Causality Assessment:

Causality is an assessment procedure used for the determination of relationship between a drug treatment and the occurrence of an adverse drug event.

When a causal relationship is identified, then adverse drug event (ADE) would be called as adverse drug reaction (ADR).

The assessment of causality is a common procedure in pharmacovigilance, which is done at different levels which included physicians, investigators, professionals working in drug safety department of a pharmaceutical company and national health authorities which can assist in taking regulatory decisions.

Causality is the key factor for identification of new signals, measuring the strength of evidence, and in evaluating benefit risk profile of pharmaceutical medicinal products.

Methods of causality assessment

There are several methods published to perform causality assessment. However, there were no internationally agreed upon standards or criteria for assessing causality in individual case safety reports (ICSRs).

Below two methods are widely accepted and used for assessing causality globally.

1. WHO UMC causality assessment
2. Naranjo causality assessment

1. WHO UMC causality assessment

The World Health Organisation (WHO) and Upsala Monitoring center (UMC) at Sweden has developed a system for causality assessment in consultation with the National Centers participating in the International Drug Monitoring Programme.

It is meant as a practical tool for the assessment of causal relationship in ICSRs.

It is basically a combined assessment considering the clinical-pharmacological aspects of the case history and the quality of the documentation of the observation.

Assessment criteria:

Below key concepts will aid in ease understanding of various criteria for assessing causality.

1. Temporal relationship: It is the time relationship between the drug administration (Date of therapy start date, therapy duration) and occurrence of adverse event (Event onset date/date of initial symptoms observed).
2. Abnormal Laboratory tests: There are some adverse event incidences which cannot be ruled out from the causal relation with drug based on unusual or abnormal values in the laboratory investigation.
3. Dechallenge: The assessment of the outcome of adverse event followed by suspension/withdrawal of drug/reduced dose of drug in response to the adverse event. Based on outcome of AE, it is further classified into two categories:

• Positive Dechallenge: The complete or partial resolution of adverse event followed by suspension/withdrawal of drug/reduced dose of drug
• Negative Dechallenge: There is no change in the outcome of AE. It is persisting irrespective of drug suspension/withdrawal and reduced dose.

4. Rechallenge: This is applicable in the positive dechallenge scenario. The re‑introduction/restarting of drug therapy after the event resolution.

      It also can be classified into below two categories:

• Positive Rechallenge: Re-occurrence of adverse event after restarting of drug.
• Negative Rechallenge: Adverse event has not recurred even after drug restart.

5. Alternative causality: Other contributory factors for the cause of adverse event. Below are the possible contributors attributed to an AE.

• Medical conditions: Underlying concurrent medical conditions of patient (e.g., diabetes, heart diseases, autoimmune disease etc.,) or past medical history and prior or ongoing surgical procedures.
• Other medicinal product use: Concomitant medication details and past drug history.

• Social life: Alcohol use, smoking (both history & concurrent use), obesity, diet, profession etc.,
• Risk factors: Age (both paediatric and geriatric patients), hepatic and renal impairment patients etc.

The following causality terms are defined based on their respective assessment criteria.

Causality term	Assessment criteria
Certain	Event or laboratory test abnormality, with plausible time relationship to drug intake Cannot be explained by disease or other drugs Response to withdrawal plausible (pharmacologically, pathologically) Event definitive pharmacologically or phenomenologically (i.e. an objective and specific medical disorder or a recognised pharmacological phenomenon) Rechallenge satisfactory, if necessary
Probable / Likely	Event or laboratory test abnormality, with reasonable time relationship to drug intake Unlikely to be attributed to disease or other drugs Response to withdrawal clinically reasonable Rechallenge not required
Possible	Event or laboratory test abnormality, with reasonable time relationship to drug intake Could also be explained by disease or other drugs Information on drug withdrawal may be lacking or unclear
Unlikely	Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) Disease or other drugs provide plausible explanations
Conditional / Unclassified	Event or laboratory test abnormality More data for proper assessment needed, or Additional data under examination
Unassessable / Unclassifiable	Report suggesting an adverse reaction Cannot be judged because information is insufficient or contradictory Data cannot be supplemented or verified.

 

Below table will aid in identification of causal criteria based on the assessment of various factors.

 

Category	Temporal Relationship	Concomitant medication use/Concurrent Diseases (Alternative causalities)	Dechallenge positive	Rechallenge positive
Certain	Yes	Yes	Yes	Yes
Probable	Yes	Yes	Yes	No
Possible	Yes	No	No	No
Unlikely	No	No	No	No
Unclassifiable	NA	NA	NA	NA

 

2. Naranjo causality assessment

In the year 1991, Naranjo and co-workers from the University of Toronto developed the Adverse Drug Reaction (ADR) Probability Scale to determine the likelihood of whether an ADR is due to the medicinal product rather than the result of other contributory factors.

It is often referred to as the Naranjo Scale which is simple to apply and widely used.

ADR probability scale: The Naranjo Algorithm, or Adverse Drug Reaction Probability Scale, is used to assess whether there is a causal relationship between an adverse drug experience and a drug using a simple questionnaire to assign probability scores.

The questionnaire scale consists of 10 questions that are answered as either “Yes”, “No”, or “Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer.

Listed below are the ’10’ questions:

Question	Yes	No	Do Not Know	Score
1. Are there previous conclusive reports on this reaction?	1	0	0
2. Did the adverse event appear after the suspected drug was administered?	2	-1	0
3. Did the adverse event improve when the drug was discontinued, or a specific antagonist was administered?	1	0	0
4. Did the adverse event reappear when the drug was re-administered?	2	-1	0
5. Are there alternative causes that could on their own have caused the reaction?	-1	2	0
6. Did the reaction reappear when a placebo was given?	-1	1	0
7. Was the drug detected in blood or other fluids in concentrations known to be toxic?	1	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	1	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	1	0	0
10. Was the adverse event confirmed by any objective evidence?	1	0	0
	Total Score:

 

The total scores range from “-4 to +13”

Criteria based on score:

Based on the total score, causality is assessed, and the strength of relationship is defined.

Definite:

If total score is ‘greater than or equal to 9’. A strong temporal relationship, positive dechallenge and rechallenge scenarios. No alternative explanation for attribution/absence of confounding factors.

Probable:

If the total score lies in ‘between 5 and 8’. A reasonable temporal sequence, and a recognised response of reaction outcome with respect to action taken on suspected drug. Presence of alternative explanatory conditions like patient current conditions, medical history etc.,

Possible:

If the total score lies in ‘between 1 and 4’. Attribution due to a reasonable temporal association or presence of positive reaction outcomes with respect to action on drug administration (dose reduction/suspension/withdrawal)

Doubtful:

If the total score is ‘less than or equal to 0’. Having alternative explanations with a strong confounding factors which included medical history, concurrent illness, age group, population (paediatric, geriatric), social habits (alcohol, tobacco use) etc.,