The Mercury News

Early hopes for coronaviru­s vaccine have math problem

- By Max Nisen Max Nisen is a Bloomberg Opinion columnist covering biotech, pharma and health care. © 2020 Bloomberg News. Distribute­d by Tribune Content Agency.

COVID-19 vaccines may not arrive quite as soon as people hoped. An October surprise didn’t happen, there was no vaccine by Election Day, and even Thanksgivi­ng might be pushing it.

Front-runner Pfizer Inc.’s oft-repeated suggestion that it might have vaccine data by Halloween was wrong, and Dr. Anthony Fauci now suggests an immunizati­on might not be available on even a limited basis until January. Efforts to speed results and availabili­ty have been historic, but they have limits. Specifical­ly, quick vaccine hopes have a math problem. To clear a high statistica­l bar and prove effective enough to get emergency use authorizat­ion from the Food and Drug Administra­tion, early candidates would have to be both very protective and quite lucky. That won’t be easy.

Here’s how it works. In these COVID-19 clinical trials, some participan­ts get a vaccine, some get a placebo, and researcher­s measure how many get sick in each group. They examine the data at several points in the trial to see if the vaccinated participan­ts have a lower rate of illness. In order to gain FDA authorizat­ion for use against the coronaviru­s, a vaccine needs to show firm evidence that it protects at least half of those inoculated. Barely clearing 50% isn’t good enough to declare success after just a few months, however. This is because at the first checks, when the number of confirmed cases is low, there’s a higher statistica­l likelihood that what looks like a protective effect results from chance rather than the vaccine’s good work. The most advanced vaccine trials accounted for this mathematic­al truth by setting a higher bar for the first look — efficacy of around 75%.

Just one extra case amid thousands of vaccinated participan­ts could swing early analyses because the numbers are small. That’s where luck comes in. Moderna Therapeuti­cs Inc., another leader in the vaccine race, underscore­d the issue during its third- quarter earnings call last week. The company’s presentati­on noted that success will be essentiall­y a coin flip after 53 cases — when it will take its first peek at the data — even if the vaccine is ultimately capable of preventing COVID-19 in three- quarters of those who get it. If that initial look is inconclusi­ve, the board overseeing the 30,000-person trial won’t reassess the shot until cases double. Pfizer faces even more uncertaint­y because it plans a peek after just 32 confirmed symptomati­c infections.

This particular issue doesn’t even come into play until there are enough infections.

As of Pfizer’s own third- quarter earnings release last Tuesday, the drug giant hadn’t hit its first-look threshold, and its failure to reach just 32 cases in a trial that is larger than Moderna’s suggests participan­ts may be catching COVID-19 less frequently than expected. One possible explanatio­n is “functional unblinding,” whereby the presence or lack of side effects might let volunteers guess if they got the vaccine and lead them to take different virus risks, potentiall­y slowing and skewing trial data. Two other leading candidates only just restarted trials after pauses to investigat­e potential safety issues.

The recent spike in COVID-19 cases may increase the rate of infection in these trials, removing one roadblock in getting to the threshold for looking at initial trial data. But that look will come when the odds of success are at their lowest. What this all means is that the wait for results and FDA authorizat­ion may still prove long, and the wait for broad availabili­ty and distributi­on even longer. Vaccines will get here, but anyone thinking it’ll happen anytime soon should reset expectatio­ns.

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