Clinical Trial Safety Monitoring

1. Clinical Trial Safety Monitoring Janice M. Soreth, M.D. Deputy Director FDA Europe Office Liaison to EMA

2. Acknowledgement • Cynthia F. Kleppinger, M.D. • Senior Medical Officer • Division of Good Clinical Practice Compliance • Office of Scientific Investigations • U.S. Food & Drug Administration

3. Who Drives Safety Decisions? Regulator Ethics Committee Sponsor Protocol Investigator Product Patient

4. Safety Monitoring • The goals of safety monitoring in trials • Ensure the safety of participants • Assess the risks of the study intervention

5. Safety Monitoring Plan • A Safety Monitoring Plan should address two general areas: • Protection of subjects (including trial conduct directly relevant to subject safety and well-being) • Monitoring of adverse events that occur during the trial

6. Points to Remember • Oversight of monitoring activities is distinct from the monitoring itself • Method and degree of monitoring should be related to degree of risk involved • Monitoring is conducted in various ways by various entities

7. Information Flow Investigator Staff Laboratory Investigator Hospital Staff Subject’s Family Sponsor Regulator Monitors Other Regulators Publications All Investigators IRB/Ethics Committee Subject

8. Potential Safety Hints • New molecular entity • Class of drug • Mechanism of action • Animal studies • Pharmacokinetic/ pharmacodynamic studies

9. Elements of a Safety Monitoring Plan (1) • Identified study medical monitor • Identified safety monitoring committee (SMC) • Single protocol SMC vs. Data and Safety Monitoring Committee • Safety assessments to be performed • Qualifications required of study staff to perform the assessments

10. Elements of Plan (2) • Procedures to ensure that only subjects of appropriate medical risk are enrolled (inclusion/exclusion criteria) and can continue in the study • Acute medical conditions, if not excluded, are adequately treated or cleared for study participation and that subjects temporarily absent from the study for medical reasons are medically cleared to return to the study in accordance with protocol specifications

11. Elements of Plan (3) • Subjects requiring discontinuation are appropriately withdrawn from the study for medical reasons • Any health condition/complication occurring during the course of the trial will be appropriately handled • e.g., Pregnancy • Criteria for withdrawal for medical reasons should be specified before the trial begins

12. Elements of Plan (4) • Any clinical conditions (or adverse events) that are known to be associated with the intervention or the patient population should be identified • Possible laboratory abnormalities known to occur • Possible problems known to occur when the study drug is ingested with other agents • There can be other non-medical risks arising simply from participation in a clinical trial

13. Elements of Plan (5) • Adverse Event Monitoring • Should provide definitions that are consistent throughout development of the product • Can further refine these definitions (expand or limit), to reflect what is clinically and scientifically appropriate to the particular study • Should describe and specify the extent of the data to be recorded • Should describe how the data is to be captured • Should specify how AEs would be elicited - via open-ended questions, by specifically probing for them, etc.

14. AE Monitoring (cont.) • Should provide procedures for AE reporting to all relevant parties as well as timeframes for reporting expedited and non-expedited AEs • Should specify the duration of AE monitoring • Only during the active intervention period, or until a set duration post intervention? Until the participant completes the study, or completes active treatment or follow-up, or until final study closure?

15. AE Monitoring (cont.) • Should specify the person(s) who will determine whether the AE meets the criteria for being a serious adverse event (an SAE) • Should identify who will determine event severity, relatedness to the intervention(s), outcome of the event, and any action to be taken regarding study status • What kind of source documentation would be necessary regarding collection/reporting of AE

16. Elements of Plan (6) • Should provide statistical methodology to detect harm from the interventions being tested • Should provide considerations for stopping rules • Should clearly indicate the cut off time point for follow-up of AEs

17. Elements of Plan (7) • Serious adverse events • Should state whether regulatory definition is modified • Should specify any exemptions from normal SAE collection/reporting (elective surgery, etc.) • Should include the process of notification for all personnel expected to receive notice of SAEs, and the notification timeframes (expedited vs. non-expedited).

18. Safety Reporting

19. FDA Regulations • IND safety reports (21 CFR 312.32) • Expedited (7-day and 15-day) reports from the sponsor to FDA and all participating investigators • Investigator reports (21 CFR 312.64(b)) • Reports from the investigator to the sponsor • Safety reports for bioavailability (BA) or bioequivalence (BE) studies (21 CFR 320.31(d)) • Expedited reports from the person conducting the study to FDA and all participating investigators

20. http://www.fda.gov/downloads/Drugs/.../Guidances/ UCM227351.pdf

21. Causality Assessment Difference between U.S. and ICH E2A • U.S. – Serious unexpected suspected adverse reaction • Investigator provides sponsor with an assessment of causality, but sponsor determines whether the event meets the criteria for reporting (i.e., “reasonable possibility”)

22. Causality Assessment Difference between U.S. and ICH E2A • ICH E2A and European Commission Clinical Trial Directive  (SUSAR  - suspected unexpected serious adverse reaction) • Causality assessment (“reasonable suspected causal relationship”) is based on the view of either the sponsor or investigator

23. Issues to Consider • Study endpoints • Unblinding • Investigator’s brochure • Implementation concerns • Post-marketing

24. Thank you