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In today’s talk I’d like to cover 3 main aspects of the RMP compliance program – why does RMP compliance matter? what is TGA’s approach to monitoring sponsor’s RMP commitments? and what happens if sponsor wishes to change its commitments after these were agreed?.
By the end of this short presentation I’m hoping you will have noted: (1) the RMP compliance program’s aim of ensuring RMP commitments are implemented in a timely fashion, (2) the importance of ensuring there is a clear mutual understanding of RMP commitments at the time they are agreed to and (3) value of using our new updated ASA template to record RMP commitments.
With this preview you may choose to end the journey here or perhaps hang in there with me for another 10 min of your time prior to final wrap-up session of the day:O)
During process of enabling a medicine to be supplied in Australia, a company has agreed to apply risk mgmt measures necessary for treating risks posed by product and to monitor and review product risks over time. This is communicated in the RMP.
Read first dot point aloud.
The RMP document is a written agreement of your commitments with respect to patient safety and is applied as a legally binding condition of registration. Compliance to your plan forms part of legal and ethical duties with respect to ensuring patient safety. The product approval letters you receive from TGA outline the legal provisions of the TG Act concerning non-compliance with conditions of registration.
Compliance activities ensures our combined partnership activities are not wasted.
It is noteworthy that for higher-risk products, specific conditions of registration may sometimes be applied in addition to implementation of the RMP document itself, including PV and Risk min activities. Such conditions of registration may be time bound and/or also have activities associated with them.
Check-in with you all on where we are at with the compliance program..…
As part of Medicines and Medical Devices Reforms (MMDR), TGA implemented a proactive system for monitoring compliance with the risk minimisation and pharmacovigilance activities committed to by sponsors in a product’s RMP. This RMP compliance program forms part of the enhanced post-market monitoring of medicines that accompanies a suite of reforms including the introduction of expedited approval pathways.
Ensuring ongoing patient safety is why we are doing this
Reassuring you that nothing that new is happening here, we just have some more time and energy to be making a list of your commitments and checking on it
There will be more information on how we do this over time, for now what we are trying to do is educate sponsors about the need to be specific and clear about what your RMP commitments are, how you are going to evaluate them and when you will report this to TGA because that is the basis on which TGA will monitor
As covered in an earlier session, TGA has recently updated the RMP guidance and ASA template to be clear on what TGA’s expectations are. Our primary aim is to make sure you are clear about that, and you’d do the things you said you would do because in the end that is what benefits patient safety.
The main aim of the program is educating sponsors on the need to ensure timely implementation of RP commitments and how to comply with commitments, not to ‘name and shame’ in the event of non-compliance
TGA’s overall compliance framework sets out approach to ensuring uniform and proportionate responses where non-compliance with regulatory requirements is identified. There are details on the TGA website about that.
In the next 2 slides I’ll talk about how the RMP Section will align its approach under the umbrella of the TGA’s compliance framework to ensure sponsor’s are complying with their commitments.
Accompanying documents: a Reminder email then a Formal Warning Letter – requires response within a specified timeframe, states how the non-compliance is to be addressed (e.g. CAPA required )
Escalation via internal processes in worst-case may lead to issuance of infringement notices, enforceable undertakings, civil or criminal penalties
In order to make this program effective and achieve its aim, TGA will not undertake desktop compliance audits for all products. Activities will be prioritised for compliance monitoring in a risk-based manner – that is how the program has been operating since 2018 and how it will continue. Read slide.. To reiterate, desktop audit doesn’t mean we are visiting you on site, it means that we are looking at the records we hold to determine whether sponsor has met its commitments.
We will also undertake random desktop based audit of sponsors’ RMP compliance to ensure non-prioritised requirements are met
Ensure post-market commitments are clear, specific, measurable and time-bound in the ASA Provide detailed commitments in the updated ASA template tables. There is now a revised ASA template following consultation. This is part of TGA’s continuing efforts to ensure that the industry is clear on our requirements.
Visual of the ASA updated template. *refers to requirement to submit clinical study protocols or reports as a condition of registration or to fulfil RMP commitments. This is what compliance officer is interested in knowing about.
Visual of the ASA updated template
Visual of the updated ASA template
Ensure timely communication with TGA when situation changes and you think your commitments may be compromised and heading towards non-compliance. This has come back in consultation feedback queries a few times on if sponsors are required to tell TGA every time they want to change something in the RMP.
Perhaps an example to use here would be that you are relying on an EU study for demonstrating effectiveness, and you hear from global that it is going to be late because of recruitment issues.
