07 what is casuality assesment

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  • This is a table which shows you the way in which a drug -event relationship can be established You can either start with the drug or the adverse event.
  • In this case, the patient above experienced severe pain and swelling after receiving TT vaccine. She had received several doses of TT vaccine during campaigns and pregnancy. To alleviate the pain she put a glass bottle (Coke bottle) of boiling water and applied it to the injection site. Therefore in addition to a local reaction, the patient also developed burns to the skin. (vaccine reaction complicated by mismanagement by the patient). One could discuss what should be done in this situation.
  • ? Time of onset, ? Prior history of seizures
  • 07 what is casuality assesment

    1. 1. INTRODUCTION TO CAUSALITY ASSESSMENT
    2. 2. HAS THE VACCINE CAUSED THE REACTION? <ul><li>Reasons for asking this question </li></ul><ul><ul><li>patient care </li></ul></ul><ul><ul><li>science </li></ul></ul><ul><ul><li>legal </li></ul></ul><ul><ul><li>policy </li></ul></ul>
    3. 3. WHAT IS CAUSALITY ASSESSMENT? <ul><li>The relating of cause to the effect produced </li></ul><ul><li>The assessment and classification of the likelihood of a causal association between a drug (including vaccines) and an adverse event </li></ul><ul><li>Terms used in causality assessment definite/likely, probable, possible, unlikely, unclassified/unclassifiable </li></ul>
    4. 4. EVIDENCE FOR CAUSALITY Biologic hypothesis Individual cases Epidemiologic studies Uncontrolled observational studies Cohort Case control
    5. 5. BIOLOGICAL HYPOTHESIS <ul><li>Causal association makes scientific sense </li></ul><ul><li>Sequelae of natural infection/administration coincides with vaccine adverse event </li></ul><ul><li>Animal experiments show similar reaction as humans </li></ul><ul><li>Proposed mechanism demonstrated in vitro/in vivo </li></ul>
    6. 6. SINGLE CASES/ UNCONTROLLED OBSERVATIONAL STUDIES Meyboom et al.: 1992 Pharmacological effects Previous knowledge Clinical characteristics Lab findings Data quality Likelihood/exclusion of other causes CAUSALITY Association (time, place ) Biological Plausibility Temporal association Geographically associated Local reactions Reproducibility Reliability Rx, risk factors, susceptibility, progamme error Confident diagnosis of lesion lab results favour causation
    7. 7. 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 Diet Genetics Compliance Other factors Programmatic errors
    8. 8. VACCINES: CAUSALITY ASSESSMENT DIFFICULTIES <ul><li>Challenge/ rechallenge/ dechallenge </li></ul><ul><ul><li>a tenuous association with time </li></ul></ul><ul><li>Dose-related effect </li></ul><ul><li>Lack of specific marker/ pathognomonic syndrome </li></ul><ul><li>Adverse event in the background of health at a vulnerable age </li></ul><ul><li>Complex composition </li></ul><ul><li>Immunology versus pharmacology </li></ul><ul><li>Simultaneous vaccinations </li></ul><ul><li>Short duration of exposure </li></ul><ul><li>Vaccine-related/programmatic/coincidental or a combination of these </li></ul>
    9. 9. 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 disease or outcome - Controls - People without disease/outcome Past Present //
    10. 10. (3) EPIDEMIOLOGIC STUDY: COHORT STUDY Study population Free of disease Have outcome already (exclude) Risk factor + drug A Risk factor - No drug A Disease/outcome + Disease/outcome - Disease/outcome + Disease/outcome - // Present Future
    11. 11. EPIDEMIOLOGICAL STUDIES Case control studies Cohort studies Adverse event Yes No Total Vaccine Yes a b a+b No c d c+d Auriche M, Loupi E. Drug Safety 1993; 9 (3): 30-35 Risk ratio= Risk in vaccinated: A/A+B Risk in unvaccinated: C/C+D
    12. 12. SIGNAL <ul><li>WHO Definition for drugs </li></ul><ul><li>Reported: possible causal relationship between adverse event and drug </li></ul><ul><li>Relationship: previously unknown or incompletely documented </li></ul><ul><li>Number of reports for signal - depends on seriousness of event and quality of information </li></ul>
    13. 13. Knowledge of the adverse drug effect (%) // 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 //
    14. 14. A TYPICAL ADR SIGNAL <ul><li>“ Diphtheria-tetanus (DTP) - testis disorder </li></ul><ul><li>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. </li></ul><ul><li>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.” </li></ul>
    15. 15. HOW WOULD YOU HANDLE THIS? <ul><li>Is there sufficient evidence for an association? </li></ul><ul><li>Do you think this is important? </li></ul><ul><li>What would you do with this information? </li></ul><ul><ul><li>Panic and become defensive </li></ul></ul><ul><ul><li>Ignore it - “it is poor science” </li></ul></ul><ul><ul><li>Investigate further to validate/invalidate it (if so, how?) </li></ul></ul><ul><ul><li>Wait and see </li></ul></ul><ul><ul><li>Inform other EPI and NRAs internationally </li></ul></ul>
    16. 16. GOALS OF POST-MARKETING AEFI SURVEILLANCE <ul><li>Early detection of problems requiring investigation </li></ul><ul><ul><li>clusters,signals and triggers </li></ul></ul><ul><li>Appropriate and quick response </li></ul><ul><li>Lessen the negative impact </li></ul><ul><li>Monitor programme and product quality </li></ul><ul><li>Estimate rates of occurrence of serious events </li></ul><ul><li>Compare products </li></ul><ul><li>Determine risk-benefit of vaccine/immunization </li></ul><ul><li>Validate pre-licensure data </li></ul>
    17. 17. WHO DEFINITIONS FOR VACCINES <ul><li>Cluster </li></ul><ul><ul><li>>= 2 AEFIs, especially if symptoms are similar, occurring in same place and/or associated with same batch number </li></ul></ul><ul><li>Trigger event </li></ul><ul><ul><li>medical incident that stimulates a response, usually a case investigation </li></ul></ul>
    18. 18. YOUR DECISION ON CAUSALITY WILL DETERMINE HOW YOU AND OTHERS WILL REACT ...
    19. 19. CAUSALITY ASSESSMENT EXERCISES (1) <ul><li>Case 1 </li></ul><ul><li>Child (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. </li></ul>Child was rushed to hospital and given oxygen, Promethazine (orally) heart rate 180, respiratory rate 24. IV attempted but not successful, child recovered.
    20. 20. CAUSALITY ASSESSMENT EXERCISES (1) <ul><li>Is this a </li></ul><ul><ul><li>a) vaccine reaction? </li></ul></ul><ul><ul><li> i) expected? </li></ul></ul><ul><ul><li>ii) unexpected? </li></ul></ul><ul><ul><li>b) programmatic </li></ul></ul><ul><ul><li>c) coincidental </li></ul></ul><ul><ul><li>d) unknown </li></ul></ul><ul><ul><li>e) injection reaction </li></ul></ul><ul><li>What is your level of certainty? </li></ul><ul><ul><li>likely, probably, possible, unlikely or unclassifiable </li></ul></ul><ul><li>What factors were considered when deciding on causality? </li></ul>
    21. 21. CAUSALITY ASSESSMENT EXERCISE (2) <ul><li>Case 2 </li></ul><ul><li>2 month old child was given 2 nd 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. </li></ul>
    22. 22. CAUSALITY ASSESSMENT EXERCISES (2) <ul><li>Is this a </li></ul><ul><ul><li>a) vaccine reaction? </li></ul></ul><ul><ul><li> i) expected? </li></ul></ul><ul><ul><li>ii) unexpected? </li></ul></ul><ul><ul><li>b) programmatic </li></ul></ul><ul><ul><li>c) coincidental </li></ul></ul><ul><ul><li>d) unknown </li></ul></ul><ul><ul><li>e) injection reaction </li></ul></ul><ul><li>What is your level of certainty? </li></ul><ul><ul><li>likely, probably, possible, unlikely or unclassifiable </li></ul></ul><ul><li>What factors were considered when deciding on causality? </li></ul>
    23. 23. CASE 2 (FINDINGS OF INVESTIGATIONS) <ul><li>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. </li></ul>
    24. 24. CAUSALITY ASSESSMENT EXERCISES (3) <ul><li>Case 3 </li></ul><ul><li>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. </li></ul>
