Updates from the Pharmacovigilance andSpecial Access BranchDr Grant PeggDirector, Signal Investigation UnitSarah MayLead Inspector, Risk Management SectionARCS Conference6 August 2019

Updates from the pharmacovigilance and special access branch Using new sources of data in PharmacovigilancePharmacovigilance Inspection Program (PVIP) updateInternational collaboration activitiesAdverse Event Management System (AEMS)Q and A1

Data in pharmacovigilance Where are we? Where do we want to be?2

Using new sources of data in pharmacovigilance Expert Review of Medicines and Medical Devices Regulation (MMDR)– Recommendation 27:§ The Panel recommends that the Australian government develop a more comprehensive post-marketmonitoring scheme for medicines and medical devices. Such a scheme to include: Better integration and timely analysis of available datasets, including analysis of matched deidentified data from the Pharmaceutical Benefits Scheme, Medical Benefits Scheme, eHealthrecords, hospital records, private health insurance records and device and other relevantregistries and datasets3

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, eg IQVIA Linked datasets– Sax Institute 45 and Up study– National Data Linkage Demonstration Project dataset– *coming soon* National Integrated Health Services Information Analysis Asset4

Using health data for pharmaco-epidemiologyStrengths– Potential for large cohortnumbers– “Real-world” exposure– Better population coverage– Better generalisabilityWeaknesses– Lack of certain types ofinformation - residualconfounding– Requires exposure andoutcome to be measurablein the available dataset5

Impact of pharmaco-epi on medicines egulation Examples of studies which have lead to productinformation document changes6

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 dataset7

Signal identification: PSSA PBS data Dispensings of a particular medicine (frusemide)used as a proxy for an adverse event (heart failure)The prescription sequence can be visualised, as shown below.Figure 1: Temozolomide compared to frusemideASR: 4.64, lowerlimit of 95% CI 3.26 Imbalance between dispensings of the proxymedicine before or after initiation of other medicinesin the dataset (index medicines) Expressed as a ratio between the number of patientswho received the index medicine before the proxymedicine compared to those who received the indexmedicine after the proxy medicine. Positive signals (lower 95% confidence interval 1)investigated further.8

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 hadindependently identified the signal and submitted an SRR to update the Product Information during thisprocess9

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 ofstate/federal administrative health datasets. Examined the risk of intracranial haemorrhage with direct-acting oral anticoagulants compared withwarfarin. 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 warfarintreatment), and lack of information on the indication for treatment.10

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 datasets11

towards national level linked health data Investigating signals of interest– Rapid investigation§ Number of individuals in the datasetexposed to the medicine§ Number of relevant outcome events– If sufficient numbers of exposed individualsand outcome events, proceed to a full studywith appropriate confounder management(different methodologies possible dependingon the question, e.g. cohort, case-control,case-crossover).12

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 Universities13

Other types of data Sales data– Useful for products not on the PBS, or wheremedicines are being prescribed privately, and forover-the-counter products. Using IQVIA sales data to analyze the impact of theupscheduling of codeine– Converted number of packs to mg of codeine suppliedto the market– Projected quantity of codeine that would have beensold if no upscheduling, based on supply trends overthe previous 4 years.– Amount supplied following upscheduling was 46%less than projected, equivalent to a decrease in over6900kg codeine supplied. mount-codeine-supplied-australians14

Lessons learnt Importance of appropriate expertiseValue of collaboration with academic partnersUsing health data for this purpose is time intensiveNot all medicine safety signals can be analysed using thismethod Australia is a small country à insufficient sample size forrare adverse events for highly specialised medicines.15

Future directions Build rapid response capability Concurrent analysis of Australian andCanadian linked administrative health data Collaborate with international agencies on‘big data’ in PV16

Pharmacovigilance Inspection Program (PVIP) update Overview of PVIP to date findings of interest common findings around significant safety issues - a review of––––LegislationManagementReportingTGA actions17

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 theTherapeutic Goods Act 1989)18

Overview of the PVIPPILOTPVIPOctober 2015 to May 2016September 2017 to July 2019Sponsor selection: volunteersSponsors selected based on 2018 riskassessment survey and internal intelligence10 PV Inspections16 routine PV InspectionsAverage inspection time: 2.5 daysAverage inspection time: 3 daysConducted by 1 - 2 inspectorsConducted by 2-4 inspectors25 significant findings (critical, major)60 significant findings (critical, major)18 other findings (minor, observations)37 other findings (minor, observations)19

PVIP metrics 2017-201920

Findings of interest (2019)Social listening- collection of ADRsRogue social media sites- business rules for set up and management includingmonitoring of any social media by ANY staff memberSales Managers/Representatives using up to date marketing materials and PI/CMIensure timely communication of new material and that out of date material isreturned/destroyedDue diligence in medical enquires- where individuals are enquiring about an ADR or usein 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 data21

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 AustralianrequirementsCompany clinical services not being considered as part of the sponsors remitDue diligence in Market research activities- ensure contractors have valid contracts(with PV language), regular training of all staff, reconciliation of any ADRs and review ofdata.Use of CRM software and free text fields- who is monitoring this for ADRs22

