Updates from the Pharmacovigilance and Special Access Branch Dr - - PowerPoint PPT Presentation
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 Updates from the pharmacovigilance and special
Dr Grant Pegg Director, Signal Investigation Unit Sarah May Lead Inspector, Risk Management Section ARCS Conference
6 August 2019
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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
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– 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
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– – – – – – 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
in the available dataset
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information document changes
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– 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
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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
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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
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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.
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– 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
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§ § – 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
case-crossover).
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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
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Useful for products not on the PBS, or where medicines are being prescribed privately, and for
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
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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.
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Concurrent analysis of Australian and Canadian linked administrative health data Collaborate with international agencies on ‘big data’ in PV
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Overview of PVIP to date findings of interest common findings around significant safety issues - a review of
Legislation Management Reporting TGA actions
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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)
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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)
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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
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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
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A significant safety issue is:
considered by sponsor in relation to their medicines that requires urgent attention of the TGA because of:
which could warrant prompt:
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Actions taken by comparable international regulatory agencies:
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
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“Examples of significant safety issues include:
international regulatory agencies…”
SSI reporting purposes relate to our
regulators (CORs)
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For example:
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
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Day 0 - Australian sponsor becomes aware of a safety issue
counterparts, such as regulatory team, signal detection team etc.
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
Australian sponsor in a timely manner.
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We expect you to use your professional judgement in determining whether:
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:
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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
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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
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.
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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
remove a medicine from the market
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For pharmacovigilance inspection-related enquiries: Pharmacovigilance.Inspections@health.gov.au
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Medsafe (New Zealand), FDA (United States), Health Canada (Canada), Health Sciences Authority (Singapore), Swiss Agency (Switzerland) and MHRA (United Kingdom)
network if needed
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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
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store and analyze adverse event data.
Drug Reaction System
the system to system transfer
EDI = Preferred method Online = 2nd best Email = 3rd best M ail/ fax = Last resort
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5000 10000 15000 20000 25000
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10 20 30 40 50 60 Consumer Health Professional Sponsor State/Territory Other % reports received Reporter type 2018 2019
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71% 26% 1% 2%
Email Online EDI
32% 9% 59% 0%
Email Online EDI
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Local PSAB, Signal Investigation Unit International Data sent
WHO (E2B R3 format)
Transparency
Publication Database of Adverse Event Notifications (DAEN)
90 day lag
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