expectedness/unexpectedness assessment_katalyst hls

Training for Drug Safety Associates, Drug Safety Specialists, Senior Drug Safety Specialists, Medical and Drug Safety Managers, Medical Monitors and Drug Safety Physicians

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Katalyst Healthcares & Life Sciences

Expectedness/Unexpectedness Assessment

│ GLOBAL REACH │ THERAPEUTIC EXPERTISE │ EXPERIENCED PROJECT TEAMS ││ ACCELERATED STUDY START-UP LPI │ MANAGEMENT OF TECHNOLOGY INTEGRATION │

05/03/23

Objectives for Expectedness/Unexpectedness Training

Understanding frequently used terms

Defining Expectedness & Unexpectedness

Defining the importance of Expectedness & Unexpectedness Assessment

Using Reference Safety Information as a resource for Expectedness & Unexpectedness Assessment

Expectedness & Unexpectedness Assessment

Showing examples of Expectedness & Unexpectedness

Determining Expectedness using the Investigator Brochure

Determining Expectedness using the SmPC

General Assessment of Expectedness vs. Unexpectedness

Helpful CIOMS Rules Good Practice Rules for

Pharmacovigilance Projects


Frequently Used Terms and Definitions

Adverse Event (AE): 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.

Adverse Drug Reaction (ADR): All noxious and unintended responses to a medicinal product related to any dose should be considered an ADR.

Serious Adverse Event/Experience/Reaction (SAE): is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity or, is a congenital anomaly/birth defect.

Expected ADR: is one for which its nature or severity is consistent with that included in the appropriate RSI such as the IB or CCSI for an unapproved product or a package insert or a SmCP for an approved product.

Unexpected ADR: an adverse reaction, the nature or severity of which is not consistent with the appropriate RSI such as the IB or CCSI for an unapproved product or a package insert or a SmCP for an approved product.Katalyst Healthcares & Life

Sciences


Expectedness means the AE whether serious or not is already listed in the IB or SmPC.

Unexpectedness: the AE whether serious or not is not listed in the IB or SmPC.

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.

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.

Marketing Authorization Holder (MA): is the pharmaceutical sponsor/client holding the investigational drug.



Reference Safety Information (RSI): is information in the form of an Investigator Brochure or CCSI for investigational drugs that have not been approved or pre-marketed drugs. RSI can also be a IB, SmPC, package insert 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(R1), 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. Katalyst Healthcares & Life

Sciences

What is Expectedness/Unexpectedness & Expectedness/Unexpectedness Assessment

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?- Expected does not mean that the AE

could have been anticipated, e.g., from the known pharmacological properties of the medicine.

- 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?- 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.

- 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.


Why is Expectedness/Unexpectedness Assessment Important?

- It defines whether a reported AE is expected or unexpected.

and- It determines expedited reporting requirements.

NOTE: Expectedness/Unexpectedness assessment must take place once a case is validated.


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 what should 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.


What resources to use for Expectedness/Unexpectedness Assessment

Examples of RSI documents for investigational

medicinal products: Investigator Brochure (IB) Development Core Safety

Information (DCSI) in an IB

Examples of RSI documents for marketed medicinal products:

Company Core Safety Information (CCSI)

Company Core Data Sheet (CCDS) Official local data sheet

In the US, it is the Package Insert In the EU it is the EU SmPC or local

SmPCs

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

For recent approved medicines in the EMEA, SmPCs can be accessed at the EMEA site http://www.emea.europa.eu/htms/human/epar/a.htm

Local UK SmPCs can be accessed at http://emc.medicines.org.uk/


http://dailymed.nlm.nih.gov/dailymed/about.cfm

http://www.nlm.nih.gov/medlineplus/medicines.html

http://www.emea.europa.eu/htms/human/epar/a.htm

http://emc.medicines.org.uk/

How to Assess Expectedness/Unexpectedness(2 Levels of Decision Making)

1st Question Is the AE/ADR mentioned in

the appropriate section of the reference safety information (RSI)? Any reaction not mentioned is supposedly new and therefore unexpected.

If the actual term is not listed in the RSI – is a synonym listed?

2nd Question Based on the medical information

contained in the case report, is the AE different regarding its nature, severity, specificity or usual outcome relative to the term or description used in the RSI?

More difficult – requires well documented cases.

If sufficient information is absent – the AE should be regarded as unexpected (i.e. SAE starts out as expected b/c listed in RSI but follow-up sae is unexpected b/c PI updated the term as more severe.)


Examples of Expected Adverse Events

1. AEs are expected if their nature, severity, specificity and frequency are consistent with the information in the relevant Reference Safety Information (RSI).2. Generally, further anatomical specification or synonym of a labelled AE should be considered labelled.3. AEs associated with specific indications, dose specifications, dose forms or circumstances are only expected for those specific conditions (i.e. “situational” expectedness).4. An overdose, whether intentional or accidental, is expected if listed in the RSI. AEs associated with an overdose are expected if described in the overdose section or if listed as expected elsewhere in the RSI.

• Note: When AE has been reported only in association with an overdose, than that same AE at ordinary (usual) doses should be considered unexpected.

