Recently, Professor Dorit Rubinstein Reiss wrote two articles, one about an anti-vaccine book and another debunking claims from Steve Kirsch, which focused on one issue — anti-vaxxers don’t understand anything about vaccine clinical trials.

Anti-vaxxers have jumped on this “not tested against a placebo” aspect of vaccine clinical trials as their “gotcha.” They think, without a stitch of evidence, that this proves that vaccines are unsafe or ineffective. Of course, those of us who use science and understand clinical trials, accept the fact that vaccine safety and effectiveness are settled science.

Although Professor Reiss did an outstanding job in debunking the anti-vaccine claims about placebos and clinical trials, I wanted to get into the weeds about clinical trials themselves. This should show anyone with a good sense of science and logic that the anti-vaxxers are wrong.

You can find a lot of claims on social media about vaccine testing versus placebo, but I’m not going to deal with all of his ridiculous points in the letter, I’m just going to focus on a small part, that is, his claim that vaccine clinical trials do not include a placebo for comparison. As I said in the introductory paragraph, Bigtree is completely wrong.

Del Bigtree and vaccine clinical trials

Because there are a lot of websites that repeat the false claims about vaccine trials, I thought I would focus on a letter to the US Department of Health and Human Services (HHS) from Del Bigtree, the producer of the fraudmentary Vaxxed, who has approximately zero credibility on vaccines. 

Bigtree, and his anti-vaccine organization, Informed Consent Action Network, pushed all kinds of debunked claims in an 88-page screed against the CDC and FDA with regard to vaccines. I don’t have the time or the willingness to read all of those lies put in 88-pages, so I will stick with the point of this article — his claims about vaccine clinical trials, especially the use (or not) of placebo controls.

Here’s what Bigtree asked of HHS in his pseudoscience-filled letter:

…we asked that HHS identify the clinical trial data showing that the safety of pediatric vaccines was carefully studied prior to licensing and injecting them into millions of American children. In response, HHS did not cite any such data. Instead, HHS merely made conclusory assertions regarding pediatric vaccine clinical trials that contradict HHS’s published documents. We take each point in HHS’s letter regarding vaccine clinical trials in turn below.

His claims about these trials would be valid, except it exposes Bigtree’s lack of knowledge and scientific acumen regarding clinical trials. We’re going to focus on his first giant claim — the lack of placebo controls in pediatric vaccine clinical trials.

Now, I’ve seen these claims dozens of times over the years. They always get debunked, and the anti-vaxxers slink away to their conspiracy-filled dungeons, just to come back like brain-dead zombies to repeat the claims again. Then, like the good zombie hunters that we are, we use logic and science to send them back to that dungeon. But it does get boring after a while.

Anyway, Bigtree, using the age-old methodology of all science deniers, attempts to use a gigantic strawman argument, that there are no placebo-controlled vaccine clinical trials, to claim that we don’t know that vaccines are safe. That argument betrays his ignorance of medical research, and I’m here to point it out.

The typical vaccine development process

Let’s back up for a moment to review the whole vaccine development process. I remain convinced that anti-vaxxers think that anyone with a blender in their garage can “invent” a new vaccine, inject it into a few kids, and, voila, they are making billions of dollars forcing kids to get this “untested” vaccine.

However, the real development timeline of a new vaccine is long and arduous. And it contains many points at which a vaccine can be shown to be unsafe or ineffective. This is the normal timeline (pre-pandemic) process for vaccine development (with the approximate amount of time it takes):

Month 0-24, Preclinical. This is the period of time when scientists attempt to determine if they can identify a part of the virus that stimulates the immune memory so that the immune system can quickly destroy the pathogen before it can do harm. They also need to isolate and culture a lot of viruses to be used in preclinical studies. 

For example, these steps will help scientists understand the pathogen’s characteristics and pathophysiology in humans. Since it would be unethical to do these studies in actual humans, researchers need to develop an animal model that mimics a human. Also, researchers need to determine if the vaccine is safe and triggers an adaptive immune response in that animal model.

Month 24, IND application. The sponsoring organization (probably a Big Pharma company, called the “sponsor”) must make an Investigational New Drug (IND) application to the FDA’s Center for Biologics Evaluation and Research (CBER) to begin clinical trials. CBER reviews the IND, which will include preclinical data, and the sponsor can proceed with the clinical trial within 30 days if the FDA does not find cause to stop it from moving forward. This is the process in the USA, but it’s much the same in most developed countries.

Month 24-60 (or more), clinical trials. Then the sponsoring organization must get Institutional Review Board (IRB) approval to proceed with clinical trials (see this article for more information about the process).

These clinical studies must go through three phases like all drugs, although the process could be shortened if the data is very clear and there is a public need (like the COVID-19 pandemic) using an Emergency Use Authorization (EUA).

