Updated reporting requirements for safety issues – understanding changes to the PV Guidelines - Webinar #2

Jessica Tidemann

Thanks. Welcome, everyone, and thank you for coming along. We hope today will be a useful session for you. We know that since we’ve been talking about the update to these Guidelines, and now finally being able to deliver them, that there’s been a lot of interest from sponsors. So hopefully today is an opportunity to come together to work through some of the changes.

So, as it says there on the title, and many of you would be aware, last week Tuesday, late on Tuesday, we published Version 3 of the Pharmacovigilance responsibilities of medicine sponsors, or briefly called the PV Guidelines. What we’ll be covering today is just the updated reporting requirements for safety issues.

That is the key part of this update, and so that’s what we’ll be focusing on and, in our initial presentation, giving you a high-level look at the key changes and then spending a large amount of… the bulk of the time, hopefully, on Q&A, as we know how important it is to be able to work through some of your specific questions and concerns.

So as many of you might have seen when registering, we are holding essentially this same webinar again on Monday. It will be covering the same content. Obviously, with different attendees, we expect there will be some variation in questions.

And then we do plan to hold another webinar towards the end of the six-month implementation period, because we recognise that we expect to get feedback and work through things over this period. So that will be… We’ll do some communication about that down the track. But this won’t be the last time that we’ll be available, is the key message there.

So, coming to… Actually, I will, just before I get into this… As Nishie mentioned, the Q&A will be opening for new questions later in the presentation. But you will see, and I can see many of you are already upvoting questions, we received many questions pre-submitted at the time of registration, thank you, as was an option.

And so, we’ve taken questions that were submitted for people registering for both today and Monday’s webinars, and we’ve put those in the Q&A to make sure that we work through those. So please feel free to upvote, and you will have the opportunity later in the presentation to submit new or separate questions. So just wanted to stress that.

So why have we made these changes? So, the key thing is to support timely responses by us, the TGA, to new safety information, and particularly from you as sponsors. We know from consultation that was done a number of years ago now, and ongoing feedback, that the previous version, Version 2.2 of the PV Guidelines, did not clearly explain reporting requirements, particularly for significant safety issues, and there was a lot of confusion about what did and did not fit the definition.

And as a result, we regularly received notifications either too early, where there wasn’t enough information available, or certain key pieces of information weren’t included, and noting that that created burden for sponsors and also then challenges for us in determining next appropriate actions for those issues. So, we made changes. And we have talked about this at ARCS for the last couple of years and did a consultation at the end of last year. And so, the aim, as I said, is to support timely response by us to new safety information.

The change is that we’re not intending to lessen the current requirements, so to speak, or leave safety issues out, but what we’ve wanted to do is better define which issues do genuinely need to be reported urgently in that significant safety issue or SSI category to allow more time for the appropriate review of non-urgent or other safety issues, or OSIs, which I’ll come to.

So, the hope being that the quality of notifications should be increased by making it clear to sponsors that there is more time to make the majority of notifications and enable the TGA to then act on all safety issues in a timeframe proportionate to the risk to public health.

And as we’ve said throughout this project, a key aim is to reduce burden on sponsors, particularly associated with that SSI short timeframe, and to ensure also that we’re best able to do our job properly with that information. Oops, I’m going backwards. Excuse me, learning to drive PowerPoint.

So, what are the key updates, which is of course what you’re all wanting to know. So, the key updates in Version 3, the most significant change being the two-tiered reporting system, which I will go into in more detail in a subsequent slide. We’ve also provided clarification that… And this is something that came up in response to our consultation, is to make it clear that serious quality defect issues or quality defect issues that could result in serious adverse effects are in scope or may be in scope of SSI reporting, depending on the issue.

So, this is where the defect issue or safety issue associated with it is likely to require prompt regulatory action by the TGA because it’s associated with a potential major impact to the benefit-risk balance of the medicine and/or public health. And as I said, I will articulate this further when I cover SSIs.

We’ve also refined… So, where a safety-related action is requested by a comparable overseas regulator, we have introduced an alternative procedure for sponsors of generic medicines to notify the TGA of this type of safety issue via a timely submission to align their generic product PI with the innovator product PI, where one exists.