Another example might be that you have agreed a risk min plan with the TGA during evaluation but then pre-launch you receive advice that makes you feel that the plan agreed is impractical and you wish to propose a change.
In both cases, contact TGA with proposed changes, with reasons, so that RMP can be updated if needed and you have new set of clearly agreed commitments.
In the RMP compliance space, basically if you are changing a commitment that is a significant part of the RMS should engage with TGA on the proposed changes – e.g. reclassified safety concerns with similar RM might be fine to manage through a routine RMP update, but things we are really interested to know in compliance area is for instance where you have committed to have a controlled access program in place that you now want to stop or change that OR you have educational materials in place and are significantly changing the key messages or want to stop it. The updated RMP guidance talks about when to submit an RMP update and the need to seek agreement from us for significant changes.
We take a pragmatic approach to this. We may accept that you have an EU RMP in place, that global has negotiated with EMA, that from time-to-time EMA is going to ask you to change the summary of safety concerns or other things will change in the global RMP & in those cases would seek to understand why these things had happened. But unless there was good reasons for things to be different in Australia we’d be unlikely to ask you to do things differently from in EU. But things that pertain to Australian-specific RM or that TGA has specifically requested, then those things must be agreed with us before the change.
Here is a final example of an RMP compliance program activity: I’d like to work through a sponsor’s commitment to undertake a local additional risk minimisation activity and how this is likely to be monitored and tracked by an RMP compliance officer. The example is for the supply of an educational guide to GP prescribers
The sponsor stated that they were going to distribute EM to this group of HCP and they were going to evaluate it by using an EU knowledge and awareness survey with prefined success criteria included in the survey protocol and TGA had accepted that the market was sufficiently similar there for this product. It was agreed in the RMP evaluation that Sponsor would show effectiveness of EM in Australia based on the o/s survey result and by local EM distribution data and all this would be submitted in an evaluation report to TGA by May 2020.
Talk through the slide first on compliance vs non-compliance
There are a few matters that came up when that relate to compliance but are different from compliance, that are worth addressing at this point too.
-talk about the fact that the sponsor should be able to describe whether RMP will change as a result of evaluation
- What if the EU survey indicated lack of effectiveness? – this is not ‘non-compliance’ but indicates need to change risk min. Evaluation should provide sufficient info to draw some conclusions about reasons for lack of effectiveness, or sponsor should have plan to address this
- What if the Australian info indicated lack of effective implementation? – sponsor should be able to describe how it would improve implementation – would expect you to be able to demonstrate that you had undertaken distribution/implementation activities as planned
The RMP Guidance has been updated to provide clarification.
there will not be periodic audits for all products desktop based program, partnering with PVIP in some circumstances risk based–program focused on highest priority activities mentioned in earlier slide and ensuring sponsors are aware of the need to comply, there may also be random non-prioritised audits sponsors will be notified in the event and the communication will state any expected course of action and timelines for responding. So, no naming and shaming on TGAwebsite unless you have been ‘naughty’ and are operating in the opportunistic or intentional non-compliance space Only publish for serious non-compliance actions which are escalated to the enforcement team and result in actions like enforceable undertakings or suspensions or cancellations. RMP activities are carried out in the interest of patient safety/public health
Action should be driven by the nature of the risk and criticality of the RM activity to address it Company should already be thinking about this in the initial design of RM How critical is it that the measure proposed be viable and effective for patient safety? What is the threshold criteria for success of a measure? What is the plan if the measure proves ineffective? Communicating the negative outcome to TGA as soon as becomes known and provide information on your CAPA (e.g. if the routine PV is throwing up increased frequency of events compared to clinical trials data, and you know there is RM activity underway which should be addressing, need to do interim check-in – don’t always need to wait until outcomes are known. Decide to change strategy -initiate dialogue with TGA let them know….
Elspeth – I’d appreciate if you could cover the following feedback in your early presentation as that will be of most interest/alarm to audience.
Please clarify what type of compliance decisions/actions TGA proposes to publish (e.g. only those cancelled/suspended or prosecuted, not where an issue is identified initially?) and what level of detail would be expected to be published.
Not sure will use these for talk unless comes up in Qs: The RMP Guidance & ASA template has been updated to provide clarification.
Not sure will use these for talk unless comes up in Qs: ASA has been updated.
A wrap up? Talking points:
Presentation: Risk Management Plan compliance monitoring
Risk management plan (RMP)
Evaluator, Risk Management Plan Evaluation Section,
Pharmacovigilance and Special Access Branch
Why does RMP compliance matter?
