Pharmacovigilance forum Risk Management Plans (RMP) - a TGA update Dr Jane Cook Branch Head Post-market Surveillance Branch Monitoring and Compliance Division, TGA ARCS Scientific Congress 2015 6 May 2015

Why have RMPs been required? Limited information from clinical trials (CTs) Not always representative of real world usage due to inclusion and exclusion criteria in CTs Potential risks identified but not fully characterised during CTs Missing information in certain population groups – children, pregnant women and the elderly Pharmacovigilance forum

What is a risk management plan for? Outlines the risk management system for a medicine once it is available for use in Australia Comprises: Known safety profile Identified and potential safety concerns and where appropriate how they will be mitigated Missing safety information where this is known or can be predicted and how this will be managed Focuses on: Monitoring – Pharmacovigilance Plan Minimising risks associated with the use of the product – Risk Minimisation Activities Provides: Coverage of the life cycle of the product Assurance that all risks related to the use of a medicine have been considered and acted upon Pharmacovigilance forum

Risk minimisation activities Routine risk minimisation activities include: Product Information Consumer Medicines Information directions for use document the labelling the pack size and design the legal (prescription) status of the product Additional risk minimisation activities include: education programs for patients health care professional education programs Dear Health Care Professional letters controlled access programme Activities commonly misclassified as risk min or PV – be clear about what is what.  For each safety concern a risk minimisation activity is assigned in the RMP Pharmacovigilance forum

Pharmacovigilance Plan Routine pharmacovigilance includes: collection, follow-up and reporting of adverse events analysis of data and reporting in Periodic Safety Update Reports (PSURs) Additional pharmacovigilance includes: clinical trials post-authorisation safety studies drug utilisation studies patient registries physician surveys prescription event monitoring  For each safety concern a pharmacovigilance activity is assigned in the RMP Pharmacovigilance forum

Workflow of a RMP evaluation Pharmacovigilance forum

Guidance RMP Questions and Answers Australian-specific Annex Template Mandatory requirements for an effective application EMA Guideline on good pharmacovigilance practices: Module V – Risk management systems RMP co-ordinator (rmp.coordinator@tga.gov.au) Pharmacovigilance forum

ARCS-TGA RMP workshop At the workshop in March, we discussed: The new Q&As When an RMP is required The purpose and format of the Australian-specific Annex (ASA) When to submit post-market RMP updates How to evaluate the effectiveness of risk minimisation activities There’s no ‘one-size-fits-all’ approach to RMPs Refer to guidance Use judgement Ask us if uncertain about requirements and process Workshop presentations now available on TGA website We found the workshop a valuable opportunity to meet people working on RMPs in industry so we could: Better understand some of the challenges you face Break down the barriers to communication Pharmacovigilance forum

Revised RMP Q&As Proposed updated Q&As and ASA template sent to Medicines Australia and GMIA for members’ comment (Nov 2014) Main themes of feedback: reduce duplication, clarify process Final revised Q&As and ASA template provided to workshop attendees in March No substantive changes to requirements ASA template better described Clearer explanation of process and requirements Ability to add further questions and answers as they arise Will soon be available on the TGA website The RMP Questions and Answers provide guidance to industry about how the TGA treats RMPs We provided you with the revised RMP Q&As to workshop attendees in March. To recap: Before this, the last time the Q&As were updated was in 2012 In late 2014, the TGA sent out a proposed revised Q&A for members of Medicines Australia and GMIA to comment on. We also provided a more detailed template for the ASA than we had previously provided, as this was something that sponsors had consistently asked us for. The revised ASA template was started by an ARCS working group – who we thanks for their work – and we built on what they had done We had a good number of responses to the consultation, and these were constructive and comprehensive – thanks The key themes of the responses were: Reduce duplication in the ASA template: sponsors felt they were being asked to extract info from the EU RMP and reproduce it verbatim in the RMP – the value of this was questioned Clarify processes, especially around: When an RMP is required or not required and what to do if you’re unsure When to submit an updated RMP to the TGA We revised the Q&As and ASA in response to this feedback, and the final version of the doc was provided to attendees at the workshop in March. The revised Q&As document will soon be up on the TGA website – we have been doing some further work on it to make it simpler and clearer. The document that goes up onto the TGA website will look a little different from the one you received at the workshop, but there are no changes to our requirements or the overall substance of the document. If you would like a copy of the Q&A document in the meantime, please contact the RMP co-ordinator – but the document should be up on the website in the coming days. Pharmacovigilance forum

