19. Causality Assessment

Causality assessment is the assessment of relationship between a treatment drug and the occurrence of an adverse event. It is also used to evaluate and to check that the particular treatment is the cause of an observed adverse event or not and also to understand how close is the relationship between treatment drug and event.

As part of the case-level review, regulatory authorities mandated assessment of causality relationship between the use of a product and the adverse event for better evaluation of the benefit/harm profile of drugs, signal detection and to evaluate ADR reports in early warning systems. 

For any individual case safety report, it is rarely possible to know with a high level of certainty whether the event was caused by the product. To date, there are no internationally agreed upon standards or criteria for assessing causality in individual cases, especially for events that often occur spontaneously (e.g. stroke, pulmonary embolism).

Causality assessment in different type of reports: 

For clinical trial cases the assessment of whether there is a reasonable possi­bility of a causal relationship is usually made by the investigator. In the absence of information on causality from the reporting investigator, the sponsor should consult the reporting investigator and encourage him to express an opinion on this aspect. The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, the opinion of both the investigator and the sponsor should be provided with the report. 

For literature reports as per validity criteria only suspected adverse reactions are considered as events and author will provide the causality assessment in article. 

For all spontaneous reports of serious unlabelled reactions made by medical professionals should be considered as expedited reports. However, submission of such a report does not necessarily constitute an acceptance of causality by a manufacturer.” (CIOMS Guidance). For spontaneous reports, the applicant should assume that an adverse experience or fatal outcome was suspected to be due to the suspect drug or biological product (implied causality).” (FDA Guidance)

Along with reporter causality the manufacturers also need to perform causality assessment.

Data required to perform causality assessment in individual case safety reports: 

1. Medicinal products: All medicines that patient receiving during the time of the event onset – Including start date and stop date, doses and indications
2. Adverse event: The detailed event description – Including date of onset, duration to onset and outcome of the event
3. Dechallenge & rechallenge information. 
4. Patient medical history – including past diseases of importance (e.g. hepatitis) and other current diseases (co-morbidities) (e.g. tuberculosis, diabetes)

Points to be considered to perform causality assessment from the data: 

1. Medical products: 

• Occurrence of the adverse event in the expected time (e.g., type 1 allergic reactions occurring within days of therapy, cancers developing after years of therapy)
• Need to check existence of supporting evidence from preclinical studies,  medical literature, the official labeling of the manufacturer’s files clinical trials, and/or pharmacoepidemiologic studies. From the evidence we need to understand the frequency of the reported event with the product, assess if event is pharmacologically predictable. 
• Consistency of the event with the established pharmacological/toxicological effects of the product, or for vaccines, consistency with established infectious or immunologic mechanisms of injury
• Consistency of the event with the known effects of other products in the class.
• Predisposing factors related to product exposure (overdose, mode of administration, medication error – e.g., prescribing/order process, dispensing process, administration process)
• Apart from suspect medication if patient is taking any concomitant medication then we need to check potential suspects apart from the suspect drug or any potential for a drug–drug interaction.

2. Adverse Event:

• Whether event is drug-related in general (e.g., aplastic anemia, bullous toxidermia, fixed-drug eruption, neuroleptic malignant syndrome, acute liver failure, statins and rhabdomyolysis, SSRIs and the serotoninergic syndrome, anti-HIVs and lipodystrophy, isotretinoin and congenital anomaly, amiodarone and corneal cat’s paw deposits)
• Available clinical or laboratory data of the AE generally suggestive of a drug reaction (e.g., drug-induced hepatitis).
• Event is the location specific (e.g, Site of application (skin…), transit (esophagus), concentration (kidney…), excretion (lithiasis…).
• Time to onset: A short time to onset is often very suggestive but its duration should be plausible and consistent with the pharmacodynamics and the kinetics of the suspect product.
• Duration of AE before stopping or reducing the dosage or after a single dose
• Response to corrective treatment

3. Patient’s History:

• Event is exacerbation of pre existing condition or not.
• Absence of symptoms related to the event prior to product exposure
• History including same event before taking the medicine, if yes then understand the cause of prior exposure whether it is because of same medicine (pre-challenge) or class of medicine and circumstances lead to the condition.
• Predisposing factors present related to the patient’s condition (e.g., renal failure, allergy, age, sex, weight…)

4. Dechallange and Rechallenge information: 

A positive Dechallange and positive Rechallenge suggest favoring causality. 

Dechallenge: The withdrawal of a drug from a patient; the point at which the continuity, reduction or disappearance of adverse effects may be observed. 

• Positive Dechallenge: If the patient showed reduction or disappearance of adverse effects after withdrawal of a drug is Positive Dechallenge.
• Negative Dechallenge: If the patient did not show reduction or disappearance of adverse effects after withdrawal of a drug is Negative Dechallenge.

Rechallenge: The point at which a drug is again given to a patient after its previous withdrawal 

• Positive Rechallenge: If the patient showed return of adverse effects after restart of a drug is Positive Rechallenge.
• Negative Rechallenge: If the patient did not show return of adverse effects after restart of a drug is Negative Rechallenge.

Confounded cases: cases with adverse events that have possible etiologies other than the product of concern 

Relationship categories in causality assessment:

• Level 4 – Definite ( > 95% confidence in causality)
• Level 3 – Probable (50% to 95% confidence in causality)
• Level 2 – Possible (5% to 50% confidence in causality)
• Level 1 – Unlikely, doubtful ( <5% but not 0% confidence in causality)
• Level 0 – Causality assessment impossible (insufficient case data)
• Level -1 – Causality ruled out (after reviewing the case data)

Next post will be on detailed review of Relationship categories …..