E7: What is pharmacogenetics? Professor Graeme Suthers

In the final episode of this season,  past RCPA President Dr Michael Dray speaks with Prof Graeme Suthers. Prof Suthers is the National Director for Sonic Genetics and is one of Australia's most respected experts in the field of genetics.  

This episode delves into the world of pharmacogenetics and its demonstrated clear benefits. Pharmacogenetics is standard practice in many other countries, it is still underrepresented in Australia and New Zealand.

Copyright © 2021 The Royal College of Pathologists of Australasia. All rights reserved.

Transcript

[Voiceover] Welcome to The Pathologist Cut podcast. This RCPA podcast highlights the critical work of pathologists and the integral part pathology plays in medicine and health care.

[Dr Michael Dray] It's my pleasure to talk with Professor Graeme Suthers today. He is one of Australia's most respected experts in the field of genetics, he is currently the national director of genetics for Sonic Healthcare Australia, where his current role involves the development of genetic services for patients and families across Sonic's clinical and laboratory services Australia wide.

Welcome, Graeme. It's really nice to meet you virtually and to put some time aside to meet with me this afternoon. I know you're a very busy man. One of the things that we're going to talk about this afternoon, or this morning is pharmacogenetics.

Now, I'm a humble anatomical pathologist, and when I think of genetics, I think of it in terms of oncology, diagnosis, testing to prognosticate. This is tumour going to behave well or poorly, and also to predict response to a particular chemotherapeutic regime.

But pharmacogenetics, I suspect, isn't that. And so I'd be interested in you describing what is pharmacokinetics and where does that fit into the broader realm of genetics and genetic pathology?

[Prof Graeme Suthers] So pharmacogenetics goes back quite a long way, actually. Michael, it's back in the 1960s. When the term was first introduced.

And the authors on a key paper in British medical literature gave a series of adults a standard dose of isoniazid, an anti-TB medication. It was a standard dose, and they were getting a certain dose of milligrams per kilo body mass of the patients. So in that sense should have been an adjusted dose so everybody would end up with the same concentration of Isoniazid in their bloodstream.

And what the clinicians found was when they measured the concentration of Isoniazid in the bloodstream of these patients after a standard interval a few hours. It wasn't a smooth distribution, with a range of people having some people being very low level. So people having high levels. Most people in the middle? No, no, no. What they found was it was a binary distribution. There were two or bimodal distribution. There were two groups of people have had a high level of Isoniazid and then those who had a low level.

And this pointed to it there being an underlying genetic factor, which was, a binary factor. It was either present or absent. And that had influence on how the isoniazid was absorbed and distributed in these different patients. 

Now the concept there is actually a fundamental one that when we are exposed to a chemical whether it be in a medication or whether it be a toxin in the environment or whatever, there are genetic genes that vary in the body to produce enzymes that will differ between people that will change how that chemical is handled.

And so this was recognised a long time ago and the concept of pharmacogenetics, this interaction of gene and drug was identified back in the early sixties, but for much of the last 60 years, the development of drugs and choice of drug and dose of drug has been run on the assumption that we're dealing with the average person. You do a drug trial; you have a range of patients who have a particular medical problem and you work out what on average is the best dose and duration of drug therapy for that person. And what pharmacogenetics can potentially do is instead of treating each patient as the average patient, it can treat the patient as an individual. And personalise the drug choice and the drug at dose for an individual patient. 

And that was the concept, but it's really only in the last ten to 15 years that we've got now the sufficient genetic testing and got the price down to such a point where it can be done. At comparatively low cost. And where we've got sufficient data about different genes and drugs to be able to make confident predictions about that.

And it's got to the point where this is now well-established in many parts of the world, but having a gene test to work out how your medications should be titrated or adjusted for your individual metabolism is standard of care in many parts of the world today.

[Dr Michael Dray] It's really interesting, and I'm intrigued by this concept because I've had general practitioner colleagues ask me about pharmacogenetics testing when they hear that I'm a pathologist and from my background, I can't answer those questions because I'm not that familiar with what the technology is and what its offering. So I get a sense that there is a desire for a for an interest in and the broader medical community, but perhaps not quite so much on the laboratory community, is that is that a true sense?

[Prof Graeme Suthers] It's a good observation and I find it when I'm giving presentations and discussing this topic, I need to very much provide a disclaimer not about any professional affiliation that I have, that I'm coming into this discussion as a pathologist.

