Editor’s Note: This will be the last month that Sharon Humiston, MD, MPH, FAAP, from Immunize.org will be authoring the “Technically Speaking” column. We wanted to take this opportunity to thank Sharon for her important and timely contributions and for her friendship.
On May 1, The New York Times reported the following:Health Secretary Robert F. Kennedy Jr. on Thursday announced plans to require all new vaccines to be tested against placebos…A spokesman for the Department of Health and Human Services called the requirement for placebo testing “a radical departure” from existing standards. But that will depend on how the department defines “new,” because most new vaccines are already tested either against placebos — inert substances — or, in some cases, against vaccines for other diseases.
We interviewed John D. Gräbenstein, RPh, PhD, a pharmacist who has specialized in vaccines since 1983. Over the decades, his work with the U.S. Army and various vaccine developers gave him insights into the regulatory and communication aspects of vaccinology. We asked Dr. Gräbenstein to help us better understand the heritage of testing vaccines in comparison to various placebos. Our conversation has been edited for length and clarity.
Please describe the testing vaccines undergo before they come into widespread use in the United States.
Before any vaccine can be widely used, we need to know if it is safe and if it provides any protective value (“efficacy”). This takes the form of phase 1, phase 2, and phase 3 studies. Testing vaccines against comparison products in phase 3 studies has been the norm with vaccines licensed in the U.S., and around the world, for the last 75 years.
When vaccines are tested, outcomes in a vaccinated group are compared to outcomes in an unvaccinated group. The most scientifically convincing studies can be described as “randomized, double-blinded, placebo-controlled” studies. Each of those terms has a specific meaning.
- Randomized: Participants are assigned to the experimental (e.g., vaccinated) or control (e.g., unvaccinated) group randomly. Whether someone ends up in the experimental group is like the flip of a coin.
- Double-blinded: The process of assigning participants to groups and following them throughout the study is done in a way that neither the investigators nor the participants know whether they are in the vaccinated or unvaccinated group.
- Placebo-controlled: For decades, U.S. law has required vaccines (and all other medications) to be tested in a manner that enables us to learn about the intervention, such as by comparing the potential product (i.e., vaccine) against a placebo. This allows the effects of the potential product to be compared to unrelated events that may happen randomly.
Please explain what exactly is in the placebo.
There are several valid options when choosing a placebo:
- Saline (or salt) solution may be used. A 0.9% solution of sodium chloride (also known as normal saline or physiologic saline) has the same osmotic pressure as human tissue fluids and blood. The poliovirus vaccine trial conducted by Jonas Salk in 1954, one of the most famous vaccine studies of all time, administered a saline placebo to the control group.
- A liquid that differs from the vaccine only in the antigenic content (that is, the part that evokes a specific immune response) may serve as a placebo. For example, a candidate vaccine containing an adjuvant, a component that helps increase a protective immune response, may be compared to a solution that contains only the adjuvant. This option may be chosen if the adjuvant is known to cause injection-site side effects, such as a sore arm. A benefit of this approach is to observe adverse reactions due to the antigenic content in addition to what the adjuvant itself would induce.
In the United States, are vaccine studies ever performed without using a placebo in the control arm of the study?
Yes, there are several ways this may be done. These studies are still robust, randomized, double-blinded studies, but the comparison may be a previously tested product to ensure the study is ethical. The comparison product can take several forms, depending on situational considerations.
- An alternate vaccine: A vaccine that protects against a different disease may serve as the control intervention. This is known as an “active control.” This option may be chosen so that every study participant can benefit from their participation in the study. Such an option may be preferred in low-resource countries to ensure ethical participation. An example would be evaluating an investigational cholera vaccine against a licensed typhoid fever vaccine.
- An earlier or existing version of the vaccine: When a vaccine is already widely accepted as a standard of care, there are challenges when trying to improve on the existing product. When testing a newer version — either a possibly improved version by the same manufacturer or an existing version of another brand, it would be unethical for participants randomly assigned to the control arm to be denied vaccination and, thus, denied protection against a potentially deadly infection. Examples here include the pneumococcal vaccines with broader serotype content. For these vaccines, participants in the studies received a previously licensed vaccine or the newer vaccine.
- The same vaccine, delayed in time: In unusual circumstances, researchers may use other options to make the study well controlled. For example, after initial safety testing, an Ebola vaccine trial used a time-delayed vaccination group for comparison, because the researchers considered it unethical to have a group that did not receive potential protection against such a dangerous pathogen.
Who decides what control intervention would be used in a pre-licensure vaccine trial?
The FDA and the vaccine developer agree together before the study begins regarding the study design. The choice of comparator depends on what is already known, what the specific goals of the study are, and what is ethical. In this way, we can continue to study new vaccines even when a placebo group may not be a feasible option.
Please share any good references you have for people who want to read more about use of placebos and other controls in vaccine testing before licensing.
- Vaccine Science: Process of Vaccine Development
- The Saline Placebo Pyramid
- Randomized Clinical Trials for Vaccine Safety, Efficacy and Effectiveness
- Debunking myths about vaccine testing and safety
- Controlled Vaccine RCTs (Living List)
Contributed by: Sharon G. Humiston, MD, MPH, FAAP
Editor’s Note: This will be the last month that Sharon Humiston, MD, MPH, FAAP, from Immunize.org will be authoring the “Technically Speaking” column. We wanted to take this opportunity to thank Sharon for her important and timely contributions and for her friendship.
