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Presentation: Updates from the Pharmacovigilance and Special Access Branch
The document provides updates from the Australian pharmacovigilance and special access branch, focusing on the use of new data sources for pharmacovigilance, including the development of a comprehensive post-market monitoring scheme. It discusses signal detection and validation studies utilizing various health data sets, emphasizing the importance of collaboration and expertise in pharmacovigilance activities. Additionally, it outlines findings from inspections and the management of significant safety issues within the regulatory framework.
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Presentation: Updates from the Pharmacovigilance and Special Access Branch
- 1. Updates from thePharmacovigilance and Special Access Branch Dr Grant Pegg Director, Signal Investigation Unit Sarah May Lead Inspector, Risk Management Section ARCS Conference 6 August 2019
- 2. Updates from thepharmacovigilance 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 1
- 3. Data in pharmacovigilance •Where are we? • Where do we want to be? 2
- 4. Using new sourcesof 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-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 3
- 5. Using health datafor 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 Asset 4
- 6. Using health datafor 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 5
- 7. Impact of pharmaco-epion medicines egulation • Examples of studies which have lead to product information document changes 6
- 8. TGA use ofhealth 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 7
- 9. 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. The prescription sequence can be visualised, as shown below. Figure 1: Temozolomide compared to frusemide ASR: 4.64, lowerlimit of 95% CI 3.26 8
- 10. 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 9
- 11. Signal validation: 45and 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. 10
- 12. TGA use ofhealth 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 11
- 13. …towards national levellinked 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). 12
- 14. TGA use ofhealth 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 13
- 15. Other types ofdata • 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. • www.tga.gov.au/media-release/significant-decrease- amount-codeine-supplied-australians 14
- 16. Lessons learnt • Importanceof 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. 15
- 17. Future directions • Buildrapid response capability • Concurrent analysis of Australian and Canadian linked administrative health data • Collaborate with international agencies on ‘big data’ in PV 16
- 18. 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 17
- 19. Pharmacovigilance requirements • TherapeuticGoods 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) 18
- 20. Overview of thePVIP 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) 19
- 21.
- 22. 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 21
- 23. 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 22
- 24. Pharmacovigilance Risk AssessmentSurvey 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 23
- 25. 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 24
- 26. Examples SSIs reportedto 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 25
- 27. Comparable international regulatoryagencies “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) 26
- 28. Comparable international regulatoryagencies 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! 27
- 29. Safety information notconsidered 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 28
- 30. 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. 29
- 31. 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 30
- 32. 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 31
- 33. SSI reporting Report SSIto 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. 32
- 34. TGA management ofSSI 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 33
- 35. Contact us • Forpharmacovigilance-related enquiries: Pharmacovigilance.Enquiries@health.gov.au • For pharmacovigilance inspection-related enquiries: Pharmacovigilance.Inspections@health.gov.au 34
- 36. International pharmacovigilance collaboration •International Post-market Surveillance Teleconference (IPMST) • Issue specific working groups • Medsafe/TGA collaboration/information sharing 35
- 37. 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 36
- 38. 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 37
- 39. Adverse Event Reporting •Adverse Event Management System • Electronic Data Interchange • AE data visualisation 38
- 40. What are AEMSand the EDI? • Used by the TGA to collect, store and analyze adverse event data. • Replaced the former Adverse Drug Reaction System Adverse Event Management System • Functionality which supports the system to system transfer of adverse event data. • International format (E2B R2). Electronic Data Interchange 39
- 41. Current state –reporting adverse events AEMS EDI = Preferred method Online = 2nd best Email = 3rd best Mail/fax = Last resort 40
- 42. AE reports receivedby the TGA over time 0 5000 10000 15000 20000 25000 Case Count per year 41
- 43. Source of AEreports received by the TGA 0 10 20 30 40 50 60 Consumer Health Professional Sponsor State/Territory Other %reportsreceived Reporter type 2018 2019 42
- 44. Changing input channelfor sponsor reports 71% 26% 1% 2% Jul-Sep 2018 Email Online EDI other 32% 9% 59% 0% Apr-Jun 2019 Email Online EDI other 43
- 45. Feedback on dataquality 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 44
- 46. What do wedo with reports? TGA Report Signal Detection Local PSAB, Signal Investigation Unit International Data sent overnight to WHO (E2B R3 format) Transparency Publication Database of Adverse Event Notifications (DAEN) 90 day lag 45
- 47. Better ways ofengaging with AE data… 46
Editor's Notes
- #5 While spontaneously reported adverse event monitoring systems are the backbone of pharmacovigilance, population level administrative health datasets offer benefits in terms of availability, relative cost to access and potential insights that might be gained into real world use of medicines. This was recognised in an independent review of the TGA’s regulatory functions, completed in 2016. One of the recommendations to come out of the review, which was accepted by the Government, was that post market monitoring be enhanced by a number of actions, including use of existing datasets relating to prescriptions and health services, and other clinical datasets. PSAB subsequently investigated how to meet this recommendation, and incorporate use of this data into our core business.
