Vaccine Phase III Trial Protocols & Other COVID-19 News
Moderna, Pfizer/BioNTech, Novavax and Astrazeneca/Oxford all released the protocols for their Phase III vaccine trials against SARS-CoV-2 in late August/September. [1–4]
The question on everyone’s mind is timeline. When are they happening and more importantly when are they done and have an answer? A precise date is not possible to determine, which is explained by looking at the published protocols.
All trials employ event-driven interim and endpoints. What this means is that when the studies are considered complete will depend on when certain numbers of COVID-19 cases occur in the enrolled patients.
Broadly speaking, each trial will take patients and randomly allocate them to receive either the vaccine being tested or a placebo. Neither doctors nor patients know which shot the patients received (this classifies the trial as “double-blind”.
Once a certain number of patients contract SARS-CoV-2, the results will be “unblinded”; this means that it will be revealed which patients received the vaccine and which the placebo. Then, the data will be analysed to see how effective the vaccine is.
For example, consider examining the data after 1000 patients fall ill with COVID-19. If 500 patients who received the vaccine were infected, then the vaccine failed to provide protection. This is because an equal number of patients contracted the disease despite having received a placebo.
Conversely, if all 1000 patients who were infected received placebo, the vaccine appears to have protected the other patients completely and it would be said to be 100 % effective.
In reality, the data will not be so clear cut. So, one could have a scenario where e.g. 583 patients on placebo were infected. Is this a real effect, or just noise? This is the reason trials employ complex and powerful statistical methods to figure out if their vaccine is effective at protecting patients and if yes, to what extent.
The goal of a trial is called the “objective”. The endpoint describes the data which are required to assess whether the objective has been reached. Trials often have multiple objectives and endpoints.
The trials will examine data more than once, in the hopes that effectiveness might be demonstrated in a shorter time period, but also to ensure that their vaccine is not causing harm instead of providing protection. These points of examination are called interim analysis points.
Moderna and AZ/Oxford have made it clear that results in the interim analyses will not stop the trial, but will continue in order to evaluate longer term efficacy and safety.
The Pfizer/BNT protocol is less clear on that point.
Novavax clearly states that they may stop after the interim analysis depending on the result.
AZ/Oxford will analyse when ~75 events (infections) are recorded (50% of the overall target).
Moderna will perform their first interim analysis when ~53 events (35% of total) are recorded and a second one when ~106 events (70% of the total) are recorded.
Pfizer will analyse when 32, 62, 92 and 120 cases are recorded.
Novavax will examine the data when 66 events are observed and again when 110 are seen, with the final call at 152 events.
Overall, we are waiting for the trial participants to contract SARS-CoV-2 so we can see the effectiveness of these vaccines.
It is not clear what the approach of both the companies and the various regulatory authorities will be. It is assumed that if robust efficacy is demonstrated at any interim analysis, an Emergency Use Authorisation (EUA) will be granted with great haste.
One last thing to note is the period of time between potential demonstration of vaccine efficacy, any EUAs and distribution & innoculation of the general population.
All the vaccine manufacturers (n.b. Oxford, being a university, is not one of those, production and manufacturing is handled by Astrazeneca) have set targets for production that extend to the end of 2021. Essentially, this means that even if any one vaccine is approved via EUA in the next couple weeks, the majority of the population of even the countries most involved in its development would not have broad access for many months to come. The pandemic will not magically end once a vaccine is approved.
Public health experts express the concern that the efforts to contain COVID-19 are cutting into the efforts for malaria control, especially in Africa. They estimate that this indirect effect of the pandemic could have a large impact. [5]
Yet another trial of remdesivir claims a benefit with respect to time to recovery for non-critical patients. The benefit is rather small and in a subset of patients, consistent with previous studies. [6]
References
- https://www.modernatx.com/sites/default/files/mRNA-1273-P301-Protocol.pdf
- https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol.pdf
- https://s3.amazonaws.com/ctr-med-7111/D8110C00001/52bec400-80f6-4c1b-8791-0483923d0867/c8070a4e-6a9d-46f9-8c32-cece903592b9/D8110C00001_CSP-v2.pdf
- https://www.novavax.com/download/files/protocols/2019nCoV302Phase3UKVersion2FinalCleanRedacted.pdf
- https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30700-3/fulltext
- https://www.nejm.org/doi/full/10.1056/NEJMoa2007764?query-featured_coronavirus=
