18. i. Listedness/Expectedness assessment – Introduction

There are two principal criteria that control the priority for documenting, validating, evaluating and regulatory-reporting of ADR cases: seriousness and expectedness. 

The concept of expectedness refers to events that may or may not have previously been observed and documented. It does not refer to what might be anticipated (expected in a different sense) from the known pharmacological properties of the medicine. Nor does it refer to what may occur in the course of the treated disease such as in the case of disease progression and/or lack of drug effect.

An adverse reaction will be unexpected in the regulatory sense unless it is mentioned in the appropriate reference safety information (RSI) document(s) for the drug, even if it is a medical occurrence expected for the disease being treated. 

Depending on the status and circumstances of the drug, RSI may be one or more of the following:

1. Investigator Brochure (IB)

CCSI for investigational drugs that have not been approved or pre-marketed drugs. 

RSI can also be a CCDS, IB, SmPC, package insert (USPI) and product insert and these apply to drugs that have been approved or post-marketing drugs.

Investigator Brochure (IB): a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product (s) in human subjects.

Package Insert/Product Insert (PI): is a document provided with a prescription medication to provide addition information about the drug.

Summary of Product Characteristics (SmPC): is a definitive statement, agreed by a manufacturer and the European Communities, of facts and recommendations regarding the prescription use of a medical product approved for marketing. The SmPC is used by healthcare professionals, such as doctors, nurses and pharmacists, and explains how to use and prescribe a medicine. (This document is the same as the package insert in the US.)

Company Core Safety Information (CCSI): a clinical safety reference of all relevant safety information contained in the company core data sheet prepared by the MAH and that the MAH requires to be listed in all countries where the company markets the drug, except when local regulatory authority specifically requires a modification. It is the reference information by which listed and unlisted are determined for the purpose of periodic reporting for marketed products, but not by which expected and unexpected are determined for expedited reporting.

Company Core Data Sheet (CCDS): a document prepared by the manufacturer, containing all relevant safety information, such as adverse drug reactions, which the manufacturer requires to be listed for the drug in all countries where the drug is marketed. It is the reference document by which labeled and unlabelled are determined for the purpose of international ADR reporting. Also referred to as CCSI.

• According to ICH E2C, the CCDS covers material related to safety, indications, dosing, pharmacology, and other information concerning the product.

Development of Core Safety Information (DCSI): an independent section of an IB identical in structure to the CCSI that contains a summary of all relevant safety information that is described in more detail within the main body of the IB. It is the reference safety document that determines whether an ADR is listed or unlisted.

To ensure proper classification and specificity of ADR terms, ideally three conditions should be fulfilled:

1. case reports must be sufficiently well documented,
2. there must be no ambiguity regarding the nature, severity and outcome of the event, and
3. there must be no ambiguity regarding the section(s) in the RSI where the appropriate information is placed.

Many different terms are currently used to indicate expected or unexpected:

1. Expectedness means the AE whether serious or not is already listed in the IB or SmPC.
2. Unexpectedness: the AE whether serious or not is not listed in the IB or SmPC.
3. Labeled/Unlabeled: For a product with an approved marketing application, any reaction which is not mentioned in the official product information is unlabeled. If it is included, it is termed labeled. Official product information refers to SmPCs, package inserts, or product data sheets.
4. Listedness/Unlistedness: any reaction which is not included in the Company Core Safety Information within a company’s core data sheet for a marketed product is unlisted. If it is included it is termed listed.

What is Expectedness?

Expectedness refers to the AE being previously observed and documented in Reference Safety Information (i.e. IB, SmPC, Package Insert, CCSI).

What is not Expectedness?

1. Expected does not mean that the AE could have been anticipated, e.g., from the known pharmacological properties of the medicine.
2. Expected does not refer to what may occur in the course of the treated disease such as in the case of disease progression and/or lack of effect.

What is Unexpectedness?

– Unexpectedness refers to AE not being observed or documented in the Reference Safety Information.

What is Unexpectedness Assessment?

1. Unexpectedness assessment is deciphering whether the reported adverse event is different in its nature, severity, specificity or usual outcome relative to the term/description used in Reference Safety Information. This is determining unexpectedness.
2. An AE will be unexpected in the regulatory sense unless it is mentioned in the appropriate RSI, even if it is a medical occurrence expected for the disease being treated.

What is Expectedness Assessment?

Expectedness assessment is deciding whether the adverse event presented is listed (expected) or not listed (unexpected) in the appropriate section of the Reference Safety Information.

What resources to use for Expectedness/Unexpectedness Assessment:

• Reference Safety Information (RSI) documents should be used in the determination of expectedness.

• Much safety information may be contained in various sections of the RSI – this may create confusion or ambiguity about whatshould or should not be considered ‘expected’.

• The CIOMS V working group advises that expectedness should be based on inclusion of an AE in the AE/ADR section of the RSI.

• Even if an AE/ADR is mentioned in the clinical pharmacology, contraindications, warnings, precautions, or other sections of the RSI, it should also be included in the AE/ADR section, which is the comprehensive repository of expected AEs/ADRs.

Each company maintain their own RSI document library which is used by Pharmacovigilance associate for labelling assessment and there are few online links available for public to know the expectedness:

E. g. In the US the package Insert can be accessed at http://dailymed.nlm.nih.gov/dailymed/about.cfm or at http://www.nlm.nih.gov/medlineplus/medicines.html or http://www.emea.europa.eu/htms/human/epar/a.html

For recent approved medicines in the EMEA, SmPCs can be accessed at the EMEA site. Local UK SmPCs can be accessed at http://emc.medicines.org.uk/