Not since the polio vaccine became available in April 1955 have Americans been so excited about getting a shot. After a year of isolation, fear, and death, most of us can hardly wait to get vaccinated against Covid-19. Grandparents want to be able to hug their grandchildren. Doctors and nurses want to care for their patients without having to wear the equivalent of a body condom, and many workers actually want to go back to the office. The two of us are grateful to be among those who have already gotten our shots.
From everything we know about the various Covid-19 vaccines, normal life, or some semblance of it, could return as early as late summer or fall in the United States. The first two vaccines, made by Pfizer and Moderna, appear to be more than 90 percent effective. The Johnson & Johnson vaccine also looks to be quite effective. Thus far, the side effects seem tolerable. If there’s a problem with the vaccines, it’s that production has not kept up with demand and rich countries are scooping up the majority of available doses, leaving poorer countries to fend for themselves.
But behind the scenes, there’s a lot we don’t know, especially about the vaccines made by Pfizer and Moderna, which employ a completely novel technology involving mRNA, a type of genetic material. The reason we don’t know it is because of a decision made back in December by the U.S. Food and Drug Administration (FDA). The agency allowed manufacturers to effectively stop their clinical trials as soon as they were authorized to market their vaccines. While the early results from the clinical trials look incredibly promising, we don’t actually know with any precision just how effective and safe they really are – and we probably never will. That might sound like the kind of hairsplitting that hardly matters when a pandemic is raging and people’s lives are at stake, but it does matter for future vaccination campaigns. It’s worth considering why the FDA did it and whether or not that’s how vaccines and other medical products should be regulated in the future.
First out of the gate was Pfizer’s vaccine, which then-President Donald Trump pronounced a “medical miracle” on December 11 that would “save millions of lives and end the pandemic once and for all.” The FDA granted the vaccine an emergency use authorization (EUA) in record time. By January, thousands of essential workers in the United States had already been vaccinated with either the Pfizer or Moderna shot. The FDA grants an EUA based on preliminary data only in emergencies, and obviously the pandemic qualifies. Full approval is withheld until clinical trials are complete. In the case of the Covid-19 vaccine trials, a lot of experts were praying the FDA would require the companies to continue the trials for a full two years as originally planned.
That’s because many vaccines, along with drugs and medical devices, look “miraculous” at first – only to turn out to be less so as more data comes in. Most of these “medical reversals” occur because the product is less effective than it first appeared. But some products wind up being far more dangerous – like the pain medicine Vioxx, which killed 55,000 Americans before it was finally pulled from the market, and the Sprint Fidelis pacemaker, a device with faulty wires that caused hundreds of deaths and put another 150,000 people at risk of sudden death.
Even before the first vaccine came out, there were worries the FDA would not hold the companies’ feet to the fire and make them finish the trials. In an editorial published on September 10, Howard Bauchner, the editor in chief of the Journal of the American Medical Association and colleagues wrote, “prematurely approving a vaccine could undermine Covid-19 vaccine efforts and erode confidence in vaccines more generally.”
Bauchner and others also predicted that once the shots were available to the public, study volunteers would leave the vaccine trials in droves in order to find out if they had gotten the real vaccine or a placebo (dummy shot) – so they could get the vaccine as soon as possible if they were on placebo. That would undermine the studies, effectively stopping them after just a median of two months of data had been collected. Once the studies were stopped and the vaccines were released to the general population, it would be very hard to track side effects and efficacy.
It seemed like a dilemma with no solution. The pandemic was raging and early results from the trials looked highly promising. The FDA could hardly withhold authorization of seemingly effective vaccines in the face of a raging pandemic and a desperate public. At the same time, the positive early results from the trials, showing the vaccines to be extremely effective with virtually no side effects, might not stand the test of time.
