Modified COVID Vaccines: FDA Shifts To Superiority Standard For Immune Response To Variants
Executive Summary
Updated guidance says variant-directed vaccines should demonstrate statistically superiority to the prototype vaccine in a comparison of geometric mean titers against the particular variant of concern; seroresponse rates can be assessed on the basis of either noninferiority or superiority.
New variant-directed, COVID-19 vaccines should demonstrate superior, rather than merely noninferior, antibody response against the targeted variant relative to the original prototype vaccine, the US Food and Drug Administration said in a revised guidance released on 31 March.
With these new, more stringent recommendations for demonstrating immunogenicity of modified vaccines, both for the primary series and booster doses, the agency is setting a higher bar that must be met before making the switch from the prototype COVID-19 vaccines to new formulations directed at specific variants.
The FDA previously recommended an immunogenicity comparison based on noninferiority of seroresponse rates and geometric mean titers (GMTs) between the variant-directed vaccine and the original vaccine.
With the new recommendations on immunogenicity clinical data, FDA is saying “it doesn’t make sense to make a whole new vaccine with a new variant unless it performs in a superior way against that variant when compared to the prototype vaccine.” – Georgetown University’s Jesse Goodman
The agency now says the primary analysis should be a comparison of GMTs against the particular variant of concern (VOC) in a study powered to demonstrate statistical superiority. The second coprimary analysis should be a noninferiority comparison of seroresponse rates, although an acceptable alternative approach would be to test for superiority of seroresponse rates.
Better Than What We Had Before
With the updated recommendations, the FDA is setting out minimal criteria for the immunogenicity data needed to shift to a new vaccine formulation, said infectious disease specialist Jesse Goodman, director of Georgetown Center on Medical Product Access, Safety and Stewardship.
“The FDA is saying that for variant-directed vaccines, “you should really be able to show that it actually is superior in generating antibody against the variant, not just that it’s the same,” said Goodman, who previously served as FDA chief scientist and director of the Center for Biologics Evaluation and Research. “They’re saying it doesn’t make sense to make a whole new vaccine with a new variant unless it performs in a superior way against that variant when compared to the prototype vaccine.”
The revised guidance, Emergency Use Authorization for Vaccines to Prevent COVID-19, also prioritizes immunogenicity comparisons between the modified and prototype vaccines against the particular VOC, rather a comparison relative to the prototype’s ability to elicit an antibody response against the original virus.
The guidance acknowledges that certain aspects of the immunogenicity evaluation recommendations may be challenging.
“In situations where available data support that certain studies or analyses would be infeasible, we would consider alternative approaches with appropriate justification,” the guidance states. “The assessment of effectiveness of a modified COVID-19 vaccine will take into account the totality of the immunogenicity data from the primary, secondary and descriptive analyses.”
The FDA said the revised guidance on clinical data to support effectiveness of a modified vaccine “provides the most up-to-date recommendations based on lessons learned during the COVID-19 public health emergency and submissions by sponsors.”
The revised recommendations were issued just days ahead of a Vaccines and Related Biological Products Advisory Committee meeting on considerations for COVID-19 vaccine booster doses and the process for vaccine strain selection to address current and emerging variants. Discussions at the 6 April meeting will include the role of the FDA and VRBPAC in decisions on the composition of COVID-19 vaccines in the US, and the situation and conditions that would indicate a modified vaccine is warranted. (See sidebar for story.)
‘Super’ Vs. ‘Simple’ Superiority
In February 2021, the FDA updated its vaccines EUA guidance to add immunogenicity study recommendations for variant-targeted changes to existing vaccines.
At that time, the agency said studies should be adequately powered for primary immunogenicity analyses to demonstrate statistical noninferiority of seroresponse rates and GMTs elicited by the modified vaccine, or the booster dose, against the variant of interest compared to seroresponse rates and GMTs elicited by the prototype vaccine against the original virus. The recommended noninferiority margins were -10% for seroresponse rates and 1.5-fold for GMTs. (Also see "US FDA Sets Immunogenicity Bar High For Changes To COVID-19 Vaccines" - Pink Sheet, 22 Feb, 2021.)
In the updated recommendations specific to the primary vaccination series, the agency said sponsors should conduct an immunogenicity study in which previously unvaccinated persons are randomized to receive either the modified COVID-19 vaccine or the prototype vaccine.
The primary analysis should be a comparison of GMTs against the particular VOC elicited by the modified and prototype vaccine. “The study should be designed and adequately powered to demonstrate statistical superiority of the GMT elicited by the modified vaccine as compared to the prototype vaccine,” the guidance states.
“Ideally, the primary analysis would test for ‘super’ superiority (margin of >1.5-fold for GMT ratio) to statistically exclude noninferiority of the prototype vaccine compared with the modified vaccine,” the guidance states. “However, it would be acceptable to test for ‘simple’ superiority (margin of >1-fold for GMT ratio) in the primary analysis and to test for ‘super’ superiority as a secondary immunogenicity analysis.”
A second co-primary analysis should be a comparison of seroresponse rates against the particular VOC elicited by the modified and prototype vaccine. “The study should be designed and adequately powered to demonstrate noninferiority of the seroresponse rate elicited by the modified vaccine as compared to the prototype vaccine, using a noninferiority margin of <5% for seroresponse rate difference.”
“Alternatively, the co-primary analysis of seroresponse rates could test for superiority (‘simple’ superiority margin of >0% or ‘super’ superiority margin of >10% for seroresponse rate difference),” the guidance states.