And the field of pharmacogenetics, yes, it does involve pathology, particularly around the genetics of these genes, but it also involves pharmacology. And it's involves the prescriber. So we've actually got three domains of knowledge that are coming together and at that intersection we have pharmacogenetics the use of this genetic test to inform the prescribing decisions that the clinician is making. And I think that they would be very few practitioners who would claim to be an expert in each of those domains.

So this is very much a field of genetic testing that sits at significant crossroads.

And we need to be able to work with colleagues who are on the prescribing side of the desk, if I can put it that way. We need to work with the pathologists, who are in the laboratory setting up and reporting on these investigations. And we need to engage with pharmacists, pharmacologists who have expertise about medicines. And if we can get the three groups to work together, this then does become very effective.

Now to put this in context. About 12, 13 years ago now, there was a major study in Australia documenting the costs of in-hospital care that could be attributed to adverse drug reactions in patients. So the patient is given the medication and for whatever reason that medication causes some toxicity or serious problems and the patient ends up in hospital. And the numbers were huge back then it was. So we're talking about 2008 dollars. It was about $1,000,000,000 per year in the health care system. That was the cost of managing these sorts of problems.

And a separate study recently who suggested that up to one in 50 patients, when admitted to hospital have some form of medication misadventure. Resulting in either significant toxicity or side effects or lack of effectiveness, lack of efficacy. So it's important that we recognize that the medications can be a very effective tool. There's no doubt about that, but they can also carry hazards.

And this is where pharmacogenetics is not the solution. But this part of the solution to improving effectiveness and reducing the toxicity of the medications in use.

[Dr Michael Dray] That seems to be that you've described large numbers and huge impact on public health from this poor uptake. Will this poor usage of the role of pharmacokinetics? Have things changed in recent years? You were quoting 2008 figures. Where are we at in 2021?

[Prof Graeme Suthers] Well, in 2021, I regret to say that we're no further advanced in terms of MBS funding, Medicare funding for pharmacogenetic tests. We're seeing more interest in pharmacogenetics and using these tests to inform prescribing among doctors. But I'd say we're still quite a long way behind where our counterparts across North America and in Europe. 

Let me just give you a quick idea of some of the challenges here. You have a number of. times which you could do a pharmacogenetic test. It might be the doctors dealing with a patient who has developed side effects or toxicity or for whom the drug isn't working. And the doctor says this is a problem. I'll do a pharmacogenetic test to see if we can work out the explanation in hindsight, if you will, for this patient's problems. And that's a situation where you're asking a very key question, and it'll take about two weeks now to get a comprehensive pharmacogenetic report back from a laboratory. So there is a two week delay, but at least the answer you get coming back can be very specific to the question being asked.

Similarly, a doctor might be about to prescribe medication for which it's known that the pharmacogenetic genes can have significant influence. So rather than prescribe it today, I'll order the test by two weeks to get that result back, and that can modify a treatment. 

But there is a third approach which touches on the issue, that you've just raised, which is instead of this sort of reactive testing to a problem or proactive testing to avoid a potential problem, it's called pre-emptive pharmacogenetic testing. 

We do the test ahead of time. Well for there's any intention to prescribe a particular medication.

And this result then sits as a latent opportunity, if you will, in the patient's medical record. And when the doctor does come to prescribe, down the track. That information is already there and can be factored into the doctor's prescribing decision. Now this would have pre-emptive testing has the great advantage that the information is sitting there ready to be used. 

It has a potential disadvantage, in that the return, the benefit you get from the genetic test is now a bit uncertain because at some undefined. Point in the future. Nonetheless, the appeal for this sort of pre-emptive testing is evident, and there are a number of major trials that are going on across the US and Europe looking at pre-emptive testing to determine whether the utility is such as to justify government funding of pre-emptive testing.

So every time a person goes into hospital, before presenting at this hospital, they would have that test. Which would then sort of instance follow them for the rest of their health care journey. Or perhaps it is something that’s done, for everyone who walks up to a GP the first time they're there. The pharmacogenetic test is done and that information is retained for their lifetime. So these are the sorts of models that are being explored. There have been some preliminary studies done through major hospital settings in the US, where they've certainly demonstrated that a substantial proportion of their patients do have a pharmacogenetic finding in some import and that is useful and is sort of embraced by those hospitals. This is one of the reasons that pharmacogenetics has got such a strong following in the US.

But what these other studies need to do is actually look at it from the Minister of Health point of view to say, do we have evidence that this is really worth the bucks?

It's the bang on with the buck. And we await the outcome of these trials with great interest. I should note that we don't have any such trials or pre-emptive testing for pharmacogenetics in Australia as yet for New Zealand.

