Ethical prescribing, hydroxychloroquine and COVID-19

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COVID-19 has presented enormous challenge to our health system and to society in general. But for those of us seeing patients, it can be hard to know what to do, if anything, apart from echoing public health messages.

Coming into this, there have been no real precedents for therapy beyond supportive care and there's real morbidity and mortality that we have a collective responsibility to address as well as we can. So it's possibly natural for us, individually, to try and seek out a proactive prescribing step to try and gain some added control in an uncertain world.

At the same time, prescribing for COVID-19 in the absence of truly meaningful evidence involves navigating many risks, uncertain clinical efficacy and potential context-specific toxicity, but also in an era where we all have to work together, potentially harming the greater good. The situation around hydroxychloroquine has shown how a little bit of speculation can lead to real drug shortages with the potential for patients with proven indications, like lupus and rheumatoid arthritis, to miss out.

So how can we navigate responsible ethical prescribing in these difficult times? I'm David Liew, your host, and today on the podcast we look at some of these issues. We are joined by Ian Coombes, Director of pharmacy at the Royal Brisbane and Women's Hospital, and Andrew Redmond, an infectious diseases physician at the same institution. They're two of the authors on an Australian Prescriber online first article about the principles of ethical prescribing during COVID-19 with particular reference to hydroxychloroquine. So Ian and Andrew, welcome to the program.

IC: Thank you for inviting us.

AR: Thanks very much, David.

So perhaps Ian, you can tell me a little bit about why in the middle of a pandemic we're talking about ethical prescribing and medication rationalisation.

IC: Thank you, David. It's a very practical question. I think it comes down to the fact that a lot of us, both clinician, researchers who also have a sort of management role in health care and I think whilst there's a very strong burning desire for all of us to do everything we can for what is, obviously, a disease with very high morbidity and mortality, we're also in a situation where we have to make sure that we're balancing acceptable evidence to drive our practice against the need to manage the ongoing burden of our chronic disease in our population at large.

I think that what we've done with our group at the Royal Brisbane, really, was to sort of come together to say maybe there's some key messages here that we need to share with the wider healthcare team around the importance to balance the evidence versus the risks versus getting some guidance on where perhaps there is treatment, if there is any treatment, but at the same time trying to really urge against the kind of risky toilet-roll stacking inappropriate behaviour, which some of my community pharmacy colleagues have sort of flagged with me quite a few weeks ago now with sort of a rush on certain medicines and hydroxychloroquine being one of them, which was sort of quite unprecedented, but probably driven by, again, not very good evidence and some slightly misinterpreted messaging from some high-profile people, not just in Australia, but particularly overseas.

I think we have to accept in today's world, we have to be able to rationally manage our limited supplies, be it for all therapies for chronic diseases versus our acute-phase sort of treatment of patients.

I guess it's really understandable that when you've got a new threat where no one's really sure what to do, and there's a lot of ambiguity globally, that this might be a time when people aren't necessarily making rational ethical decisions, which represent the best use of our limited resources.

IC: Yes. I mean Andrew can comment as well. Probably give you the little vignette scenario that a local pharmacist contacted myself, as Director of pharmacy at the Royal Brisbane, to access hydroxychloroquine and because they'd had a run on it, this is probably four weeks ago now, but it also, unfortunately, described effectively overt behaviour of practitioners writing prescriptions for each other and sort of asking for hydroxychloroquine prescriptions and the repeat and then sort of, when asked, giving vague explanations of some bizarre diagnosis of some inflammatory disorder.

In other cases, I think we've seen in the literature, it's really been quite widespread and inappropriate prescribing. That really, to us, ran a flag up the flagpole around the fact that we need to be a little bit cautious. When we started looking at what our drug supplies were, it was actually a potential issue because there was only the normal drug supplies for the chronic ongoing therapies. I think that really did raise a question amongst the pharmacy community, but then very rapidly when we started discussing with medical colleagues who we work very closely with, it was something that we needed to take account.

Perhaps you can actually just give us an idea as to how this article has come about. It's great to see a multidisciplinary team as the authors in this type of time.

Thank you. So Alex Markwell is an ED physician, but she's also the Chair of the Queensland Clinical Senate. The clinical senate were very quick to pull together a forum to discuss the ethical considerations around the management of COVID and approached Jason and Andrew and I to talk on a panel and put together a few key points and messages, which the senate had a process, they had about 150 people attending, to really take some key messages, including consumers as well as clinicians, and see whether or not they really resonated. They, in fact, did and the senate endorsed them.

Then we also thought it appropriate to get our Head of human research ethics, Gordon McGurk, and our Head of rheumatology, also pharmacologist, Paul Kubler, was very keen to be involved to ensure maintaining therapy for his patients. So I think it's a nice approach between sort of infectious diseases, rheumatology, pharmacology, high-level research practitioners in infectious diseases and intensive care, as well as myself as the Director of pharmacy, because it just shows that it needs a multifaceted approach to deal with these issues and how we can ensure that we manage appropriately going forward.

Absolutely. Maybe Andrew, you can talk us through this a little bit in terms of how is this manifesting in practice? I mean, for starters, where do you see hydroxychloroquine, at this point in time, on April 18, 2020, where does it seem to fit in practice in COVID-19?

AR: Thanks, David. So I guess we've really been worried about there being a massive tidal wave of patients and there was a lot of concern that the hospital services and the health care in general were going to be overwhelmed, we were going to run out of ventilator beds, we were going to lose capacity to deliver ordinary health care. It really seems that, in Australia, we're very fortunate with our geographic isolation and that the public health measures have been very effective.

But when it all started, people were very worried about losing capacity to provide health care and were really reaching for whatever straws were available. There was in vitro evidence that hydroxychloroquine or chloroquine and some other drugs could inhibit viral replication. There were also some studies of MERS and SARS that were suggestive that there were experimental therapies that might be efficacious. Then the Chinese had started a bunch of clinical trials and started a bunch of experimental therapies.

But really, despite the rapidity of publication, we're unable to show that any of them were effective and because they're public health, once they got going was so amazing, they actually ran out of capacity to finish any of these studies. So we've seen lots of preprints of single-arm studies or other small studies looking at surrogate end points that were suggestive there might be some benefit or some antiviral activity, but really actually no hard clinical benefit. So we were in this circumstance of people being afraid of health system capacity, people being afraid of the severity of disease and really having very poor information to make good clinical decisions about. We had clinicians wanting to use unproven medications both for prophylaxis and for treatment, and saw them just flying off the shelves.

I guess it is understandable that in a period of time where there’s that level of uncertainty, people might not necessarily act in the most rational or logical kind of way, especially when it comes to unproven medications or emerging drug studies.

AR: Yeah, I think it's tough. It's one thing to repurpose a drug like lopinavir/ritonavir that actually has very limited use and if it had been helpful, then that would've been great. But really the preprint in the New England Journal really suggested that it had very slender evidence of any significant clinical activity.

But for a drug like hydroxychloroquine where there's a clear role, clear benefit and a clear use for patients with rheumatoid arthritis and systemic lupus erythematosus and chronic Q fever endocarditis, re-purposing a drug that is in limited supply just really has very interesting and troubling ethical connotations.

It does sound, from what we're talking about, this classic situation where a vacuum of information leads to all the poor-quality evidence coming to the surface. But I guess we live in a time where there's almost unprecedented anticipation for results from trials, obviously both within the scientific and medical communities, but also more in the broader community and politically with enormous political and economic implication.

Andrew, how do you think this reflects in practice? Because in terms of making decisions as to what we're going to do to our COVID-19 patients, what we're potentially going to do for people who might be at high risk, say healthcare workers or people more broadly in the community, how'd you think that this data is getting applied in practice and this uncertainty has been dealt with in practice?

AR: It's a great question, David, and those are, I guess, three critical groups, the people who've got the disease, healthcare workers caring for people with the disease and then the general community in terms of just understanding and having faith in process. So I think we're very fortunate in Australia that the team from the Doherty Institute led by Steve Tong and Justin Denholm have been in a great place to be able to initiate a multicentre, randomised controlled trial, have put together a great team around them in order to secure medications for the study. I have been able to leverage people like David Patterson to help fundraise for the study.

So it's great that we've got this opportunity to do this and I think we are well placed to provide as good evidence as anyone, apart from the fact that our public health has been effective. Probably the United States is a better place to do it because their public health has been so ineffective and they have hundreds of thousands of cases.

So what about health care workers? Well, obviously, there's a great amount of fear. There's been many healthcare workers around the world infected and some healthcare workers have died from coronavirus, although really we're lacking in very good detail about how those healthcare workers got infected. The WHO report or mission that went into China, Bruce Aylward, reported that the factors seem to be fatigue or non-use of PPE were the risk factors for healthcare acquisition of coronavirus, but it would be great if we could be confident that there was an effective chemoprophylaxis.

There are at least two large studies of chemoprophylaxis going on using hydroxychloroquine and it would be great if we knew that it was effective or knew that it was not effective. But I think in the absence of that, I don't really think there's a clear role for chemoprophylaxis at this stage. The risks seem likely to outweigh the benefits.

