An overview of reform initiatives relevant to prescription medicines pharmacovigilance arising from the Review of Medicines and Medical Devices Regulation.

1. Spotlight on prescription medicine post-market reforms
Enhanced monitoring and compliance
Dr Claire Behm
Director, Signal Investigation Unit
Pharmacovigilance and Special Access Branch
Medicines Regulation Division, TGA
2017 ARCS Annual Conference

2. Background
• 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:
1. 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;
2. Establishment and maintenance of registries for all high-risk implantable devices;
3. Implementation of a scheme to alert practitioners and consumers that a drug is newly registered and to
encourage reporting of any adverse events;
4. Provision for electronic reporting of adverse events; and
5. Enhanced collaboration with overseas NRAs to share information relating to safety or efficacy.
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3. Background
• Government response to MMDR recommendation 27
The Commonwealth accepts Recommendation Twenty-Seven, with the exception of part 2. Consideration of
registries for high-risk implantable devices is being deferred until other work is undertaken (Recommendation
Twenty-Two). The development of a more comprehensive post-market monitoring scheme will enhance
consumer protection and complement existing post-market monitoring processes.
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4. Polling question
• Have you read our consultation paper on strengthening monitoring of
medicines in Australia? (yes/no)
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5. Summary of enhancements
• Black triangle scheme
• PI reformat
• Adverse events management system
1. Enhanced adverse event reporting
• Pharmacovigilance inspection program
• RMP compliance monitoring
2. Enhanced compliance with post-market requirements
• Adverse events management system
• Use of linked data sets to support signal investigation
3. Enhanced collection and use of data
4. Enhanced international collaboration
5. Changes to pathways for accessing unapproved medicines
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6. Black triangle scheme▼
• Provides means to identify new medicines
• Encourages the reporting of adverse events associated with their use
• The symbol and text will appear on the PI and CMI, and TGA-related materials
PI:
CMI:
▼This medicinal product is subject to additional monitoring. This will allow
quick identification of new safety information. Healthcare professionals are
asked to report any suspected adverse events.
▼This medicine is subject to additional monitoring. This will allow quick
identification of new safety information. You can help by reporting any side
effects you may get.
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7. Black triangle scheme
Inclusion criteria
• All new medicines, except:
– Biosimilars
– Seasonal influenza vaccines
• Medicines with a provisional extension of
indications
• Extensions of indication into significantly
different conditions or patient groups may be
included
– E.g. for an oncology to rheumatology indication
Implementation
• Scheme starts in January 2018
• 5 year duration for standard registration
• 5+ years for provisional registration
 Provisional registration period ± additional period
• Inclusion automatically lapses at the end of the
agreed period
• Intensive communication planned for health
professionals and consumers from late 2017 –
2019
▼
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8. Comparison to EU black triangle scheme▼
• Australian Black Triangle Scheme similar to EU:
– Wording that accompanies the symbol:
 the same (excluding reference to information about reporting adverse events in SmPC)
– Inclusion of symbol on medicine information is similar to EU:
 Will appear on Australian PI and CMI
– Inclusion criteria:
 Biosimilar medicines excluded in Australia, but not in EU
 In EU, medicines can be included based on PRAC advice
– Duration of inclusion is the same in EU
 5 years in EU for new medicines
 Duration for ‘conditional approval’ linked to post-market commitments
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9. PI reformat
• The PI is being reformatted to:
– Improve its usability for health professionals, by bringing critical clinical information to the front
of the PI
 indications, dosage and administration, contraindications, precautions, adverse events
– Align format with European Summary of Product Characteristics (SmPC), and NZ Data Sheet
• Transition to the new format will be over 3 years
– New medicines and any medicines with new PI information will be in the new format
 E.g. extended indications, safety updates
• All PIs in the market will be in the new format by the end of 2020
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10. PI reformat – high level changes
Current format
– Name of the medicine
– Description
– Pharmacology
– Clinical trials
– Indications
– Contraindications
– Precautions
– Adverse effects
– Dosage and administration
– Overdosage
– Presentation and storage conditions
– Name and address of the sponsor
– Poison schedule of the medicine
– Date of approval
Proposed format
1. Product Name
2. Qualitative and Quantitative Composition
3. Pharmaceutical Form
4. Clinical Particulars
5. Pharmacology
6. Pharmaceutical particulars
7. Medicine Schedule (Poisons standard)
8. Name and address of the Sponsor
9. Date of first approval (ARTG entry)
10.Date of most recent amendment
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11. PI reformat – detailed changes of interest
Current format
– Name of the medicine
– Description
– Pharmacology
– Clinical trials
– Indications
– Contraindications
– Precautions
– Adverse effects
– Dosage and administration
– Overdosage
– Presentation and storage conditions
– Name and address of the sponsor
– Poison schedule of the medicine
– Date of approval
Proposed format
4. Clinical Particulars
4.1. Indications
4.2. Dosage and administration
4.3. Contraindications
4.4. Precautions
Use in hepatic impairment, Use in renal impairment, Use in the
elderly, Paediatric use, Effects on laboratory tests
4.5. Interactions with other medicines and other forms of interactions
4.6. Fertility, pregnancy and lactation
Effects on fertility, Use in pregnancy, Use in lactation
4.7. Effects on ability to drive and use machines
4.8. Adverse effects
4.9. Overdose
