This concept involves determining whether any adverse drug reaction or adverse drug event is already known/already documented/already observed in subjects/patients who are under treatment with the investigational/marketed medicinal product.
It determines the expeditious nature of an ICSR (Individual case safety report) by formulating the regulatory due timeline for submission to health authority (7/15 days).
For example, In SUSAR (Suspected, [Unexpected/Unlisted/Unlabelled] Serious Adverse drug Reaction) ‘U’ is crucial in classifying an ICSR either to expedited or non-expedited case. Hence, this concept is essential for identifying potential expedited cases (SUSAR ICSRs) which follows prioritization for case processing and submission to respective health authorities.
The terms ‘Listed/Labelled” are used during assessment for the “Marketed products”.
The term “Expectedness” is used during assessment for “Developmental drugs or Investigational molecules.”.
Before going into definition of what exactly Listed/Labelled and expectedness mean, we will know about the “Reference Safety Information”.
Reference Safety Information (RSI)
For Developmental Drugs/Investigational molecules:
Investigational Brochure (IB): During development phase of pre-marketed medicines which are not “Yet” approved, the information pertaining to Safety Experience of molecule under investigation gained during the study period or clinical phase development is documented in a detailed manner. The name of the document used for this purpose is “Investigational Brochure” (IB).
IB is the reference safety information (RSI) document for assessing whether occurrence of any adverse reaction associated with investigational medicinal product is as part of existing safety knowledge or not.
The terminology used here is Expectedness.
Expected: If any adverse reaction is already encountered by any subject in clinical trial for that molecule under investigation and it is “Well Documented” in the IB, then adverse reaction is considered ‘Expected’.
Unexpected: If it is a strange adverse drug reaction and “Not Well Documented” in IB, then it is classified as ‘Unexpected’.
For Marketed Medicinal products:
After attaining authorization and approval for marketing a medicinal product, Sponsors will prepare a Package Information Leaflet (PIL), Prescribing Information document, company core safety information (CCSI) documents, core data sheets (CDS) etc.,
Region-Specific Labelling documents:
Each Marketing Authorisation Holder (MAH) maintains a reference safety document specific to the region. Also, each national regulatory authority maintains product specific monographs which includes drug safety information.
Some of the region-specific labelling documents presented below-
- Summary of Product Characteristics (SmPC): The RSI for European Medicines Agency (EMA) region or any country specific document for national competent authorities in Europe.
- United States Prescribing Information (USPI): Country specific labelling document for United States of America.
- Japanese Prescribing Information (JPI): Country Specific labelling Document for Japan.
- Canadian Monographs (CM): Country Specific labelling Document for Canada.
Labelled: If any adverse reaction experienced by patient is “Well Documented” in its corresponding region-specific RSI for that medicinal product.
Unlabelled: If the adverse reaction experienced by patient is strange and it is “Not Well Documented” in its corresponding region-specific RSI for that medicinal product.
Region-specific documents have the safety knowledge pertaining to a medicinal product which was accumulated/originated at region level.
Sponsor-Specific documents:
A company’s common core data sheet (CDS) or Company’s Core Sheet Information (CCSI) are the “Global Reference Safety Information” documents maintained by the sponsor (marketing authorization holder for medicinal products)
CCSI or CDS have the complete safety information of medicinal product gained from patient experience globally and updating the same whenever required.
Listed: If any adverse reaction is Well Documented in the CDC/CCSI, it is classified as Listed.
Unlisted: If any adverse reaction is Not Well Documented in the CDC/CCSI, it is classified as Unlisted.
So, based on the type of medicinal product (developmental or marketed) and type of RSI (IB, CCDS, CCSI, USPI, SmPC etc.,) different terminologies are used (Expected/Listed/Labelled) during assessment.
Concept of Assessment:
Here, we have specified ‘Well Documented’ and ‘Not Well Documented’ in the above classifications. Now let us see what exactly the Well Documented means.
Well Documented: Any AE/SAE (event) or ADR/SADR (reaction) is considered Well Documented only when it is completely a known event and also its “Nature, Severity, Specificity and Outcome” are Consistent with the available safety information presented in the Reference Safety Information (RSI) document.
Not Well Documented: When any AE/SAE (event) or ADR/SADR (reaction) reported for a patient is completely ‘new’ or a ‘new aspect’ of already known event/reaction as per the RSI.
If a reported adverse event or reaction is completely new, it is straight away considered unexpected/unlabelled/unlisted (as per the type of RSI referred for assessing).
If a reported adverse event or reaction is already documented in RSI, however it is not consistent with the available documented information. i.e., a new aspect of already known reaction is reported. then it is considered as a ‘not well documented‘ reaction.
A new aspect can be change in nature, change in severity, change in specificity, change in outcome for an already known reaction.
Possible new aspects of a documented adverse drug event/reaction are described below:
Nature: If an AE/ADR is described in RSI and when an ICSR is comprising the same/similar event/reaction of different nature.
Example:
An ICSR states that patient developed squamous cell carcinoma after treatment with a medicinal product X.
RSI contains ‘skin cancer’ (already known and documented event/reaction for X)
The reported safety information (squamous cell carcinoma) is not consistent with the available safety information (skin cancer) in terms of its nature and squamous cell carcinoma would be considered unexpected/unlisted/unlabelled (as per type of RSI).
Severity: When the severity of reported adverse event from the ICSR case is not consistent with presented severity for the same event in the RSI document.
Example:
Reported AE/ADR in an ICSR is ‘severe hypertension’.
RSI contains ‘mild hypertension’.
‘severe hypertension’ is not consistent with available safety information in RSI (mild hypertension) in terms of its severity. It would be considered as a new aspect of already known reaction and classified as unexpected/unlisted/unlabelled (as per type of RSI).
Specificity: Based on the specificity of adverse reaction reported for a patient in an ICSR, it can be considered as a new aspect of known reaction.
Example:
Reported AE/ADR in an ICSR is ‘Right leg oedema’.
In RSI, left leg oedema is described.
Right leg oedema is inconsistent with the available safety information (left leg oedema) based on the specificity and it is a new aspect of already known reaction and can be classified as unexpected/unlisted/unlabelled (as per type of RSI).
Outcome: An adverse event outcome plays a key role in listedness assessment
Example:
In an ICSR case, patient died due to pneumonia (i.e., pneumonia with fatal outcome). Whereas in the RSI, only “pneumonia” is described. In this scenario, “fatal pneumonia” is inconsistent with the available safety information (pneumonia) with respect to outcome and it is considered as a new aspect of known reaction could be assessed as unexpected/unlisted/unlabelled (as per type of RSI).
Relevant section/sub-section of RSI
In addition to the above points while assessing expectedness/listedness, it is important to consider the section/sub-section of RSI where the event/reactions are specified. i.e., determination of consistency of ‘reported’ & ‘available’ safety information should be done in accordance with relevant section/subsections like contraindications, special warnings, and precautions for use, pregnancy and lactation, drug interactions, undesirable effects etc.,
Example: An ICSR contains an AE/ADR of hallucination experienced by a patient under ‘normal dose’ medication.
RSI contains hallucination only under ‘overdose’ section. In this scenario, hallucination is considered unexpected/unlisted/unlabeled (as per type of RSI).
Change in frequency of expected/listed adverse event occurrences is also considered as a new aspect for already known reaction. (This usually identified/performed during aggregate safety report- case analysis and signal evaluation process).