by Reynald Castaneda in London, with additional reporting by Jennifer C Smith

The FDA’s revocation of chloroquine and hydroxychloroquine’s Emergency Use Authorization (EUA) after three months could mean the FDA may raise the bar for Covid-19 vaccines, requiring early protection data. Vaccines are sensitive to public scrutiny, specifically with limited data. However, the EUA is also sensitive to political pressure, even if it is designed to be evidence-based.

Nevertheless, manufacturing capabilities could also be a deciding criterion. This added factor could impact vaccines based on new technologies or developers with less production experience.

While National Institute of Allergy and Infectious Diseases (NIAID) director Dr Anthony Fauci has said a vaccine is possible by the end of the year or early 2021, some interviewed experts differed. The burden of evidence suggests it would be tough to grant a vaccine an EUA before year’s end. While there are ways to speed up data collection—like those that offer early protection insight—they come with notable caveats.

There are more than 100 Covid-19 vaccines in preclinical testing, according to GlobalData, while 14 companies have moved their candidates into clinical trials, including Sinopharm’s and China-based Sinovac Biotech’s inactivated virus vaccines and Germany-based CureVac. Initial or additional trial data are expected in the next few months from Novavax’s protein subunit vaccine NVX‑CoV2373, CanSino Biologics’ adenovirus-vectored vaccine Ad5-nCoV, Inovio’s DNA plasmid vaccine INO-4800 and BioNTech’s mRNA-based vaccine BNT162.

Moderna’s mRNA-1273, also an mRNA vaccine, and AstraZeneca’s adenovirus-vectored vaccine Ad5-nCoV are in the lead, with planned or ongoing Phase IIIs. Estimating an annualised 1.5% incidence rate this summer, a Phase III trial would likely need 25,000–30,000 volunteers and would follow participants for two years, this news service reported 14 May.

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EUA execution inconsistent so far

There is no set amount of data needed for an EUA, but as long as there is a trend showing the benefit outweighs risks and that any delay in access could cost lives, then an EUA could be granted, noted Dr Benjamin Rome, health policy researcher, Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston. Yet, the FDA has been inconsistent with EUAs, making it challenging to predict benchmarks for success, he noted, pointing to the two therapeutic EUAs issued thus far.

The agency granted chloroquine and hydroxychloroquine an EUA on 28 March based on early in vitro and anecdotal patient data, only for the authorization to be revoked 15 June. In contrast, remdesivir was granted an EUA on 1 May based on data from the NIAID’s Phase III adaptive treatment trial (NCT04280705) showing remdesivir saved four days of hospitalisations versus the comparator arm. But generic hydroxychloroquine has been available for a long time, which could have contributed to decisions, noted a Washington, DC-based Republican healthcare lobbyist.

An FDA spokesperson said for vaccines, an assessment will be made on a case-by-case basis depending on the characteristics of the product, preclinical and clinical trial data and the totality of available evidence. A BioNTech spokesperson declined to comment if it plans to submit for an EUA; other front-runner companies did not respond to a comment request.

While the EUA is not a political tool and is meant to be based on scientific evidence, it is nevertheless at a high risk of political interference, Rome said. There is also pressure from the public to get a vaccine out as early as possible, added Sandra Crouse Quinn, PhD, senior associate director, Maryland Center for Health Equity, School of Public Health, University of Maryland, College Park.

On the other hand, there could be the concern of corners being cut to speed up access, Quinn added. Premature authorization for vaccines is risky, as it is prone to negative public perception, especially with limited evidence, said former FDA official Dr Peter Lurie, president, Center for Science in the Public Interest, Washington, DC.

But according to the lobbyist, the FDA is fairly insulated from political influence. For example, the agency revoked hydroxychloroquine’s EUA despite political figures pushing for its use, he said. If the FDA showed any sign of political influence, it would tarnish its reputation, he noted, adding scientists are also placing pressure on the agency to stick to the data.

However, a former FDA official who is now a drug industry consultant said in the nearly 20 years he worked at the agency, he had never seen the level of political interference in FDA decision-making that is now apparent under US President Donald J Trump. The FDA has also had issues with Covid-19 antibody tests, with unreviewed tests pulled from the market after initially getting the go-ahead, noted Lurie. The agency withdrew at least two dozen antibody tests last month on the heels of more agency oversight. The agency could have started from the testing misstep and may be more cautious on granting the next EUA, a Washington, DC-based healthcare lawyer said.

