- 22 Feb 2021
- 24 min
- 22 Feb 2021
- 24 min
In this episode, recorded on 17 February 2021, NPS MedicineWise CEO Adj A/Prof Steve Morris is joined by the head of the Therapeutic Goods Administration (TGA) Adj Prof John Skerritt to hear the latest information about COVID-19 vaccination in Australia, which is rolling out from this month. They discuss how the TGA makes decisions about which vaccines to approve in terms of both safety and efficacy, and how potential adverse events from the vaccines will be monitored as the vaccine is rolled out.
This information was current as at 17 February 2021. For up to date information please visit our Further Reading links.
COVID-19 vaccines – TGA approval process [video]: www.health.gov.au/resources/videos/covid-19-vaccines-tga-approval-process
TGA information on COVID-19 vaccines: www.tga.gov.au/covid-19-vaccines
Report a problem or side effect to the TGA: www.tga.gov.au/reporting-problems
Vaccines and COVID-19 – NPS MedicineWise article: www.nps.org.au/vaccines-and-covid-19
Welcome to the NPS MedicineWise podcast, helping health professionals stay up to date with the latest news and evidence about medicines and medical tests.
Hi, I'm Steve Morris, CEO of NPS MedicineWise, and welcome to our very timely episode of our podcast on COVID vaccines. I'm really pleased to welcome Professor John Skerritt, Deputy Secretary, Health Products Regulation Group. Hi, John.
Yeah, look, John, and thanks for making the time in what’s been an extraordinarily busy time for you. My first question to you is as at 17th of February , which is when we're recording this podcast, where are things up to with approval and availability of vaccines for COVID in Australia?
Well, we've approved two vaccines with what’s called in the Australian system provisional registration. That’s a full review, but it does reflect the fact that there's certain things no one knows about these vaccines, such as the duration of protection. So, the two vaccines that have been approved are the Pfizer one, that was on the 24th of January, and then on the evening of the 15th of February, we approved the AstraZeneca vaccine. We have two other vaccines for which a provisional designation has been applied for, the Janssen one (Johnson & Johnson) and the Novavax vaccines. We don't have full submissions from those vaccines because the clinical trials are still underway, in particular in the case of the Novavax vaccine.
Thank you, John. And what have we learned from international experience in terms of, I suppose, real-world experience of vaccine rollout?
We've learnt a lot. I mean, we talk to international regulators several times a week. For example, tonight, I think between 10:30 and midnight, I'm involved in yet another teleconference of heads of regulators. And one of the things that's being discussed, they're not only are regulatory considerations, but we do get to talk about how vaccine rollout is going, both in terms of preliminary evidence for efficacy, and there's some promising signs from Israel and from the UK on the early impact of vaccinations, but also we have discussions about any safety signals that are emerging. And again, there were some earlier reports of anaphylaxis for the Pfizer vaccine and so forth, but it's going pretty well as far as there are very few serious safety signals.
Thank you, John. And obviously, something that's been in the media quite a lot is about the efficacy of vaccines against emerging strains such as the South African variant.
The South African variant does appear to be a particularly tricky one, and we're still learning a lot about it. There was a study on a number of subjects – who on average were aged 31, so it’s a younger cohort, and indeed the efficacy of the AstraZeneca vaccine in that younger cohort did appear to be relatively low. However the Janssen vaccine, which uses similar technology, had higher efficacy against the South African one. It was lower than against other variants, but it was still quite high against serious disease. So, I think the jury's still out about the protection against the South African variant. We also don’t know how well these vaccines will perform in older age groups against this variant. The good news is that against the UK variant and the Brazilian variant, the vaccines still seem to be quite efficacious. There does seem to be some decrease in efficacy, but it is still the view of regulators overall that it’s important for people to be vaccinated where those variants are present. And, of course, a number of the vaccine companies have announced that they’re developing updated vaccines against the variants.
Now, variants of viruses, it comes with being a virus. Just about all viruses do mutate and some more than others. The most infamous, of course, are the seasonal influenza viruses where every year we have to have new vaccines because of strain changes. So, there's four main strains of that vaccine, and generally, at least one and sometimes two and even three have to change between years. Now, what this means for the rollout of COVID vaccines is governments worldwide, including here, are saying, "You'll still get good coverage. So, go ahead and please get vaccinated with the vaccines that are available."
It may well be that in 12 months' time, or even in eight or nine months' time if a strain such as the South African one becomes very prevalent in Australia, there'll be a need to have a booster with a vaccination that is targeted more on that strain, but it's an active area of vaccine development. But it's no reason not to be vaccinated because, quite frankly, there will be changes in strains of this virus. Just what it means in the long-term, no one knows, but the important thing is to have confidence to get vaccinated now.
Yeah, no, that's a really, really important message, John. Look, a lot of our listeners will be broadly aware of possibly the process of the TGA, but could you just give us a bit more insight into how the TGA goes about making decisions about vaccine approval in terms of safety and efficacy?
Sure. Well, what we don't have is a big dartboard in the tea room. So, we actually are data and evidence-based, and trust me, there's a lot of data. I was recounting the story with the AstraZeneca vaccine, it was. We just asked a particular question about toxicology in mice, and it was one element of a sub-element. And 859 pages later, we got the data from the study. So, we literally have tens of thousands of pages of data on these vaccines. And so, really, to look at it in three broad strands, clearly, the first and most important thing we look at with any vaccine is safety. And that ranges from experimental animal toxicology, teratogenicity, is there an effect on fetuses and the pups of, say, of mice and rats and other experimental animals right through to, with the initial phase one clinical trials where human safety is looked at through to the larger phase two and phase three trials.
So, both the common and the uncommon side effects have to be reported in a regulatory submission. And even if an efficacy cutoff is reached, in other words, numbers of patients protected versus those in the control arm is reached early, all regulators have asked that with the big clinical trials, participants have to be followed for at least two months. And that's because serious adverse events, if they do manifest, tend to manifest four to six, at most eight weeks, after the final vaccine dose. As it happens, we have a lot of safety information for many months longer than that because we're now six or eight or more months from when the first patients were vaccinated in these trials. And, of course, we also have a real-world experience of literally millions of people having had vaccines in the Northern Hemisphere now.
So, safety is first and foremost. Clearly, efficacy is absolutely important, and that's both from looking at the clinical trial arms of how many patients, say, in a US or a European environment where there's a lot of COVID around get COVID if they've been vaccinated with either a relevant vaccine or a saline versus the candidate vaccine. But, increasingly, on all patients vaccinated with both the placebo and the vaccine itself, the immune responses are looked at and these are both antibody responses, but a number of also indicators of cellular immunity. And so, they're also important measures for the potential efficacy of a vaccine. The final thing, which again, is also really important for vaccines is manufacture. It's much harder to consistently manufacture a biological product such as a vaccine to consistent standards, say, compared with a small molecule such as aspirin or a small molecule such as a statin medicine. It's much hard to make a biological molecule, especially some of these ones where it's relatively new technology, such as RNA technology or DNA vectors, and so forth.
And of course, you've got to make sure when a vaccine is made at several sites globally, and we are aware that the AstraZeneca vaccines, both being manufactured at various European sites, it's also being manufactured in Asia and also here in Australia, that it is consistent between those sites. And so, we look at the consistency, that it's the same product. We also look at contaminants, and we also look at the potency and stability of the vaccine. And individual batches of vaccines, unlike medicine, individual batches of vaccines are tested by our labs before they can be supplied. So, it's the work before an approval is very comprehensive, but as I'm sure we'll talk about later, it's really only the end of the beginning because the biggest piece of work with any medicine or vaccine is the post-market pharmacovigilance.
Yeah, thanks, John. Look, and in terms of post-marketing surveillance, what approaches do TGA take in terms of post-market surveillance, and how do you encourage consumers and healthcare professionals to report adverse events?
Okay, well, to go to your first question, what do we actually do with post-market surveillance. Well, we encourage reporting from consumers. There will be a healthdirect site that we'll talk about, symptom checker, because one thing with most vaccines is that there's what we call reactogenic responses. That can mean you can have a temperature. You can have pain at the injection site. You can have maybe even diarrhoea and perhaps even nausea, and you can have some myalgia. But these are quite common symptoms after many vaccines and they go away in 12, 24, 48 hours maximum. And while they can be unpleasant, it's certainly much less unpleasant than catching COVID-19. So, really, they're expected. And often just with a bit of counseling from whoever's doing the vaccination and paracetamol, if needed, people realise they'll have a bit of a fever or chills, but it'll pass. The things that regulators are particularly interested in are the more serious adverse events.
