Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition). William Gregory
for serious and expected. The FDA does not define this phrase in 21CFR312.32(a) or use this phrase formally for cases, though application of the concept is similar and relevant.
Unexpected Adverse Event — FDA
Pre-marketing: “Unexpected” as applied to clinical trials is defined by FDA in 21CFR312.32(a): An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed, or if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral vascular accidents. “Unexpected”, as used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
Post-approval (Marketed) Products: This takes account of any adverse drug experience that is not included in the current labeling (Package Insert or Summary of Product Characteristics (SmPC)) for the drug product. This includes events that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differ from the event because of greater severity or specificity. FDA provides an example in 21CFR314.80(a): Hepatic necrosis would be unexpected (by virtue of greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis.
AEs that are considered “class-related” (i.e., allegedly seen with all products in this class of drugs) and are mentioned in the labeling (Package Insert or SmPC) or investigator brochure but are not specifically described as occurring with this product are considered unexpected.
Unexpected Adverse Reaction — EMA
An adverse reaction, the nature, severity or outcome of which is not consistent with the Summary of Product Characteristics (SmPC) (Article 1(13) of Directive 2001/83/EC67). This includes class-related reactions which are mentioned in the SmPC but which are not specifically described as occurring with this product. For products authorized nationally, the relevant SmPC is that approved by the Competent Authority in the Member State to whom the reaction is being reported (often in the local language). For centrally authorized products, the relevant SmPC is the SmPC authorized by the European Commission. During the time period between a CHMP Opinion in favor of granting a marketing authorization and the Commission Decision to grant a marketing authorization, the relevant SmPC is the SmPC annexed to the CHMP Opinion (EMA GVP Module Annex I definitions).
These adverse reactions, when the SmPC is used as the reference document, are referred to as unlabeled. This is quite different from unlisted (see below).
Note: For products registered in the EU, the EU SmPC is the single document to consider, even for clinical trial ICSRs; the investigator brochure is the reference document for clinical trial ICSRs, but only if the product is not registered.
Unlisted Adverse Reaction — EMA
An adverse reaction that is not specifically included as a suspected adverse effect in the Company Core Safety Information (CCSI). This includes an adverse reaction whose nature, severity, specificity or outcome is not consistent with the information in the CCSI. It also includes class-related reactions which are mentioned in the CCSI but which are not specifically described as occurring with this product (GVP Annex IV, ICH-E2C(R2).
Expected (Listed versus Labeled)
As opposed to “unexpected”, “expected” refers to an event that is noted in the investigator brochure or labeling (Package Insert or SmPC). One complication is that two different reference documents (labels) are available for marketed drugs for expectedness. One is the regulator-approved prescribing information (e.g., Package Insert or SmPC, etc.), which may vary from jurisdiction to jurisdiction, and the other is the company’s core safety information (CCSI). The latter is provided to regulators, but it is a company-driven document that does not ordinarily need approval by regulators. Usually, these are quite similar if not identical, but not always. The CCSI contains the company position on the minimum safety information that should be in every regulator-approved label wherever the product is authorized for marketing. An event/reaction not found in the CCSI may be included in the regular-approved label, but not vice-versa. If the event/reaction is not found in the SmPC, it is considered unlabeled. If it is not found in the core labeling, i.e., the product’s CCSI, it is unlisted. If it is not found in the PI or SmPC, etc. it is unlabeled. The CCSI is used to determine “listedness” for periodic aggregate reports in the post-marketing phase.
Thus, an event in the United States is expected or unexpected depending on whether it is found in the reference safety information (RSI): the investigator’s brochure for unapproved products or the FDA-approved labeling for marketed products. In the European Union, it is the same for unapproved products, but for marketed products, an unexpected event/reaction may be unlabeled (not in the SmPC) or unlisted (not in the CCSI).
In practice, these definitions are rather murky and confusing. They also change periodically. For a good summary of post-marketing pharmacovigilance definitions used in the EU (and often elsewhere), see the GVP Annex I Definitions, referenced above. This is a comprehensive document with definitions from the EMA. They are very similar to the FDA definitions.
AEs are unintended “bad things” that occur when taking a drug (or biologic or vaccine, etc.). They may or may not be due to the drug itself (the “active moiety”, or “active pharmacological ingredient” (API)), the formulation, excipients in the product (e.g., the inactive ingredients, fillers), the packaging (e.g., leaching of products from a container into the liquid drug product), a contaminant, manufacturing problems, the underlying disease, or some other unknown cause or causes. Thus, an AE does not imply that the drug (i.e., the active component) necessarily caused the bad thing to occur.
An AR is an AE in which there is “reasonable possibility” of a causal relationship between the drug and the AE. Some interpret this to mean that the relationship cannot be ruled out. This is probably too extreme as it implies that unless causality can be absolutely, positively ruled out, it is “possibly related” or that there is a “reasonable possibility” of causality. FDA in its guidance on IND Safety Reporting of December 2012 (https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm227351.pdf) discussed this at length and indicated that they do not want to see cases reported as expedited IND reports if there is “not enough evidence to suggest that there was a reasonable possibility that the drug caused the AE”. This is done to increase the likelihood that the information sent to FDA will be “interpretable and will meaningfully contribute to the developing safety profile of the investigational drug and improve the overall quality of safety reporting”. The notion of causality is discussed in much greater detail in Chapter 22. Thus, an AE possibly or probably due to the drug is an ADR or AR.
These terms are being replaced in practice by SAR, which emphasizes the suspicion that the drug is a possible cause of the bad thing or is the possible cause of the bad thing. Following logically from this, we now have the phrase suspected, unexpected, serious adverse reaction. The addition of the words “serious” and “unexpected” to the SAR term represents the criteria