You are here

TGA Internet site archive

The content on this page and other TGA archive pages is provided to assist research and may contain references to activities or policies that have no current application. See the full archive disclaimer.

Presentation: Updates from the Pharmacovigilance and Special Access Branch

TGA presentations given by the TGA at the 2019 ARCS Annual Conference, Sydney, 6-8 August 2019

10 September 2019


These presentation papers are provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.

The Australian Government Department of Health (of which the TGA is a part) advises that (a) the presentation papers should not be relied upon in any way as representing a comprehensive description of regulatory requirements, and (b) cannot guarantee, and assumes no legal liability or responsibility for, the accuracy, currency or completeness of the information contained in the presentation paper.


  • Presented by: Dr Grant Pegg and Sarah May
  • Presented at: 2019 ARCS Annual Conference
  • Presentation date: 6 August 2019


Updates from the Pharmacovigilance and Special Access Branch

Dr Grant Pegg
Director, Signal Investigation Unit
Sarah May
Lead Inspector, Risk Management Section

ARCS Conference, 6 August 2019

Slide 1 - Updates from the pharmacovigilance and special access branch

  • Using new sources of data in Pharmacovigilance
  • Pharmacovigilance Inspection Program (PVIP) update
  • International collaboration activities
  • Adverse Event Management System (AEMS)
  • Q and A

Slide 2 - Data in pharmacovigilance

  • Where are we?
  • Where do we want to be?

Slide 3 - Using new sources of data in pharmacovigilance

Expert Review of Medicines and Medical Devices Regulation (MMDR)

  • The Panel recommends that the Australian government develop a more comprehensive post-market monitoring scheme for medicines and medical devices. Such a scheme to include:
    • Better integration and timely analysis of available datasets, including analysis of matched de-identified data from the Pharmaceutical Benefits Scheme, Medical Benefits Scheme, eHealth records, hospital records, private health insurance records and device and other relevant registries and datasets

Slide 4 - Using health data for pharmacoepidemiology

  • Types of available data
    • Prescription and dispensing, e.g. Pharmaceutical Benefits Scheme (PBS) data
    • Medical services, pathology, imaging, e.g. Medicare Benefits Scheme (MBS) data
    • Hospital discharge data
    • Birth and Death registries (state-based in Australia)
    • Australian Cancer Database
    • General Practice clinical data, e.g., NPS MedicineInsight data
    • Sales data, e.g. IQVIA
  • Linked datasets
    • Sax Institute 45 and Up study
    • National Data Linkage Demonstration Project dataset
    • *coming soon* National Integrated Health Services Information Analysis Asset

Slide 5 - Using health data for pharmaco-epidemiology


  • Potential for large cohort numbers
  • "Real-world" exposure
  • Better population coverage
  • Better generalisability


  • Lack of certain types of information - residual confounding
  • Requires exposure and outcome to be measurable in the available dataset

Slide 6 - Impact of pharmaco-epi on medicines egulation

Examples of studies which have lead to product information document changes

Slide 7 - TGA use of health data for pharmacovigilance

Two feasibility studies:

  • Signal detection: using prescription sequence symmetry analysis (PSSA) of PBS data
  • Signal validation: using the Sax Institute's 45 and Up study dataset

Slide 8 - Signal identification: PSSA

  • PBS data
  • Dispensings of a particular medicine (frusemide) used as a proxy for an adverse event (heart failure)
  • Imbalance between dispensings of the proxy medicine before or after initiation of other medicines in the dataset (index medicines)
  • Expressed as a ratio between the number of patients who received the index medicine before the proxy medicine compared to those who received the index medicine after the proxy medicine.
  • Positive signals (lower 95% confidence interval >1) investigated further.

