CRP 112 Lecture 5

Question 1

Measuring Quality

Answer 1

missing data entries per CRF page

Site Metrics
% monitoring visits done on time
% of evaluable participants with no PVs
% SAEs reported within 24 hrs to REB & sponsor
% properly executed ICFs
# queries per CRF page
Data Management Metrics
% database errors
% of queries manually generated
Time: last participant out to database lock
# times locked database is opened
Statistical Analysis
% of Tables, Listings, Graphs (TLGs) with numerical/formatting errors
% of SAS programs adequately validated
Time: database lock to final TLGs

Question 2

Internal Process Audits

Answer 2

 Employee training
 SOP compliance
 Regulatory compliance
 QC compliance
 Need documentation of all!

Question 3

Site Audits – how are sites chosen?

Answer 3

 High participant enrollment
 High staff turnover
 Either too many or too few AEs
 Enrollment rate either too high or too low
-complaints from staff
-high query rates
-risk-based

Question 4

Quality Surveillance

Answer 4

 This occurs after trial ends
 Ensures:
 Tables, Listings, Graphs (TLGs) match database
 Clinical Study Report (CSR) is based on TLGs
 Data Management processes are compliant with SOPs and GCP

Question 5

The BIG Question
Should Quality be an independent
entity within an organization?

Answer 5

Quality by Design principle says
An organization should have
* An independent entity to measure/review
quality standards
* An integrated system to continuously verify
analyze, correct and prevent issues from arising

Question 6

Quality by Design Step 1

Answer 6

Identify Critical To Quality factors for
each specific trial
-protocol design
-study conduct
-third-parties
-feasibility
-patient safety
-study reporting

Question 7

Quality by Design Step 2

Answer 7

Discuss potential risks related to each CTQ identified that
impact study quality (participant safety or credibility of
results etc.)

Question 8

Quality by Design Step 3

Answer 8

 Mitigate risks that could lead to errors that matter
 Determine how to quickly ID & react when issue exists

Question 9

Your Quality Philosophy Should
Encompass

Answer 9

 Proactive analysis and identification of risk factors
 Apply Lean 6-Sigma techniques
 QRM systems and analytical tools (Quality Risk Management)
 timely implementation of CAPA
 Coach, motivate & develop winning staff through effective team building and communication

Question 10

Build Quality in by

Answer 10

 Implementing standard processes/procedures (SOPs)
 Effective GCP training / Refresher training
 Define clear roles & responsibilities
 Effective management oversight and accountability
 Continuous assessment of Risk Factors
 Adequate study-specific training:
Perform mock patient visits, study procedures walk-through, etc.

Question 11

QA Audit Plan purpose

Answer 11

 Specific guideline to be followed when conducting an audit
 Independent and separate from monitoring and quality control
Purpose:
 To evaluate trial conduct and compliance with protocol, SOPs,
GCP and regulatory requirements

Question 12

QA audit plan elements

Answer 12

 # sites & vendors to be audited
 Selection criteria for audits
 Internal processes to be audited
 Audit team members specified
 Standards for audit to be conducted against (protocol, CRF completion guidelines, SOPs, ICH GCP, regulations)
-specify: documents requires, location/dates/duration, timeline for report of audit
-prepare by reviewing essential docs

Question 13

Traits of QA Auditors

Answer 13

 Detective-like analytical skills
 Ability to influence people, even when they have no authority over them
 Detail oriented
 Can see the big picture
Process thinking:
 Past – problem solving
 Present – decision making
 Future - planning & innovation

Question 14

Goals of Audit based on

Answer 14

 Importance of trial re submissions to regulatory authorities
 Type and complexity of trial
 Level of risk of trial
 Any previously identified problems

Question 15

Compliance audit

Answer 15

 Do activities, process & systems meet requirements
 Usually a Pass or Fail

Question 16

Performance audit

Answer 16

1. Compliance to the rules
2. Effectiveness of those rules in use
3. Suitability of those rules to achieve the organization’s goals

Question 17

Specific objectives of audit

Answer 17

 Pre-qualification of organizations involved in clinical trial
 Compliance with human participant protection
 Confirm appropriate conduct of trial
 Confirm credibility of data obtained
 Confirm condition of record keeping at institutions and internally
 Confirmation of monitoring conduct
 Confirmation of clinical study report credibility
 Early detection of problems with a system or process – ability to apply CAPA
 Early detection of problems at an institution doing study

Question 18

Who/What is Audited?