So, this is to avoid again an issue that has come through strongly in consultation, of this potential issue of duplicate notifications, where you’ve got multiple sponsors in the market. So, sponsors of generic medicines will still have an obligation to maintain, to identify and report other safety issues with respect to their products. And again, I will cover this in more detail further down.

We have, as many of you will already be aware, introduced a safety issue reporting web form in place of… We were proposing throughout this process a form to make it clear what information we want and to introduce some consistency to reporting. But we have been able to actually develop a web form, with the aim to facilitate correct and complete reporting of safety issues.

And finally, we’ve also included a safety issue reporting decision tree, which is an appendix to the Guidelines, to provide a simplified reference when navigating specific issues. You will notice that there are other changes to the Guidelines, including some major formatting changes, particularly to the introduction and to the regulatory reporting requirements sections. And there’s also some other more minor content changes.

These, particularly the formatting changes, when making changes to specifically safety issue reporting requirements, it wasn’t possible to do that and make it clear without some of these changes. There’s also… We’ve worked in conjunction with the Pharmacovigilance Inspections team too… There are some other small changes.

So please make sure that you do explore the new, updated document and familiarise yourself with it. We certainly haven’t… Nothing is hidden. And today, in the webinar, as I said, we are going to be focusing on safety issue reporting requirements and those bigger changes.

So, as I said, probably the biggest change is this two-tiered reporting system, where we’ve essentially introduced a second category. We’ve got the significant safety issues and we’ve introduced the other safety issues. And this is, in large part, to assist with clearer definition of what is not a significant safety issue, but also to make it clear that we do want to know about these other safety issues.

So, the definition and scope of SSI reporting has been amended with the intention that only the most urgent and significant safety issues require reporting to us under this category. This SSI definition, we have somewhat aligned it to the EMA’s definition of ESI, or emerging safety issue, because we recognise the benefits of that.

But we ask you to understand that we are a significantly smaller regulator, and we have very different legislative underpinnings and requirements. So, these categories or definitions cannot be aligned entirely with the EMA’s ESI definition. But it’s certainly something that we’ve taken into consideration.

The 72-hour timeframe for SSIs does remain, noting that one of the other changes in this version of the Guidelines is that there is now a requirement to communicate, for SSIs to be communicated from global personnel to the Australian affiliate within 3 calendar days. So, for those working with global affiliates, then that is 3 days from global to Australia, and then in the event that it’s an SSI, a 72-hour timeframe that begins once the Australian affiliate is aware.

So, we got a lot of feedback about this timeframe, and I can tell you that we thoroughly considered that feedback, and there was a lot of internal discussion. But we ultimately determined it to be in the best interests of the Australian public to maintain the 72-hour timeframe to ensure we receive these genuinely urgent notifications in a timely fashion.

But we’re also identifying that the majority of these issues won’t be identified locally within Australia, and so we didn’t want to risk any increase in timeframes to our awareness of those, noting that there’s already a delay of up to 6 days, taking into account that 3-day global to Australia and then 72 hours, Australian affiliate awareness to the TGA. So that has been maintained.

I think it, and I’ll come to that, is that we expect SSIs to be the minority of issues, and I will come more to that in a subsequent slide. So, for other safety issues or OSIs, these are safety issues that may require action by the TGA but do not need to be actioned urgently, like an SSI, as they’re issues that are unlikely to significantly alter the benefit-risk balance of the medicine.

So, they might be changes recommended by a comparable overseas regulator to the product information or labelling that don’t fit the definition of an SSI. And we note that we want to know about these, regardless of whether the sponsor agrees with the conclusions of the comparable overseas regulator or not.

So it may be that a comparable overseas regulator has made a recommendation that you, as the sponsor, don’t agree with that. We still want to be notified of that issue, and then we can have our own discussions with you about that.

They may also be safety issues from any other source that have been internally assessed. So, you identify your own internal signal from adverse event reporting, literature, whatever that might be, and assess and determine internally that additional risk mitigation strategies are required. And again, we would want to be notified of those.