Slide 9 - Signal identificaton: PSSA


  • 684 medicines included in the final analysis
  • 26 potential signals for heart failure detected
    • Majority were indicated for
      • Cancer
      • Glaucoma
      • Migraine
  • The heart failure signal was verified for one medicine during our internal evaluation; the Sponsor had independently identified the signal and submitted an SRR to update the Product Information during this process

Slide 10 - Signal validation: 45 and up study cohort analysis

  • The Sax Institute 45 and Up study
    • Cohort >250,000 participants, broad consent for linkage of survey data with a large number of state/federal administrative health datasets.
  • Examined the risk of intracranial haemorrhage with direct-acting oral anticoagulants compared with warfarin.
  • Results concordant with studies published using international data sources, including FDA mini-Sentinel, and New Zealand population data.
  • Limited by a small sample size, uncertainty about exposure classification (e.g. duration of warfarin treatment), and lack of information on the indication for treatment.

Slide 11 - TGA use of health data for pharmacovigilance

  • Two feasibility studies:
    • Signal detection using prescription sequence symmetry analysis of PBS data
    • Signal validation using the Sax Institute's 45 and Up study dataset
  • Increased resources for in-house data analysis
    • Recruitment of a biostatistician and an epidemiologist in PSAB
    • Access to population level linked administrative datasets

Slide 12 - ...towards national level linked health data

Investigating signals of interest

  • Rapid investigation
    • Number of individuals in the dataset exposed to the medicine
    • Number of relevant outcome events
  • If sufficient numbers of exposed individuals and outcome events, proceed to a full study with appropriate confounder management (different methodologies possible depending on the question, e.g. cohort, case-control, case-crossover).

Slide 13 - TGA use of health data for pharmacovigilance

  • Two feasibility studies:
    • Signal detection using prescription sequence symmetry analysis of PBS data
    • Signal validation using the Sax Institute's 45 and Up study dataset
  • Increased resources for in-house data analysis
    • Recruitment of a biostatistician and an epidemiologist in SIU
    • Access to population level linked administrative datasets
  • Academic partnerships and collaboration
    • Experts in pharmacoepidemiology from a number of Australian Universities

Slide 14 - Other types of data

  • Sales data
    • Useful for products not on the PBS, or where medicines are being prescribed privately, and for over-the-counter products.
  • Using IQVIA sales data to analyze the impact of the upscheduling of codeine
    • Converted number of packs to mg of codeine supplied to the market
    • Projected quantity of codeine that would have been sold if no upscheduling, based on supply trends over the previous 4 years.
    • Amount supplied following upscheduling was 46% less than projected, equivalent to a decrease in over 6900kg codeine supplied.
  • Significant decrease in the amount of codeine supplied to Australians

Slide 15 - Lessons learnt

  • Importance of appropriate expertise
  • Value of collaboration with academic partners
  • Using health data for this purpose is time intensive
  • Not all medicine safety signals can be analysed using this method
  • Australia is a small country → insufficient sample size for rare adverse events for highly specialised medicines.

Slide 16 - Future directions

  • Build rapid response capability
  • Concurrent analysis of Australian and Canadian linked administrative health data
  • Collaborate with international agencies on 'big data' in PV

Slide 17 - Pharmacovigilance Inspection Program (PVIP) update

  • Overview of PVIP to date
  • findings of interest
  • common findings around significant safety issues - a review of
    • Legislation
    • Management
    • Reporting
    • TGA actions

Slide 18 - Pharmacovigilance requirements

  • Therapeutic Goods Act 1989 (section 28(5e), 29A and 29AA)
  • Therapeutic Goods Regulations 1990 (Regulation 15A)
  • Pharmacovigilance responsibilities of medicine sponsors - Australian recommendations and requirements (Pharmacovigilance guidelines)
  • Conditions - standard and specific (Applying to registered or listed therapeutic goods under Section 28 of the Therapeutic Goods Act 1989)

Slide 19 - Overview of the PVIP


  • October 2015 to May 2016
  • Sponsor selection: volunteers
  • 10 PV Inspections
  • Average inspection time: 2.5 days
  • Conducted by 1 - 2 inspectors
  • 25 significant findings (critical, major)
  • 18 other findings (minor, observations)


  • September 2017 to July 2019
  • Sponsors selected based on 2018 risk assessment survey and internal intelligence
  • 16 routine PV Inspections
  • Average inspection time: 3 days
  • Conducted by 2-4 inspectors
  • 60 significant findings (critical, major)
  • 37 other findings (minor, observations)