Then lastly, I guess the public and just how good a job do we do at communicating this, it's been quite a challenging message to deliver in a nuanced way. Our mainstream media has such a short attention span and really wants a 10-second grab at the most. Trying to explain nuanced ethical ideas, uncertainties about effectiveness and safety of treatment and prophylaxis is challenging and I think it's going to remain so.

I guess with the nuance and particularly with hydroxychloroquine has been quick to disappear and especially when it's something where there's clearly a balance that's required in terms of the considerations that need to be made. A lot of the things that you talked about involve hydroxychloroquine and, on the other side of it, are two sets of things in my mind, the toxicity, but then also which I think we can talk about more in a moment, but I guess the importance for patients that have proven indications for it and the fact that there's limited supply.

I think it's easy to forget in amongst this that systemic lupus patients don't just need hydroxychloroquine to treat their disease. They need hydroxychloroquine to prevent serious, potentially life-threatening flares. That hydroxychloroquine is a kind of drug which is able to improve the lifespan of lupus patients, it has a mortality benefit, stops patients like that being hospitalised and that we know that even a two-week break from hydroxychloroquine is enough to put patients at increased risk of flares and death.

So I guess that's the flip side of things and, Ian, I think you'd probably have seen this that as much as there's a lot of talk about ramping up production of hydroxychloroquine, right now in mid April 2020 we don't have unlimited hydroxychloroquine in this country or globally, do we?

IC: No. Thank you. It's a very good question. I'll answer that first because I think it'd be useful to go back and ask about some of the data of patients taking hydroxychloroquine chronically in your cohort, David. But our hospital, we are very fortunate as a state, we have sort of a central pharmacy store and we have sort of bulk purchasing power.

But one of the things we've been doing is we've been keeping very tight monitoring on our meds and access. We would have only three months' supply for chronic disease in our normal usage based on the previous 12 months prior to any of the COVID rush on activity. But you suddenly start having people appearing for 200 tablets at a time and you will drain that stock very, very quickly. The generic manufacturers, as well as the originator brands, are not sort of geared up to just suddenly turn out the product. We have, in fact, through, as Andrew mentioned, for the ASCOT study, managed to get extra batches provided by the manufacturer, which we probably can't mention on Australian Prescriber, and we're actually the coordinating pharmacy site for the country and for New Zealand. So we've actually got a protected supply for that study because my first concern, when I heard the eloquent David on the television and the radio and spoke to him, was where are we going to get the drug from? So that was fantastic that the Doherty team managed to lobby the company to access the drug for that study. So for that point of view, that's fantastic.

It's the off-trial use, which was going to worry us very quickly and, in fact, we've been doing outside prescriptions for patients because in discussion with our rheumatology and immunology colleagues and nephrology colleagues that we, obviously, are very conscious. We want to maintain that therapy for the beautifully described clinical end points that we're trying to both maintain the disease management, but also prevent exacerbation. So I think that the company are, I know, very quickly trying to work, to ramp up the supply, but these things don't happen overnight, as we all understand, with the pharmaceutical companies.

Our community colleagues have also, obviously, been conveying the same message and met with a lot of resistance from a very worried and, obviously, anxious population who wanted to get their full prescription in one dispensing. But if we did that, we would've then rapidly reduced all of the country’s stock. So I think it’s been actually, again, something Australia has done very sensibly and I have to really credit the Therapeutic Goods Administration for very quickly acting to both work with Medicare and the general pharmacy and medical world to restrict people obtaining sort of multiple supplies and using the old Reg 24/49 opportunity because that would’ve just drained all of our supplies. You might treat the first five, you wouldn’t treat the next 20 patients.

Absolutely. I guess the other side of it is when we talk about a drug like hydroxychloroquine are the potential adverse events. It’s a kind of thing where I think previously when we’ve seen it in a rheumatic disease population, hydroxychloroquine is a very well-tolerated drug in general with some notable side effects, but generally are very well tolerated. But that doesn’t necessarily translate to a COVID-19 population or to the kinds of combinations of medications that hydroxychloroquine is used in COVID-19. Would that be fair to say, Ian?

IC: Oh, absolutely. Again, you're as well-versed to this. People are aware that people get gastrointestinal side effects and they're sort of relatively can be relatively well-tolerated. But we're talking about patients who themselves are potentially critically unwell. We know that we've got patients who particularly can be dehydrated. They have got underlying comorbidities, a very high proportion of the patients who are being admitted to hospital and certainly those ending up in intensive care have comorbidities such as heart disease and diabetes and renal impairment.