The proposed clinical trials will be posted to a US government website that tracks all clinical trials worldwide (and must be posted there before a drug can get US FDA approval).

Phase 1 clinical trials usually include around 100 healthy patients (that is, they have no comorbidities and generally lack any chronic health conditions). This study is not randomized or blinded, as there is only one group, those that receive the vaccine. Phase 1 clinical trials rarely give any information about the safety and effectiveness of the vaccine – it really only tells the researchers if there are some significant safety signals.

Phase 2 clinical trials usually include around 200-300 patients. This study is a randomized, double-blind trial that is too small to observe small differences in effectiveness and safety. However, it helps researchers to determine if there is sufficient data to move forward.

Phase 3 clinical trials, sometimes called pivotal studies, include around 2-3 thousand patients, although many vaccines have included tens of thousands of participants. These studies must be randomized, double-blinded, and placebo-controlled (or versus a standard of care control). 

Phase 2 and 3 clinical trials are often published in peer-reviewed journals (unless they’ve failed to show anything, then the vaccine is shelved or reworked). Sometimes, the two phases are combined, but that’s rare. The phases were combined with the COVID-19 vaccines because of the necessity of speed to get the vaccine before the pandemic killed more people.

Combining the two phases does not mean we had less information. In most drug development, phase 2 helps decide if the sponsor wants to go to a larger, much more expensive phase 3. And if there are strong safety signals or issues with effectiveness, then the FDA or the sponsor could call it off. In the case of the COVID-19 vaccines, phase 2 would have just delayed getting the vaccine, so they jumped directly to phase 3. Frankly, the phase 2 and 3 trials were huge, with over 50,000 patients for each vaccine, much larger than a typical drug or vaccine phase 3 trial.

Despite the really weird claims of the anti-vaccine crowd, phase 3 clinical trials are thorough and statistically powerful. They truly allow us to know if a vaccine is safe and effective. 

After each phase, the sponsor must present the data to the FDA (or other regulatory agencies) for review before the sponsor can move to the next phase. This is a check on the safety and effectiveness at each phase so that a dangerous, useless drug does not go further in clinical development.

Month 60-78, regulatory review, and approval. After all of the preclinical and clinical research is completed, the sponsoring organization must make a Biologics License Application (BLA) to CBER. Although this process is what is done in the USA, it’s similar in most other countries (and some countries accept FDA review for their own country.

Part of the review usually requires a thorough review by the Vaccines and Related Biological Products Advisory Committee (VRBPAC), which is made up of leading scientists. They have frequently required further testing, or they could even reject an application for a vaccine. 

In addition, every clinical trial employs a Data Safety and Monitoring Board (DSMB) which is made up of an independent group of medical ethics experts, statisticians, patient advocates, and, in the case of vaccines, vaccine experts. They monitor patient safety and drug effectiveness, and they have the power to proceed with or stop a clinical trial. 

In other words, in a normal vaccine development process, there are several independent agencies and groups that make certain that only safe and effective vaccines are available to the public.

At the same time, and outside of the clinical trial process, a manufacturing plan has to be developed. People seem to think that a vaccine is simple to manufacture, but it really isn’t.

So, new manufacturing facilities will need to be built so we have more capacity. Of course, these facilities also need to be reviewed and approved by regulatory authorities. 

The timeline I provided above is generally one that I would think is fairly optimistic. Nevertheless, this is a thorough process that weeds out vaccines that lack the safety and effectiveness expected of vaccines. And yes, the FDA has stopped vaccines from moving forward many times, so this is not a slam dunk that is claimed by anti-vaxxers.

Placebo-controlled clinical trials

The first point is that many, if not a majority of, clinical trials test an experimental drug (or device) versus the standard of treatment. So if we have XYZ drug that kills small cell lung cancer, we don’t put one arm of that study of patients receiving a saline placebo. That is beyond unethical – giving a patient with small cell lung cancer something that doesn’t work, a placebo, just to see if the new drug is better than the placebo.

The actual study would test the experimental drug versus the standard of pharmaceutical treatment for that cancer. If the drug is safer and at least equivalent to the older methods, it might get FDA approval. If it’s the same, it may or may not receive approval.

This is the same for vaccines. If we have a new measles vaccine, we are not going to test it against a placebo, because it is unethical and immoral to place half of the trial group at risk of measles because they receive nothing. Anti-vaxxers, like Del Bigtree and Steve Kirsch, seem to be clueless about this point.

Let’s stick with this new measles vaccine as an example. Before a clinical trial would begin, the sponsor, Big Vaccine Corporation, would need to set up a clinical trial by recruiting researchers and establishing a protocol. If that protocol said, “Well, we’re going to have a placebo group because ignorant, unscientific anti-vaccine cretins think that’s the only way to do it.”

