The document provides an update on the Therapeutic Goods Administration's (TGA) post-market regulatory requirements, particularly focusing on the Pharmacovigilance Inspection Program (PVIP) aimed at ensuring compliance and safeguarding patient safety. Key topics include the inspection process, common deficiencies identified in pharmacovigilance practices, and support mechanisms for regulatory compliance. It emphasizes the importance of effective compliance systems and outlines the need for timely reporting and adherence to safety guidelines.

1. An update on post-market regulatory requirements
Elspeth Kay
Director, Risk Management Plan Evaluation Section
Pharmacovigilance and Special Access Branch
ARCS Conference
23 August 2018

2. Overview
• TGA’s regulatory compliance framework
• Pharmacovigilance Inspection Program
• RMP Compliance Monitoring Program

3. TGA’s approach to monitoring

4. TGA’s approach to compliance
Low compliance risk High compliance risk
TGA’s approach to compliance
Help and support
• Make ongoing
compliance easy
Inform and advise
• Help to become and stay
compliant
Correct behaviour
• Deter by detection
Enforce
Regulated entity – attitude to compliance
Voluntary compliance
• Effective compliance
systems
• Management is
compliance oriented
Accidental non-compliance
• Ineffective and/or developing
compliance systems
• Management compliance
oriented but lacks capability
Opportunistic non-compliance
• Resistance to compliance
• Limited or poor compliance
systems
• Management not compliance
oriented
Intentional non-compliance
• Deliberate non-
compliance
• No compliance systems
• Criminal intent
"Committed to doing the
right thing"
"Trying to do the right thing but
don't always succeed"
"Don't want to comply but will
if made to"
"Decision to be non-
compliant"

5. Pharmacovigilance Inspection Program
• PV requirements and inspections
• When will I be inspected?
• The inspection process: how to make an inspection a smooth process
• Summary of common findings
• How can we help?

6. What are your pharmacovigilance requirements?
www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors

7. Pharmacovigilance Inspection Program (PVIP)
• The PVIP began on 1 September 2017, with inspections starting in January 2018.
• The PVIP applies to all sponsors of medicines on the ARTG including:
– Listed or registered
– prescription medicines
– over the counter medicines
– complementary medicines.

8. Pharmacovigilance Inspection Program Guidelines
www.tga.gov.au/publication/pharmacovigilance-inspection-program-guidance-medicine-sponsors

9. Aims of the PVIP
• safeguard patient safety by ensuring the ongoing positive risk-benefit balance
of a medicine in the Australian context
• verify sponsor compliance with their pharmacovigilance reporting
requirements (serious ADRs, significant safety issues) and other related
legislative requirements
• educate sponsors to assist them to meet their requirements
• promote continuous improvement in pharmacovigilance
‒ PVIP is part of an enhanced vigilance framework for the TGA

10. Scheduling of inspections
• Risk-based scheduling
– Routine inspections prioritised based on the risk we have assigned to a sponsor or their
pharmacovigilance system.
• How we assess risk:
– Risk assessment survey: open 31 January-31 March 2018: obtained data on inherent product, sponsor,
system and inspection-related risk factors. Now using the data obtained from this survey to assist in risk
based scheduling of inspections.
– Internal intelligence: may include whistleblower information, information from regulatory compliance,
previous PV inspection history, overseas agency data
– Non-compliance with other TGA requirements: PSUR submission, RMP commitments, GMP findings,
PV reporting requirements, updating PIs
• In addition to routine inspections, sponsors may be selected for random or “for cause” inspections

11. Current risk areas that are being prioritised for inspection
• Uncertainty about a medicine’s risk profile (including new classes of medicines and provisionally
registered medicines)
• Whether the medicine’s registration requires specific safety conditions
• Products with known or emerging important safety concerns
• Evidence that a sponsor has failed to comply with TGA regulatory requirements such as legislative
pharmacovigilance requirements, good manufacturing process, RMP activities or the submission
of PSURs
• Compliance history, including previous pharmacovigilance or other inspection findings
• Information on non-compliance with pharmacovigilance requirements from whistleblowers

12. The Inspection Process
• Notification, planning and preparation
• Agenda, logistics and initial document requests
Pre-inspection
• Opening meeting
• Interview sessions and document reviews
• Closing meeting
Inspection
• Issuance of inspection report
• CAPA response
• Close-out of the inspection
Post-inspection

13. What we inspect
Management
of AE Reports
Signal
Detection
Report
significant
safety issues
Reference
safety
information
PSUR and
RMP
Commitments
QMS
QPPVA
oversight
Contracts and
Agreements
Collection of
AE Reports

14. How to prepare for an inspection (a few pointers)
• Ensure you have nominated an Australian contact person for PV through eBS
• Ensure an appropriate quality management system is in place as a basis for an effective PV
system, including up to date SOPs, training and auditing
• Ensure all potential sources are being monitored for ADRs, including but not limited to marketing
programs, medicines information, product quality complaints, literature, company sponsored
internet sites and social media, post market clinical trials etc.
• Ensure you have a robust and secure system to collect, process and analyse safety data
• Ensure all serious Australian ADRs are being reported to the TGA within required timeframes
• Ensure ongoing monitoring for safety signals is occurring on a regular basis and includes ALL
safety data
13

