EMA releases guidance for COVID variant vaccine development

Regulatory NewsRegulatory News | 25 February 2021 |  By 

The European Medicines Agency (EMA) has published a reflection paper laying out what data are needed to support approval of vaccines that protect against variants of SARS-CoV-2, the virus that causes COVID-19.
“[I]t is an urgent public health priority to define an expedited regulatory process for the adaptation of vaccines to protect against current or future variants,” wrote the agency in announcing the new guidance. The document comes less than 2 weeks after a variant-focused workshop held by the International Coalition of Medicines Regulatory Authorities (ICMRA).
At the workshop, co-chairs Marion Gruber, PhD, chair of the US Food and Drug Administration’s (FDA’s) Office of Vaccines Research and Review and Marco Cavaleri, PhD, chair of EMA’s COVID task force, led a discussion that reviewed current global knowledge about variants of concern and their potential impact on therapeutics as well as vaccines.
The ICMRA workshop focused on hammering out minimal requirements for regulatory approval of vaccines against variant strains of SARS-CoV-2 and also addressed the regulatory pathway of updating approvals for new formulations of vaccines already approved. EMA’s guidance falls in line with ICMRA’s regulatory harmonization efforts, as does the guidance released by FDA earlier this week. (RELATED: FDA updates EUA guidance, addressing vaccines against COVID variants, Regulatory Focus 22 February 2021)
Underlying EMA’s data requirements for vaccines designed to be effective against new virus variants is the assumption that the fundamental technology and platforms for adjusted vaccines would be the same as the original COVID-19 vaccines.
The guidance does not foresee the need for large-scale clinical trials to examine safety and efficacy, but rather calls for smaller immunogenicity studies to look specifically at how each variant vaccine performs against the variant strain or strains in question. Larger trials are both unnecessary and “would present feasibility constraints,” wrote EMA.
In the guidance document, EMA gives developers recommendations for how to conduct clinical trials when the variant vaccine is intended to replace the “parent” vaccine as the only vaccine to be marketed, when the variant vaccine will also protect against the parent strain, and when the parent strain of SARS-CoV-2 is still actively circulating in the EU. EMA recognizes that there may be overlap between the intended uses of the variant vaccine.
EMA does recommend one clinical trial in unvaccinated individuals who have not had SARS-CoV-2. Additionally, the guidance recommends that a “small group of subjects” be selected for a bridging study to receive either the parent vaccine or the vaccine adjusted for variants. Data from this study would show whether the immune response generated by the variant vaccine is as robust as that produced in response to the parent vaccine. EMA clarified that comparison with prior parent vaccine data would suffice if vaccination with the parent vaccine is infeasible or becomes unethical.
As FDA does in its recently released guidance document for variant vaccine development, EMA calls for seroconversion rates against variant strains for individuals vaccinated with the variant vaccine to be no more than 10% less than the seroconversion rate against the parent strain after receipt of the parent vaccine. (RELATED: FDA updates EUA guidance, addressing vaccines against COVID variants, Regulatory Focus 22 February 2021)
EMA also provides guidance for procedures if its human medicines committee (CHMP) should in future on an immune correlate of protection. Currently, no immune correlate of protection against infection with SARS-CoV-2 has been identified.
Manufacturers should look at efficacy of a variant vaccine as a single booster dose to previously vaccinated individuals as well; they should also plan for post-authorization studies to track safety and efficacy long-term.
EMA is not requiring additional nonclinical data for vaccines to address variants.
In terms of quality and manufacturing, EMA formulated its guidance with the expectation that adjusted vaccines will be made by the same manufacturer “and in line with processes and controls used for the parent vaccine.” The vaccine producer will have to provide quality data showing the variant vaccine matches up with the parent vaccine. If a multivalent vaccine is developed, “additional evidence may be required to ensure the quality of the active substances and the finished product,” wrote EMA.
Updates to Module 3 will depend on the platform used for the parent vaccine, but EMA is looking for an update of starting materials and testing of “critical quality attributes” such as purity and content. Though shelf life should theoretically not be different for a variant vaccine as compared to its parent, “confirmation of the suitability of the active substance and finished product registered shelf life needs to be demonstrated,” with post-approval provision of real-time stability data.
“Unless there were safety concerns for the parent vaccine and/or safety concerns emerge from trials with the variant vaccine, the safety data collected during immunogenicity trials with the variant vaccine as outlined above should suffice for approval,” according to the guidance.
EMA reflection paper


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