07 what is casuality assesment

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


- 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


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

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of th

e ad

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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.


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.




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.


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.

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.


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.

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


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.

07 what is casuality assesment

Health & Medicine

adverse drug effect

adverse drug reactionvs

drug relationship

drug safety

drug diseases

b risk

adverse event terms

risk factors