If the co-primary analysis of seroresponse rate tests for noninferiority, the agency expects that additional descriptive analyses of seroresponses against clinically relevant variants, including the particular VOC, will support the benefit of the modified vaccine over the prototype vaccine. “Determination of an appropriate seroresponse definition should be based on available data.”
The FDA’s previously recommended primary analysis is now relegated to a category of “additional immunogenicity analyses.” The guidance states this secondary analysis should evaluate noninferiority of seroresponse rates and GMTs induced by the modified vaccine against the particular VOC, and the prototype vaccine against the original virus, with noninferiority margins of 10% and 1.5-fold, respectively.
“Additional descriptive analyses should compare the seroresponse rates and GMTs in each group against other clinically relevant VOCs (e.g., currently or recently circulating variants) and against the virus upon which the prototype was based,” the guidance states.
Recommendations On Booster Data
For the first booster dose, sponsors should conduct an immunogenicity study in which individuals who previously completed primary vaccination with the prototype product are randomized to receive a booster of either the modified vaccine or the prototype.
For the second booster dose, subjects who received the primary vaccination series and first booster with the prototype vaccine should be randomized to receive a second booster with either the prototype vaccine or the modified vaccine. The guidance allows for study designs that enroll subjects who completed the primary vaccination series or first booster with any authorized or approved vaccine.
The primary immunogenicity analyses recommendations for a first and second booster dose mirror those for the primary vaccination series, with a recommendation for superiority testing for the GMT comparison.
The agency also wants to see descriptive analyses of various comparisons for both first and second booster doses, including seroresponse rates and GMTs following booster against other clinically relevant variants.
The types of immunogenicity comparisons that the FDA expects to see for a modified vaccine “are challenging to do, but it’s going to be really important data to decide if and when to pull the trigger on a variant vaccine,” Goodman said. “You’ll want to know is there a likely advantage and then are there potential benefits against the other variants as well. I think this is all essential data to take into consideration.”
Contemporaneous Vs. Historical Comparator
The recommendations for assessing immunogenicity of a modified vaccine against a particular VOC generally describe studies with a contemporaneous comparator arm of individuals that receive the prototype vaccine.
“However, serum samples from study subjects administered the prototype vaccine in a previously conducted study, if available, may be used in lieu of a contemporaneous comparator group if evaluated using the same assay(s) and provided that the prototype vaccine and modified vaccine groups are well-balanced with respect to factors that may affect interpretation of the immune response,” the guidance states.
Goodman said this allowance for use of historical comparator data is potentially problematic given the fast-changing nature of the virus and the periodic spikes in infection caused by different variants.
The immunity of the population is changing all the time, Goodman said, noting that there were a lot more people infected with Omicron. “Comparing levels after immunization from a study done eight months ago with one done now may have differences that you couldn’t predict.”
Deleting The Placebo
Also in the revised guidance, the FDA said it no longer expects that following submission of an EUA request for a COVID-19 vaccine, the sponsor would continue to collect placebo-controlled data in ongoing trials. The updated guidance states only that data should continue to be collected.
The feasibility of collecting placebo-controlled data after EUA was a major issue at the time of, and immediately following, the initial authorizations for the Pfizer Inc./BioNTech SE and Moderna, Inc. mRNA vaccines. However, sponsors’ decision to offer placebo subjects an opportunity to crossover to active vaccine after EUA did not substantially hinder the FDA’s ability to assess safety data for the vaccines' biologics license applications. (Also see "Placebo Unblinding Process For Pfizer’s COVID Vaccine No Detriment To US FDA Safety Analysis" - Pink Sheet, 26 Nov, 2021.)
The agency said it removed the recommendation for collection of placebo-controlled data “in recognition that the pandemic has evolved, and safe and effective COVID-19 vaccines have been authorized and approved. Thus, it may not be feasible to continue to collect placebo-controlled data when an effective vaccine is authorized and available for study participants.”
The revised guidance retains language from a May 2021 update regarding prioritization of EUA requests for COVID-19 vaccines and stating the agency may decline to review and process EUA requests other than those for vaccines whose developers who have engaged with the agency in an ongoing manner during the development of their manufacturing process and clinical trials. (Also see "Novavax Readies COVID-19 Vaccine Request For EUA, But How Much Longer Will The Door Be Open?" - Pink Sheet, 6 Jan, 2022.)
“These COVID-19 vaccine developers will have had the benefit of FDA feedback early and throughout the development process. Therefore, their EUA requests are more likely to contain the comprehensive data and information needed to demonstrate that issuance of an EUA is appropriate, and the agency is more likely to be able to confirm the validity of the clinical and manufacturing information submitted in the EUA request,” the FDA said.
On 4 March, Ocugen Inc. announced that the FDA had denied its EUA request, submitted in November, for use of Covaxin in children and adolescents. However, this rejection was not surprising given that several aspects of Ocugen’s data package did not appear to meet the FDA’s publicly stated expectations for pediatric use of a COVID-19 vaccine, including previous authorization in a US adult population. (Also see "COVID-19 Vaccines: Ocugen’s EUA Request For Covaxin In Kids Faces Steep Climb At US FDA" - Pink Sheet, 10 Nov, 2021.)
“Ocugen intends to continue working with FDA to evaluate the regulatory pathway for the pediatric use of Covaxin,” the company said.