Let No Good Pandemic Go to Waste

John Massie

I'd like to welcome everybody to Grand Rounds and the opening plenary session of the 12th National Paediatric Bioethics Conference. As a New South Wales man, I've often found it curious thinking of the parochialism of Victoria. However, on this occasion, I think we're justified to host a national pediatric bioethics conference considering the resource provided to us by the RCH Foundation and the Friends Auxiliary and the talent amongst our clinical ethicists and the research team at the center. And I think that that gives us the pull to attract an incredible national group of speakers and international group of speakers to our conference this year. I'd like to start by acknowledging the traditional owners of the land on which the hospital is placed, the Wurundjeri people of the Kulin nation and pay our respects to elders past, present and emerging and for those who are not in Wurundjeri country to think of the local group where you are. I'd like now to ask Professor Matt Saban to say a few words and officially open the conference. Matt.

Matt Sabin

Thanks, John. So it's my great pleasure to welcome everybody to the 12th National Paediatric Bioethics Conference, which is organised obviously by the Children's Bioethics Centre here at RCH and on the Melbourne Children's Campus. Now, over the years, the Children's Bioethics Centre has become integral to the provision of high quality health care to children through the advice that's provided to the clinicians on very difficult ethical issues. They support many departments with education sessions, they build great staff capacity through their popular grand rounds and also provide advice to the RCH executive, myself and the CEO on very difficult complex and clinical ethical issues. Now, more recently, of course, the Bioethics Centre has continued to develop even further with an exciting online platform with podcasts, e-learning modules, and useful resources on their website as well. And I'd encourage anybody to try and spend a bit of time on the website and listen to some of those podcasts. They really are informative.

Matt Sabin

Now, the Children's Bioethics Centre is funded by the Betty Cosgrove Endowment through the RCH Foundation. And we're very grateful to them for that ongoing resource, which has allowed the Children's Bioethics Centre to continue to grow in its presence year on year. Now, the work of the Children's Bioethics Centre is also supported by the Friends of the CBC Auxiliary, who raise money to support the educational initiatives of the centre. And in particular, of course, to bringing you the annual conferences, which this year, of course, is all being delivered virtually. So that brings me on to 2020 with its particular challenges, of course, and nobody is immune to the news of COVID-19 and the reasons why, of course, we're delivering this from a studio with masks on our faces. And I think everybody in the world knows the current challenges that are for everybody. Nobody seems to be immune of the challenges. And I'm really grateful to John and Lynn and Claire and others for being so dynamic and being able to sort of... um move very quickly to think about how to deliver this this conference virtually now the cbc of course is led very uh ably by the academic director professor lynn gillum here uh as well as uh clinical ethicist professor claire delaney and of course uh congratulations to john on his uh very recent appointment as the new medical director from uh for the children's bioethics center taking over from jill sewell

Matt Sabin

So I'm pleased that the team at the CBC have been able to overcome the hurdles of 2020 to put on this conference. They've worked really hard to put together this very innovative and interesting conference. Over the last two or three days, I've had many people contact me to say that they're really impressed with this year's programme and they're very much looking forward to it. So I'm grateful to the team for the hard work on that. And I think although the conference obviously has a real focus on COVID-19, it's clear to us that the learnings that we'll get from this conference will be with us for some time. And I think not just in terms of the way in which we think about COVID-19 and the pandemic, but how some of those ethical issues that we're dealing with really will translate into sort of ongoing healthcare.

Lynn Gillam

So it gives me

Matt Sabin

great pleasure for all who will join over the next few days to welcome you to the 2020 Children's Bioethics Centre 12th National Conference. and officially declare the conference open, which normally, of course, we'll get a round of applause, but in a virtual studio, that's difficult to do, but we are very happy that this conference is underway. I'll hand back over to John. He'll introduce today's plenary grand round speaker and also talk about the now nicely named Jill Sewell Plenary, which is how it's named. Talk about how that came about.

John Massie

Thank you, Matt, and thank you for those kind words. We've named the plenary for the conference, the Jill Saul Plenary to acknowledge Jill's contribution to the Children's Bioethics Centre. Jill was our second director from 2014 through to 2019, following on from Hugo Gold. They were big shoes to fill and she very ably led the centre for five successful years, building the reputation of the Children's Bioethics Centre at RCH. and nationally and internationally. So if we can, even a quiet applause in our own places, we'd just like to thank you for your contribution. It's now my great pleasure to introduce our keynote speaker for today, Professor John Lantos. John is a professor of paediatrics at the University of Missouri, Kansas City, and director of the Children's Mercy Hospital Bioethics Center. John is really the leading pediatric bioethicist in the United States. He has many publications, a number of books, and many national roles with bioethics. It's a real privilege to be able to have John join us today. We wish it was in real time and real person, John, but thank you for making the effort. It's after nine o'clock, which I think I inferred anyway was John's bedtime.

John Massie

What I'd just like to let everyone know is how we'll run today. John's going to talk through the standard Grand Rounds time from about 12.30ish or we might get underway early and then we'll have some questions and answers. Grand Rounds usually finishes about 1.30 so people can get off to their afternoon activities but if you'd like to stay on please do and we have John through until about two o'clock. If you have questions, use the chat function in the meeting. The questions will be curated by myself, by Lynn Gillum, and by our education officer, Georgina Hoare. And we'll put those questions to John and hopefully have a lively discussion. John, are you there in Kansas City, Missouri? Yes, sir. John, just... Because I think people will be confused by Kansas, Kansas City, and Missouri. So where on earth are you? Where is it?

Dr. John Lantos

We're smack dab in the center of the United States, the geographic center.

John Massie

I understand there's two Kansas cities.

Dr. John Lantos

Is that right? Kansas City, Kansas, and Kansas City, Missouri, divided by State Line Avenue.

John Massie

And which one won the Super Bowl?

Dr. John Lantos

Well, the whole city was behind it. It was one of the rare times when both Kansas cities were not at each other's throats.

John Massie

And is Kansas City famous for anything in particular, John? Apart from yourself.

Dr. John Lantos

Well, there's barbecue. People come to Kansas City for barbecue tours, three meals a day for a long weekend with a lot of home-brewed or craft breweries to... wash the ribs and brisket down. Kansas City also has more fountains than any city in the world except Rome. So

John Massie

I'm sure that's probably a source of income, is it, for the bioethics center, people putting their money in the fountains?

Dr. John Lantos

Throwing their money in and just, we're just overrun with tourism. I mean, Rome, Kansas City, you know, they're big destination cities.

John Massie

And that's what we like to think about Melbourne too, John. John, what I might do is ask you to present the plenary, Let No Pandemic Go to Waste, How the COVID Crisis Could Lead to Better Healthcare Delivery. Thank you, John.

Dr. John Lantos

Thank you, and thank you so much for inviting me. I was really looking forward to a trip down there. I'm sad that I can't be there in person, but this is the next best thing and a lot less jet lag, so that's good. I'm unmasked because I'm home and nobody's around. Let me just see if I can share my screen here.

Dr. John Lantos

There we go. Is that up now?

Dr. John Lantos

So I'm going to talk about the title is Let No Pandemic Go to Waste. This comes from a quote attributed to Rahm Emanuel, who was Obama's chief of staff in his first term. And you may remember Obama took office in the midst of a big financial crisis. And Rahm Emanuel said, you never want to let a serious crisis go to waste. This crisis provides us the opportunity to do things that you could not do before. from the brother of Ezekiel Emanuel, a famous bioethicist who I'll mention later in the talk. Let's see. Why am I? OK. The quote probably came from community organizer Saul Alinsky, who had a slightly different version of that. He said, in the arena of action, a threat or a crisis becomes a precondition to communication. So I'm going to talk a little bit about how I think COVID-19 might change the world. I'll give a few slides about sort of bigger non-bioethics issues, but spend most of the talk focusing on how COVID-19 might change both clinical practice, but the bulk of my talk will be about how it might change clinical research.

Dr. John Lantos

As far as changes, I think we're all getting used to having our temperatures taken Everywhere we go, it's become a fact of life. We've gotten used to wearing masks, gotten used to social distancing. And we've gotten used to thinking about how this crisis might eventually change things. And Yuval Harari, who wrote a couple of books about the history of mankind, said we could choose to deal with the crisis by improving totalitarian surveillance regimes, or by empowering citizens and ensuring greater government transparency. We could use this as a catalyst to rebuild our transport system and energy sector on much greener foundations. I'm sure he was thinking about telecommuting as well, or to just focus on narrow economic recovery. So there's choices to be made here about how to respond. the former prime minister of Denmark, who said, we know what's needed, properly resourced health care, smart and compassionate social security, well-regulated markets. Businesses serve societies rather than the other way around. Again, seeing this as a

Dr. John Lantos

crisis that's also an opportunity that might make things possible, as Rahm Emanuel said, that were not possible before. We also know that human relationships will change, maybe forever. The fact that you're sitting there wearing your masks is one indication of the fact that we do social distancing wherever we go. And doctor-patient relationships are one of the relationships that's changing the most. Our hospital immediately, as the crisis began, developed massive capacity for telemedicine.

Dr. John Lantos

We shifted 60% of our outpatient visits to virtual visits within a couple of weeks, something that proponents of telemedicine had been advocating for years. We've found some advantages to that. Parents, for the most part, love it. Some doctors say it gives them a much more comprehensive portrait. It's like making a house call to see families. in their home environment, which is a little ironic because in the hospital, there's less family-centered care. We don't allow many visitors. Often, specialists don't go in. There are very few family conferences or team meetings. So the approach of seeing parents as part of the health care team, which is something we've been working on for decades, went out the window immediately. And whether and when it will come back is unclear at this time. We've all learned to go virtual with professional meetings like this one and even staff meetings within departments in our bioethics center. We rarely see each other anymore. We just see images on the screen.

Dr. John Lantos

One of the biggest changes though and what I'm really going to focus on for the rest of the talk is how research ethics has changed during the pandemic and whether some of those changes might be beneficial, whether they knocked out some structures for research oversight that may have been clinging for life and ready to be let go, or whether there are risks to the new approach to research oversight.

Dr. John Lantos

When this all started, what did we need to know? Well, everything. It was a new disease. We didn't know how it was spread. We didn't know how it was prevented or treated. We didn't know the natural history. We didn't know whether it was different in adults or kids. We didn't know what the risk factors were. And when people started thinking about therapies, there were some drugs that could be repurposed, like chloroquine or steroids. There was the thought of using immunoglobulins and convalescent serum. There were many antiviral medications, none of which had proven effective for COVID, but had been used for other coronaviruses and other viruses. Antibiotics seemed to help. Angiotensin converting enzyme inhibitors seemed to help. And there was always the thought of vaccines. Each of these can be used in almost any possible combination. And because many of them were already approved, there was plenty of off-label use. So the question of how in this complex mess to figure out what was the best treatment was a challenging issue. And research had to be done quickly and effectively to try to answer these questions.

John Massie

So initially, it seemed

Dr. John Lantos

there were two views of how this should go. One was, given the crisis, We need to do things differently. We can't pretend that the ordinary rules apply. We need to do studies more quickly. We need to publish them more quickly. We need to publish them prior to peer review. We need to get them up, in many cases, without proofreading or editing. The crisis demands change. The other view that was articulated by Alex John London and Jonathan Kimmelman was, no, no, no, that's exactly wrong. The rules are good rules, and we need to avoid what they called pandemic research exceptionalism. Pandemic is an important crisis, but the research rules were good rules, and we needed to stick to them and follow them. They sort of parodied the proponents of COVID exceptionalism

Dr. John Lantos

by portraying their view as this, some evidence now, even if flawed, seems preferable to expending greater resources on more demanding studies whose benefits will only materialize later. We need to balance scientific rigor against speed. Let's just get the studies done and then figure out whether they're flawed later. And London and Kimmelman responded that bad data is worse than no data. If we believe that there is such a thing as good data, because bad data will become entrenched in practice, we'll never be able to do the studies that will show us what really works. Another view of COVID exceptionalism is that key features of rigorous research, like randomization or placebo comparators, conflict with clinicians' care obligations. And the response to that is that They do not when clinicians don't know what is the best treatment. They have an obligation to be honest with their patients about their uncertainty and figure out how to do studies to answer important questions, as we'll talk about the ways that different doctors in different countries tried to find the sweet spot or the balance between these two different views varied pretty widely.

Dr. John Lantos

There are plenty of examples of bad data from COVID exceptionalism, that is, studies that were rushed into print in many cases by top journals and were later shown to be flawed. Perhaps the most prominent one was a Lancet study of chloroquine and hydrochloroquine, which was billed as a multinational registry analysis and was as I say, published in The Lancet, claimed to be giving data from 600 different hospitals in 90 different countries and reported that in the control group that did not get hydroxychloroquine, chloroquine, or an antibiotic, the in-hospital mortality was 9.3%. And in the groups that got the drugs, it was at least or about twice as high or higher than that. They also looked at

Dr. John Lantos

all these potential confounders, age, BMI, ethnicity, coronary artery disease, et cetera, et cetera, and found that all these drugs were independently associated with an increased risk of in-hospital mortality. This made international news. It led the World Health Organization to suspend its ongoing randomized controlled trial of chloroquine. It seemed to be convincing data until people looked at it more closely. And then it turned out that there were some quirks to the data, like the mortality rates at all 600 hospitals looked too close to be accurate. And so they queried the authors about where the data came from. And the authors had bought it from a for-profit firm that refused to release the original data to The Lancet. And within three days of the publication of the study and the World Health Organization stopping its study, the paper was deemed flawed and was retracted by The Lancet. So there clearly were examples of bad studies. Another example was the first study published in the New England Journal of the antiviral agent remdesivir.

Dr. John Lantos

This was one of the key graphs in that study where they broke down the days since the initiation remdesivir and the cumulative incidence of clinical improvement broken down by age. The youngest patients did the best, but in every age group, people seemed to improve. The problem with this study, which got through the New England journals, usually rigorous peer review process, is that the authors had made a fundamental statistical error in their Kaplan-Meier analysis. And within two days, the New England Journal got a bunch of letters pointing this out. The authors erroneously censored the data on deceased patients at the time of death. And when the paper was analyzed, it still showed a benefit, but the benefit was about half as great as was initially suggested. My favorite bad data study was this study published not, thankfully, in a top peer reviewed journal. Can smoking protect against COVID-19? And this was a meta analysis of 13 observational studies, altogether a few thousand patients. And the outcome that they chose to look at was among hospitalized patients, how many were current smokers. And they showed that there was a much lower percentage of smokers among patients hospitalized with COVID-19 than there are smokers in the general population. Most of these studies were from China, and therefore suggested that maybe

Dr. John Lantos

smoking is actually protective against COVID-19. This, again, is a basic methodological error that biostatistics courses is called a table two error. It's failure to control for obvious confounders. Later studies showed that smoking is in fact a risk factor for severe disease. Smokers with COVID have more worse outcomes and people with lung disease may be more likely to quit smoking and then less likely to be hospitalized with COVID. So the COVID highlights some of the problems with existing research oversight, not so much reflected in this bad data, but in the ways that we think about how to gather data and test hypotheses about what works and what's not.

Dr. John Lantos

The basic problem is that much clinical practice is not very evidence-based. We know from studies pioneered by John Winberg and replicated by many others that there's vast amounts of idiosyncratic practice variation. Similar patients are treated differently by well-meaning doctors based on the way they've been trained, their reading of the literature, et cetera, but in ways that usually aren't disclosed to patients. So patients are not informed or given meaningful choices. about everything from how to treat a hip fracture to treatments for prostate cancer to treatments for coronary artery disease. We also know that much research, particularly rigorous prospective randomized controlled trials, tends to be narrowly focused with strict eligibility criteria, defined endpoints, and rigorous oversight and meticulous attention to informed consent so that research studies answer narrow questions that then allow the results to be generalized in ways that often aren't justified by the data and may lead to this practice variation. But that extrapolation from the actual results of the study is not overseen in as rigorous or meticulous a way. And so it seems that clinical practice oversight is too lax, and in some ways, research oversight is too rigorous. As I say, COVID highlights these problems because it compresses them all into a

Dr. John Lantos

situation that's on the news every night and in which doctors and hospitals are overwhelmed by the number of patients and they have to make clinical decisions in the absence of good evidence.

Dr. John Lantos

The problem goes back to many of the frameworks that were developed to oversee research that make a sharp distinction between clinical practice and research. These quotes come from the Belmont Report, or the

Dr. John Lantos

Common Rule, which grew out of the Belmont Report, which is the guiding set of regulations in the United States, but similar. Distinctions are made in the CIOMS guidelines and in most national guidelines. Clinical practice, the purpose is to provide diagnosis, preventive treatment, or therapy to enhance the well-being of an individual patient with a reasonable expectation of success. Whereas research is seen as an activity designed to test a hypothesis, allow conclusions to be drawn. and develop or contribute to generalizable knowledge. There's this idea that we know what practice is, that when doctors do it, they're doing what's best for their patients. Research has a different goal. And the tension between these two is highlighted by research oversight committees. This was a quote that was sent to the lead investigators. of the support study in the United States, a study of oxygen saturation targets for tiny premature babies. And the Office of Human Research Protections, OHRP, the federal agency that oversees IRBs, or research ethics committees, said there's a fundamental difference between the obligations of clinicians and those of researchers. Doctors are required, even in the face of uncertainty, to do what they view as being best for their individual patients. And researchers do not have that same obligation. The letter went on to say that researchers, in fact, have an obligation to do good science, even if that sometimes means they're sacrificing the interests of their individual patients.

Dr. John Lantos

Not everyone agrees, and Jay Katz, who was one of the pioneers of bioethics in the United States and was writing before the Belmont Report, so the Belmont commissioners would have known of his work, said research and therapy, pursuit of knowledge and treatment are not separate, but they are intertwined. Or Keith Barrington, who's a neonatologist,

Dr. John Lantos

who participated in the Canadian version of the support study said, yes, I have a fiduciary obligation to provide optimum treatment. I also have a moral obligation to know what the optimum treatment is and a moral obligation to keep trying to find out what the best treatments may be. In other words, Barrington did not see a conflict of obligations, but instead saw a confluence of obligations between his fiduciary responsibilities as a clinician, but also his, you might call them epistemological obligations as a researcher. So COVID highlights these problems because doctors are treating the sickest of the sick, patients with a high mortality rate. And at the outset, there was no good research to guide their treatment. So the question arises when they're doing this, are they doing research? Are they doing clinical practice? If they treat using their best clinical judgment, and then analyze the results as they go. It would seem to be an activity that combines clinical research and treatment.

Dr. John Lantos

That's necessary, I think, because the risks of research are balanced or in some ways less than the risks of non-validated therapy. Research at least allows a time limit on the period in which therapy will be non-validated and generates answers that then help others. So in many cases, as highlighted by COVID, this distinction between research and practice is unhelpful and may even be obsolete. Research and practice both can and should generate evidence that can and should be analyzed and can and should change practice. which then generates more data so that it becomes a self-perpetuating iterative loop in which we're constantly gathering, analyzing evidence in ways that both protects patients and leads to generalizable knowledge.

Dr. John Lantos

I like an analogy between this old distinction to the distinction between a telephone and a computer. That is, we used to know What they did, a telephone was a way to communicate and a computer was a way to analyze data. Now our smartphones have more computing power than the first Apollo moon mission. And I am sitting here at my computer talking to you in Melbourne, the distinction between phones and computers, sort of like the distinction between practice and research. Or to put it visually, this used to be the way we thought about research, a standard approach. randomized control trial where people were allocated to one intervention or another, they were followed up, the data was analyzed and a single report was published that answered a single research question testing a particular single

John Massie

hypothesis.

Dr. John Lantos

Whereas the way things are starting to work and COVID illustrates this is that we have these early translational steps that lead to clinical trials. clinical practice guidelines, performance measures, outcomes, with various oversight mechanisms at each step along the way. Measurement and education are continuous processes in what some people have called the learning healthcare system. We're not there yet. Sort of like telemedicine, people have been talking about learning healthcare systems for at least a couple of decades now. and they don't seem to have developed, but nudged by COVID, I think we're starting to make more progress than we have in decades.

Dr. John Lantos

So the COVID-19 pandemic gives us basic options to shape the evidence generation ecosystem as we go forward. And I think it leads us to this fork in the road where we could either make changes to deal with the emergency and then go back to the good old days or learn from the innovation and implement changes in this evidence generation ecosystem. Let me shift gears a little bit now and use that background to talk about some of the studies that have been launched, how they're being done and how they illustrate both the opportunities and the challenges of this brave new world of warp speed science. I'll talk about three domains, the studies of epidemiology and risk of transmission

Dr. John Lantos

and the risk factors for infection, talk a little bit about some of the treatment and prevention trials that have been launched, and finish talking about some of the challenges presented by vaccine development. And then I'll wrap up and look forward to questions and comments. So there's lots of questions about transmission. And one of the biggest ones is, how often do people have asymptomatic infections? And if they do have an asymptomatic infection, how transmissible is SARS-CoV-2? And what is the population of trivial fraction of transmission? that comes from people with asymptomatic infections. And the first studies of these were observational studies where there had been an outbreak in a confined space with a defined population. And you can see some of those on the left there, a Los Angeles homeless shelter, an aircraft carrier, New York City obstetric patients, et cetera. And what they found was when they tested people who came in contact, And many of these people were asymptomatic. The percentages of people who were positive but asymptomatic were really high, ranging from a low of 6% up to a high of 96% in a prison population.

Dr. John Lantos

This was frightening in terms of all sorts of screening programs trying to identify people who were infected in order to prevent spread. But other studies came up with wildly different estimates. Here, the meta analysis showed that the average number of people who were asymptomatic was about 15%, with a range from about eight to about 41%. So taking these two studies together, it seems like we're all over the map with no idea. A study that just came out this month, JAMA Pediatrics suggests that about 22% of children who have a proven COVID infection have no symptoms whatsoever.

Dr. John Lantos

So these studies have a wide range of results that don't really help us much in answering these questions. And they can lead to that sort of bad science that we talked about, to ambiguity, to mistakes. confusions. The World Health Organization got into trouble when one of their officials, Dr. Maria Van Kerkhove, said at a press conference that there's a difference between asymptomatic and pre-symptomatic, that pre-symptomatic people can spread COVID, but asymptomatic people cannot. The only problem with these definitions is that the only way to tell an asymptomatic person from a pre-symptomatic person is to follow them over time. If they become symptomatic, then they were pre-symptomatic. If they do not become symptomatic, then they were asymptomatic. But whether the transmission rate in both these populations is the same or different remains to be seen. The ability to pin down the rate of transmission has huge implications for testing, for contact tracing. and therefore for decisions about when schools and businesses can reopen. The only way to rigorously study this would not be to take these isolated incidences, but somehow try to study it prospectively. That would

