Emergency Use Authorization — at our peril
Emergency Use Authorization.
Sounds pretty great.
It is not!
Yes, this is an emergency. And, yes, we all want a vaccine as soon as possible.
Emergency use authorization (EUA) is not the way to get that vaccine any sooner.
Emergency use authorization in this context is dangerous and costly.
EUA will delay the proper evaluation of an effective coronavirus vaccine for months or even years.
EUA for the use of convalescent plasma illustrates these problems.
Because of poorly designed, uncontrolled studies, followed by EUA, we still do not know whether convalescent plasma is helpful or dangerous. Based on what we know about serum, it could be either. Or it could be a useless and expensive diversion of time and money, delaying the development of truly effective therapies. And now that it is available for use, it is almost impossible to conduct the proper randomized control trials that could quickly provide the answers to these uncertainties.
There are many reasons that randomized control trials (RCT) are needed to establish the safety and efficacy of any therapeutic. These reasons are hard-learned lessons from disasters that occurred when the principles for arriving at a scientific conclusion are not followed.
Properly designed randomized control clinical trials for potential drugs can be carried out relatively quickly. For a potential drug, we can test it on a group of already infected individuals. If the group that receives the treatment does far better that the group that receives the placebo or other control treatment, the answer will be quickly apparent.
Unfortunately, vaccines are different. We need to test large groups of people because we do not know who might be exposed to the virus. In order to determine if the vaccine works, we need to have a very large group and wait long enough to establish that there are no differences between the treatment group and the control group that might be due to chance. The exposed groups need to be almost identical in terms of age, sex, race, underlying conditions, etc. That takes time. Based on the current prevalence of the virus, only a small fraction of those who receive any candidate vaccine or the placebo will actually be exposed to the virus.
Unlike drugs, which may act over the course of hours, the immune systems may take days or even weeks to fully respond to the immunological priming induced by the vaccine. Additionally, the time needed to determine efficacy is increased by the fact that most of the vaccines candidates require multiple boosters, spaced out in time.
Determining safety may require even more time. Unlike medications, vaccines are intended for use in large numbers of uninfected individuals, so they must be exceedingly safe. The need for safety also requires the testing of very large numbers of diverse individuals and waiting for long enough to be assured that the risk of adverse events is extremely low or very mild. While the benefits of vaccination may suggest that we may not want to wait to see if events as rare as one in a million occur, we will certainly want to know about events that are as common as one in a thousand. In addition, it will clearly take more than a few weeks to discover adverse events that may develop over a period of months.
There is a big difference between the testing of medications and vaccines. For vaccines we need to know if the protection they provide is enduring, and for how long. For medications, we do not need to assess if the dose we took six months or a year ago is still working. For a vaccine, that information is critical. Clearly, it takes time to know how long a vaccine will last. It cannot be known with certainty even after a few months.
The saying “Haste makes Waste” is nowhere more true than when it comes to vaccine assessment.
EUAs for coronavirus vaccines are particularly dangerous when they are based on “surrogate endpoints”. The argument for the use of surrogate endpoints is that instead of actually determining if a vaccine is safe and efficacious, we can use rapid alternatives such as a rise in antibody levels. But we still do not know what aspects of the immune response determine true protection, so these alternative endpoints may give us an erroneous assessment of the vaccine’s efficacy. It is hard to imagine what could convincingly substitute for actually measuring safety. (not sure about the safety of this sentence)
Once all the data has been collected, it needs to be analyzed by researchers, reviewed in an unbiased fashion by experts who were not part of the actual study, and made public for general scrutiny.
Although this information is publically available, it is not widely appreciated that only 5 of coronavirus vaccine candidates are currently in Phase III clinical trials and none of them has a designed endpoint prior to 2021. Even under “Operation Warp Speed” conditions, none of these trials will be completed before the end of the year!
Even after a vaccine has been shown to have acceptable safety and efficacy, it needs to be manufactured and distributed, along with educational materials for providers and recipients.
One way to greatly speed up the availability of candidate vaccines is to build the manufacturing facilities before we have proven safety and efficacy. The problem with this strategy is that it encourages the inappropriate use of EUAs. The gamblers fallacy is the false intuition that “I have already wasted this much money, I can’t stop now. My luck is bound to change.” In this case, we cannot afford to gamble with licensing a poorly evaluated vaccine in order to salvage the investment of large pharmaceutical companies. Before we proceed with manufacture, we need solid evidence that a vaccine is safe and that it works.
If anyone is eager to get a vaccine, they should volunteer to be in a clinical trial. As soon as possible. Being in a clinical trial has a number of potential benefits. There is a 2 out of 3 chance you will not be in the placebo group. There is a chance that the vaccine you receive might work. There is a sense of “doing something”. You will be greatly contributing to science and hastening our ability of answer the question of which, if any, of the vaccine candidates may be safe and effective. People of all ages and demographics are needed to participate in these trials.
What a clinical trial will not do is eliminate the need for using all the public health measures that prevent infection. At least until we have clear answers about safety and efficacy.
And anyone who balks at the possibility of being in a clinical trial should certainly steer clear of any drug or vaccine that was approved by an EUA. In the latter case, they are just in an experiment that is mostly likely to be completely useless.
Some people have suggested that vaccine trials could be hastened by so-called “challenge experiments” in which vaccine recipients are exposed to wild virus. Many people have even volunteered for these studies. Because of the need to determine if a vaccine works for all types of people, particular those at risk for complications, challenge experiments are unethical, dangerous, and unlikely to give answers that are helpful or timesaving.
So do not be deceived by politicians touting EUA.
Emergency authorization of research funding is a good idea. Emergency mechanisms for sharing scientific information will also help. But we must not allow the short cutting of scientific procedures to prematurely authorize the use of vaccines that have not been properly tested. Without delay, we need to get unambiguous answers about vaccine safety and efficacy. This is by far the quickest way to achieve safe immunity for all.
Many thanks to D. Scott Smith for his very helpful suggestions.
Robert David Siegel, MD, PhD
September 8, 2020