randombio.com | commentary
Saturday, April 18, 2020. Updated April 30 2020

Placebo-controlled trials are essential

Judging the efficacy of drugs like Remdesivir on the basis of uncontrolled trials could lead to many unnecessary deaths

T he excitement over Gilead's announcement that “only” two patients died in its recent clinical trial underscores the shallowness of the public's hatred of big pharma. The news media are going wild, and Gilead's stock has shot up. Suddenly big pharma can do nothing wrong.

Maybe it's cruel to take away hope. I get it. But to those of us who follow pharma, the sudden upbeat statement unaccompanied by new data is all too familiar. What's more, it comes only a week after their paper in the New England Journal of Medicine which showed the exact opposite.

Update Apr 30 2020 A new placebo-controlled randomized trial at Beijing has just found zero effect of remdesivir. See here for details.

In that report, the only meaningful result was that invasive ventilation does not increase mortality but appears to prolong recovery times. It didn't show anything about the efficacy of Remdesivir because there was no control group. There was no mention of any benefits from Remdesivir other than to say that “clinical improvement was observed in 36 of 53 patients (68%).” No measurements of viral load, fever, or disease severity were made. Over half had signs of liver toxicity.

In the NEJM paper, the authors explicitly say that a placebo group will be essential. They wrote:

"Measurement of efficacy will require ongoing randomized, placebo-controlled trials of Remdesivir therapy."

Doctors sometimes worry that if a drug turns out to be effective they will have risked those patients that were in the control group. Laymen often question the value of placebos. They ask what patient with a potentially fatal illness would ever volunteer to be in a study where they had a 50% chance of getting a sugar pill. Yet patients do it all the time because they know it's the only way we have of gaining knowledge.

It's a hard decision to make. No doctor wants their own patients to die. But ethically the decision is clear: it is unethical not to do a placebo control.

Why is a control group so important?

Humans are not like lab rats: they vary enormously. People in one hospital are different from people in another. In some parts of the city smoking is high. In others people exercise daily. Still others live in a so-called food desert or are exposed to chemicals that affect their immune system. Standards of care differ even in hospitals on the same street. This means that without a control group, neither you nor your patients can know whether the treatment made them better or worse. If others believe your treatment works, they could treat people for months only to discover that the drug is no better than sugar. Or they could unnecessarily abandon a cure because something unusual was going on in your clinical center.

I know of one clinical trial where doctors did everything by the book: subjects were matched for age, race, sex, and disease severity in a randomized, placebo-controlled, double-blind study. At the end they found that the treated patients had dramatically improved. It looked miraculous until they looked at the controls. They too had improved, even more than the treated patients. No one ever found any explanation.

Some people might say that a drug for COVID-19 is so urgently needed we don't have the luxury of a controlled trial. But doing a control is not a luxury. It's no more time-consuming than doing a drug-only test, and it's the only method that tells us at all whether the drug works.

What about compromises?

Some trials on COVID-19 have used untreated patients in other hospitals as their control. This is not a good solution: without an in-house control group there's no way to account for the variation in different locations. In the Gilead study, for example, we know nothing about how those Gilead patients might have differed from patients in other studies.

Other trials made a better compromise: they offered alternative treatments such as lopinavir/ritonavir, an antiviral used to treat AIDS. Or they used Arbidol (which isn't approved in the USA) as a control. Even hydroxychloroquine and antibiotics have been used as controls. And the study end point can easily be adjusted to take a patient getting worse as a reason to put them on the drug.

In the Mahevas study of hydroxychloroquine in Paris, they tried a different compromise: 84 subjects got HCQ from the start, and 97—the controls—got it only after a 48 hour delay. Conclusion: HCQ had no effect. Does this mean HCQ doesn't work? Or that the compromise wasted everyone's time and risked abandoning a drug that could save hundreds of thousands? Is losing a cure because the doctor wants to do everything for the patients really the most ethical choice?

Indeed, by this logic, it would be unethical not to give every patient every drug under the sun. Why not give them chicken soup, IV vitamin C, interferon, and azithromycin as well, just in case? Lest we forget, many tens of thousands of other patients across the globe are also not getting Remdesivir.

For some diseases we can use a crossover design, where the treated and placebo groups are switched halfway through the study. This is probably the best trial design because each patient can be their own control. But it's only useful in diseases that progress slowly over a long period of time.

Soon this pandemic will be over and it'll be impossible to find infected patients. Ongoing clinical trials will grind to a halt for lack of subjects. We need clinical researchers to take a stand now and inform the public why it's unethical not to run controls. Unless we start getting some randomized placebo-con­trolled studies, we'll have no idea what to do when the virus returns, as it is likely to do, next winter.

Lest anyone forget, the reason clinical researchers are testing a drug is that they don't know whether it's effective. If they knew, they wouldn't have to test it. And there's a strong possibility that the drug could make the disease worse. It's happened many, many times. So the argument that doctors are “sacrificing” some of their patients by running a control is bogus. Suppose HCQ turned out to exacer­bate the disease. Those doctors who skipped the placebo control would be sued, and rightfully so.

Skipping a placebo control in the belief that your drug will do what you want is worse than wishful thinking—it's dangerous.

apr 18 2020, 7:24 am. Updated April 30 2020

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