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  • CAUSALITY ASSESSMENT OF SUSPECTED ADVERSE DRUG REACTION

  • INTRODUCTIONSpontaneous reporting system data acquisition, assessment, presentation and interpretation.Causality assessment part of the 1st step in case assessment and is based on a general system that is intended for all reactions and all drug.

  • Standardized case causality assessment has become a routine at pharmacovigilance centre around the world.Decrease the ambiguity of the data and prevention of erroneous conclusionIt neither eliminates nor quantifies uncertainty but, at best, categorizes it in a semi quantitative way

  • Causality It does not matter if there if uncertainty about whether the reaction is associated with the drug being taken;if there is a suspicion that this is the case, then it should be reported.

    Factors to consider in assessing causality:

    Nature of the reaction

    There are some adverse reactions which are commonly caused by medicines; for instance acute dystonias,blood dyscrasias and skin reactions ( Stevens Johnson syndrome,toxic epidermal necrolysis).When such conditions seen you should consider the possibility that they have been caused by a medicinal product.

  • 2.Timing The time from when the drug was started until the reaction develops may be a characteristic of the reaction. For example ,anaphylaxis usually develops with in a few minutes of parenteral drug admini.Alternatively some reactions develop months or years later and may be related to a cumulative effect of the traditional drug.In very rare cases the effect may be observed in the next generation for example diethylstilbestrol and vaginal cancer.

  • 3. Relationship to dose Adverse reactions are often dose related and may be minimized by reducing the dose of the drug being taken. If the symptoms resolve when the medicine stopped, this suggests that the symptoms were associated with the medicine although it could be coincidental. The process of recovery after stopping a suspected medicinal product is classified as positive dechallenge.In contrast ,if a medicine is reintroduced and the symtoms recur,this strongly suggests that the medicine is responsible. This process is classified as positive rechallenge.However following serious ADR, rechallenge is seldom justifiable.

  • 4. Other possible causesYou may need to consider other possible causes for the symptoms being experienced.For instance could the symptoms be manifestations fo the patients underlying illness or another disease. The patient may be taking other medicines( including prescriptions and self medications) which could be responsible, also possibility of an interaction between two medicines .

  • A careful analysis of spontaneous reports can only alert signal and cofirm an association. In certain circumstances one high quality and carefully documented report with a succesfull dechallenge and a positive rechallenge may have sufficient internal validity to decide a causal association. Othe than this scenario spontanious case reports cannot demonstrate a definite causal relationship

  • Uses of Causality AssessmentWhat it can do?

    - Decrease disagreement between accessor.- Classify uncertainty - Mark individual case reports- Improve the scientific basis of assessment

  • Methods of Causality AssessmentThere were several method that can be use to make a causality assessment of ADRs reports.The literature (9 points of consideration Morges, Switzerland , 1981)Probability calculation (Bayes Theorem)Aetiological Diagnostic Systems (Bnchious group method)French imputation systemsThe European ABO SystemsThe US Reasonable Possibility SystemsThe Naranjo ADR Probability ScaleWHO Causality Categories

  • The literature (9 points of consideration Morges, Switzerland , 1981)

    Drug given prior to event?Reaction at site of application?Drug/ADR interval compatible with the event?ADR immediately follows drug administration and is of acute onset?Rechallenge positive?Dechallenge positive?Were concomitant drugs stopped at the same time?Same adverse reaction to this drug before?Adverse reaction known with the suspected drug?

  • Probability calculation (Bayes Theorem)

    The Formula Pr(DCE I AC) = Pr (AC I DCE) x Pr (DCE) Pr(OCE I AC) Pr (AC I OCE) Pr (OCE)

    Pr ProbabilityAC Additional characterDCE Drug Cause EventOCE Other Cause Event

  • Aetiological Diagnostic Systems (Bnchious group method)

    Using a diagnosis scheme:Diseases definitionClinical appearance and pathologySigns of severityAetiology (various possible causes) and diagnosisEvidence implicating a drugChronological criteriaManagement

  • French imputation systems

    Intrinsic Factor

  • French imputation systems

    Extrinsic Factor

  • The European ABO Systems

    Using 3 basic causality categories A Reports including good reasons and sufficient documentation to assume causal relationshipB Reports containing sufficient information to accept the possibility of causal relationship .O Reports where causality is, for one or another reason not assessable.

  • The US Reasonable Possibility Systems

    Using a criteria- Temporal relationship- Similar problem with the same drug- Similar problem with a related drug- Confounding by drug- Confounding by disease- Clinical plausibility- Dechallenge/rechallenge- Quality of reports need follow up- Discuss with clinical experts

  • The Naranjo ADR Probability Scale

    QuestionsYesNoDont Know1) Are there previous conclusive reports on this reaction? +1002) Did the ADR appear after the suspected drug was administered? +2-103) Did the ADR improve when the drug was discontinued? +1004) Did the ADR appear with re-challenge? +2-105) Are there alternative causes for the ADR? -1+206) Did the reaction appear when placebo was given? -1+107) Was the drug detected in blood at toxic levels? +1008) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1009) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +10010) Was the ADR confirmed by any objective evidence? +100

  • The Naranjo Probability ScaleThe score :-

    > 8 = Highly probable5-8 = probable1-4 = possible0 = doubtful

  • WHO Causality CategoriesC1 CertainC2 ProbableC3 PossibleC4 UnlikelyC5 Unclassifiable

  • WHO Causality CategoriesC1: Plausible time, not related to underlying condition, concurrent disease, other drugs or chemicals, related pharmacologically, +ve dechallenge, +ve rechallenge C2: Reasonable time, unlikely to be related to concurrent disease, other drugs,+ve dechallenge, no rechallenge

  • CAUSALITY ASSESSMENTC3: Reasonable time, may be due to concurrent disease, other drugs, no information on dechallengeC4: Improbable temporal relationship, other confounding factors such as drugs, chemicals, underlying diseaseC5: Insufficient information to analyse the report

  • Case causality assessmentHow close is the relationship between drug and event?Did the drug cause the event?

  • How to assess causality?

  • Assessing the strength of the relationship between the drug and the event.Can seldom say without any doubt that a specific drug caused a specific reactionUse the accumulation of case reports at national level is immensely valuable providing the means for determining real cause and effect.Use epidemiological studies to confirm causality

  • DefinitionsDechallenge withdrawing the drug(s) and recording the outcome improved or not improvedRechallenge giving one drug again under the same conditions as before and recording the outcome recurrence or no recurrence.

  • Literature Sources for ADR InformationWHO Publication- Pharmacovigilance A to Z- Dictionary of Pharmacovigilance- Stephens Detection of New Adverse Drug Reactions- To Heal and Harm- WHO Pharmaceutical Newsletter- Signal Analyses of ADR in WHO Database

  • Electronic Reference SearchesE-mail Alerts USFDA MedwatchElectronic Table of Content (E-ToC)- Lancet (http://thelancet.com)- BMJ (http://www.bmj.com)- NEJM (http://content.nejm.org)SCIRUS for scientific information only(http://www.scirus.com/srsapp)Free medical journal(http://www.freemedicaljournals.com)PLoS Medicine(http://medicine.plosjournals.org)

  • Medscape (http://www.medscape.com)Medical News Today(http://www.medicalnewstoday.com)Medsafe, New Zealand(http://www.medsafe.govt.nz)Lareb - Netherland Pharmacovigilance (www.lareb.com)WHO Vigisearch, Vigibase, Vigimed (Sorry!!! This is for members only)

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