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)
One month Expected number Agranulocytosis TEN Guillain Barre Synd P of 3 cases One year Expected number P of 3 cases

0.150 0.030 0.625

0.0005

1.800

0.27 0.006 0.98

0.00000 0.360 4 0.026 7.500

Proportional reporting rate

Drug of interest A All other drugs B D

PRR AD/ BC

Reaction of interest All other C reactions

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