Causality assessment of ADRs

Causality assessment of ADRs

Determining which adverse event is caused by drugs with reasonable certainty is an essential though difficult part of documenting ADRs. The development of a symptom or detrimental outcome while taking a medication does not establish the drug as the cause of the injury. Likewise, development of an event or a disease remotely in time from the use of a drug does not exonerate the therapy from being the source of the problem. In order to initiate appropriate measures to prevent further occurrence of ADRs, it is necessary to identify the causative drug. This can be done by carrying out the causality assessment of the suspected drug. Causality assessment is carried out to establish a causal relationship between a drug and ADR.

Causality assessment of ADRs is the structured and standardized assessment of individual patients/ case reports of the likelihood of a causal relationship between suspected drugs and adverse medical events. In the early 1980s, in an attempt to reduce ambiguity in the evaluation of adverse drug reactions, different standardized causality assessment scales were introduced  at pharmacovigilance centers in many centers in many countries around the world. The assessment of reported ADRs takes place in two stages:

i. The assessment of individual case reports and

ii. Interpretation of aggregated data.

In the first stage, routine causality assessment is made upon receipt of the case report based on a general system that is intended for all reactions and all drugs. It assesses all the possible relevance and quality of the report, like unknown reactions, seriousness, etc. During the second stage of aggregated assessment, causality assessment is likely to be repeated with all available data and the use of a specific etiological- diagnostic system may be more appropriate.

Currently, a wide variety of causality assessment scales exist, which attribute clinical events to drugs in individual patients or in case reports. These include World Health Organization (WHO) assessment scale, Naranjo’s scale, Karch and Lasagna’s scale, European ABO system, Bayesian Neural network, etc. Each of such scales have their own advantages and limitations and the categorization of causal relationship between a drug and a suspected ADR varies with the scale adopted. A worldwide procedure for causality assessment of suspected ADRs is yet to be established. The causality categories vary with the countries as different countries use different causality categories.

 WHO Collaborating Center for International Drug Monitoring has used six different terms for causality categorization, with a set of definitions as follows:

1. Certain: A clinical event, including a laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallange) should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary.

2. Probable: A clinical event, including a laboratory test abnormality, with a reasonable time sequence to administration of drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallange). Rechallenge information is not required to fulfill this definition.

3. Possible: A clinical event, including a laboratory test abnormality, with a reasonable time sequence to administration of drug but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.

4. Unlikely: A clinical event, including a laboratory test abnormality, with a temporal relationship to drug administration which makes causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations.

5. Conditional/ Unclassified: A clinical event, including a laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination.

6. Unassessable/ unclassified: A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.

Naranjo’s scale: A simple method to assess the causality of ADRs in a variety of clinical situations was developed by Naranjo et al in 1981. In this scale, the probability that the adverse event was related to drug therapy was classified as definite, probable, possible or doubtful, with each classification having the following definition:

I. Definite: A reaction that:

1. Followed a reasonable temporal sequence after a drug or in which a toxic drug level had been established in body fluids or tissues

2. Followed a recognized response to the suspected drug and

3. Was confirmed by improvement on withdrawing the drug and reappeared on re-exposure. 

II. Probable: A reaction that:

1. Followed a reasonable temporal sequence after a drug

2. Followed a recognized response to the suspected drug

3. Was confirmed by withdrawal but not by re- exposure to the drug and

4. Could not be reasonably explained by the known characteristics of the patient’s state.

III. Possible: A reaction that:

1. Followed a temporal sequence after a drug

2. Possibly followed a recognized pattern to the suspected drug and

3. Could be explained by characteristics of the patient’s disease

IV. Doubtful: A reaction that was likely related to factors other than a drug.

 Categorization of ADRs using Naranjo scale: Different factors used to establish a causal association between drugs and adverse events viz temporal sequence, pattern of response, withdrawal, re-exposure, alternative causes, placebo response, drug levels in body fluids or tissues, dose- response relationship, previous patient experience with the drug, and confirmation by objective evidence are analyzed and scored using the Naranjo ADR scale (See below). Each question can be answered positive (yes), negative (no), or unknown/ inapplicable (do not know). The ADR is assigned to a probability category from the total score as: Definite: ≥ 9, probable: 5 to 8, possible: 1 to 4, doubtful: ≤ 0.

Criteria for determining causative drug’s relationship to ADR

(Naranjo Algorithm)

 The total score calculated from this table defines the category as: possibly (total score 1-4), probably (total score 5-8), definitely (total score > 9)

S. No	Particulars	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 advrse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0
4.	Did the adverse reaction reappear when the drug was readministered?	+2	-1	0
5.	Are there alternative causes (other than the drug) that could solely 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 the blood (or other fluids) in a concentration 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 reaction or similar drugs in any previous exposure?	+1	0	0
10.	Was the adverse event confirmed by objective evidence?	+1	0	0