番茄社区

In the first of two exclusive video interviews, 番茄社区's Editor-in-Chief Marty Makary, MD, MPH, of Johns Hopkins in Baltimore, speaks with Vinay Prasad, MD, MPH, a hematologist-oncologist at the University of California San Francisco and author of , on the backroom problems of medicine and science in terms of deficiencies in the clinical trial apparatus in the U.S. during the COVID-19 pandemic.

The following is a transcript of their remarks:

Makary: I'm Marty Makary, and I'm here with Vinay Prasad, one of the great minds in healthcare, and it's just such a cool honor to be here with you, Vinay. You do such great work and it's just really cool to be able to talk to you. Thanks for joining.

Prasad: Thanks for having me, Marty. It's a pleasure to be here, a pleasure to finally get to chat with you.

Makary: It's interesting, your book Malignant came out really just in the front end of the pandemic.

Prasad: Yeah.

Makary: I'm sure it wasn't designed to address issues of the pandemic, but yet I found that it was so applicable to the issues of the pandemic because what we're seeing is a research infrastructure that is not set up to do rapid evaluation and to be resilient and respond to a health crisis. It's set up for, it seems like, long-term analyses of drugs with marginal small differences and lifestyle medications. It's this channel. Can you talk about that?

Prasad: I think you hit the nail on the head that COVID-19 has brought many of the backroom problems of medicine and science to the dinner table. Everyone's talking about them now and some of those problems include: you have a pandemic, you're getting thousands of people pouring into New York City hospitals, you could so easily do some very simple randomized controlled trials.

"Should we do regular anticoagulation or high-dose anticoagulation? Should we give steroid, no steroid? Should we give tocilizumab [Actemra], no tocilizumab?" What you find is that most patients in the United States are being treated off protocol.

Doctors are just improvising, giving combination kitchen-sink approaches that they have no certainty, help or hurt, and they're taking those patients away from controlled clinical studies. Now, we're several months in a pandemic. We still don't know the answer for what's the best anticoagulation strategy. That's a deficiency in the way in which we conduct clinical trials.

Our colleagues in the U.K. are telling us that dexamethasone is a life-prolonging, a life-saving intervention in COVID-19, in severe COVID-19, in the RECOVERY trial. I congratulate them. They did a great service to the world for finding that out, but I feel a bit ashamed as an American investigator that we, with nine times as many cases, ten times as many cases, we have to wait for the folks in the U.K. to answer that question for us.

It has sort of unmasked major deficiencies in the clinical trial apparatus in the U.S. and it's also unmasked deficiencies in so many other things, the chronic underfunding of public health. It's so easy to say public health is over-funded, it doesn't matter, except when of course you need them. Had you funded public health to the tune of tens of billions of dollars, you would have saved several trillion dollars in this pandemic, if we had really strong public health systems in place, which we do not.

It's also unearthed, I think, some great failures in leadership, which perhaps veer a little bit off the theme of this podcast. But it's unearthed great failures, and I encourage people to check about all of the ways in which we've failed in the pandemic and how the greatest nation was brought to its knees by a virus.

Makary: It is kind of embarrassing that not only did the RECOVERY trial out of the U.K. do a basic analysis... it wasn't really an elaborate phase I, level I trial. It was a basic analysis of those who got dexamethasone and didn't. It found a massive difference.

The most embarrassing thing is how late it came out in the pandemic. It came out like in June when dexamethasone had been on the shelf of every ICU in the country for this whole time and had been used for similar conditions like sepsis.

I had heard that the U.S. was invited to participate in the RECOVERY trial and basically declined it because they thought the study design was not sophisticated enough. I don't know if you heard that as well.

Prasad: No, but there's something similar, which was ... the point you're making is that many, many people had COVID and died of COVID before we learned that a drug could be lifesaving. The failure here is that why didn't we randomize the first 10,000 people, the first 50,000 people globally? We would have answered all these questions, tocilizumab, dexamethasone, remdesivir, lopinavir, and ritonavir [Kaletra]. We would have answered them all earlier had we committed to randomization.

I think one of the things that points to that is there is a great article that came out of Mount Sinai -- well, it's not a great article, it's an article that I'm critical of. It's where they changed their practice and gave thousands of people in Mount Sinai Hospital full-dose anticoagulation. They could have randomized them to our current anticoagulation strategy or full-dose anticoagulation and we would have known the answer if it's beneficial or not. They chose not to participate in randomized studies and do that uncontrolled experiment instead.

I think what it's unearthed is a philosophical question in medicine, which is when you are facing something grave, uncertain, and that you're fearful, do you try first or do you do a trial first? Do you just try things out or do you test them in a rational, scientific manner?

There are many powerful forces that would say "try first." There's an emotional appeal to just try things, but the reality is we have learned painfully over 20, 40, 50, 60 years that the smart thing to do, the cerebral thing to do, the rational thing to do, and actually the compassionate thing to do, and ethical thing to do, is to do the trial first, sort out what works and what doesn't work. You will benefit an order of magnitude more people and you will answer questions in a timely fashion. That's a commitment that we still lack in the United States, and even to some degree globally.

