INTRODUCTION TO
CAUSALITY ASSESSMENT
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HAS THE VACCINE CAUSED THE REACTION?
Reasons for asking this question patient care science legal policy
WHAT IS CAUSALITY ASSESSMENT?
The relating of cause to the effect produced
The assessment and classification of the likelihood of a causal association between a drug (including vaccines) and an adverse event
Terms used in causality assessment definite/likely, probable, possible, unlikely, unclassified/unclassifiable
EVIDENCE FOR CAUSALITY
Biologic hypothesis
Individual cases
Epidemiologic studies
Uncontrolled observational studies
Cohort Case control
BIOLOGICAL HYPOTHESIS
Causal association makes scientific sense Sequelae of natural
infection/administration coincides with vaccine adverse event
Animal experiments show similar reaction as humans
Proposed mechanism demonstrated in vitro/in vivo
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SINGLE CASES/ UNCONTROLLED OBSERVATIONAL STUDIES
Meyboom et al.: 1992
Pharmacological effects Previous knowledge
Clinical characteristicsLab findings
Data quality
Likelihood/exclusion of other causes
CAUSALITY
Association (time, place)
Biological Plausibility
Temporal associationGeographically associatedLocal reactions
ReproducibilityReliability
Rx, risk factors, susceptibility, progamme error
Confident diagnosis of lesion lab results favour causation
ADVERSE DRUG REACTION VS. ADVERSE EVENT
Adverse drug reaction(event attributed to drug)
Adverse event
All spontaneous reports
Events not attributed to drug
Diseases
Other drugs
Environment
DietGenetics
Compliance
Other factors
Programmatic errors
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VACCINES: CAUSALITY ASSESSMENT DIFFICULTIES Challenge/ rechallenge/ dechallenge
a tenuous association with time Dose-related effect Lack of specific marker/ pathognomonic syndrome Adverse event in the background of health at a
vulnerable age Complex composition Immunology versus pharmacology Simultaneous vaccinations Short duration of exposure Vaccine-related/programmatic/coincidental or a
combination of these
Classify and compare
(3) EPIDEMIOLOGIC STUDY: CASE-CONTROL STUDY
//
Begin
Risk factor + Drug A
Risk factor -No drug A
Risk factor + drug A
Risk factor -No drug A
- Cases -People with diseaseor outcome
- Controls -People without disease/outcome
Past Present //
(3) EPIDEMIOLOGIC STUDY: COHORT STUDY
Study population
Free ofdisease
Have outcomealready(exclude)
Risk factor +drug A
Risk factor -No drug A
Disease/outcome +
Disease/outcome -
Disease/outcome +
Disease/outcome -
//Present Future
EPIDEMIOLOGICAL STUDIES
Case control studies
Cohort studies
Adverse event
Yes No Total
Vaccine Yes a b a+bNo c d c+d
Auriche M, Loupi E. Drug Safety 1993; 9 (3): 30-35
Risk ratio= Risk in vaccinated: A/A+BRisk in unvaccinated: C/C+D
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SIGNALWHO Definition for drugs
Reported: possible causal relationship between adverse event and drug
Relationship: previously unknown or incompletely documented
Number of reports for signal - depends on seriousness of event and quality of information
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Kno
wle
dge
of th
e ad
vers
e dr
ug e
ffec
t (%
)
//Signal assessment
Time
Signal generation Strengthening
Signal Signal
DISCOVERY OF AN ADVERSE EFFECT
Follow-up
Meyboom RHB et al Drug Safety 1997;17(6):374-389
0
100
70
20
50
//
A TYPICAL ADR SIGNAL “Diphtheria-tetanus (DTP) - testis disorder
There are 5 reports from Canada of testis disorder with DTP vaccine in male infants aged from 4 months to 4 years. The suspected reaction occurred on the day of immunization in 4 patients and 20 days later in the 5th. The reports were submitted between 1991 and 1995. Three of the children simultaneously received Haemophilus influenzae type B (Hib) and Sabin (live oral polio) vaccines, 1 received Hib only and 1 Sabin vaccine only, with the DTP. Three children also became febrile, 2 of whom had an allergic reaction which, in 1, included salivary gland enlargement and lymphadenopathy. Two children became hypotonic and 1 had pain and vomiting ALL recovered without sequelae.”
HOW WOULD YOU HANDLE THIS?
Is there sufficient evidence for an association? Do you think this is important? What would you do with this information?
Panic and become defensive Ignore it - “it is poor science” Investigate further to validate/invalidate it (if so,
how?) Wait and see Inform other EPI and NRAs internationally
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GOALS OF POST-MARKETING AEFI SURVEILLANCE
Early detection of problems requiring investigation clusters,signals and triggers
Appropriate and quick response Lessen the negative impact Monitor programme and product quality Estimate rates of occurrence of serious events Compare products Determine risk-benefit of vaccine/immunization Validate pre-licensure data
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WHO DEFINITIONS FOR VACCINES
Cluster >= 2 AEFIs, especially if symptoms
are similar, occurring in same place and/or associated with same batch number
Trigger event medical incident that stimulates a
response, usually a case investigation
YOUR DECISION ON CAUSALITY WILL DETERMINE HOW YOU AND OTHERS WILL REACT...
