GCPs V Adverse Event Monitoring and Reporting

1. GCPs VAdverse Event Monitoring and Reporting

2. FDA Inspection • Common Deficiencies • Inadequate consent 51% • Protocol Non-adherence 31% • Records Inadequate/Inaccurate 26% • Drug Accountability Inadequate 20% • IRB deficiencies 11% • Investigator Failure to report Adverse Events http://www.irbforum.org/documents/documents/Module4.pdf

3. Reporting of Adverse Events • An Adverse Event (AE) is any untoward medical occurrence in a subject administered a drug (biologic, device). • It does not necessarily have a causal relationship with the treatment/usage.

4. Adverse EventsExamples • Signs/symptom of an illness • Abnormal lab findings • Concurrent illness or accident • Exacerbation of pre-existing illness • Consequences of withdrawal, misuse, or overdosing of study drug

5. Serious Adverse Events • Serious Adverse Event (SAE) are those that result in: • - Death • - Life threatening • - Require hospitalization (>24 hours) or prolonged hospitalization • - Persistent or significant disability or incapacity • - Congenital anomalies or birth defects

6. AE Reporting Requirements • Serious adverse events occurring in research subjects enrolled at the PI’s site must be reported to the IRB within 7 calendar days • Unexpected adverse events occurring in research subjects enrolled at the PI’s site must be reported to the IRB in writing within 15 calendar days • Adverse events that necessitate a change in the informed consent must be reported within 7 days to the IRB • Serious unexpected adverse events reported by the study sponsor to the PI should be submitted to the IRB upon receipt • Data and Safety Monitoring Board (DSMB) reports or summary adverse event reports should be submitted upon receipt

7. Three days after receiving study vaccine, the child is admitted to the hospital after an apparent seizure at home which resolved spontaneously after about 5 minutes time. Mental status was normal on admission. • What are the investigator/study staff responsibilities?

8. Adverse Event • An untoward medical occurrence in a subject enrolled in a clinical investigation involving administration of a drug or device. Does NOT necessarily have a causal relationship with the research drug or device. May or may not be expected. Includes laboratory abnormalities. • Adverse events need to be evaluated by the investigator and reported to the sponsor within specified time periods (ICH E6 4.11.1,2 and E2A)

9. Be sure to document (and report to sponsor if required) possible adverse events at study visits or as the study staff is aware. • Grade all laboratory reports using protocol toxicity tables. Follow appropriate action outlined in the protocol and document the action. • Use a log to follow-up on adverse events. • When in doubt, report to sponsor.

10. Is an Internal Adverse Event a Serious Adverse Event (SAE)? • Definition • Results in death • Life-threatening • Requires or prolongs hospitalization • Results in persistent/significant disability/incapacity • Congenital anomaly/birth defect • OR action on the part of a physician is necessary to avert any of the above (ICH E2A) • Some sponsors/protocols include Grade III and IV laboratory abnormalities as requiring “expedited reporting”

11. Serious Adverse Events • A SERIOUS Adverse Event is a regulatory, not clinical definition • Reporting for SAEs is expedited. • Industry standard is to report all SAEs within 24 hours to the sponsor who then must report to FDA within 7 days (death, life-threatening) or 15 days (other SAE). • Notify EC of those events meeting institutional criteria for expedited reporting within two working days of becoming aware of the event.

12. IND Safety ReportsExternal SAEs • External Adverse Events (occur at other sites) are reported by the sponsor to other investigators as IND Safety Reports • Summaries sent from sponsor to other sites on a periodic basis (within 15 days if SAE). • Must be assessed by the PI and may need to be reported to EC. • PI and IRB must decide if report of External AE impacts risk/benefit for subjects at this site and if so, decide on course of action. • Intended as addenda to the Investigator’s Brochure. • (21CFR312.32)

13. Safety reporting • Adverse events (annual) • Serious Adverse Events (SAEs) • (within 7 days) • Serious Adverse Reactions (SARs)   • (within 7 days) • Suspected Unexpected Serious Adverse Reactions (SUSARs) • (expedited)

14. Expedited reporting • Fatal or life threatening SUSARS:not later than 7 days after the person responsible for pharmacovigilance received information that the case fulfilled the criteria for a fatal or life threatening SUSAR, and any follow up information within a further 8 days. • All other SUSARs:not later than 15 days after the sponsor for pharmacovigilance had information that the case fulfilled the criteria for a SUSAR.