Pharmacovigilance Risk Assessment SurveySecond survey will be released in Early 2020Will be similar to the survey published in 2017 With some further clarification in some areas Some modified questions to define risk further23

Significant Safety Issues (SSIs)A significant safety issue is: new safety issue validated signalconsidered 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 healthwhich could warrant prompt: regulatory action communication to patients communication to healthcare professionals24

Examples SSIs reported to TGA in 2019Actions taken by comparable international regulatory agencies: Publication of safety alerts Request for additional safety data Request to update the PI relating to: Contraindication Precaution SADRValidated signalsEmerging Safety Issue (in-line with the definition in EU GVP Module IX)A change in the nature, or frequency, of a known SADR25

Comparable international regulatory agencies“Examples of significant safety issuesinclude: safety-related actions by comparableinternational regulatory agencies ” Generally, comparable internal regulators forSSI reporting purposes relate to ourorganisation’s list of comparable overseasregulators (CORs)26

Comparable international regulatory agenciesHowever, significant safety issuesmay arise from safety actionsundertaken in countries not on thisCORs list.Use your clinicaland professionaljudgement!For example: withdrawal of a product in Japan due to deaths or a life-threateningcondition, or cessation of a clinical trial being undertaken in China due to very seriousadverse reactions identified.27

Safety information not considered SSIsPublication on HA website in relation to the commencement of a study project or review relating toa safety issue where no further information is available to the sponsorChanges to study protocols due to non-safety related reasonsSafety 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 PSUR28

SSI management – step 1Day 0 - Australian sponsor becomes aware of a safety issue Consider developing local SOP, allowing prompt communication between AU-QPPV and global or localcounterparts, such as regulatory team, signal detection team etc. Since Australian definition of SSI may differ from overseas definitions of safety issues (e.g. from emergingsafety 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 toAustralian sponsor in a timely manner.29

SSI management – step 2We 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 ajustification 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 toconsider: the medicine the risks involved the regulatory context30

SSI management – step 2 Safety issue leading to international regulatory action is considered to be significant and hence reportableregardless 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 time31

SSI reportingReport SSI to the TGA within 72 hours of awarenessReporting timelines are based on calendar days, including weekends and public holidays, and relate to theAustralian sponsor In writing to the PSAB Signal Investigation Coordinator, via email to: [email protected] 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’ LetterIf no regulatory action is planned in response to the significant safety issue, you should providejustification for why this is the case in the Australian context.32

TGA management of SSIRemember to keep the TGA informed as you review the issue and decide on any actionsWe 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 holdWe use the information you report to take appropriate regulatory actions, where necessary. After review wemay: 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 market33

Contact us For pharmacovigilance-related enquiries: [email protected] For pharmacovigilance inspection-related enquiries: [email protected]

International pharmacovigilance collaboration International Post-market Surveillance Teleconference (IPMST) Issue specific working groups Medsafe/TGA collaboration/information sharing35

International Post-market SurveillanceTeleconference (IPMST) Current members: TGA (Australia),Medsafe (New Zealand), FDA (UnitedStates), Health Canada (Canada), HealthSciences Authority (Singapore), SwissAgency (Switzerland) and MHRA (UnitedKingdom) Meet bi-monthly Started over 10 years ago Ability to facilitate rapid response amongstnetwork if needed36

International working groups Issue specific Usually co-ordinated by one leadagency with other participants withinexisting MOU arrangements Objectives are information sharing,co-ordination and harmonisationacross jurisdictions Teleconferences/email groups asrequired37

Adverse Event Reporting Adverse Event Management System Electronic Data Interchange AE data visualisation38

What are AEMS and the EDI?AdverseEventManagementSystem Used by the TGA to collect,store and analyze adverseevent data. Replaced the former AdverseDrug Reaction SystemElectronicDataInterchange Functionality which supportsthe system to system transferof adverse event data. International format (E2B R2).::39

Current state – reporting adverse eventsOnline 2nd bestEDI Preferredmethod:8*AEMSEmail 3rd best Mail/fax Last resort40

AE reports received by the TGA over timeCase Count per year250002000015000100005000041

Source of AE reports received by the TGA60% reports nalSponsorState/TerritoryOtherReporter type42

Changing input channel for sponsor reportsApr-Jun 2019Jul-Sep 2018EmailOnlineEDIotherEmailOnlineEDIother0%1% 2%32%26%59%71%9%43

Feedback on data qualityIndividual sponsor feedback- Sponsors contacted when issues identifiedAE reporting FAQs- Identify common data quality issues and provide advice to all sponsorsUpdates to pharmacovigilance guidance- Consider clarifying reporting requirements in guidance44

What do we do with reports?TGAReportSignalTransparencyDetection90 day lagLocalPSAB, SignalInvestigation UnitInternationalData sentovernight toWHO (E2B R3format)PublicationDatabase of AdverseEvent Notifications(DAEN)45

Better ways of engaging with AE data 46

Use of CRM software and free text fields- who is monitoring this for ADRs. 22 . Pharmacovigilance Risk Assessment Survey Second survey will be released in Early 2020. Will be similar to the survey published in 2017 . amendments to the packa