Dr. John Lantos

create some challenges for research ethics. But there is a study going on in Germany where they got 4,000 people who went to a concert to agree to be followed rigorously. They were all screened before they went in. They all wore masks. They were all given hand sanitizer with a dye on it so that everything they touched could be mapped. And they will then use geotrackers on their phone to study each of these people's contacts. And that sort of prospective study may be the best we can do. It does require exposing people voluntarily. That is, the people we're told of the risks, but exposing them to what could become an event that spreads a lot of COVID, but it will be done with strict oversight and therefore probably in a safer way than such gatherings would be in the absence of research. Let me talk a little bit about treatment and prevention trials because they've also been designed and launched in a remarkable and unprecedented way. One study that was launched in the United States was a pragmatic clinical trial called the HEROES study, a study in which the goal was to randomize 15,000 health care workers to hydroxychloroquine or placebo as prophylaxis in order to see whether taking this for a month would lead to lower rates of infection. It used a network of research sites called PCORnet, the patient-centered outcome research net. They had patients pre-screened, they were randomized, they then did web-based check-ins for symptoms, side effects, and exposure to minimize the burden of the research. At the end of the study, everybody got cheek swabs for viral shedding and serum tests to see whether they had seroconverted during the study. What's remarkable about this study is how it was designed and launched. March 25th was the first meeting of the PCORI Protocol Advisory Committee. Two days later, they had a stakeholder planning meeting. Four days later, the PCORI board approved the trial. Within a week, they had IRB approval from a centralized IRB. Two days later, the PCORI contract with the 40 sites was signed, and a couple weeks later, the trial was launched. So less than a month from the first meeting to talk about the trial to the first patients being enrolled. Ordinarily, a complex study like this would take at least months to get off the ground. Interestingly, in the meantime, some much smaller studies were done. Bulwer published a study in the New England Journal on post-exposure prophylaxis, that is, asymptomatic participants who had a household or occupational exposure, and they were randomized to hydroxychloroquine or placebo. And the outcome was whether they ended up with either a lab confirmed or a clinical diagnosis of COVID. One of the problems with warp speed science is these studies were being rolled out before most labs had the capacity to test for COVID. And so they relied on clinical diagnosis, which is known to be wildly inaccurate in predicting who actually has COVID by the criteria they used, fever, cough, body aches, or loss of taste and smell. For any one of those, about 90 percent of clinical diagnoses when tested turn out not to be COVID.

Dr. John Lantos

Nevertheless, these were the results they got. They showed that the group that got the hydroxychloroquine, 11.8% got a confirmed or probable COVID infection compared to 14% in the placebo group. That led to a p-value of 0.35. And they concluded that, based on this, hydroxychloroquine did not work as post-exposure prophylaxis.

Dr. John Lantos

But it's interesting. There was a 20% difference between hydroxychloroquine and placebo. So it raised the question of either whether the study was just underpowered or maybe a more important question of what counts as a significant difference. For many people, a 20% reduction in their chance of getting COVID if hydroxychloroquine is safe would be a risk worth taking.

Dr. John Lantos

The HERO study then had to decide, as did the World Health Organization, whether to continue their studies based on the results of this small one-center trial. The editorial that accompanied this paper in the New England Journal said that other studies could continue. The HERO Data Safety Monitoring Board and investigators decided to continue their study, but in part based on... the Boulware study, and in part just based on the politics surrounding hydroxychloroquine in the United States, they've had problems recruiting patients. So whether it will ultimately answer the question or not remains to be seen.

Dr. John Lantos

Another example of a remarkable study launched at warp speed was the recovery trial in the UK. Here, every COVID-19 patient in the UK was invited to participate. And initially, patients were being randomly assigned to one of five arms pictured here on this slide. The main outcomes are death, discharge, need for ventilation, or need for renal replacement therapy. This study was designed and launched even more rapidly than the HERO study. March 10th was the first draft protocol. By March 16th, they had regulatory approval. And a letter went out to every hospital in the National Health Service. The IRB approval was received two days later. And nine days after the first draft of the protocol, the first patient was enrolled. And in less than a month, 1,000 patients had been enrolled. And they continue to enroll patients in what I think is the best example that I've seen in the world of warp speed science done right. a good study in national participation because it was in the National Health Service. The costs of doing follow-up were lower than they would be in other places. The agreements for data linkage were worked out over a weekend. It is a pragmatic and adaptive study design so that the data is regularly reviewed, effective treatments are quickly identified, ineffective treatments are identified and dropped, and as new drugs or promising ones become available, they will be added to the protocol as it goes. So it's an ongoing adaptive prospective randomized trial that's already generated some remarkable data that I'll show you in a minute.

Dr. John Lantos

The informed consent form was simple. There was a two-page information sheet and a one-page consent form. There was the option for witnessed consent. and the option for a legal representative because the studies

Dr. John Lantos

have been mostly published as preprints. The question of how many people did not consent, I'm not aware of. This is one example of their early publications. The first striking result from the recovery trial was that dexamethasone, lowered mortality among the sickest patients, that is those who required mechanical ventilation. The usual care arm, 41% of those patients died. In the dexamethasone arm, that was 29%. So it reduced deaths by one third in the ventilated patients. Among patients receiving oxygen, there was less of a difference in those with no respiratory support. Dexamethasone did not make any difference at all. Note this was published as a preprint. That is not yet peer reviewed on June 16th. Remember, the trial was designed on March 10th. So within a little over two months, they had enrolled 6,000 patients, gathered the outcome data, the 28-day outcome data, and had the results available for scholarly scrutiny. These were the graphic depictions of the patients who all participants in those with mechanical ventilation. They also added to the case against hydroxychloroquine. These were the results of the recovery trial on hydroxychloroquine. The 28-day mortality for the

Dr. John Lantos

1,500 patients who got hydroxychloroquine was 28% compared to 25% who got usual care. Again, this didn't reach statistical significance, but it was... another bit of evidence that hydroxychloroquine for the treatment of acutely ill patients was at least probably not beneficial and possibly harmful.

Dr. John Lantos

Talk about another study that illustrates a different aspect of warp speed science. This was a study that, again, was recently published as a preprint from the Mayo Clinic. as the lead institution, but they managed to get over 2,000 different sites, mostly in the United States. About 1,000 of them had given convalescent plasma to at least 10 patients. The patients had to have lab confirmed COVID that was judged to be severe by their clinicians. This was a non-randomized pragmatic trial in which there were no limitations on the other therapies that patients could be getting. What they found was that the overall 30-day mortality for these COVID-proven patients with severe disease was 24.5%. Those who got convalescent plasma transfusion in the first three days after admission did better than those who got a transfusion later with 21% versus 26%. and a significant p-value.

Dr. John Lantos

Again, this study, if anything, was overpowered, 47,000 patients, so that even small differences were statistically significant. Also, a fascinating thing about this study was that when they used the convalescent serum, they rushed it right from the donor to the patient. and didn't measure the titer of antibody in the plasma before it was transfused, although they saved a little to measure the titer later so they could retrospectively analyze whether patients who got high titer plasma did better than patients who got low titer plasma. And they found that, in fact, they did, that the mortality for the high titer patients was 22% compared to nearly 30%.

Dr. John Lantos

Based on this, the FDA gave an emergency use authorization for convalescent plasma, although that was a controversial decision. This is just a graph table to show all the different treatments at the different time periods across the study, April, May, June, up to 35,000 patients. Some were getting ACE inhibitors. azithromycin, remdesivir, steroids, et cetera, et cetera. None of this was controlled in this study. And this is just the graph showing that patients who received the high titer plasma did better than the low titer plasma. Many experts urged caution in the interpretation of these results because it wasn't a prospective randomized trial. Peter Bach,

Dr. John Lantos

a policy analyst at Sloan Kettering, said there's no way to be sure of the ultimate benefit. If we'd just done the randomized trials, we would know. Or Harlan Krumholz, director of the Yale Center for Outcomes Research, says it raises the question, what strength of evidence is needed to treat during a pandemic? I mean, there's an interesting question whether either prior to this study or now knowing the results, how many patients, if told these results, would consent to be randomized to placebo. It's unclear. Rob Califf had an editorial in JAMA where he talked about using electronic health records to contribute to making a system of continuous learning as feasible. In some cases, observational findings merit adoption into practice. But in most cases, he says, this should be used to identify promising treatments and designing proper large-scale trials. Investigators said this is why, oops, let's see if I can get back to that.

John Massie

I don't know

Dr. John Lantos

how to go backwards.

Dr. John Lantos

Well, investigators said the reason they felt it was justified to do this was because there would be difficulty in getting people to consent. The treatment was available. off-label, even without FDA approval. And they thought it was justifiable given the crisis, the COVID exceptionalism, to simply try this treatment that had been used in many other similar situations. This being the United States in the era of President Trump, the FDA grossly misrepresented the data and said it led to a 35% reduction in mortality.