And while there can be some that emerge very soon after vaccination, and I guess the one that's been talked about most are a small but rare number of people who have had an anaphylactic reaction with the messenger RNA vaccines. And it's actually, probably not to the vaccine itself, but to the component in the vaccine solution, rather than the messenger RNA. What regulators are really interested in are the serious adverse events, serious, but rare. And talking about vaccines in general, and what we're looking at with the COVID vaccines, are neurological adverse events, such as Guillain-Barre syndrome, immunological adverse events, and this can be a multi-system inflammation, or it can be whether a vaccine enhances disease, acute respiratory distress, and cardiac injury coagulation disorders, and so forth.
Now, there hasn't been a strong association of those things, but the challenge that we have is, of course, cause and effect. We know that, and here's a rather sobering but sad statistic, in Australia, 160,000 people die every year of disease, of all sorts of things, of what we used to call old age. Do the maths, that comes down to about 3,500 a week, give or take. Divide by seven, that comes down to 500 people a day. Now, what that means is that just purely on the statistics, there will be dozens, if not hundreds of people in Australia who will die a couple of hours, a couple of days, a couple of weeks after having a coronavirus vaccination.
And so, the challenge for us is to see whether that heart attack, that stroke that person had, or something that isn't fatal but that development of Guillain-Barre, or multiple sclerosis, or another diffuse neurologic condition, was there attribution to the vaccine. And we do it a number of ways. We look at the background rates both in the target populations. What is the average 70 to 80-year-old cluster? What is the background rate of say, Guillain-Barre syndrome? And then you'll look at a vaccinated cohort. Has it increased? Is there a signal from that? We also look at every individual case report. So, if we get four or five case reports of people who have had myocardial infarction post-vaccination, we look at the detail in a forensic way with our medical officers, epidemiologists, and statisticians.
We also work closely globally with other regulators on adverse event reports because in the countries like the US where they’re not only are they several weeks ahead of us in rolling out the vaccine, of course, with a much larger population there, they have a greater chance of detecting rare but hard to track down and hard to attribute adverse events. And so, it's a global job looking at potential safety signals from vaccines. Where does the information come from and how to report? Well, companies are required to report all the reports that they have received and any significant signals globally. The agreements that the government is striking with GPs, and for a later phase of a rollout, pharmacists, require the GPs and the pharmacists to report adverse events. The state and territory systems that will be involved in the first lots of vaccinations are also, as a notifiable disease, they also must have adverse event reports received, processed, and submitted to us.
So, we will get a large range of adverse event reports. But individuals can also report adverse events directly to us. And there's a mobile-friendly web app. It does require a certain amount of information because just saying, "I had a shot and I don't feel well," obviously doesn't help us. So, we do drill down and ask some specific questions. So, that's what's generally known as spontaneous reporting. There will also be a program of so-called active surveillance, and that's based on text messages. It's going to go out to certain targeted groups of people and they'll receive text messages at various intervals after being vaccinated. And that information will also flow into our systems. So, we will have a very big piece of work in analysing adverse event reports and in drilling down to whether there's any significant safety signals from these vaccines.
So far, the global experience has been quite encouraging. But our role with this product and these products and every medicine and vaccine is to do a thorough job of detecting any possible safety signals. We then have to work out what an appropriate regulatory action is. And it could well be for a group of patients who might have a cluster of neurological conditions, they might be contraindicated from being a population of being vaccinated. At the moment, there aren't very many specific contraindications. There's obviously things such as have a discussion if someone's immunosuppressed and so forth, but there isn't a list of conditions where there's an absolute contraindication.
Yeah, thank you for that comprehensive overview, John. What's the message to clinicians and consumers in terms of the action they should take if they do believe they experience an adverse event or reaction to a vaccine?
Well, first and foremost, report. So, if it's a clinician, and we are working on further simplifying it for clinicians, but as clinicians will understand, we need to have a certain amount of information for a report to be useful and actionable. So, there are reporting contacts available on our website. There's a web-based form that's usable both on a smartphone, but also on a computer. And we are looking at even simplifying that system further with GP software in the coming weeks. But at the moment, as it always has been, doctors, and patients, and individuals are very strongly encouraged to report adverse events.
