By Linnea Anderson, chief of staff with the UMN Human Research Protection Program
We find ourselves at a time when public trust in experts and science is at a low point, even though our health and well-being is dependent upon them. Now more than ever we need to increase the public’s understanding of how human subjects research is conducted and the processes in place to evaluate the safety and efficacy of new drugs and vaccines. Plain-language explanations of these processes and the protections in place in federal regulations may help the public make informed decisions about their health.
One thing that is critical for the public to understand is the difference between and the overlap of research and clinical care. These lines, which can get blurred under normal circumstances, can become even more so when we are confronted by a new health threat for which there is no known cure, treatment, or vaccine. In such situations, physicians may use any Food and Drug Administration (FDA) approved drug to treat their patient if deemed appropriate.
Early in the COVID-19 pandemic, hydroxychloroquine, a drug used to treat malaria, lupus, and arthritis, was considered potentially promising to treat and possibly prevent COVID-19 infection. Some of those patients who were prescribed hydroxychloroquine got better and some who were taking the drug as a prevention measure did not contract COVID-19. On June 15, the FDA announced that hydroxychloroquine “showed no benefit for decreasing the likelihood of death or speeding recovery.” How did we come to know that hydroxychloroquine was not as effective as initially hoped? Answering this question requires some knowledge of how clinical trials are conducted.
How Clinical Trials Test Drugs
To know whether a drug causes a desired outcome, researchers must achieve a consistent result in testing while controlling for other variables. Clinical trials employ several techniques designed to isolate the effect of a drug under evaluation. Researchers develop a protocol to define as precisely as possible how the research will be conducted so that the effect of the drug can be isolated and observed. Many factors may make it difficult to interpret whether a good or bad outcome was related to the drug and not to some other factor.
Common techniques used in clinical studies include control groups, placebos, randomization, and blinding. Participants in a control group will not receive the drug under study (but may receive an approved drug or a “fake” drug called a placebo) so that researchers can compare their outcomes to those who do receive the drug. Randomization means the selection of participants who will and will not receive the study drug is determined by chance, not by the participant, researcher, or a doctor. The term “blinding” is used when the participant doesn’t know whether they have received the experimental drug or not, and in “double blinded” studies neither the participant nor the researcher knows who has received the drug under study.
Clinical Trials Are Not Clinical Care
When someone agrees to participate in a clinical trial, they are agreeing to receive treatment as defined in the protocol and the researcher is committing to delivering that treatment according to the protocol. This highlights the most significant difference between clinical care and research.
The purpose of clinical care is to improve health or relieve suffering. Choices made about a patient’s care outside of a research study are determined by employing the best known interventions to treat a condition. Based on how the patient is responding, a physician may modify, start, or stop a course of treatment.
When someone agrees to participate in research, however, the primary purpose is to answer a research question. The treatment they receive will be determined by strictly following the protocol. In fact, some participants may experience worse outcomes than those not participating in the research. This is not uncommon and is a part of the research process. One potential result of research is determining a drug or intervention as prescribed does not work even when there were good reasons to believe it might have.
If a physician prescribed hydroxychloroquine to a patient with COVID-19 and the patient recovered, we are conditioned to believe that the drug caused the effect, even though some people recover from COVID-19 without that treatment. Because there was reason to believe hydroxychloroquine could be effective, the FDA issued an emergency use authorization (EUA). An EUA allows an unapproved medical product or an unapproved use of an approved medical product to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions for which there are no adequate, approved, and available alternatives.
Believing hydroxychloroquine is effective is not the same as proving it to be so. Emergency use lacks the controls and protections against bias that research provides, so it cannot move us from suspecting, believing, or wanting something to be true to actually proving that it is. Through the conduct of large, randomized clinical trials, evidence suggested that hydroxychloroquine may not be as effective as hoped and had the potential to cause very serious side effects (though hydroxychloroquine is still under study, the FDA revoked its EUA of the drug on June 15).
To learn this, very sick people (or their loved ones) had to agree to participate in the trial and allow elements of their treatment to be left to chance. Those who participated had to accept that, while they may not receive a drug that might benefit them, their participation would advance our knowledge about COVID-19 and potential treatments.
While some people approached to participate in research may consider their participation a selfless act that increases our knowledge of how best to treat others in the future, others may feel vulnerable, scared, or like they lack other treatment options. For this reason, there are many protections in place to ensure people are fully informed about their decision, that they are not coerced into participation, and that the risks of their participation are appropriate given the benefit that might be gained.