# Presentation: 018687

## Causality Assessment in postmarketing adverse events

- Anshu Vashishtha MD PhD
- Watson Pharmaceuticals

## Evaluation of causality (Question 3)

- Pros and Cons
- Criteria to consider
- Examples of methods of assessment- WHO Index cases, PRR, Global Clinical Assessment, broad categorization
- Going forward

## Evaluation of causality

- Individual level
- Case Collection
- Importance of Case definition (confirmation of diagnosis): CIOMS , MSSO
- Importance of quality
- Necessity: reported adverse event maybe related to concomitant medication or coexisting disease

## Individual adverse event causality assessment -Pros

- Better case quality and follow up
- Surfaces confounding factors and follow- up needs while case is fresh
- Allows ongoing signal assessment by number of reports considered probably, possibly or unlikely to be related

## Individual adverse event causality assessment -Pros

- More meaningful Package insert
- If reported cases are not considered causally related, may keep those events out of package insert
- If assessed as causally related, allows true risks to be communicated better

## Individual adverse event causality assessment -Cons

- Takes time and resources - some approaches more conducive to large scale application
- Limited by lack of all relevant data in several instances
- Legal liability of sponsor?

## Criteria to consider for causality assessment 

- positive rechallenge
- positive dechallenge (resolution upon stopping suspect drug, in absence of other intervention or treatment)
- known class effect
- biological plausibility
- lack of alternative explanation - concomitant drug or disease
- “typical” adverse drug reaction (low background rate)
- Reference: Guidelines for preparing Core Clinical Safety Information on Drugs
- Report of CIOMS Working Group III, 1995

## Criteria to consider for causality assessment -2

- Dose response
- Lack of concomitant factors (clean subject eg. child)
- Consistency of time to onset eg. early for immediate hypersensitivity or long term for tumorigenesis
- High frequency of reported cases
- Similar findings in toxicity studies
- Reference: Guidelines for preparing Core Clinical Safety Information on Drugs
- Report of CIOMS Working Group III, 1995

## Criteria to consider for causality assessment -3

- Positive *in vitro* test eg. IgE antibodies to allergen and elevated serum serum tryptase in anaphylaxis
- positive *in vivo* test eg. Intradermal or prick test for immediate hypersensitivity or patch test for delayed
- Identified subset at risk or predisposing factor
- Reference: Guidelines for preparing Core Clinical Safety Information on Drugs
- Report of CIOMS Working Group III, 1995

## Criteria to consider for causality assessment -4

- Protopathic bias: drug given to treat early symptoms may appear temporally associated with the subsequent illness
- Stimulated Reporting- recall bias after publicity

## Methods for causality assessment 

- Evaluating Clinical Differential Diagnosis or algorithms
- Factors to judge (Lane and Hutchison , 1986)
- Repeatability
- Explicitness
- Explanatory culpability
- Completeness
- Biological Balancing
- No *a priori* constraints
- From “Detection of New Adverse Drug Reactions” Editor, MDB Stephens, JCC Talbot, PA Routledge, 4th edition

## Methods for causality assessment : WHO index cases

- WHO (Edwards et al , 1990): Three index cases
- “Substantial” Index case has information on all eleven major items and lack of confounding variables (“feasible” on first six)
- Information on source of case, identification of case, description of reaction, name of drug, treatment dates, reaction date,
- age, sex, all drugs with doses and dates, indication for treatment/ underlying disease, outcome
- 1 index case= 2 substantial or 4 feasible cases
- From “Detection of New Adverse Drug Reactions” Editor, MDB Stephens, JCC Talbot, PA Routledge, 4th edition

## Probability of 3 cases occurring with 300,000 treated patients (Begaud et al, 1995)

## Proportional reporting rate 

- PRR AD/ BC
- Signal (PRR >3) + (Chi -squared >5) +(Number of cases>3)
- Remains one aspect of causality assessment subject to usual biases inherent in spontaneous reporting (Waller 1998)

## Evaluation of causality- broad categorization

- Example
- Category A: Good reasons and sufficient documentation to assume causal relationship
- Category B: connection uncertain and even doubtful, eg. Because of missing data
- Category O: Not assessable because of missing or conflicted data
- Causality classification at Pharmacovigilance centers in the European Community;  Meyboom RHB and Royer RJ, Pharmacoepidemiology and Drug Safety , Vol 1: 87-97(1992)

## Evaluation of causality- way forward

- Individual level- research European agencies’ experience (eg. French require causality assessment by sponsors)
- Case Collection- necessary for signal evaluation- WHO, algorithms or global introspection as a guide
- Importance of Case definition (confirmation of diagnosis), good case quality
- Grades of causal likelihood- role of algorithms needs evaluation

## Evaluation of causality- way forward- 2

- Need to
- evaluate existing methods and experience on worldwide basis
- agree on approach to categorization into broad “zones of likely relationship” of reported adverse events
- conduct retrospective evaluation for utility of causal assessment - initially using existing data from FDA database
- consider pilot on certain drugs
- determine overall guidance based on above results