Adverse drug reactions reporting

[Music] Welcome to the Australian Prescriber Podcast. An independent, no-nonsense podcast for busy health professionals.

Pharmacovigilance is a topic which is getting hotter and hotter. We rely on a system where the medicines and the vaccines that we prescribe and administer are as safe as they can be, but not all risks are evident at the time of registration. Some risks take time to emerge, and it's important that we are looking at these risks from the right way. Post-marketing surveillance that is looking for safety signals for the medicines already on the market, it's critical in helping us prescribe and practise safely. I'm David Liew, your host for today. I'm joined today by Claire Larter [Medical Officer, Pharmacovigilance Branch of the Therapeutic Goods Administration]. She and her team have written an article in the Australian Prescriber about how the process works, the intricacies required to do it well and what we need to do to support our system. Claire, thanks for joining us for today's episode.

Thanks so much for having me, David.

So Claire, let's drill down on this. Why is adverse event reporting important in this day and age?

Well, as you mentioned in your introduction, we do everything we can at the TGA to make sure medicines are safe and effective for their intended purposes before they're registered and permitted for use in Australia. However, as you identified, not all adverse events can be picked up in clinical trials. Rare adverse events that might only occur one in every 10 or 20,000 people, this can't be seen reliably in clinical trials. So when these medicines are approved for use, we need to make sure we continue to monitor their safety profile, so that any new and emerging safety issues can be picked up and most importantly communicated back to the people using prescribing and taking those medicines.

Are there particular reasons why we don't see those signals come up during the registration pipeline? Why does it take 5 or 10 or more years for some of these things to come to light?

So there's a couple of reasons. We have a thing called the rule of 3, which essentially means for an adverse event to be picked up, you need 3 times as many people as the rate of that adverse event. So say it only happens one in 10,000 people, you'd need 30,000 people in those clinical trials, and it's just not practical to have that many people in those trials and still get medicines to the market in a timely manner. Clinical trials are also tightly controlled to make sure we get really good quality evidence about the efficacy and effectiveness of medicines. But that does mean that not all populations are included in the trials and frequently, you won't have people that are as reflective of a real world usage, who have multiple diseases, multiple other medications, and just that more diverse patient population. So that's why we can't pick them up during every clinical trial. We do get a really good idea of the safety profile, but we do need to keep watching those medicines once they're in the market.

I guess the other thing that's really the weight on that post-marketing surveillance process is the changes that have occurred over time with the way that medicines are approved to try and get effective medicines to us more quickly. Can you talk us through a little bit about that and how that's reflected in the work that you do?

So there's a number of ways where we can get new medicines that are really promising to market more quickly. It doesn't involve cutting corners in the whole research and development programme, but there are some steps that can occur more quickly. The TGA does have a provisional approval pathway, which means that a really promising medicine that meets a clear and unmet clinical need can be approved on the basis of early clinical trial data. So those medicines are certainly watched more closely in our pharmacovigilance system, as well as there being ongoing requirements for clinical trials and further evidence to support their use.

And I think that's the kind of thing which we are starting to realise when we get medicines early that we get the chance to use them early, but we know that we've got to look for those safety signals. So tell us a little bit about how this works in practise. Who reports adverse events, and how do they get to you?

We have lots of ways people can report adverse events to us. For our pharmaceutical companies, which we call our sponsors, they have mandatory reporting requirements. So they must report any serious adverse events to us within a certain timeframe, and they also have ongoing obligations to monitor the safety of their medicines too. So if they detect a serious safety issue, they have to report that to the TGA as Australia's medicine regulator much more quickly than just the individual adverse event reports. But in terms of health professionals, we actively encourage, although do not have any mandatory requirements. We don't regulate health professionals at the TGA, but we really work cooperatively and strongly encourage health professionals to report any suspected adverse events to us. One of our key messages is you don't need to be certain, just suspicious because often it can be really difficult, particularly when a patient's starting a new medicine to know if the medicine has caused an issue or if it might be a coincidence or perhaps part of the underlying disease that you're trying to treat.

So we can report to the TGA through our online portal. We still accept fax and email, but we do much prefer the online portal because it gives a structure to the data comes in. And then we also encourage patients to report to us as well. So there is a 1300 medicine's line that patients can ring. We work in collaboration with 1300 medicine. They're staffed by pharmacists who can give that patient some advice as well. Whereas as a regulator, it's not our role to be giving individuals clinical advice.

