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18.ii. LISTEDNESS/ EXPECTEDNESS ASSESSMENT – Reference safety information documents

18.ii. LISTEDNESS/ EXPECTEDNESS ASSESSMENT – Reference safety information documents

As per regulatory authorities an adverse reaction will be unexpected unless it is mentioned in the appropriate reference safety information (RSI) document(s) for the drug. The purpose of RSI is, of course, not limited to the determination of expectedness. Apart from adverse events RSI document also contain the information about dose, indications, usage, administration, contraindications, warnings and precautions, drug interactions, use in specific population, overdose, clinical studies information, drug pharmacology and toxicology information. Hence for expectedness assessment we need to refer particular sections in RSI documents. 

Before we go into the sections to be referred we need to know few important points about RSI: 

  1. Inclusion of safety information in the adverse reactions/undesirable effects section of the RSI is strictly limited to reactions which have been observed and documented in humans, and for which the causal role of the drug has been reasonably established or inferred. 
  2. Special types of reactions, such as those occurring under conditions of overdose, drug interaction or pregnancy are included in this section, with a cross-reference to other relevant RSI sections for details.
  3. If an ADR has been reported only in association with an overdose, then that same ADR at ordinary (usual) doses should be considered unexpected. 
  4. RSI documents cover all the drug-induced situations which may be encountered and also cover medical conditions with comparable clinical properties, namely, their nature, severity, specificity or usual outcome; situations with different clinical attributes would be ascribed different terms. 

Depending on marketing status of the product the availability of reference safety documents vary, refer below table; 

Determining Expectedness According to the Investigative Brochure: 

Events are considered to be expected according to the currentapproved IB if:

  1. 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)
  2. 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.

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

For example:

  1. Events NOT attributable to the product.
  2. Events mentioned which occurred with placebo or control drugs only.
  3. Events mentioned which occurred with placebo or control drugs only (Note: Some US pharmaceuticals consider an event expected even if the event in the IB clearly in the placebo group).
  4. Events associated with animal data only.
  5. Events of different nature, or greater specificity, severity or frequency than identified in the IB.
  6. 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 (SmPC)/Package insert (PI)/Core data sheet (CDS):

Expected AEs identified under any of the following sections of the SmPC/PI/CDS include:

  1. Special Warnings and Precautions for Use
  2. Undesirable Effects/adverse reactions
  3. Interactions – 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.
  4. 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/CDS/PI include:

  1. Events associated with animal data only.
  2. Events of greater specificity, severity or frequency than specified.
  3. Events associated with specific indications, dose specifications or circumstances are only expected for those specific conditions.
  4. Class labelling which does not mention the specific product being marketed.
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