Moderna on Thursday took the unusual step of making public the detailed study plan for the company's large coronavirus vaccine trial, becoming the first developer in late-stage testing to do so amid calls for greater transparency by researchers and public health experts.
Hours later, fellow coronavirus vaccine frontrunner Pfizer quickly followed suit, hurrying to share its own blueprint after initial reluctance to do so. AstraZeneca, also far along in testing a vaccine, published online the plan for its Phase 3 study on Saturday.
So-called study protocols, lengthy documents that are typically closely kept while testing is ongoing, give outside observers a better sense of how the trial is being run. Most importantly, the plans help clarify how — and when — independent committees in charge of reviewing study data would determine whether a vaccine is safe and effective.
"We want to ensure that what we know is shared with the public, with the media, with clinicians who aren't part of the company so we can develop confidence," said Stéphane Bancel, Moderna's CEO, in an interview.
"Submitting the protocol online is another step," he added. "We want the world to know they can trust us."
Trust has been in short supply, however. As Moderna, Pfizer and AstraZeneca have raced through early-stage testing, scrutiny of the companies and their clinical programs has ratcheted up. All three are now studying their experimental shots in late-stage trials involving tens of thousands of volunteers each.
Their rapid progress has brought concerns that they, or regulators, may rush to declare a vaccine ready for use before having sufficient data in hand to prove their shots are safe and effective. In the U.S., the question is intensely political, as President Donald Trump has said a vaccine could be available before election day on Nov. 3.
Government officials, including the head of the Trump administration's vaccine initiative, have indicated that's unlikely, although Pfizer anticipates the first results from its Phase 3 trial could come by the end of October.
Moderna expects an initial readout from its late-stage study a little later, likely in the latter half of November, Bancel said. The company recently slowed enrollment to ensure it recruits a more diverse group of trial volunteers.
AstraZeneca is further back, having briefly paused vaccinations in all of its trials to assess an unexplained illness in one participant in the U.K. While its studies in the U.K. and Brazil are back on, the large trial it started in the U.S. remains on hold.
Moderna and Pfizer's timelines could still slip, should infection rates in the U.S. decline further. Their trials, as with AstraZeneca's, measure vaccine effectiveness by comparing the number of COVID-19 cases in vaccinated participants to those who received placebo, meaning the study's outcome is dependent on infections occurring.
Moderna had previously said that an independent data monitoring committee would compare the vaccine to placebo at two interim time points, when 53 and 106 cases were confirmed. The principal comparison will take place after 151 cases.
Pfizer has planned for four interim data looks, at 32, 62, 92 and 120 cases before the primary analysis takes place at 164 cases. AstraZeneca's study, meanwhile, features a single interim analysis, at approximately 75 cases.
The trial protocol shared by the companies fill in some missing details on how their respective study committees will conduct those analyses.
Summary tables included in Moderna's protocol, for instance, indicate the vaccine would need to be at least 74% effective for the trial to be considered positive at the first interim data check. The trial would not be stopped early in the event of a positive interim analysis, according to the protocol.
Pfizer's vaccine, by comparison, would need to prove more than 77% effective by the first analysis for the trial to be positive.
The protocols also reveal statistical assumptions the developers made to design their studies, such as what percentage of participants will develop COVID-19, as well as more unusual features. The data monitoring committee in Moderna's, as one example, reports to a study oversight group composed of representatives from the company and two government agencies that have helped fund and test its vaccine.
Disclosure of the protocol is a "gesture of good faith," said Walid Gellad, an associate professor at the University of Pittsburgh and a director of the Center for Pharmaceutical Policy and Prescribing there, in an interview.
"Everyone is on edge," he added. "[Disclosure] is more symbolic than a necessity but in this kind of environment I think it can help."
The companies rush to share comes a week after they and six other vaccine developers vowed they would not ask for authorization or approval of their shots until they had safety and efficacy data from a rigorously conducted Phase 3 trial.
Bancel said positive interim data from Moderna's trial would meet the bar for requesting an emergency authorization — a special type of clearance granted during a public health crisis — but not for a full approval.
The unconventional vow was aimed at shoring up public confidence. Yet AstraZeneca's recent safety review, and the company's limited release of further details, renewed fears that rarer and more serious side effects may be missed in hurried testing. Typically, vaccine trials run for several years to ensure safety is well documented, a luxury developers and regulators don't have during the pandemic.
Health authorities in the U.S. and the U.K. haven't formally commented on the study halt. A participant information brochure for U.K. volunteers, updated Sept. 11, indicated investigators weren't able to conclusively determine whether the illness was or was not related to vaccination.
The case heightened calls for vaccine developers to be more transparent about their trials. Pfizer seemingly responded this week by sharing, in atypical fashion, blinded safety results collected from its Phase 3 trial through late August. The data, from participants receiving either vaccine or placebo, showed side effects were mostly mild to moderate.
Moderna and AstraZeneca have received billions of dollars in funding from the U.S. government's Operation Warp Speed program, which aims to deliver tens of millions of vaccine doses to Americans by the end of the year and 300 million by mid 2021. While Pfizer has not taken money to support its vaccine testing and manufacturing, the U.S. government has contracted to buy 100 million doses for nearly $2 billion.
On Wednesday, the U.S. government released plans for how those doses would be distributed, but government officials offered conflicting estimates for when the first shots would be available, and how many.
Editor's note: This story has been updated to include additional comment, and to reflect Pfizer and AstraZeneca's sharing of their own trial protocols Thursday morning and Saturday afternoon, respectively.