ASSESSING CAUSALITY OF ADVERSE DRUG REACTIONS: GLOBAL INTROSPECTION AND ITS LIMITATIONS

 Introduction

Causality assessment essentially means finding a causal association or relationship between a drug and a drug reaction. It is an evaluation of the likelihood that a particular treatment is the cause of an observed adverse event (AE).

This is an important and challenging part of pharmacovigilance, in which attempts are made to find out the exact drug responsible for causing drug reactions. This is important in clinical practice as more and more drugs are flooding the market and are used by our patients and are more likely to cause side effects besides its effects. In the pursuit of efficacy, the safety of these drugs is usually ignored. As the safety of the patients is more important than efficacy, identifying the culprit drugs becomes much more essential. The principles and methods of causality assessment or causality assessment tool (CAT) help clinicians to identify the culprit drugs. There are multiple criteria or algorithms available as of now for establishing a causal relationship in cases of adverse drug reaction (ADR), indicating that none of them is specific or complete. 

Need for Causality Assessment in Dermatology

Causality assessment is important in every discipline of medical practice. Identifying the culprit drug or drugs can be lifesaving or helpful in preventing further damage caused by the drug to our body systems. In dermatology practice, this is much more important and relevant because many etiologies can produce a similar cutaneous manifestation. Many a time, multiple drugs are taken by the patient and it is difficult to ascertain the exact drug responsible for causing a drug reaction and when the underlying disease is capable of producing the same cutaneous manifestation as caused by the drug. Unfortunately, there are no specific diagnostic tests. Although histopathology can provide a clue for the diagnosis of drug reaction, it is not sufficient to point toward a particular drug. Tests such as intradermal tests or patch tests require further standardization in terms of test formulation, timings of the test, etc., and are thus inadequate. However, identifying the exact drug is of paramount importance as it directly influences decision-making by a clinician either to continue or to withdraw the likely drugs.

Principles of Causality Assessment

All causality assessment methods or tools follow 4 cardinal principles of diagnosis of ADR: 

1. temporal relationship of drug with the drug reaction, 

2. biological plausibility, 

3. dechallenge,

4. rechallenge. 

When dechallenge or rechallenge has occurred in the past, it is called a positive prechallenge or negative prechallenge.

Difficulties or Challenges in Developing Causality Assessment Methods

 Identifying causality in polypharmacy is a tricky situation as dechallenge–rechallenge analysis is not possible or permitted for every individual drug that is a part of polypharmacy. Furthermore, there are no objective immunological tests in allergic drug reactions as drug is an incomplete antigen or hapten. Due to these factors, most of the causality assessment methods mentioned below are not full-proof.

Methods of Causality Assessment

Causality assessment methods are broadly classified into clinical judgment or global introspection, algorithms, and probabilistic methods. The total number of methods included in the above classification is 34 methods based on the results of a systematic review. Needless to say, all these methods require input or information from a clinician and thus they are useless unless a clinician gives his/her opinion on a given case.

Clinical Judgment/Global Introspection

Knowledge and experience of the clinician play a very important role in performing global introspection. Dermatologists are at an advantage because many ADRs encountered in dermatology practice are seen on the skin surface and dermatologists are familiar with the pattern of various cutaneous drug reactions. Some of the drugs such as dapsone, phenytoin sodium, and carbamazepine are so notorious to produce some severe cutaneous adverse drug reactions (CADR) in dermatology practice that dermatologists by their prior experience and knowledge are unlikely to miss the ADR and most of the times causality assessment in individual cases can be very accurate. Sharing information about the suspected case of drug reaction with colleagues or experts through e-mail or WhatsApp or with the help of newer tools of communication has helped clinicians in general and dermatologists in particular to improve their clinical acumen or judgment. This has added to the likelihood of establishing a causal relationship in actual clinical practice.

 To impart some degree of uniformity, two methods have been suggested. These are the Swedish method and World Health Organization–Uppsala Monitoring center (WHO–UMC) scale, which is clinic-based or clinical judgment-based CAT. 

Algorithmic Methods

Algorithms are simple and mostly questionnaire-based CAT in which scores are assigned to answers to its questions and the given ADR is categorized into categories such as definite, probable, possible, or unlikely. Some of the commonly available criteria used across the globe are Naranjo's algorithm, Kramer algorithm, Jones algorithm, Karch algorithm Bégaud algorithm, Adverse Drug Reactions Advisory Committee guidelines,, etc. Many of them are also modified. Algorithms are inflexible and have been designed to reduce intra-rater and inter-rater variability to make this CAT more reproducible and valid. 

REFERENCES 

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  WRITTEN BY

 Name: D TIRUMALA

Qualification: MSC MICROBIOLOGY

 ID: CSRPL_INT_ONL_WKD_164/0922

 Email Id: DURVASULATIRUMALA@GMAIL.COM