15. How to prepare for an inspection (a few pointers)
• Ensure there are procedures in place to receive notification of significant safety issues from global
counterparts and report to the TGA within required timeframes, where required
• Ensure you have safety agreements in place with required partners and contractors
• Ensure PSURs are complete and submitted on time
• Ensure any RMP commitments are being met
• Ensure the Australian person responsible for PV has appropriate oversight of the system
• Ensure CAPA from any previous PV inspection has been completed
• Ensure all safety data is being held indefinitely for the life of the product and for 10 years after its
removal from the ARTG
14

16. How to ensure the inspection runs smoothly
• Have a designated point of contact for the inspectors and sponsor staff to liaise through (prior to and during
the inspection)
• Make sure you know who to go to in the company for requested information – who does what (i.e. market
research program management, contract management, training of sales representatives etc.)
• Have a database expert available to run requested reports (if applicable)
• Ensure IT systems and any teleconference/video conference facilities are working
• Provide documents in an accessible way to the inspectors i.e. via USB or hardcopy
• Label each document with the specified number given so it can be easily tracked
• If you don’t understand a request - ASK!
• If you cannot provide what we are asking for - TELL US!
15

17. Inspections update
• 10 inspections scheduled for 2018; 5 completed
Critical Major Minor
Nil 25
• failure to report significant
safety issues
• deficiencies in case collection,
follow up and seriousness
assessment
• late reporting of serious cases
• delay in updating reference
safety information (PI and CMI)
12
• deficiencies in safety data
exchange agreements and
company SOPs
• deficiencies in
pharmacovigilance training
• quality management system
procedures
16

18. Some common deficiencies identified
Communication of significant safety issues
• Deficiencies in communicating significant safety issues
– Sponsors must report all significant safety issues to the
TGA within 72 hours (Pharmacovigilance Guidelines)
– Significant safety issues may include:
 actions taken by comparable international regulatory
agencies for safety reasons
 identification of new safety issue or risk factors that may
impact on the safety or benefit-risk assessment of the
product
17

19. Some common deficiencies identified
AE case collection and processing
• Late submission and non-submission of serious Australian cases to
the TGA
– All serious adverse reactions occurring in Australia must be reported to
the TGA within 15 days of receipt by the sponsor (Pharmacovigilance
Guidelines).
• Non-conservative seriousness assessments
– Seriousness assessments should be an independent process to medical
evaluation, causality and validity of the case i.e. based on the adverse
event alone
– Where outcomes or treatment information is not available, a conservative
approach should always be taken

20. Some common deficiencies identified
ADR case collection and processing (cont’d)
• Identification of ADRs
– Care should always be taken to determine if an enquiry involves an adverse event for
collection and reporting purposes.
– Literature search processes should be structured to identify both ADRs and general safety
information and occur regularly.
– Follow up should be performed where information is unclear or lacking, including following
up directly with consumers who may hold valuable medicine safety information.
• Deficiencies in the pharmacovigilance contracts and training of vendors
– Omissions, errors and discrepancies in contracts for post-marketing initiatives (e.g. patient
support programs and market research), sales, promotion and distribution partners.
– Contracts must ensure all safety information is collected and communicated to the medicines
sponsor effectively; include provisions for reconciliation of safety data and training of staff.

21. Some common deficiencies identified
Maintenance of Reference Safety Information
• Delays in updating Australian Product Information documents
– From when the sponsor became aware of the need to initiate a reference
safety change
– TGA expectation is a variation will be submitted within 6 months from
identification of any safety related change required
• Delays in updating PI and CMI documents
– PI and corresponding updated CMI document must be lodged with the TGA
within 2 weeks of the date of registration (for registered products-
Conditions of Registration)

22. How can we help you?
• What further information or clarification of the guidance would help you meet your PV obligations?
• Would any of the following be useful in helping you understand either the inspection process or PV
responsibilities:
– FAQs on PV
– Specific training on the inspection process
– Specific training on your regulatory responsibilities, the guidelines and our expectations
– Specific training on how to produce corrective and preventative action plans
– More information on common findings and issues identified
– All of the above?
– Other ideas?
Email: Pharmacovigilance.Inspections@health.gov.au

23. RMP Compliance Monitoring Program
• Part of the MMDR reforms for enhanced
medicines vigilance
• Aim: ensure timely implementation of
RMP commitments
• Approach: cooperative compliance,
aligned with the TGA’s regulatory
compliance framework
Agree
activities for
monitoring
Identify
potential non-
compliance
Review
compliance
status
Update RMP
as required

24. RMP Compliance – help & support, inform & advise
• General information in revised RMP Guidance
• RMP evaluation will ensure RMP commitments
are:
– clearly documented
– feasible and measurable
• If we identify potential non-compliance, we will:
– contact you to clarify compliance status
– support you in developing a plan to achieve
compliance
– continue to monitor to ensure future
compliance

25. RMP Compliance – correct behaviour and enforce
• If we identify continued non-compliance, we
will:
– formally request information on how you
will achieve compliance
– continue to monitor to ensure future
compliance
• Serious non-compliance may be referred to
Regulatory Intelligence and Enforcement:
– outcomes of these regulatory actions may
be published on the TGA website

26. Risk-based prioritisation of activities for monitoring
• High priority activities may include:
– Confirmatory studies for provisionally registered
products
– Local additional risk minimisation activities
 Including provision of educational materials
for review
– Australian-specific additional pharmacovigilance
– Local studies to measure effectiveness of
additional risk minimisation
– Some conditions of registration

27. Questions