• 26 March 2024
  • 17 min 37
  • 26 March 2024
  • 17 min 37

Jo Cheah chats with clinical pharmacologist Richard Day about off-label prescribing. Ric explains why off-label prescribing occurs, the barriers to getting new indications added to a drug’s approved label, and the potential risks of off-label prescribing without sufficient evidence. Read the full article by Richard Day in Australian Prescriber.


The more indications for a drug that are starting to appear, then the company could be asked, over and over again, to update this product information each time with a cost and time resources.

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

Hi. Welcome to the Australian Prescriber Podcast. My name is Jo Cheah. I'm a hospital pharmacist in Melbourne and your host for this episode. It's a pleasure to be speaking with Richard Day, Professor of Clinical Pharmacology at the University of New South Wales Sydney and St Vincent's Hospital Sydney. Welcome, Ric.

Thank you. Thanks for having me.

Ric has written about the ongoing challenges of off-label prescribing in Australian Prescriber. I found this article really interesting because I work in a paediatric hospital, so where off-label prescribing is very common. And I also do work in clinical trials, and we will go into it a bit in the episode, where we talk about why certain patient populations are excluded from clinical trials. So I'm very keen to get into it. So, Ric, just to start off today, can you start by defining off-label prescribing?

So what it is is that a drug or medicine, when it's registered in Australia by the TGA, Therapeutic Goods Administration, it is registered for particular indications and oftentimes for particular age groups of people. In addition, there are other parts of the indication [related to] how the drug's going to be given. Is it given by mouth, or is it given by the vein? So what happens is that the sponsor of the drug applies to the TGA to have the drug registered for these particular purposes under these particular conditions, age groups etc. If the drug is being used for something that isn't covered in those indications, that's considered off-label.

Off-label prescribing is much more common in vulnerable patient groups like children, pregnant women, people with mental health disorders, and older people, as these patient groups are often excluded from clinical trials. Can you discuss why these patients are excluded from clinical trials in the first instance?

It's harder to do clinical trials, perhaps for ethical considerations, in young children. Of course, the child's parents need to give consent, and parents are very protective, rightly. Similarly, very elderly patients are difficult to study and have included in trials again sometimes because of their location and inability to come to research centres.

Also, the matter of gaining consent there could be difficult, and you can see how that extends to certain disadvantaged groups, socioeconomic groups, people with mental illness. A big one, of course, is pregnant women where, again, there's a great concern about being exposed to any medicines. So it's more difficult, and it's more expensive, and there's sort of resistance points. There's ethical resistance points. There's design-of-study points that all make it harder. So this leaves large swathes of patients who need medicines really without official indications for medicines, for important conditions or routes of administration of medicine.

Yes, and it's good that you've mentioned that it's not only the indication which would make certain prescribing off-label, but it can be the route of administration where you can imagine in paediatrics often formulations of products are changed or altered in order for us to get it into a child.

So why can't product information be updated to include other indications, doses, routes, or patient groups, especially when there's good evidence to support the medication’s use outside of the product information?

Yeah. So it's an excellent question, and people ask this all the time. Here's a medicine that is very important to treat common things. Yet the drug is not indicated for this particular use which is going on. Because that would seem to be a safety risk, a lack of guidance for prescribers and patients.

What you have to understand is that the product information – the official TGA-approved information about the medicine when it's registered – really is the property of the sponsors of the drug. That's the drug company that developed the drug and submitted it for registration. So if people start to use it for other indications, even when the studies that have been undertaken (not by the company necessarily) really show that this is a reasonable thing to do, it still requires in most instances, that the company actually resubmits to the TGA and says, "We now have this new indication. We now have a new way we'd like to be able to have the drug administered. Here's the evidence. If you approve that, can we change the product information or label?" So that seems straightforward. There are a couple of problems, one, that costs money and it's a moderate amount of money. The second is it requires studies which, in their own right, are difficult, challenging. We've talked about that a bit. They cost money. The TGA charges for the work. So the more indications for a drug that are starting to appear, then the company could be asked, over and over again, to update this product information each time with a cost and time resources.

And, oftentimes, the medicine appears to be being used anyway. So you can ask the question, why would they bother? Well, as we've already intimated, there's this matter of safety and good advice. And one of the other big things that's worth noting is that drug companies can't advertise for indications or routes of administration or for subgroups of people unless it's in the approved product information. So you've got this other perhaps incentive. But there again, in lots of ways, they don't have to because if the prescribing community starts to prescribe and it appears with guidance in other publications and resources that prescribers and patients use, for example, the Australian Medicines Handbook or Therapeutic Guidelines, then the company's got to ask the question, "Is it really in our interest to do that?" So that's probably the biggest impediment to getting product information updated.

There is one situation where the product information must be updated, and that’s if a serious safety issue emerges, Joanne. So then the company's obliged, as always, to report serious adverse events to the TGA. And if this is serious enough and is occurring enough times to warrant it, then the product information will be updated for safety.

And what are some common examples of off-label prescribing?

Probably the most dramatic recently, I think, has been the drug semaglutide, trade name Ozempic. Now, this is a drug that's indicated for people with type 2 diabetes. And technically, it re-establishes the mechanism of some insulin release. But one of the effects that was surprising and very dramatic was weight loss. And because the weight loss was so dramatic here, we saw a major uptick in prescribing of this medicine, because of the prescription for people without type 2 diabetes because people wanted to lose weight and they did. So this is challenging because the evidence that the drug did cause this weight loss is very strong. The drug’s registered for this indication overseas in the US with a different trade name, but it’s the same drug. But much more powerfully, the citizens became aware through social media and influencers and magazine articles and so great clamour to access the drug. For a big period of time, essentially, we ran out of medicine for people who legitimately needed it with type 2 diabetes.

