Training on entering event information in Argus Safety database

1. Training on entering event information in Argus Safety database Global Pharmacovigilance department

2. Case form: EVENTS • Mention all the adverse events experienced by the patientafter the start of Aurobindo drug therapy.

3. Events screen Event start date As reported by the reporter As populated in above field, else overwrite MedDRA codes If patient has experienced the same event previously Seriousness of the event Term highlighted by the reporter: Event for which the case was reported by the initial reporter. Select Yes or No from the codelist

4. autocalculated if the event occurs after the suspect drug was discontinued. Can also be manually entered Event stop date As reported by the reporter Duration of the event Event start date As populated in above field, else overwrite Do not use If treatment received for the event Frequency of adverse event If patient has experienced the same event previously Applicable to the clinical trial cases. Seriousness of the event Do not use

5. Intensity • Mild: Symptoms barely noticeable to the patient or does not make the patient uncomfortable. The AE does not influence performance or functioning. Prescription drugs are not ordinarily needed for relief of symptom(s). • Moderate: Symptoms of a sufficient severity to make the patient uncomfortable. Performance of daily activities is influenced. Treatment of symptom(s) may be needed. • Severe: Symptom(s) of a sufficient severity to cause the patient severe discomfort. Severity may cause cessation of treatment with the drug. Treatment for symptom(s) may be given.

6. Outcome of Event • Recovered/Resolved • Recovered/Resolved with sequelae • Recovering/Resolving • Not Recovered/Not Resolved • Fatal • Unknown

7. MedDRA Browser: for coding event terms Selecting a LLT will populate the MedDRA terms under PT, HLT, HLGT and SOC. Search and select for the appropriate term in MedDRA. Press the select button and the term will be coded.

8. Note: If two adverse event terms map to the same MedDRApreferred term, do not code them separately. e.g. ‘Headache/pain in head’, therefore requiring only one MedDRA code selection, or MedDRA should be thoroughly searched to find an alternative suitable preferred term. • Diagnosis, Signs and Symptoms: If a definitive diagnosis and a set of symptoms are given, the diagnosis should be coded. • Example: If ‘rhabdomyolysis with myalgia and acute Renal Failure’ is reported, the LLTs ‘Rhabdomyolysis’ should be entered and coded. Always enter and code signs/symptoms not associated with the diagnosis. • A provisional diagnosis may be described as “suspicion of”, “probable”, “presumed”, likely”, “rule out”, “questionable”, “differential”, etc. If a provisional diagnosis and a set of symptoms are given, only the signs/symptoms should be entered and coded NOT the provisional diagnosis. This is because the diagnosis is provisional and subject to change.

9. If on receipt of a case the information included in the report indicates that the patient had another event on Aurobindo drug therapy prior to the reported adverse event, a second case should be created to reflect each event. Both cases should have the same initial receipt date. • Medical judgement should be used if an exact match cannot be found and the most appropriate existing term should be selected. Only current MedDRA LLTs should be selected.

10. Duplication of reaction terms: MedDRA terms should not be duplicated unless the dates indicate two separate events. A separate case should be created if a patient experienced the same reaction on different dates. This is not a positive rechallenge as the patient did not stop taking the suspect drug. • Reaction occurring at multiple body sites: If a reaction is reported to occur at more than one body site, and if all of those LLTs link to the same PT, then a single LLT that most accurately reflects the reaction should be selected. For example, if the reaction is described as “Skin rash on face and neck”, then the LLT ‘Skin rash’ should be selected (rather than ‘Rash on face’ and ‘Neck rash’ as both of these LLTs link to the PT ‘Rash’).

11. Withdrawal reaction classification • Drug withdrawal reactions are reports where the reporter describes reactions which occur after withdrawal of the suspect drug. • The MedDRA LLT ‘Withdrawal reaction’ should only be used to classify a reaction when the reporter has stated this. In addition to this all the symptoms associated with the withdrawal should also be classified and coded as reactions. • In instances where the reporter states ‘Withdrawal reaction’ as the only reaction and gives no detail on the reactions suffered, these cases are still considered valid and should be expedited if they meet the minimum criteria for expediting reporting. However these cases should also be followed up for symptoms of the withdrawal reaction.

12. Drug interaction • At least two suspect drugs should be classified for reports involving a drug interaction. When the reporter specifically states that an interaction occurred, an appropriate interaction term should be selected in addition to term(s) for any reaction(s) described.

13. Product substitution • If a report states that the reaction occurred after the patient switched to taking a different product, having previously been taking a different product containing the same active, it may be useful to code this by using an appropriate MedDRA term such as ‘Product substitution issue’, ‘Product substitution issue brand to brand’,’ Product substitution issue brand to generic’, ‘Product substitution issue generic to brand’ or ‘Product substitution issue generic to generic’

14. No Adverse event • The LLT ‘No adverse effect’ should be included in cases of overdose, pregnancy, medication error etc where it is specifically mentioned that the patient did not experience any adverse event. These cases would not normally be expedited as there is no reaction.

