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Objective of the working group will be to review the final version of the white paper and get approval for submission from the group by consensus. Presentations given will be aimed at resolving any issues that arise during the writing.

Biomarkers – Minimum Standards Initiative Working Group Dinner Session

The Biomarkers Working Group will primarily focus on biomarkers associated with schizophrenia. It has completed its work on imaging biomarkers and will now address non-imaging biomarkers in schizophrenia, and an additional focus on minimum standards.

The FDA is developing a list of minimum standards for submitting and reporting clinical trials. The lack of minimum standards of information has limited the development of generalizable biomarkers and hampered meta-analyses. The ISCTM Biomarkers Working Group dinner will develop input based on its methodological experience to support the FDA in their work on the minimum standards initiative.

Developing Treatments for Schizophrenia in the 21st Century: Preventing Disease Progression—A Novel Paradigm for Research

Since the revolutionary introduction of antipsychotic medication over 60 years ago, little progress has been made in the treatment of schizophrenia. Research since that time has largely focused on the acute and long-term management of positive symptoms and on improving the safety profile of medications. Additional progress towards improving quality of life, functioning, and long-term outcome of persons with schizophrenia that was anticipated in the years immediately following the discovery of antipsychotic treatments has not been realized. Instead, recidivism, hospitalization, incarceration and suicide rates remain high, and overall quality of life remains unsatisfactory.

In particular, little effort has been devoted to understanding the progression of schizophrenia. The disease follows a relatively benign course in some patients, while there is a significant deterioration in all aspects of behavior, functioning and quality of life in many patients. It is unclear if the disease is characterized by brain changes over time that account for the worsening of symptoms, or the changes that appear later reflect the consequence of the initial insult. Indeed, we have little true understanding of phenomenology of its progression or the biological processes underlying it. For example, we do not know if schizophrenia progresses uniformly across the spectrum of patients with the condition nor which, if any, of the symptom domains are reversible at any point after the onset of the disorder. Prediction of which patients will progress is hampered by lack of phenotypic and genotypic markers. Biological correlates of progression have not been reliably identified. The absence of this knowledge means that our ideas about what and how to target changes in disease progression are at best speculative. Further, we are not really sure of what should be measured when trying to develop treatments that modify treatment progression.

The new frontier in managing schizophrenia must be to arrest , or significantly attenuate the progression of the disease after the first episode. Achievement of significant breakthroughs in schizophrenia requires knowledge of how, and in whom does the disease progress, what domains does progression affect, what measures can chart the worsening, what separates the patients who progress from those who do not, and what influences the rate of progression. The answers to these and similar questions need to be addressed prior to identifying biological mechanisms that could influence modulate disease progression in schizophrenia. Experience suggests that it is unlikely that modulation of neurotransmitters alone will achieve meaningful and long term benefits to patients, or alter the course of the disease.

Academia, industry, and governments must work together on identifying and filling the knowledge gaps for this endeavor to be viable. This ground-breaking session will include an international , multi-disciplinary faculty of speakers who will examine the concepts and challenges faced in developing new treatments that may modify the course of schizophrenia. The longitudinal course of schizophrenia will be reviewed and measures that could characterize the progression of symptom domains, and/or biological markers that correlate with disease progression will be examined. In addition, we will discuss directions for identifying better disease modifying treatments as well as considerations regarding the design of clinical trials required to demonstrate disease modification. This will include discussion of the regulatory and developmental challenges associated with such treatment development.

Innovations in Clinical Trials: Opportunities for Research Using Practice-Based Networks

Co-chairs: Robert Heinssen, PhD; Joanne Severe, MS

Traditional randomized clinical trials (RCT) are considered the “gold standard” for inferring causality. Three elements that make RCTs so valuable are: randomization to treatments for control of systematic bias, standardization of the interventions being tested, and independence of evaluation. But RCTs are expensive, often take a long time to yield information, and are limited in generalizability due to several factors including patient selection and the rigors of clinical trial methodology. This session will seek to define the potential role of the practice-based patient setting in CNS intervention development and refinement. It will explore whether the most highly valued attributes of RCTs can be achieved on practice-based networks, or if not, do the networks provide other ways to address reduction of bias and clarity of the interventions? Can data already being collected as part of routine clinical care satisfy the standards of research data? Are there advantages to practice-based networks such as long-term history data and the ability for longer-term follow-up that are especially valuable? The session will also aim to help identify the circumstances where practice-based networks will not be useful so that researchers may invest in “traditional” more costly RCTs where they are likely to have the greatest return.

Speakers will address the following issues: A National Institute of Mental Health perspective on an agenda for intervention development and testing in CNS mental health from experimental targets through comparative effectiveness research; development and experience with innovative clinical trial methods utilizing practice-based networks in non-CNS research at the National Heart Lung and Blood Institute; experience from the Mental Health Research Network using a data warehouse and EMR data in setting up clinical trials; the potential role of practice-based networks in CNS development from an industry perspective; and a biostatistical and methodological view of the potential pitfalls and biases in interpretation and generalizability of clinical trials launched on such networks.