The FDA has at times seen undue political influence, but it has been limited to specific products like tobacco, the lawyer said. However, there has not been a time where the White House has been involved in a global health crisis like this pandemic, which has allowed for more interactions between the agency and administration, he added. A second lawyer added she is concerned about the FDA’s long-term reputation with alleged political pressure on regulatory decisions.

On 18 June, the US House of Representatives’ Committee on Oversight and Reform addressed a letter to FDA commissioner Stephen Hahn calling for information on the processes surrounding Covid-19 vaccine decisions. Rome testified at the US House of Representatives’ Committee on Investigations & Oversight on 19 June on drug approval during the pandemic, also calling for EUA transparency. He pointed out that at the time of remdesivir’s EUA, the only publicly available data were from a press release.

Still, after the FDA’s experience with chloroquine and hydroxychloroquine, it may be more risk-averse in granting an EUA, especially for a vaccine, Lurie noted. Clinical trial data showing a vaccine’s ability to offer protection will likely be needed, agreed Frances Richmond, PhD, director, DK Kim International Center for Regulatory Science, University of Southern California, Los Angeles.

Manufacturing capabilities could raise EUA bar, early protection data loaded with caveats

Considering a tenet of an EUA is to improve access, there is a chance vaccine scalability could be part of the EUA equation, Rome said. Several vaccines are based on brand new technology, and so there could be added hesitance on granting an EUA, noted former Maryland health secretary Dr Georges Benjamin, executive director, American Public Health Association, Washington, DC. There are no FDA-approved mRNA or DNA plasmid vaccines, technologies used by Moderna, BioNTech and Inovio, but the former two are reportedly part of the US Administration’s Operation Warp Speed initiative.

On top of established vaccine technologies having an edge, companies with experience in manufacturing vaccines would have an added advantage, Richmond noted. BioNTech is working with Pfizer to develop its vaccine. AZD1222, also reportedly part of Operation Warp Speed, was initially developed by Oxford University, which then partnered with AstraZeneca on 30 April. In the past months, the various front runners have announced fundraising milestones, be it from government funding, debt financing or converting stocks to help develop their respective vaccines, in addition to collaborations or acquisitions to assist with reaching research and manufacturing targets.

Yet, with six months left in 2020, it is borderline unrealistic to have a vaccine granted an EUA by the end of the year, Richmond said. Optimistic timelines do not make room for front runners potentially having poor efficacy results, Lurie noted. A vaccine that stimulates both neutralizing antibody titres and cell-mediated immune response are more likely to induce protection. However, of the front runners, Novavax, Moderna and BioNTech do not have cell-mediated endpoints in their ongoing trials, with AstraZeneca’s Phase II/III and Moderna’s forthcoming Phase III investigating prevention of symptomatic Covid-19, this news service reported 25 June.

Phase III trials are likely to have Data Safety and Monitoring Boards and predetermined checkpoints that could allow early insights into efficacy and safety, which would support an EUA, Quinn said. If protection data collection is taking longer than expected but there are safety assurance and immunogenicity data, then an EUA could be granted, a UK-based biostatistician said. However, Phase II immunogenicity data are unlikely to forecast Phase III protection results, this news service reported on 14 May. Registrational trials will have many operational obstacles, even though they may only need to reach the lowest success bar of 50% protection over at least six months.

Another potential way to have an early indication of protection is via a ring vaccination study, also referred to as a postexposure prophylaxis design, explained Dr Matthew Laurens, director, Malaria Research Group, Center for Vaccine Development and Global Health, University of Maryland, Baltimore. In this design, contacts of a Covid-19 patient are either vaccinated or given a placebo. It can be challenging to have well-established contact tracing facilities, but it was achievable in West Africa in certain Ebola vaccine trials that used mobile phones to track people, he noted.

A human challenge trial design could also potentially shorten trial durations, Richmond added. But operational and ethical hurdles are weighty enough to tip the risk-benefit balance negatively, this news service reported 18 May.

An umbrella trial design investigating a variety of vaccines in a single trial is another attractive option, Lurie said. Umbrella trials of Covid-19 therapies have been able to provide clinically relevant information, he noted.

However, the umbrella trial approach may be hard to pull off for vaccines, considering efficacy data is dependent on volunteers getting infected, which could lead to variability between arms, creating the false impression one vaccine is more effective than another, said Dr Stanley Perlman, professor, Department of Microbiology and Immunology, University of Iowa. Also, the vaccines are in various stages of development, Lurie added. The healthcare lobbyist said keeping the trials separated would mean that competition could help speed up development.

Reynald Castaneda is Associate Editor and Jennifer C. Smith is Senior 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.