Coronavirus in Context: The Need for COVID-19 Clinical Trials

Hello, I'm Dr. John Whyte, Chief Medical Officer at WebMD, and welcome to today's edition of Coronavirus in Context. We're going to talk about the need for clinical trials, and my guest is Dr. F. Perry Wilson. He's an Associate Professor of Medicine at Yale University School of Medicine. Thanks for joining me, Dr. Wilson.

Thanks so much for having me.

You know, we're in the middle of a pandemic, and people are talking about, let's just get those drugs out there, whether it's hydroxylchloroquine, whether it's monoclonal antibodies. Why do we need to do trials right now? We don't have time.

Yeah, I mean, that's one of the biggest concerns I hear from people out there. People are really scared. And to be honest, physicians are scared too, and we all want a drug that works. There's nothing we'd like more, to be honest. The fact of the matter is that what people often don't realize is that doing randomized trials actually is a faster way to find the right drug for the right disease than not doing clinical trials.

So there's this idea that you're trading speed for scientific accuracy or something like that. That's not entirely true. One of the most important things we learn in clinical trials is what drugs don't work. And at the beginning of a pandemic like this, you have, as you mentioned, multiple candidate agents. If we just proceed to kind of throw things at patients and see what happens, we'll never learn which of those are false starts, which are blind alleys.

And the history of drug development has shown us time and time again that promising agents, things that look on paper like they might work, end up not working. So in fact, if your goal is to get to a treatment that is going to save the most lives possible, honestly, the quickest way to get to that goal is to do rigorous, randomized clinical trials because you will stop wasting time on those agents that aren't going to prove to be fruitful.

Well, walk us through that timeline because a lot of folks will be thinking, there's no way it's quicker. So what's that timeline? We talk about phases of clinical trials. Some people are saying it's three months for a vaccine. Others are saying it's 18 months. What's the real answer for treatments?

Sure. There's two big things to think about in terms of timeline when it comes to drug trials like this or treatment trials like this. And the big question at the beginning is is this a new drug that has never been tested before, or is it an old drug that we could potentially repurpose? So for a brand new drug, a chemical compound that has never been put into a human's body before, it does take some time because we need to make sure it's safe.

So these drugs go through animal testing first then they go into very small scale, what we call phase one human testing in healthy adults, just to see if they cause any toxicity because we don't, obviously, want to give something to people that ends up making them worse. Then you move that forward into effectiveness studies -- again, small -- to see if there's any signal of the benefit before you go to the large-scale studies.

So for new drugs that have never been tried in humans before, yeah, the process does take some time. One of the big determinants of that amount of time, though, is how quickly the outcomes happen. So when you see that drug trials can often take 10 years or something like that, remember, those are often trials that are looking at things like heart attacks and cardiovascular disease, things that happen over the course of years. The double-edged sword here of the coronavirus epidemic is actually that the outcomes happen pretty quickly. We will know within a month or so of starting a drug whether the patient is getting better or not, which is not something we have.

How would we know that?

F. PERRY WILSON: Because the course of the disease is so short. So we're not talking about a cholesterol drug that might work over the course of years or even decades. We're talking about drugs that you're going to get for a relatively short period of time, maybe a month, and you'll see. Most patients hopefully will get better within that time period. Some, obviously, won't.

But what about those drugs that are already on the market, that are already indicated for something? We use drugs off label all the time without doing trials. So why do we need to do the trials now? Let's just get them out there and test. Is that a reasonable approach?

F. PERRY WILSON: It is, actually, and the truth is, they are out there. Physicians are using, for example, hydroxychloroquine, which has come up quite a bit, off label for the treatment of COVID-19 and have been for some time now.

And other drugs, to be fair. We're talking about some other antivirals, monoclonal antibodies, et cetera. Hydroxychloroquine is a lot in the news, but there's other ones that we're doing too, not just drugs for malaria.

