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The Theory and Definitions of Drug Safety (Pharmacovigilance)
What is an adverse event (AE)? A serious AE? An adverse drug reaction (ADR)? A suspected adverse drug reaction (SADR)? A suspected, unexpected, serious adverse reaction (SUSAR)? A suspected, expected, serious adverse reaction? What do expected and unexpected mean?
Note: Unless otherwise noted, the words “drug” or “drug product” should be taken in this book to include “biologics” and “vaccines” too.
The Theory
There have been many variants on the terms and definitions used to talk about safety issues over the years. The terminology is somewhat confusing and is explained below.
The “official” and accepted definitions in most countries are based on the International Conference on Harmonization (ICH) E2A Guideline and are as follows:
Adverse Event—ICH
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment (ICH E2A).
Any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of any dose of a medicinal product, whether or not considered related to the medicinal product (ICH E2A).
Adverse Event/Adverse Experience—EMA
Any untoward medical occurrence in a patient or clinical-trial subject administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment (Article 2(m) of Directive 2001/20/EC). An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product (EMA, Volume 9A).
Adverse Experience/Event—FDA
The FDA uses the term adverse event/experience and defines it as follows for postmarketing cases:
Any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action (21CFR314.80(a)).
For clinical trial cases, FDA revised the definition effective March 2011 to read as follows (21CFR312.32):
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.
In practice most people use the term adverse event (AE) to refer to any “bad thing” that occurs during the use of a drug without implying that the bad thing is due to the drug. The bad thing may be due to the drug substance, excipients, packaging, or storage issues, and may or may not be due to the active ingredient.
Adverse Reaction
In the preapproval (i.e., not yet marketed, experimental) phase of a product, the definition is as follows: “All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.” This means “that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out” (ICH E2A).
For postapproval (i.e., marketed) products, the definition is as follows: “A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function” (ICH E2A).
Note that this is one of the few areas where the preapproval definition is different from the marketed definition. The issue here revolves around implied causality (see Chapter 13).
Serious Adverse Event and Serious Adverse Reaction
A serious adverse event (experience) or serious adverse reaction is any untoward medical occurrence that at any dose:
- Results in death
- Is life-threatening
Note: The term life-threatening in the definition of serious refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe:
- Requires inpatient hospitalization or prolongation of existing hospitalization
- Results in persistent or significant disability/incapacity or
- Is a congenital anomaly/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse (ICH E2A).
The Food and Drug Administration (FDA) (21CFR312.32, 21CFR314.80(a)) and EMA (Volume 9A and 10) definitions are similar but do differ somewhat. Note that an event or reaction may meet one or more of the criteria for seriousness simultaneously. Only one is needed, however, to consider the event or reaction to be serious. For an individual case safety report (ICSR) to be serious, it takes only one serious AE out of all the AEs present. To be a nonserious ICSR, all the AEs must be nonserious.
FDA’s definition of “serious” for clinical trials (21CFR312.32(a)):
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
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