Dr. John Lantos

or what the head of the FDA said was 35 of every 100 patients could be saved with this. In fact, the relative risk was 35%. In today's New York Times, Zeke Emanuel has an op-ed praising the UK's recovery trial and criticizing the plasma convalescent trial and, in essence, the entire US approach to rolling out new treatments without doing the randomized control trials that could give more rigorous answers. I love the idea of doing randomized control trials. I'm not sure this data is as uninterpretable as people say. That is, it would be tricky, I think, to come up for an explanation for why for really sick patients, there's a difference between getting this early rather than late or getting a high titer rather than a low titer. that doesn't rely on the fact or that doesn't conclude that this treatment is in fact more effective than what is in essence a poor man's placebo that is the low titer convalescent plasma. So

Dr. John Lantos

probably a randomized trial would have been better and would have gotten an answer quicker. The answer probably would have been more rigorous but randomized trials also have problems both in enrollment and also in generalizability. And it may be that while we would have had an answer about whether convalescent plasma works for the particular patients who are eligible for randomized control trial, we still would have had questions about how to extrapolate that data to other populations. So pragmatic trials like these, controlled or uncontrolled, I think are the most effective way to quickly get preliminary answers. Like all studies, they raise as many questions as they answer. But because they can be designed and implemented quickly, the question arises, should they be the new normal for at least emergency or crisis situations like COVID? Or are they just what we might call crisis standards of research oversight? that is acceptable because we're in a crisis but not acceptable in normal times.

Dr. John Lantos

I'll give some conclusions about it at the end. But first, I just want to say a word about studying vaccines and the ways that that is presenting some challenges as well. Vaccines are probably one of the most difficult interventions to study because you need large numbers of healthy people. people who are at risk for infection. If the people don't get the infection, the studies won't yield meaningful results. You need long-term follow-up to see whether there are both short-term and long-term benefits. For COVID in particular, one of the challenges is that there are many vaccine candidates, at least 15 or 20 at last count, and there's lots of competition to get to market first. And there's lots of pressure on both governments and pharmaceutical companies to get these studies done as quickly as possible. One proposal to speed up the process that's been ethically challenging has been to do what's been called human challenge trials. Here's what a human challenge trial looks like. Instead of having to get 20 or 30,000 patients and hope that some of them get a COVID infection so that you'll be able to see whether the vaccine is effective or not. You line up a bunch of volunteers who have never had COVID, preferably healthy young people living in areas with high rates of COVID. You tell them about the risks and benefits. You then challenge them with COVID after they've been randomized to vaccine or placebo. The studies would be done in special biosafety facilities so that the virus could be contained. subjects would, of course, be informed of the risks and benefits.

Dr. John Lantos

To do this would mean deliberately exposing healthy young people to a potentially fatal disease. And not surprisingly, that has generated some controversy. There is a history to this. Walter Reed, in his yellow fever studies, enrolled soldiers who were working on the Panama Canal and had a consent form that said, the undersigned understands perfectly well that in case of the development of yellow fever in him, that he endangers his life to a certain extent. And people who agreed to enroll were given $100 for enrollment, another $100 if they got yellow fever. And if they died, the family got another $100.

Dr. John Lantos

those studies were carried out and helped show that mosquitoes were the vector for yellow fever. With regard to the human challenge trials for COVID, ethicists are lining up on both sides. Ruth Macklin says that such trials are only acceptable when there is an accepted treatment for study participants who develop severe disease. There isn't for COVID, and so those trials should not be done. Jeff Kahn says informed consent would be impossible because we don't know enough about the disease or the vaccines. Art Kaplan and a colleague say these studies should be done. The risks are manageable. And with informed consent, volunteers should be lauded and their altruism encouraged. And Nir Eyal, a bioethicist at Rutgers, says that when we think about the risks of being in this study, We have to also remember that there are risks of not doing a study of a vaccine quickly. And that if we're going to look at the lives that might be lost, we need to balance the lives that are lost every day that we don't have a vaccine with the lives that could be saved if we could do a study quickly and show that a vaccine is effective.

Dr. John Lantos

Josh Morrison is not a bioethicist, but he founded an organization called One Day Sooner. to try to get volunteers to sign up to participate in these trials. He's gotten over 30,000 people to say they'd be willing to participate today, even knowing the risks. And he has made the analogy to other situations where we allow healthy people to take risks, like kidney donation, where people take risks of 1%, 2%, or 3% potential mortality.

Dr. John Lantos

either short term or diminished life expectancy. And they are not only permitted to do so, both to donate to a family member, but also to donate to a stranger. They are encouraged to do so. And as Kaplan says, lauded and their altruism is encouraged. Carl Elliot, who's been a big critic of Big Pharma, had an editorial or an article in the New York Review of Books where he said, Yeah, you could do these. Of course, you'd have to have meticulous attention to inform consent. He said that volunteers shouldn't be paid. They should all get health insurance. That's a uniquely American problem. They should be provided compensation for research-related injuries, lifetime financial support for permanent injuries. And the studies should only be done if the companies that are doing them guarantee a fair price, universal access of the vaccine and the study data. is made public in a timely fashion. Again, on the theme of this talk, Eliot suggests that these would be good rules not just for human challenge trials in COVID, but as a way of thinking about an appropriate system of oversight for research more generally that should outlast the COVID pandemic. I think these are good rules. I think the debate about human challenge trials is fascinating. I tend to come down more on the side of Nir Eyal and Art Kaplan. Although, interestingly, I don't think any of the companies that's developing vaccines are attempting to do human challenge trials. So what can we conclude from all of this data? As far as long-term impact, I think, I hope, that changes taken in response to COVID are likely to change the way we think about the real world evidence and the evidence generating ecosystem that we use to discover what treatments work and the risks of new treatments. And in that new evidence generating ecosystem or what might be thought of as a robust learning healthcare system, Nothing should be considered purely treatment. Nothing should be considered purely research. Instead, everything should be considered an opportunity to generate data that can be continuously analyzed to improve quality, safety, and outcomes. Sometimes that sort of analysis can give sufficient answers about what works. Other times, the data can inform the design of prospective randomized control trials. by identifying situations where

Dr. John Lantos

after analyzing the non-prospectively gathered data, we remain in a state of uncertainty about which treatment is better.

Dr. John Lantos

I think the other lesson from COVID-19 that applies across the board to medicine is we don't yet know the answers. We need to continuously gather and analyze data. And there's no one size fits all gold standard for evidence generation. Randomized control trials are often called the gold standard, but that overlooks the particular flaws they have in terms of cost and efficiency and lack of generalizability. They're very good as a gold standard for answering one specific question in a very inefficient way, but they're not good for study. the effects of treatments as they're delivered in the real world. Rob COVID, who is former chief of the FDA, gave a great grand rounds at the NIH Collaboratory called Rethinking Clinical Trials. And he says the essential next steps that he hopes COVID will catalyze will be to evaluate what has and hasn't worked in the changes we've made in response to the crisis, and then allocate funding to transition issues in the evidence generation ecosystem at the interface of medicine and public health so that we can begin to develop the sort of infrastructure that seems to exist in the UK, but not so much in most other countries. And then create methods for deciding the most important questions and rewarding behavior that gets those questions answered quickly. There, I think, the public-private partnerships around vaccine development may be the best example of rewarding behavior that at least promises, hasn't yet, but promises to have an effective vaccine ready for widespread public use in absolutely record time. So we may be able to improve research. We may be able to improve care by studying what's worked and what hasn't. With that, I'll stop. Thank you again very much for having me virtually down under and happy to take questions.

John Massie

Thank you very much, John. That was a fantastic presentation and wide ranging and prescient. And I think one of the things that we've been talking about in our ethics group are the lessons that we're going to to take forward but we're still in in the pandemic and so i wanted just to just draw two threads together first i love the slide about humility we don't we don't know it all but i also wanted to bring sort of i think what is your quote that uh in ethics that a decision has to be made can we attribute that to you is that one of your uh things And so, you know, we're not going to have all the information. There's an incredible rush for a vaccine. I think that's going to be the next big thing in COVID. Russians have released Sputnik. Chinese, pretty advanced. Australia's signed up to an Oxford vaccine with AstraZeneca, but have their own University of Queensland product. And I sense America will probably go for an American product. And the FDA will be right in there. even leading up to the COVID, the FDA

John Massie

wasn't as rigid as it had been previously in terms of accepting the evidence. And it seemed that certain drugs were being approved with softer and softer evidence and whether they were economic or political influences. So can you just let us know how you think that might play out? So we've got to decide on a vaccine. We won't have all the evidence. What do you think will happen in the States? Where do you think the FDA will come down?

