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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

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Presentation

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

Transcript

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

Strengths

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

Weaknesses

  • 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

Results

  • 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

Pilot

  • 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)

PVIP

  • 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

ADD IMAGE

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: si.coordinator@health.gov.au
    • 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

AEMS

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

Slide 41 - AE reports received by the TGA over time

ADD IMAGE

Slide 42 - Source of AE reports received by the TGA

ADD IMAGE

Slide 43 - Changing input channel for sponsor reports

ADD IMAGE

ADD IMAGE

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

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