15. Relationship button You can associate the signs/symptoms to a diagnosis by clicking on the “Relationship” button. The following pop up screen is displayed: To associate the events select

16. Coding Pregnancy cases

17. Events in the mother Scenario I: Patient became pregnant while receiving product Scenario II: Pregnant patient receiving medication experienced adverse event Note: LLT Pregnancy should also be selected for medical history, concomitant condition

18. Events in the child or foetus

19. Adverse events associated with a product complaint • Where a report of suspected adverse reactions is associated with a suspected or confirmed quality defect of the product, the MedDRA LLT code of the term corresponding most closely to the product issues should be coded along with any observed ADRs

20. Suspected transmission via a medicinal product of an infectious agent • If a report of transmission of an infectious agent via a medicinal product is received, select the MedDRA LLT for the transmission. If the infection is identified, select a second term for the specific infection. If appropriate, a product quality issue term can be selected. Example:

21. Fatal reactions • For reactions that occur over a period of time and which result in an outcome of death, the stop date should be the date of death. A start date may be included if this has been stated by the reporter. • For cases with an event of ‘Death unexplained’, the date of death can be used as the start and stop date. The same applies for completed suicides. • Reports of death e.g. “Death unexplained”, “Sudden death”, “Sudden death unexplained”, “Sudden unexplained death in epilepsy” and “Completed suicide” can only have a reaction outcome of fatal. Under no circumstances should these reaction terms be classified with any other outcome. • If you have a death case the two following sections must be completed: • Note: The age of the patient, shown on the patient screen, will automatically be calculated using ‘Onset Date/Time’ and the ‘Date of Birth’ in the ‘Patient Information’ screen.

22. Seriousness criteria • This field should be selected as appropriate for each coded term. Seriousness assessment should be done separately for every reported adverse event within a case. For the cases which include drug interaction, overdose, abuse, misuse and medication errors etc. the events would inherit the assessment of the reaction term to which the nature of the event relates. • Events would be ranked in order of seriousness with the most serious event ranked first.

23. Where a seriousness criterion has been assigned, an ‘F’ will appear on the event tab if the event was fatal, 'LT' if the event was life-threatening, and 'H' if the event was hospitalisation; an ‘S’ will appear in the corner of the tab for all serious events. Multiples of these flags will appear if multiple seriousness criteria are selected.

24. Event Assessment • This section displays all the coded events reported in the case and compares them against all the company suspect products which have been coded according to the Aurobindo drug dictionary. The comparison of each product against each event allows the user to capture causality and labelling information for each combination. The resulting information can then be used to control the automatic scheduling and priority of regulatory reports. • Clicking on the ‘Recalculate’ button creates records for event assessment only if the following conditions are met: - At least one Aurobindo Suspect Drug (coded) exists. - At least one event is encoded. Save case and repeat ‘Recalculate’ if no event assessment records are generated in spite of meeting both of these prerequisites. • Please note that pressing the “Recalculate” button will rearrange the data if new suspect drugs or events are added. • Symptoms of a diagnosis are listed underneath the diagnosis, and are identified as symptoms by the letter 'S' in the 'D/S' column.

26. Always click on the ‘Recalculate’ button prior to entering or checking the assessment. The events will be displayed in the ‘Event Assessment’ field. This is important to update all licenses in the case e.g. new EMEA or FDA approval. • You may select the letter 'D' from the drop down list in the 'D/S' column to show only leading diagnoses (subordinate symptoms are then hidden) to assist with the event assessment.

27. Causality • By definition a spontaneous report contains suspected adverse reactions (i.e., a possible causal relationship is suspected but not established). • If an event is spontaneously reported to a company about the patient who took that company's drug, and the relationship is unstated, it implies a suspected causal relationship to the drug. If the company has a different opinion from the reporter, state that the causality with the same drug is unrelated or unlikely and the same should be mentioned in the sender comments.

28. guide for assessment of causality based on WHO-UMC causality assessment system

29. Listedness • An ADR whose nature, severity, specificity, or outcome is not consistent with the term or description used in the PI or SPC should be considered unlisted. • When it is uncertain whether a reaction is listed or unlisted, the ADR should be treated as unlisted. • An listed ADR with a fatal outcome should be considered unlisted, unless the SPC specifically states that the ADR may be associated with a fatal outcome. • “Class ADRs” should not automatically be considered to be listed for the subject drug. “Class ADRs” should be considered listed only if described as specifically occurring with the product. For example: • As with other drugs of this class, the following undesirable effect occurs with Drug X. • Drugs of this class, including Drug X, can cause... • If the ADR has not been documented with Drug X then statements such as the following are likely to appear