So, the timeframe for this, and this is a point that I appreciate can be a bit confusing, is within 30 days of the Australian sponsor’s awareness of the assessed safety issue or a determination being made. So, we’re not asking you to report these within 30 days of being aware of a potential issue. It’s actually that you’ve assessed and confirmed that there will be some sort of regulatory outcome undertaken. And I’ll come more to that shortly.

So, for SSIs, as I’ve said, they include major safety related actions by comparable overseas regulators, such as the withdrawal or suspension of the medicine’s availability, modification or removal of an indication, or perhaps the addition of a box warning or a new contraindication to the labelling.

It may also be major safety issues identified in non-clinical studies, so perhaps post-registration studies or trials or other issues that might be reported in published literature. And as I mentioned earlier, it may also be a quality issue or defect in the event that that issue could pose an immediate risk to public health, in which case it should also be reported as an SSI.

And this is where professional judgement needs to be exercised. And we’d love to be able to definitively say here what will and won’t be, but the reality is that it will vary case by case. And sponsors, internal staff will need to use professional judgement to determine whether or not something is a significant safety issue, and again, stressing that considering the seriousness and potential major impact to the benefit-risk balance of the medicine or to public health.

So, as I’ve said, that we expect these to be reported as soon as possible, but no later than 72 hours following the Australian sponsor awareness of the issue and reiterating again that new requirement of 3 calendar days for global personnel to communicate to Australian affiliate.

So just stressing again that SSIs, OSIs, regardless of the type of safety issue, these should all be notified to us via the new medicine safety issue electronic form. And so that is linked in the Guidelines. It’s also linked down the bottom of the webpage that the Guidelines are on.

And stressing that for an SSI, we recognise that when reporting within such a short timeframe, we don’t expect that you will necessarily have completed an assessment of the issue. You may be aware, and within 72 hours is a short time, so we don’t expect you to have all the answers at that point.

We do want you to make a notification. We want you to tell us about it. And then we can continue to work with you as further information becomes available or decisions are made. So, we acknowledge that for SSIs, that is not necessarily going to be a full, detailed notification, and the form has been set up to reflect that.

And as I say, again, we expect SSIs to be uncommon. There really are very few that meet this criteria, so addition of box warning, perhaps a contraindication because a new serious risk, potentially fatal, is identified for a particular population. We know this doesn’t come up often. So hopefully, this will be the minority of issues. That’s certainly what we expect.

Which then brings us to OSIs, which is essentially just about everything else. So, as I mentioned earlier, these are safety issues that do not meet the definition of SSI. There’s further detail on page 17 of the Guideline document. And so, this is issues that we want to have the opportunity to assess, but they don’t require our urgent attention.

And so, we’re asking for notification of these, as I said, once you’ve completed that internal assessment. And so within 30 days of a completion of an assessment, that is when we expect these to be notified. And I am going to shortly come to an explanation of what do we mean by assessed.

So, it is worth noting that the Guidelines do not define a timeframe for the completion of that assessment, but we expect your internal procedures to not allow for inappropriate delays in these assessments. And that is something we’re aware of, but again, we recognise that that varies, depending on the issue.

So again, they should also be notified to us via the medicine safety issue web form, and the different… As I said, with these other safety issues, we do expect that the notification should be complete, because that assessment should be complete. So, there should be detail of what the issue is, what actions you expect to take or not, and if not, why not.

So, this really covers the additional amendment to product labels, really Sections 4.4 through to 4.9, if there’s actions taken by a comparable overseas regulator. It might be internally identified and confirmed safety issues that you, as a sponsor, have identified that don’t meet the criteria of a SSI.

It’s worth noting here, we will be working on further specific examples to be included in an updated FAQs or frequently asked questions document, which we will be publishing after these initial two webinars, because we wanted to get the questions and see what came up to be able to inform that update to that document.

Just quickly, what do we mean by internally assessed, is it’s whatever you need to do to be able to give us a description of the safety issue. So, we don’t just want a couple of words of what’s the drug and what’s the issue. We actually want information about what’s the origin, the source, key dates, any available supporting evidence, which might be a summary of what the sponsor has undertaken, it might include key relevant documents in the event of recommendations or actions by a comparable overseas regulator.

