CRP 112 Lecture 11

Question 1

POL-0030: Risk Based Approach to Inspections: Sponsors, CROs, SMOs

Answer 1

 Type and degree of experience
 Protocol non-compliance, ICF issues, inadequate AE
reporting (i.e., integrity of data)
 Level of risk to Canadians
 Volume of activities
 Compliance history
 Status of CAPA from earlier inspections
 Number participants enrolled
 Number of SUADRs submitted to HC
 Type of tasks delegated to CROs/SMOs
 Complaints

Question 2

POL-0030: Risk Based Approach to Inspections: QIs

Answer 2

 Type of sponsor
 Type of site
 Geographic location
 Level of risk to Canadians
 Type of IP
 Novel therapies/dosages
 Complexity of CT design, including participant population
 Observations from past inspections
 Number of CTs at site
 Number of participants at site
 Number of SAEs at site
 Complaints

Question 3

POL-0030: Risk Observations

Answer 3

 Critical – Risk 1
 Major – Risk 2
 Minor – Risk 3

Question 4

POL-0030: At end of Inspection

Answer 4

 Exit meeting
 Opportunity to clarify prior to report finalization
 Final Inspection Exit Notice issued
 Outlines observations
 C or NC
 Drug & Health Products Inspections Database
 Preliminary overview published
 CAPA within 30 calendar days
 60 calendar days if a Notice of Suspension

Question 5

Health Canada GUI-0043

Answer 5

 Observation defined as deficiency or deviation from the regs
 Critical – risk 1
 Major – risk 2
 Minor - risk 3
 All observations in the final inspection exit notice require
CAPA

Question 6

Health Canada – Clinical Trial Compliance Program (CTCP) scope and activities

Answer 6

-Inspection of on-going
trials at qualified
investigator (QI) sites
-System-based inspections
of sponsors, CROs &
SMOs (cyclical inspection
approach)
-Bioequivalence trial
inspections (clinical and
lab sites), open/active or
closed.
-CT inspections in support
of a drug submission, in
Canada or at a foreign
site
-For-cause inspection:
compliance verification
(and investigations)
-Compliance readiness
inspections (COVID-19
related trials)
-International
collaboration/coordination
-Compliance promotion:
publication of guidance
documents and delivering
training sessions at
stakeholders events.

Question 7

CTCP Program
Inspection Approach: Risk-based approach

Answer 7

-Clinical trial design complexity
* Subject population and size
* Novel therapies/dosage forms
* Significant or frequent adverse events
* Protocol deviations
* Parties involved (e.g., Site Management Organization (SMO), Contract
Research Organization (CRO), etc.)
* Collaboration with HPFB clinical trial divisions and review bureaus
* Collaboration with international partners

Question 8

FDA Remote Inspection

Answer 8

 Staff must be available for interviews a & other virtual interactions
 If facility unable to support virtual interactions, FDA may
terminate and perform an inspection
 Utilize electronic systems for documents, records etc.
 Use livestream to examine facilities
 Will not issue a Form 482 (notice of inspection) for remote
inspections
 FDA uses its own platforms and equipment
 Expect all documents provided to be in electronic format or
accessible by screen sharing
 FDA needs remote viewing and verification of documents
 No FDA 483s will be issued but still need 15 biz days for
responses
 These are not true inspections

Question 9

Remote Interactive Evaluations (RIEs)

Answer 9

FDA Remote Inspection
 Review of documents, records & other information
 Use of video to examine facilities, operations & other information
 Interviews and meetings to address questions & concerns
 Evaulation of facility’s corrective actions
 Verbal updates on observations & outstanding issues

Question 10

Hybrid Inspections

Answer 10

 Mechanism to balance regulatory oversight vs risks of
individual exposure to COVID-19
 Some systems remotely, followed by on-site visit
 Follow up later to verify activities that could not be performed
remotely
 Assessment of QMS & Procedures followed by on-site data
review

