals.  We recognize that innovation does not readily lend itself to following prescribed paths and expect that there will very likely be course corrections. Please signal your interest in participating  in the  Working Group by signing up for this initial workshop.

Co-Chairs: Holly Posner, MD; Philip Harvey, PhD

The goals of this working group continue to be further understanding the challenges in assessing for meaningful improvement or decrement in cognition during the 6 month to 2 year period of a typical clinical trial of AD and its precursors.  This includes thinking within the context of re-analyzing existing clinical trial data to enhance signal detection of existing psychometric instruments from pooled assessments using sophisticated statistical techniques. We will also present the latest data on assessment developments in cognitive neuroscience that may inform assessment development in the future. We also are working to further our awareness of the full cognitive profile of people who might enroll in such trials and to expand understanding of assessment of areas where potential treatment-related improvements may be clinically significant.

Co-chairs: Richard Keefe, PhD; Amir Kalali, MD

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. The working group will initially prioritize a focus on the impact of multiple cultures and health systems on key outcome measures. One area that needs immediate attention in CNS clinical trials is the procedures for harmonizing various types of outcome measures (patient-reported outcomes, clinical rating scales, performance-based cognitive measures) across cultures in a regulatory context. 

Following an identification of the specific area of focus, the output of the Working Group will be a guidance document or data driven manuscript on the specific topic.

Co-Chairs: Stephen Marder, MD; David Daniel, MD

This workshop will focus on recent clinical trials results and analyses of the NEWMEDS data base that inform best practices in design and measurement tool selection for negative symptom studies.

Chair: Ginger Haynes, PhD

In a number of diseases that are primary CNS clinical research targets, such as MDD and schizophrenia, there are a substantial number of effective medications already available globally, many at generic prices. Superiority to placebo is often the threshold for regulatory approval; however, patients, physicians, and payers are interested in how newer medications compare to those already in existence. Historically, the studies to generate answers to these important questions would lag regulatory approval for years, if they were executed at all. One method to explore comparative effectiveness is to identify a targeted subpopulation in which a new agent demonstrates advantage over standard of care. Adaptive population enrichment designs can efficiently identify subpopulations in which newly approved medications are superior to other medications. The ISCTM Adaptive Design Working Group will walk through an adaptive population enrichment design for a Phase IIIB/IV study in a CNS disorder. During the workshop, the group will discuss the performance of the design via simulation and the business and practical implications of various design element decisions.

Co-chairs: Stephen Marder, MD; David Daniel, MD

Dr. Marder reviewed all the studies of negative symptoms posted on clinicaltrials.gov. All the trials were studying add-on treatment.  A study by Amgen of a GlyT1 compound, AMG747, was new.  The duration of the study is 12 weeks, not as long as the studies being conducted by Roche.  The studies generally include ages 18 to 55, 60, or 65.  Many studies are using the SANS as the scale for primary outcome measure.  Roche is using the PANSS negative factors and Amgen and Lilly are using the NSA-16.  Almost all trials require limitation on severity of positive symptoms. 

The group reviewed a summary of the recommendations that resulted from the NewMeds meeting in Florence in April 2012.  Several issues had been agreed upon prior to the meeting and others were agreed to at the meeting.  Among the recommendations agreed upon were:

1. Subjects entered into negative symptom trials should have no fewer than two negative symptoms and at least one should be rated as moderate or greater. 
2. Ratings for negative symptoms should include a single global score.
3. Ratings for negative symptoms should include global scores for major domains such as expressiveness and apathy/asociality.
4. Subjects currently treated with clozapine should not be excluded in negative symptom trials of co-medication.
5. Patients in proof-of-concept studies should be under the age of 65.
6. Patients should be excluded for the presence of depressive symptoms that do not overlap with negative symptoms.  Patients with a co- diagnosis of MDD should be excluded.
7. Functional measures should not be required as co-primary endpoints but they should be key secondary measures. 

Some of the issues agreed to at the NewMeds meeting were discussed and debated.  Should the population be one where negative symptoms predominate?  Should global measures be used?  Are apathy and asociality the symptoms most sensitive to drug effects?  It was suggested on the last point that the answer to the last question will depend on the mechanism of action of the drug.   Avolition, apathy, and amotivation responded best and correlated well with function. 

There was agreement that items measuring negative symptoms have function embedded within them.  Functional endpoints are useful if the clinical relevance of an endpoint is not understood.  Both the NSA and the PANSS were thought to correlate well with functional outcomes. 

The question of whether we are targeting a subset of patients with predominant negative symptoms or whether these symptoms were symptoms of schizophrenia in general was discussed at length.  While there was not full agreement, the majority seemed to believe that the is a distinct subset of patients with predominant negative symptoms and these patients, and not patients with simply prominent negative symptoms should be the population studied, at least in phase 2 studies. 

