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Regulatory Focus™ > News Articles > 2020 > 7 > ICMRA outlines shape of Phase 3 COVID-19 vaccine trials

ICMRA outlines shape of Phase 3 COVID-19 vaccine trials

Posted 09 July 2020 | By Kari Oakes 

ICMRA outlines shape of Phase 3 COVID-19 vaccine trials

A new report provides a roadmap for Phase 3 clinical trials for developers of candidate vaccines for the novel coronavirus SARS-CoV-2, the virus that causes COVID-19. The report indicates which clinical and preclinical data will indicate a vaccine is ready for Phase 3 trials; it also lays out key considerations in designing Phase 3 clinical trials of vaccines for COVID-19.
The report reflects consensus reached at a 22 June 2020 teleconference convened by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) under the auspices of the International Coalition of Medicines Regulatory Authorities. At the workshop, 100 representatives from 28 countries and 20 regulatory authorities worked together to “harmonize regulatory requirements and streamline the development of COVID-19 vaccines.”
Success criteria should be “stringent”
Though regulators reached agreement on many details of when a vaccine should proceed to Phase 3 trials and what those trials should look like, they stopped short of defining exact success criteria. “There was also broad agreement that clinical studies should be designed with stringent success criteria that would allow a convincing demonstration of the efficacy of COVID-19 vaccines. However, whether a vaccine would be considered as acceptable for approval is assessed case-by-case on the basis of all available data on its safety and efficacy,” said EMA in announcing the report.
Some specifics regarding efficacy criteria mentioned in the report include establishing efficacy points estimates that are congruent with the efficacy desired for bot the interim and final efficacy analyses. Though studies should be adequately powered for robust estimation of efficacy, “more conservative stances” on success criteria should help “rule out licensure of weakly effective vaccines that could do more harm than good,” according to the report.
When will a candidate vaccine be ready for Phase 3?
The transition to Phase 3 clinical trials, workshop participants said, will require certain supporting data. Nonclinical animal model data regarding vaccine-induced immune response should include a special regard for the potential for enhanced respiratory disease (ERD) in vaccinated individuals who later are exposed to the novel coronavirus.
The realities of the global pandemic mean that post-vaccination challenge data in nonhuman primates may not be available to inform evaluation of ERD risk for a candidate vaccine. Reassuringly, notes the report, preliminary animal data do not show evidence for increased risk of ERD after vaccination by vaccines currently in the pipeline.
Postvaccination challenge data in nonhuman primates, however, should be used to guide the transition to Phase 3 trials; the final determination for that progression will happen on a case-by-case basis according to the totality of data available for a given vaccine construct.
Additionally, each candidate vaccine should have clear characterization of both safety and immunogenicity for each proposed dose level and each age group that will be included in the Phase 3 trial.
Earlier-phase clinical data that characterize the immune response provoked by the vaccine should include immune markers for ERD, such as functional versus total antibody response as well as T-helper 1/T-helper 2 ratio. If individuals older than 55 years are included in Phase 3 trials “preliminary safety and immunogenicity data from these populations are also needed,” agreed workshop attendees.
What will a Phase 3 trial of a COVID-19 vaccine look like?
Phase 3 clinical trials with efficacy endpoints “will need to enroll many thousands of participants, including those with medical comorbidities, to generate relevant data for the key target populations,” according to the workshop report.
Phase 3 trials of vaccines for SARS-CoV-2 should be randomized, double-blinded and controlled with either placebo or active comparator. If an adaptive study design is adopted for a Phase 3 trial, criteria for adaptation should be pre-specified. In all cases, interim analyses should look for futility, but also for evidence of increased risk of enhanced disease among those vaccinated.
Endpoints should be standardized across Phase 3 trials to allow an apples-to-apples comparison of safety and effectiveness of vaccine candidates, agreed workshop participants.  For all trials, the primary endpoint should be laboratory-confirmed COVID-19 disease “of any severity,” says the report. Hospitalization, mechanical ventilation, and death should be tracked to record disease severity. Infection with SARS-CoV-2 should be monitored and confirmed by virologic methods; alternatively, investigators could use serologic methods that measure antigens not contained in the vaccine.
In terms of safety evaluations, previous vaccine research can inform the size of the safety database, duration of follow-up, and which solicited and unsolicited adverse events are tracked. Pre-specified safety criteria should include surveillance for a signal of vaccine-induced enhanced disease, with clear specification of which criteria trigger a trial pause or stoppage.
Though safety and efficacy for individuals who have not been exposed to the novel coronavirus should be key outcomes, those designing trials should also plan for those with prior infection to be exposed to candidate vaccines as well, noted the report. This is because it’s likely that – in the absence of near-universal screening – some individuals with prior SARS-CoV-2 infection will receive vaccines. However, the primary population for establishing efficacy endpoints should be SARS-CoV-2-naïve participants.
Study populations should be racially and ethnically diverse; Phase 3 trials should include older individuals and those with comorbidities, agreed workshop participants. Safety and immunogenicity data from earlier-stage trials in younger, healthy participants can inform guidelines for trial participation of older and more infirm individuals, to include those aged 75 years and older.
In terms of study power, Phase 3 trials should be able to determine efficacy across all subgroups, but the design should not require power to determine efficacy at the subgroup level.
Pediatric safety and effectiveness assessments should be planned for, since these outcomes may vary between children and adults.
“Sponsors should provide their plans for accruing data in pregnancy,” consider having both pregnant women and women who are potentially childbearing and not actively avoiding pregnancy participate in Phase 3 trials, agreed the regulators. However, decisions about inclusion of pregnant women should be informed by safety and immunogenicity data from earlier-phase trials that include women of childbearing potential. Case-by-case decisions for each vaccine trialed will have to factor in “the totality of data available for the vaccine construct,” says the report.
The minimum post-vaccination follow-up for COVID-19 outcomes should be one year, so that investigators can monitor the duration of immune response and risk of disease enhancement, as well as other safety signals, as antibody titers decrease over time.

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