One more example that might register with our GP audience. So the drug quetiapine, it's an antipsychotic drug that is associated with less adverse effects than some of the older antipsychotics. So, therefore, it's widely used. However, it's also used for conditions that aren't described as psychosis. So if you look up the product label for quetiapine, you won't find it's being available for elderly people, for example, who have transient behaviour problems or levels of disturbance related to perhaps dementia or even delirium. So it's not unusual to see this prescribed in hospitals. And then, the individual patient goes home or goes back to the aged-care facility, and the general practitioner in charge is now confronted with, "Will I prescribe this drug off label?" That would be a very common occurrence that would potentially concern GPs in this situation.

Two really good examples there. Thanks, Ric. I guess we can carry on from what you were just mentioning there. What are some of the risks of off-label prescribing for both patients and clinicians?

It comes down to really how good is the argument/evidence for prescribing the drug or a medicine to any of our patients. And the evidence is never completely black and white, and sometimes it's pretty grey, even for medicines that are registered for this particular indication you're going to prescribe for. So without that registration step, the prescriber and the patient start to become a little bit exposed because we don't know as much potentially about this indication and the risks as we would otherwise.

So then you get to the point, well, what is the evidence that isn't captured in the product information, and where do you find it? And as I mentioned, there are things or resources like Australian Medicines Handbook, which is a superb resource. And you'll find there for a drug quite a few indications and uses that aren't included in the product informational label. And that's because [of] the accumulation of evidence from properly conducted trials of all sorts, but particularly randomised control trials done well, is sufficient or even overwhelming that this is a legitimate use of this drug. It becomes more of a problem when the information about this indication is not in resources like Australian Medicines Handbook. And there are not enough studies or convincing work that you could be totally confident about. So you're moving there towards less and less evidence-based reasons for prescribing. So the risks obviously increase depending on the amount of evidence that is available to support the use and also the evidence about risks. So that's what it comes down to.

I was very intrigued to learn about leakage, which is a practice that can lead to an increased cost to the health system if a medicine is prescribed and dispensed under the PBS, but in this instance for an off-label, non-PBS approved indication. So can you talk us through some of the issues that can arise from this practice of leakage?

To be on the PBS, you need to have this indication and the route of administration, and all the things we talked about, registered by the TGA before the PBS, in almost all instances, will consider an application, again from the sponsor, to actually make the medicine available for prescription.

So there's oftentimes a period where there's negotiations going on, submissions being made, negotiation about the price and so on. So in that sort of window, there is a little bit of a temptation where prescribers and patients can push the envelope a little bit and see if they can squeeze themselves into the criteria for access. So, for example, a person who's overweight, maybe with a family history of diabetes, and the prescriber and the patient feeling like it's inevitable they'll get diabetes, you can think of a number of scenarios where the temptation to gild the lily, push the envelope is there.

And to give you other examples, way back when the new drugs... new biologic drugs for rheumatoid arthritis first became available, the tumour necrosis factor inhibitors, the first one registered could only be prescribed for people who had a blood test, a rheumatoid factor positive. Now, people could have rheumatoid arthritis just the same whether they've got this factor or not, but the evidence that had been submitted to the PBS didn't include people or enough people with the negative rheumatoid factors.

So this seemed to be unfair because there was data from elsewhere. So again, this is the sort of thing that led to an appropriate pressure and campaign to present more evidence and get this new listing. But in that period, there is this risk of leakage, so not a good thing. Therefore, the more we can talk about it, and understand it, and educate, the better.

But I might just add briefly that for some fairly technical drugs for rarer conditions where there's never going to be enough evidence to put before the TGA or the PBS where there is a legitimate reason for thinking and maybe some evidence that this drug will work. That's where hospitals and drug committees can look at this, and organisations that support them can look at the evidence and say, ‘Well, this would be reasonable, should it be potentially a clinical trial?’

Yeah. And definitely on the topic of rare diseases as well, sometimes the drug sponsors might have a cost share program or extended access programs as well.

I guess it does indicate that our system of registering all the information about a medicine and capturing that on the product information isn't working optimally. If this is meant to be a contemporary, up-to-date description of the use of this medicine, all its features in all the situations that we're talking about, well, it doesn't do that.

As we've discussed, there are workarounds but avenues to have broader listings of indications that don't come completely from the sponsor. So incentives and help for consumer groups, professional groups such as disease-focused professional groups, to actually take the lead in having modifications to this key information would be really good.

And do you foresee these consumer groups or even professional-led groups having the opportunity to have the lead in these sorts of medicines registrations process in Australia in the near future?

Yes, I do. And in fact, there've been a number of good examples where that's actually happened, and that the information in the product information and that the PBS has dealt with, has changed. So there certainly is precedent. It's not easy, a lot of work, a lot of commitment, but worth it in some celebrated cases, in my view.

Very interesting discussion today, Ric. I really enjoyed the article and speaking with you. So, unfortunately, that brings us to the end of the episode.

Thank you very much. I've enjoyed it. Thanks for inviting me, Joanne.

Thank you, Ric.


Ric's full article is available on the Australian Prescriber website. Since Ric’s article was published and this podcast was recorded, the Therapeutic Goods Administration has launched the Medicines Repurposing Program. This program aims to improve patient access to medicines in Australia by identifying new therapeutic uses for existing medicines and supporting sponsors in seeking the regulatory approval and subsidy of the new use. The program is designed to address some of the barriers to registration of new indications that Ric highlights.

The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. I'm Jo Cheah, and thanks again for listening to the Australian Prescriber Podcast.