Dr. John Lantos

I mean, it's a little awkward being a citizen of the United States at this point in time.

John Massie

You can take the second. Is it the Second Amendment? The Fifth Amendment? The

Dr. John Lantos

Fifth. We'll get rid of the Second Amendment.

John Massie

It was one of those.

Dr. John Lantos

That's the right to bear arms.

Dr. John Lantos

Because, I mean, in many ways, the US has been the poster child of bad policy at every step along the way.

Dr. John Lantos

So that said, what the FDA has been doing has been largely in response to critics of the nanny state, critics of government oversight. It's a continuation of what's been called the Right to Try movement. It's this idea that patients have rights to use whatever they want, and the FDA has no role telling me what I can put in my body or whether I should wear a mask. It's the view that's been portrayed in popular movies like Lorenzo's Oil and Dallas Buyers Clubs, where Matthew McConaughey said, screw the FDA, I'm going to be DOA. I'm going to start importing drugs. my own drugs from Mexico, every drug that he imported or the real character on which he was based was later studied and showed to be either useless or ineffective. So there's lots of reasons why having a rigorous barrier to entry based on evidence is a good idea. The question, though, is how rigorous? And so before we get to vaccines, I mean, the convalescent plasma study is a good example. Should this study have been done in the first place? Maybe not. But convalescent plasma was available. Lots of people were using it. There was good historical evidence from other situations that it might be beneficial. People were dying.

Dr. John Lantos

Yes, I think a randomized trial would have been a good idea early on. But the evidence that was accumulated in that trial is not meaningless. It's simply more difficult to interpret than would rigorously designed randomized controlled trial would have been if the rigorously randomized controlled trial managed to enroll patients who knew that the drug was available outside the trial. Maybe it would, maybe it wouldn't. The HERO study that I talked about can't enroll patients as evidence accumulates about the efficacy or lack of efficacy of hydroxychloroquine. The FDA can do, and that's what they've been doing with both remdesivir and convalescent plasma, is what they call an emergency use authorization, which isn't actual FDA approval, but it says it's sort of a compassionate use exemption that the FDA approves, and people should continue to collect data and do randomized control trials. With the vaccines in the US, I anticipate, given that this is an election year, that some vaccine will be approved sometime in October before the election. The FDA has been highly politicized.

Dr. John Lantos

Trump has been promising a vaccine since the outbreak started. And so I think that will happen. I think there are studies that are far enough along that it won't be, again, in the absence of evidence. It will be bending the rules to accept somewhat less rigorous evidence. And probably, given the way people are talking about how the initial doses of vaccine will be allocated, probably first made available to health care workers and first responders. So I mean, health care workers, including first responders. at least it will be first used in a relatively informed subset of the population. And it will be fascinating to see how many doctors and nurses and EMTs either trust the FDA or look at the evidence themselves and decide to take a vaccine that maybe hasn't been studied as rigorously, but if it seems to have a good safety profile, may. still be deemed acceptable.

John Massie

As long as we get given the information, John, that we need to make that decision. But that's perhaps

Dr. John Lantos

conspiracy theorists. Yeah, well, that was Carl Elliott's point about transparency and having all the data made public. I mean, I think that's going to be crucial both for the health. I mean, health care workers are, I think, the most pro-vaccine subpopulation. at least in the U.S., and the degree of vaccine hesitancy in the general public is way higher. And so I think

Dr. John Lantos

making the data public and convincing people the vaccine is safe and effective will be crucial if we want to get the kind of uptake we're going to need.

John Massie

John, we've had a lot of fantastic comments coming in throughout your talk, and Lynne and Georgina Hall have been curating these. So, Lynne, I might pass to you. Have you got a question that you'd like to... to be asking.

Lynn Gillam

Yes, thanks, John. So early on, I made a comment in the chat because what John was saying was making me think about other changes in treatment, not just around treatment of COVID, but other ways in which we deliver health care. And I wondered if there's any research going on about the effects of those changes. And Harriet Hiscock had a response in the chat, which I just wanted to ask her to speak to before she goes to give us some idea of what other sorts of research are going on. at the moment.

Harriet Hiscock

Thanks Lynne and this is a collaborative effort across the Murdoch and across the state as well but I think early on in the pandemic there was a great tweet that came out that looked at the footprint in healthcare of a pandemic so the acute phase recovery from COVID but what is the impact of care foregone on various conditions and people within our community and what is the mental health impact so I won't go on too much but there's some great work going on at RCH but more broadly across the life course looking at the impact of you know our change in presentations to GPs emergency medicine departments our loss of maternal and child health nurse face-to-face visits which has seen more babies coming to our hospital we've seen a greater increase in mental health presentations to our ED so we're looking at statewide data to understand who's being affected how across the life course and what is the the equity in that. So looking at differences in this by family socioeconomic status, Aboriginal and Torres Strait Islander status, for example, and private health insurance or not, for example. So that will be statewide data with the Melbourne Academic Centre for Health and Monash Partners and Western Alliance that we're leading out of MCRI.

Lynn Gillam

Thanks, Harriet. That sounds like it's really important work to be doing. So we'll be looking forward to hearing the outcomes of that. Thanks, John. Next question.

Dr. John Lantos

A couple of quick

Matt Sabin

comments on that

Dr. John Lantos

one. Yeah, of course. I mean, two big areas that we've seen and worried about. One is routine childhood immunization. Kids aren't coming in for their well-childhood.

Harriet Hiscock

Yeah, Margie Danson's leading that work. Yes, we're doing that too, John.

Dr. John Lantos

Yeah. And then Travis Ryder had a thing on the bioethics forum of the Hastings Center that just came out today talking about the opioid crisis and the effect that COVID has had on that. Funding is down, but more importantly, social isolation increases people's use of all sorts of drugs, including opiates. So the fact that they can't go to meetings or talk to friends is increasing opioid deaths after they've been going down for a couple of years in the United States.

John Massie

It's going to be a big fallout, isn't there, from COVID. And I think also, John, just the long-term effects if you're infected by COVID. And I think we're only beginning to learn about those. Georgina. What have we got a question?

Georgina Hoare

We've got lots of questions coming through. I might just start by sharing one that we've had from an Indonesian counterpart who's wondering what your view, John, is on the role of bioethics, the contribution of bioethics in a pandemic situation and sort of in particular the role that the bioethicists could play in countries or contexts where the general COVID program is not really adequately in place, let alone specifically scientifically or ethically sound research?

Georgina Hoare

It's a big one.

Dr. John Lantos

It's been challenging to figure out

Dr. John Lantos

the most useful role for bioethics in this. Early on, many bioethicists worked hard to develop resource allocation, triage policies, anticipating horrific scenes like we saw in Italy in the early days and in New York City in the early days, where ICUs were overwhelmed and we would have to make those tough decisions about who should get life-sustaining treatment. So bioethicists participated on the policy level. There's been some work, some indication that ethics consultations may have gone up in some places, particularly because of difficulties communicating with patients, families not being present at the bedside. But I think there have also been some, you might call them non-traditional roles. The amount of stress and moral distress among health care workers has been astronomical, I think, through this, both because of the risks that they were facing early on, the shortage of personal protective equipment, but also the

Dr. John Lantos

social isolation, learning the new rules. I mean, people can't go to lunch with their colleagues and talk. We did social distancing in the cafeterias. Many people were working from home, and many people have families at home, both elderly parents and small children, and so the tensions between

Dr. John Lantos

professional obligations, personal obligations, work-life balance. At our place, the bioethics people have been working closely with our employee wellness initiative to talk about how much of this is psychological stress, how much is moral distress, and trying to do proactive sessions in the ICUs to help. It hasn't been as big an issue in children's hospitals because there haven't been very many kids with

Georgina Hoare

COVID. I would like to think this is going to be a quicker answer, but I'm starting to doubt myself. John, if there was a vaccine that was thought to be effective, who would you... prioritize to give it to? Would it be healthcare workers, elderly, or the young people who, as we sort of know, may be super spreaders?

