Do you know what's in your placebo? It matters more than you realize
Randomized, placebo-controlled, double-blind studies are considered the “gold standard” in research, offering the most reliability when assessing new drugs or procedures. However, a group of researchers has recently discovered that sometimes, those running these trials are less than reliable inproviding informed consent to their volunteers.
While this may seem a matter of concern only for those few thousand people directly affected, the implications go far beyond the trials themselves. Why? Because when a placebo is not a placebo but only masquerading as one, a drug portrayed as safe and effective may be anything but.
Designed to deceive?
The Merck pharmaceutical company tested its new quadrivalent Gardasil vaccine (for the HPV virus) on thousands of people back in the early 2000s. In a series of trials conducted in Denmark, researchers recently discovered, trial volunteers were told that the placebo arm of the trial involved being injected with an “inert” substance, or alternatively, with “saline solution” (saltwater). In fact, those who were randomized to placebo received either an aluminum-based adjuvant (a substance that enhances the action of the vaccine) or a “carrier solution” which contained various non-inert substances.
According to the FDA, the control group in a vaccine study need not be given a genuine placebo at all. New vaccines may be tested against a placebo but may also be tested against another another vaccine or "another substance:”
These vaccine studies typically also include a control group consisting of people who may receive an FDA-approved vaccine, a placebo, or another substance. People receiving the vaccine under study are compared to people in the control group.
But trial volunteers have an established right to informed consent when entering a trial; they should always be told what will or might be injected into their bodies, not merely that the possibilities include "another substance."
Most people enrolling in clinical trials do so for lofty motives of advancing scientific knowledge and helping to save lives. They would not enroll in a clinical trial for a vaccine if they did not believe in the benefits of vaccination, which is why they are willing to accept the risk of being injected with a new and untested chemical substance. However, there is no reason to assume that they accept any risk of being injected with something presented as a placebo given that this would seem to serve no purpose whatsoever with regard to advancing science.
In the Denmark study, thousands of people who volunteered to test the Gardasil vaccine were told that they would be given either the vaccine or a placebo.
The informed consent form contained the following language: “One half of the participants will receive the active vaccine, while the other half will get the placebo vaccine (meaning a vaccine without active substance).”
Merck’s advertisement aimed at potential trial volunteers, however, described the options as Gardasil or “saline”:
The original study revealing this deception was authored in 2020 and published in the British Medical Journal (BMJ). Four years later, the facts were presented in another article in a different journal, the International Journal of Risk & Safety in Medicine (IJRSM). Merck has suffered no consequences in the interim and the FDA has not amended its guidelines or issued any clarifications or warnings.
Is blinding always appropriate?
While it’s impossible to know for sure why Merck misled trial volunteers into thinking that the placebo arm of the trial received an inert substance, the pharmaceutical company did at least explain why they used AAHS (their amorphous aluminum hydroxyphosphate sulfate adjuvant) instead of saline or some other inert substance. The company’s rationale was provided in three of its clinical study reports, stated as follows:
The inclusion of aluminum adjuvant in both vaccine and placebo preserved the blinding of the study because it allowed the vaccine and placebo to be visually indistinguishable.
A double-blind study is one in which neither the participants nor the researchers know who is in which cohort, until the study ends. Using two visually distinct substances would make it obvious who got what and could potentially skew the results.
However, in a different Gardasil trial Merck used carrier solution without AAHS for the placebo arm. Then, in a later trial they actually did use saline.
How, then, did they preserve the blinding when the placebo (saline) did not resemble the test substance (Gardasil)? It turns out that it was quite simple. The researchers recruited an outside person to administer the substances, someone who was otherwise unconnected with the trial and who divulged nothing to anyone.
But there’s another reason why Merck’s justification for using a non-inert “placebo” in HPV trials is invalid, one that isn’t obvious given the way in which the trial results are presented. Follow-up was (as is customary in clinical trials) a matter of months. However, what Gardasil is supposedly protecting against is the development of cancer, many years down the line. Therefore, as the Cochrane Centre points out in a letter of complaint to the European ombudsman regarding the safety of HPV vaccines, it was hardly critical that the blinding in the trials should be so rigidly enforced:
It seems unlikely to the extreme that a woman’s cervical cells will respond differently depending on whether she thinks she got a placebo or a vaccine decades earlier.
If a drug’s adverse event profile includes crippling pain, should the placebo cause that too?
Using non-inert “placebos” is actually common in clinical trials, although this is not widely known. In Tamiflu trials, for example, the placebo contained dehydrocholic acid, a bitter-tasting substance, because oseltamivir (Tamiflu) is also bitter-tasting.
The trials could therefore be labeled “double-blind” for this and another reason - both Tamiflu and dehydrocholic acid cause stomach upset. However, there is a difference between a placebo that mimics the immediate effect of the drug being tested (e.g., redness at the injection site, feeling dizzy right afterward), and one that mimics longer-term side effects. For the purposes of blinding, is it really necessary for a placebo to have the identical adverse effects to the drug being tested, or is there another, less legitimate reason for toying with placebos in this way?
Placebos that are so much worse than ‘doing nothing’
All these concerns have been voiced for many years. Back in 2014, Professor David Haslam, chairman of the National Institute for Health and Care Excellence, wrote to the then-UK Health Secretary regarding statin drugs, and the points he makes are applicable to virtually all clinical trials. His letter contains a wealth of important information; for the purposes of this article, we will focus on his discussion of placebos.
Prof. Haslam points out a number of intriguing facts. Firstly, in all the statin trials he has examined, the rate of adverse events is virtually identical in both the placebo and the active cohorts. Secondly, the rate of adverse events varies tremendously from one trial to another.