We would say, however, that people need to keep in mind that a range of relatively benign but still at times unpleasant events can happen with any vaccine within 24, 48 hours of getting it. There will be people who will get diarrhoea. There will be people who will have not insignificant muscle pain and may even have to spend a day in bed. But by and large, these are transient effects that go, and I guess in an earlier day and age, we would have said that's evidence of a vaccine starting to work. So, vaccines often are associated with these short-term so-called reactogenic effects. But what we're specifically interested in are the more serious ones that may manifest potentially soon but often when and if they do manifest, they come along some weeks later.
Yep, yep. Thank you, John. And just finally, what are your top critical messages to our listeners?
Well, the first message is we've been very busy looking at all the data on these vaccines. The vaccine development has happened in a relatively short time, but that is a reflection of the absolute size of the effort. There has not been an area of medical development that's had as many people, as many organisations, and to be crass, as much money thrown at it and thrown on it as well as COVID vaccine development during 2020 and 2021. And the fact that we have these vaccines developed in under 12 months is remarkable, but it also reflects the fact that literally billions of dollars have been thrown at the development and now the deployment of these vaccines. So, it is, to use that cliche, unprecedented. And that's why we're here where we are, plus we have some technologies that have enabled vaccine development to be much more rapid than the traditional methods.
I guess the second message is, similarly, TGA has done a very thorough and full review of these products, working collaboratively with some of the best global organisations in the world, such as European Medicines Agency. This has not been a rushed or a superficial evaluation at all. And so, while the end-to-end time was quicker than normal, it reflected that we had the receipt of data coming in what we call a rolling submission. So, as soon as companies have the data, they'd give it to us rather than wait until it was all complete. Normally, a company waits until they have a thousand pieces of data all assembled, beautifully organised in a wonderful file, all searchable, but we got each piece of data as it came through, and we had to put it together because then we could start looking at it as soon as we got it. I had several teams working at once rather than sort of in sequence.
And thirdly, and I've got a few people who are very, very tired, we've had teams working right through what normally would be the holiday period. I remember saying in the media in November that I'd told my staff to put away their swimsuits and towels this summer. Now, for better or worse, it was actually a fairly cool and wet summer everywhere so there wasn't much beach weather. But they wouldn't have had a chance to go to the beach anyway, most of them, and it's been a very busy summer. So, we've got the first two vaccines out there.
But, look, the final message is that we have committed to absolute transparency. So, we've put up information on what we do, but also on what we don't know about the individual vaccines on our website, www.tga.gov.au. We've also put up information on - so, that information includes all the considerations of safety and quality and the data that we still don't have, such as how long these vaccines last, or some of the bigger trials that will be ongoing for another 6 or 12 months. But the most important message is that people can have confidence that we have two very good vaccines out there. And if there are any safety issues that arise, we will be publishing every week a dashboard with some commentary on the major safety issues that have emerged. If there are significant issues, even those reported overseas, we'll report on it.
So, a few weeks ago, when there appeared to be some deaths in a nursing home or in a series of nursing homes, again, with people vaccinated with one of the vaccines, we reported that immediately plus the investigation. And then, when it was found that sadly, statistically, those people, and from looking at the individual cases, those 30 or so people had died of old age. They were very frail and probably in the last, in any event, the last week or two of life, there was no effect of the vaccine, we also have published that straightaway. So, we have a commitment to absolute transparency here. So, the bottom line is get vaccinated, even if you're young and fit and not worried about the impacts of COVID itself. Because of the emerging evidence that these vaccines do seem to assist in reducing transmission, you could prevent transmission to a little old lady in the queue in front of you at Woolworths, your mother, your grandmother, and so forth. So, you're actually doing it for the broader community, not just for yourself.
Yep. Thank you, John. Look, and thank you for the kind of comprehensive overview of the process of assessment, post-marketing surveillance. I think all given our listeners a real understanding of what's been put in place and also, as you alluded to, the sheer commitment of yourself and your staff in the TGA to do what needs to be done in such a short space of time. So, I thank you for that, and I'm sure our listeners will also appreciate the work that TGA's done. In terms of COVID vaccine rollout, it's likely to dominate health care for the foreseeable future. So, John, we'll probably invite you back on in six months' time to see how we're progressing then.
Okay, thanks, John.
Righty-o. Bye bye.
Thank you. Thank you for listening.
For more information about the safe and wise use of medicines, visit the NPS MedicineWise website at nps.org.au.