Well, guess what all of those researchers will say? You got it, that would be a big fat “no way.”

But let’s say you believe that Big Vaccine Corporation will throw a few million dollars, euros, yen, or gold coins to those researchers to overlook their ethics. Well, these researchers do not get to suddenly set up a clinical trial whenever they want.

Before researchers can commence their study, an Institutional Review Board (IRB) must review and approve any study that involves the institution, usually a hospital or academic institution (which usually are one and the same for most clinical trials). The IRB reviews and approves (or rejects) any proposal to do research on humans. They monitor this research from beginning to end. They reject any clinical research that is unethical or dangerous to humans.

In fact, the FDA requires IRB approval for any clinical research – they are part of the ethical watchdogs that make sure ethical standards of research are met. So what do you think an IRB would say about clinical research that would ask to put 50% of the study group at risk of measles for this new measles vaccine? That also would be a big fat NO.

But let’s say you are convinced that all IRBs can be easily manipulated by Big Vaccine Corporation to move ahead with this study. Well, then we hit the final point – parents whose children will be included in this study.

What do you think they will say if this unethical researcher, supported by an unethical IRB, told a parent that their child would be included in a trial for a new vaccine, but they have a 50% chance of receiving nothing, putting their child at risk of a deadly disease?

Their answer would probably be filled with expletives followed by their finding a new pediatrician. Since over 90% of Americans (with similar numbers in almost every country with a strong healthcare system) favor vaccination, these parents want their children vaccinated.

Now, I’ve heard some anti-vaccine ignoramuses say, “I’d volunteer my child for a placebo.” Of course, this shows their callous disregard for the health of their children, but we’ll overlook that point for now. Once a test subject gets to choose which arm of the study they are in, it destroys the randomization and blinding of said study. It becomes filled with all kinds of biases such as observer bias. We wouldn’t know if the placebo or experimental arm of the study gave us any information whatsoever.

I’m sure such a study would be useful to the anti-vaxxers to publish in their predatory, worthless journals. They could tout them as “science,” when it would be useless. But then again, Big Vaccine Corporation, the IRB, and the investigators would all not agree to such a study, because it would be worthless. And one more thing – the FDA would break ribs laughing at any BLA being presented to them.

So, let’s be clear here. Any new vaccine that replaces an older vaccine will never ever ever be tested in a placebo-controlled study. Maybe I shouldn’t be so black and white – maybe a replacement vaccine could be used in a randomized, blinded placebo-controlled study – I’m wracking my ancient reptilian brain to figure out how one could be done ethically, but I can’t see it.

Now, the anti-vaxxers will claim that you can’t tell safety because you might be comparing it to an unsafe vaccine. Except, that is a completely false claim. The antecedent vaccine will have been studied in numerous large observational studies, like case-control or cohort studies, each of which is powered to find small differences in safety and effectiveness.

If the antecedent vaccine has safety issues discovered through these observational studies, the vaccine would be removed from the market. For example, the original whole-cell pertussis vaccine was replaced by the acellular vaccine because of false claims about the safety of the whole-cell vaccine.

So, comparing a new version of the vaccine to an old one is scientifically and logically sound. In almost every case, the newer version of vaccines is safer and more effective than the antecedent vaccine. And the antecedent vaccine is safe and effective.

From every scientific aspect, clinical trials that show the safety and effectiveness of the new vaccine compared to the antecedent vaccine are valid. They are good science, and the only thing the anti-vaxxers are trying to do is attempt to create a red herring, which has nothing to do with science.

In case you’re wondering if I’m the only person that says this, another real scientist, Orac (and I’ll use his pseudonym, but anyone with one functioning neuron knows who they really are), states that:

If an effective treatment for a condition for which you’re testing a new drug or an effective vaccine against a disease you’re testing a new vaccine for exists, it is unethical to do a placebo-controlled trial because that would require leaving the control group untreated or unprotected. The only ethical way to test such new therapeutics or vaccines is against the existing standard of care; that way no subject in the trial is intentionally left untreated or unprotected. I know that Bigtree knows this because science advocates have been telling him this ever since he emerged as the darling of the antivaccine movement; so here he’s clearly being intentionally deceptive, knowing that his audience won’t question his claim and will eat it up.

Some vaccine clinical trials contain a placebo

Of course, as I stated, there are conditions when a randomized, blinded, placebo-controlled clinical trial is ethical and useful. That’s when we have a brand new vaccine, so there is no standard of vaccine protection.

The chickenpox vaccine was studied in such a way (see Note 2). These trials were performed with a placebo control because, wait for it, there were NO antecedent vaccines for chickenpox.

