PART ONE: The way we run vaccine clinical trials is bizarre, unethical, and must change

We do not use "active comparators" instead of true placebos for other drugs. Why are the standards lower for vaccines? Yet despite an FDA promise of new rules last year, nothing has changed.

(Part 1: The trouble with vaccine trials)

Randomized placebo-controlled trials are the heart of medicine. They’re how doctors know new treatments work and have acceptable side effects compared to their benefits.

Except for vaccines. Vaccine trials often use a different, lower standard that makes it impossible to tell how serious their side effects are.

The loophole is especially bizarre because most vaccines are not given to sick people who need immediate help but prophylactically to healthy children.

Last year, Robert F. Kennedy Jr. and Food and Drug Administration reformers promised to make vaccines follow the same standards as other medicines. But, after loud and misleading pushback from reporters, health bureaucrats, and drug companies, the FDA didn’t.

Now the reformers have been run out of town. And kids and adults will continue to be pushed (or sometimes forced) to use vaccines approved without honest safety data.

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So how does this loophole work?

Clinical trials typically split patients into two groups. One receives the new medicine being investigated. The other gets either an older treatment for the same disease or, if no older drug exists, a placebo, like a sugar pill or saline shot.

Because the patients are split at random before receiving the treatment, scientists can assume changes afterwards come from the treatment itself — not from some hidden difference between patients who take the drug and those who don’t.

That’s why clinical trials are as close to proof that a medicine has real benefit as we can get. (This is, of course, a major oversimplification about how clinical trials and drug development work. For more information, read this footnote.¹)

But clinical trials don’t just measure benefits. All medicines have side effects. Trials let regulators, doctors, and patients see how a new drug’s risks compare to a placebo or older medicine.

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But vaccine trials frequently have a crucial difference from those used for other medicines.

In vaccine trials, instead of testing new jabs against placebos, drug companies often use what they call “active comparators” — other vaccines.

To be clear, these are not situations where companies are testing new vaccines for diseases like measles, where older jabs for the same disease already exist. In those cases, it may be unethical to offer a true placebo arm.²

These are trials for entirely new vaccines treating diseases for which no approved treatment exists.³ In this case, the comparator is typically a vaccine for a different disease, one the trial is not testing.

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(I said sugar pill, not Skittles!)

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For example, in the pivotal 37,000-infant trial of PCV7, a vaccine against bacteria that can cause pneumonia and ear infections, infants and toddlers were given multiple shots of PCV7 or a vaccine against meningitis that itself wasn’t even approved at the time.

The effect of this sleight-of-hand is to make side effects for the vaccine being tested seem far more modest than they are, since the “active comparator” vaccine will have much worse side effects than a saline shot would.

Imagine a test that compared injuries from being hit by a sledgehammer to those from a baseball bat, instead of a sledgehammer and a styrofoam sledgehammer.

In turn, that deception fundamentally biases the trial to favor approval, since the FDA is of course supposed to consider side effect profiles when deciding on new products.

And side effects should be especially important in considering vaccine approval, since vaccines are usually given to healthy children or teens who often face a minimal risk of ever becoming gravely ill from the disease the shot is supposed to prevent.

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(Another colorful graphic. So much science-y science! So many new pneumococcal vaccines. Too bad they forgot the placebos.)

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In a 2014 paper in the journal Vaccine, a World Health Organization scientific working group wrote that “randomized, placebo-controlled trials are widely considered the gold standard for evaluating the safety and efficacy of a new vaccine.” (The WHO was considering whether placebo trials are acceptable even when a working vaccine already exists. It found that many times even in that case the answer was yes).

So why are vaccines different? Why are placebo-controlled trials not required in every instance?

Their advocates offer two primary justifications. Neither holds up.

The first is that vaccines have such intense side effects that using saline will tip people in the trial to whether they are getting the vaccine or the placebo — it will “functionally unblind” the trial and bias the outcomes.

But the same potential unblinding holds for non-vaccine medicines. Many antidepressants have sexual side effects, for example, but no one suggests that men in the placebo arms of antidepressant trials be given blood pressure medicines (which can cause impotence).

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Further, the fact that vaccines cause such serious side effects that the only possible way to keep a trial blinded is to use other vaccines in placebo arms is hardly a general argument for vaccine safety.