- #6 Administrative health data refers to data that is generated through the routine administration of health care programs. That is, its primary purpose is for something other than research. Examples include the data that is generated when a prescription is processed and dispensed under the Pharmaceutical Benefits Scheme, or when your doctor bills Medicare for an appointment, or an operation in a private hospital, pathology test or xray. Within these datasets, individuals have certain data elements that are used to identify them, such as date of birth, address, medicare number. These identifiers can be used to link other datasets so that we can see a bigger picture of an individual’s health, and interactions with the health system. For example, if we linked prescribing data to the cancer registry, we could look at the risk of developing certain types of cancer with specific drugs, and compare them to other drugs. Obviously there are lots of concerns about privacy and security of these datasets, which is why in Australia, we currently don’t have a national level dataset combining all of these elements. The division of responsibility for healthcare funding between state and Commonwealth means that we need agreement from all the states and territories to include data that they own (hospital data). There are a couple of datasets that have linked across a number of administrative datasets and different states, including the Sax Institute’s 45 and Up study, the National Data Linkage Demonstration and the National Integrated Health Services Information dataset (still in construction) which are coordinated by the Australian Institute of Health and Welfare.
- #8 Pharmacoepidemiological studies utilising administrative health datasets have already been used in for regulatory action internationally and in Australia. The Scandinavian countries have well established health datasets that cover the entire population of their countries and these are used extensively for research. In addition, private health insurance providers in the United States have extensive datasets that have been used for this type of research as well. These are three publications that have lead to PI document updates internationally.
- #9 Our first forays into using administrative health data involved two projects. One designed to evaluate signal detection using PBS data and a technique called Prescription Sequence Symmetrey Analysis, and the other was to validate using an Australian linked dataset to investigate a drug/adverse event association.
- #10 PSSA uses individuals as their own controls, so a separate control group is not needed. Using dispensings of certain medicines as proxies for adverse events ( in this case, we used frusemide as a proxy for heart failure), we look at the number of people who received dispensings of this proxy medicine and other medicines, and the balance between those who received the proxy before the other medicine and those who received it afterwards. This gives us a ratio which is adjusted for prescribing trends. For example, the figure shows that there are more people who received frusemide after commencing on another drug, temozolamide, than who received it before temozolamide was started. The arrow indicates when temozolamide started. We investigated this signal further and concluded that the evidence wasn’t supportive of a causal association, given the indication for temozolamide prescribing, but this demonstrates how signals might be detected using this technique.
- #11 In the end, we did find that the PSSA technique was a valid tool, although it was limited in how we might be able to apply it in future. One of the key benefits is that the technique only uses a single source of data, which is relatively easy for us to access as it is held by the Department of Health. We also find the PBS dataset informative regarding drug utilisation in the population, which gives greater context to the numbers of adverse drug reaction reports which we receive.
- #12 The signal validation project used the Sax Institute’s 45 and Up study cohort to examine the risk of intracranial haemorrhage with direct acting oral anticoagulants compared with warfarin. This was chosen as an example because there were other studies conducted on other datasets that we could compare results with, as well as protocols we could learn from. This particular study has broad consent from participants to link the results of a health-related questionnaire with multiple datasets, including PBS, MBS, Hospital, death and cancer registries. Our results were consistent with what has previously been published, but we did struggle with sample size given the limited population.