CAUSALITY ASSESSMENT EXERCISES (1)
Case 1Child (4 years old) received measles vaccine as part of campaign at 11h00. Got home and 5 minutes later complained of dry mouth (scratching tongue with fingers), started turning blue around the mouth with shortness of breath.
Child was rushed to hospital and given oxygen,Promethazine (orally) heart rate 180, respiratory rate 24. IV attempted but not successful, child recovered.
CAUSALITY ASSESSMENT EXERCISES (1)
Is this aa) vaccine reaction?
i) expected? ii) unexpected?b) programmatic c) coincidentald) unknowne) injection reaction
What is your level of certainty? likely, probably, possible, unlikely or
unclassifiable What factors were considered when
deciding on causality?
CAUSALITY ASSESSMENT EXERCISE (2) Case 2
2 month old child was given 2nd dose of OPV, Hib, hepatitis B vaccine & measles (first dose). Child had blocked nostrils but otherwise in good health. Baby had protruding umbilical hernia. Mother was asked about any illness and stated he had a blocked nose. Nurse prescribed paracetamol syrup x 3 days and gave stat dose of nasal decongestant for blocked nose. Nose was blocked at first immunization as well. Mother lives on farm – too far from hospital. Baby breast fed later and last feeding was 02:00 that night. Mother became worried when child was breathing very rapidly. Mother-in-law was called and told mother that child probably had cold symptoms and told mother not to worry. Mother went back to sleep and awoke at 5am. Child was found dead beside her.
CAUSALITY ASSESSMENT EXERCISES (2)
Is this aa) vaccine reaction?
i) expected? ii) unexpected?b) programmatic c) coincidentald) unknowne) injection reaction
What is your level of certainty? likely, probably, possible, unlikely or unclassifiable
What factors were considered when deciding on causality?
CASE 2 (FINDINGS OF INVESTIGATIONS)
Mother reported that she gave the child paracetamol syrup that afternoon as she thought the injection site was painful. Post mortem done and found that cause of death was food aspiration.
CAUSALITY ASSESSMENT EXERCISES (3)
Case 3
A 4 year old female immunized against measles and polio at school and was brought to office 15 minutes later by teacher because she was found lying beside her chair. She was administered promethazine, was allowed to sleep and pulse, respiratory rate and colour were observed. She decided to go out and play and again was light-headed and pale and instructed to lie down. Mother was called.
CAUSALITY ASSESSMENT EXERCISES (3)
Is this aa) vaccine reaction?
i) expected? ii) unexpected?b) programmatic c) coincidentald) unknowne) injection reaction
What is your level of certainty? likely, probably, possible, unlikely or unclassifiable
What factors were considered when deciding on causality?
FINDINGS (CASE 3)
The mother reported that over the weekend the little girl’s brother, who was asthmatic, was admitted to hospital and she saw him having an IV infusion which had upset her. In addition, the child had not eaten much for breakfast.
CAUSALITY ASSESSMENT EXERCISES (4)
Case 4 A 21 month old child received her 4th
dose of DTP on her left thigh and measles (site unknown). She developed an injection site abscess which required treatment at a hospital. It was not possible to trace the mother or the child for follow-up.
CAUSALITY ASSESSMENT EXERCISES (4)
Is this aa) vaccine reaction?
i) expected? ii) unexpected?b) programmatic c) coincidentald) unknowne) injection reaction
What is your level of certainty? likely, probably, possible, unlikely or unclassifiable
What factors were considered when deciding on causality?
FINDINGS OF CASE INVESTIGATION (4)
Immunizer was not assessed as there were no babies to vaccinate at the clinic at the time. Cold chain, storage and handling investigated with no problems found. Open multidose vials had not been dated when first used.
CAUSALITY ASSESSMENT EXERCISES (5) 7 month of child with history of neonatal asphyxia
No prior history of seizures Developed repeated generalised clonic and
occasional myoclonic seizures after DTP3 (29/7). Onset – 24 hours – high fever and seizures Seizures continued even after fever. Increasing frequency of seizures not responsive to
carbamazepine Some improvement with benzodiazepine
Delayed milestones CT scan – mild cortical atrophy
Assessment: possible precipitation of
underlying neurological problems with febrile episode post-injection
18 month old male developed abscess after DPT 3 or measles given at outreach centre. Time to onset unclear No other injections given at site. Taken to district hospital Treated unsuccessfully Mother states child was given some medication which increased the swelling. “Haematoma” developed Currently in renal failure.
Diagnosis: Likely Programmatic error complicated by possible mismanagement
CAUSALITY ASSESSMENT EXERCISES (6)
CONCLUSIONS Assessing causality between vaccines and AEFI
can be challenging Are vaccines really different from other drugs? Detailed case investigations improve ability to
assess causality Several methods required to establish causality
of new vaccine reactions (i.e. biological,clinical and epidemiological)
Speculation should be kept to a minimum Causality assessment of individual cases should
consider more than just a temporal relationship Assessment of causality is the first step to
action/inaction
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UNRESOLVED ISSUES... Deciding on trigger events Choosing an appropriate documentation
model/ database Causality assessment model specific to
immunization Differentiate programme-related from
vaccine-related Role of auxiliary data e.g. lab. tests, etc.