approaches to risk-based monitoring
DESCRIPTION
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 CenterTRANSCRIPT
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
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
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
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
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
Health AuthoritiesTransition 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)
Monitoring vs. Auditing
Monitoring Auditing
- Continuous process - Snapshot in time
- On-site/off-site - On-site
- All patients on trial - Subset of patients
- Data driven - Compliance driven
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
Adaptive Design
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)
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
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)
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
AACI/CRI
RRisk AAssessment TTool
Network and Sub sites SIGAdopt Risk Based Monitoring
• Number of Meetings:
2011 – 2013 (12 meetings)
• Risk Based Monitoring23 participants and 17 centers on last 2 call
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
Risk Assessment per Trial
What is risk?
– Risk to the patients safety– Risk to future patients data– Risk to provider financial– Risk to sponsor litigation
AACI/CRI supported the development of a tool to determine potential risk to the institution as the sponsor.
AACI CRI Trial Complexity FormTool for Determining Institutional Monitoring Standards for
Investigator Initiated Trials
1. Funding Source
2. Phase
3. IND/IDE
4. Affiliate sites
5. International sites
6. Drug Administration
7. Number of modalities
8. Agent, Device, Treatment
9. GMP Facility
10. Collection of blood, tissue
11. Recruitment practices
12. Investigator and staff experience
Monitoring Levels
Monitoring Levels Ranges Action
Low 0 – 15 points Audit review only
Moderate 16 – 29 points Central monitoring and audit review
High > 30 points Site and central monitoring, and audit review
WorkshopAACI/CRI Annual Meeting
July 2013
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
Result of Tool1
Institution2
Institution3
Institution 4
InstitutionAverage Risk Across
Institutions PerProtocol
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
Workshop Reveals
• More risk– Inexperienced PIs– PKs and biologic sampling– Multiple sites
• Less risk– IND holder
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.
Institutional Challenges
• Staffing
• Funding
• Appreciation for the
importance and rigors of compliance
Discussion