5. Lack of drug effect is typically treated as expected, with exceptions; e.g. Oral Contraceptives.Katalyst Healthcares & Life Sciences

Examples of Unexpected Adverse EventsAEs are generally considered unexpected if:1. The reported AE is different in nature, or greater in specificity,

severity or frequency than AEs mentioned in the RSI.2. The reported AE has a fatal outcome, unless the possibility of a

fatal outcome from the AE is stated in the RSI.3. The reported AE is only cited in data from clinical trials, unless the

same AE has been included in the ADR (Undesirable Effects) section of the RSI.

4. The reported AE has only been described in Investigator Letters that are appended to an Investigator’s brochure (IB) and not contained in the safety attachment on the current approved IB.

Note: Medication Error is generally treated as unexpected unless specifically stated in the RSIKatalyst Healthcares & Life

Sciences

Determining Expectedness According to the Investigative Brochure

Events are considered to be expected according to the current approved IB if:

Events are found in the Core Safety Information or Development Core Safety Information (DCSI) section in the current approved IB under possible sections entitled: Warnings, Precautions, ADR/Undesirable Effects or Efficacy and Safety. (NOTE: Not all IBs have these sections)

Medical judgement must be used to determine expectedness if an AE is in the Overdose, Discontinuation Effects, Pregnancy section etc. Note: Medical judgement refers to the principal investigator and/or the medical monitor.


Determining Expectedness According to the Investigative Brochure (cont.)

Other events may be mentioned in the body of the IB, but are NOT considered expected according to the IB.

For example: Events NOT attributable to the product. Events mentioned which occurred with placebo or control drugs only.

Note: Some US pharmaceuticals consider an event expected even if the event ia in the IB clearly in the placebo group.

Events associated with animal data only. Events of different nature, or greater specificity, severity or frequency than

identified in the IB. Events described in Investigator Letters appended to an IB. An AE term is considered to be unexpected/unlabelled until the new AE is added to

the appropriate section (s) of the IB. (i.e. The term expectedness can only be used with current approved version of the IB or IB addendum).


Determining Expectedness According to the Summary of Product Characteristics (cont.)

Expected AEs identified under any of the following sections of the

SmPC include: Special Warnings and Precautions for

Use Undesirable Effects Interaction

Drug Interactions are only considered expected if the product is listed as an interacting drug and the associated AE is listed as occurring as a result of the drug interaction.

Medical judgement must be used to determine expectedness if an AE is in the Overdose, Discontinuation Effects, Pregnancy section etc.

Unexpected Adverse Events according to the SmPC include:

Events associated with animal data only.

Events of greater specificity, severity or frequency than specified.

Events associated with specific indications, dose specifications or circumstances are only expected for those specific conditions.

Class labelling which does not mention the specific product being marketed.


General Assessments (when expectedness seems unexpected vs. when unexpectedness seems expected.

A laboratory value that is representative of the definition of the diagnosis (labelled in the RSI) is expected, for example, if the expected term is thrombocytopenia then decreased platelet count is expected. While PI is reporting decrease platelet count but RSI says

thrombocytopenia, it is expected even though the terms are different but the meaning is the same.

Diagnoses are not equivalent to lab values for example,: if the expected term is raised liver enzymes (meaning if the RSI states exactly this), then hepatitis (diagnosis) is not expected because it is not listed in the RSI. Only a medic can provide a diagnosis.

Symptoms/signs listed in the RSI are expected but diagnoses not listed in the RSI equals unexpected.Katalyst Healthcares & Life

Sciences

Helpful CIOMS Rules

Helpful CIOMS Rules:These are meant to be guidelines and the Sponsor/Marketing Authorization Holder has their own rules, the sponsor rules should be followed.


Helpful CIOMS Rules[1]

Further anatomical specification of a labelled AE does NOT make it unlabelled: E.g., fibrosis of upper left lobe is equivalent to lung fibrosis However: if arteritis is expected, temporal arteritis should be

considered unexpected due to the associated additional risks and poorer prognosis

Extra histological specification does NOT make, per se, a labelled AE unlabeled: E.g., liver biopsy shows hepatic necrosis [labelled] with the

presence of eosinophiles [not mentioned in labelling] However: e.g., cerebral thrombo-embolism or cerebral

vasculitis would be unexpected [by virtue of greater specifity] if the labelling only listed cerebral vascular accidents.

Interstitial nephritis should be considered unexpected when only acute renal failure is expected.Katalyst Healthcares & Life

Sciences

Helpful CIOMS Rules [2] cont.

If a labelled AE is not normally accompanied by an additional sign or symptom, AE should NOT be considered labelled: E.g., if the labelling mentions gastrointestinal irritation, then

‘gastrointestinal irritation associated with melena’ would be unlabelled.