- #13 These two projects enabled the TGA to invest further in our internal capacity to undertake research of this nature. We subsequently recruited a biostatistician with expertise in handling large datasets, and an epidemiologist to form a new sub-team within the Signal Investigation Unit. We expanded our access to available data, including to the National Data Linkage Demonstration Project, and hopefully we will soon have access to the NIHSI.
- #14 Our aim is to be able to take newly detected signals, and to undertake rapid investigations of them within available datasets. These may involve simply a quick look at the number of individuals taking the medicine, and the total number of outcome events in the population, or if there are sufficient numbers in the dataset, proceeding to an adjusted study to investigate the association with appropriate comparators.
- #15 To assist us in this endeavour we are engaging with some of Australia’s leading researchers in this field from the University of Melbourne, the University of New South Wales, and the University of South Australia. These collaborators also bring with them access to other data sources, as well as invaluable experience and expertise.
- #16 To complement the current access to administrative health data, we have also procured IQVIA sales data to gain insight into utilisation of medicines not on the PBS, or where private prescription is common, or for OTC products. We used IQVIA data to evaluate the impact of the recent codeine upscheduling. The results of this were summarised in a TGA web statement, and we plan to publish more detailed findings in the future.
- #17 Our initial experiences with this new field of work in pharmacovigilance have taught us several lessons…
- #18 Through our academic partnerships we look forward to expanding our work in this area, and in particular we anticipate being able to undertake concurrent analyses of Australian and Canadian datasets.
- #25 Taking on board feedback received and the risk scored obtained in the first survey
- #27 FDA request new contraindications regarding a drug interaction PRAC recommendation to add warnings regarding a serious ADRs to the SmPC Health Canada request to issue DHCPL regarding a new serious ADR Company decision based on PSUR to update CCDS with new warnings regarding a serious ADR Company decision based on ongoing safety analysis to update CCDS with new warnings regarding a serious ADR HA request for a controlled distribution program (change in marketing authorisation) to address serious risks
- #28 In our PV guidelines, the definition of SSIs refers to ‘comparable international regulatory agencies’… These are international regulatory companies we consider to have similar pre- and post-market regulatory activities and guidelines.
- #30 Some examples of safety information that we receive that aren’t considered to be SSIs include
- #34 Provide updates as you complete reviews of the issue.
- #41 AEMS was launched in June 2018. It replaced the former Adverse Drug Reaction System. Electronic Data Interchange (EDI) functionality was introduced with AEMS. This functionality supports the system to system transfer of adverse event data in the international format E2B R2 which will make it easier for sponsors to undertake their adverse event reporting requirements. Online reporting forms were also enhanced. We have made recent enhancements to the EDI to improve internal notifications where unsuccessful processes occur in the gateway; introduce the ability to resend E2B R2 ACK messages to our trading partners and the addition of a prefix to the ACK file name for easier identification. > 20 sponsors are using the EDI. > 6600 cases submitted via the EDI
- #42 Bernadette
- #46 So what happens after we conduct and identify data quality issues? If we find discrepancies we will notify sponsors and request to change these. We are looking into putting together a FAQ in the future, after further review of cases. We also want to update the PV guidelines to reflect the new EDI. We review our data in a number of ways, we use Qlik sense for our data analytics, now before I go on, I would like to stress the importance of submitting appropriate reports with the correct medical terminology. For best practice and consistency we require you to match the ARTG/ingredient list. Where possible if you have the trade name please submit this, this is our preference. Now back to Qlik data analytics. We review data by using different variables; we can review trends by searching ingredients, trade names, reactions etc. We further conduct CLLs exporting this in a tabular format allowing for in-depth identification of coding errors. Such coding errors may include: Death as an ADR – this is an outcome. Name of disease followed by disease progression. Using MedDRA to code this, it will code up to the Disease, therefore it will appear as if the drug is causing the disease it is indicated for.
- #47 TGA uses these reports internally for signal detection but also sends them to the WHO for inclusion in the global PV database. This occurs every night via the E2B R3 format. Previously monthly in an older format. TGA also publishes accepted cases (ie meeting the criteria for a valid report) on the publically available DAEN, with a 90 day lag to allow for data capture.