So it sounds like you're getting really a breadth of different types of reports to try and capture different types of problems from different sources. It must be really hard to be able to put those all together and know what to do with them.

Yeah. So luckily we work with a lot of very clever people, and we've got great systems that have been developed not only in Australia but globally, which is looking for statistical signals in that data. So occasionally, we might start a safety investigation off the back of an individual adverse event report, but much more commonly, it will be a signal of a safety concern. So there might be a disproportionate number of reports for a certain adverse event for a particular medicine. And if we pick up that disproportionate signal in our data, we then look a little bit deeper, consider the medical literature, look at what our international regulatory counterparts are doing as well to see if other regulators have seen this issue. We also look at global adverse event reporting data. Australia is only a small country, so again, for those very rare adverse events, we might not have enough people taking that medicine to see those signals.

So maybe you can talk us through a recent example of when you've had a signal that's come up from adverse event reporting go on to be a TGA alert.

A good and recent example that's probably at the forefront of many people's minds is some of the adverse event reports that we saw with COVID-19 vaccines. So COVID-19 vaccines were developed more quickly in response to a very clear and unmet public health need, and they had very robust clinical trials. But again, it wasn't until they were used in a broader population that we did see some emerging signals of those really serious safety concerns. So thrombosis with thrombocytopenia syndrome is now a known risk of the AstraZeneca vaccine for COVID-19. But at the time those vaccines were developed, it wasn't clear that it would occur. Obviously, it was a very serious adverse event. So the first signal of those adverse events did come from overseas, and we were working really closely to share information with our international regulatory counterparts, which did mean that when we did get the first suspected case of this syndrome in Australia, we were able to identify, convene one of our vaccine safety investigation groups and look at the evidence available initially for that one case.

As the information evolved, case definitions were developed, which enabled us to continue to apply a standardised approach to looking at those suspected cases of thrombosis with thrombocytopenia syndrome. We got really good engagement from the community and particularly medical practitioners for reporting. We communicated to the public very quickly the occurrence and the information as it evolved.

At the other end of the spectrum, there's increasing awareness of the potential for peripheral neuropathy to occur with high doses vitamin B6. So vitamin B6, it's one of our Listed [Aust L] medicines, is regularly used by people and often as part of a supplement. So it has been known that high doses of vitamin B6 are associated with peripheral neuropathy for quite a long time. What the adverse event data has shown us though is that there are cases that occur at lower doses or in people taking multiple supplements leading to an unexpectedly high dose in those individuals.

So our investigation has determined that additional regulatory controls are required for these products. We've reduced the thresholds for which label warnings are required and also communicated to both consumers and health professionals to raise awareness of that potential safety concern.

You've got this beautiful table in the article in Australian Prescriber about some of the misconceptions about adverse event reporting, and I'd love to talk through them and to get your take on it. The first one that you've got here, the misconception is about adverse events should only be reported if serious recurrent or proven. I think a lot of people probably think that instinctively. What would you say to that?

So again, we'll use our favourite line of, you don't have to be certain, just suspicious. It can be really difficult to determine the causal relationship for an adverse event. And even when we have lots of information, it can be difficult. That's why we need volumes of data. So even with something like myocarditis, which is known for the COVID-19 vaccine, distinguishing for an individual whether it was a vaccine or perhaps an underlying infection that caused their myocarditis is really difficult. However, at a population level, which is really where the TGA is working as the regulator, we can see in our data if there's more cases than we would normally expect. So if our number of observed cases exceeds the expected number of cases, that's a really strong piece of evidence that that medicine might be associated with that adverse event. So if everybody waited to be certain for their individual patient, it actually makes our job a little bit harder.

We're looking at the whole data, medical literature, adverse event reporting, global adverse event international regulatory actions. So if you think it might be an adverse event, particularly if it's a serious one and/or one that you don't expect for that medicine, then please report it.

So I think another misconception commonly is that the adverse event reporting should only occur if they [the drugs] are prescribed medicines and vaccines, and other things that might be taken might not be relevant. Is that true or not?