[Dr Michael Dray] So I'm interested to hear that it's basically one test and you can then test a whole panel of different and known molecular markers or genetic abnormalities that relates to a specified range of medications. And that one test has to be done once and you can choose the time.

So this is a test once used often. But I guess the other point they'd have to flag is that the world of pharmacogenetics is changing. Quite rapidly, and it's changing in two ways. If you had the test today, the genetic results that comes back today will be correct and that will in fact not change over time. 

But if you were to have the test next year, it may be that there would be other genes being included on the panel at that point, which would in a sense update your genetic profile wouldn't change it, but it would expand the information available. 

The other dimension, though that can change, quite markedly, is the interpretation of that genetic information for a particular medicine.

So there is an enormous, there's an iceberg of information about gene drug interactions. But only a fairly small portion of that iceberg currently sits above the surface, if you will. That is to say that there is sufficient evidence to say this information should be incorporated into prescribing decisions. There's a lot of stuff that has the potential to get there, but it'll take time for more evidence to come and what will change over time. Is that the way the iceberg floats or how much information sits above the surface of the water will change over time.

You might have your pharmacogenetic test today. That genetic test result will remain stable over time, but the interpretation that I provide to you this year may be different to the interpretation that I would provide on the same genetic data in two or three years time.

[Dr Michael Dray] So you can still have the one test, but the raw data is kept that you can then retest the data at some later stage with new understanding. Or does one then need to redo the whole test?

[Prof Graeme Suthers] At the moment, we would re-interrogate the database that informs our prescribing information because we work with a partner organisation and this is the way we do it in that particular laboratory. But other labs will have potentially different strategies. We do the wet lab component, the genetic analysis in our Australian laboratories. And then work with an international service provider who's in the cloud to get an interpretation of our genetic data and we then bring that back to our laboratory and issue a report from there. So that interpretation is changed and the depth of that every time you ask whether, in fact, it may be necessary to repeat the test in the future and I think they'll come down to the economics of it. In some ways, I could envisage it being, simpler to have a straightforward pathway where a sample is taken, analysed, reported comes back into the electronic media record for the patient. 

And it could be simpler to repeat that every two to three years the entire process, rather than only updating the interpretation that's a bit further down the track. We're not ready to tackle that question yet. I think we got some much more immediate issues to tackle to make this readily accessible.

So that technology is capable of doing the testing. But it's the systems and the patch, the funding, the sort of other outside laboratories sort of issues that are the stumbling blocks for the uptake of pharmacogenetics.

I would identify three barriers to the effective utilisation of pharmacogenetics The first is awareness and understanding. So it's clinicians need to be advised about the availability and the potential utility. They also need to be able to make wise decisions about using this. So this is not a panacea it's not going to answer every situation.

I think that if I look more broadly, pharmacogenetics in the last decade has been perhaps overhyped and underutilised. And we need to somehow find the sweet spot in the middle where we are utilising this type of testing in the most appropriate way for our patient population. 

So education is one key area, and I think the College of Pathologists has a really important role in fostering that both among Pathologists but also more broadly across healthcare providers.

The second issue is not around the laboratory testing per se. I think that side of things. There are plenty of opportunities and that'll continue to develop and grow. That's not my concern. I think the big concern is actually getting the interpretation back into the patient's electronic medical record, having a piece of paper or a PDF report that lists the various gene variants that this patient has and what the prescribing advice. That's better than nothing, but it's still a very unwieldy way to handle this information.

And what we really should be aiming to do is to have this pharmacogenetic information and its interpretation sitting there in the patient's electronic health record so that when the doctor goes to prescribe anything in the future, there is an automatic check that proactively comes up. Onto the screen to say you're about to prescribe Drug X. For this pit of patient that might be green tick, prescribe as normal. Or it might be, there is a caution here if this patient has variance in the following genes and dosing and half the usual starting dose is recommended.

Or it might be a red flag. Do not use this drug, but that needs to be point of care information, rather than something to be buried in the patient's medical record. So we don't have those systems in Australia yet. They're implementing them across North America and in Europe. I think there is the potential for that in Australia, and it would be an enormous boost. And the third area is we need to address the funding issue for patients who are on many medications for whom a pharmacogenetic test would be particularly useful. These are the very patients who are often socially disadvantaged, for whom having to pay a private fee for the patient is a real problem.

And so I think we do need to look at marshalling the right evidence to justify testing in certain situations and potentially broadening that down the track.

But we do need to address this funding question.

