Risk-Based Monitoring in Clinical Trials: A Cross-Functional Approach Sharon Herbert, PhD. - Senior Medical Research Manager Tyson Rogers, MS - Senior Principal Medical Research Biostatistician
Clinical Trial Risks Inadequate human subject protections Untrained investigators / coordinators Inaccurate data Incorrectly performed study procedures Unreported adverse events Fabricated data Monitoring on-site is the traditional tool to detect these events Relatively effective, but costly and inefficient
What is Monitoring? Monitoring is a quality control tool for determining whether study activities are being carried out as planned, so that deficiencies can be identified and corrected 1. Traditional Monitoring: Monitoring a clinical trial by applying the same rules to each site / subject On-site & 100% SDV Risk-Based Monitoring (RBM): Monitoring a clinical trial by identifying risks to patient safety and data quality and then tailoring monitoring methods to address those risks. RBM may include: Centralized monitoring Targeted monitoring Reduced monitoring Remote monitoring 1 US FDA Guidance: Oversight of Clinical Investigations A Risk- Based Approach to Monitoring. August 2013
Risk-Based Monitoring Centralized Monitoring Reduced Monitoring Risk- Based Monitoring Targeted Monitoring Remote Monitoring An adaptive approach to monitoring that directs monitoring focus and activities to the evolving areas of greatest need, which have the most potential to impact subject safety and data quality.
Benefits of RBM over Traditional Monitoring? Not just: Reduced SDV and remote monitoring Reduction in overall cost Identify and prioritize risk Improve data quality and accuracy Mitigate risk Make data-driven decisions Improve patient safety
Transition to Risk-Based Monitoring is underway UK MRC/DH/MHRA Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products. October 2011. US FDA Guidance Oversight of Clinical Investigations A Risk-Based Approach to Monitoring. August 2013. European Medicines Agency Reflection Paper on Risk Based Quality Management in Clinical Trials; EMA/269011/2013. September 12, 2013. Japan Ministry of Health Basic Rules of the Risk-Based Approach to Monitoring Clinical Trials. July 2013 International Council for Harmonisation (ICH) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). June 2015 (expected to take effect in 2016)
Key to Effective Risk-Based Monitoring? TECHNOLOGY??? CROSS-FUNCTIONAL APPROACH Assess study risks Tune mix of centralized, targeted, reduced, and remote monitoring Align site training with risk assessment Tailor key risk indicators (KRIs) to study Interpret metrics / analyses Effective action and resolution All of the above depend on an expert cross-functional team
Critical to have the right RBM partner Growing expectation from regulators that sponsors can: Provide documentation of a detailed risk assessment Provide clear rationale for choosing one monitoring strategy vs. another, that is documented Demonstrate appropriate oversight and follow-up Demonstrate the process is data-driven Provide an audit trail of actions and adjustments made during the course of a study
NAMSA s Risk-Based Monitoring Philosophy NAMSA takes a cognizant and thorough approach to creating and implementing global Risk-based Monitoring NAMSA applies an interactive approach to continually assess the data integrity and patient safety at the site and study levels NAMSA utilizes technology, cross-functional tools, intellect and resources to provide easyto-use reports for Risk-based Monitoring Focused, adaptive, customized, cross-functional approach: Upfront planning Ongoing data review Faster data-driven decisions Improved data quality
NAMSA Implementation of RBM Study Risk Profile (SRP) Risk- Based Monitoring Plan (RBMP) Centralized Data Monitoring Plan (CDMP) Periodic Review of RBM Site Metrics (Dashboard)
NAMSA s Risk-based Monitoring Approach Risk-based Planning Joint effort by Sponsor and a cross-functional team from Clinical, Data Management and Biostatistics Assess if the design and regulatory phase of the protocol are amenable to RBM Determine critical data and processes Develop study-level monitoring plans that incorporate risk assessment and mitigation Focus remote, centralized and on-site monitoring efforts on critical data and processes in order to achieve high quality compliant data with the most efficient utilization of resources
NAMSA s Risk-Based Monitoring Approach Data-driven statistical modeling of site-level risk based on rates of protocol deviations and AEs time to closure of monitoring action items and data queries subject withdrawal rates frequency of missed visits time to data entry coordinator engagement, PI oversight Utilize results to modify amount and type of site oversight as needed in order to preserve data and compliance integrity
NAMSA s Risk-Based Monitoring Approach Monitor Training Monitoring strategy & criteria that will drive adjustments to the strategy Activities performed onsite vs. remotely RBM-specific monitoring visit reports Communicating monitoring findings & following up on action items triggered by centralized monitoring Increased communication with sites Site Training Discuss RBM expectations during site qualification visits Source document transmission to support remote monitoring Electronic Trial Master File (etmf) Address concerns regarding increased burden on sites
Planning for Risk-Based Monitoring Develop Risk Profile and Identify Critical Data and Processes Determine Metrics for Effective Oversight Study Level Risk Perform Risk Assessment Relative to Critical Data and Processes Develop Monitoring and Mitigation Strategies to Address Risks
Implementation of Risk-Based Monitoring Implement Type and Level of Oversight From Monitoring Plan Continuously Review Metrics of Oversight Effectiveness Site Level Risk Update Study Level Risk Assessment as Necessary Mitigate Risk with Targeted Action (site follow- up, on- site monitoring, CAPA, etc.)
Study Oversight Metrics and Statistical Modeling Time to closure data queries and monitoring action items Rates of protocol deviations Time to data entry Subject withdrawal rates Frequency missed visits High/Low AE rates High/low procedure failure High/low within or between site variance Coordinator and PI engagement Site Level Risk Metrics of Oversight Effectiveness
Risk Metrics and Threshold Customization Identification of critical protocol deviations Key inclusion/exclusion criteria Correct device use Endpoint assessments Tolerable attrition / missing data rate Historical studies Sample size calculation assumptions Site performance expectations Time to data entry Response to queries Sensitivity level for adverse event rate variation
Risk Metrics Review Objective and Subjective Metrics Green/Yellow/Red Thresholds Adapt to Volume of Data Overall and Recent Time Window Risk Mitigation Action Tracking and Trending Dashboard + Drill-Down Detail Augmented by statistical data anomaly detection
Evidence for RBM & Centralized Statistical Monitoring TransCelerate Recent publication 1 on detection of fabricated data (3-10% prevalence) showed sensitivity ~80%, specificity ~70% Need to account for number of enrollments to determine site threshold ADAMON trial Compare traditional 100% SDV to riskdetermined monitoring strategy TEMPER study Evaluate metrics/thresholds by comparing triggered sites to matched untriggered sites on proportion with major finding NAMSA To conduct case study with 100% SDV performed after completion of RBM to evaluate any missed findings 1 Knepper D, et.al. Statistical Monitoring in Clinical Trials: Best Practices for Detecting Data Anomalies Suggestive of Fabrication or Misconduct. Drug Information Journal March 1, 2016 50: 144-154
Takeaways Risk-Based Monitoring is becoming the standard Ongoing evaluation of data integrity and study/site risk Tailored to study Sophisticated technology platform is not sufficient Requires expert cross-functional team integration into standard processes (with documentation)
Questions / Contact If you have any questions for our presenters, please email them to education@namsa.com.