Not at all. We really want to hear about any suspected adverse event for any product. If you're not sure if it's food or a medicine, don't worry. We work closely with our counterparts at Food Standards Australia and New Zealand. So if it comes to us [and] it should go to them, we share that information. Listed medicines are generally low risk, but that doesn't mean they're no risk. And we do absolutely monitor the safety of those medicines as well. And adverse events can also sometimes be a symptom of a [product] quality issue too. So if you have any concern, please let us know. It's really important when you're reporting to tell us all the medicines that your patient or you as an individual are taking. That can help us put the puzzle together.

I think another misconception is about the idea that only the person prescribing the medicine should be the one to report. What would you say to that?

Again, not at all. We're happy to take an adverse event report from anyone, and we'd prefer to get it 2 or 3 times than not at all. Pharmacists play a really key role in talking to patients about the medicine they're on, and patients often seek advice from their pharmacist when starting a new medicine. So they're a really key reporter of adverse events to us. Similarly, someone's GP may be the first to hear about an adverse event for a new medicine.

What about if I've just got one adverse event, should I bother reporting it? Should I wait for a few to come up, so they've got something more to take to the TGA?

We encourage you to report for any adverse event you're concerned about because again, if it's one of those very rare adverse events, hopefully, you won't be seeing many more, but we still, as a regulator, would want to know so we can determine if it's an adverse event that's related to that medicine, so we can then let other prescribers and consumers know.

The last misconception on this table is one which people might not always say out loud, but is a key one to address, this idea that it's actually hard to report. It isn't in practise, is it? Can you talk us through where we go to report and what we should be including in reports?

So our preferred method for people to report is through our online portal. So if you go to the TGA website or you type into your favourite search engine, ‘report adverse event TGA’, you'll very quickly get directed to our adverse event management system, which is our online reporting portal. There's some recently developed modules on the Australian Commission on Safety and Quality in Healthcare that talk you through the reporting process as well. So we encourage people to familiarise yourself with the reporting process through those modules. When you are reporting an adverse event, there's really 4 key things that we need to know. The first is about the reporter, so basic details about who you are and how we could contact you if we do need some more information. We also need information about the patient. We don't need to know who the patient is. We don't need any identifiable patient information. But things like age and sex are really helpful in characterising those adverse events. Obviously, we need to know what medicine it is that you are concerned about, and also what other medicines the patients are taking.

And lastly, we need to know what happened. What are the adverse events that occurred? What's the story of that adverse event occurring?

That sounds simple and achievable, and I think we've heard very clearly about why it's important. Any types of adverse events that you particularly want to hear about, even though they're all important? Are there things that we are really seeking to focus on right now?

Absolutely, and we know it's not practical for every adverse event to be reported to us. So the ones we really would like people to focus on, if they only have time to report a few adverse events, so it's really those serious adverse events, even if they are known, but particularly for known adverse events if they're more severe than would otherwise be expected. Unexpected adverse events are really important; that's how we find out those new safety signals. And also adverse events for new medicines. As we talked about earlier, clinical trials can't pick up all adverse events. So when a new medicine is being used, or even when an older medicine is being used in a new way or in a new population, that's the times when we expect we might pick up some new safety signals.

I can imagine in this environment, your team's constantly trying to make the process smoother and more effective. Are there things that you're working on at the moment, beyond those Commission education pieces, which will help to improve the process?

We certainly are. We're always looking for ways to make it easier to report adverse events, particularly for consumers and health professionals who we recognise are very busy. At the moment, we are making some changes in the background to our adverse event management system to modernise it, and we're very hopeful that these changes place us well for the future to really streamline that reporting for health professionals. I think we could all agree that the ‘Nirvana state’ for adverse event reporting would be that push of a button from either a prescribing or dispensing software, so that we're not re-entering data. So to be able to integrate reporting into the day-to-day practise of health professionals is really where we'd like to be. We're constantly looking for ways to improve how we work, not only with our international regulatory counterparts, but collaborating with academics and other organisations. We recognise that pharmacovigilance is a very big job and like most big jobs, it's best done in collaboration.

Well, thank you for all the work that you and your team put in to help us practise in the best way that we can. Thank you for joining us on the podcast today as well.

Thanks, David. It's been a real pleasure talking to you.

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The views of the guests and the host on this podcast are their own and may not represent Australian Prescriber or therapeutic guidelines. I'm on the PBAC Drug Utilisation Sub-Committee and Claire is a employee of the TGA. Thank you once again for joining us on the Australian Prescriber Podcast.