[Dr Michael Dray] So, so education, both of clinicians, the public and the laboratory sector, the sophistication of the sort of the electronic record. So you've got that entwining of the pharmacogenetic data with the prescriber and the medication and then the funding issues.

And I get the sense that it's not a hot topic for the funders. It's not directly related to a specific medical activity that's happening. It's more a screening tool. I know some funders are less inclined to do screening type activities. You get that sense in Australia?

[Prof Graeme Suthers] It's a good question. And there are two issues at play here. The first is that the field has unfortunately been, I think, damaged in Australia by some of the over-hyping of pharmacogenetics. Particularly in some overseas centres which has made claims. It really can't be sustained about the value of pharmacogenetics. And that, unfortunately has led to people dismissing all claims about the potential benefits of pharmacogenetics.

And it's important that we do take a sober review of the evidence for the utility and why, pharmacogenetics in appropriate situation where there is clear evidence of benefit, so we need to work on that mindset. 

But I think the other problem is that at least in Australia, I'm not sure the situation in New Zealand, but in Australia we have significant silos of health care funding and the silo that it might be responsible for paying for pharmacogenetic test, is not necessarily the silo that sees the benefit from the pharmacogenetic test, and that acts as a barrier. 

If you have a more integrated situation where the whoever is paying for the test also gain some benefits out of that because of reduced length of stay or fewer days off work or whatever then it's easier to make the economic case for this.

So this is a challenge that I've faced a number of times with this test talking to different stakeholders. Now, having said that, it's important to note that a couple of years ago, be the Minister for Health, Greg Hunt did issue a special request for applications for research. Applications to do work about the place of pharmacogenetics in Australian healthcare. And this has been funded out of the Medical Research Future Fund.

I'm aware of a number of studies happening in Australia. We're involved in one study looking at the impact of pharmacogenetics on the treatment of depression in the community, and the particular question is whether pharmacogenetics results in more effective prescribing.

And a greater proportion of patients having remission of their symptoms. And there are other studies looking at other variations on that theme as well. So I'm pleased to see some of these green shoots as it were. Around pharmacogenetics both the interest and also doing the necessary groundwork in the Australian situation.

I'm not aware of similar activity happening in New Zealand, but I may stand to be corrected about the status of PDX research. The question of which drugs is a very broad range of medications now for which there is good evidence linking genetic variants and the recommendations about dose or use of the particular medication. The particular test that comes out of our laboratory, we provide a report for about 80 or so different medications. It is very broad. 

One area that is of particular interest in the packing a lot of attention at the moment is the use of pharmacogenetics in the management of depression that's a significant issue within that communities generally and it's a condition for which drug therapy is. It can be a part of the solution and certainly. Not the only part of it, but if you look at the drug therapy management. depression, it's a very drawn out process because people need to have exposure. So, they sort of have a trial of the medication and see whether in fact it is working and it might take four to six weeks for that assessment to be made. And if it's not working, then it's a matter of weaning them off that medication onto a new medication before you have another trial and error. 

So we've now been a number of randomised trials looking at the potential benefit of pharmacogenetics in this situation and there was a meta-analysis association of five trials across three continents that came out a year or so ago, which showed that the community management, the outpatient management of depression pharmacokinetics, results in a 70% increase in the probability of disease or depression remission at the end of a twelve week period. 

So this is a 1.7 fold improvement in the rate of remission for patients who are having the pharmacogenetic testing. And that's significant in itself when you actually drill down into this. Remember, I said that the pharmacogenetics is there to help personalise the patients prescribing. And so there'll be many people who have a pharmacokinetic test for whom the test recommends no change in care. So in a sense, for them the pharmacogenetics to provide no benefit, I think to the change. But it's for the minority with the pharmacogenetics do something different. Those are the ones who really do benefit.

And in this meta-analysis there was a very interesting observation from one of the studies where they had looked at the second question. They looked at patients who had pharmacogenetic results, which said you should consider changing the recommended dose. And I looked at those patients who were on non-concordant medication to say their own medicines that the PDX tested don't use.

And they then followed them up. About half of those patients ended up on the informed prescribing and I looked at the difference between those two, so these are people who could have what we call an actionable pharmacogenetic test, we can do something about this.

Some stayed on the inappropriate or non-concordant medications. Others moved to the appropriate or concordant medications. And there was a 2.5-fold difference in the frequency which the depression resolved. For those who were getting the informed medication and moved on to appropriate medication. So this is a very powerful effect to be seen for such a chronic and indeed expensive disorder. The sort of study is the basis of at least one of the projects now running in Australia using the federal funding, as I mentioned a moment ago.