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12. PI reformat – detailed changes of interest
Current format
– Name of the medicine
– Description
– Pharmacology
– Clinical trials
– Indications
– Contraindications
– Precautions
– Adverse effects
– Dosage and administration
– Overdosage
– Presentation and storage conditions
– Name and address of the sponsor
– Poison schedule of the medicine
– Date of approval
Proposed format
5. Pharmacology
5.1 Pharmacodynamic properties
Mechanism of Action, Clinical Trials
5.2. Pharmacokinetic properties
Absorption, Distribution, Metabolism, Excretion
5.3. Preclinical safety data
Genotoxicity, Carcinogenicity
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13. Pharmacovigilance inspection program (PVIP)
• PVIP being implemented from 1 September 2017:
– Sponsor information sessions in Sept/Oct
– Inspections to commence in 2018
• PV inspections will enable us to:
– verify sponsor compliance with their pharmacovigilance requirements (reporting AEs, significant safety
issues) and other related legislative requirements;
– educate sponsors to assist them to meet their requirements; and
– promote continuous improvement in pharmacovigilance
– safeguard patient safety by ensuring the ongoing positive risk benefit balance of a medicine in the
Australian context
 collect and collate current information on the safety and efficacy of your medicines(s)
 assess the risk/benefit balance of your medicine(s)
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14. Pharmacovigilance inspection program (PVIP)
• Routine inspections of sponsors will be prioritised based on risk, assessed
according to:
– Biannual PV risk assessment survey to be completed by sponsors
– Internal intelligence: including whistleblower information, information from
regulatory compliance, previous PV inspection history, overseas agency data
– Non-compliance to other TGA requirements: PSUR submission, RMP
commitments, GMP findings, PV reporting requirements, updating PIs
– Product risk profile
• Further guidance and information for sponsors will be published in a new PVIP
section of the TGA webpage from 1 September 2017
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15. Polling question
• Do you think your company is ready for a pharmacovigilance inspection
(yes/no)?
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16. RMP compliance monitoring
• Program to monitor sponsor compliance with additional risk minimisation and pharmacovigilance
commitments to begin in 2018
• Products will be prioritised for ‘active monitoring’. Actively monitored products are likely to include:
– Provisionally registered products
– NCEs that are members of new classes
– Products with serious safety concerns
– Products for which significant additional risk minimisation or pharmacovigilance activities are required (e.g.
restricted access or pregnancy prevention programs, registries)
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17. RMP compliance monitoring
• TGA will contact sponsors to determine status of activities when commitments fall due, for example:
– Have confirmatory safety and efficacy studies for provisionally registered products been completed on
time?
– Have additional risk minimisation activities been conducted as agreed and evaluation completed?
– Have proposed educational materials been provided for TGA review within required timeframes?
• TGA will work with sponsors to support compliance and correct non-compliance where necessary
• Monitoring will require up-to-date records of RMP commitments, so sponsors will need to ensure that:
– Dates and outcomes for important RMP milestones are clearly described
– Proposed changes to RMP commitments are notified to TGA promptly
• Further details in updated RMP guidance to be released for consultation in September 2017
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18. Adverse event management system
New and improved Adverse Events Management System (AEMS)
• AEMS will support system to system exchange of adverse event reports using standardised
international message formats. This will make it easier for sponsors to send adverse event
information to the TGA.
• The new system will also assist the TGA in enhancing its signal management capabilities through
more advanced signal detection and data analysis processes.
• Currently the TGA is:
– evaluating feedback from Sponsors as part of Beta testing of the EDI which is due to conclude
at the end of August; and
– developing an enhanced online AE reporting capability.
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19. Analysis of de-identified health data sets to support
pharmacovigilance
• Two feasibility projects in progress:
1. Prescription sequence symmetry analysis of PBS data to enhance signal detection
2. Analysis of data from the SAX institute 45-and-up study and linked services datasets to enhance signal
verification
• The results of these projects will inform future initiatives to used linked datasets to enhance post-market
monitoring in Australia
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20. Enhanced international collaboration
• Regular liaison with international regulatory agencies including:
– Post-market surveillance teleconferences
– Participation in International Coalition of Medicines Regulatory Agencies (ICMRA) pharmacovigilance
working group projects
– Work-sharing projects
– Information sharing projects
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21. Changes to pathways for accessing unapproved goods
Special Access Scheme
• SAS Category A – no change - notification
• SAS Category B – no change - application
• SAS Category C
– New access pathway under SAS
– notification pathway which allows health practitioners to supply goods that are deemed to have an
established history of use without first seeking prior approval. The goods deemed to have an established
history of use are specified in a list along with their indications and the type of health practitioner
authorised to supply these products for the respective indications
Authorised Prescriber scheme
• there is now an process which only requires submission to TGA of:
– Completed new Application form – which includes the previous Agreement to Treat form; and
– Ethics endorsement letter (or specialist college endorsement)
• Potential for increased duration of authorisation/approval times
Developing on-line portal for electronic submission of SAS and AP
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