Randomized Clinical Trials for Vaccine Safety, Efficacy and Effectiveness

Some of the misinformation regarding vaccines includes an argument that vaccines have not been tested against a saline placebo in a double-blinded randomized clinical trial. This misinformation is aimed at confusing the wealth of evidence regarding the safety and effectiveness of immunizations. In this blog post, we will explain what a blinded randomized clinical trial is, when this study design has been used in the development of immunizations, and why it is not used as often anymore.

What Is a Randomized Clinical Trial?

First, we need to understand what goes into running a double-blinded randomized clinical trial (RCT). In such a trial the group of participants is randomly assigned into either a control group or an experimental group. This assignment is completely at random, and the people going into either group are not aware of what group they’re in. The researchers also do not know what group the participants are. The intention behind this is to obtain experimental and control groups that are similar to each other in every way, such as age, gender or ethnicity.

Blinding the participants and the researchers further does away with bias because the participants are not aware if they are receiving the real deal (thus making them less likely to underreport or overreport outcomes) and the researchers also don’t know (thus making them less likely to more closely observe one group over the other). At the end of the study, the number of outcomes are counted in each group and the resulting rates compared. Only then are the groups “unblinded,” allowing for the researchers to know which group had the better or desired rate of outcomes.

Examples of Clinical Trials, Randomized and Non-Randomized

An example of this trial in the history of vaccines is the trial of the polio vaccine in 1954. In that trial, 1.3 million children were randomly assigned to either receive a placebo, the polio vaccine or nothing at all (the last group being “observed controls”). They didn’t know which group they were in, and neither did the researchers. One year later, the results were announced: the vaccine was safe and effective. In the decades since, the vaccine has come very close to completely eradicating polio from the planet.

Another example of clinical trials in the development of vaccines are the trials that went into testing the measles vaccine that used the Edmonston strain of measles. (Named after David Edmonston, who recently talked to the Washington Post about his experience.) The researchers went to the Walter E. Fernald State School near Waltham, Massachusetts, a school for special-needs students. Even though the ethics standards of the time did not require it, physician Samuel Katz explained the risks and benefits of the vaccine to the parents of the children. (The researchers had already vaccinated themselves to check for ill effects after they saw none in the lab monkeys.)

With the parents’ approval, Dr. Katz and his team vaccinated children at the school. Over the next few days, blood samples and throat swabs were taken from the vaccinated children. Although the vaccine had a live, attenuated virus in it, no virus was recovered from the blood or the throats (measles is a respiratory infection) of the children. The children did, however, have an immune response to the vaccine. Armed with that evidence, similar trials were done in other parts of the United States. The researchers then waited to see if any of the vaccinated children developed measles, as was usually the case in the late 1950s and early 1960s. None of them did, pointing to the high efficacy of the measles vaccine we still see today.

See Dr. Katz talking about the vaccine trials in this video:

When Is an RCT Necessary?

Next, we need to understand when an RCT is necessary. In the case of the polio vaccine, it was necessary to know if the vaccine was better than what was available at the time to prevent polio, which was nothing at all. If there is already a known vaccine that is safe and effective, it is unethical to randomize children into an unvaccinated group because we would be denying them the benefits of being vaccinated. Furthermore, parents who are against vaccination would likely not allow their children to be randomized into a vaccinated group, leading to bias in the understanding of the results. Finally, parents who are not likely to see a physician – and instead opt for Supplements, or Complementary and Alternative Medicines – would probably not bring a child with an infection to a physician, further biasing the results of a study.

Other Types of Studies That Are Just as Informative

When an RCT is not ethical, the field of epidemiology does allow other studies that are just as powerful in identifying statistically significant (of clinically impressive) differences between vaccinated and non-vaccinated children. These include cohort studies, where researchers follow a cohort of children over time. All children are born unvaccinated, and then the researchers note when children are vaccinated (if they are vaccinated at all). The researchers then note any illnesses or syndromes and compare the rate between vaccinated and non-vaccinated children. This is the design behind the recent (and rather large) Danish study on the association between the MMR vaccine and autism. That study found no association between the MMR vaccine and autism, like so many other studies have done.

Another study is a case-control study, the study design most often used in outbreak investigations. In this study design, cases of sick children are compared with healthy children (controls). The odds of being vaccinated given that a child is sick or not sick are calculated and compared between the two groups. If the odds of being sick in the outbreak setting are higher for a vaccinated child (or that a child who is sick has higher odds of being vaccinated), then we have a problem and all sorts of measures are taken to find out what is going on. This design has been used to assess vaccine efficacy, effectiveness and safety. It does, however, suffer from the problem that it is hard to know which came first, the exposure (vaccine) or the disease. Case-control studies can only show an association between the two factors, not a causal relationship.

Who Conducts This Research?

The universe of people and organizations monitoring vaccine safety is rather large. It includes the manufacturers of the vaccine, as they want to make sure their product is safe since it would fall out of favor by consumers (and banned from use by the government) if it wasn’t. Competing manufacturers keep an eye on the safety and efficacy of their own competitors’ vaccines, since an opportunity to put to market their own product would arise if their competitors’ products were not as effective and safe as stated. Then there are the government agencies like the FDA and CDC who are charged with protecting the public’s health. Of course, one cannot forget the state and local health departments that also monitor the health of the public. Then there are healthcare institutions that have analyze their own data and would detect an aberration. Next are academic researchers who analyze data or conduct their own studies on vaccine safety and effectiveness. Finally, there are the dedicated healthcare providers (physicians, physician assistants, nurses and others) who treat children. Many of them have not seen a case of measles, mumps or polio in their entire careers because vaccines have done such a good job at reducing the incidence of those diseases that were once common.

Conclusion

That universe is made up of millions of people, all working every day in the trenches of public health and medicine. They know firsthand what vaccines can do for a population, and how now more than ever vaccines are safe. They also know that a randomized clinical trial for vaccines that we know work would not be ethical if it used a saline placebo that would leave a child susceptible to a deadly disease. This is why we don’t see such studies today like we did in the 1950s and 1960s. Yet we might see such studies if an HIV or malaria vaccine is developed. The misinformation talking point that there were no RCTs conducted in the testing of vaccines for safety, efficacy and effectiveness can be easily refuted just by looking back at history. There are plenty of documented trials out there… One just needs to look at reliable sources.

Author: René F. Najera, DrPH

I am the editor of the History of Vaccines site, an online project by the College of Physicians of Philadelphia. All opinions expressed on these blog posts are not necessarily those of the College or any of my employers. Check out my professional profile on LinkedIn: https://www.linkedin.com/in/renenajera Feel free to follow me on Twitter: @EpiRen

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