[Dr Michael Dray] So certainly, mental health is such a big issue in our community, and you've highlighted described some quite striking improvements and differences that a laboratory and pharmacokinetic testing can make. I'm slightly amazed that there actually hasn't got more traction than it does, and that leads on to the next question of where to from here.

What can we, as pathologists do to try and encourage greater awareness of this topic?

[Prof Graeme Suthers] So I think for the individual pathologist with respect and being a pathologist, I think I can get away with saying this is not going to be too many opportunities where the individual pathologist can have a voice here. I say that because pathologists generally don't talk to doctors about what they're prescribing. The pathologist is talking to the doctor about what we think the underlying disease process is, whether we've got it from the anatomical pathology as in your case Michael, or looking at a blood film or whatever. But the next step is to do what medication could be used to have them up used, which is typically something that a pathologist doesn't get involved in. 

Now there's one important exception and this is in the area of therapeutic drug monitoring, where a clinical chemist, one of the subspecialties within pathology is involved in measuring the concentration of a drug within the patient's bloodstream. And this is quite a busy and active area of pathology where I think the pathology community at the individual level could become more engaged.

This is for the clinical chemists to be aware of the availability of pharmacogenetics and how that might be very relevant for a patient who's having therapeutic drug monitoring.

And so we recognise it would be the group of folks I work with. We recognise the importance of this and we're working to build those linkages. But I think it'd be very helpful to have that those linkages fostered more broadly across the clinical chemistry community in Australia. 

I think the broader issue of how to raise awareness is very much something for the Royal College of Pathologists of Australasia to pursue because there is a professional organisations, the peak body for pathology in Australia and New Zealand. The college does have  an opportunity to engage with those parts of the health care provision who are involved in prescribing. And so I think there is a great opportunity for the RCPA to engage with the College of Physicians or cardiologists, obstetricians, whatever it might be, it's those other colleges that are doing the prescribing. And for the RCPA to be saying, there is this field, the testing now available and perhaps we could sit down together and work out, how could this be useful to your patients?

What we do need is some Australian and New Zealand guidance on which patients should have this sort of testing? And then we can benefit from the international guidance out there about what to do with the test result.

[Dr Michael Dray] Sounds like you've given us a job.

[Prof Graeme Suthers] I know you have so little on your plate in the midst of this kind of pandemic. But I just thought it needed a bit of firing up.

[Dr Michael Dray] All right. Well, I think no, we certainly do have some guidelines or some documentation in the colleges, as you well know. But maybe we could look at promulgating a better and starting to make those connections again with our prescribing colleagues.

I was also just thinking when you were talking about that, pathologists don't really discuss much with prescribing. I think the microbiologists also have some input with regard to antibiotic selection.

Its been really interesting Graeme, talking to you about pharmacogenetics, there's obviously just a small part of your day to day life and you've built a wonderful career and genetics and done so much for the broader community. What would you say to a young aspiring medical student or young doctor who's considering a role in pathology?

[Prof Graeme Suthers] It's been a fascinating journey. Michael, I had the privilege of being a late-comer to pathology, and I spent the first part of my medical career working as a as  clinician, a specialist clinician and I very much enjoyed that and I enjoyed the interaction. But as I learned more about the genetics, I became increasingly drawn to the laboratory side and have really appreciated having a deeper understanding of the genetic basis for diseases and also the genetic tools like pharmacogenetics that can help us to provide better therapies.

Some of my clinician friends said, you know, you're going to miss the patients and you're going to miss the interaction, just sitting in the laboratory, staring down a microscope or whatever. And it wasn't the case at all because being a pathologist, you are very much interacting with colleagues, both within the laboratory and beyond the laboratory, and you're very much concerned with patient care and welfare. I have found that enthralling to be in a position. And I would strongly encourage anyone with an interest for knowing the ‘why’ to embrace pathology. It's an area that is changing very dramatically. We urgently need more genetic pathologists, please. And this is an almost desperate. shortage of genetic pathologists in Australia, and it would be great to have some new people coming into this field.

And picking up on the enthusiasm and the period of tremendous change happening across pathology in general and genetic pathology in particular.

[Dr Michael Dray] That's it's a wonderful answer. Graeme and I really know where you're coming from. That's been a real honour and a pleasure talking to you today. I'd like to thank you very much for your time. Thank you.

[Prof Graeme Suthers] You're most welcome. Thank you.

[Voiceover] You have been listening to the Pathologists podcast with RCPA President Dr Michael Dray. For the latest RCPA updates, make sure you're following us on Facebook and Twitter.