Dr. John Lantos

You want a quick answer to that one? Yeah. The general principles that people talk about are maximizing societal benefit, fairness, transparency, and

Dr. John Lantos

Well, those are the big three. But how do you define societal benefit? Health care workers are usually put in that first tier because of their instrumental value. Without health care workers, other people who get COVID can't be saved. But how far does that go? Who else is essential? Sanitation workers, grocery store delivery workers,

Dr. John Lantos

electric line repair people. I mean, you can go down the list, and it turns out there are many more essential workers than perhaps we tend to think of in non-crisis situations. In this particular pandemic, with this particular virus, I think it's easier to make the call between old people and young people because it looks like most young people are not super spreaders and old people are particularly vulnerable. And so allocating the vaccine to the most vulnerable populations in that case makes sense. There are also other ways to prevent spread. You all are exemplifying them there with your social distancing and your masks. And so using the vaccine where it can be the most good, where other interventions might not do as good. The trickier issue, I think, has to do with if there are populations within the general population at higher risk because of sociodemographics. In the United States, that would be African-Americans and Latinx populations whose mortality rates have been two or three times higher than white people. Should they be given priority for a vaccine? I would say yes, although I haven't yet seen an allocation official guideline that

Dr. John Lantos

makes that argument accepted in the most oblique ways.

John Massie

And John, we have a similar question potentially in lower socioeconomic groups who are living in high density housing. We recently had just near the hospital for high density housing places shut down, locked in because of a and obviously there was a lot of contention as to protection of the public versus victimization of people living in these places. And so I think in this pandemic, we've seen a social aspect of disease and healthcare all get mixed up. And that was another group. You alluded to the instrumental value of healthcare workers. Could I just tease you out a bit more because our morning session talked about whether healthcare workers should be somehow valued more in the pandemic for various reasons, which might be because they put themselves on the line, but it might be because they're needed for services to be provided, which would be an instrumental look at it. Could you like to say something a little bit more about that? So particularly thinking perhaps it's provision of PPE, or it's if a health care worker gets sick and decisions have to be made about how they might be cared for, would they get a different style of care because they're health care workers?

Dr. John Lantos

At least two different questions wrapped up in there, I think. runs the Harvard

Dr. John Lantos

Bioethics Center wrote a response to a proposal that Zeke Emanuel published in the New England Journal that said healthcare workers should get priority. And Trug said, I don't think they should. And one powerful argument for that is that healthcare workers are already prioritized for PPE. Healthcare workers tend to be taken care of better than other subpopulations. And so they may actually be at lower risk than groups like high density housing or just lower socioeconomic status or police and firefighters who may not get the face shields they need or may not

Dr. John Lantos

have adequate PPE but are also putting their lives on the line to protect people, just not necessarily in a health care setting. So I think it's at least an open question whether this assumption that goes into most allocation schemes is a bit self-serving and whether health care workers

Dr. John Lantos

obviously should be prioritized or whether that might depend on the circumstances.

Dr. John Lantos

I mean, for people who work in children's hospitals particularly, I mean, there aren't a lot of COVID cases in our children's hospital. I don't know what the situation is for you, but should all 3,000 nurses be prioritized or should it be the small subset who are working in the ED and the COVID ward and perhaps the ICU or doing aerosol generating procedures? There was a second half of your question, though.

John Massie

I've probably forgotten it, too, I think, John. I think you've answered that. And I think that the sentiment at our morning meeting was that health care workers didn't feel particularly special if there was any

Dr. John Lantos

reason. Whether health care workers should be treated differently if they get it. They get priority for a ventilator. That one is easier to me. And I would say no.

Dr. John Lantos

You know, that gets more to, I think, a social worth criteria than an instrumental value criteria, because a health care worker who needs a ventilator is unlikely to be back to work anytime soon, saving lives. And anybody who gets COVID got it because, you know, through no fault of their own. So I think health care workers should not get special treatment or priority for acu resources

John Massie

i'm not coming to kansas city missouri anytime soon john but i agree i absolutely agree too lynn

Lynn Gillam

can i go next um john there's lots of questions in uh the chat uh about various aspects of research and research ethics and i'd like to um put one forward from nigel crawford who says uh interested in thoughts that countries that are not controlling covert well could help answer some of these research questions. But I guess that raises the question about doing research in probably low and middle income countries that have less control. I'm worrying about this now. But can we, in some sense, get good from the bad of uncontrolled COVID?

Dr. John Lantos

I mean, a lot of the vaccine trials are being done in Brazil for just that reason.

Lynn Gillam

Sorry, John, COVID vaccine trials are being done there.

Dr. John Lantos

Yeah.

Lynn Gillam

What do you think about that?

Dr. John Lantos

I don't have a big problem with it because I

Dr. John Lantos

think doing studies in places where there's lots of infection is the only efficient way to do a study, it's the only way that's gonna answer the research question. They are being done in the United States as well, which has rates even higher than Brazil, so it doesn't seem to be based on exploiting people based on low SES or something like that. So as long as people are just in looking at places where the rates of infection are the highest and doing the studies there, That's OK. If those all turned out to be low income countries,

Dr. John Lantos

to the extent that vaccine trials are well designed, carefully monitored, I don't think there's a harm to being in a study. In fact, I think there's a benefit. The usual problem is that if the vaccine works, people who were in the placebo arm claim they were denied the benefit. it's possible that a vaccine will have unforeseen complications and harms, in which case it will appear that people have been exploited. But informed consent, I think, is the only solution to that.

John Massie

Glenn, that's not a different problem from many vaccines which are tested. Guinea-Bissau is a famous country in Africa, which has been involved in a lot of studies for meningococcal. vaccines amongst other things. And so I think COVID is not necessarily different in that. You'd like to think people in the placebo might at least be offered the vaccine if it's proven to work as a thank you for their contribution.

Lynn Gillam

And I guess, John, there's a broader question around whether the vaccine becomes available in the country where the vaccine has been trialled. But as you say, that's a question that... predates COVID and will continue after COVID. Georgina, have we got other questions

Georgina Hoare

coming up? Well, there's an interesting one, which I guess does sort of bring us back to the paediatric context specifically from Jill Sewell, who says that family-centred care, as you said, John, is being diminished at this time with visitor restrictions, no visitor rules, virtual teams, no parents, telehealth. And Jill says that it's... taken a lot of time to develop the principles of family-centred care and she's just wondering whether we're going to have to have a strong emphasis to sort of drive it back to that place post-COVID or whether you think there's enough sort of dynamism and oomph behind it for it to just bounce back by itself. What do you think it's going to do to that whole sort of concept of family-centred care?

Dr. John Lantos

I think it's all going to depend on availability of vaccines. I mean, I think as long as

Dr. John Lantos

we think more visitors create more risk for vulnerable patients, we will continue to have the sort of restrictions that we have now. Once we don't, I think we'll bounce back pretty quickly. Because although, as the questioner says, No good measures of the efficacy of family-centered care and outcomes. Everybody loved it anyway. Families love it. Doctors have learned to love it. And I think it will be back in a hurry. People miss it.

Dr. John Lantos

At least in the US.

Georgina Hoare

Yes, indeed. I do love the quote that I'm going to really take away from your presentation, John, was where you said, we have a broken system where research is considered more risky than it actually is, and non-evidence-based clinical care is actually considered less risky than it actually is. So do you think this is really bringing into stark relief that it's sort of... it seems that research has been sort of the bad guy or the poor cousin or the dirty little secret. And now that maybe research, because there are no answers, there is no treatment, there is no vaccine, that it really is an opportunity for research to come into the light, if you like. And I don't know, for all the system cogs to sort of start turning to bring about these research trials and all the issues of informed consent into sort of much sharper focus.

Dr. John Lantos

Yeah, I'm glad that's what you took home. I mean, I think that's, for me, the key take-home message here. It's my fond hope that COVID would stimulate that sort of change. And just as it's nudged telemedicine along, just as it's speeded up the process of study design and approval, that it might also speed up the development of You could call it a learning healthcare system or a robust evidence generation ecosystem, but it seems like we should be able to look at this and say, wow, we can do that for COVID. Let's do it for cancer. Let's do it for heart disease. Let's do it for HIV.