For instance, in the WOSCOPS study, rates of myalgia were 0.06% in the statin arm, and 0.06% in the placebo arm. However, in the METEOR study, rates of myalgia were 12.7% in the statin arm, and 12.1% in the placebo arm.
He outlines a similar pattern in eight different statin studies, where the rate of “placebo” adverse events varied between 2.7% and 80.4%.
Curiously, the adverse effect rate of the statin is always very similar to that of placebo. However, placebo adverse effect rates range from 2.7% to 80.4%, a thirty-fold difference.
What Haslam does not discuss in this letter are background rates for adverse events. If a study finds that 12 percent of people enrolled in a clinical trial experience nausea (for example), including those in the placebo cohort — while background rates in the population are just 1 percent, what does this say about the placebo?
More importantly, what does this say about the drug being tested? This is where things become murky.
What’s a vaccine without an adjuvant?
Aluminum adjuvants are not added to vaccines for their visual appeal. Merck uses AAHS in its vaccines (not only Gardasil) for a very good reason. AAHS, like other adjuvants, has a strong immunostimulatory effect. It has been known for almost a century that adding aluminum adjuvants to drugs enhances the drugs’ effect on the immune system. AAHS is not the only type of adjuvant, but Merck has been using it since 1987 and they consider it to be a “most potent inducer of antibody responses,” as the IJRSM article describes, adding that it can “induce exceptionally high and long-lasting antibody responses.” Without AAHS, Gardasil would have a far smaller effect.
Unfortunately, AAHS’s effects are not all positive. The researchers in the IJRSM article cite numerous studies showing the harms caused by aluminum adjuvants — they cause tissue damage, particularly in the liver, as well as a slew of other symptoms including headache, fever, nausea, dizziness, allergic reactions, contact dermatitis, myalgia, cognitive dysfunction, chronic fatigue syndrome, and muscle weakness.
All these adverse effects were observed in the Gardasil trials — in both the active and “placebo” cohorts.
How to make a drug appear harmless: Compare it to a sham 'placebo'
What all this means is that adding AAHS (or any other adjuvant) to the placebo is far more significant than merely making the placebo injection and the drug injection look the same.
In a trial where both the drug and the “placebo” have a similar rate of adverse effects (because the placebo appears to be designed to mimic the drug’s adverse effect profile), the drug can be presented as “no worse than placebo” in terms of side-effects. That is to say, “no worse than doing nothing” in the minds of most casual readers of clinical studies, or the news articles that write them up. Most people won’t notice that the rates of adverse effects in both cohorts are still much higher than those in the general population who didn’t participate in the trial.
Another consequence of tampering with placebos is that the AAHS or other adjuvant, etc., is presented as inert and harmless. Understandably, Merck and other pharmaceutical companies are not interested in having their “carrier agents,” “adjuvants,” and “fillers” subject to intense scrutiny. That would complicate matters and add considerably to the costs of running trials — in the best case scenario, where the adjuvant would be proven safe. In the worst case scenario, for Big Pharma, the adjuvant would be banned as a dangerous substance, and the vaccine minus adjuvant would likely have a far smaller effect.
90 percent or 0.0054 percent efficacy?
The clinical trials of quadrivalent Gardasil discussed here were not actually designed to assess the safety of the drug, which was already considered safe at the time. Rather, the aim was to assess the benefit of Gardasil (which includes allowing for harms caused). Therefore, as the BMJ article points out, muddying the results with non-inert placebos means that making an accurate assessment of Gardasil is impossible.
Nonetheless, the trial results were still interesting and illuminating.
To date, the most cited study allegedly demonstrating significant “real world” reduction of invasive cervical cancer in Gardasil recipients included 528,347 unvaccinated and 518,319 vaccinated Swedish girls and young women between 10 and 30 years of age. During the study period, 538 women who had not received the Gardasil vaccine were subsequently diagnosed with cervical cancer compared to only 19 who had been vaccinated (adjusted incidence rate ratio (IRR) 0.37, 95% CI 0.21-0.57). The fully adjusted IRR for cervical cancer among women who were vaccinated before 17 years of age was 0.12 (95% CI 0.00-0.34). These results were hailed in the press as showing nearly 90% reduction in invasive cervical cancer incidence in girls vaccinated before 17 years of age [emphasis added].
A 90-percent reduction in cancer sounds very impressive (much like the 95-percent efficacy rate of the COVID shots, as presented in mainstream media).
However, when you look at reduction of absolute risk, it’s a very different story.
Incidence rate ratio, otherwise known as relative risk, compares the rates of disease in the placebo and active arms of the trial. In the real world, however, that’s not what matters to people’s lives. A person may have a 90-percent-less chance of getting a certain disease if he takes a certain shot — but 90 percent less of what?
Background rates of invasive cervical cancer, the type allegedly addressed by Gardasil, are very low in most of the West — they stand at around six women in every hundred thousand. Therefore, this 90-percent reduced incidence translates to a drop from 6 women in every 100,000 getting this type of cancer, to 0.6 women — a drop of 0.0054 percent.
It is when we look at the absolute risk of invasive cervical cancer for women either injected or not with Gardasil that we get a clearer picture of what this drug does. When the results are presented according to age-group, there are actually some groups where those women who received the vaccine were more likely to develop invasive cervical cancer. And even in the age groups where Gardasil showed most benefit, the actual drop in likelihood of getting this type of cancer was just 0.027 percent.
The WHO has set a goal of reducing the incidence rate of this type of cancer to 4 women per 100,000. In order to reach that goal, it states, it wants to see 90 percent of girls "fully vaccinated with HPV vaccine by age 15 years ... to be on the path towards cervical cancer elimination."
Meanwhile, as an article published in the Annals of Medicine noted back in 2013,
In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination.
In which case, injecting 90 percent of girls with the HPV shot may put them on the path toward something very different.