The HPV vaccines were also studied in double-blind, randomized, placebo-controlled clinical trials because it was a novel vaccine. In fact, there are systematic reviews, considered the most powerful studies in the hierarchy of biomedical research, that have reviewed all of the clinical trial data for HPV vaccines (here and here) – their conclusions were that the HPV vaccines were as safe and more effective than placebos.

I am going to repeat myself because sometimes people miss the point. The studies for the HPV and chickenpox vaccines could be done in a double-blinded, randomized, placebo-controlled method because there were no antecedent vaccines available to clinicians. So, getting physician investigators to participate was smooth and easy. Getting IRB approval did not require overlooking ethical issues. And recruiting patients to participate did not need investigators to convince parents to put children in harm’s way.

Bigtree and Kirsh, both being clueless about how clinical trials work, don’t get it. But They are only pushing the tropes and myths that anti-vaxxers love to use to try to say “gotcha” about vaccines.

But there’s more

Of course, science doesn’t just depend on clinical trials, placebo-controlled or not. There’s a belief among the uninitiated that Big Pharma gets FDA to approve a drug, throws it on the market, and awaits the bags of cash being delivered to corporate offices so that the executives can dive into a swimming pool of gold coins like Scrooge McDuck.

As I mentioned previously, that’s not how it works. Big Vaccine Corporation has several systems that provide ongoing evidence of the safety and effectiveness of their new vaccines. I know I wrote this before, but let me reiterate:

1. Phase IV clinical studies, sometimes called post-marketing surveillance, either sponsored by the company or run independently by investigators, continue to examine the new vaccines for “safety signals,” potential adverse events that arise in randomized studies, or for any effectiveness issues. These studies go on for 10 or more years after the vaccine is first marketed.
2. Large case-control or retrospective cohort epidemiological studies are often more powerful and robust methods to detect even rare adverse events compared to the general population. These studies continue long past the release of a new vaccine and usually provide us with the best evidence for the safety and effectiveness of new vaccines (and all pharmaceuticals).
3. Real scientists, not the pseudoscientists like Bigtree and Kirsch, who cherry-pick anything that supports their ignorant beliefs about vaccines, like to formulate conclusions from a large body of data. Epidemiological studies that support fundamental clinical trials often provide the best information about a new vaccine. That’s why we know that there are no safety signals with the HPV vaccine. That’s why we know that the HPV vaccine prevents cancer. Not the uninformed and laughable claims of a misinformed fool like Bigtree.

Summary of placebo and vaccine trials

• Anti-vaxxers, like Bigtree and Kirsch, are usually wrong again about everything regarding any vaccine, but they are particularly wrong about his demand for some magical placebo-controlled clinical trials.
• Randomized, double-blind, placebo-controlled clinical trials should be done for vaccines only if it is ethical, meaning that it is a novel vaccine where the placebo arm of the trial doesn’t endanger the health of children or adults.
• Ethics matter in clinical trials, despite the fanciful claims of the anti-vaccine world.

Notes

1. Although I am focusing on the regulatory requirements of the FDA, it is similar across the world. Many countries allow preclinical and clinical data used in a BLA or NDA in one country to be used in another. Most countries do not expect or require a pharmaceutical company to repeat clinical trials in their own countries. In fact, most clinical trials these days have research sites that are global.
2. There are dozens of published articles in the late 1980s and early 1990s that establish the safety and effectiveness of the chickenpox vaccine, I just chose one that had a readable abstract, since I know most people don’t ever get the actual paper to read. If Big Medical Publisher would get rid of the paywalls, maybe more anti-vaxxers will be impressed by what it takes to do real scientific research. Well, that’s a battle to be fought another time.

Citations

• Arbyn M, Xu L. Efficacy and safety of prophylactic HPV vaccines. A Cochrane review of randomized trials. Expert Rev Vaccines. 2018 Dec;17(12):1085-1091. doi: 10.1080/14760584.2018.1548282. Epub 2018 Nov 29. PubMed PMID: 30495978.
• D’Addario M, Redmond S, Scott P, Egli-Gany D, Riveros-Balta AX, Henao Restrepo AM, Low N. Two-dose schedules for human papillomavirus vaccine: Systematic review and meta-analysis. Vaccine. 2017 May 19;35(22):2892-2901. doi: 10.1016/j.vaccine.2017.03.096. Epub 2017 Apr 25. Review. PubMed PMID: 28455170.
• Englund JA, Suarez CS, Kelly J, Tate DY, Balfour HH Jr. Placebo-controlled trial of varicella vaccine given with or after measles-mumps-rubella vaccine. J Pediatr. 1989 Jan;114(1):37-44. PubMed PMID: 2535873.