Absolutely, and that's fine. But what we have to realize is that when you give patients those drugs in the context outside of a study, you're not able to learn very much from it. So we still need to do those rigorous studies. And one of the problems when anecdote and case reports start kind of flooding the public consciousness is that, ironically, it becomes harder and harder to do the randomized trial because as you can imagine, for a patient who's going to be consented, you're now saying, listen, we really need to figure out if this drug works or not.

There's a 50-50 chance if you join this trial that you'll get the drug. There's a 50% chance you'll get the placebo. Patients may not be willing to do that. And then all of a sudden, what we're left with is this world where all patients are getting different drugs based on the opinion of the doctor, and we don't actually learn which one of these many, many drugs is the actual one that's going to work, and that's a bad situation. Do they have to be randomized, placebo control in this instance? You're a big proponent of different clinical trial design. Do we need that here? Do we have time?

I think we do. You can do a randomized trial in as short a period of time as you can do an uncontrolled trial.

What's uncontrolled? Explain that to the audience.

Uncontrolled trial is one where you're enrolling patients, and you're just saying, OK, I want to study you while you take this drug, this antiviral. And I'm going to measure blood, and I'm going to do a bunch of things, and please consent to this study. There's nothing that adds a particular amount of time to add the portion of that consent that says, and by the way, you might at random be chosen to get placebo, and all of the other procedures will be the same. That's not really the rate-limiting step.

The rate-limiting step is finding those patients and for people to be willing to try to advance the science as quickly as possible. And again, it really is going to be quicker to find the answer if we do randomized trials. Now you said there's many different types, and that's true. We do not need 10,000, 50,000 patient randomized trials.

We can do this on small scale, at multiple sites at the same time, what are called pragmatic studies where it's really easy to enroll patients. Not a lot of exclusions, everyone can get in, but you still keep that randomization because that makes sure that you're not secretly choosing patients that might do a little better to get the drug. We don't want people to get the drug because the doctors think they've got a better shot. We want to know, is this going to work in anyone?

Every drug has side effects. Are you concerned about side effects of some of the medications that we're currently talking about?

Oh, absolutely. And that's something that's often underplayed. Just because a drug has been in use for a long period of time doesn't mean it's side-effect-free. And please ask anyone who has taken hydroxychloroquine for a long period of time about those side effects. They'll tell you about them, some of which can be quite severe, for example, cardiac arrhythmias and things.

One of the other reasons docs are so focused on this idea of finding the evidence, really knowing if it's beneficial through a randomized trial is because we took that Hippocratic Oath that said, first, do no harm. That is our first thing. It's not first, try your best, and then if possible, don't harm the patient. So we all take that incredibly seriously, and we know that every drug is potentially harmful. Most drugs are not going to be beneficial in this particular disease, but every drug has side effects. So at the start, the weight of evidence says we shouldn't do something that can harm a patient unless we have good reason to believe it might help. And we need to build that evidence base as quickly as possible, and there is no quicker way to build the evidence base than doing randomized trials.

So you're a listener, and you have a loved one who's battling coronavirus. What do you tell them when they're hearing all this talk about different medications? What's your advice to them?

My advice is to have a discussion with your doctor who's taking care of you. There is limited data right now on any therapy for coronavirus. This will change on the order of months. We'll have more and more data coming in. But right now, we are flying blind. So it's OK if your doctor wants to go with their gut and take a chance on a given drug. That's OK. In the absence of better information, that's fine.

But if you're given the opportunity to enroll in a clinical trial to help figure this out for those people in the future who are going to continue to get this disease, I consider that a particular honor. As much as the scientists doing those trials are advancing science, the patients and participants of those trials are advancing the science, too. And it might be scary to sign on that line and know you might be getting a placebo, but that is something that is going to save lives in the long term.

Well, thank you, Dr. Wilson. We definitely need to focus on science, even during a pandemic.

Absolutely.

And thank you for watching Coronavirus in Context. I'm Dr. John Whyte.