Key parameters in the Phase 3 Moderna COVID-19 vaccine protocol: Symptomatic infections, interim analyses and an oversight group 

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By Daniel R. Lucey M.D., MPH, FIDSA

Moderna and Pfizer-BioNTech on Sept. 17 publicly posted their ongoing Phase 3 efficacy vaccine trials. Initially today for the Moderna trial, some of the key points are emphasized below on how the primary endpoint for vaccine efficacy is defined, and when the two interim analyses are planned. After the second dose, 14 days are required before a symptomatic case (defined below) of COVID-19 would be counted in the efficacy analyses.The Moderna vaccine protocol defines the primary efficacy endpoint as:

“to prevent the first occurrence of COVID-19 starting 14 days after the second dose of investigational product (IP), where COVID-19 is defined as symptomatic disease based on the following criteria:

  • The participant must have experienced at least TWO of the following systemic symptoms: Fever (≥ 38ºC), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR
  • The participant must have experienced at least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographical evidence of pneumonia; AND
  • The participant must have at least one NP swab, nasal swab, or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.”

Of note, protection against either asymptomatic infection with SARS-CoV-2 or severe COVID-19 disease are listed as secondary efficacy endpoints.

The protocol calls for two interim analyses. The first — “IA1” — when 53 cases have occurred (i.e., 35% of the total 151 cases calculated to occur in the complete study), the second — “IA2” — when 106 cases (70% of total 151 cases) have occurred. (See p.97-98 and Table 13):

“Interim Analyses There are 2 planned IAs at 35% and 70% of total target cases across the 2 treatment groups….There is no intention to stop the study early if the efficacy has been demonstrated at any of the IAs…The DSMB will review the IA results and make recommendations to the Sponsor in terms of study results reporting and unblinding based on the boundaries of early efficacy as described in this section, safety data, and data external to this study…“The second IA will occur when approximately 70% of the total cases have been observed…”

Notably, for the two interim analyses the traditional Data Safety Monitoring Board will be involved; however, the DSMB makes recommendations based on their findings on efficacy and safety to an “Oversight Group” that will include the Sponsor (Moderna), as well as a voting member from HHS/BARDA and from NIAID/NIH, as specified below (p. 80-81):

”At the interim analyses, the DSMB will review the interim analysis results and make recommendations to an Oversight Group in terms of study results reporting and unblinding based on the boundaries of early efficacy as described in Section 9.6 of the protocol. The Oversight Group will be comprised of a voting member each from the Sponsor, Biomedical Advance Research and Development Authority (BARDA), and NIAID.”

The full 135-page Moderna Phase 3 protocol can be found here.

In a separate document, as of Sept. 16, 25,296 (84 %) of the total 30,000 participants in this “COVE Phase 3 Study” have been enrolled. Two-doses of vaccine or placebo (saline) separated by 28 days are required.

Dr. Daniel Lucey

Daniel Lucey, M.D. MPH, FIDSA, FACP, is an infectious diseases physician and adjunct professor of infectious diseases at Georgetown University Medical Center, a senior scholar at the Georgetown University O’Neil Institute, Anthropology Research Associate, Smithsonian Museum of Natural History and a member of the Infectious Diseases Society of America Global Health Committee.He has served as a volunteer medical responder to outbreaks that included the West Africa Ebola crisis. He has collected information on outbreaks starting in 2001 with cases of anthrax in 2001, and including smallpox vaccination 2002, SARS 2003, H5N1 Flu 2004, MERS in 2013, and Ebola in April, 2014, He has gathered, and  updated information on the spread of the coronavirus here since Jan. 6.

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