When Placebos are Not Inert

To Trust the Science, the Science Must Be Good

As recently as May 1, 2025, the Secretary of HHS, Robert F. Kennedy Jr., instituted a requirement that all new vaccines are to be tested against an inert substance known as a placebo before they can be made available, which represents a "radical departure from past practices."

Most Americans, and indeed most consumers worldwide, understand that a placebo is a substance that is not biologically active and is completely inert. It is used to identify the number and type of adverse reactions that may occur compared to the test substance. In other words, a genuinely harmless substance is employed to assess the safety of the new drug or vaccine being introduced to the market.

As early as 2002, vaccine researchers raised questions about randomized, placebo-controlled trial design, highlighting ethical concerns regarding the participants in the control arm. Were they being deprived of “the benefits” of an existing vaccine? Furthermore, they challenged the scientific standard by questioning the gold-standard study hypothesis: Is an experimental vaccine more efficacious than one already in use?

In much the same way that pharmaceutical companies co-opted the word “vaccine” and applied it to the COVID-19 bioweapon, the concept of placebo has been altered in research. The use of a “comparator”—a substance that has already been determined to be “safe and effective”—is now being substituted in clinical trials and used as a “placebo.”

New Definition of Placebo

In 2013, a panel of 20 experts from 11 countries convened to discuss the issue of placebo use and develop recommendations for the World Health Organization (WHO). The results were released in a document titled Expert Consultation on the Use of Placebos in Vaccine Trials, which outlined the development standards for researching new vaccine candidates. Buried within its technical language is a critical and troubling shift in how vaccine trials are currently structured.

The paper can be boiled down to these two guidelines:

1. Placebo use in vaccine trials is clearly acceptable when no efficacious and safe vaccine exists.

2. Placebo use in vaccine trials is clearly unacceptable when a “highly efficacious and safe vaccine exists” [one that has previously been FDA/EMA approved] and is accessible in the public health system of the country in which the trial is planned.”

The document clarifies that researchers are encouraged, even required, to use an “active comparator” (an existing vaccine) instead of an inert placebo in clinical trials for a new vaccine. This marks a fundamental departure from traditional ‘gold standard, scientific rigor,’ where testing involves a double-blind, PLACEBO-controlled trial to isolate a new product’s true effects and risks.

WHO's rationale framed this change as an ethical concern: If a vaccine is already licensed and available, then denying protection to trial participants is deemed unethical. In theory, using the existing vaccine in the trial protects participants in the control arm of the trial from being “deprived of a beneficial intervention.”

The same convoluted reasoning is used to avoid conducting a large study on vaccinated vs. unvaccinated children: the idea that it is unethical to withhold a “known treatment of value” for a clinical study.

However, in practice, using a comparator undermines the very foundation of a placebo-controlled trial—the gold standard that must be upheld to protect vaccine recipients from harm. By using another vaccine as the placebo, the ability to detect the full range of adverse events, both common and severe, is negated.

Furthermore, the theory that the comparator protects against the illness that the new vaccine is being tested for collapses because the vaccine used as the comparator is usually designed to protect against a completely different disease. For instance, in the trial for the pneumococcal conjugate vaccine (PCV-9), the comparator may include the DTP-Hib vaccine instead of a simple saline placebo. The meningitis C vaccine is frequently used as the comparator, even though it is an active vaccine.

And the list of similar studies goes on and on.

…And the adverse effects of the new vaccine may be the same as those caused by the comparator.

When the list of adverse events for the trial vaccine and the comparator is the same, investigators say the new vaccine is “as safe as placebo.” A deceptive truth.

The comparator-as-placebo is often the same vaccine tested against itself. In last week’s Substack, I pointed out that in the Rotarix and RotaTeq trials for the prevention of rotavirus diarrhea, the identical chemical-containing solution of the test vaccine was used as the placebo. The difference? The placebo didn’t contain the active virus. The trial vaccine was tested against itself…for safety.

Another example: in a recent trial, a new 5-antigen meningitis vaccine was compared against an existing 4-antigen meningitis vaccine.

This practice allows regulatory agencies and manufacturers to claim that a new vaccine has the “same safety profile as a placebo” without ever having to show it was tested for safety against a neutral baseline. It is a statistical sleight of hand that lowers the bar for safety and undermines informed consent because study participants—and the public—are led to believe that a vaccine was tested against nothing when, in fact, it was tested against something that was biologically active. It’s deceptive for the uninformed.

The WHO’s guideline paper institutionalized this approach, reshaping what had long been considered acceptable in vaccine development. Research is no longer about discovering the truth about a new product’s risks and benefits. It is about expediency, optics, and the protection of existing vaccine policies.

Substituting another vaccine and calling it a “placebo” enables manufacturers to expedite products to market, asserting they’ve met ethical and scientific standards, when in reality, the crucial element of an inert comparison has been omitted. This is not merely a technical footnote; it represents a systemic issue that undermines the integrity of the entire vaccine approval process. When the benchmark for safety is not evaluated against zero but instead against another potentially hazardous intervention, we are no longer engaging in science.

We are managing perception.

Finding the comparator-as-placebo

As I noted in the previous substack:

It took more than four hours of research using Google, PubMed, the FDA website, ClinicalTrials.gov, and two AI tools (Grok and ChatGPT) to identify the placebo for these two rotavirus vaccines. Rotarix was more straightforward and clearly stated but hard to find; the placebo Rotateq vaccine had to be derived because it was not specifically found in any of those resources.

Vaccine package inserts typically list the vaccine’s composition, indications, and safety data, but they seldom include information about the placebo used in the clinical trials. This information is supposed to be found on sites that list the trial’s protocols, study publications, and regulatory submissions, but the comparator used is rarely listed. It can take hours of research to identify what was used as a placebo, if it can be identified at all.

Future Concerns

The researchers concluded in this 2014 paper that,

“The ultimate judgement about the acceptability of using a placebo control when an efficacious vaccine exists will depend on the specifics of the given trial.”

That is concerning, but it opens a window to restoring ethical research.

With the current Administration demanding adequate testing of vaccines—because none have been tested against a placebo for safety—I implore Secretary Kennedy and FDA Commissioner Makary to make a clear decision and issue a strong directive that the new trials are to use truly inert placebos, such as a shot of saline.

With the continued expansion of mRNA and the even more dangerous sa-RNA vaccines into the vaccine schedule for children, adults and animals, my concern is that the anticipated new studies will use the vaccines that have long been approved as “comparators,” allowing the mRNA technology to be approved by calling them “as safe as placebo.”