Finally, many vaccines are given to infants and toddlers — who will have no way of knowing they are in a clinical trial, much less realizing that the side effects they suffer are the result of a vaccine. In other words, the risk of functional unblinding should be lower, not higher, in trials for kids.

The second justification is that everyone participating in a vaccine trials “deserves” the benefit of some vaccine for participating. Last year, Dr. Steven Black, the lead investigator in the PCV7 trial, told PBS the trial had not been placebo controlled

due to the ethical concern of requiring the more than 15,000 control patients in the trial having to receive four doses of a placebo vaccine with no potential for benefit.

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This is… not how clinical trials work. As Dr. Black should know.

The point of a clinical trial is not to benefit the people in it. Yes, they may benefit from getting a new treatment that other people haven’t received. But they may also be harmed, if the drug does not work or has severe side effects.

The point of running the trial is to test the medicine and find out. It is to gain information that will help future patients, not the ones in the trial.

This is one reason that researchers are strongly discouraged from enrolling prisoners or other people at risk of feeling coerced into joining clinical trials. Offering large payments is also unacceptable, though small ones for time and inconvenience are reasonable. (In very-early stage trials where a few healthy people face the risk of a compound never before tested in human beings, payments can be higher.)

In other words, potential trialists (or their parents, in the case of trials for children) should join trials freely, without hoping for any benefit other than the potential gain from a new drug — and the chance to altruistically help science and medicine.

This potential lack of benefit may seem wrong at first.

It’s not.

Not as long as no one is forced to participate in a trial, doctors clearly explain the potential risks and benefits to the people who enroll, and the people running the trial have a reasonable belief that the new drug will work and isn’t too risky.

We need clinical trials. Without them, all we have is guesswork.

And without true placebo arms, clinical trials are far less valuable, if not close to useless.

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The key fact here, the one that vaccine advocates seem to forget: Vaccines are no different than other drug classes. They aren’t magic. Doctors, regulators, and most of all the people who receive them deserve clean and reliable information about them, including their side effects — just as they do with other drugs.

That’s what Dr. Vinay Prasad tried to say in November, when, as the chief medical officer of the FDA, he wrote in a memo that “vaccines will be treated like all other medication classes.”

And that’s what Robert F. Kennedy promised in April 2025, when he said the FDA would require placebo-controlled clinical trials for vaccines.

But Prasad is gone. And the FDA’s guidance on vaccines remains unchanged.

That’s not an accident.

(First of two parts. Coming soon: the misleading pushback from the media and health bureaucrats that derailed vaccine trial reform.)

1. In general, the development of new medicines progresses in three stages in humans.

In the first stage, a company gives a new compound to a few healthy volunteers to make sure it doesn’t unexpectedly kill anyone. In the second, which can cover anywhere from a few dozen to a few hundred people, the company figures out the best dose, the one that will have the most impact on the disease with the fewest side effects.

Then, in the third or pivotal stage, the company tests that dose in a large trial or trials, hoping to prove its medicine or vaccine will have a “statistically significant” impact on the disease.

The outcome being measured doesn’t necessarily have to be deaths or hospitalizations; an anti-migraine drug might be tested to see if it reduces the number of days each month a person has migraines. If the drug hits the goal the company has set in a way that is unlikely to be due to chance, the trial has succeeded and the drug is approvable — assuming its side effects are not too bad.

Even this length explanation deeply oversimplifies the drug development process and elides many crucial details. For example, a very large trial may be able to capture small differences between a drug and placebo, enabling a company to submit a drug for approval even if it may make little real world difference to patients. Or a company hoping to speed the process may begin the third, largest stage before finishing the second.

Further, in the case of diseases that are very rare or invariably fatal or both, regulators may accept less rigorous trial designs — a seemingly compassionate choice that has often led to later grief.

2. Even then the trial ethics are somewhat complex, because the effectiveness of new treatments can subtly decline over multiple generations of seemingly successful trials, ultimately leading to the introduction of new drugs that don’t work as well as older ones.

3. The mRNA Covid vaccine trials were a rare example of a trial for a novel vaccine run against true saline placebo. And not surprisingly, people who received the mRNA reported much severer side effects than those who given saline.