Question 11

Remote Inspections - Facility Tours

Answer 11

Aided by hardware & software to provide appropriate field
of vision, clarity and picture stabilisation
 Simultaneous conversation between inspector and tour host
 Pre-recorded video tours ONLY in exceptional circumstances
 May not be permitted in some countries – need to obtain
permission from inspectees

Question 12

Remote Inspections – Source Data Review

Answer 12

 Provide inspectors read-only access to computerized
systems
-Provide member of staff to access system under direction of
inspector – more time consuming and not always suitable
 Often need access after closing meeting to aid in writing
inspection report or to clarify a deficiency

Question 13

Remote Inspections – IT Considerations

Answer 13

 Involvement of IT representatives from inspectorate and
auditee is advantageous
 Use of dry runs help to test the system to identify glitches
beforehand
 Bandwidth and signal strength must be adequate
 Security important consideration for privacy &
confidentiality

Question 14

Remote Inspections - Logistics

Answer 14

 Generally longer inspections vs on-site due to turnaround time of
requests – not immediate
 Time zone impacts
 Subject matter expert availability
 Translation requests have not been spontaneous or in a timely
manner
 Learning curve of inspector and inspectee
 Important to set up video conferencing

Question 15

Remote Inspections – Regulatory
Considerations

Answer 15

 Training of new inspector challenges
 Collaboration with other authorities – limited experience
 Need to ensure inspectors are not contactable internally
 No need to sign separate confidentiality agreements (no
different than on-site inspections)

Question 16

Remote Inspections - Limitations

Answer 16

Site interviews not as effective (body language, evasive & nervous
behaviours)
 Meetings less conducive to free flow of information
 Paper based source documents not amenable to remote
inspections- need to request in advance
 Cannot assess site design features
 Undue additional burden on paper-based sites
 For GMP, cannot smell or hear – risk re alarms, machinery

Question 17

Ratings from FDA

Answer 17

 NAI – No Action Indicated - no objectionable conditions or
practices were found during inspection
 VAI – Voluntary Action Indicated - objectionable conditions
found but problems did not justify further regulatory
action. Corrective action is left to investigator to take
voluntarily
 OAI – Official Action Indicated. Objectionable conditions
were found and regulatory and or administrative sanctions
by FDA are indicated

Question 18

Outcome FDA Inspection

Answer 18

 Establishment Inspection Report (EIR)
 Brief history of prior inspectional findings, including any
action taken by FDA or corrective action taken by firm in
response to previous inspection
 Inspector’s narrative report
 Any refusals, voluntary corrections, or promises made by
the firm’s management
 Copies of forms the FDA issued to the firm during the
inspection, including the FDA Form 483

Question 19

Form 483

Answer 19

 Observations from inspection
 Always communicated with site before leaving premises
 Observations in descending order of importance
 Snapshot – does not include everything

Question 20

Warning Letter

Answer 20

 After a 483, inspector completed the Establishment
Inspection Report
 Then, potentially a Warning Letter from agency
 Senior FDA officials after review believe serious violation may
exist
 Evidence collect to support observations
 Background of warnings if further action required by FDA
 Either hand-delivered OR agency invites top corporate
management to a meeting

Question 21

What does the auditor need to know?

Answer 21

1. Who is the client?
2. Who is the auditee/Contact information?
3. Audit Objectives?
   oQualification? Re-Qualification?
   oCompliance? For cause?
4. Timeline

Question 22

scope of audit may include

Answer 22

 Qualified Investigator oversight
 Protocol Compliance
 Personnel and training
 Facility and equipment
 Informed Consent process
 Essential Documents
 Document management/filing/archiving
 Case Report Form/Data Entry and Queries
 Monitoring and Site Management
 Safety Reporting
 Source Data Verification
 Investigational Product Management
 Laboratory samples
 E-System access/security
-Applicable Guidelines/Regulations

