Serious Adverse Events

1. GCP Workshop: Ethics Committee Members Serious Adverse Events C.Adithan

2. Objectives To make the EC members understand the • importance of adverse event (AE) • differences between AE and ADR • importance of serious adverse event (SAE) • regulatory requirements in reporting SAE • Investigator’s responsibility in SAE • sponsor’s responsibility in SAE • timelines for SAE reporting • responsibilities of IEC in case of SAE

3. Adverse Event (AE) Any untoward medical occurrence including • undesirable signs & symptoms • disease or accidents • abnormal lab. finding ( leading to dose reduction / discontinuation / intervention ) during treatment with a pharmaceutical product in a patient or a human volunteer that does not necessarily have a relationship with the treatment given. • After signing the Informed Consent Form • Related / unrelated to the study drug

4. Adverse Events: Sources • Hospital / physician / nurses notes • Patient’s diaries • Assessment forms • Concomitant medications (indications) • Abnormal lab. results • Reasons for withdrawal and drop outs • Missed visits

5. Adverse Events: Why to report ? • Ethical requirements • Regulatory requirements • Legalrequirements A joint responsibility of the sponsor & the investigator

6. Adverse Drug Reaction (ADR) For approved pharmaceutical product: A noxious and unintended response at doses normally used or tested in humans For a new unregistered pharmaceutical product: A noxious and unintended response at any dose A response to a drug which is noxious & unintended and which occurs at doses normally used for prophylaxis, diagnosis or therapy of a disease or for modification of a physiological function. --- WHO

7. What is the difference between AE and ADR? AE event: does NOT imply Causality ADR: A causal role is suspected

8. Serious Adverse Event (SAE) An AE or ADR that is associated with • Death • Inpatient hospitalization • Prolonged hospitalization • Persistent or significant disability or incapacity • Congenital anomaly or birth defect • Otherwise life threatening ---- GCP guidelines

9. What is a life threatening event? Places the patient , in the view of the investigator, at immediate risk of death from the event as it occurred Does not include an event that, had it occurred in a more severe form, might have caused death

10. AE is reported: What next? • Evaluate AE based on protocol & seriousness of the event • Medical care for the subject • Document appropriately • Notify sponsor & others • Verify and maintain all data contained in CRF & supporting source documents

11. Adverse Event Recording • Duration (Date of onset & resolution) • Severity (Mild, Moderate, Severe) • Assessment (Serious / Non serious) • Relationship to study medication • (Suspected / Not suspected) • Action taken(discontinued/dose ) • Outcome (Recovered, Improving, Unchanged, • Deteriorated, Permanent Disability, • Death, Unknown)

12. When to record AE? Docomplete an SAE form if: • an adverse event caused the patient to be hospitalized • the hospitalization is related to a deterioration of the disease state under investigation or a pre-existing condition

13. When not to record AE? Do notcomplete an SAE form if the hospitalization: • was planned prior to the patient entering the study • is part of the regular treatment for the disease under study and there is no deterioration e.g. seizure monitoring • occurs for a situation that is elective in nature • involved only treatment in the emergency room and no admission as an in-patient, unless other criteria of seriousness are met

14. SAEs – What to report ? • Minimal information for “regulatory” reporting • an identifiable patient • an investigational drug • an identifiable reporter • a serious adverse event • Initial SAE form to be sent as soon as the above minimum information is available • Recurrent episodes or complication of a previous reported SAE occurring at different time intervals should be always reported as a follow-up (= regulatory requirement)

15. Data Elements for reporting SAE Patient details: Pt. identifier, initials, sex, age, Wt. etc Suspected drug: generic name, indication, dates of admin., dose, starting & stopping date and time Other treatments Details of suspected ADR Outcome Details about the investigator Date reporting to Licensing authority Date reporting to Ethics Committee Signature of the Investigator Schedule Y, 20, January 2005

16. WHO causality algorithm • Certain • Temporal relationship • Probable • Concomitant Medication • Possible • Concurrent Illness • Unlikely • +Ve De-Challenge • Unclassifiable • +Ve Re-Challenge

17. Investigator Notification / Alert • If an SAE is: • ‘serious’ • ‘unlabelled’ (i.e. not noted in the Investigator’s Brochure) • and ‘suspected’ of being related to trial drug • An Investigator Notification may be issued to: • keep the investigator aware of potential safety issues • enable sponsor to meet it’s global regulatory requirements • (An IN does not necessarily mean that the • SAE was caused by the trial drug)

18. Investigator’s responsibilities Record all AEs in the CRF Report all SAEs immediately to sponsor Ensure adequate follow-up and inform sponsor Report the event to IEC Report any Investigator Notifications to IEC

19. Sponsor’sresponsibilities Adequate training of investigator and team Expeditious reporting of all SAEs to HA verification of the SAE Form data against source documents Consistency of SAE Form data with the CRF data Generate “Investigator Notifications” when required Generate periodic safety updates

20. Timelines for Reporting SAE I E C Sponsors • Investigator • notices SAE • 7 days 24 h 14 calendar days DCGI

21. What Ethics Committee can do? • Modification of Protocol • Updating the clinical IB • Obtaining additional consent from • ongoing Patients • Stopping the study

22. Group Exercises

23. Thank you...