News just broke that the FDA may announce more "rigorous" standards for a coronavirus vaccine to get approved. This indicates a willingness to listen to some of the critics of the perceived rushed job.
The specific rules mentioned in this Washington Post article are:
1) Participants must be followed for a median of at least two months, starting from when they receive the second dose
2) The analysis must be conducted after at least five severe cases of Covid19 have been observed in the placebo arm.
3) The analysis must be conducted after some minimum cases of Covid19 in older people has been recorded.
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Rules 2 and 3 are fine in spirit. It's important that the vaccine works for severe cases and older people. These rules ensure that all trial analyses include the two groups that are of great concern to the medical community.
Recall that the case definition uses mild symptoms instead of severe symptoms. Since a lot more people develop mild symptoms, it's possible that the interim analysis contains only mild cases. It's also possible because of self-reporting that the cases used in the interim analysis involve only younger people.
I suspect those scenarios are unlikely anyway. Because testing is triggered by self-reporting, severe cases are more likely to surface than mild cases. So long as they have sufficient older participants in the trial, they should show up in the interim analysis because older people tend to have more severe illnesses.
Nevertheless, if the vaccine is approved by the end of 2020, it will be on the strength of an interim analysis. Such analyses are never designed to make statistically reliable statements about subgroups, such as older people or severe cases. This is another reason why the trial should run to completion even if the FDA grants interim approval.
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Revised rule 1 is misleading and potentially worrying.
Let's talk about its good intention first. Rule 1 sets up a second criterion for triggering the interim analysis. Previously, the only criterion is to exceed a prespecified total number of cases. This creates the potentially undesirable scenario in which enrollment is supercharged (either by pushing marketing, or relaxing admission standards), or the true case rate is markedly higher than assumed, such that the first interim analysis is triggered when most participants have barely taken the second dose.
By setting observation time as a second criterion, the new rule provides more confidence that the protection afforded by an approved vaccine lasts at least 2 months.
As I explained in this previous post, Moderna does not count cases until 2 weeks after the second dose. So if they track people for two months, it's really only 1.5 months of observation time. That isn't a lesser worry. What perturbs me is the use of the word "median".
Median is the middle person so the statement actually allows up to half of the participants to be observed for fewer than 2 months. Further, it is highly unusual and in fact statistically fallacious to perform analysis in which different participants are observed for different amounts of time. I hope this is a communications faux pas, a misunderstanding on the part of the journalist. The sensible rule is to require every participant (not the median participant) to be observed for at least 2 months (preferably longer) after the second dose.
P.S. [10/6/2020: A group of scientists and medical experts agree! STAT News writes about their pushback on rule #1. They want "a minimum of two months' observation for all participants".]
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