Question 23

Project Plan

Answer 23

Agreed upon between sponsor & auditor prior to audits.
Project Plan at a minimum:
 Provides consistency in how the audits are being conducted
 Clarifies which SOPs/templates are being used
 Includes the audit timelines
 Includes the notification process for critical observations
 Includes the Final Report process/distribution

Question 24

Investigator Site Notification

Answer 24

Email/Telephone contact with QI or main study contact:
 Introduction
 Agree on audit dates/time/attendees/flow
 Gather information
 Enrolment #s
 SAEs #s
 Ancillary Departments (i.e. pharmacy, laboratory)
 Type of Source – electronic, paper, hybrid
 Internet access

Question 25

Formal Notification for audit

Answer 25

 Send Audit Notification Letter and Agenda (if required)
 Protocol title/number
 Dates/time
 Documents required for audit (i.e. ICFs, ISF, SOPs, training
records)
 Auditees to interview/departments to virtually visit
 Virtual Facility tour

Question 26

Audit Preparation

Answer 26

Documents required in order to adequately prepare for the audit:
 Protocol/protocol amendments
 Approved Informed Consent Forms
 Monitoring Visit Reports and visit pre/post letters
 Investigator’s Brochure
 Clinical Monitoring Plans, Data Management Plans, Safety Management
Plans
 Tracking logs (i.e. SAEs, Protocol Deviations, Issue Escalation)
 Access to the eTMF when possible

Question 27

Audit Flow

Answer 27

-Opening Meeting
 Investigator Site File
 QMS/Training Records
 Informed Consent Form/Process
 Source data review with CRFs
 Interviews, visits to ancillary departments and tour of
the facility are scheduled at a time convenient to the
auditees
 Exit Meeting

Question 28

Post Audit

Answer 28

 Debrief with Sponsor
 Report Critical observations within 24 hours
 Write an objective and factual report supporting each observations with a relevant
regulation/guidance citation
 Submit for internal QC Review
 Provide draft to Sponsor for comments/feedback
 Submit final report to Sponsor who is responsible for obtaining CAPA from all
affected parties
 Issue an Audit Certificate
 May be involved in CAPA review

Question 29

Classifications - Critical

Answer 29

 Adversely affect:
 rights, safety or wellbeing of the participants and/or
 quality and integrity of the data
 Direct violation of regulations -could lead to data rejection
 May include a pattern of deviations classified as major, bad
quality of the data and/or absence of source documents
 Fraud/Non Compliance

Question 30

Classifications - Major

Answer 30

 Might adversely affect:
 Rights, safety or wellbeing of participants and/or
 Quality and integrity of the data
 Serious findings –direct violations of GCP principles
 Data may be rejected
 May include pattern of deviations and/or numerous minor
observations

Question 31

Classifications - Minor

Answer 31

 Not expected to
 adversely affect rights, safety or well being of participants and/or
 quality and integrity of data
 Indicate need for improvement of conditions, practices &
processes
 Many minor observations might indicate a bad quality and
the sum might be equal to a major finding with its
consequences

Question 32

Remote Auditing: Benefits

Answer 32

 Reduce CO2 emissions
 Less stressful for auditor
 Utilise experienced staff usually cannot audit due to
personal travel restrictions
 Reduces costs (travel expenses)

Question 33

Remote Auditing: Planning Phase

Answer 33

 VERY clear scope and objectives!
 Pre-audit questionnaire
 What information can be provided for pre-audit reviews
 SOPs
 Contracts
 Audit timing, taking into consideration time zones
 Determine document exchange process (secure repository?)
 System access taking into account confidentiality

Question 34

Remote Auditing: Conduct

Answer 34

 Opening meeting
 Scope, process and discuss potential challenges
 Interviews – more possible for misunderstandings and
misinterpretations – listen well!
 Agree on timelines for receipt of requested documents
 Allocate time for document reviews
 Keep auditees informed
 Closing meeting
 Discuss main issues and auditee performance

Question 35

Remote Auditing: Report

Answer 35

 As per usual report
 MUST address remote nature of audit
 Note what was not done and what was done remotely (e.g.
facility tour)