On May 1, The New York Times reported the following:Health Secretary Robert F. Kennedy Jr. on Thursday announced plans to require all new vaccines to be tested against placebos…A spokesman for the Department of Health and Human Services called the requirement for placebo testing “a radical departure” from existing standards. But that will depend on how the department defines “new,” because most new vaccines are already tested either against placebos — inert substances — or, in some cases, against vaccines for other diseases.
We interviewed John D. Gräbenstein, RPh, PhD, a pharmacist who has specialized in vaccines since 1983. Over the decades, his work with the U.S. Army and various vaccine developers gave him insights into the regulatory and communication aspects of vaccinology. We asked Dr. Gräbenstein to help us better understand the heritage of testing vaccines in comparison to various placebos. Our conversation has been edited for length and clarity.
Please describe the testing vaccines undergo before they come into widespread use in the United States.
Before any vaccine can be widely used, we need to know if it is safe and if it provides any protective value (“efficacy”). This takes the form of phase 1, phase 2, and phase 3 studies. Testing vaccines against comparison products in phase 3 studies has been the norm with vaccines licensed in the U.S., and around the world, for the last 75 years.
When vaccines are tested, outcomes in a vaccinated group are compared to outcomes in an unvaccinated group. The most scientifically convincing studies can be described as “randomized, double-blinded, placebo-controlled” studies. Each of those terms has a specific meaning.
- Randomized: Participants are assigned to the experimental (e.g., vaccinated) or control (e.g., unvaccinated) group randomly. Whether someone ends up in the experimental group is like the flip of a coin.
- Double-blinded: The process of assigning participants to groups and following them throughout the study is done in a way that neither the investigators nor the participants know whether they are in the vaccinated or unvaccinated group.
- Placebo-controlled: For decades, U.S. law has required vaccines (and all other medications) to be tested in a manner that enables us to learn about the intervention, such as by comparing the potential product (i.e., vaccine) against a placebo. This allows the effects of the potential product to be compared to unrelated events that may happen randomly.
Please explain what exactly is in the placebo.
There are several valid options when choosing a placebo:
- Saline (or salt) solution may be used. A 0.9% solution of sodium chloride (also known as normal saline or physiologic saline) has the same osmotic pressure as human tissue fluids and blood. The poliovirus vaccine trial conducted by Jonas Salk in 1954, one of the most famous vaccine studies of all time, administered a saline placebo to the control group.
- A liquid that differs from the vaccine only in the antigenic content (that is, the part that evokes a specific immune response) may serve as a placebo. For example, a candidate vaccine containing an adjuvant, a component that helps increase a protective immune response, may be compared to a solution that contains only the adjuvant. This option may be chosen if the adjuvant is known to cause injection-site side effects, such as a sore arm. A benefit of this approach is to observe adverse reactions due to the antigenic content in addition to what the adjuvant itself would induce.
In the United States, are vaccine studies ever performed without using a placebo in the control arm of the study?
Yes, there are several ways this may be done. These studies are still robust, randomized, double-blinded studies, but the comparison may be a previously tested product to ensure the study is ethical. The comparison product can take several forms, depending on situational considerations.
- An alternate vaccine: A vaccine that protects against a different disease may serve as the control intervention. This is known as an “active control.” This option may be chosen so that every study participant can benefit from their participation in the study. Such an option may be preferred in low-resource countries to ensure ethical participation. An example would be evaluating an investigational cholera vaccine against a licensed typhoid fever vaccine.
- An earlier or existing version of the vaccine: When a vaccine is already widely accepted as a standard of care, there are challenges when trying to improve on the existing product. When testing a newer version — either a possibly improved version by the same manufacturer or an existing version of another brand, it would be unethical for participants randomly assigned to the control arm to be denied vaccination and, thus, denied protection against a potentially deadly infection. Examples here include the pneumococcal vaccines with broader serotype content. For these vaccines, participants in the studies received a previously licensed vaccine or the newer vaccine.
- The same vaccine, delayed in time: In unusual circumstances, researchers may use other options to make the study well controlled. For example, after initial safety testing, an Ebola vaccine trial used a time-delayed vaccination group for comparison, because the researchers considered it unethical to have a group that did not receive potential protection against such a dangerous pathogen.
Who decides what control intervention would be used in a pre-licensure vaccine trial?
The FDA and the vaccine developer agree together before the study begins regarding the study design. The choice of comparator depends on what is already known, what the specific goals of the study are, and what is ethical. In this way, we can continue to study new vaccines even when a placebo group may not be a feasible option.
Please share any good references you have for people who want to read more about use of placebos and other controls in vaccine testing before licensing.
- Vaccine Science: Process of Vaccine Development
- The Saline Placebo Pyramid
- Randomized Clinical Trials for Vaccine Safety, Efficacy and Effectiveness
- Debunking myths about vaccine testing and safety
- Controlled Vaccine RCTs (Living List)
Contributed by: Sharon G. Humiston, MD, MPH, FAAP