In the midst of growing public and scientific concern regarding the integrity of clinical trials for COVID-19 vaccines, Moderna publicly released its 135-page clinical study protocol. Of biopharma companies with a COVID-19 vaccine candidate in phase 3 trials, Moderna is the first to publicly release its study protocol. The overall goal or primary endpoint of the Moderna’s phase 3 trial is to show that mRNA-1273 has a vaccine efficacy (VE) of 60% in preventing COVID-19. In biostatistics parlance, the VE is [1-HR], or 1 minus the hazard ratio. That is, the goal is to show that healthy participants who receive Moderna’s vaccine are 40% as likely to develop COVID-19, compared to participants that receive placebo. In the trial, a case of COVID-19 is defined as:
With 30,000 total participants, the trial will be unable to confidently  claim a vaccine efficacy of 60% until 151 participants develop COVID-19. Assuming that participants receiving placebo have a 0.75% chance of developing COVID-19 in a 6-month window, it will take 10 months for participants in Moderna’s phase 3 trial to develop 151 COVID-19 cases. The first participant (Dawn Baker in Savannah, GA) received her first dose of mRNA-1273 on the morning of July 27, 2020; per Moderna’s protocol, vaccine efficacy data won’t be available until approximately 10 months after the first participant received her first dose of mRNA-1273, or the end of May 2021.
Moderna’s phase 3 trial includes 2 planned interim analyses at 35% and 70% of 151 COVID-19 cases. That is, the target goal is to analyze vaccine efficacy after 151 COVID-19 cases develop; however, in case Moderna’s vaccine is particularly efficacious, an independent data safety monitoring board (DSMB) will assess available data after 53 and 106 COVID-19 cases develop, which will occur at approximately the end of December 2020 and the end of March 2021. The goals of the interim analyses are to confidently claim that the vaccine efficacy is above 30% . If the true efficacy of Moderna’s vaccine is 60%, the chances that vaccine efficacy can be demonstrated in December 2020 and March 2021 is 4.6% and 61.5%, respectively.
The DSMB will also monitor for lack of vaccine efficacy and any harm caused by Moderna’s mRNA-1273 vaccine candidate.
So far, Moderna has enrolled over 25,000 participants in its phase 3 vaccine trial. In total, 30,000 participants will be part of Moderna’s trial.
 90% power to detect a 60% reduction in hazard rate (60% VE), while rejecting the null hypothesis that VE is less than or equal to 30%
 The WHO recommends that COVID-19 vaccine efficacy is at least 50%. Further, clinical trials ought to be designed such that the “true vaccine efficacy” is greater than 30%; that is, the 95% confidence interval should exclude a vaccine efficacy of 30% or less. The FDA’s recommendations for Development and Licensure of Vaccines to Prevent COVID-19 (Guidance for Industry) includes this lower limit of 30% as a criterion for vaccine licensure and early detection of efficacy at an interim analysis.
Moderna is to be commended for publicly releasing detailed info on its phase 3 COVID-19 vaccine trial. Interestingly, its protocol suggests that the timeline for a readout on vaccine trials extends into the middle of 2021.
In the USA, political pressure has sparked hopes & anxieties that a vaccine may be broadly available prior to the presidential election on November 3, 2020. Interestingly, Pfizer recently claimed that it expects “a conclusive readout” on vaccine efficacy by the end of October 2020, though it did not provide details or data supporting this ambitious timeline.
In contrast, Moderna’s protocol suggests it does not expect a conclusive readout on the efficacy of its vaccine until the end of May 2021. Because Moderna’s timeline is based on a number of assumptions, it’s possible that its timeline may change. First, if participants receiving placebo develop COVID-19 at a higher rate than expected, then a conclusive readout may be possible earlier than May 2021. Second, if Moderna’s vaccine is especially efficacious in preventing COVID-19 (e.g. 75%, 85%, or 95% efficacious), then its interim analyses may demonstrate sufficient efficacy for Moderna to seek partial regulatory approval at an earlier date.
It’s likely, per Moderna’s CEO Stephane Bancel, that it would seek regulatory approval for FDA Emergency Use Authorization for a “very limited population”, such as healthcare workers and the elderly. Moderna will gather more data on vaccine safety prior to seeking full FDA approval. Per Moderna’s protocol, “there is no intention to stop the study early if the efficacy has been demonstrated at any of the interim analyses.”
It’s also plausible that a conclusive readout for Moderna’s vaccine may occur later than expected. For example, a secondary endpoint for Moderna’s trial to evaluate the efficacy of its vaccine in preventing severe COVID-19. In the trial, a case of severe COVID-19 includes any of the following:
Some scientists may argue that a vaccine’s ability to prevent severe COVID-19 is paramount. However, it would certainly require more time to demonstrate vaccine efficacy in preventing cases of severe COVID-19, compared to preventing cases of COVID-19 (any severity).
Finally, it’s interesting that Pfizer/BioNTech have a more optimistic timeline for a conclusive readout on the efficacy of their vaccine. Pfizer’s phase 2/3 vaccine trial and Moderna’s phase 3 vaccine trial started on the same day, July 27, 2020. It’s possible that Pfizer, by enrolling participants in the USA, Brazil, and Argentina, expects that its participants receiving placebo will contract COVID-19 at a high rate. In comparison, Moderna’s trial only enrolls participants in the USA. In addition, Pfizer expanded its trial’s target enrollment to be approximately 44,000 participants. Still, we await data supporting Pfizer’s optimistic projections on the milestones for its vaccine trial.