Today Moderna announced almost identical positive results to those from the Pfizer trial reported last week. Although there are differences in dosage, storage and manufacturing, the two vaccines themselves are very similar. This is good news as the Moderna results provide an independent validation of the value of an RNA vaccine which gives support to Pfizer and other companies pursuing the same approach. But there could be an issue in the way that results from these trials are being communicated and acted upon.
Anything more we learnt about RNA vaccines from the Moderna trial?
- Reassuringly, as implied above the results from Moderna were almost identical to the Pfizer data
- Moderna in their press release announced that even though there were a few cases of Covid-19 in the active vaccine group, all of the 11 with a severe disease had received the placebo vaccine
- Moderna also reported some mild side effects (nothing was mentioned in the Pfizer press release on this) but they were minor
- Both vaccines require two doses
- As widely reported, the Moderna vaccine is easier to store at conventional deep freezer temperatures and transport, making the logistics easier leading to probably to a cheaper vaccination programme
Of course, we have the same unknowns..
- Will the vaccine be effective in the elderly (we don’t have enough numbers to know that)?
- Will the vaccine be effective for longer than just the 1-2 months so far studied? We need to wait and see – but this might be the problem!
How long should the clinical trials run for?
- The trials were all designed to follow up the participants for a full two years to see how long the protection lasts for
- Not unreasonably, given the urgent national public and political interest, we are getting the preliminary results issued as press releases, as soon as there is evidence of a real effect
- Scientifically reviewed publications will follow, but there is now the expectation that these vaccines will be approved and rapid introduction of their use will follow
- But what happens to the thousands of people in the trials who had the placebo vaccine and will continue to be followed up?
- On the one hand, if we do not continue to obtain data on the relative success of the active vaccine versus the placebo, we can’t know whether the advantage persists for the 2-year period
- On the other hand, if vaccines are approved, then the participants in the trials who had the placebo vaccines will want to ‘convert’ to the active vaccine
- A fascinating article in last week’s New Orleans Picayune Times* suggested that the latter indeed would happen
This is what he wrote:
*Thanks to RS for pointing this article out to me!
Does this matter?
- At first sight the trials are likely to come to a premature end: what had been planned as 2-year trials could be stopped after 2 months
- One could argue that this is ethical, and indeed it would be unethical in an active pandemic to allow participants in these trials to continue with the placebo vaccine unprotected once something is now known to work
- Does this mean though that we will not now have the reliable longer-term comparison data on success of the vaccine?
- It is not unusual in clinical trials to have a stopping rule, which would terminate a trial if a treatment is shown to work before the planned end date
- Think about a cancer treatment trial which shows a survival benefit with a new treatment: it would be unethical not to allow the group of patients who had received the old treatment to switch to the new drug
- So, what happens now?
- It is likely that the trials will stop the true comparison stage earlier than planned, but there will be an unblinded follow up of everyone to see what the rate of new Covid-19 cases is over time
- This follow up provides information on how long the protection from the vaccine will last
- But, if say 10% of those vaccinated get Covid-19 infection during the next 2 years, what we won’t be able to do is say how much higher that rate would have been if they had not been vaccinated
- If, over this time period, it does prove to be the case that there are new infections occurring in those who had had the Covid-19 vaccine, then we will need different research trials which for example – in people who had had a course of a successful vaccine – could compare the following groups:
- just continued follow up
- with a booster of the same vaccine after say 6 months or a year
- or with a second, different vaccine after a shorter interval
Conclusion
From a scientific perspective an early end to a randomised trial, with some key questions unanswered, is not ideal, though there is a strong case for unblinding the trials once a vaccine is licensed and widely available. Hopefully the long-term benefits of any of the vaccines under test will persist, but we will not know exactly what might have happened without the vaccine.
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Making sense of CoVid-19 with Silman 