30. The ADR should not be considered as listed for Drug X if: Other drugs of this class are reported to cause Drugs of this class are reported to cause, but no reports have been received to date with Drug X. • The following guidelines proposed by the CIOMS group will be considered: • Further anatomical specification of a labelled AE does not make it unlabelled (e.g. fibrosis of the left upper lobe is equivalent to lung fibrosis; left sided chest pain is equivalent to chest pain). • Extra histological specification does not make, per se, a labelled AE unlabelled (e.g. a liver biopsy shows hepatic necrosis [labelled] with the presence of eosinophils [not mentioned in labelling]). • If a labelled AE is not normally accompanied by an additional sign or symptom, the AE should not be considered labelled (e.g., the labelling mentions gastrointestinal irritation and a report is received of gastrointestinal irritation associated with melena). • Mention of any additional symptom or sign usually associated with an already labelled AE does not merit upgrading the event to unlabelled (e.g. the labelling mentions thrombocytopenia, and a report is received of thrombocytopenia associated with petechia; labelling mentions pseudomembranous colitis and report is received of pseudomembranous colitis associated with dehydration).

31. In general, the medical view is that if a labelled AE is often life-threatening or often results in death, a fatal outcome in a particular case does not make the AE unlabelled, even if death is not mentioned in the labelling as a possible outcome (e.g. myocardial infarction is mentioned in the labelling, but fatal myocardial infarction is not). However, if the labelling does not specifically mention death as a possible outcome of an AE, and a report is received where a patient died from the AE, the AE should be reported as unlabelled. • If a reported AE is significantly more severe than the labelled AE, it should be considered unlabelled (e.g. circulatory collapse when hypotension is labelled). This is particularly true if the outcome of the AE is fatal (death from hepatic necrosis when hepatic failure is labelled). A report of hepatic necrosis would be unlabelled (by the virtue of greater severity) if the labelling only referred to elevated hepatic enzymes or hepatitis. • If an AE is not medically more important than a labelled AE, the case need not to be considered unlabelled (e.g. vertigo when dizziness is labelled; raised liver function tests when hepatitis is labelled).

32. Although it is suggested that any AE with a fatal outcome, whether labelled or not, should be reported internationally, death from a condition diagnosed prior to treatment is not a reportable event — in fact it is not an event at all. This is assuming that death is a possible normal outcome of the condition (e.g. bronchogenic carcinoma). The exception would be where there is an exacerbation of the condition following treatment leading to death. • An unlabelled diagnosis which relates to a group of symptoms or signs which are labelled, the new case is not in itself labelled (e.g. anaphylaxis when hypotension, wheezing and urticaria are all labelled). In other words, the diagnosis must be expressly stated in the labelling. • If a diagnosis is a labelled AE, then the signs and symptoms which comprise the diagnosis are also considered to be labelled. For example, if anaphylaxis is labelled, then a report of a patient who experienced hypotension, wheezing and urticaria would be considered to be labelled. • If the label lists an AE which is specified to be transient, but it persists in the new case, the case is unlabelled and should be reported (e.g. prolonged elevated liver function tests when the labelling states transient elevated liver function tests). • A Green sphere will always appear on the assessment field because of the change from the default ‘Unknown’. The justification for the change is not requested. Any further changes to the labelling assessment will require a justifying comment. • The default value for listedness in Argus safety is unknown. Select either labelled/unlabelled from the codelist.

33. Product-Event details This tab allows user to add information regarding the dechallenge and rechallenge results.

34. Dechallenge • Dechallenge: Discontinuing treatment with a drug is called dechallenge. • Positive Dechallenge: If the drug is stopped and the patient recovers  • Negative Dechallenge: If the drug is stopped and the patient does not recover. • Not Applicable: Dechallengeis to be considered “Not Applicable” in the following situations: • In drug exposure in-utero • If the reaction occurred after the drug was discontinued • If treatment is provided after the drug is withdrawn and the patient recovers • Special situations like lack of efficacy, overdose, pregnancy etc. • If the drug is withdrawn and treatment is provided and the outcome of the event is unknown. • Unknown: Dechallenge is to be considered as unknown in the following scenarios: • If the drug was withdrawn and the outcome is unknown • If it is unknown whether dechallenge was completed Note:Dechallenge may sometimes be used to designate a simple reduction of dose of the suspect product without completing stopping it. This may occur if the reaction is dose dependent and regresses or stops after this dosage change.

35. Rechallenge • Re-administration of the drug is called Rechallenge • Positive Rechallenge: If the drug is reintroduced, and the same symptoms reappear. • Negative Rechallenge: If after reintroduction of the drug the symptoms do not reappear. • Not applicable: Rechallenge should be considered as not applicable in the following scenarios: • The suspect drug was a one-dose treatment • The drug was not discontinued and reintroduced • The event/reaction occurred after the drug was discontinued. • Unknown: If it is known that the Rechallenge was done but the result of Rechallenge in unknown. This field should be left blank, if it is unknown whether Rechallenge was done. • Note:If the patient experiences a different reaction on Rechallenge or a more serious reaction then this should be recorded as a reaction term and not a Rechallenge.