We've got the fact that there are cardiovascular toxicities which are not just necessarily a chronic therapy, which some people initially thought, but can occur acutely. There's certainly case reports of patients and healthcare workers who have been presented to hospital with cardiotoxicity and gastrotoxicity where they’ve been self-dosing. But then you add in the fact that you've got, of course, some limited evidence of a addition of a macrolide antibiotic such as azithromycin and you've got two drugs that both can prolong the QT interval. So your risks of being proarrhythmic and torsades etc. in a critically ill, unwell population who are already going to be cardiovascularly challenged really tips the scales really between very limited poor evidence versus potentially increased risks.

I think that's where the ethics as well of making sure that patients are aware and consented with regards to if we're going to be using these things compassionately, we need to make sure people are aware of what the risks are versus the benefits.

There's also other studies which are occurring to really try and determine what an effective concentration is, particularly in critically ill people, because, obviously, side effects of these drugs, some of them are idiosyncratic like some of the unfortunate skin reactions, but there's also others that aren't going to be dose-related. If we don't know the effect of drug concentrations in these critically ill people, then we potentially are going to push the drug and expose patients to much higher incidents of serious adverse effects. So well-managed studies, which are based on the best available evidence, which is also looking at the dose and the adverse effects and capturing that data, is going to help us further refine the ongoing doses because I think that's an important nuance related to how we treat this.

In terms of taking this to kind of a patient-by-patient basis, Ian, what kind of things are relevant in thinking about ethical prescribing in a pandemic on an individual patient basis?

IC: Yeah. The strong advice to pharmacists at this time particularly is to effectively refuse the dispensing where there isn’t an ongoing clear indication for the chronic diseases that we’ve already talked about. Excuse me. That’s, obviously, apparent from either people’s medical records or actually just a conversation with their prescriber, be it the GP or the specialist who’s initiated it. We’re very fortunate in this state that because we have a very responsive Medicines Advisory Committee for the state, that we’ve actually just put out a really good guideline developed with rheumatology, with immunology, with nephrology, with infectious diseases to actually clearly say that we are very much supporting, but restricting the use of the drug and the initiation of therapy to this cohort of prescribers with supporting for these management of diseases.

Outside of that, obviously, there may be case-by-case basis. But, again, it needs to have good governance, as Andrew related to, and that good governance needs to say that we’re going to be applying evidence, looking at individual patients, looking at the availability of the product, looking at the risks and the benefits.

I think that we’re lucky that sort of the pharmacy societies and bodies did convey that early, but not without an undue amount of pressure. Because I think the community pharmacists are often the ones on the frontline in a number of these cases because the patients are presenting and believing because we can do emergency supply, which we are. In some cases, we’ve done further ongoing emergency supplies in the hospital outpatients for people whose prescriptions have expired for lupus and rheumatoid arthritis so we can ensure that ongoing treatment.

I guess there’s a lot of pressure on frontline prescribers as well. Do you have any advice for those prescribers in that kind of situation as to what to do?

IC: One of the key points that we really wanted to make in our article was that there's really a few questions you've got to ask yourself. If you are prescribing outside of your normal scope of practice, if you are prescribing for a medicine that you're not actually that familiar with, which is just general principles of therapeutics and prescribing, and then if you're actually doing this for what's even closer to a serious ethical question for a family or a friend, you've really got to weigh up whether this is sort of a objective and independent decision that's being made. I think that there's a few nice points that our co-authors made around the fact that you've really got to ask yourself, what would your peers think about this? Is it consistent with good practice, balanced against the anxieties that Andrew's very rightly said are for some of our frontline clinical healthcare teams or patients who believe they are vulnerable, who are attempting to get a prescription for some of these medicines to take prophylactically.

Because I think you've really got to then ask the question about what would happen if there is an adverse event, be it from a professional perspective and how that would be reviewed by professional bodies, be it AHPRA or the health ombudsman and particularly how would that affect your relationship if it's a family member? Because I think it is a very significant balance between the beneficence of actually ethically trying to do the right thing for the patients versus the risk of harm both to the individual and to you as a healthcare professional.

Important reminder for us, Ian, thank you so much for that. And thank you to both of you for your time today in this ongoing crisis. We're all just trying to do the best we can, so thank you very much for making the time.

IC: That's great. Thank you very much for inviting us.

AR: Thanks very much, David.

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The views of the guests and the host on this podcast are their own and may not represent NPS MedicineWise or Australian Prescriber. I'm David Liew and, once again, it's been a pleasure joining you on the Australian Prescriber podcast.

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