Future Plans: 1) Address the following unresolved issues: a) Subject selection with respect to predominant vs. prominent negative symptoms and age; b) most appropriate indicators of clinical stability; c) best tools for interview based and objective  negative symptoms assessment ; d) selection of functional capacity and real world functioning tools for negative symptoms trials; differentiation of depressive and negative symptoms. 2)  Monitor results of ongoing clinical trials as they impact methodological issues and potentially publish an update to the working group’s previous publication in Schizophrenia Bulletin.  

Co-chairs: Hank Riordan, PhD; Steven Potkin, MD

The fall dinner session was hosted by Henry Riordan, Paul Song and Steve Potkin.   Dr. Riordan began the session by recounting the reasons for the formation of the BWG including the need to ensure that the interests and expertise of the International Society for CNS Clinical Trials and Methodology are thoughtfully considered and communicated to the Society’s members updating attendees regarding the mission and activities of the BWG.  By way of background he reasserted the important role of various biomarkers in informing clinicians about the relative safety, tolerability and efficacy of a range of CNS drugs and products.  In addition, biomarkers can aid in the development of novel therapeutic agents, identify susceptible populations, provide endpoints for clinical trials and even serve as predictor variables.  As such an emphasis of the BWG is to determine which imaging biomarkers are predictive of treatment response.

Dr. Riordan briefly reviewed the process and methodology utilized by the BWG to offer support for imaging biomarkers in future schizophrenia trials.  He then briefly summarized the qualitative evaluation of the utility of imaging biomarkers in schizophrenia as a measure of treatment response. Schizophrenia treatment studies that included the structural or functional imaging modalities, including vMRI, fMRI, FDG-PET, receptor occupancy PET & SPECT, and DTI were identified, categorized, and evaluated with strongest evidence being in support of volumetric MRI which exhibited the highest overall qualitative rating.  Therefore, this imaging modality was chosen for more quantitative analyses.  Brain regions examined included whole brain, lobar volumes, basal ganglia and ventricular volumes, as well as grey and white matter.  Analysis of intervention effects on brain volume revealed a moderate but non-significant overall effect size. However, significant decreases in brain volume were associated with treatment were noted for a total white matter that was seen early in treatment and grew in response to study duration.  Interestingly some evidence was also noted for an increase in grey matter for two atypical antipsychotic medications.  An analysis of homogeneity including all studies revealed no significant variance among effect sizes that would support examining the effects of moderator variables While these initial results did not fully support the qualitative evidence grading they did suggest that it is

Paul Song then reviewed the process and services offered by Dr. Evidence that could potentially be utilized by the BWG in future activities.  The mission of Dr. Evidence is to improve clinical outcomes by finding, delivering, and making relevant and readable medical evidence that enables clinicians to support informed decisions.  This is accomplished through a suite of evidence based medicine methodologies and analytic tools that are unified in a singular technology platform.  The services most likely to be utilized by the BWG include a comprehensive library management system equipped with a robust search engine, data extraction and quality control with accompanying QUOROM charts to identify why studies are not chosen for evaluation, automated evidence tables, and meta analysis complete with funnel and forest plots.  Importantly, once data is extracted the meta analysis tool is customizable so that effect sizes can be obtained for subsets of studies and even types.  Corroboration of the prior quantitative results via meta analysis with a QUOROM Flow diagram of rejected references is planned.

Finally Steve Potkin reviewed the literature suggesting the power of an integrated approach to biomarkers by assessing brain imaging and genetic factors simultaneously to provide new targets fordrug development, enrich study populations for Proof of Mechanism and Target Engagement studies. The function of genes on behavior can be determined by brain imaging. Brain function is strongly influenced by genetic factors; therefore,  studying  the integration of imaging and genetics offers the possibility of greater understanding that studying each independently.

Chairs:  Larry Alphs, MD, PhD; Michael Davidson, MD

This session will examine different approaches to conceptualizing the pathophysiology of schizophrenia and how these conceptual models differentially affect treatment development.  The session will open with presentations on the challenges facing the field in terms of identifying new treatments for schizophrenia. This will be followed with conceptualizing schizophrenia as  1) a disease of neurotransmitters; 2) a genetic disease and 3) as a disease of neurocircuits.  It is recognized that these conceptualizations are not necessarily mutually exclusive, but presentations supporting each of these viewpoints will attempt to demonstrate how these different ways of conceptualizing schizophrenia will lead to different approaches to developing treatments in terms of study design, methodological hurdle, statistical challenges and regulatory impact.  Issues will be identified and initial solutions presented followed by discussion amongst the speakers’ panel and the audience.