Second wave of late-phase Covid-19 vaccine trials unlikely to require a higher efficacy bar for FDA authorisation

GlobalData Healthcare 28th October 2020 (Last Updated October 28th, 2020 15:02)

Second wave of late-phase Covid-19 vaccine trials unlikely to require a higher efficacy bar for FDA authorisation

by Reynald Castaneda in London.

If at least one of the Covid-19 vaccine frontrunners is granted an FDA Emergency Use Authorisation (EUA) before the end of the year, the second wave of vaccines are unlikely to be required to reach a higher efficacy bar, experts said. This is primarily due to the huge market for such vaccines, as even a slightly inferior vaccine could still be authorised, they said. However, it would be best for these second-wave vaccines to detail their ideal subpopulations or manufacturing and storage advantages to help support their uptake, experts added.

With an authorised vaccine in the market, the FDA may require a noninferiority head-to-head trial for subsequent authorisations, but such trials may be hard to stage and so are generally rarely considered, experts said. While matching authorised vaccines’ immunogenicity data could be a shortcut to argue for the EUA designation, the different technologies used by the vaccines may draw pause for such an approach, they noted.

Possible second-wave vaccine candidates include CureVac’s Phase IIa CVnCoV and Sanofi /GlaxoSmithKline’s (GSK’s) unnamed protein subunit vaccine, which is in Phase I/II trial. Novavax’s NVX-CoV2373 is already in a UK-based 10,000-volunteer Phase III trial (NCT04583995), but a Novavax spokesperson said there is still no firm date on a Phase III trial in the US. Inovio Pharmaceuticals, which was once a frontrunner, received a not-yet-lifted FDA partial clinical hold for its planned Phase II/III INO-4800 trial due to its delivery device.

A CureVac spokesperson said its Phase III is being prepared and so it cannot provide details. Inovio did not return a request for comment. CureVac and Inovio have market caps of $8.9bn and $1.8bn, respectively. Sanofi did not return a request for comment by press time and has a $123.83bn market cap. GSK’s market cap is $87.61bn.

Efficacy bar likely the same between first and second-wave vaccines

The FDA is likely to face pressure to raise the efficacy bar for authorisation if there are one or two Covid-19 vaccines with EUA, said Dr Pierre Van Damme, chair, Vaccine and Infectious Disease Institute, University of Antwerp, Belgium. According to an FDA briefing document for the Vaccine Advisory Committee meeting held on 22 October, the primary efficacy endpoint for a placebo-controlled trial should be at least 50%, with a lower bound point estimate of more than 30%. The document does not note the second wave of vaccines should have a higher efficacy bar than the first wave, noted Dr Maria Elena Bottazzi, associate dean, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas.

However, the second wave of vaccines should be aiming for a higher efficacy, similar to the measles, mumps and rubella (MMR) vaccine, said Dr Scott Halstead, professor, Uniformed University of Health Sciences, Bethesda, Maryland. The MMR vaccine is 93% effective versus measles, 78% effective versus mumps, and 97% effective versus rubella. These diseases and Covid-19 are all transmitted via the upper respiratory tract, so such rates should be replicated, Halstead said. Aiming for this higher bar could prevent safety issues later, he noted. For example, a lower efficacy vaccine could lead to vaccine hypersensitivity response, which may make the vaccine receiver more susceptible to the disease, he explained.

While a higher bar would be ideal, a 50% benchmark is still valuable for protection as it mirrors the efficacy rate of influenza vaccines, noted Dr Paul Goepfert, director, Alabama Vaccine Research Clinic, Birmingham. Additionally, the Covid-19 vaccine market is so large the first wave of vaccines are unlikely to completely meet the demand, added Peter Smith, professor of tropical epidemiology, London School of Hygiene & Tropical Medicine, UK. Even if a second-wave vaccine may be slightly inferior to an authorised vaccine, it could still be granted EUA to meet demand, he added.

Nonetheless, second-wave vaccines would need to emphasise their advantages to be able to succeed in the long term, Bottazzi said. For example, specific subpopulation data would be ideal to help identify which people would benefit from the vaccine the most, she noted. On 29 September, this news service reported vaccines given an authorisation based on interim analysis data are unlikely to offer granular information about their ideal subpopulations. Any insight on vaccine efficacy duration is still lacking among the first wave of vaccines, added Dr Gordon Douglas, Jr, professor emeritus of medicine, Weill Cornell Medical College, New York.

Another way to emphasise a vaccine’s advantage is via transportation and storage, Bottazzi added. mRNA frontrunner vaccines such as Pfizer /BioNTech’s BNT162b2 and Moderna’s mRNA-1273 have significant freezing requirements, which can be a challenge even within the US, Goepfert said. In contrast, Sanofi/GSK’s and Novavax’s protein subunit vaccines may be less demanding regarding refrigeration, added Goepfert.

Nevertheless, the public should be informed about how waiting for a high-efficacy vaccine to be approved later on is not an ideal approach, Bottazzi said. If a person is ideal for the first-wave vaccine, they should take it as it would be better than no protection, especially as Covid-19 cases are still increasing, she added. If the first-wave vaccine wanes in efficacy, a booster with a second-wave vaccine could be used later, she noted.

Ripple effect on trial design with an authorised vaccine

EUA is likely to be given to any vaccine frontrunner with a strong data trend suggesting the Phase III would be positive, Bottazzi said. If there are one or two authorised vaccines in the market, a head-to-head trial between an authorised vaccine and second-wave vaccine is a possibility, Goepfert said. This is particularly the case if the authorised vaccine has an efficacy of more than 50% protection, he added. Noninferiority trials are not unusual in the infectious disease space, as seen with antibiotic therapies, Goepfert noted.

However, head-to-head trials are rare in vaccines due to the significant challenges of running them, Smith said. For example, such a trial would need even more volunteers than the ongoing placebo-controlled trials, he noted. A larger number of patients is needed to determine differences between vaccine arms even if the trial is designed for noninferiority. In a placebo-controlled trial, the vaccine is being investigated against no protection, he added. Frontrunner vaccine trials recruit 30,000–60,000 volunteers.

An ongoing challenge for large Covid-19 vaccine trials is finding locations where there is a sufficient rate of Covid-19 in the community to ensure the trial reaches a high enough number of events to support protection efficacy data, Van Damme said. This issue would be heightened if there is already a vaccine being used by the general population, he added. To overcome the challenges of large-scale trials, the second wave of vaccines may only need to match the immunogenicity data of an authorised vaccine, Smith said. This option has been used in meningococcal vaccine development when large-scale trials are not possible as community infection rates are not high enough, Goepfert said.

The second wave of vaccines may be superior versus the first-wave vaccines regarding their respective immunogenicity data, Bottazzi said, adding Novavax and Sanofi/GSK seem to have more robust data for their vaccines than the frontrunners. However, hinging authorisation on immunogenicity data may be flawed as these are different technologies, Smith noted.

Challenge trials, which were previously hard to stage, could be considered by these second-wave vaccines, Smith noted. On 18 May, this news service reported a small-scale human challenge trial design has the advantage of delivering speedy safety and efficacy results, but the associated operational and ethical hurdles are weighty and include the lack of reliable rescue therapy. News reports from 20 October show the UK government has chipped in GBP 33.6m (USD 43.5m) to fund the first Covid-19 challenge trial, which is aiming for a January 2021 start. Today (23 October), the FDA has given Gilead Sciences’ Veklury (remdesivir) full approval for hospitalised Covid-19 patients.

Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.