And again, as I said, a really key part is what is your assessment of the risk and potential impact of the safety issue in the local context, and any actions that you propose to take in Australia, or, as I say, in the event that you’re not taking action in Australia, is a justification for not taking further action. And so, for these OSIs, given the much more generous timeframe, we really expect that information to be complete at the time a notification is made.

Just clarifying what I mentioned at the beginning as one of the key changes, this alternative procedure for sponsors of generic medicines. So, this is a new requirement, and a timely submission to align the generic medicine PI to the corresponding innovator product PI will be considered as a notification of that safety issue.

So, it is really important to be aware that in the event that there is no identifiable innovator in the Australian market or, for example, sometimes the innovator product might have withdrawn from the ARTG, that obligation to identify and report the safety issue lies with the generic sponsor, as per the standard SSI and OSI requirements and timeframes.

So, I think this will be something that generic sponsors need to consider case by case, because it really is for those products where there is a clearly identifiable Australian innovator and you have the option to update the PI to align with the innovator.

So generic sponsors also still have an obligation to identify and report all other SSIs and OSIs. So that is perhaps if they internally identify a signal. So, this new procedure is really for those comparable overseas regulator actions, to minimise that duplicate reporting. And so, this was introduced based on a similar approach used by Swissmedic.

So just a word on the reporting form. So, as I said, it’s linked in the Guidelines and also at the base of the page that the Guidelines are on. And we can make sure that’s available. And this is where we want all safety issues, significant safety issues and other safety issues submitted via this form. We want a separate submission or form for each separate safety issue you wish to report. So again, that will depend. If there are multiple different issues, perhaps for a same product but they’re otherwise unrelated, we do want those separate.

And when you submit a notification via this form, on the web page you will receive a notification that it has been successfully submitted, and you will automatically be emailed a copy of that form submitted for your records. So, at the beginning of the form, for those who haven’t used it yet, you will put in your contact email, and you will then receive a copy of that submission notification to your email.

At the moment, unfortunately, we had hoped to have the facility for direct upload of supporting documents to the form. That is in progress, and we didn’t want to delay getting this update out to you any further than we already had. So, in the event… So, in that email, you will also… It will note that you can then reply to that email to attach any relevant supporting documents, so as I mentioned, if you’ve got an assessment or summary document, if there’s a report from a comparable overseas regulator, anything else.

I want to stress, this is an interim measure, and our web team are working on the functionality so that direct upload of those documents will be available hopefully in the near future. I also wanted to acknowledge that we’ve already gratefully received feedback about the form via email, also some questions submitted for these webinars, and we are considering this.

So, this form is new. We wanted it to be easier. We don’t want to make things more difficult. And so, we are absolutely open to changes that are possible that would make this more straightforward for you. So, I just wanted to acknowledge that. And we will keep working with our web team, because we don’t want to build a web form that is supposed to make things easier that everybody curses every time they use it.

And finally, before we move into our Q&A section, just a note on the implementation period. So, as we’ve touched on, there is a 6-month implementation period for these changes relating to safety issue reporting requirements.

So, this period began on 1 August, last week, with the publication of the updated Guidelines, and will conclude on 31 January 2024. So, this is really from the point of view of recognising that it’s not appropriate or feasible to have an immediate switchover when there’s inspection requirements linked to these Guidelines.

So, we want to stress that during these six months, the requirement to report SSIs is still there, as per Version 2.2 of the Guidelines, and with that same 72-hour timeframe. All other changes to the PV Guidelines are encouraged and you are welcome to implement them into your internal processes as soon as… Immediately, if that’s preferable, and start reporting based on this two-tier significant safety issue and other safety issue categories.

However, what we’re saying is that the changes in the new Guidelines will not be enforced or inspected against until after that 6-month period. So, all existing, not-changing requirements in the PV Guidelines will continue to be enforced, but anything new in Version 3.0 will be in full effect from 1 February 2024. So, not landing that on you for immediate effect. And we’ll wrap it up. Thank you.