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Key Considerations and Data Requirements for the Design and Conduct of Phase 3 Clinical trials of COVID-19 Vaccine

Summary of ICMRA SARS-CoV-2 Vaccines Workshop #2

The June 22, 2020 teleconference of global regulators convened jointly by EMA and US FDA under the auspices of ICMRA, discussed preclinical and clinical data requirements to support proceeding to Phase 3 clinical trials with SARS-CoV-2 vaccine candidates. In addition, participants discussed concepts of trial design for these studies including trial population, endpoints and statistical considerations.

The following represents generally agreed positions among global regulators in attendance.

Pre-clinical data

  • Vaccine-induced immune response derived from animal models vaccinated with clinically relevant doses of the SARS-CoV-2 vaccine candidate
  • An evaluation of immune markers of potential enhanced respiratory disease (ERD) outcomes, e.g., assessments of functional immune responses (such as neutralizing antibody) versus total antibody responses and Th1/Th2 balance
  • Postvaccination challenge data using nonhuman primates to evaluate the potential for ERD. Data from other challenge models, e.g. hamsters, ferrets, transgenic mice, can provide valuable supportive evidence

Clinical data from Phase 1 & 2

  • Adequate characterization of safety and immunogenicity for each dose level and age group to be included in late stage trials, to support general safety and immunogenicity of the respective vaccine candidate.
  • An evaluation of immune markers of potential enhanced respiratory disease outcomes, i.e., assessments of functional immune responses (neutralizing antibody) versus total antibody responses and Th1/Th2 balance. If older subjects (e.g., subjects older than 55 years) are included in Phase 3 clinical studies, preliminary safety and immunogenicity data derived from these populations are also needed.
  • Favourable safety and immunogenicity data in women of childbearing potential derived from early Phase clinical trials

Prerequisite of Phase 3 Trial

Study Participants

  • To demonstrate vaccine efficacy, it is needed to enrol many thousands of participants, including those with medical comorbidities, to generate relevant data for the key target populations
  • Study should be powered to assess the overall vaccine efficacy across subgroups enrolled. Trial will not be powered to demonstrate vaccine efficacy by subgroup, e.g., age
  • To include diverse populations, e.g. race and ethnicity, in Phase 3 clinical trials to enhance confidence that vaccines are safe and effective for everyone in the indicated populations
  • To include older adults (e.g., over 55 years of age) including those with co-morbidities
  • To plan for paediatric assessments of safety and effectiveness for SARS-CoV-2 vaccines
  • To accrue data in pregnancy and consider the following eligibility criteria for Phase 3 clinical trials a) pregnant women and b) women of childbearing potential who are not actively avoiding pregnancy.

Study Design

  • Randomized, double-blind and controlled either using placebo or active comparator
  • If using adaptive design, elements should include pre-specified criteria, e.g., for adding or removing vaccine candidates or dosing regimen.
  • Follow-up of study participants for COVID-19 outcomes should be long enough (i.e., 1 year or longer post-vaccination) to evaluate safety, duration of immune response and risk of disease enhancement as antibody titres wane.


Primary endpoint

  • Laboratory-confirmed COVID-19 of any severity

Other endpoints

  • SARS-CoV-2 infection monitored for and confirmed either by virologic methods, or by serologic methods evaluating antibodies to SARS-CoV-2 antigens not included in the vaccine
  • Severity of disease as measured by hospitalization, mechanical ventilation or death

Safety endpoints

  • Solicited local and systemic adverse events
  • Unsolicited adverse events
  • Serious or other medically attended adverse events

Size of the safety data base and follow-up time should be in the same range as for other preventive vaccines. The protocol should include pre-specified criteria for study halt or pause, based on signals of potential vaccine-induced enhanced disease.

Statistical considerations

  • Stringent success criteria to ensure that SARS-CoV-2 vaccine has adequate efficacy
  • Study should be adequately powered to estimate vaccine efficacy as robustly as possible
  • To include interim analyses to assess risk of enhanced disease and futility



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