GCP Workshop Ethics Committee Members Serious Adverse Events

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

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

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

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

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

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

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

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

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

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

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)

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

When not to record AE? Do not complete 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

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

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

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

Investigator Notification / Alert If an SAE is: ‘serious’ ‘unlabelled’ (i. e. 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)

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

Sponsor’s responsibilities 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

Timelines for Reporting SAE Sponsors 24 h Investigator 7 days notices SAE 14 calendar days DCGI IEC

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

Group Exercises

Thank you. . .