13th Annual Working Group Dinner Session Descriptions
Abuse Liability: A lethal combination: Clinical trial design considerations to evaluate the nature of opioid and benzodiazepine interactions (Setnik, Sokolowska, Klein)
During this session, study methodologies will be discussed to further evaluate and characterize opioid-benzodiazepine and other drug interactions with CNS drugs that may pose serious safety concerns. Furthermore, such studies may also evaluate the potential of new analgesics or sedatives that may have decreased risk of respiratory depression. Considerable variability exists between studies in terms of the criteria for defining respiratory depression.
Furthermore, a discussion of defining clinically meaningful respiratory depression in the context of a clinical trial will be held. This session will introduce non-invasive methods to evaluate respiratory depression in a clinical setting evaluating the safety risks associated with drug-drug interactions in healthy volunteers.
Behavioral and Psychiatric Symptoms in Dementia (Ereshefsky, Miller, Pani)
1. Collaboration between ISTAART, NPS PIA and ISCTM BPSD WG
Co-Chairs – Krista Lanctôt, Joanne Bell PIA
• Report on joint NPA PIA and BPSD ISCTM activities including featured research symposium submitted February 1st to AAIC
• Other activities related to ongoing collaborations, including ISCTM involvement in the PIA Day and Paris ISCTM meeting
2. Discussion with drug sponsors providing insights:
• Agitation/Psychosis/BPSD (lessons learned, update on drug development strategies)
3. Apathy
• How do lessons learned from sponsor-regulatory experiences guide our development of a strategy to facilitate tx of apathy in dementia?
Pseudospecificity, diagnosis, assessment, primary and secondary endpoints, effects of the progression of illness
• To assess the feasibility/desirability for ISCTM to support a consensus group.
–Identify necessary steps (workshops and ISCTM programming).
–Activities required beyond meetings and conference calls
• Identify opportunities and pathways for collaboration with the Biomarkers Consortium even though the FNIH Endpoints Working Group was not funded
4. Neurocircuitry/Biomarker strategies
• How do reward and hedonic pathways relate to apathy studies in AD?
• Discussion on role of MBI (mild brain injury) in apathy, neurocircuitry/biomarker studies, differentiation with depression?
5. Deliverables:
• FRS proposal in collaboration with ISTAART PIA submitted by February 2017 -Done
Final adjustments to the program for ISCTM Paris 2017
• Identification of additional ISCTM supported activities to move towards a consensus group on treatment of Apathy in AD
Prevention Trials of Alzheimer’s Disease – Ongoing Optimization and the Roles of Biomarkers and Cognitive, Performance, and Functional Assessments (Posner, Harvey)
This working group has recently been focusing on prevention trials and our previous two publications concentrated on optimal trials design and performance/cognitive outcome measures. In the execution of clinical development for new compounds, however, there has been a movement toward the rapid assessment of treatment strategies centering on biomarkers. In this next meeting we will compare and contrast biomarkers versus performance based and cognitive outcome measure for both subject selection and outcome measures.
Cognitive Dysfunction (Parker, Fava)
Background: There is increasing evindence supporting that cognitive dysfunction in psychiatric disorders is not limited to Dementia or Schizophrenia but may also play a key role in additional disorders, including those such as mood disorders that are episodic in nature. Cognitive dysfunction has been recognized as an important feature of bipolar disorders, and a recent Institute of Medicine panel convened to discuss the role of cognitive dysfunction in Major Depressive Disorder (MDD). Addtionally, at a recent Advisory Committee, FDA endorsed the idea of Cognitive Dysfunction as a legitimate target for drug development. Further evaluation of approaches for rigorous evaluation of cognitive dysfunction in the context of psychopharmacological studies appears warranted.
Objective: To further advance the understanding of cognitive dysfunction in psychiatric disorders and, with a diverse group of stakeholders, provide guidance on potential development pathways for future therapeutics.
Methodological Challenges in International CNS Clinical Trials (Kalali, Pappadopulos)
While great progress has been made with expert and regulatory guidelines for the cross-cultural adaptation of patient reported outcomes (PROs), similar guidance for ClinROs have yet to be established. At the spring session, the working group members will continue their work refining, gathering input and gaining consensus on the draft guidelines for Clinician Rated Outcomes (ClinROs). To date, the working group has reviewed the literature and developed a draft position on ClinRO translation and adaptation for international clinical trials. These guidelines will not revisit well-established standards for technical translation/adaption, but rather focus uniquely on CNS measures with the goal of maintaining measure integrity and validation while balancing the ideal/desirable versus what is possible/realistic in the current CNS drug development environment. As we are reaching our objectives with the current project, we will also conduct a survey and gather recommendations for the future goals and deliverables
Missing Data (Lim, Samad)
In the 2014 concept paper for the ICH E9 (Revision 1) “Addendum to Statistical Principles for Clinical Trials on Choosing Appropriate Estimands and Defining Sensitivity Analyses in Clinical Trial”, the authors emphasized the need for a “golden thread” linking clear trial objectives with selection and prioritization of endpoints and hypotheses for statistical testing or targets for estimation. The authors make the case that this “golden thread” could be provided by a clear description of what was to be estimated by the analysis – the “estimand” of the analysis, and also noted the ‘Absence of a framework for conducting and interpreting sensitivity analyses.’ These problems could lead to inconsistencies in inference and decision making within and between regulatory regions. Consequently, an ICH E9(R1) Expert Working Group has been formed to provide recommendations on these problems, with a draft Addendum expected to be released in the second half of 2017.
During the Feb 21st ISCTM Missing Data Working Group meeting, the framework (to be recommended by the future ICH E9 Addendum) for setting objectives and estimands for a clinical trial will be discussed in the context of different clinical decisions and perspectives, as well as disease and treatment considerations. CNS clinical trial examples will be used in the discussion. This framework will create the foundation for the selection of the design, primary and sensitivity analyses for a clinical trial in the presence of missing data and other treatment confounders.
Negative Symptoms (Marder, Daniel)
Schizophrenia clinical trials utilizing negative symptom endpoints remain challenged by issues such as high placebo response, measurement error, secondary effects from improvement in positive symptoms and potential different pharmacological responses of different negative symptom domains. This may explain – in part – the confusing results from recent trials. At the most recent meeting of the ISCTM Negative Symptom Workgroup it was decided to reconvene when new information from trials is available. With this in mind, the group will discuss the new results and when available, data mining of recent negative symptom trials with the aim of informing future methodology. An update on the performance of negative symptom endpoints such as the BNSS will be presented as well.
Mitigating Nonadherence (Shiovitz, McCann)
Nonadherence is a substantial problem in clinical trials and contributes to study failure. This working group has published its recommendations on ways to mitigate the effects of nonadherence in clinical trials (Shiovitz et al., J Clin Pharmacol 56: 1151, 2016). Such recommendations, however, can only be effective if stakeholders are made aware of them in a way that facilitates their implementation. At the February, 2017 ISCTM meeting, the nonadherence working group will continue to discuss ways to promote awareness of the recommendations. The group will also discuss a new ISCTM initiative on obtaining sponsor data to answer key methodological questions (e.g. relationship of study size and other factors to study success, effects of nonadherence and nonadherence mitigation strategies). What questions should be addressed? What data should be obtained from sponsors? Is this initiative feasible?