CAUSALITY ASSESSMENT OF SUSPECTED ADVERSE DRUG REACTION

1. CAUSALITY ASSESSMENT OF SUSPECTED ADVERSE DRUG REACTION

2. INTRODUCTION Spontaneous 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.

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

4. Uses and limitation of Causality Assessment What it can do? - Decrease disagreement between accessor. - Classify uncertainty - Mark individual case reports - Improve the scientific basis of assessment

5. What it cannot do? Give and accurate quantitative measurement of the likelihood of a relationship. Distinguish valid form invalid cases Quantify the contribution of a drug to the development of an adverse event Change uncertainty to certainty

6. Methods of Causality Assessment There 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 (B�nchiou�s group method) French imputation systems The European ABO Systems The US Reasonable Possibility Systems The Naranjo ADR Probability Scale WHO Causality Categories

7. 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?

8. 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 � Probability AC � Additional character DCE � Drug Cause Event OCE � Other Cause Event

9. Aetiological � Diagnostic Systems (B�nchiou�s group method) Using a diagnosis scheme: Diseases definition Clinical appearance and pathology Signs of severity Aetiology (various possible causes) and diagnosis Evidence implicating a drug Chronological criteria Management

10. French imputation systems Intrinsic Factor

11. French imputation systems Extrinsic Factor

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

14. 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

15. The Naranjo ADR Probability Scale

16. The Naranjo Probability Scale The score :- > 8 = Highly probable 5-8 = probable 1-4 = possible 0 = doubtful

17. WHO Causality Categories C1 � Certain C2 � Probable C3 � Possible C4 � Unlikely C5 � Unclassifiable

18. WHO Causality Categories C1: 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

19. CAUSALITY ASSESSMENT C3: Reasonable time, may be due to concurrent disease, other drugs, no information on dechallenge C4: Improbable temporal relationship, other confounding factors such as drugs, chemicals, underlying disease C5: Insufficient information to analyse the report

20. Case causality assessment How close is the relationship between drug and event? Did the drug cause the event?

21. How to assess causality?

22. 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 reaction Use 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

23. Definitions Dechallenge � withdrawing the drug(s) and recording the outcome � improved or not improved Rechallenge � giving one drug again under the same conditions as before and recording the outcome � recurrence or no recurrence.

24. How to do the causality assessment Case 1 A 42-year-old female experienced vomiting during treatment with 200mcg Pulmicort at night by inhalation for her asthma. The onset of the reaction was on 3rd August 2006 until 5th August 2006. She been prescribed this drug since end of July. The drug was stopped on the 5th of August and patient recovered. No rechallenge performed and her doctor change the drug.

25. Case 2 A 68-year-old male patient was started with Crestor on the 29th Jan. 2007 for his hyperlipidaemia. On the 2nd of Feb. 07, patient felt very ill. Upon admission, the diagnosis was myositis and abnormal hepatic function (ALT: 100 units/ml). Patient also took Sandimmun Neoral for his bone � marrow transplant rejection since October 2006. Crestor was discontinued and patient recovered a few days later. No rechallenge been performed.

26. Case 3 A 67-year-old woman, whose medical history included diabetes mellitus, hypertension and also been diagnose with Alzheimer�s Disease. This woman been on long term treatment of Amlodipine 5mg/daily, Metformin 1gm/bd and Glibenclamide 5mg/bd. She started receiving daily oral Exelon� (Rivastigmine) 6mg daily.

27. After 5 months she was hospitalised for dizziness and syncope. On admission her BP was 90/60mm Hg, her pulse rate was 34 beats/min, and complete heart block was evident on 12 lead ECG. The woman received a temporary transvenous pacemaker, and Exelon� and amlodipine was discontinued. Angiography showed normal coronary anatomy. After 3 days admission her heart block spontaneously resolved and sinus rhythm was restored.

28. Oral Exelon� was restarted that day, and complete heart block recurred on day 4. the woman received a VVI permanent pacemaker the following day. Amlodipine was restarted and Exelon� was continued at the same dosage. She had not experienced further syncopic episodes or dizziness at follow up 3 months later.

29. Case 4 A 50-year old man received Imipramine and Escitalopram previuosly and now switch to Duloxetine 30mg daily. He started to experience irritability, akathisia, insomnia and difficulty concentrating. His depression worsened over the next 10 days and he became hopeless.

30. Finally in an attempt to commit suicide, he lacerated both radial and popliteal arteries, resulting in significant blood loss. He was unconscious and severely hypotensive. The man was hospitalised in ICU and given transfusions, before being transferred to a psychiatric ward several days later. He was commenced on Setraline and remained on this drug at last follow up.

31. Literature Sources for ADR Information WHO Publication - Pharmacovigilance A to Z - Dictionary of Pharmacovigilance - Stephen�s Detection of New Adverse Drug Reactions - To Heal and Harm - WHO Pharmaceutical Newsletter - Signal � Analyses of ADR in WHO Database

32. Electronic Reference Searches E-mail Alerts � USFDA Medwatch Electronic 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)

33. 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)