Mention of any additional symptom or sign usually associated with an already labelled AE does NOT merit upgrading the event to unlabelled: E.g., labelling mentions thrombocytopenia, then a report on

‘thrombocytopenia associated with petechia’ would be labelled;

E.g., labelling mentions pseudomembraneous colitis, then a report on ‘pseudomembraneous colitis with dehydration would be labelled;



CIOMS rule: In general, the medical view is that if a labelled AE is often life-threatening or often results in death, a fatal outcome in a particular case does NOT make the AE unlabeled, even if death is NOT mentioned in the labelling as possible outcome: E.g., myocardial infarction is mentioned, but fatal

myocardial infarction is not. However, as a policy decision, company adopted the

overall conservative approach for world-wide reporting, that all fatal outcomes are assessed as unexpected, unless explicitly mentioned in the RSI.



If a reported AE is significantly more severe than the labelled AE, it should be considered unlabeled: E.g., circulatory collapse would be unlabelled when

hypotension is labelled E.g., death from hepatic necrosis would be unlabelled

when hepatic failure is labelled Rash does cover morbiliform rash, but not Steven

Johnson Syndrome Fulminant hepatitis should not be considered expected

if only ‘liver injury’ is mentioned



If an AE is not medically more important than a labelled AE, the case need not be considered unlabelled: E.g., vertigo, when dizziness is labelled; E.g., raised liver function test when hepatitis is labelled

Death from a condition diagnosed prior to treatment is NOT a reportable event – in fact, it is not an event at all ! E.g., death in pre-existing bronchogenic carcinoma Exception: exacerbation of the pre-existing condition

following treatment leading to death



AE with causality disclaimer – are considered expected (including those listed in a frequency table). E.g., "The following adverse events have been

reported in association with the drug, but a causal relationship has not been established”

However: if the AE disclaimer states that the events have been reported but not been considered drug-related (negative causality statement), then the AE should be assessed as unexpected



An unlabelled diagnosis which relates to a group of symptoms or signs which are labelled, the new case is not in itself labelled: E.g., anaphylaxis is unlabelled, even if hypotension,

wheezing and urticaria are all labelled (DIAGNOSIS must be stated in the label to make it expected)

If a DIAGNOSIS is labelled, then the signs and symptoms which comprise the diagnosis are also considered to be labelled. E.g., anaphylaxis is labelled, then hypotension, wheezing

and urticaria together would be considered to be labelled



HOWEVER: Even though a diagnosis or syndrome is expected, if the usually accompanying signs and symptoms are reported in the absence of a clear diagnosis (i.e., as one or more isolated signs and symptoms), those terms should not be considered as expected unless already in the RSI. It is impossible to ascertain that their appearance alone or together necessarily reflects a mechanism similar to that of a labelled diagnosis (e.g., isolated nausea, or asthenia, or gastralgia, when liver injury is labelled; isolated pallor, or hypotension or pruritus when anaphylactic reaction is labelled).

If the label lists an AE which is specified to be transient, but it persists in the new case, the case is unlabeled and should be reported: E.g., prolonged elevated liver function tests, when

labelling states transient elevated liver function testsKatalyst Healthcares & Life

Sciences


If an AE/ADR has been reported only in association with an overdose, then that same AE/ADR at usual doses should be considered unexpected.

If an AE/ADR occurs in a different indication, it is assessed unlabelled unless it is described in the adverse events section applicable for a specific indication or patient population.

If an AE/ADR follows a different route/formulation of drug administration, the event labelled for one presentation cannot be considered labelled for another presentation.



Drug exposure during pregnancy: Abortion, stillbirth, congenital abnormalities and maternal/new-born hazards are considered unlabelled unless explicitly specified in the RSI. Pregnancy/drug exposure in utero or normal babies are considered

labelled. Note: Pregnancy, drug exposure in utero, and delivery of a healthy

newborn are no adverse events per se! Drug abuse, drug dependence, maladministration: unlabelled

unless explicitly specified in the relevant sections of the RSI. Lack of efficacy and resulting signs or symptoms are considered

labelled events. However, if treatment directly exacerbates the treated condition then exacerbation is considered unlabelled unless specifically mentioned in the RSI.

If an AE/ADR is due to a specific drug-drug interaction, it is considered labelled but only in the context of the drug-drug interaction.Katalyst Healthcares & Life

Sciences


Death as an Outcome: Unless the RSI specifies a fatal outcome, then the case should be

considered as unexpected as long as there was an association between the adverse reaction and the fatality

A fatal outcome to a suspected ADR should not be mentioned in the RSI unless it has been reported to occur and is thought to be causally related to the ADR.

In the absence of special circumstances, once the fatal outcome is itself expected (labelled/listed), reports involving fatal outcomes should be handled as for any other serious suspected ADR in accord with appropriate regulatory requirements.


Good Practice Rules for PV Projects

Identify relevant RSI documents Identify relevant safety sections within RSI documents Discuss with client the basis for expectedness/unexpectedness

assessments or any areas of ‘Special interest’ for the product. Develop internal project specific guidance following the

general rules as stated in this presentation Document project specific expectedness/unexpectedness rules

and reach consensus with client Include in project specific documentation


Sources:

CIOMS V – Current Challenges in Pharmacovigilance: Pragmatic Approaches. CIOMS Geneva, 2001.

CIOMS VI – Management of Safety Information from Clinical Trials. CIOMS Geneva, 2005.


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