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Causality assessment,methods,pharmacovigilance

pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com

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Causality assessment,methods,pharmacovigilance

  1. 1. CAUSALITY ASSESSMENT Gaurav Chhabra M-Pharm II Sem. (Pharmacology) UIPS, Panjab University, Chandigarh
  2. 2. INTRODUCTION PHARMACOVIGILANCE Pharmaco + Vigilance (Medicines) (To Watch) According to WHO-:  Science and activities relating to the detection, assessment, understanding and prevention of adverse effects and any other drug related problems.  This applies throughout the life cycle of a medicine equally to the pre-approval stage as to the post approval.
  3. 3. Adverse reaction: “A response to a medicine which is noxious and unintended, and which occurs at doses normally used in man” Adverse event: Any new clinical experience that occurs after starting a medicine, not necessarily a response to a medicine, and is recorded without judgement on its causality.
  4. 4.  These adverse drug reactions (ADRs) not only add to the suffering of patients but also increase morbidity and mortality along with a financial burden on society.  The overall incidence of ADRs in hospitalized patients is estimated to be 6.7 %( range 1.2–24.1%) and that of fatal ADRs 0.32% (0.1– 0.85%)  Data indicates that in patients who experience ADRs death rates are 19.18% higher and the length of hospital stay is 8.25% higher.  Total medical costs for patients with ADRs are increased by an average of 19.86%  So to minimize the suffering of the patient from ADRs, there is an establishment of causal relationship is done between drug and their adverse events, called as Causality Assessment.
  5. 5. CAUSALITY ASSESSMENT Definition:-  Causality assessment is the assessment of relationship between a drug treatment and the occurrence of an adverse event.  It is also used to evaluate and to check that the particular treatment is the cause of an observed adverse event or not.  It is an essential part of ADR report and important task, conducted by National Pharmacovigilance Programme in each country.
  6. 6. Objectives of Causality Assessment  Provide relationship between the drug and events.  Signal detection(“a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously".)  Provide better evaluation of the benefit/harm profiles of drugs.  Plays as an essential part of evaluating ADR reports in early warning systems and for regulatory purposes.
  7. 7. How The Causality Assessment is Performed ? (Methods Of Causality Assessment)  Many researchers developed various methods of causality assessment by using different criteria like- Chronological relationship between the administration of the drug and the occurrence of the ADR, Screening for drug and non drug related causes, Confirmation of the reaction by in vivo or in vitro test, Previous information on similar events etc.  But there is No universally accepted method for assessing causality of ADRs.
  8. 8. METHODS Classified under three broad categories Expert Judgement/ Algorithms Probabilistic Methods Global Introspection Dangaumou’s french method Australian method  Swedish method by Kramer et al. method Bayesian Adverse Reactions Wilholm et al Naranjo scale Diagnostic Instrument (BARDI)  World Health Organization Balanced assessment method MacBARDI spreadsheet (WHO) - Uppsala Monitoring Drug Interaction Probability Centre (UMC) causality Scale(DIPS) etc. assessment criteria Causality Assessment Of Vaccine Related Adverse Events
  9. 9. (A) EXPERT JUDGEMENT/GLOBAL INTROSPECTION  It is a process in which an expert expresses judgement about possible drug causation by considering al available data relevant to a suspected ADR.  Assessment of ADR is either done by single expert evaluator or by a group of expert evaluators.  As evaluation and assessment of ADR by these experts is purely based on their respective knowledge and experience about the subject of interest.  Two methods based on expert opinion or global introspection. (1) Swedish method by Wilholm et al. (2) World Health Organization (WHO) - Uppsala Monitoring Centre (UMC) causality assessment criteria.
  10. 10. (A)(2) World Health Organization (WHO) - Uppsala Monitoring Centre (UMC) causality assessment criteria  Widely and globally accepted method.  WHO-UMC system provides practical tool for assessment of case reports for International drug monitoring  System is used to detect unknown and unexpected adverse drug reaction. Assessment is based on following four criteria-: a) Time relationships between the drug use and the adverse event. b) Absence of other competing causes (medications, disease process itself). c) Response to drug withdrawal or dose reduction (de-challenge). d) Response to drug re-administration (re-challenge).  the level of causal association is grouped into four categories which are based on a number of the above criteria being met. CONTI……….
