Here is my argument. First, let's review some definitions.
The U.S. Code of Federal Regulations (21 CFR 312.32) defines an adverse event as
- any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.
Untoward is an adjective meaning unexpected, inappropriate, inconvenient. (Oxford Dictionary). Synonyms include inconvenient, unlucky unexpected, surprising, unusual.
A medical occurrence is more difficult to define. I take it to mean a medical condition: i.e. disease, disorder, injury, or transient physiological state that impairs or may impair health.
Taking all of this into consideration, my working definition of an Adverse Event is any unexpected medical condition (disease, disorder, injury, transient physiological state) that impairs or may impair health and emerges or worsens after a medical intervention (e.g. drug use).
Notice that I broaden the definition to medical interventions such as medical device use, or medical procedure, because AEs in those scenarios are equally relevant from a public health perspective.
With these definitions in mind, I think one of the pitfalls in causality assessments is wrong use of the term adverse event. I believe Adverse Events are medical conditions. Medical conditions fluctuate over time. An AE can remain stable, improve, or resolve over time. It can also worsen to the point where the patient dies. All of these are potential outcomes of an AE.
Here is a hypothetical case of crazy conclusions that can emerge if our definitions are not precise. Imagine that one is developing software to automate AE causality assessments.
Consider an 13 y/o male on chronic treatment with Drug X for seizures. Over the course of the year, he grew 4 inches and gained 25 lbs, yet his dose of anti-convulsant medications did not change to keep pace with his increased body mass. Towards the end of the year, he was having breakthrough seizures with a documented low therapeutic level of Drug X in his blood. A computer program may select the following concepts for further causality assessment:
Suspect Drug: Drug X
Adverse Events:
Seizures, Weight Gain
A computer program would look at this and ask did Drug X cause weight gain and seizures in this case? On a superficial level, it is a fair question since the subject was on Drug X when those events happened.
But wait a minute. A human assessor immediately recognizes the frivolity of such a question in this case. Clearly the growth and weight gain are consistent with puberty-associated growth spurt. The problem is the dose of Drug X wasn't increased in response to the increased body mass.
The fact that the causality question even arises is a misinterpretation of an Adverse Event. Applying our working definition of an AE, Seizure is not an Adverse Event in this case. It's in fact the Indication, a medical condition that is the target of a medical intervention (i.e. anticonvulsant therapy). But, you say, it's also a medical condition that worsened with treatment. The key here is that it didn't unexpectedly worsen. A sub-therapeutic dose of an anticonvulsant can be expected to result in breakthrough seizures.
How about weight gain? Again, this is not an AE. It's an observation, well technically it's an analysis of two (or more) observations, body weight, over time. Is it indicative of an AE? Not necessarily. In this case, it is the consequence of normal growth. Obesity, on the other hand, would be an AE depending on how it's defined. There is no evidence in this report of obesity.
So what is the causality assessment for this case? The assessment cannot be done. There is no adverse event.
Here's another case: A person takes Ambien, gets drowsy and drives a car and is involved in a motor vehicle accident.
Suspect Drug: Ambien
Adverse Event: Motor Vehicle Accident (MVA)
Based on our definition, an MVA is not an Adverse Event since it is not a medical condtion. The AE here is drowsiness. The MVA is a consequence/outcome of the AE.
So let's get back to death? It's commonly listed as an AE in safety reports. Is it a Medical Condition? No. Death marks the end of a complex physiologic process we call Life and it happens to all living organisms. Death (like an MVA, or a bad fall) is or may be a consequence/outcome of a Medical Condition. In the case of Death we call it the Cause of Death. The cause of death may or may not be an AE.
This reminds me of the clinical data lifecycle: Observations lead to Assessments/Adjudications to diagnose/assess Medical Conditions (including AEs) which leads to Interventions to (treat, mitigate, cure, prevent) those conditions, which leads to more Observations. In turn Medical Conditions have consequences/outcomes sometimes beyond our control, like Death (or Falls, or Motor Vehicle Accidents).
These information buckets are well established and distinct in clinical medicine. We save a lot of confusion and misinterpretation of clinical data when we classify them appropriately. We need to do a better job of distinguishing AEs from observations, and not confusing the consequence(s) of an AE from the AE itself. Recognizing this distinction is important to automate adverse event assessment, including those resulting in death.
But wait a minute. A human assessor immediately recognizes the frivolity of such a question in this case. Clearly the growth and weight gain are consistent with puberty-associated growth spurt. The problem is the dose of Drug X wasn't increased in response to the increased body mass.
The fact that the causality question even arises is a misinterpretation of an Adverse Event. Applying our working definition of an AE, Seizure is not an Adverse Event in this case. It's in fact the Indication, a medical condition that is the target of a medical intervention (i.e. anticonvulsant therapy). But, you say, it's also a medical condition that worsened with treatment. The key here is that it didn't unexpectedly worsen. A sub-therapeutic dose of an anticonvulsant can be expected to result in breakthrough seizures.
How about weight gain? Again, this is not an AE. It's an observation, well technically it's an analysis of two (or more) observations, body weight, over time. Is it indicative of an AE? Not necessarily. In this case, it is the consequence of normal growth. Obesity, on the other hand, would be an AE depending on how it's defined. There is no evidence in this report of obesity.
So what is the causality assessment for this case? The assessment cannot be done. There is no adverse event.
Here's another case: A person takes Ambien, gets drowsy and drives a car and is involved in a motor vehicle accident.
Suspect Drug: Ambien
Adverse Event: Motor Vehicle Accident (MVA)
Based on our definition, an MVA is not an Adverse Event since it is not a medical condtion. The AE here is drowsiness. The MVA is a consequence/outcome of the AE.
So let's get back to death? It's commonly listed as an AE in safety reports. Is it a Medical Condition? No. Death marks the end of a complex physiologic process we call Life and it happens to all living organisms. Death (like an MVA, or a bad fall) is or may be a consequence/outcome of a Medical Condition. In the case of Death we call it the Cause of Death. The cause of death may or may not be an AE.
This reminds me of the clinical data lifecycle: Observations lead to Assessments/Adjudications to diagnose/assess Medical Conditions (including AEs) which leads to Interventions to (treat, mitigate, cure, prevent) those conditions, which leads to more Observations. In turn Medical Conditions have consequences/outcomes sometimes beyond our control, like Death (or Falls, or Motor Vehicle Accidents).
These information buckets are well established and distinct in clinical medicine. We save a lot of confusion and misinterpretation of clinical data when we classify them appropriately. We need to do a better job of distinguishing AEs from observations, and not confusing the consequence(s) of an AE from the AE itself. Recognizing this distinction is important to automate adverse event assessment, including those resulting in death.
