Approaches to Risk-Based Monitoring

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Presented by Sherrie Reynolds, QA Supervisor, Clinical Trials Unit, Seidman Cancer Center; Joy Ostroff, RN, BSN, OCN, Administrative Director - Clinical Research, UNC Cancer Network, UNCH Lineberger …

Presented by Sherrie Reynolds, QA Supervisor, Clinical Trials Unit, Seidman Cancer Center; Joy Ostroff, RN, BSN, OCN, Administrative Director - Clinical Research, UNC Cancer Network, UNCH Lineberger Comprehensive Cancer Center

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  • Plan – Quality objectives and metrics, risks to quality; quality management
    Do – Conduct study
    Check – Measure/monitor
    Act – Respond to deviation
  • Risk:
    Patient and institution
  • 4 tables, 8-10 people at a table = 40
  • Tab


  • 1. Joy Ostroff, RN, BSN, OCN© Administrative Director, UNC Cancer Network Sherrie Reynolds, RN, BSN, CCRP® QA Supervisor Seidman Cancer Center Risk-Based Monitoring Onsemble September 18, 2013
  • 2. Overview • Past methods of monitoring – Resource intensive – Applied uniformly through life of the trial – High cost • $1.2 billion (pre-clinical to market) • 25-30% of clinical trial costs – No quarantine of good data, compliance, or safety • Health authorities transition to risk-based approach • Institute of Medicine (IOM) reports US Cancer Crisis • AACI CRI supports SIG looking for ways to explore, define and operationalize best practices
  • 3. IOM Report (9/10/2013) “Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis” • • • Crises – growing demand – costs of cancer care – shrinking work force – complex disease and treatment 1.6 million new cases each year (14 million survivors) 2.3 million (45% inc.) new diagnoses 2030 (18 million survivors) Year Cost of Cancer Care 2004 72 billion 2010 125 billion 2020 173 billion
  • 4. Recommendations • Engage patients • Adequately staffed, trained, and coordinated work force • Evidence-based cancer care • A learning health care information technology system • Translation of evidence into practice, quality measurement, and performance improvement • Accessible and affordable cancer care – Fee-for-service reimbursement system encourages a high volume of care, but fails to reward the provision of high-quality care
  • 5. Change Monitoring Practices • Rising costs of clinical trials – More sites, less patients at each site – Complexity of the trial – Wider geographic area (International) • Real time assessment – Study status ,data, site performance • Acceptance of adaptive approach – Scientific and business models • Acceptance by regulatory agencies and health authorities • EMR, CTMS, Internet
  • 6. Health Authorities Transition to Risk-Based Monitoring Federal Drug Administration (FDA) • Guidance on Monitoring of Clinical Investigations, 1988 • Guidance on Providing Clinical Evidence of Effectiveness for Drug and Biological Products, acceptance on different levels of documentation of data quality, 1998 • Human Subject Protection/Bioresearch Monitoring (HSP/BIMO) Concept Paper, 2007 • Guidance for Industry Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring, Draft 8/ 2011 • Guidance for Industry Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring, Procedural 8/ 2013 International Conference on Harmonisation (ICH) • ICH E6 addresses flexibility in how trials are monitored which includes reduced or no on site monitoring, 1996 European Medical Agency (EMA) • Reflection Paper, 2011 Medicines and Healthcare products Regulatory Agency (MHRA) UK • Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products, 2011 The Clinical Trials Transformation Initiative (CTTI) • Public-private partnership (2007) identifying practices to increase quality and efficiencies TransCelerate BioPharma • Risk-Based Monitoring Methodology, Position Paper (2013)
  • 7. Monitoring vs. Auditing Monitoring Auditing - Continuous process - On-site/off-site - All patients on trial - Snapshot in time - On-site - Subset of patients - Data driven - Compliance driven
  • 8. Risk-Based Monitoring An adaptive approach to clinical trial 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. Position Paper: Risk-Based Monitoring Methodology Final 30May2013 TransCelerate BioPharma Inc
  • 9. Adaptive Design
  • 10. Current Monitoring Practices There is a wide range. • 4-8 weeks intervals on site with 100% source verification • Web based platforms can be monitored and queried daily • Every 3 year audit (cooperative groups)