15. Adverse Events • An adverse event (AE) is any untoward medical event that occurs in a subject receiving a pharmaceutical product: it does not necessarily have a causal relationship to the treatment • Quick Reference Guide

16. AE OR NOT AE?(That is the question) • Patient goes to dentist for a scheduled cleaning • NO • Patient goes to dentist for toothache, has root canal procedure • YES (Toothache is the AE, Root Canal is the treatment – recorded on the con meds page) • Patient goes to gynecologist for scheduled annual exam, is prescribed HRT as a prophylactic • NO (but it is a change in con meds) • Patient has a cosmetic procedure scheduled before start of study • NO (but record treatment as a con med) • Patient has a cosmetic procedure scheduled after start of study that is performed during the study • NO (but record treatment as a con med)

17. Adverse Event Recording • If a procedure is planned and scheduled before a patient enters a clinical trial then that procedure and associated underlying condition are not considered as (S)AEs. The underlying condition should be recorded as medical history. • If a procedure is scheduled after the patient enters a clinical trial and the procedure occurs during the trial without aggravation of the underlying condition then the procedure is recorded as an (S)AE and the underlying condition is medical history.

18. Adverse Event Recording • If a procedure is scheduled after the patient enters the clinical trial due to aggravation of the underlying condition then the underlying condition is recorded under medical history the aggravation is recorded as an (S)AE, the procedures is treatment of the (S)AE.

19. Adverse Events ALL untoward medical events need to be recorded as AEs, including exacerbations/ recurrences of pre-existing conditions e.g. Subject with a history of migraine headache reports a headache while on study – headache is an AE Treatment (drug and procedure) of AEs must be recorded on concomitant medications page

20. Adverse Event Narrative • Subject 99-045 (Initials ABC) comes in at the day 14 visit (6-Jun-2005), and reports a migraine on 31-May-2005 lasting an entire day (24 hours). Subject mentioned they could not get out of bed and had to take migraine medicine every time they woke up to relieve the pain. When asked the patient indicates treatment as Excedrin Migraine approximately every 8 hours. • Now fill out the AE document

21. Let’s fill out the AE Page • Subject: 99-045 • Event: Migraine • Onset Date: 31-MAY-2005 • Resolution Date: 1-JUN-2005 • Severity: • Relation to Study Drug: • Action Taken: Medication (Excedrin Migraine) • Outcome: Recovered • Serious: NO

22. AE Page

23. Concomitant Medications All medications need to be recorded (including, supplements, vitamins and topical medications) Get as much information (dose, route, frequency etc) as you can the first time Make sure that AE form is completed if the conmed indication was an AE

24. Let’s fill out the Con Meds Source Page • Medication: Excedrin Migraine • Dosage: 2 Tablets • Administration • Route: Oral • Frequency: Every 8 hours • Indication: Migraine • Date Started: May 31st, 2005 • Date Stopped: June 1st, 2005

25. Con Med Source Document Page

26. Helpful Hints • If a medication changes, ask why, the underlying cause may need to be recorded as an adverse event • Document Reasons for all missed visits or out of window visits • These may be due to an AE that may need to be recorded

27. Overall Some Helpful Hints • KEEP ALL STUDY RELATED DOCUMENTS • Even if they seem outdated – file in the regulatory binder or in patient binders • Write EVERYTHING down, before you forget • Put subject numbers on every piece of paper • So you know which subject it belongs to • Address all issues in your monitor follow up letters ASAP • Initial and date everything • When in doubt initial and date anyway