1. Introduction to Quality Risk Management in GCP
DIA GCP/QA SIAC Teleconference
March, 16th
Dr. Peter Schiemann

2. Current approach not scalable Identification of systemic /
Today's significant challenges – QA needs to take a lead role in taking these on
Current approach not scalable
Early detection of critical issues before they become problems
Increasing expectations & scrutiny of regulators
Mgmt QA QC
Identification of systemic /
underlying issues

3. The current approach covers less than 2% of the active entities involved in Clinical Development
Scope of Quality Management
Entities Where Risks Occur
GCP compliance in clinical trial phase I to IV
101 HQ functions
102 Affiliates
Audits
16,000 Entities
<
2% Audit Coverage
CROs
Labs
Manuf .
Others
103 Partners
Pharmacovigilance over entire product life cycle
104 CRTNs
CRTN: Clinical Research Trial Number, Combination of Investigator, Center, and Protocol for a specific project

4. In the future we will need to go beyond the detection of individual quality issues to identify systemic issues
Traditional Approach
Future Requirement
Detection of Individual Quality Issues
Detection of Systemic Quality Issues
Sample analysis of quality risks
Detail information on individual functions/ sites
Fragmented fact base on critical quality issues
Continuous evaluation of many/ all entities and risk areas
Focused sets of information on many / all entities
Identification of systemic quality issues based on comprehensive set of information

5. Increased FDA Emphasis on GCP Risk Management
Rapidly evolving FDA GCP guidelines describe the need for Quality Risk Management
Increased FDA Emphasis on GCP Risk Management
“The essence of risk-based approaches (is) doing less in low risk/impact areas to achieve more in higher risk/impact areas”
According to the new FDA guidelines Risk Assessment activities entail
“Risk identification”
“Component analysis: What factors might contribute to the identified risk”
“Assessing relative risk: (Nature) x (Severity) x (Incidence)”
“Prioritization”
To achieve effective GCP Risk Management, the FDA requires to
“Plan prospectively (Quality must be ‘built-in’; it cannot be ‘inspected-in’)”
“Avoid over-delegation (Internal and Outsourcing)”
“Make use of indigenous systems and standardize where appropriate”
“Balance monitoring and auditing; evaluate role and performance”
“Train in risk-management approaches”
“Use ‘failure analysis’ appropriately”
Source: David A. Lepay, FDA Advisor for Clinical GCP Program - FDA GCP Quality Risk Management Approaches and Initiatives
Establishment and Operation of Clinical Trial Data Monitoring Committees (Mar 06)
Using a Centralized IRB Process in Multicenter Trials (Mar 06)
Update to 40+ GCP Guidances planned

6. In Development we examine existing data for indications of quality risks in a standardized/automated way
Use the existing data…
… to identify areas with increased quality risks
Safety data
# S/AEs …
QRM Dashboard …
Trial info … …
Clinical data
Allowing for different views:
Product/Project View
Process View
Geographical View … … …

7. QRM-Analysis: Selected Results for Key Risk Indicator “Monitoring”
QRM analysis of monitoring visits in a study revealed that monitoring is a high risk in many countries
QRM-Analysis: Selected Results for Key Risk Indicator “Monitoring” 60
43%
Analyzed for all centers with at least one patient registered
72% 40
56%
47%
# of centers
97%
95%
75% 20
53%
67%
75%
80% 7%
30%
90%
90%
56%
56%
11%
13%
38%
57%
67% 0%
20% 0%
100% 0%
60%
100% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
# of centers with NO monitoring report
# of centers with monitoring > 8 weeks --> "LATE"
# of centers with monitoring within 8 weeks --> OK

8. Similar as Protocol Violations in Trial X in Country A, Country C, D and E might have to be investigated further, too
“Protocol violations”
Description
Higher than average number of protocol violations and waivers
Rationale
Possible indicator for inadequate monitoring, site-staff training, resourcing or workload
Results A B C D E 6 5 4 3 2 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
Threshold (>1,2)
Ration (see formula)