Causality Assessment in Pharmacovigilance: WHO-UMC Scale and Naranjo Algorithm Explained

Causality assessment is a fundamental activity in pharmacovigilance that evaluates whether a medicinal product is responsible for an adverse event experienced by a patient. Determining the causal relationship between a drug and an adverse reaction is essential for identifying potential safety risks and supporting regulatory decision-making.

This article explains the key factors considered in causality assessment and the commonly used methods, such as the WHO–UMC scale and the Naranjo algorithm, used in pharmacovigilance practice.

Introduction

Causality Assessment: It is the process of evaluating the relationship between a drug and an adverse event. 

To understand basic pharmacovigilance terms such as adverse events, ADRs, and ICSRs, read our article on Key Terminologies in Pharmacovigilance Explained.

Why is Causality Assessment Needed?

• Identifies whether a drug caused the adverse event
• Helps differentiate drug-related reactions from other causes
• Supports patient safety and risk minimization
• Assists regulatory authorities in safety decisions
• Improves the quality of pharmacovigilance data

Causality assessment is closely related to the identification and evaluation of adverse drug reactions. Learn more about ADR classification in our article on Adverse Drug Reactions (ADR): Types, Minimum Criteria and Challenge-Dechallenge-Rechallenge.

Key Factors Considered in Causality Assessment:

The Key Factors that are considered in causality assessment are:

1. Temporal Relationship: 

• It refers to the timing between the administration of a drug and the onset of an adverse event. For a causal relationship to be considered, the adverse event should occur after the drug is taken and within a biologically plausible time frame.
• Temporal relationship is one of the first factors assessed in causality evaluation and forms the basis for further analysis, such as dechallenge, rechallenge, and evaluation of alternative causes.

      2. Dechallenge: 

• It refers to the withdrawal or dose reduction of the suspect drug to observe whether the adverse event improves or disappears. It supports a possible causal relationship. Lack of improvement, however, does not always rule out causality.

      3. Rechallenge: 

• It refers to the reintroduction of the suspect drug after it has been stopped, to observe whether the adverse event recurs. Rechallenge is rarely performed due to ethical and safety concerns, but when available, it provides strong support for a causal link.

      4. Abnormal lab findings: 

• These are changes in test results, such as liver enzymes, kidney tests, or blood counts, that may occur after taking a drug. 
• In causality assessment, we check if these changes occur after drug use and if they improve when the drug is stopped (dechallenge).
•  Lab changes alone don’t prove the drug caused the effect—they must be considered with the patient’s overall condition.

      5. Alternative reasons 

• It includes other factors that may cause an adverse event, such as comorbid conditions, concomitant medications, infections, lifestyle factors, or other medications. 
• During causality assessment, these are checked to see if they can explain the event. If a clear alternative cause exists, the chance that the drug caused it is lower.

In pharmacovigilance case processing, causality assessment is performed as part of the Individual Case Safety Report (ICSR) evaluation. Learn more about the workflow in our article on ICSR Processing in Pharmacovigilance: Step-by-Step Workflow.

Common Causality Assessment Methods

Causality assessment methods provide structured ways to determine whether an adverse event is likely caused by a drug. These methods help pharmacovigilance professionals evaluate cases consistently and objectively. 

The two most widely used approaches are 

1.  WHO–UMC scale 
2. Naranjo Scale

1. WHO-UMC Scale:

• It is an internationally accepted, validated, and well-standardized causality assessment scale, used to study the causal relationship between the drug and adverse event
• It is an algorithm-based scale.
• This scale has been developed by world-health organization and the Uppsala Monitoring Center

The table below summarizes the WHO–UMC causality categories, including their key criteria, and practical examples to illustrate each category.

Category	Criteria & Dechallenge/Rechallenge	Example
Certain	- Reaction occurs after drug intake - Cannot be explained by other causes -Positive dechallenge (improves after stopping) -Positive rechallenge (reaction returns if restarted)	A patient develops a rash immediately after taking Drug X; it resolves after stopping and recurs when restarted
Probable / Likely	- Reasonable time link between drug and reaction - Improves on dechallenge - Alternative causes are unlikely - Rechallenge not required	Liver enzymes rise after starting Drug Y and return to normal after stopping; no other cause found
Possible	- Reaction occurs after drug intake - Other causes (disease, other drugs) may explain it - Dechallenge info unclear or unavailable - Rechallenge is usually not done	Patient develops a headache after Drug Z, but also has a history of migraines
Unlikely	- Timing makes drug causation improbable - Alternative explanations more likely - Dechallenge/rechallenge is usually irrelevant	Fever in a patient on Drug A, but the patient also has a confirmed infection
Conditional / Unclassified	- More data required - Case is being followed for updates - Dechallenge/rechallenge data may be missing	Patient reports abnormal labs, but further testing or history is needed
Unassessable / Unclassifiable	- Insufficient or contradictory information - Cannot decide if the drug caused the reaction - Dechallenge/rechallenge not possible	ADR report missing drug start date or event details

2. Naranjo Scale

• The Naranjo Scale is a widely used structured tool for assessing the likelihood that a drug caused an adverse event. 
• It is a probabilistic scale
• Unlike the WHO–UMC scale, which is qualitative, the Naranjo scale uses a questionnaire-based scoring system to categorize causality into definite, probable, possible, or doubtful.

The Naranjo Algorithm uses a standardized questionnaire to assess causality. Each question is scored as Yes, No, or Do Not Know, as shown in the table below.

S. No	Question	Yes	No	Do Not Know
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 reaction improve when the drug was discontinued, or a specific antagonist was given? (Dechallenge)	+1	0	0
4.	Did the adverse reaction reappear upon readministration of the drug? (Rechallenge)	+2	-1	0
5.	Are there alternative causes that could 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 any body fluid in toxic concentrations?	+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 the past?	+1	0	0
10.	Was the adverse event confirmed by any objective evidence?	+1	0	0

After answering all 10 questions in the Naranjo questionnaire, the individual scores are added to obtain a total score. The total score determines the likelihood that the drug caused the adverse reaction, as shown in the table below.

Total Score                Causality Category

≥ 9                               Definite

5–8                                Probable

1–4                                 Possible

    0                                    Doubtful

Causality assessment is important in pharmacovigilance to check whether a drug really caused an adverse event. The WHO–UMC scale and Naranjo Scale help assess this relationship in a clear and structured way. Proper causality assessment improves patient safety and supports better regulatory decisions.

Method	Type	Main Use
WHO–UMC Scale	Qualitative	Used in global pharmacovigilance programs
Naranjo Algorithm	Scoring system	Structured probability assessment

Frequently Asked Questions (FAQs)

1. What is causality assessment in pharmacovigilance?

Causality assessment is the process of determining whether a drug is responsible for an adverse event reported in a patient.

2. What are the commonly used causality assessment methods?

The most commonly used methods are the WHO–UMC scale and the Naranjo algorithm.

3. Why is causality assessment important?

It helps identify drug-related adverse reactions, improves patient safety, and supports regulatory safety decisions.

Conclusion

Causality assessment plays a vital role in pharmacovigilance by helping determine whether a medicinal product is responsible for an adverse event. Methods such as the WHO–UMC scale and the Naranjo algorithm provide structured approaches for evaluating drug-event relationships. Accurate causality assessment strengthens pharmacovigilance reporting, supports regulatory decision-making, and ultimately contributes to improved patient safety.

A strong causality assessment strengthens pharmacovigilance outcomes and ultimately contributes to safer healthcare.