Taking Personalized Medicine Seriously – Biomarker Approaches in PhaseIIb/III Studies in Major Depression and Schizophrenia

The efficacy of standard antidepressants in comparison to placebo is low. Approved standard of care antidepressants lead to just one more responder out of ten patients in comparison to placebo. There is also a trend toward smaller effect sizes and higher failure rates for schizophrenia trials. This is possibly due to variability among patients diagnosed with either depression or schizophrenia, both from a perspective of syndromal differences, but more so on a pathophysiological level. The aim to identify a suitable compound for a given subject for either disorder is far from being achieved, but the foundations have been laid. With the progress of easy to handle functional biomarker approaches this goal has now become feasible. One distinction in the utilization of these methodologies is important: 1. characterization of baseline pathology; 2. characterization of (dose related) target engagement for a given subject. Following a presentation of the regulatory environment and requirements for acceptance of biomarkers, case studies will be presented to showcase feasibility and opportunities of this approach in both depression and schizophrenia.

1. Thomas Laughren, Laughren Psychopharm Consulting: “Regulatory aspects of the use of predictive biomarkers in late stage clinical development of psychiatric drugs”.

2. Femke Lamers; Psychiatric Clinic of the University of Amsterdam, Netherland, PI of the NESDA study: “Biological differentiation of depression subtypes: Salivary Cortisol, inflammatory markers, heart rate variability”.

3. Rosalind Picard, MIT, Boston: “Physiological sensor technology for objective clinical data in psychiatry”.

4. Harald Murck; Covance, Princeton and Psychiatric Clinic of the Philipps-University Marburg, Germany: “Target based biomarker selection – mineralocorticoid receptor related biomarkers and treatment outcome in depression” (Highlights the combination of slow wave sleep, heart rate variability, salivary endocrine markers for a functional characterization of mineralocorticoid function and its change during antidepressant treatment)

5. Sebastian Walther; University Clinic, Bern, Switzerland: “Actigraphy for the differentiation of schizophrenia subtypes – effects of medication”.

2013 Autumn Conference Poster Awardees

Innovations in Clinical Neuroscience – ISCTM Supplements

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2013 Autumn Workshop: Biomarkers: The Advantages and Challenges of Sharing Biomarker Data

Co-Chairs: Steven Potkin, MD; Larry Alphs, MD, PhD

Recent advances in brain biology, neuroimaging technology and genetics have greatly expanded our understanding of neuroscience; however,they have yet to lead to novel treatment interventions. The advent of noninvasive neuroimaging techniques such as diffusion imaging and resting-state functional magnetic resonance imaging (MRI) has led to the development of the new field of connectomics, where neuronal connectivity is comprehensively mapped at the macroscopic level (studying long-distance pathways for the whole brain) and at the microscopic level (studying axons, dendrites and synapses in a small region of the brain). Similarly, recent developments in virtual computer modeling techniques now allow for assessment of abnormalities at the cellular level and exploration into the ways that they contribute to neuropsychiatric disease symptoms, thus providing vast new insights into how more effective treatments can be developed. While this progress has enormously expanded our potential to understand and address the etiological basis of brain dysfunction, it has not yet been matched by major treatment breakthroughs. For example, psychotic disorders remain poorly understood and continue to represent a significant and, indeed, increasing global disease burden. In fact, considerable genetic, imaging, and treatment response data has been collected by both industry and academia. However, to this point this information has not been optimally shared so as to maximize it value for drug development and so support better treatment for those suffering from psychotic disorders. This workshop will provide an update on an initiative begun at ISCTM 3 years ago on how to bring pharmaceutical industry databases together in a non-competitive environment to accelerate the development of novel neuropsychiatric treatments using some of the emerging techniques of big data management and modeling. Opportunities, challenges and next steps in the organization of this consortium will be discussed.

2013 Autumn Conference – A Return to Rational Drug Development: De-Risking Phase 3 Development Through Rigorous Early Phase Drug Evaluations

Co-Chairs: Steven Romano, MD; Richard Keefe, PhD

Over the past several years, we have seen a movement of R&D investment out of CNS drug development and into disease areas where a better understanding of human biology and genetics can lead to greater confidence in the identification of relevant targets and the advancement of specific pharmacological therapies. R&D funding, even in some of the largest pharmaceutical companies, is limited and this has led to intense competition for dollars and a shift of portfolios towards other areas of medical need such as diabetes, oncology and inflammation. How might those of us working on CNS disorders help to reverse this trend? Many of our attempts to improve the success of our CNS development programs have been directed at the challenges of Phase 3 design and conduct. But other solutions lie earlier in drug discovery and research, with the acknowledgment that if early phase development can resolve certain key risks, late phase development success will be significantly enhanced. This meeting will address these developmental challenges, highlighting the fundamentals of early phase development. The session will also address the process of moving from early phase development to full development, and the operational complexities associated with executing global development programs.

Author Archive

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