It is possible to receive millions of adverse drug reaction reports. This represents a huge chunk of data, which can be analyzed to find both new and already existing relationships. It is also important, as a pharmacovigilance centre to constantly do research.
Pharmacovigilance is an interesting and ever changing field; new topics are being discussed and innovative methods are frequently introduced into the field. This is why constantly updated data should be an essential part of any pharmacovigilance centre’s activities.
Individual case assessment
The establishment of relationship between medicine intake and occurrence of adverse events is an important activity in pharmacovigilance. Different national pharmacovigilance centres have different procedures for carrying out case causality assessment, driven sometimes by differing philosophies on the need for and importance of case causality assessment. The material below is reproduced from the WHO Manual “A practical handbook on the pharmacovigilance of antiretroviral medicines” authored by Dr. David Coulter, formerly Director of the Intensive Medicines Monitoring Programme in New Zealand (WHO, 2009).
Establishing causality or a relationship between a drug and an adverse event involves two basic questions. These questions need to be addressed separately:
- Is there a convincing relationship between the drug and the event?
- Did the drug actually cause the event?
Objective and subjective assessments
The objective phase
This takes into account actual observations and establishes the relationship.
The subjective phase
This is the process of making an attempt to establish a firm opinion about causality in those events for which a close relationship has been established. It takes into account the plausibility of the drug being the cause of the event, after having considered the (known) pharmacology, other experience with the medicine or related medicines, and inferences made from epidemiological observations and statistical evaluations.
General understanding of causality/relationship assessment
Establishing causality is a process which begins by examining the relationship between the drug and the event. The relationship in a single case-report can be established by checking the way in which the diagnosis has been reached with positive reasons supporting the diagnosis with the drug as a cause, and the exclusion of other possible causes. It may not be possible to establish a firm opinion on causality until a collection of such reports is assessed or new knowledge is gained. The ultimate goal of assessment of each event, or a cluster of events being treated as a signal, is an answer to the question:
Did the drug cause the event(s)? Yes or no?
Causality for individual reports, even those with a close relationship, can seldom be established beyond doubt and our assessments are based on individual case probability, the increasing support of a case series and then controlled observational or even interventional studies.
A causality assessment should be seen as provisional and subject to change in the light of further information on the case, or new knowledge coming from other sources.
General understanding of causality/relationship assessment
- Did the event begin before the patient commenced the medicine? This may seem an obvious consideration, but reports are received in which this has not been taken into account, and a careful check has then revealed that the event preceded the use of the suspect medicine and therefore there was no relationship.
- Is there any other possible cause for the event?
- Could the event be due to the illness being treated?
- Could it be due to some other co-existent disease?
- Could it be due to some other medicine being used concurrently?
- Is the duration to onset of the event plausible?
- Is the event likely to have occurred in the time frame in question?
- Did it occur too quickly to be related to the particular medicine, taking into account its pharmacological action?
- Did the patient take the medicine for a long time without any problems? (Delayed reactions after long-term exposure does occur, but most reactions will occur soon after the patient starts to take the medicine.)
The nature of the event should be considered when assessing the significance of the period of exposure, for example:
- some events take a long time to develop (e.g. cancer);
- some develop quickly (e.g. nausea and headache);
- allergic reactions to first-time exposure to a drug generally take around 10 days to appear. On repeat exposure they may occur immediately.
- did the event occur after the commencement of some other medicine?
If the event began shortly after commencing another medicine, then two possibilities should be considered: The new medicine may have caused the event or there may have been an interaction between the two drugs and the interaction caused the event.
- Did the event occur after the onset of some new illness? If so, the event may be due to the new illness.
- What is the response to withdrawal of the medicine (dechallenge)?
- Did the patient recover?
- Did the patient improve?
- Was there no change?
- Did the patient get worse?
- Is the response to dechallenge unknown? If this is the case, then it should always be recorded as unknown.
If more than one medicine has been withdrawn, and if rechallenge is considered appropriate, it should be performed with only one medicine at a time.
- What is the response to rechallenge?
Conditions for a positive rechallenge are:
- the patient recovered on initial withdrawal;
- the patient developed the same problem again when re-exposed to the same medicine alone, although it may be of different severity;
- the patient recovered when the medicine was withdrawn once again;
It should be noted that it is not always safe to subject the patient to a rechallenge; if the response to rechallenge is unknown, this should be recorded.
Categories of relationship:
The WHO International Drug Monitoring Programme uses six standard categories of relationship or causality between a drug and an adverse reaction or event. These are: