The COVID-19 pandemic has set the stage for research and development of new treatments and vaccines targeting the SARs-COV2 virus. Amidst these discussions, the public may be hearing terms such as “randomized control trials” and “placebo control trials” and may not be certain what the terms mean or why they are important. This post will outline these terms and will discuss some of the ethical implications of placebo control trials in the context of vaccine development.
What do these different trials mean in practice?
A randomized control trial, also sometimes called a placebo control trial, means that people who consent and are enrolled in the study will be randomly placed into the group receiving the drug (or treatment; also called the intervention) being studied or into a group receiving a placebo (a saline solution, for example). The importance of this is that some portion of the people in the study are receiving essentially nothing in terms of a treatment while the other portion are. Scientists consider the randomized placebo control trial the gold standard of clinical research. The drug being tested is being compared to a placebo and thus any effects – both good and bad – observed in the group receiving the drug can be attributed, with high likelihood, to the drug.
What is the standard for an ethical research trial?
Emanuel et al. have outline 7 essential requirements for determining whether a clinical research trial is ethical: the social and/or scientific value of the study, scientific validity, fair participant selection, favorable risk-benefit ratio, independent review, informed consent, and respect for potential and enrolled participants. Any clinical research study must undergo a review by what is referred to as the Institutional Review Board, or the IRB (which is the independent review Emanuel et al. refer to). This independent review is designed to protect the safety of the individuals who will participate in the study.
An important component of the review is a risk-benefit analysis. The level of risk that is acceptable may be above minimal risk depending on the nature of the study. For example, some individuals first enrolled in human drug studies may pose above minimal risk to those participants. Here, there is every effort to enhance the potential benefits to the participant and to society. In these instances the informed consent process must clearly outline what these risks might be so that potential participants can make informed, deliberate decisions about their participation.
Over the years there have been questions raised about the ethics of placebo control trials. The concern is that the people in the placebo control arm are not receiving the treatment. This, of course, is not an issue when there is no treatment available. Another instance in which using placebo poses no ethical concerns is when the new treatment is being tested with patients who are non-responsive to standard of care. For these patients the existing treatment (standard of care) is ineffective. When there is a treatment available, and the study participants are responsive to it, the notion of denying people any type of treatment (standard of care or the new treatment being study) seems ethically problematic.
Some have argued that even when a treatment exists, it may be acceptable to use placebo controls for studying a new treatment if research participants are not exposed to irreversible harm. They may be exposed to less serious risks of symptoms and lasting harm for short time frames, if the study design and conduct meet strict ethical standards and guidelines. These strict ethical standards and guidelines include that the trials must have scientific and clinical merit; risks are minimized and justified by anticipation of generating scientific knowledge and possible expected benefits to participants; informed consent is obtained from study trial volunteers; and short-term individualized treatment optimization to volunteers is offered, as appropriate, at completion of research participation.
What happens in the context of COVID-19 vaccine trials?
A question that has arisen in the context of the COVID-19 vaccine clinical trials is whether those in the placebo arm of the trials should be offered the vaccine right now. The argument is that they participated in the trial and in essence earned the benefit of being vaccinated. These individuals would receive the vaccine regardless of where they fall in the established prioritized schema of vaccine distribution that have been developed by for example, the Advisory Committee on Immunization Practices to the Centers for Disease Control and Prevention.
There are opponents to this, however. They argue that there is still much to be learned from the placebo control trial. To no longer have the placebo arm, which is what would happen if participants in that arm were vaccinated, would mean we would lose valuable long term data about the vaccine. In addition, they also state that health equity and health risks need to be considered. The vaccine distribution prioritization that the Advisory Committee on Immunization Practices has created is based on ethical frameworks that incorporate notions of equity and risk. To go outside of the prioritization would compromise the careful deliberation that went into creating an ethical and equitable distribution plan.
An aspect that goes into this thinking is that continuing in the trial in the placebo arm does not pose any additional risk to the individual participants because they would not be eligible to be vaccinated outside of the trial. Of course, if they were eligible to be vaccinated outside of the trial, that is their prioritization group was up for receiving the vaccine, then continuing in the trial would pose additional risk, and they can withdraw from the trial, should they choose to do so.
A second question that has arisen in the context of the vaccine trials is whether it is ethical to have a placebo group now that at least two of the vaccines are in use. Risk to the participants is of course important to consider as is the social value of conducting the placebo control trial. For individuals who are at low risk to getting COVID-19 and are not able to be vaccinated outside of the trial, the risk to being in the placebo arm would not be any more than if they were not participating in the trial. And there is notable social value from the data collected from the well-designed randomized placebo control trials.
Going forward, it is likely that discussions about the ethics of placebo control trials will continue. It is important to know what it means to be in a placebo control trial and to understand the nuances of the debates. Most important, if one is considering enrolling in any clinical trial, regardless of whether it is placebo control or not, it is important to be clear about the risks and benefits and what exactly the trial entails.