Adverse Reaction Reporting and IMMP
Causality Assessment of Suspected Adverse Medicine Reactions
Nature of the event
Temporal relationship
Dose relationship
Dechallenge and rechallenge
Exclusion of confounding factors
Clinical plausibility
Definitions of causality
Reporting adverse reactions
Clinical judgement is involved in deciding whether or not a medicine is responsible for a particular adverse reaction. Regular reporters to the Centre for Adverse Reactions Monitoring (CARM) have substantial experience at causality assessment and take a number of factors into account. These factors include the nature of the event, the temporal relationship of event to medicine administration, dose relationship, dechallenge or rechallenge effects, possible confounding factors and clinical plausibility of the event.
Nature of the event
Some clinical events such as acute dystonias, blood dyscrasias and some skin reactions are typically medicine-related. Other adverse events may be caused by a number of factors. For example hepatitis may be caused by infection, other disease, alcohol abuse, a medicine or a medicine interaction.
Temporal relationship
Timing can substantially strengthen a causal association, as in the case of anaphylaxis occurring immediately after parenteral medicine administration. Alternatively the timing of the adverse event may be misleading, for example cholestatic jaundice caused by flucloxacillin may manifest days to weeks after completion of therapy.
Dose relationship
The majority of adverse reactions reported are idiosyncratic and are not dose related. Examples of such reactions are rash with penicillins and thrombocytopenia with thiazide and loop diuretics. However, adverse events associated with the primary pharmacological effect of the medicine or those caused by its other effects are dose related and typically appear or worsen with a dose increase and abate with dosage reduction. Skin atrophy with topical steroids, ototoxicity and nephrotoxicity with aminoglycosides, and sedation with the first generation H1-antagonists, are examples of these effects.
Dechallenge and rechallenge
Recovery after medicine withdrawal is an important pointer to a causal relationship. Although deliberate rechallenge is often not ethical, recurrence on rechallenge is strongly suggestive that the medicine was responsible.
Exclusion of confounding factors
As mentioned above some adverse clinical events have more than one possible cause. The underlying illness or newly manifest disease may be the cause of the symptoms. Often the patient is taking more than one medicine and the event may be caused by any one or an interaction between two medicines. Dechallenge may be helpful to identify the cause in such cases. For some reactions, laboratory investigations may be required to confirm the cause. For example, plasma concentrations may confirm a drug interaction, immunological studies may implicate the medicine, and drug-induced pneumonitis or hepatitis may be demonstrated by biopsy.
Clinical plausibility
Clinical plausibility can be checked by referring to the data sheet in the New Ethicals Compendium. But, even if the event is previously unreported, the other factors mentioned above may be sufficient to support the suspicion of causality.
Definitions of causality
At the CARM, criteria developed by the WHO are used to define causality. A "probable" causal association is considered to be one where there is a reasonable time sequence, the event is unlikely to be attributable to concurrent disease or other medicines and a clinically reasonable response follows withdrawal. Rechallenge information is not essential to fulfil the definition. A "possible" causality assessment also requires a reasonable time sequence, but the event may also be explained by concurrent disease or other medicines and information on withdrawal may be lacking or unclear.
Reporting adverse reactions
The CARM welcomes all adverse reaction reports but particularly requests serious or unexpected reactions. As one of the main objectives is to identify hitherto unrecognised reactions, prescribers should not be deterred by uncertainty regarding cause and effect. For products on the Intensive Medicines Monitoring Programme all adverse clinical events should be reported, whether or not they are thought to be related to the use of the medicine.