21 CFR

 

Causality Assessment in Pharmacovigilance: Understanding the Likelihood of Adverse Drug Reactions

Pharmacovigilance is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. One important aspect of pharmacovigilance is causality assessment, which involves evaluating the likelihood of a suspected adverse drug reaction (ADR) being caused by a particular medication.

         Causality assessment helps to identify and quantify the risks associated with the use of medications, which can inform regulatory decisions, prescribing practices, and patient education. It is also a complex and challenging process, requiring careful consideration of multiple factors and a thorough understanding of the pharmacology and pathophysiology of the drug and the suspected ADR.

What Causality assessment can do?

Causality assessment in pharmacovigilance serves several important purposes, including:

1. Identification of potential safety concerns: Causality assessment can help identify potential safety concerns with drugs by identifying adverse events that may be related to the use of a particular drug or class of drugs. This information can be used to inform decisions about the use of the drug and to develop appropriate risk management strategies.

2. Signal detection: Causality assessment is an important component of signal detection in pharmacovigilance. By identifying potential adverse drug reactions, causality assessment can help to detect signals of previously unrecognized or underreported drug-related harms.

3. Risk management: Causality assessment can help inform risk management strategies for drugs by identifying potential adverse events and providing information about the likelihood of these events being related to the drug. This information can be used to develop appropriate risk minimization measures, such as changes to product labeling or restrictions on the use of the drug.

4. Pharmacovigilance research: Causality assessment is an important tool in pharmacovigilance research, as it allows researchers to investigate the relationship between drugs and adverse events and to identify potential risk factors for these events. This information can be used to improve drug safety and to inform future drug development.

What Causality assessment cannot do?

While causality assessment is a valuable tool in pharmacovigilance, there are some limitations to what it can do which include:

1. Determine causality with absolute certainty: Causality assessment can only provide an estimate of the likelihood that a particular adverse event is related to the use of a particular drug. It cannot determine causality with absolute certainty, as there may be other factors that could contribute to the occurrence of the adverse event.

2. Substitute for clinical judgment: Causality assessment should be used in conjunction with clinical judgment, as the interpretation of adverse events requires a comprehensive understanding of the patient's medical history, clinical course, and other relevant factors.

3. Account for all possible factors: Causality assessment may not account for all possible factors that could contribute to the occurrence of an adverse event, such as other medications the patient is taking, underlying medical conditions, or lifestyle factors.

4. Predict future events: Causality assessment cannot predict the likelihood of future adverse events, as this will depend on a range of factors that may be difficult to predict.

5. Provide definitive evidence of causality: Causality assessment can provide evidence that a particular drug is associated with an adverse event, but it cannot definitively prove causality. Additional research may be required to establish a causal relationship between the drug and the adverse event.

Factors that are considered in causality assessment include:

1. Temporal Relationship: The timing of the ADR in relation to the drug exposure is an important factor in determining causality. If the ADR occurs shortly after the administration of the drug and resolves after discontinuation of the drug, this suggests a causal relationship.

2. Dose-Response Relationship: A dose-response relationship between the drug and the ADR can also provide evidence of causality. If the severity of the ADR increases with higher doses of the drug, this suggests that the drug is responsible for the ADR.

3. Rechallenge: If the ADR recurs when the drug is re-administered after being discontinued, this provides strong evidence of a causal relationship between the drug and the ADR.

4. Alternative Explanations: It is important to consider other possible explanations for the ADR, such as underlying medical conditions or concomitant medications, before concluding that the drug caused the ADR.

5. Pharmacological Plausibility: It is important to consider the pharmacological properties of the drug and the pathophysiology of the ADR to determine whether a causal relationship is biologically plausible.

Methods for conducting causality assessment in pharmacovigilance include:

1. The Naranjo algorithm: The Naranjo algorithm is a widely used method for causality assessment that was developed in 1981 by a Spanish psychiatrist named César A. Naranjo. It consists of 10 questions that assess the likelihood of a drug causing an adverse event, with scores ranging from -4 to +13. The algorithm is easy to use and has been validated in several studies, but it has some limitations, such as the subjective nature of some of the questions and the fact that it does not take into account patient-specific factors.

             Here is a table summarizing some of the criteria used in the Naranjo algorithm:

Criteria	Score
Are there previous conclusive reports on this reaction?	+1
Did the adverse event appear after the suspected drug was administered?	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1
Did the adverse reaction reappear when the drug was    readministered?	+2
Are there alternative causes that could have caused the reaction?	+2
Did the reaction reappear when a placebo was given?	-1
Was the drug detected in the blood or other fluids in concentrations known to be toxic?	-1
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1
Was the adverse event confirmed by any objective evidence?	+1

2. The WHO-UMC system: The WHO-UMC system is a causality assessment method developed by the World Health Organization's Uppsala Monitoring Centre. It consists of six levels of causality, ranging from "certain" to "unlikely," based on a combination of factors such as the temporal relationship between the drug and the adverse event, the clinical course of the event, and the presence of other factors that could explain the event.

3. The CIOMS/RUCAM scale: The CIOMS/RUCAM scale is a method developed by the Council for International Organizations of Medical Sciences (CIOMS) and the Roussel Uclaf Causality Assessment Method (RUCAM). It consists of seven domains that assess the likelihood of a drug causing an adverse event, with scores ranging from -5 to +10. The domains include factors such as the time to onset of the event, the course of the event, the dechallenge/rechallenge effect, and the risk factors for the event.

4. The Liverpool Causality Assessment Tool (LCAT): The Liverpool Causality Assessment Tool (LCAT) is a method developed by the University of Liverpool that consists of seven domains that assess the likelihood of a drug causing an adverse event, with scores ranging from 0 to 14. The domains include factors such as the timing of the event with regard to exposure to the drug, the known association of the drug with the adverse event, and the response to rechallenge or dechallenge.

Here is an example of the Liverpool Causality Assessment Tool (LCAT) applied to a hypothetical case:

Evidence	Weighing
Timing of event with regard to exposure to drug	3
Known association with drug or class of drugs	3
Response to rechallenge or dechallenge	2
Plausibility of mechanism of toxicity	1
Other causes excluded	2
Previous conclusive reports on this reaction	0
Total	11

A score of 6 or more indicates that the adverse reaction is possibly, probably, or definitely related to the drug.

5. The use of imaging in causality assessment: Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) can be used to visualize drug-related changes in organs or tissues. For example, CT scans can detect drug-induced liver injury, MRI can detect drug-induced neurotoxicity, and 

PET can detect drug-induced changes in brain function. However, the interpretation of imaging studies requires expert knowledge and should be used in conjunction with other criteria and methods of causality assessment.

Conclusion:

Causality assessment is a critical component of pharmacovigilance, providing valuable information on the safety of medications and informing regulatory decisions and patient care. It is a complex process that requires careful consideration of multiple factors, and the use of standardized tools can help to ensure consistency and accuracy in the assessment.

References:

1. World Health Organization (WHO). The Importance of Pharmacovigilance 2002. https://www.who.int/medicines/services/inn/pharmacovigilance/en/

2. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30(2):239-245. doi:10.1038/clpt.1981.154

3. The Uppsala Monitoring Centre. WHO-Uppsala Monitoring Centre Causality Assessment System. 2018. https://www.who-umc.org/global-pharmacovigilance/who-causality-assessment/

4. Liverpool Drug Interactions Group. Liverpool Causality Assessment Tool. 2020. https://www.liv.ac.uk/drug-drug-interactions/causalityassessment/

Student Name: Kusum Bang

Student ID: 025/022023

Qualification: M. Pharmacy

E-mail Id: Kusumbang26@gmail.com