We examined the benefits of combining operational risk identified by routine data monitoring by the sponsor, with clinical risk identified by Cronos’ proprietary data monitoring algorithms applied to the Clinician-Reported Outcomes (e.g., PANSS, CGI-S, C-SSRS, PSP), in an ongoing, phase 3 schizophrenia trial. Of the 122 sites in 20 countries, 9% had no operational or clinical risks, 7% had operational risks only, 30% had clinical risks only, and 53% had both operational and clinical risks. While often considered independently, the correlation between risk factors suggests a cumulative score is important in understanding the full picture, i.e., whereas a site may appear reasonable from an operational or clinical perspective alone, the combination provides a clearer indication of true risk and an opportunity for earlier mitigation. The results were presented at the International Society for CNS Clinical Trials and Methodology (ISCTM) 15th Annual Scientific Meeting, Washington, DC, USA (February 2019).

Cronos aggregated metrics from 5 global psychiatry studies where sites used the role-based and criteria-based workflow scheduling tool, CIRP, to coordinate study-related events across multiple vendors and patients. Activities included online scheduling of blinded, remote raters for conducting clinical assessments, and automated reminders to patients to perform at-home biometric sampling. Of the 24,000+ completed activities, more than half encountered some form of operational disruption that had the potential to impact protocol compliance. By using a system that allows operational burden to be monitored in real time, preventative actions can be taken to minimize the risk to data completeness and quality. Brian K. Saxby, PhD, Vice President of Business Development, presented the results at the CNS Summit, Boca Raton, FL, USA.

Cronos analyzed data from a double-blind, placebo-controlled, multicenter study of an adjunctive treatment to a monoaminergic antidepressant in adults meeting DSM-5 diagnostic criteria for Major Depressive Disorder (MDD) to determine the presence and frequency of an anxiety-somatization factor on the HAM-D, and if this presence impacted treatment response. Dr. Christian Yavorsky, Chief Scientific Officer, presented the results at the International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn Conference, Marina del Rey, CA, USA (October 2018).

The methodological considerations and system requirements necessary to establish an effective, real-time, risk-based data monitoring platform in CNS trials are examined in a paper published in Therapeutic Innovation & Regulatory Science. Dr Cynthia McNamara, Director of Clinical Operations, and colleagues from Cronos co-authored the paper in collaboration with William (Bill) Potter from the National Institute of Mental Health. The article presents specific considerations for CNS studies where endpoints are more subjective, relying on Clinician-Reported Outcomes (ClinROs) and Patient-Reported Outcomes (PROs) to determine efficacy. Key risk indicators are discussed, alongside issues of inadequate rater training, rater drift, and potential fraud, as well as the need for a prospective plan of corrective and preventive actions. When applied correctly, real-time monitoring of clinical ratings in CNS trials has the potential to minimize risk and enhance the quality of clinical trial data.

Using the Rater Applied Performance Scale (RAPS), we reviewed audio recordings of 550 MADRS assessments conducted over the telephone in a global clinical trial of depression to determine if the clinical interview skills of remote raters were related to scoring accuracy. We also evaluated the relationship between the severity of illness and rater performance. Dr. Nina Engelhardt, Director of Clinical Content, presented the results at the International Society for CNS Clinical Trials and Methodology (ISCTM) 14th Annual Scientific Meeting, Washington, DC, USA (February 2018).

Dr. Christian Yavorsky, Chief Scientific Officer, co-authored a review in the current edition of Innovations in Clinical NeuroScience (ICNS) on the challenges and solutions for maintaining the consistency of PANSS ratings in clinical trials. The article brings together leaders in the field from Cronos, MedAvante-ProPhase and Bracket to present the current thinking and future directions. Particularly relevant to the work we do at Cronos is the impact of in-study data monitoring, combining data-based algorithms with expert clinician reviews to mitigate rater drift and reduce the impact of non-informative data throughout the course of a trial.

Dr. Christian Yavorsky, Chief Scientific Officer, and Dr. Nina Engelhardt, Director of Clinical Content, presented data from a double-blind, double-randomization, placebo-controlled study of the efficacy of intravenous esketamine in adults with Treatment-Resistant Depression (TRD). The study, sponsored by Janssen, showed that esketamine has a different response profile to existing classes of antidepressants, and that the Montgomery-Asberg Depression Rating Scale (MADRS) effectively captured the rapid changes in mood. The results were presented at the American College of Neuropsychopharmacology (ACNP) 56th Annual Meeting, Palm Springs, CA, USA.

Cronos CCS, Inc. is delighted to announce the appointment of Brian K. Saxby, PhD, as Vice President of Business Development. Dr. Saxby has worked in the clinical trial industry for almost two decades, and held a number of scientific, business development and management positions. He brings a wealth of knowledge of neurology and psychiatry trials, and has published over 30 papers on topics including depression, dementia, stroke, hypertension and aging. Dr. Saxby has a proven track record of product and service development, and we are excited to welcome him to the Cronos team. His appointment strengthens our ability to help clients meet the logistical and measurement challenges of conducting CNS clinical trials.

The Cronos Integrated Research Platform (CIRP) has been enhanced for use on mobile devices (e.g., smartphones, tablets), and all iOS, Android, and Windows operating systems. CIRP is utilized to proactively eliminate clinical trial protocol violations through implementation of protocol-specific validations and effective management of communication. This latest release maintains the same ease of use, while making the system even more convenient and accessible.

Cronos CCS, Inc. has completed a multi-year study with the prestigious Dutch research institute, The University of Groningen, Neuroimaging Centre, demonstrating the equivalence of Cronos PANSS training to that traditionally taught to medical students. The Cronos e-module, which can be completed in 3 hours, was shown to be equivalent to the traditional two-day group course. The results were presented at the Schizophrenia International Research Society conference, held in Florence, Italy, in 2016 as well as at the Phrenos Psychosecongres, in Zwolle, Netherlands. Cronos e-learning innovations save resources without compromising assessment quality or rater performance.

Dr. Christian Yavorsky, Chief Scientific Officer, presented strong evidence for the value of risked-based monitoring (RBM). In all cases utilizing Risk-Based Data Monitoring, the sample size needed for hypothesis testing was reduced from the original by at least 30%, with the un-blinding sample size re-estimation following Risk-Based Data Monitoring showing the most significant reduction in the number of subjects needed. Using an adequate sample size with high quality data collection through RBM could result in more reliable results, more timely trials and fewer resources.