  11. 11. Causality association  Certain  Probable  Possible  Unlikely CERTAIN-: When all the four criteria(a,b,c,d) are met. PROBABLE-:When criteria a, b and c are met. POSSIBLE-: When only criteria a is met. UNLIKELY-:When criteria a and b are not met.  Beside these four categories, ADR can also be categorized into:- Unclassified/Conditional Unassessable/ Unclassifiable Unclassified/Conditional-: Applied when more data is needed and such data is being sought or is already under examination. Unassessable/ Unclassifiable-:Finally when the information in a report is incomplete or contradictory and cannot be verified, then it is Unclassifiable.
  12. 12. Causality term Assessment criteria (all points should be reasonably complied) Certain  Event or laboratory test abnormality, with plausible time relationship to drug intake  Cannot be explained by disease or other drugs  Response to withdrawal plausible (pharmacologically, pathologically)  Event definitive pharmacologically or phenomenologically (ie. an objective and specific medical disorder or a recognized pharmacologic phenomenon)  Rechallenge satisfactory, if necessary Probable/likely  Event or laboratory test abnormality, with reasonable time relationship to drug intake  Unlikely to be attributed to disease or other drugs  Response to withdrawal clinically reasonable  Rechallenge not required Possible  Event or laboratory test abnormality, with reasonable time relationship to drug intake  Could also be explained by disease or other drugs  Information on drug withdrawal may be lacking or unclear Unlikely  Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible)  Disease or other drugs provide plausible explanation Conditional/unclassifie d  Event or laboratory test abnormality  More data for proper assessment needed, or  Additional data under examination Unassessable/unclassif iable  Report suggesting an adverse reaction  Cannot be judged because information is insufficient or contradictory  Data cannot be supplemented or verified.
  13. 13. IN SIMPLE WAY  Certain – Good timing, no other cause, withdrawal response plausible, rechallenge “definitive”  Probable – Good timing, other cause unlikely, withdrawal  Possible – Good timing, other causes possible  Unlikely – Poor timing, other causes more likely  Unassessable – Insufficient or contradictory information
  14. 14. 14 Categories of Causality using WHO Causality Assessment Criteria Very likely Probable Possible Vaccine reaction Injection Reaction Programmatic error Coincidental events Unclassifiable Insufficient evidence to classify Unlikely Unrelated
  15. 15. EXAMPLE: CERTAIN  Dizziness ¾ hour after ingestion of an oral antihypertensive drug with no concomitant drugs – AE stops on stopping drug (positive dechallenge) & restarts when taken again (positive rechallenge).  Injection site reaction 30 seconds after a subcutaneous injection.  A large tablet gets stuck in the pharynx (obstruction) while swallowing it & it has to be removed in the ER.
  16. 16. EXAMPLE: PROBABLY  Thrombocytopenia after taking an oncology drug.  Diarrhea after ampicillin.  Vaginal candidiasis after an antibiotic for bronchitis. EXAMPLE: POSSIBLY  Abnormal liver function tests after taking an antihistamine.  Headache.  Dyspepsia after a tablet or capsule.
  17. 17. Examples: Unlikely  Cancer of the colon diagnosed after 3 doses of an antibiotic.  Myocardial infarction 3 weeks after taking a drug that has a terminal half life of 10 minutes.  Auto accident but… – Did the drug cause dizziness which caused the accident?
  18. 18. CASE REPORT-1  Female-76 years  Rx Pamidronic acid I.V. - 23/08/06  Other medications- Letrozole, simvastatin  Adr.- Synovitis, influenza like symptoms, skeletal pain. : 23/08/06  Dechallenge- Reaction abated  Letrozole, Simvastatin  Que. - Assessment related to the drug? Probable
  19. 19. CASE REPORT-2  Female-68 years  Rx Pamidronate- 30mg. - 15/01/97  Adr.-Arthrosis, Arthritis aggravated. 18/01/97  Outcome- Not recovered  Dechallenge- Negative  Que. - Assessment related to the drug? Possible
  20. 20. Case Report-3  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.  is this a a) vaccine reaction? i) expected? ii) unexpected? b) programmatic c) coincidental d) unknown e) injection reaction  What is your level of certainty?  likely, probably, possible, unlikely or unclassifiable  What factors were considered when deciding on causality? 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.
  21. 21. Case Report-4  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
  22. 22. (2) ALGORITHMS  It consists of a problem-specific flow chart with step-by-step instruction on how to arrive at an answer.  Actually, its form contain some questionnaire, whose answers provide the causality of particular ADR.  It give structured and standardized methods of assessment in a systematic approach.  Assessment of ADRs based on parameters such as Time to onset of the ADR or temporal sequence, Previous drug/adverse reaction history, Dechallenge and Rechallenge