    25. 25. CAUSALITY ASSESSMENT EXERCISES (3) <ul><li>Is this a </li></ul><ul><ul><li>a) vaccine reaction? </li></ul></ul><ul><ul><li> i) expected? </li></ul></ul><ul><ul><li>ii) unexpected? </li></ul></ul><ul><ul><li>b) programmatic </li></ul></ul><ul><ul><li>c) coincidental </li></ul></ul><ul><ul><li>d) unknown </li></ul></ul><ul><ul><li>e) injection reaction </li></ul></ul><ul><li>What is your level of certainty? </li></ul><ul><ul><li>likely, probably, possible, unlikely or unclassifiable </li></ul></ul><ul><li>What factors were considered when deciding on causality? </li></ul>
    26. 26. FINDINGS (CASE 3) <ul><li>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. </li></ul>
    27. 27. CAUSALITY ASSESSMENT EXERCISES (4) <ul><li>Case 4 </li></ul><ul><li>A 21 month old child received her 4 th 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. </li></ul>
    28. 28. CAUSALITY ASSESSMENT EXERCISES (4) <ul><li>Is this a </li></ul><ul><ul><li>a) vaccine reaction? </li></ul></ul><ul><ul><li> i) expected? </li></ul></ul><ul><ul><li>ii) unexpected? </li></ul></ul><ul><ul><li>b) programmatic </li></ul></ul><ul><ul><li>c) coincidental </li></ul></ul><ul><ul><li>d) unknown </li></ul></ul><ul><ul><li>e) injection reaction </li></ul></ul><ul><li>What is your level of certainty? </li></ul><ul><ul><li>likely, probably, possible, unlikely or unclassifiable </li></ul></ul><ul><li>What factors were considered when deciding on causality? </li></ul>
    29. 29. FINDINGS OF CASE INVESTIGATION (4) <ul><li>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. </li></ul>
    30. 30. CAUSALITY ASSESSMENT EXERCISES (5) <ul><li>7 month of child with history of neonatal asphyxia </li></ul><ul><li>No prior history of seizures </li></ul><ul><li>Developed repeated generalised clonic and occasional myoclonic seizures after DTP3 (29/7). </li></ul><ul><li>Onset – 24 hours – high fever and seizures </li></ul><ul><li>Seizures continued even after fever. </li></ul><ul><li>Increasing frequency of seizures not responsive to carbamazepine </li></ul><ul><ul><li>Some improvement with benzodiazepine </li></ul></ul><ul><li>Delayed milestones </li></ul><ul><li>CT scan – mild cortical atrophy </li></ul>Assessment: possible precipitation of underlying neurological problems with febrile episode post-injection
    31. 31. <ul><li>18 month old male </li></ul><ul><li>developed abscess after </li></ul><ul><li>DPT 3 or measles given </li></ul><ul><li>at outreach centre. </li></ul><ul><li>Time to onset unclear </li></ul><ul><li>No other injections given </li></ul><ul><li>at site. </li></ul><ul><li>Taken to district hospital </li></ul><ul><li>Treated unsuccessfully </li></ul><ul><li>Mother states child </li></ul><ul><li>was given some </li></ul><ul><li>medication which </li></ul><ul><li>increased the swelling. </li></ul><ul><li>“ Haematoma” developed </li></ul><ul><li>Currently in renal failure. </li></ul>Diagnosis: Likely Programmatic error complicated by possible mismanagement CAUSALITY ASSESSMENT EXERCISES (6)
    32. 32. CONCLUSIONS <ul><li>Assessing causality between vaccines and AEFI can be challenging </li></ul><ul><li>Are vaccines really different from other drugs? </li></ul><ul><li>Detailed case investigations improve ability to assess causality </li></ul><ul><li>Several methods required to establish causality of new vaccine reactions (i.e. biological,clinical and epidemiological) </li></ul><ul><li>Speculation should be kept to a minimum </li></ul><ul><li>Causality assessment of individual cases should consider more than just a temporal relationship </li></ul><ul><li>Assessment of causality is the first step to action/inaction </li></ul>
    33. 33. UNRESOLVED ISSUES... <ul><li>Deciding on trigger events </li></ul><ul><li>Choosing an appropriate documentation model/ database </li></ul><ul><li>Causality assessment model specific to immunization </li></ul><ul><li>Differentiate programme-related from vaccine-related </li></ul><ul><li>Role of auxiliary data e.g. lab. tests, etc. </li></ul>

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