1. Quality Management System
at the clinical research site –
a paradigm shift
Shari Sharif, CCRP
Director of Regulatory Affairs & Quality Management
2. ICH-GCP Q9
Quality Risk Management principles which are process-based
Risk = combination of probability of the occurrence of harm and the
severity of that harm
A systematic approach to ensuring that all possible and probable causes
of harm around a compound is mitigated
Harm against subjects
Harm against the viability of new therapies (valid data)
A solid assurance system within research and development (Q8 & Q10)
3. History
Pharmaceutical development (ICH Q8) has been under the
scope for years and therefore, very much interested in
reducing harm at the Site level, where subjects are seen and
data is first captured
Some trial sponsors and CROs have incorporated risk-based
principles into their Quality Assurance Systems (Q10):
Risk-Based Monitoring
Adaptive Monitoring
Quality Risk Management
Focused Monitoring
4. Focused Monitoring
Monitoring high-risk sites more frequently than others
Monitoring regulatory compliance
Monitoring focused on safety data and primary outcomes
SDV of 100% of some items (ie, ICFs, I/E, AEs/SAEs)
SDV of <100% of all other data
Remote monitoring
Utilization of technology to capture raw data (ie, eConsent,
diaries, etc.)
Utilization of an in-house CRA to ensure ISF and TMF match
5. Today
About half of the industry has begun the
implementation of RBM
(M. Massim, CEO, Florence Healthcare, Atlanta, GA)
RBM only works with cooperation from the Sites
(Todd Davies, Dir, Marshall Clinical Research Center)
6. The Site faces an increased challenge
Agency Warning Letters are still issued
We have to adapt to industry standards and current trends
Monitoring in general has changed
Studies are more complex
We can no longer completely depend on the monitor to catch
every mistake
In order to be sustainable, we have to focus on quality and not just
quantity
7. The Successful Site
Expects audits
Expects various monitoring approaches (ICH-GCP Q9)
Standard operating procedures and/or Work Instructions
Adaptable to changes in the industry and at the Site
Effective qualified staff recruitment, allocation and
retention
Clear job descriptions
8. The Successful Site
Solid ongoing staff training & development with
consistent evaluation and feedback
Site-specific
Study-specific
Balance quantity and quality
Quantity of studies , staff and subjects
Quality of selected subjects and data
Quality Management System (process)
9. Quality Management System at the Site
Build solid source documents: A preventive approach
Designate competent source document creator(s)
Streamlined according to the site’s operational flow
Tailored for the protocol, CRF and other written guidelines
Template should promote internal and external consistency of data
Reviewed/revised with each approved protocol amendment
Audited prior to use
Completed source template should be auditable by site reviewer(s)
10. Quality Management System at the Site
System to identify the critical study parameters in
every study
Phase of study and the Site’s enrollment goal
Drug safety profile
Study Coordinator preparedness and study workload
Complexity of the trial (number of study arms,
randomization steps, length of treatment)
11. Quality Management System at the Site
Informed consent process
Subject eligibility
Protocol adherence (following the investigational plan)
Primary objectives/endpoints
Safety reporting
IP administration
12. Quality Management System at the Site
IP control/accountability/maintenance of study blind
Record keeping (regulatory and subject records)
Elimination of misconduct: look for and recognize
signs of fraud
Computerized system validation
Source data verification/query response
13. Risk assessment via Audit system at the Site
Quality Management
Every day operational techniques:
Practicing GCP, ALCOA and following protocol
Audit
Review source data (and CRF) and identify discrepancies
within the chart and question non-compliance with study
protocols and/or the site’s standard practice
14. Auditing at the Site
A review system based on each study’s risk profile
Full, partial, and/or for cause
eg, investigator, coordinator or subject complaints
eg, high number of SAEs
eg, high enrollment / eligibility violations
eg, consent errors
15. Auditing at the Site
Notice and evaluate trends
Conduct root cause analysis
Review of the facility, its certificates
Review recruitment system and pre-screening
procedures/documents
Streamlined reporting system to the Investigator
16. Internal auditing contributes to a successful
Quality Management System
Communicate with the Study Team
Incorporate corrective action as a standard quality
management procedure. This shows that you are able
to identify risks and mitigate risks ahead of time
Identify a local IRB and use them as a resource
17. Quality Management System
Review Site processes for trends/gaps/deficiencies
Revise/refind systems that make the Subjects, studies and
the Site’s sustainability/reputation vulnerable
eg, system by which revised and approved ICFs are retrieved
and used
eg, system by which protocol amendment training and source
revisions occur prior to implementing the new amendment
eg, system by which monitoring follow-up letters are
reviewed and action items addressed
18. Always ask
What could go wrong?
What is the probability of it going wrong?
What are the consequences?
19. How do we ensure validity of data ?
Create accurate source data templates
Conduct our studies the sponsors intend
Report and resolve issues/errors in a timely manner
Audit of subject charts for discrepancies and non-compliance
after data collection, and feedback prior to data entry
20. Resources
ICH-GCP E6: Overseeing the progress of a clinical trial and ensuring data is recorded and
reported in accord with SOPs, GCPs and other regulatory requirements
ICH Q9: Step-by-step instructions for quality risk management
BIMO in FDA’s Compliance Program Guidance Manual