When is an RMP required? A New Chemical/Biological Entity An RMP is always required for: A New Chemical/Biological Entity Higher risk (Class 3 and 4) biologicals Biosimilars Vaccines Generic medicines where innovator product has additional risk-minimisation activities (check AusPAR, list in Q&As, ask if uncertain) Pharmacovigilance forum

When is an RMP required? An RMP is usually required (but case-by-case consideration): Where the change to indication includes the following: significantly different population paediatric patients significant change in prescriber profile Identification of a new safety concern New route of administration, dosage form or strength has inherently higher risk e.g. oral tablets vs iv injection) Significant safety issue with one or both active ingredients in combination products Requirement to submit a RMP will be reviewed at the PPF stage by the RMP team - Decrease in RMPs and consequently PSURs to be submitted - Routine pharmacovigilance activities maintained Pharmacovigilance forum

Not sure if an RMP is required? Contact RMP coordinator well ahead of PPF lodgement – it’s never too early! Provide: trade name/generic name indication (for generics: identical to innovator?) strength, dose form and route of administration (for generics: identical to innovator?) We will respond in writing Pharmacovigilance forum

RMP format EU RMP + ASA If there is no current EU RMP, then a global or core RMP + ASA RMP version most recently accepted in EU, or one under consideration in the EU? Will depend on the specific circumstances Let us know that there is a different version under consideration Contact the RMP co-ordinator for advice if uncertain If there is a new version of the EU RMP under consideration please let us know – if you can tell us when it is likely to be available this will help us to plan our effort. We don’t like surprises! Pharmacovigilance forum

Australian-specific annex Adapts the EU (or core/global) RMP to the Australian context Why is Australia different? Indigenous population Large Asian population Rurality/lack of access to specialist services State vs federal control over some aspects of how medicines are used Additional activities may require adaption to Australian systems Australian PI vs EU SmPC ASA is not a complete RMP but supplements the EU RMP (or core or global RMP) ASA should always be provided with RMP, including unsolicited submission of RMPs and RMP updates Updated template in Q&As was developed with stakeholder input, and in response to requests from industry – is more detailed than previous version and aims to minimise duplication for industry Pharmacovigilance forum

Australian-specific annex Required whenever an RMP is submitted (including updates) unless there is no EU RMP and an Australian RMP is submitted ASA template sets out preferred format Other formats are acceptable if they contain the same information Flexibility to change/add information to address different situations, e.g: additional safety concerns for Australia additional indications in Australia At workshop, a few questions were about how to identify differences between EU and Australia where there were additional safety concerns applicable for Australia that didn’t appear in the EU RMP, or where an indication was being sought in the EU that had not yet been sought/approved in the EU – the ASA is the appropriate place to highlight these differences Pharmacovigilance forum

When to submit an updated RMP Do submit an update On TGA’s request If significant changes to the RMP: new information that may change risk/benefit profile changes to safety concerns pharmacovigilance and/or risk minimisation activities added, terminated, or substantially altered Don’t submit an update Routine document updates (EU guideline) Updates unrelated to product’s safety profile Pharmacovigilance forum

When to submit an updated RMP We’ve completed a commitment in the ASA (e.g. a mail out of educational material to patients and prescribers). Should we update the ASA and resubmit to TGA? Conducting one step (e.g. a mail out) of a multi-step process as part of an ongoing risk-minimisation commitment would not appear to create a material change to the RMP, therefore no requirement to submit an updated RMP to the TGA If evaluation of effectiveness of a risk minimisation activity has been completed, can submit the results and conclusion of the evaluation TGA will need to accept any proposal to amend the RMP/ASA Pharmacovigilance forum

Top RMP tips Provide the EU RMP (if there is one) and an ASA Make sure all the information asked for in the ASA template is provided Provide all documents referred to in the RMP and ASA Address all RMP evaluator recommendations Whenever there’s an update, state clearly what has changed and why Ask us if you’re uncertain – rmp.coordinator@tga.gov.au Pharmacovigilance forum