Answer 18

 CRO
 Vendors (e.g., labs, diagnostics, IVRS etc.)
 Research Ethics Boards
 Systems
 Medical institution
 Computerized system validation
 Database
 Clinical study report

Question 19

conducting auditing

Answer 19

 Must inform sponsor about conduct of an audit in advance
 Examination & evaluation of information (e.g., Essential
documents, SOPs)
 Trial site investigation (facilities, equipment)
 Interview with auditees
 Evaluation of conformity and compliance with reference
documents
 Important to standardize the audit

Question 20

Risk Assessment and Categorization Tool (RACT)

Answer 20

1. Identifying risks which could affect patient safety, data
   integrity or regulatory compliance
2. Categorizing risks which will be managed by and affect
   the Monitoring Plan (and data review)
3. Determining baseline level of monitoring activities

Question 21

Audit Checklists

Answer 21

 Checklist needs to be a decision tree
 Everything on a checklist is not “equal”
 Need to critically think
 Keep them current
 Use as a guide only
 Always have lots of follow-up questions to each point

Question 22

TMF

Answer 22

Trial master file (trial, county and site level)
-sponsor controlled
-follows DIA reference model
-holds essential docs
-defined in ICH GCP

Question 23

ISF

Answer 23

Investigator site file
-site controlled
-part of model held at each site
-holds essential docs
-part of TMF

Question 24

DIA Reference Model TMF 11 zones

Answer 24

Hierarchical Structure
1. Trial Management
2. Central trial Documents
3. Regulatory
4. IRB or IEC and other approvals
5. Site Management
6. IP and Trial Supplies
7. Safety Reporting
8. Central and Local Testing
9. Third Parties
10. Data Management
11. Statistics

Question 25

Content of an Audit Report

Answer 25

 Trial identifiers
 Receiver of audit report & those getting copies
 Date of audit and date of report issue
 Subject of audit
 Site of audit including name/address of auditee
 Scope of audit
 Auditor identifying information
 Audit findings, including grading
 Suggestions for improvement
 Advice for CAPA
 Responses to audit findings
 Results of auditor’s confirmation of auditee’s responses

Question 26

Who gets the Audit Report?

Answer 26

 Sponsor
 Auditee usually – often just share the CAPA section with the auditee
 NOT the regulatory authorities unless a serious GCP non-compliance issue when it can be requested

Question 27

CAPA follow-up

Answer 27

 CAPA plan is provided by auditor to auditee and other key individuals
 CAPA plan must require auditee to ID root-case of audit
findings and describe corrective and/or preventive actions
 To maintain independence, auditor must NOT be involved in CAPA, falls to the project team
 Once preliminary responses to CAPA from auditee
received, audit is completed
 Follow-up generally occurs if there were significant audit findings until mutual agreement between auditor and auditee that CAPA has been addressed

Question 28

Audit Certificate

Answer 28

 Prepare by auditor
 Attached to clinical study report

Question 29

Grading of Audit Findings

Answer 29

Critical
 Adversely affect safety of participants OR integrity of trial or trial data
 Combination of multiple Major findings may result in overall Critical grade
Major
 May lead to adversely affecting rights, safety or well being of trial participant and/or integrity of trial or trial data
Minor
 Deviation from QMS and/or GCP but not expected to adversely
affect participants or trial integrity

Question 30

Auditing vs. Monitoring

Answer 30

Monitors (looks at individual trees - QC)
 ICF, eligibility, protocol compliance, SD verification, query resolution, AEs, IP
accountability, essential docs, oversight of QI
 Regular visits at each site
 Regulators have access to all monitoring reports and CAPA
Auditors (looks at the whole forest - QA)
 Assess wider study sample, evaluate trends across sites & vendors, study design, stats analysis, clinical study report.
 Snapshots in time – not regular
 Regulators do not have access unless there is a legal reason (lawsuit)