Back in September, Anthony Fauci, who was then head of President Trump’s Covid-19 task force and remains the chief of the National Institute of Allergy and Infectious Diseases, had already proposed a clever plan. He recommended a “blinded crossover design.” Volunteers who had been in the placebo group would be given the real vaccine, while vaccine recipients would receive placebo—without anybody being told which they had gotten first. In this way, all volunteers would receive the vaccine while allowing ongoing surveillance regarding long term safety and efficacy. When the FDA called in Steven Goodman, an expert in clinical trial design from Stanford, he too endorsed the blinded crossover design, which is commonly used in medical research.
The manufacturers were less than enthusiastic. They told the FDA that executing crossover studies would be “onerous.” In this case, that word translates to “expensive,” and there’s no doubt that continuing the trials would cost more money. Not to mention the fact that the longer the trials went, the more likely it would have been that the vaccines would look a little worse than they did at first, at least in some populations, like people with immune disorders. That’s precisely the kind of data the FDA needs to protect the public health. Nevertheless, with a solution offered by top experts on the one hand, and industry opposition on the other, FDA higher ups made their decision. Instead of insisting on the trials continuing, they asked the companies to “inform the agency” of their plans. Was it pressure from the Trump White House, members of Congress, or some other reason the FDA caved to industry, as often happens? We can’t be sure, but the testing design Fauci and Goodman endorsed would have let the wider public get the vaccine just as quickly.
This decision to cut the trials short could come back to haunt the FDA. For one thing, getting more data could have reassured millions of Americans who are currently “vaccine hesitant” that the agency is looking out for them. These aren’t cranks. Some are health care workers, including doctors and nurses, people you would think would be the first in line to get their shots given their exposure to the virus. We’ve talked to several people in healthcare who have eschewed the vaccine. Many of them have been around long enough that they’ve come to distrust Big Pharma and/or the FDA. Stopping the trials early didn’t help.
Another reason longer trials would have been good policy: Public health officials and individual patients would probably like to know who is least likely to be protected by the vaccines and who is most vulnerable to their side effects. Diana Zuckerman, president of the non-profit National Center for Health Research, says, “I’m especially concerned that Pfizer’s vaccine trials included only five people aged 75 and older who were diagnosed withCovid-19.” She adds: “That makes it impossible to determine how effective the vaccine is for frail elderly patients.”
There’s reason to wish we knew more about side effects for older patients. In a report from Norway, 23 frail, elderly people died shortly after receiving the vaccine. Norwegian researchers wrote that it was possible that common side effects of the vaccine, such as vomiting and diarrhea, “that are not dangerous in fitter, younger patients … may aggravate underlying disease in the elderly.” If the vaccines turn out not to be terribly effective for older people—as is the case for the flu vaccine—and their side effects pose real dangers, nursing homes and care facilities may need to use different methods to protect elderly residents and patients. As things stand, it’s very hard to know because the tests were short-circuited.
This episode in the annals of potentially wrongheaded FDA decisions bears directly on the Biden administration’s decision about who to nominate as FDA commissioner. The two top picks are Janet Woodcock, current acting commissioner and 35-year veteran at the agency versus Joshua Sharfstein, vice dean for public health practice at Johns Hopkins. Both are physicians and both have experience at the agency, and that’s pretty much where the similarity between them ends. Woodcock has presided over many of the most questionable drug approvals the FDA has made in recent memory. She sees industry as a “partner,” and she’s the preferred candidate of Pharma, device makers, and several patient groups, most of which receive industry funding – precisely because she has weakened the FDA’s oversight.
Sharfstein comes with a public health perspective and an acute awareness of the need to rebuild the agency’s reputation as independent from both politics and industry. As deputy commissioner of the FDA during the Obama presidency, he proved his mettle when he headed an internal investigation into the approval of an ineffective and harmful medical device. The investigation found that the FDA had caved to political and corporate interference by allowing the device, Menaflex, a knee implant made of cow cartilage, on to the market over the objections of agency scientists.
Whoever the Biden administration chooses, whether its Sharfstein, Woodcock or someone else, Americans need to know the agency charged with protecting their health from dangerous medical products is, as the president often says, “following the science,” rather than the pleas of industry. We should be thankful that we have Covid-19 jabs that can help free us from this plague year. But we may never have the full story on them. The FDA can do a better job in the future.