Slide 20 - PVIP metrics 2017-2019


Slide 21 - Findings of interest (2019)

  • Social listening - collection of ADRs
  • Rogue social media sites - business rules for set up and management including monitoring of any social media by ANY staff member
  • Sales Managers/Representatives using up to date marketing materials and PI/CMI - ensure timely communication of new material and that out of date material is returned/destroyed
  • Due diligence in medical enquires- where individuals are enquiring about an ADR or use in as a special situation always ask if the product has been used? Is there an ADR?
  • Request and collect Aboriginal and Torres Strait Islander ethnicity data

Slide 22 - Findings of interest (2019)

  • Dangers of automation (automated reporting, seriousness, follow up rules etc.)- continual review of business rules to ensure accuracy and compliance with Australian requirements
  • Company clinical services not being considered as part of the sponsors remit
  • Due diligence in Market research activities- ensure contractors have valid contracts (with PV language), regular training of all staff, reconciliation of any ADRs and review of data.
  • Use of CRM software and free text fields- who is monitoring this for ADRs

Slide 23 - Pharmacovigilance Risk Assessment Survey

  • Second survey will be released in Early 2020
  • Will be similar to the survey published in 2017
    • With some further clarification in some areas
    • Some modified questions to define risk further

Slide 24 - Significant Safety Issues (SSIs)

  • A significant safety issue is:
    • new safety issue
    • validated signal
  • considered by sponsor in relation to their medicines that requires urgent attention of the TGA because of:
    • seriousness
    • potential major impact on
      • benefit-risk balance of the medicine
      • patient
      • public health
  • which could warrant prompt:
    • regulatory action
    • communication to patients
    • communication to healthcare professionals

Slide 25 - Examples SSIs reported to TGA in 2019

  • Actions taken by comparable international regulatory agencies:
    • Publication of safety alerts
    • Request for additional safety data
    • Request to update the PI relating to:
      • Contraindication
      • Precaution
      • SADR
  • Validated signals
  • Emerging Safety Issue (in-line with the definition in EU GVP Module IX)
  • A change in the nature, or frequency, of a known SADR

Slide 26 - Comparable international regulatory agencies

"Examples of significant safety issues include:

  • safety-related actions by comparable international regulatory agencies..."

Generally, comparable internal regulators for SSI reporting purposes relate to our organisation's list of comparable overseas regulators (CORs)

Slide 27 - Comparable international regulatory agencies

However, significant safety issues may arise from safety actions undertaken in countries not on this CORs list.

For example:

  • withdrawal of a product in Japan due to deaths or a life-threatening condition, or
  • cessation of a clinical trial being undertaken in China due to very serious adverse reactions identified.

Use your clinical and professional judgement!

Slide 28 - Safety information not considered SSIs

  • Publication on HA website in relation to the commencement of a study project or review relating to a safety issue where no further information is available to the sponsor
  • Changes to study protocols due to non-safety related reasons Safety information published on TGA’s Medicines Safety Update (MSU)
  • Labelling changes by HA to add a new serious ADR (where benefit-risk remains unchanged)
  • PSUR review by HA resulted in request to monitor specific drug-event pair in the next PSUR

Slide 29 - SSI management - step 1

Day 0 - Australian sponsor becomes aware of a safety issue

  • Consider developing local SOP, allowing prompt communication between AU-QPPV and global or local counterparts, such as regulatory team, signal detection team etc.
  • Since Australian definition of SSI may differ from overseas definitions of safety issues (e.g. from emerging safety issues defined by EMA GVP module VI or significant post-marketing safety issues defined by FDA), make sure that your global or local counterparts understand what constitutes SSI in Australia
  • Share your local process with all relevant parties to ensure that relevant safety issues are reported to Australian sponsor in a timely manner.

