Pharmacovigilance and expedited drug approvals with Professor Jennifer Martin

Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

Hello, I'm Dr John Dowden, the editor of Australia Prescriber. In this podcast I'm talking with Professor Jenny Martin who is the Chair of Clinical Pharmacology at the University of Newcastle. I'm particularly pleased to welcome Professor Martin as not so very long-ago Jenny was our first editorial registrar at Australian Prescriber. So welcome Jenny.

Thank you.

We’re going to discuss the article you wrote for the April issue of Australian Prescriber about pharmacovigilance. Jenny perhaps I can begin by asking you to explain what pharmacovigilance is.

It's defined as a science and activities relating to the detection, assessment, understanding and prevention of adverse events or any other drug-related problem. But I guess in day-to-day language we really think of it as around drug safety. We're worried about the way we detect side effects, the way we monitor side effects and we like to be able to then use that data to prevent side effects happening.

Can you give us maybe some examples of where pharmacovigilance has added to our knowledge of adverse reactions?

Well there is actually quite a large number in Australia but the most famous one is the example of thalidomide which was over 50 years ago now, and we actually picked up that that caused side effects here in Australia by the reporting of a number of birth defects, and after a while actually becoming aware that those birth defects were related to the use of thalidomide in the first trimester of pregnancy. There's been a number of others since then. Some of the newer drugs, for example lumiracoxib, which was pulled off the market not that long ago actually, and similarly we've had a statin pulled off the market and that was shown to cause significant muscle breakdown, kidney failure and then death.

Collecting information about adverse reactions is one of the main roles of the Therapeutic Goods Administration. Now back when you were the editorial registrar at Australian Prescriber you remember we used to distribute a blue card that health professionals could use to report adverse reactions. So, we don't distribute those anymore so how do we report adverse reactions nowadays?

Well in a way it's become easier for people to report them because they don't actually have to find the card and complete the form and make sure that that's submitted. They can actually do it online through the TGA website but we're really asking people, prescribers any way, to notify pharmacists as well so people can notify someone else to fill the form in for them online, or they can go directly to the TGA. There's also a phone line. Often when I ask people why they don't fill in, remember when we had the blue card and we didn't have high rates of reporting compared to some countries, we used to say maybe the doctors just had difficulty sitting down and filling in a piece of paper, but the reporting hasn't really improved and so we think it's actually much more complicated than just having the ability to ring someone or to fill in a form. We think it's that often people don't worry so much about it or they think that it's a known side effect so why should they report it. Or they might not actually appreciate that what they are seeing might actually be a side effect and a lot won’t report if they're not 100% certain that it is a side effect from the medication. So, they'll say well we won't report it just yet, we'll actually wait until we've got some more information.

That's interesting Jenny and if it is a known adverse effect is it worthwhile reporting? For example, if someone develops a rash while they're taking a course of penicillin, is that something that should be reported?

We're trying to get everybody to report anything that they think might be a side effect. In fact for lumiracoxib that was the way we started to get information , to start with, people thought oh no this is a new drug, it's very targeted therefore it won't cause any off-target effects and so for quite a long time we didn't actually appreciate that some of the things we were seeing such as renal impairment could be related to lumiracoxib so we didn't actually report those things. What we're really aware of now is that with new drugs, even if they're so-called targeted therapies, that they're very likely to have off-target effects.

And I believe that members of the public are also encouraged to report adverse events?

That's correct and that's a very important method of reporting. Patients themselves appear more keen to report side effects than some of the prescribers and again it may be cognitive bias that we have as prescribers where we think oh well I can think of another reason why they might have that problem or it's a new drug and we think it's the latest one and therefore it's unlikely to be as dirty as the previous drug. So, we have this kind of bias against, actually even thinking that it might be related, whereas I think for an individual patient if they're going to a doctor to get a drug treatment and then they're feeling unwell with a drug they're much more likely to report that either to their practitioner or hopefully also to the drug reporting line.

So, you have all these reports coming from doctors, pharmacists, members of the public. Where do they all go and who analyses them?

So, they do all go to the Therapeutic Goods Administration and some of the reports also go to an international monitoring system. There is actually mandatory reporting and audits for new drugs that are on the market. So, for example every six months the drug company themselves has to collect reports. It means that the Therapeutic Goods Administration is actually sitting on quite a large amount of data. The TGA is then able to look at that data and make a decision as to whether this is all just noise and unlikely to be related to the drug or whether there's actually enough information there to actually suggest that there actually might be a signal that this drug is causing a particular side effect that we may not have seen earlier on in the clinical trials.