Georgina Hoare

And do you think it's happening? Like, do you think that the research is being brought into the fold? Do you think that the doors are opening and... and that we're going to get there?

Dr. John Lantos

It had been happening slowly. It seems like it is starting to happen more quickly. And I mean, in some ways, you can make the analogy to wartime, where many medical innovations take place on the battlefield because the usual rules are suspended. But then they become enshrined, and we don't go back to the way things were. Yeah, I have hope. What the

John Massie

heck? John Gillesoul, for whom this plenary is named, has also made a really prescient comment that that sense of clinical care and research all rolling up together. We have an electronic medical record that we started using the last five or six years, and I think you're probably even more familiar with those. Do you think they're an answer to harnessing patient information and spilling out useful data about all sorts of treatments? Or is it at risk of just being too pragmatic? This is what was done and we don't have good enough controls.

Dr. John Lantos

Well, the electronic health record by itself isn't going to do it. I mean, the recovery trial, I think, is

Dr. John Lantos

maybe the best example of what can be done. It relies on a national, easily accessible electronic health record system so that it's easy to track outcomes without having to build that into the cost of the study. So it's an essential backbone to doing this. But then you need somebody to say, what are the questions that we really want to interrogate? And do they involve interventions? Do they just involve observation? I mean, the recovery trial had a nice

Dr. John Lantos

way of quickly offering it to every patient in every ICU in the UK, using the electronic health record to track things, do a quick informed consent that was, I think, meaningful and adequate, but a single page. and then getting high rates of enrollment for a defined set of questions and quickly generating all sorts of data. So do I believe that could happen? Sure. Is it automatically going to happen because we have a good electronic health record? No.

Lynn Gillam

John, I wonder if I could pass on a question from Hugo Gold, because his question potentially throws a bit of a spanner in the works of enthusiasm for research. So Hugo's asked, is the right to try movement reaching a level where it might threaten our ability to actually perform meaningful research? If everyone gets a right to try outside a research study, can research studies still happen?

Dr. John Lantos

Quick answer is yes, I mean, if taken to its extreme. In fact, I don't know what the situation is in Australia, but in the US, many states have an enacted right to try legislation. But they rely on, the FDA is still in place, and right to try relies on the drug company's willingness to provide an investigational drug. And in many cases, the drug companies don't want to do that because they want to get their studies done. so that they can get their drug approved and market it. Right to Try costs the drug company's money for investigational drugs. So in this case, what may seem like perverse incentives, I think, work for good ends and limit the amount of damage that the Right to Try movement could do. That does

Lynn Gillam

make me think about people who crowdfund or have access to their own funding to try.

Dr. John Lantos

But I'm going

Lynn Gillam

to take that

Dr. John Lantos

question for a moment. It will always be done.

Georgina Hoare

There's another question just coming in from John from Bri who's in Houston, Texas. I can't imagine what time it is in Texas right now, but we might get to her question before she falls asleep.

Dr. John Lantos

You should be in bed.

Georgina Hoare

Yeah. So Brian's asking, do you really think that we're going to change our ways, especially in respect to things like the research ethics process and expediting that? She says we're all creatures of habit, or are we at a point where there's no going back and we've kind of sort of moved a good step forward?

Dr. John Lantos

Good question. I don't think we're going to come out of this and go back to exactly where we were. I don't think that every study is going to be designed and approved in a week. But I think we're going to be somewhere in the middle and do an appropriate re-evaluation of current research oversight and try to make some change.

John Massie

Do you think, John, the research oversight and the speed with which these some of the trials have gone through. And I think a lot of the researchers here at RCH and our Research Institute, Murdoch Children's Research Institute, have been really pleased with the speed with which COVID-based studies, but other studies too, have now gone through research ethics. And of course, we roll our eyes sometimes simply because it does feel tedious, but also at the same time does hold us to a very high standard of research. Do you think... the gatekeeper there. So you think we're leading in bad research by rushing too fast or, um, uh, we're doing okay. And that's a, that is a place to speed things up with more resource or more can do. I'm not sure which.

Dr. John Lantos

Well, that, that's the, that's the fear. That's the, the London Kimmelman fear of COVID exceptionalism that, uh, the system is working. It's, it's holding us to high standards and, um,

Dr. John Lantos

making the rules more lax will destroy that

Dr. John Lantos

risk reduction, I guess you'd say. Yeah, that shouldn't happen. And I mean, it helps with COVID that you have a deadly disease where everybody recognizes there's a crisis and randomized trial of you know, how many blood transfusions to give to a preemie in the NICU may not have the same

Dr. John Lantos

urgency or, oh, and so may deserve a little more scrutiny. But that's why I think we could end up somewhere in the middle. It goes back to this point, I think, that I think we overestimate the risks of research, underestimate the risks of non-validated practice. And so again, finding some sweet spot in between is, highly desirable.

Georgina Hoare

There is a question just sort of on that building on that from Andreas Flomner, who says, should hospitals or in fact states have a specified fast track, simplified ethics application pathway for emergent clinical therapies or what we might call urgent clinical therapies at the moment, but would there be any sort of merit in doing that sort of siloing them off as a specific type of research? process and ethics approval.

Dr. John Lantos

That gets back to Rob Califf's point that we ought to find a way to prioritise the most urgent questions. And I mean, that's having a special track for those would make a lot of sense.

John Massie

And certainly we've seen a lot of collaboration, haven't we? And I think in some of those, pulling those big trials together, John has been fantastic. And so I guess that's another aspect that's been really good. A lot of cooperation between disparate services and people.

Lynn Gillam

Yes, it seems that's one of the big benefits that's come out of this collaboration in research and also collaboration in clinical ethics workers we were speaking about at our workshop this morning.

John Massie

Georgina, have we got any more pressing questions? Because we're very near two o'clock, which is our wind-up time, and we have some people, it's very late at night for some of

Georgina Hoare

our guests. Yes, as we've highlighted. No, look, that's pretty much the flavour of what's coming through. A lot of it is around informed consent and research ethics, fast-tracking that. There is a bit more around the towers and, I guess, the sense of maybe discrimination of the lower socioeconomic groups within those areas. to our populations. And there's

Lynn Gillam

a set of comments around priority for vaccines and whether vaccines would be mandatory. But John, you might like to remind people that that's a whole session.

John Massie

So John, and really the rest of the group, if you've just come into this through Grand Rounds, it would be great if you'd register for the conference. And tomorrow... evening we have Julian Savulescu and Dom Wilkinson and from Oxford David Isaacs from Sydney talking exactly about that about a COVID challenge for children to promote essentially illness and efficacy of a vaccine and also whether vaccines might be considered mandatory and so that's going to be debate between Dom and Julian which is I think going to be a really fantastic session and bound to be some controversy certainly lots of interest so uh to everybody it would be great to enroll and john we'd love to welcome you back if you if you'd like to and uh i'm sure you'd have some pressing comments

Dr. John Lantos

um but

John Massie

could i Could we ask everybody to join in thanking John Lantos from Kansas City, Missouri. It's been a fantastic session, and thank you for staying up a bit later and allowing us to pump you for every last bit of information we can get from you while we have you. So, John, thank you very much.

Dr. John Lantos

Thank you, and I hope you have a great conference.

John Massie

Well, thank you. We'd love to have you back when we're all getting back together again. Could I remind everybody that our next session is at 5 o'clock this evening, and that is another keynote plenary, The Ethics of Innovative Therapies for COVID-19. And we have a big lineup from Great Ormond Street in London, Joe Briley, Sarah Aylett, and David Archard. have a good afternoon and then sign back in with us for that session. And John also mentioned about staff wellbeing that came up briefly in there and we're having a medical staff association breakfast tomorrow morning. And so again, If you haven't enrolled for the conference, enroll for the conference so you can come into that session tomorrow. Thank you to everybody for their participation, for the questions. Thank you, Lynn. Thank you, Georgina. And thank you, Creative Services studio crew.

Lynn Gillam

See you at the next session, everyone.