Slide 30 - SSI management - step 2

  • We expect you to use your professional judgement in determining whether:
    • Is it a significant safety issue?
    • Does it require urgent communication to the TGA?
  • If you determine that a safety issue is not significant and not reportable, you should document a justification for this decision (e.g. in SSI assessment tracker). If in doubt about a safety issue, treat it as significant or contact us for advice.
  • All pertinent factors should be taken into account when assessing a safety issue. Issues to consider:
    • the medicine
    • the risks involved
    • the regulatory context

Slide 31 - SSI management - step 2

  • Safety issue leading to international regulatory action is considered to be significant and hence reportable regardless of whether you agree with the recommendations and conclusions of the international regulator
  • Keep records of your assessment - we may ask you to provide this documentation at any time

Slide 32 - SSI reporting

  • Report SSI to the TGA within 72 hours of awareness
  • Reporting timelines are based on calendar days, including weekends and public holidays, and relate to the Australian sponsor
    • In writing to the PSAB Signal Investigation Coordinator, via email to:
    • When you report significant safety issues to us, indicate:
      • the points of concern
      • whether you plan to take any regulatory action in Australia for the medicine, such as:
        • changes to the risk management plan
        • amendments to the package label or product information document
        • distribution of a 'Dear Healthcare Professional' Letter
  • If no regulatory action is planned in response to the significant safety issue, you should provide justification for why this is the case in the Australian context.

Slide 33 - TGA management of SSI

Remember to keep the TGA informed as you review the issue and decide on any actions

We may request additional information:

  • the volume of sales or prescriptions of the medicine
  • details of the frequency assessment
  • copies of any relevant foreign adverse reaction reports you hold

We use the information you report to take appropriate regulatory actions, where necessary. After review we may:

  • provide further safety information to the public, e.g. via publication on TGA website
  • request updates to product information documents and labels
  • impose additional risk management interventions
  • impose additional pharmacovigilance activities
  • remove a medicine from the market

Slide 34 - Contact us

Slide 35 - International pharmacovigilance collaboration

  • International Post-market Surveillance Teleconference (IPMST)
  • Issue specific working groups
  • Medsafe/TGA collaboration/information sharing

Slide 36 - International Post-market Surveillance Teleconference (IPMST)

  • Current members: TGA (Australia), Medsafe (New Zealand), FDA (United States), Health Canada (Canada), Health Sciences Authority (Singapore), Swiss Agency (Switzerland) and MHRA (United Kingdom)
  • Meet bi-monthly
  • Started over 10 years ago
  • Ability to facilitate rapid response amongst network if needed

Slide 37 - International working groups

  • Issue specific
  • Usually co-ordinated by one lead agency with other participants within existing MOU arrangements
  • Objectives are information sharing, co-ordination and harmonisation across jurisdictions
  • Teleconferences/email groups as required

Slide 38 - Adverse Event Reporting

  • Adverse Event Management System
  • Electronic Data Interchange
  • AE data visualisation

Slide 39 - What are AEMS and the EDI?

Adverse Event Management System

  • Used by the TGA to collect, store and analyze adverse event data.
  • Replaced the former Adverse Drug Reaction System

Electronic Data Interchange

  • Functionality which supports the system to system transfer of adverse event data.
  • International format (E2B R2).

Slide 40 - Current state - reporting adverse events


  • EDI = Preferred method
  • Online = 2nd best
  • Email = 3rd best
  • Mil/fax = Last resort

Slide 41 - AE reports received by the TGA over time


Slide 42 - Source of AE reports received by the TGA


Slide 43 - Changing input channel for sponsor reports



Slide 44 - Feedback on data quality

  • Individual sponsor feedback
    • Sponsors contacted when issues identified
  • AE reporting FAQs
    • Identify common data quality issues and provide advice to all sponsors
  • Updates to pharmacovigilance guidance
    • Consider clarifying reporting requirements in guidance

Slide 45 - What do we do with reports?

TGA report

  • Signal Detection
    • Local - PSAB, Signal Investigation Unit
    • International - Data sent overnight to WHO (E2B R3 format)
  • Transparency
    • 90 day lag
    • Publication - Database of Adverse Event Notifications (DAEN)

Slide 46 - Better ways of engaging with AE data...

Slide 47 - END SLIDE

Print version

How to access a pdf document

*Large file warning: Attempting to open large files over the Internet within the browser window may cause problems. It is strongly recommended you download this document to your own computer and open from there.