• RMPs aim to ensure that the benefits of a medicine outweigh its risks by the greatest
• RMP document = written agreement applied as a condition of registration
• Compliance activities help to ensure that required risk management activities are
conducted, and appropriate risk management systems maintained
RMP Compliance Monitoring Program
MMDR reform for enhanced medicines vigilance
…..has been operating since 1 January 2018
• complementary to other established TGA activities
- RMP evaluation (2009)
- PVIP (2018)
RMP Compliance monitoring program
• Aim: ensure timely implementation of RMP
• Approach: cooperative compliance,
aligned with the TGA’s regulatory
RMP Compliance – help & support, inform & advise
• RMP evaluation will ensure RMP
– clearly documented
– feasible and measurable
• If we identify potential non-compliance, we
– contact you to clarify compliance status
– support you in developing a plan to
– continue to monitor to ensure future
RMP Compliance – correct behaviour and enforce
• If we identify continued non-compliance,
– formally request information on how
you will achieve compliance
– continue to monitor to ensure future
• Serious non-compliance will be referred
internally to TGA enforcement area:
– outcomes of these regulatory actions
may be published on the TGA website
• High priority activities, subject to periodic desktop audit, may include:
– Confirmatory studies for provisionally registered products
– Local additional risk minimisation activities (e.g. providing educational materials for review)
– Australian-specific additional pharmacovigilance
– Local studies to measure effectiveness of additional risk minimisation
– Some conditions of registration
• random desktop based audit of sponsors’ RMP compliance to
ensure non-prioritised requirements are met
General principles – 1 of 2
• Sponsor should ensure there is a clear mutual understanding of
commitments at the time they are agreed
• Contact TGA to discuss any areas of uncertainty
ASA template – Record of the PV plan
Table 2: Ongoing and planned additional PV activities
Submission to TGA*
and due date
ASA template - Record of implementation plan
Table 4: Australian implementation of additional risk minimisation activities
Target audience Implementation details,
including method(s) of
Timepoints for and
ASA template - Record of evaluation plan & deliverables
Table 5: Evaluation of additional risk minimisation activities
Additional risk minimisation activity Evaluation plan and criteria for
Submission of results to TGA:
deliverable and timeframe
General principles – 2 of 2
• Situation may change in the post-registration setting
• Ensure proposed changes to agreed commitments are
communicated to and agreed by TGA
Supply educational guide to GP
Evaluation plan and criteria for success Submission of results to
TGA: deliverable and
guide to GP
Initial and 2nd distribution completed to at
least 90% of target audience
EU survey of GP knowledge and
awareness, predefined success criteria as
per protocol in EU RMP
Evaluation report (EU survey
outcomes and distribution
information) to be submitted to
TGA by May 2020
Educational guide to GP prescribers
• What does compliance look like?
– sponsor submits EU survey outcome and report on local implementation by agreed date
– sponsor contacts TGA in advance of the due date to request change to RMP, with robust
• Signals for potential non-compliance:
– Sponsor does not submit by the due date, with no explanation
– Sponsor submits EU survey results but no report on local implementation
TGA contacts sponsor to determine status of commitment
“TGA should provide more detail, including format of the periodic audits for RMP
compliance and timelines to respond.”
there will not be periodic audits for all products
risk-based program focused on highest priority activities and ensuring sponsors are aware of the
need to comply
there may also be random non-prioritised audits
sponsors may be asked for evidence of meeting commitments during pharmacovigilance
sponsors will first be reminded of upcoming or due commitments
opportunity to respond with plan to correct deficiency
formal TGA notification in the event of non-compliance, expected course of action and timelines for
“Include guidance on what actions are required should RM measures prove to be
• Action should be driven by the nature of the risk and criticality of the RM activity to address it
• Company should already be thinking about this in the initial design of RM
̵ How critical is it that the measure proposed be viable and effective for patient safety?
̵ What is the threshold criteria for success of a measure?
̵ What is the plan if the measure proves ineffective?
• Communicate any negative outcome to TGA as soon as becomes known and provide information on
your plan to address deficiencies
Feedback on RMP guidance
“Monitoring and compliance should be stated to apply to
– Australia-specific RM activities
– implementation and effectiveness for Australia-specific RM activities
– outcomes of additional PV activities being the additional safety concerns identified by TGA
This will avoid ambiguity as to whether the monitoring extends to EU-specific activities”
TGA has published updated RMP Guidance and ASA template
Feedback on RMP guidance
“Provide additional guidance on the expected format of submission of the results of
RM effectiveness measures.”
• TGA has published updated RMP Guidance and ASA template