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US: Don’t expect a COVID vaccine before the election

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BRASILIA, BRAZIL - AUGUST 05: Gustavo Romero, professor at the University of Brasilia and coordinating doctor for tests of the Sinovac Biotech vaccine, shows the vaccine to journalists amidst the coronavirus (COVID-19) pandemic  at the University Hospital on August 05, 2020 in Brasilia. The forecast is that 850 health professionals who care for COVID-19 patients will participate in the study to test the vaccine from the Sinovac Biotech laboratory. Brazil has over 2.801,000 confirmed positive cases of Coronavirus and has over 95,819 deaths. (Photo by Andressa Anholete/Getty Images)

A vaccine made by Pfizer could seek emergency approval by the third week of November, but it likely won’t be available to the public until mid- to late 2021

During a press conference in early September, President Donald Trump was asked when he thought a vaccine for COVID-19 might become available. His prediction was upbeat: “We’re going to have a vaccine very soon,” Trump said. “Maybe even before a very special day—you know what day I’m talking about.”

Trump was referring, of course, to the presidential election on November 3. But the odds of a vaccine materializing for public use before then appear slim. New drugs and vaccines ordinarily go through a lengthy review process prior to regulatory approval. Vaccines for COVID-19, however, are widely expected to be released under emergency use authorization (EUA) protocols, which allow for the sale of unapproved medical products during national health crises. On October 6 the White House agreed to new EUA guidelines that call on COVID-19 vaccine developers to monitor their phase III clinical trial subjects for at least two months for side effects and severe disease. The U.S. Food and Drug Administration, which administers EUAs, will host a widely anticipated meeting on October 22 to address standards for efficacy, safety and manufacturing of COVID-19 vaccines. But the FDA’s recommended two-month observation period puts a preelection vaccine approval out of reach.

EUAs could, however, make the first successful COVID-19 vaccines available to frontline workers by the start of 2021, although distribution in the general U.S. population will take longer, starting with elderly and other high-risk groups and then younger, healthier people who may not have access to them until late in the year, according to Paul Offit, a pediatrician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. The FDA has already granted hundreds of COVID-related EUAs for products such as diagnostic tests, medical devices and therapies—including for convalescent plasma and hydroxychloroquine (the latter was later revoked).

“All the COVID-19 vaccine developers are going for an EUA first,” says Eric Topol, a cardiologist and head of the Scripps Research Translational Institute in La Jolla, Calif., who has directed numerous multinational clinical trials (although none for vaccines). “It makes no sense to wait for formal licensure.”

Obtaining an EUA hinges on how independent reviewers judge a vaccine’s performance during periodic readouts of phase III clinical trial data. The trials are each enrolling tens of thousands of people and are also double-blinded—meaning that neither the subjects nor the experimenters know which participants got a vaccine versus a placebo. They were designed to continue until the number of symptomatic infections reaches 150 in the vaccinated and control groups combined. If a vaccine halves the risk of symptomatic infections among the vaccinated group, it will meet the FDA’s minimum bar for approval.

Reviewers examining the interim data readouts will be looking for better protection than that. Pfizer, which began a phase III trial for its vaccine on July 27, plans to conduct its first readout when the number of symptomatic cases reaches 32. The company expects that could happen this month, making it first in line for a potential EUA. Statistical thresholds are set such that if COVID case numbers in the vaccinated group are, at that point, at least five times lower than they are among vaccinated subjects, then reviewers can declare overwhelming efficacy. In that event, the company will “consult with regulatory authorities about next steps,” which could include an EUA, says a Pfizer spokesperson. In an October 16 open letter, Pfizer chairman and CEO Albert Bourla wrote that if the efficacy data are positive, the company will apply for an EUA in the U.S. “soon after the safety milestone is achieved in the third week of November.” The company’s study protocol also includes data readouts at 62, 92 and 120 cases, respectively, although the amount of protection the vaccine has to achieve at each step declines progressively until it reaches the FDA’s minimum target of 50 percent.

Other companies racing to develop COVID-19 vaccines are taking a less aggressive approach: Cambridge, Mass.–based Moderna, for instance, plans for a first data readout when it reaches 53 cases among its study subjects and another at 106 cases. The company anticipates filing for an EUA in late November. Meanwhile Johnson & Johnson recently paused its clinical trials after a participant got sick. This delay follows a similar pause by AstraZeneca, which has since resumed its trials outside of the U.S.

A significant issue is how vaccine developers will continue to assess safety and efficacy after an EUA. The FDA has said they should include strategies for monitoring a vaccine’s long-term performance in their EUA applications and generate the data needed to support future licensing. The agency has also stressed that companies should continue collecting placebo-controlled trial data for as long as feasible. Yet Pfizer representatives said in an e-mail that if an interim readout shows overwhelming efficacy, they have the option to unblind the data, vaccinate placebo recipients and then follow all the subjects in an unblinded fashion—meaning experimenters and participants would know who got the vaccine. (A Pfizer spokesperson later said the company would only unblind the study with regulatory approval.)

scientificamerican.com

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