CRP 112 Lecture 11 Flashcards
POL-0030: Risk Based Approach to Inspections: Sponsors, CROs, SMOs
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
POL-0030: Risk Based Approach to Inspections: QIs
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
POL-0030: Risk Observations
Critical – Risk 1
Major – Risk 2
Minor – Risk 3
POL-0030: At end of Inspection
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
Health Canada GUI-0043
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
Health Canada – Clinical Trial Compliance Program (CTCP) scope and activities
-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.
CTCP Program
Inspection Approach: Risk-based approach
-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
FDA Remote Inspection
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
Remote Interactive Evaluations (RIEs)
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
Hybrid Inspections
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
Remote Inspections - Facility Tours
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
Remote Inspections – Source Data Review
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
Remote Inspections – IT Considerations
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
Remote Inspections - Logistics
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
Remote Inspections – Regulatory
Considerations
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)
Remote Inspections - Limitations
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
Ratings from FDA
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
Outcome FDA Inspection
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
Form 483
Observations from inspection
Always communicated with site before leaving premises
Observations in descending order of importance
Snapshot – does not include everything
Warning Letter
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
What does the auditor need to know?
- Who is the client?
- Who is the auditee/Contact information?
- Audit Objectives?
oQualification? Re-Qualification?
oCompliance? For cause? - Timeline
scope of audit may include
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
Project Plan
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
Investigator Site Notification
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
Formal Notification for audit
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
Audit Preparation
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
Audit Flow
-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
Post Audit
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
Classifications - Critical
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
Classifications - Major
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
Classifications - Minor
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
Remote Auditing: Benefits
Reduce CO2 emissions
Less stressful for auditor
Utilise experienced staff usually cannot audit due to
personal travel restrictions
Reduces costs (travel expenses)
Remote Auditing: Planning Phase
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
Remote Auditing: Conduct
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
Remote Auditing: Report
As per usual report
MUST address remote nature of audit
Note what was not done and what was done remotely (e.g.
facility tour)
