A new report today, which came to me via my news aggregator, reports that trial participants, in two important and ongoing SARS-COV2 vaccine trials have experienced “serious side effects”. This is an opportunity for me to explain how using the right words, especially in the context of science, medicine, and the media (and investing!) is important.
In conducting clinical trials, we do not use the phrase “side effect”. I suspect the reason for this is that the phrase connotes that trial participants have experienced something that was caused by the experimental therapeutic (ET) but is not part of its intended action. Neither of these conclusions are ever warranted in an ongoing clinical trial, especially when the ET has not yet been approved and therefore is not fully investigated. Instead, when something pejorative happens to a study participant we say that the person experienced an “adverse event”. This term does not imply anything about causation.
An “adverse event” in a clinical trial, also called an adverse experience, is defined by international agreement as “any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the use of a drug, without any judgment about causality or relationship to the drug” (https://www.fda.gov/media/93884/download). Note that no relationship with the ET is implied. During the trial, the clinical investigator will render an opinion about a potential relationship but this issue cannot be decided until the data are “unblinded”, that is the trial is over and it can be revealed who received the ET and who received placebo. For example, if a higher proportion of people who received the ET than those that received placebo develop a headache, then it might be that the fever was caused by the ET.
The severity of adverse events (AEs) that occur during a trial are graded. That is, when they occur they are rated as to whether they are mild, moderate, or severe, and/or they may be graded on a scale of 1-5. A mild or moderate AE might be a 1 or a 2, while a severe AE might be a 3. A severe AE is bad enough to interrupt a person’s daily activities and may require the administration of a medicine or even a visit to a doctor.
A “serious adverse event” or SAE has a specific definition. They include events that are, require, or result in:
- Life-threatening
- Hospitalization (initial or prolonged)
- Disability – significant, persistent, or permanent change, impairment, damage or disruption in the patient’s body function/structure, physical activities or quality of life.
- Congenital anomaly
- Requires intervention to prevent permanent impairment or damage
Of course, death (graded as a 5) is also an SAE.
Here comes the part where I explain the importance of precision in language. While the words “severe” and “serious” appear to be interchangeable, they are not. The difference can be best illustrated by a common example. A study participant might experience a very bad headache for which medicine is needed to alleviate the pain and which makes it impossible for the person to work, play, or, in general, function for a period of time. That is a severe headache. However, a headache can be something else entirely. For example, a headache can be a sign of a stroke, or a subdural hematoma, an event that can be life-threatening and requires hospitalization. That headache would represent an SAE (grade 4). Yes, it is true that if such a diagnosis is made that the event would no longer be called a headache but rather a stroke or a subdural, but you get the idea. Another example: a fever of 103o Frequire a Tylenol and some rest for a few hours (severe), or it may persist for days and require hospitalization (“serious adverse event”).
In the current example, study participants have developed fevers, some to 103o F, but they did not last and resolved relatively quickly. That is a severe AE, not an SAE, or a “serious side effect” as shouted out by the headline of this article. Even though the article is meant for lay people (and investors!) it give the wrong idea about the experiences of participants in the trials. Journalists must do better. They won’t do better until we hold them accountable.