The FDA Advisory Panel met in mid September to discuss Pfizer's application for a booster shot. This led to a partial authorization (link). The key statement is:
Today, the U.S. Food and Drug Administration amended the emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine to allow for use of a single booster dose, to be administered at least six months after completion of the primary series in:
- individuals 65 years of age and older;
- individuals 18 through 64 years of age at high risk of severe COVID-19; and
- individuals 18 through 64 years of age whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19 including severe COVID-19
In today's post, I read the FDA's Briefing Document (link to PDF), released as part of the September meeting in order to understand the science behind this decision. This briefing represents the FDA's interpretation of data submitted by Pfizer.
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The most striking discovery is that the FDA no longer requires a randomized clinical trial (RCT) to authorize vaccines. As explained in my research methods talk (link), RCTs - long considered the gold standard for data-driven medical science - have six key components: random sample of underlying population, randomization of treatment, double-blinding, control, placebo, pre-specification.
With the FDA's blessing, Pfizer offered data from two observational studies; these studies do not have most of those key components that make RCTs the standard.
The first study is a Phase 1 trial, consisting of a total of 23 people. All of them were given a third (i.e. booster) shot about 7 to 9 months after their 2nd shot.
The second study involved about 300 participants who enrolled in the big Pfizer adult trial. (Here is the link to results from that trial.) All of them were given a third (i.e. booster) shot, about 6 months after their 2nd shot.
In all, the FDA looked at two studies that enrolled fewer than 350 people, without a control group, without placebo, and not blinded. The investigators wished to generalize from about 300 to about 300 million people in the U.S. I'm unsure as to why they can't find 300 other participants from the big trial so that they could randomize treatment into extra shot versus placebo.
The FDA advisory committee apparently were not fully convinced by the data but they nevertheless authorized the booster shot for 65 plus and others at high risk. This is a curious decision.
The second study with 300 participants contained zero people aged 65 and above. The age cutoff was 55 years old. So the only older participants came from the first study, and there were N=12 such people labelled as 65 to 85 years old. Table 2 in the Briefing document revealed that despite the labeling, the 12 people's ages ranged from 65 to 75 years old so there was no data submitted for people above 75 years old. This is an example of tokenism, which I described here.
Further, the Phase 1 trial excluded all people who are at high risk of Covid-19 infection, and so all the evidence we have for 65 plus are from 12 healthy, low-risk individuals aged 65 to 75. Table 2 confirms that this dozen did not represent the diversity of Americans - not surprising given the tiny sample size. They are 100% white, 0% obese, and 0% with comorbidities.
The evidence for the second recommendation for 18-64 who are at high risk of severe Covid-19 is similarly stretched. Presumably, indicators of risk of severe disease include comorbidities and minorities. The second study only included people aged 18-55 so the only data available for the 55-64 age group came from the first study - however, none of these people are at high risk of Covid-19, let alone severe Covid-19, by virtue of the Phase 1 study's exclusion criterion.
As for those in the 18-55 age range, the second study enrolled 306, of which only 55 have comorbidities, only 28 are black Americans, and only 2 are native Americans. In short, the FDA authorization is based on observational studies that have really small sample sizes, which get attenuated further when the recommendations are restricted to subgroups. The advisors extrapolated these results to subgroups that have few or zero data based on their expert opinion. (I'm not denigrating expertise, just pointing out how it is applied.)
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The FDA has months ago told the pharmaceutical companies they no longer have to run RCTs. They said that future "modified" vaccines can be approved based on "immunobridging" analysis. In this Briefing Document, the FDA further extends the rule to booster vaccines that are not modified from the original, which is what the Pfizer booster shot is.
The logic of immunobridging is to show "non-inferiority" in antibody levels after taking the booster shot compared to after taking the two-dose series. Instead of comparing vaccinated to placebo as in an RCT, such analyses compare people who took the booster shot to people who took the first two shots. If the antibody levels are non-inferior - as defined by statistical criteria, then it is presumed that the booster shot will provide the same level of protection as the original two doses, i.e. the famous 95% vaccine efficacy.
Pfizer submitted data that showed the antibody levels after the booster shot were non-inferior, using thresholds to which the FDA has agreed.
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What is "immunobridging"? This bridge is what I'd call a "causal assumption".
You see, neither Pfizer nor the FDA can define the relationship between antibody levels and getting infected. During the Advisory Committee meeting, a Pfizer scientist acknowledged, "We actually looked at our breakthrough cases in our placebo-controlled phase 3 study, and have compared the antibody titers where we had the opportunity in individuals that got the disease versus the ones that didn’t, and we were also unable to really come up with an antibody threshold. So I think there’s probably a much more complex story and not easily just addressed with neutralizing antibodies."
What they were hoping for is a simple rule that says antibody levels > X means vaccinated person is protected. The "much more complex story" implies that the rule must involve not just antibody levels but many other factors.
We therefore know that antibody levels is necessary but not sufficient to induce immunity. The causal model requires other variables, some of which may be unmeasured. The chosen solution is to make a causal assumption: just assume that antibody levels is sufficient for protection. This is the meaning of the following sentence in the summary section of the FDA Briefing Document (link to PDF):
Effectiveness of the booster dose against the reference strain is being inferred based on immunobridging to the 2-dose primary series, as assessed by SARS- CoV-2 neutralizing antibody titers elicited by the vaccine.
Two steps are involved here: the 95% VE estimated in the adult trial is assumed to be directly caused by the vaccine producing enough antibodies to fight off infection - while assuming no other factors play a role; then, the booster shot is assumed to produce 95% VE if it induces "non-inferior" antibody levels compared to the original two shots.
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The next question is how long will immunity coming from the booster shot last. The short answer is 1-2 months; it could be more but we don't have the data since this is another interim analysis with a brief follow-up period.
The second study has the bulk of the people (about 300). The follow-up periods range from 1.1 to 2.8 months post booster shot. But we should subtract 1 month because there is a case-counting window that would start 30 days after the booster shot. Effectively, the period of time during which these 300 people can accumulate cases is as low as 3 days, and up to 1.8 months (54 days). (The first study with 23 participants has the same maximum follow-up time.)
Where does the 30 days come from? This is analogous to the 14-day period in which cases are removed if they occur in vaccinated people. The antibody measurements were taken 30 days after the booster shot and compared to measurements taken at 2D+30 days in the previous adult trial. Since we are inferring protection based on antibody levels, we can't infer protection for any time prior to 3D+30 days by measuring antibodies at 3D+30 days. Effectively, for the third dose, the case-counting window has been pushed from 14 days after the shot to 30 days after the shot. Anyone who gets sick within one month after getting the booster will not be considered "breakthrough".
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This post just scratches the surface of all the issues that arise when we don't have RCTs to evaluate medical interventions. These observational studies are small, do not have randomly selected participants, do not have a placebo/holdout arm, and are not blinded. As a result, any observed outcome could have been caused by a host of factors, including unknown or unmeasured variables. This forces data analysts to make assumptions. The quality of the analysis depends heavily on the quality of these assumptions.
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