  • 11. General Recommendations FDA Procedural August 2013 – On-site monitoring, centralized monitoring – Standard checks of range, consistency, completeness of data, unusual distribution of data between sites – Target on site monitoring for data anomalies or higher frequency of errors, protocol violations, or dropouts relative to other sites – Data trends not detected by on-site monitoring – Source data and CRFs can be assessed remotely – Data quality of real-time data entry, e.g., missing data, inconsistent data, data outliers, deviations – Statistical analyses of study data to identify sites that are outliers, evaluate subject data for plausibility and completeness – Analyses of site characteristics, performance metrics (high screen failure rates, eligibility violations, delays in reporting data), characteristics correlated with poor performance or noncompliance – Complete administrative and regulatory requirements
  • 12. Factors Influencing Study Quality and Integrity – Well designed protocol – DMP study specific • Mix of centralized and on-site monitoring practices – eCRFs or CRFs • Study objectives • Critical data • Patient safety – Qualified and trained • Investigators, staff, and monitors “The most important tool for ensuring human subject protection and high-quality data is a well-designed and articulated protocol.” (FDA Draft Guidance August 2011)
  • 13. Define Critical Data and Processes – Data supporting primary and secondary objectives – Data critical to subject safety: SAEs and events leading to treatment discontinuation – Data critical to trial design and statistical endpoints – Adherence to eligibility – Informed Consent process, prior to any study related procedures – Documentation of administration of investigational agent or treatment procedures
  • 14. AACI/CRI Risk Assessment Tool
  • 15. Network and Sub sites SIG Adopt Risk Based Monitoring • Number of Meetings: 2011 – 2013 (12 meetings) • Risk Based Monitoring 23 participants and 17 centers on last 2 call
  • 16. Risk Based • Describe the range of current monitoring practices – Survey Monkey – January 2011 • Define key quality objectives for monitoring clinical trials – Trial Complexity Form draft 2013 • Examine ways to build quality into trials to enable more focused and efficient monitoring – Next Step • Guides for a Risk Based Approach to Monitoring
  • 17. Risk Assessment per Trial What is risk? – Risk to the patients – Risk to future patients – Risk to provider – Risk to sponsor safety data financial litigation AACI/CRI supported the development of a tool to determine potential risk to the institution as the sponsor.
  • 18. AACI CRI Trial Complexity Form Tool for Determining Institutional Monitoring Standards for Investigator Initiated Trials 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Funding Source Phase IND/IDE Affiliate sites International sites Drug Administration Number of modalities Agent, Device, Treatment GMP Facility Collection of blood, tissue Recruitment practices Investigator and staff experience
  • 19. Monitoring Levels Monitoring Levels Low Moderate High Ranges 0 – 15 points 16 – 29 points > 30 points Action Audit review only Central monitoring and audit review Site and central monitoring, and audit review
  • 20. Workshop AACI/CRI Annual Meeting July 2013
  • 21. Workshop • Protocol A – Ph I/II Oxali/Docetaxel + Zactima Adv Esophagus and GE Junction • MC (4 sites), IND, IHC, EKG, placebo, Experienced PI • Protocol B – Ph I Triapine + Pelvic RT +/- Weekly Cis for Locally Adv Gyn • Single site, No IND (CTEP), biologic samples, multi modality, Inexperienced PI • Protocol C – Ph I Revlimid + Docetaxel Q 3 weeks Hem Malignancies • MC (1 site), No IND (CTEP), PK (several), Inexperienced PI • Protocol D – Ph I Rebeccamycin + Oxali Refractory Solid Tumors • MC (1 site), IND, biologic samples, Experienced PI • Protocol E – Ph II Sorafenib RCC • MC (1 site), IND, IHC, Experienced PI
  • 22. Result of Tool 1 Institution 2 Institution 3 Institution 4 Institution Average Risk Across Institutions Per Protocol Protocol A 33 24 30 30 29 Protocol B 24 34 33 33 31 Protocol C 36 37 32 29 34 Protocol D 31 24 29 24 27 Protocol E 28 20 26 29 26 Average Risk Assessment Between Institutions 30 28 30 29 29
  • 23. Workshop Reveals • More risk – Inexperienced PIs – PKs and biologic sampling – Multiple sites • Less risk – IND holder
  • 24. Process • Conduct a risk assessment. • Determine monitoring and/or auditing requirements to adequately maintain oversight. • Development a trial specific Data Monitoring Plan incorporating the proposed methodologies for oversight.
  • 25. Institutional Challenges • Staffing • Funding • Appreciation for the importance and rigors of compliance
  • 26. Discussion