[Goose]

That being said, the efficacy data is quite a bit stronger than "giving some indication" of efficacy.  Using hard endpoints, the drug does convincingly reduce the risk of COVID-19 infection.  The 95% confidence intervals robustly exclude zero efficacy, meaning that the vaccines are significantly efficacious, and the lower bound of the confidence interval is above 30%, which was the FDA's bar.  We might not for sure if it is 70% effective or 90% effective, but it is likely be above 50% effective, which is about what you get with your average flu vaccine.  You are right, however, that the MHRA has not communicated this well, and people do need to know that they can still get COVID even if they have the vaccine (this is true also of the Pfizer/BioNTech and Moderna ones, though they get closer to 95% efficacy), so some degree of social distancing is still important in the midst of the pandemic.  But all the vaccines will put a dent in the pandemic, and, promisingly, all of them seem to especially offer protection against more severe disease (requiring hospitalization, ICU admission, or causing death).


There are enough questions that I would understand a delay (especially with two highly effective vaccines already authorized), but I consider the MHRA to be aggressive but not reckless.



BC

BC, when you say "hard endpoints" aren't you talking about the phase three trial as designed, not the exploratory analysis? That would be the original protocol, not the modified one of a single dose. An exploratory analysis doesn't qualify as a hard endpoint, or does it? I am almost certain the FDA really resists to the max retrospective endpoints.

In any case, a 50% reduction in COVID-19 cases would be really welcome and would drive Reff below one, subject to the current lockdown restrictions. The problem will then arise about how much you can "ease up" the current restrictions and still control the disease. It may well be that you can't get back to "normal" or anything close to it. You may have a virus that is effectively less transmissible (due to immunity) but still capable of doing serious social damage without controls on large crowds etc. being retained. If the vaccine does in fact reduce mortality much more than 50% then having a larger Reff may be just fine, or at least acceptable. However, we don't know that yet.

One does have to say the same situation could arise with vaccines that are 90% effective, but this is much less probable. In either case the "correct" approach IMHO would be to leave the current regulations in place until the smaller Reff brings the number of cases down to a very small number. Naturally, this process will be much faster with a 90% effective vaccine than a 50% effective one. Then there would be hope that we can control the disease by more "conventional" methods and can lift the controls entirely. However, I fully expect the public and the politicians will have none of it and demand the restrictions be reduced "as soon as possible" or even before. There is also, as you point out, a parallel with the flu vaccine. I know several people who say "I got the shot, I still got the flu. You shouldn't bother getting it" which may make vaccination less than universal, eroding the 50% even more.

I also expect that taking a "more effective" vaccine later may not be safe and/or effective. A trial would have to be run to determine that. Thus, the MHRA may be wedding the public to the Astra Zeneca vaccine AND this particular protocol. That's fine if it turns out to be "good enough". Otherwise, ouch. This is a consideration that IMHO shouldn't be ignored. OTOH, there may be a protocol under which this vaccine is 90% effective. There are indications of this in the existing trial. However, a half dose (sort of) was the first administration, not a full one. I would suggest that finding that protocol should be number 1 priority and maybe outweigh the benefits of a quick administration of a single full dose. One should consider that "rushing to a failure" is often unwise. You may not require a full trial, since safety isn't the issue.

I do agree with you that the MHRA isn't being "reckless". They are making a measured evaluation that the expected benefits will outweigh the risks. I do wonder how much "political considerations" played into this evaluation. It is a cheaper alternative, it is easier to distribute (I am pretty sure there are no -80 freezers on Skye) and it was developed in the UK. It may be easier to get into more arms much faster, which would be good anywhere. That we will never know, probably.

[Goose]

That being said, the efficacy data is quite a bit stronger than "giving some indication" of efficacy.  Using hard endpoints, the drug does convincingly reduce the risk of COVID-19 infection.  The 95% confidence intervals robustly exclude zero efficacy, meaning that the vaccines are significantly efficacious, and the lower bound of the confidence interval is above 30%, which was the FDA's bar.  We might not for sure if it is 70% effective or 90% effective, but it is likely be above 50% effective, which is about what you get with your average flu vaccine.  You are right, however, that the MHRA has not communicated this well, and people do need to know that they can still get COVID even if they have the vaccine (this is true also of the Pfizer/BioNTech and Moderna ones, though they get closer to 95% efficacy), so some degree of social distancing is still important in the midst of the pandemic.  But all the vaccines will put a dent in the pandemic, and, promisingly, all of them seem to especially offer protection against more severe disease (requiring hospitalization, ICU admission, or causing death).


There are enough questions that I would understand a delay (especially with two highly effective vaccines already authorized), but I consider the MHRA to be aggressive but not reckless.



BC

BC, when you say "hard endpoints" aren't you talking about the phase three trial as designed, not the exploratory analysis? That would be the original protocol, not the modified one of a single dose. An exploratory analysis doesn't qualify as a hard endpoint, or does it? I am almost certain the FDA really resists to the max retrospective endpoints.

In any case, a 50% reduction in COVID-19 cases would be really welcome and would drive Reff below one, subject to the current lockdown restrictions. The problem will then arise about how much you can "ease up" the current restrictions and still control the disease. It may well be that you can't get back to "normal" or anything close to it. You may have a virus that is effectively less transmissible (due to immunity) but still capable of doing serious social damage without controls on large crowds etc. being retained. If the vaccine does in fact reduce mortality much more than 50% then having a larger Reff may be just fine, or at least acceptable. However, we don't know that yet.

One does have to say the same situation could arise with vaccines that are 90% effective, but this is much less probable. In either case the "correct" approach IMHO would be to leave the current regulations in place until the smaller Reff brings the number of cases down to a very small number. Naturally, this process will be much faster with a 90% effective vaccine than a 50% effective one. Then there would be hope that we can control the disease by more "conventional" methods and can lift the controls entirely. However, I fully expect the public and the politicians will have none of it and demand the restrictions be reduced "as soon as possible" or even before. There is also, as you point out, a parallel with the flu vaccine. I know several people who say "I got the shot, I still got the flu. You shouldn't bother getting it" which may make vaccination less than universal, eroding the 50% even more.

I also expect that taking a "more effective" vaccine later may not be safe and/or effective. A trial would have to be run to determine that. Thus, the MHRA may be wedding the public to the Astra Zeneca vaccine AND this particular protocol. That's fine if it turns out to be "good enough". Otherwise, ouch. This is a consideration that IMHO shouldn't be ignored. OTOH, there may be a protocol under which this vaccine is 90% effective. There are indications of this in the existing trial. However, a half dose (sort of) was the first administration, not a full one. I would suggest that finding that protocol should be number 1 priority and maybe outweigh the benefits of a quick administration of a single full dose. One should consider that "rushing to a failure" is often unwise. You may not require a full trial, since safety isn't the issue.

I do agree with you that the MHRA isn't being "reckless". They are making a measured evaluation that the expected benefits will outweigh the risks. I do wonder how much "political considerations" played into this evaluation. It is a cheaper alternative, it is easier to distribute (I am pretty sure there are no -80 freezers on Skye) and it was developed in the UK. It may be easier to get into more arms much faster, which would be good anywhere. That we will never know, probably.