Tell me, if I wanted to find out if a particular adverse reaction had been reported, is the database accessible?

Yesyou can get the data, but hopefully in time we can get a system that makes it easier for researchers and health professionals to be able to access that data.

Sure. Another area which is changing is that, in the past, new drugs had to go through extensive testing of efficacy and safety so by the time the drug was approved for general use we had a good idea about its adverse effects but in the 21st century we're seeing drugs that are being fast-tracked onto the market. Should we be concerned about the safety of these drugs?

Well the short answer is yes, we probably should be because I think we’ve even been worried about the amount of safety data that we've had even with the current reporting system. That is because most of the clinical trials are on otherwise relatively well people and we know that when those drugs get out into the real world often people are much more sick or they might be taking other drugs that interact with those therapies which , I think, why everyone's getting a bit more excited now about pharmacovigilance because having accepted and noted that we're actually realising that the new drugs that are coming through the fast-track provisional approval route will have even less data. They may not even have placebo-controlled data though they’ll just have for example early-phase clinical trial data. And look there are some merits with that sort of approach in the sense people that need access to a drug, for example with cancer or another life-threatening condition for which there's a huge unmet need, will have earlier access to that drug, but it certainly has got risks in terms of the fact that their safety has not been fully characterised.

So, it sounds Jenny like you think that there is a need for greater pharmacovigilance of these drugs which have been fast-tracked onto the market.

Yes, we do. I mean I guess sitting up in our academic and health institutions, maybe we see things differently to people that are on the ground dealing with pharmacovigilance but we would like the pharmacovigilance system to really be beefed up prior to the provisional approval pathway coming into force and I know that the Therapeutic Goods Administration have been open to discussions about this and about mechanisms to deal with it. I guess we're sitting on a timing issue because the provisional approval pathway will be up and going potentially towards the end of this year whereas a upgraded pharmacovigilance system will take a significant amount of money and it will take a significant number of people to actually think about how we’re going to streamline data collection and how we're going to be able to rapidly access that data and provide it back to prescribers.

Okay so how can we encourage health professionals to report suspected adverse reactions to these fast track drugs?

Well I think that the TGA should be acknowledged for actually moving in this area in the sense that they put a black triangle on these drugs that will go through the fast-track pathway and that should be a flag to prescribers that they don't have the usual efficacy in safety data when we're using them, and that the bar really needs to be lowered a bit in terms of what they think might be a safety concern. You know, Australian Prescriber sitting there as a key partner and has a key role in this and around its function of educating doctors that really it would be nice if we could use the skills and the people that we've got just to make sure that everyone out there is aware of what this black triangle actually means.

Sounds like an article for us to consider. Have you any other suggestions Jenny? I think in your article you mentioned possibly registry systems.

This has really given us an opportunity to think about what a world's best pharmacovigilance system should look like, and so I think that really what we were trying to do in the article is say well we don't really need to just make a few sort of improvements around the edges of the current system, really we could look at what would be a world-class system and how we could actually work towards that, and I guess we're seeing it also with the use of some of the unregistered products that are out there as well where it could be useful. So, for example, in the medical cannabis space is another area where we would really need to get much more open-minded about how we can collect this pharmacovigilance data. And registries was one idea because I think that there has been quite a lot of funding going to researchers for setting up particular registries with for example rare diseases or new drugs, but we'd still need some way of being able to ensure that that data was all collected and processed centrally by drug and therapeutic specialists that can actually look at whether this is likely to be an adverse event or not and how it should be recorded for the international registry. So I think that even if we have our own subspecialty registries here in Australia, we would still need some over-arching national system of data collection on these drugs that are used. Either because of their indication, or because they're on the provisional approval pathway, or because they're actually unregistered drugs.

Thank you for talking with us Jenny and thank you for your continuing support of Australian Prescriber.

Thank you John, my pleasure.

For those of you who want to read Professor Martin and Dr Linger’s full article it is available online in the April edition of Australian Prescriber. The views expressed by Professor Martin and myself are not necessary those of the publisher, NPS MedicineWise. This is Dr John Dowden signing off. Thank you for listening to our podcast.