  23. 23. Types Of Algorithms Method There are many algorithmic methods of causality assessment but no single algorithm is accepted as the “gold standard‟, because of many shortcomings. Important Algorithmic Methods are-  Dangaumou’s french method  Kramer et al. method  Naranjo et al. method (Naranjo scale)  Balanced assessment method (Lagier et al.)  Summary time plot (Castle et al.)  Ciba geigy method (Venulet et al.)  Roussel Uclaf causality assessment method (RUCAM)  Maria and Victorino (M and V) scale  Drug Interaction Probability Scale (DIPS)
  24. 24. (B)Naranjo et al. method (Naranjo scale)  Widely accepted method  Method used determine the likelihood of whether an ADR (adverse drug reaction) is actually due to the drug rather than the result of other factors.  It consists of ten questions that are answered as “yes‟, “no‟, “unknown” (don‟t know)  These answers are assigned via a score termed Definite, Probable, Possible Or Doubtful. Definite- when a total score of ≥ 9. Probable- when a total score of 5–8. Possible- when a total score of 1–4. Doubtful- when a total score of ≤ 0.
  25. 25. Table:- The Naranjo adverse drug reaction probability scale; To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score Yes No Do not know 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event occur after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could have on their own caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? +1 +2 +1 +2 -1 -1 +1 +1 +1 +1 0 -1 0 -1 +2 +1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Total score 0– Doubtful 1–4 Possible 5–8 Probable ≥9 Definite Limitation-: Method only explains the causality of one individual drug Not explains the causality occur due to drug interactions
  26. 26. (3)-PROBABILISTIC OR BAYESIAN APPROACHES  Causality assessment based on study of prior probability and posterior probability.  The prior probability is calculated from epidemiological information.  The posterior probability combines this epidiological background information with the evidence in the individual case.  This method allows the simultaneous assessment of multiple causes.
  27. 27. (3)(1)Bayesian Adverse Reactions Diagnostic Instrument (BARDI)  BARDI is used to calculate the odds in favour of a particular drug causing an adverse event compared with an alternative cause(posterior odds)  The posterior odds factor is calculated by considering six assessment subsets: one deals with background epidemiologic or clinical trials information (the prior odds) and the other five deal with case specific information (the likelihood ratios). PsO = PrO × LR(Hi) × LR(Ti) × LR(Ch) × LR(De) × LR(Re) • Pro(the prior odds)- epidemiologic or clinical trials information • The five likelihood ratios (LRs) deal with any information of differential diagnostic value under • patient history (Hi) • timing of the adverse event with respect to drug administration (Ti) • characteristics of the adverse event (Ch) • drug dechallenge (De) • drug rechallenge (Re)
  28. 28. (4) CAUSALITY ASSESSMENT OF VACCINE RELATED ADVERSE EVENTS  Vaccines are administered on large scale to healthy individuals, children, infants and neonates.  So vaccines must meet with high degree of safety.  Method developed by the Advisory Committee on Causality Assessment (ACCA) in Canada.  ACCA is composed of specialist in pediatrics, epidemiology, infectious diseases, immunology, neurology, pathology, adverse event surveillance, and microbiology  They review individual cases in a systematic stepwise manner to categorize them on a specially designed causality assessment form.  This causality assessment form consists of seven sections. Section one Section two Section three Section four Section five Section six Section seven
  29. 29.  Section one-: Section one relates to the reason for reporting and whether the committee agreed with both the diagnosis that was made and the statement of severity.  Section two-: Section two takes the evaluators through several important factors like frequency of occurrence of adverse events, similar events known to occur with other diseases, vaccine-event interval compatible with event, similar symptoms in past, concomitant drugs or other conditions; for assessment of causality.  Section three-: Section three relates to causality assessment by using WHO-UMC criteria.
  30. 30.  Section four-: Section four permits brief summary of case with important elements and discussion which contributed to the final assessment of causality.  Section five-: Section five permits recommendations for improving immunization or case reporting procedures to be written.  Section six-: Section six considers whether the case could be useful for Educational purpose.  Section seven-: Section seven considers whether the case could be useful for publication.
  31. 31. iamgauravchhabra@gmail.com

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pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com

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