Noah Feldman, a very smart law professor at Harvard wrote a terribly misguided column for Bloomberg on an emergency use authoritrization for a Covid 19 vaccine (https://www.bloomberg.com/opinion/articles/2020-09-04/we-should-cheer-a-covid-19-vaccine-even-from-trump-s-fda). I wrote this response and submitted it to Bloomberg but they decided not to publish it.
My mom used to tell me that just because I was able to do something, it didn’t mean I should. She would say: “think about what could go wrong first”. Well, just because the FDA has the power to issue an emergency use authorization (EUA) for a COVID-19 vaccine, doesn’t mean they should. Why? Because effectivity and safety take very different amounts of time to determine.
To see why there will be a time difference, you have to understand a bit about how vaccines are tested. The first two phases are small, often less than 500 people combined. In these phases they test for obvious safety issues (phase 1) and try to find the right dose(s) to try (phase 2). Then, if phase 1 and phase 2 trials are successful, it’s on to a much larger phase 3 trial – 30,000 people seems to be what they are using for Covid 19 trials.
In a phase 3 vaccine trial, you randomly divide the participants into two groups. Half get the vaccine candidate and the other half a placebo. Then you tell them to go about their lives. Over time, you hope to see a difference in the number of people who got infected between the two groups. You also look at the severity of the disease in people in the groups. For example, the flu vaccine protects some people and makes the disease less severe in others.
Depending on the efficacy of the vaccine, you need surprisingly few cases before you get an “efficacy signal”. For example, suppose there were 300 cases in the unvaccinated group and 100 cases in the vaccinated group. Then we will know the vaccine is 66.67% effective (300-100/300). This is way above the 50% effective threshold that the FDA said they will use for efficacy for a COVID-19 vaccine. You don’t even need a 300/100 split, even a 100/35 split would give a statistically significant signal.
So how long will it take before you get enough infections in the placebo group before you know if you have met the FDA’s 50% threshold for vaccine efficiency? For a virulent disease like Covid 19, if you are testing your vaccine in places where the disease has a high prevalence as indicated by the test positivity rate, hospitalization rates, etc., not very long. I wouldn’t be surprised if it took as little as 30 days after you have given enough people their two doses – you wouldn’t even have to have finished enrolling all 30,000 participants! That seems to be why some reckless individuals talk about “having a vaccine by November”. Still, suppose, as seems likely to me, we have an efficacy signal sometime in November, should the FDA issue an emergency use authorization? Absolutely not! There is no way we will know if the vaccine is causing low frequency (very bad) side effects by then.
Here are some examples: perhaps the scariest one occurred in 1935 when John Kolmer tested an attenuated polio vaccine. He tested in it 10,000 children (no placebo group – those were the dark ages of clinical trials). Five of these children (1 in 2000) died of polio and 10 more (1 in 1000) were paralyzed. So, these horrific side effects occurred in “only” .15% (15/10,000) of the cases. Statistical speaking this is relatively rare and so you wouldn’t necessarily find this kind of side effect that quickly.
A phase 3 trial for a proposed vaccine for Staphylococcus aureus caused more organ failure and death in patients getting the vaccine than those who didn’t get the vaccine. (It also wasn’t particularly effective.)
There is a known, though rare complication of certain vaccines called “antibody-dependent enhancement” (ADE) where a vaccine makes some people end up far worse if they catch the disease than people who never got the vaccine. The best known example of ADE has been for Dengue fever but ADE has been shown to occur with coronaviruses like the one that causes SARS and MERS in animal studies!
Let me reiterate: you simply can’t know if a Covid-19 vaccine causes low frequency bad $#%^ as quickly as you know about its efficacy.
Heck, you can’t be sure about very low frequency events even with a six month trial of 30,000 people. This is why vaccines are tracked in their first few years of use – that’s usually called a phase 4 trial. During the Ford administration, also eager for a vaccine approval before the election, the swine flu vaccine caused Guillain-Barré syndrome, a very very serious side effect, in about 1 in 5,000,000 vaccinated people.
But there is a much larger issue – even if one makes the argument that having an effective vaccine is worth risking rare side effects that might only be discovered by waiting a few more months. That is the effect on how the public sees vaccines if those rare side effects happen. Unfortunately, we live in a time where vaccines are questioned by a significant portion of the public. An EUA for any Covid 19 vaccines, based solely on a quick efficacy signal, could completely poison the well for all vaccines, we can’t risk that most of the major drug companies developing a vaccine claim they understand this. They have said they will not seek an EUA unless and until they are happy with the safety profile. I sincerely hope this is the case!