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CHAPTER
1
The Theory and Definitions of Drug Safety — Pharmacovigilance
What is an adverse event (AE)? A serious AE (SAE)? An adverse drug reaction (ADR)? A suspected, unexpected, serious adverse reaction (SUSAR)? A suspected, expected, serious adverse reaction? What do expected, unexpected, listed and unlisted mean?
Note: Unless otherwise noted, the words “drug” or “drug product” or “medicinal 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. Pharmacovigilance terminology and related initialisms are somewhat confusing; commonly used terms are explained below. Table 1 contains a list of associated initialisms. For a more extensive listing of initialisms used in pharmacovigilance, see the Acronyms section of this manual.
The “official” and accepted definitions in most countries are based on the International Conference on Harmonization (ICH) E2A Guideline and are given in the following sections. Note that the ICH changed its name to International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use in 2015. They still refer to it as ICH.
Adverse Event (AE) — 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).
Table 1. Selected Initialisms and Acronyms Used in this Manual
| Initialism | Interpretation |
| AE | Adverse Event, sometimes Adverse Drug Event (ADE) or, for FDA, also means Adverse Experience |
| API | Active Pharmaceutical Ingredient |
| AR | Adverse Reaction, sometimes Adverse Drug Reaction (ADR) |
| CCSI | Company Core Safety Information |
| CFR | Code of Federal Regulations, for US |
| DCSI | Development Core Safety Information |
| GVP | Good Pharmacovigilance Practice, for Post-marketing in the EU |
| ICH | International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (formerly International Conference on Harmonization) |
| IME | Important Medical Event |
| SAE | Serious Adverse Event |
| SAR | Suspected Adverse Reaction, sometimes Serious Adverse Reaction |
| SADR | Serious Adverse Drug Reaction, sometimes Suspected Adverse Drug Reaction, neither of which is currently in common use |
| SUSAR | Serious Unexpected Suspected Adverse Reaction, used in the EU trials and outside the US; similar in concept to FDA’s Suspected Unexpected Serious Adverse Reaction (no initialism for FDA) |
| NSAE | Non-serious Adverse Event |
| NSAR | Non-serious Adverse Reaction |
Adverse Event (AE) — 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 AE can therefore be any unfavorable 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, Good Pharmacovigilance Practices Annex I Definitions) (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143294.pdf).
In the context of pharmacovigilance and outside a clinical trial, any untoward medical occurrence in a patient to whom a medicinal product is administered and which does not necessarily have a causal relationship with this treatment.
Adverse Event/Experience (AE) — FDA
The FDA uses the term adverse event/experience and defines it as follows:
For post-marketing cases: Any AE associated with the use of a drug in humans, whether or not considered drug-related, including the following: An AE occurring in the case of the use of a drug product in professional practice; an AE occurring from drug overdose whether accidental or intentional; an AE occurring from drug abuse; an AE occurring from drug withdrawal; and any failure of expected pharmacological action (21CFR314.80(a)).
For clinical trial cases: 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 “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, storage issues or other problems and may or may not be due to the active ingredient.
Adverse Reaction (AR)
Synonyms: Adverse drug reaction (ADR), Suspected adverse (drug) reaction or serious adverse reaction (SAR), Adverse effect, Undesirable effect (see EMA GVP Module Annex 1 Definitions).
For
pre-approval (i.e., not yet marketed, experimental) products, 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
post-approval (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)
EMA (GVP Module Annex I Definitions): A response to a medicinal product which is noxious and unintended. Response in this context means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility (see GVP Annex I). An adverse reaction, in contrast to an AE, is characterized by the fact that a causal relationship between a medicinal product and an occurrence is suspected. For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated by the healthcare professional or consumer as the primary source, it meets the definition of an adverse reaction.
Therefore, all spontaneous reports notified by healthcare professionals or consumers are considered suspected adverse reactions, since they convey the suspicions of the primary source, unless the primary source specifically states that they believe the event to be unrelated or that a causal relationship can be excluded.
Serious Adverse Event and Serious Adverse Reaction (SAE/SAR)
A key difference between an “AE” and an “AR” is the concept of causality. An “event” is merely something “bad” that occurs, but a “reaction” captures the concept of a relationship between the event and drug exposure.
A serious AE (experience) or serious AR is any untoward medical occurrence that at any dose:
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 (IMEs) 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 EMA considers any suspected transmission via a medicinal product of an infection agent to be a serious adverse reaction.
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 non-serious ICSR, all the AEs must be non-serious.
FDA’s definition of a serious event or reaction for clinical trials (21CFR312.32(a)) is as follows:
An AE 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 AE, 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.
FDA’s definition of a suspected adverse reaction for clinical trials is as follows:
Any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
Non-serious Adverse Event and Non-serious Adverse Reaction (NSAE/NSAR)
An event or reaction is non-serious when it does not meet any of the criteria for seriousness.
Suspected Adverse (Drug) Reaction (SAR/SADR) — FDA
This includes any AE for which there is a reasonable possibility that the drug cau...