Makary: I couldn't agree more, and I think everybody listening loves that because we want answers. We want to be able to know how to treat our patients better and why are we learning about therapeutic anticoagulation versus prophylaxis dosing of anticoagulation as a study -- MedPage just had a piece on that report last week -- why are we learning about that here in August, right? Why wasn't that done in April?

I would submit, just speaking as a researcher, one of the reasons that I do not do that elaborate study design is sometimes the bureaucracy is just daunting. The IRB [institutional review board], the fact that you can't really study anything unless there's funding for it because the insurance companies and the hospital's not going to pay for things on a trial unless there is funding.

Then you add to that that the funding structures were set up in these old silos of kidney disease and vascular disease. There is no funding for food as medicine, and environmental exposures, and the association between chronic poor sleep and Alzheimer's, and stress management, and things that improve the quality of life in cancer patients that are not pharmaceutical. Those are sort of the real-world complaints, I would say, on the front lines of some of this stuff.

Prasad: No, I agree. I'm deeply sympathetic to those complaints. I think you're absolutely right to talk about the bureaucracy of setting up a randomized controlled trial. It is not insignificant. It is not trivial, and that's why it's very difficult to do.

I guess, to that point, I would say that one of the great, I think, sort of errors that we have made in the regulatory affairs on clinical trials is there have been some notoriously flawed critical studies that got done. In response to them, we've enacted a series of bureaucratic hurdles that trial sponsors have to jump through, but those hurdles disproportionately focus on the trivial details, the dotting of i's and crossing of t's details. They don't focus on the philosophical questions like, "Is this the right control arm? Is this the right question? Is this asked in a rational way?"

The other thing you touched upon was funding, and I guess I would say that I will frankly admit that I think the amount we spend as a public from the public purse on clinical trials is a farce. I'll put it to you this way. Just in terms of Medicare and Medicaid spending alone, we spend $1 trillion in healthcare in this country, just in those terms.

We also spend additional federal funding, of course, in subsidizing employer-based insurance programs, so we're spending trillions of dollars on healthcare. What does it cost to run some of these trials? Our federal trials budget is in maybe two orders of magnitude lower than what our spending on unproven medical practices are.

It's much, much lower, and sometimes you can run a $5 million or $10 million study and you can contradict $10 billion of federal spending. You can find $10 billion a year was being misspent. It would be irrational for a company not to chase those kinds of savings, not to run those trials, and yet in our system, we don't do those studies. We don't test all these medical practices that have dubious evidence base.

I will submit to you that the reason is that there are powerful lobbying forces that don't want us to test established, cash cow, medical practices or fields. They don't want those tested and so we don't have an infrastructure that tests all the things we could be testing at a time of peace. Then you enter a time of war with COVID-19 and the infrastructure is lacking, as you point out.

I think it speaks to broader, deeper failures that have occurred for decades. It's not the sole failure of what happened in COVID-19. It also speaks to the fact that we don't in the best of times have an infrastructure designed to answer these questions in a simple manner.

The folks in Europe, because of the ways in which money flows through the system, have invested in these things to a better degree and that's why we have to read the RECOVERY study to know that dexamethasone is lifesaving.

Makary: We've spent $16.4 billion, according to the health affairs study, in 1 year on simply collecting quality measures and reporting them up. That would be the equivalent of every physician in the United States having about 0.6 of an FTE [full-time equivalent]. If we could assign a research coordinator to every two or three doctors in the United States, what would that do to our research infrastructure?

Prasad: That's absolutely right. That's the right way to think about it, is the amount of money we're spending chasing quality in a crude way when we could be chasing in a very rational way. The other thing that people think about is we've embraced and we have used the carrot and the stick to get everyone to adopt electronic medical records [EMRs], and for many of us, it has just frustrated us. But EMR could have been a great opportunity to embed randomization.

There is a really nice study that came out of The Netherlands and . It was a randomized controlled trial of thrombectomy in myocardial infarction, ST elevation MI, and the authors built in to the routine practice of medicine the randomization, "Should we suck out the clot or not suck it out?"

They found that more than 50% of the people presenting with ST elevation myocardial infarction in The Netherlands were able to be randomized. They randomized thousands of people in a short period of time at a cost of $50 per participant, which is perhaps the lowest reported dollar per participant in a randomized study. Why did they do that in The Netherlands? Because they had invested in the infrastructure, which is what you're alluding, to run clinical trials in a timely fashion.

That would be the single greatest transformative innovation in the United States, in my opinion, would be if the average practicing doctor -- wherever he or she may be -- could easily put their patient when there is clinical uncertainty, which there so often is, to the red pill or the blue pill, to doing this or not doing this.

If we could just answer all these questions, it would be a boon, but I think we're facing an uphill battle trying to get that through because the manufacturers of some of these things simply don't want them tested ever in the life cycle.

Makary: That's so true. That's great. Vinay, good to see you again, my friend. The book and the podcast is . Great name, and with that mic that you've got, I'm sure it's the best podcast with the highest audio quality in the United States.

Prasad: Oh, I'm an audiophile, Marty. But thank you so much. It's a pleasure to talk to you, a pleasure to talk to a like-minded individual on these topics, and I really appreciate you getting the word out.

Makary: Great. Good to be with you, Vinay.

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