Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
jurisdiction before any product is used or prescribed. Because standards for usage change, it is advisable to keep abreast of revised recommendations, precautions, safety warnings, and adverse events, particularly those concerning new products.
This book is not intended to express opinions about the value of specific products or their comparative value within a drug class, even when a specific product is used to provide examples of adverse reactions. The content of this book is not meant to be used in choosing therapies in medical practice by healthcare practitioners or consumers. As with all medications and therapies, the official approved product labeling should be consulted before prescribing or using.
And finally, this manual is not meant to be a comprehensive drug development guide. We have given our opinions on many areas of safety in drug development and marketing but things change daily. Check many sources. Trust but verify. Good luck!
CHAPTER
1
The Theory and Definitions of Drug Safety — Pharmacovigilance
W hat 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.
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:
Adverse Reaction (AR)
Synonyms: