1. Fulfilling the Promise of Medicine Together New FDA Safety Reporting Requirements 2010 John McLane, Ph.D. COO & Vice President Clinical and Regulatory Affairs Clinquest, Inc. jmclane@clinquest.com

2. Fulfilling the Promise of Medicine Together 2 Safety Reporting Requirements Different requirements for Sponsors Investigators IRBs Different requirements depending on type of study and funding FDA Drug  IND vs Postmarketing Device Food Supplements Federal ICH

3. Fulfilling the Promise of Medicine Together 3 FDA: Sept 2010 Guidance for Industry And Investigators: Safety Reporting Requirements for INDs and BA/BE Studies New Regulations 21 CFR 312 IND Safety Reporting 21 CFR 320 BA/BE Studies Refers to Drugs and Biologicals Closer alignment to ICH/EMA requirements

4. Fulfilling the Promise of Medicine Together 4 Why New Regs and Guidances? Too many reports unfiltered SAE reports associated with Manifestations of the disease morbidity for stroke Common in study population Strokes in elderly population Study Endpoints Confusion with phrase: “associated with the use of the drug” and “reasonable possibility” Refine definitions

5. Fulfilling the Promise of Medicine Together 5 Define: Adverse Event (AE) Same as adverse experience Untoward medical occurrence associated with the use of a drug Whether or not considered drug related Note separation from causality Unfavorable or unintended sign or symptom Temporally associated with any use of the drug

6. Fulfilling the Promise of Medicine Together 6 Define: Suspected Adverse Reaction (SAR) Any AE reasonably possibility that drug caused AE Decreased level of certainty then an adverse reaction 1 st use of “reasonable possibility” The SAR & use of “reasonable possibility” is consistent with concepts about causality defined in ICH E2A

7. Fulfilling the Promise of Medicine Together 7 Define “reasonable possibility” Single occurrence of an uncommon event AE know to be associated with drug exposure Ex. Stevens-John syndrome 1 or more events not commonly associated with drug exposure Not common in the study population Aggregate analysis of events that occur more frequently in tx arm

8. Fulfilling the Promise of Medicine Together 8 Define: Unexpected AE or SAR Safety event: Not described in IB or protocol Event is of greater severity/specificity than previously described Hepato-necrosis is a Unexpected AE if IB has only hepatitus Event is described as seen in similar drugs (class effect) but not yet observed with this drug First occurrence of this type of event is a UAE

9. Fulfilling the Promise of Medicine Together 9 Define: Serious (SAE) Similar to prior use: Death Life-threatening Excludes AE or SAR that had it occurred in more serious form might have caused death In-patient hospitalization Prolongation of hospitalization Congenital anomaly/birth defect Refines the use of medical judgments by either investigator or sponsor

10. Fulfilling the Promise of Medicine Together 10 Safety Monitoring Sponsor Evaluate Safety of Drug for subjects Serious, Expectedness, Reasonable Possibility Analysis with other events related to drug use

11. Fulfilling the Promise of Medicine Together 11 Review of Safety Information Get safety information from all sources Domestic/foreign trials Foreign data to US: Safe Harbor Requirements Clinical epidemiology studies Annual literature review for safety Animal or in vitro expts. Report in safety reports ID all IND safety reports similar in nature previously reported Notify FDA and all “participating investigators” 15 day reports

12. Fulfilling the Promise of Medicine Together 12 SUSARS For the first time FDA recognizes SUSARs Three criteria Suspected adverse reaction Serious Unexpected Expedited IND safety report

13. Fulfilling the Promise of Medicine Together 13 Conclusion Move towards harmonization FDA will accept CIOMS I forms Use of SUSAR Clear definition Replace “associated with the use of the drug” with “reasonable possibility”

14. Fulfilling the Promise of Medicine Together 14

15. Fulfilling the Promise of Medicine Together 15 Relationship between AEs and UAPs The diagram illustrates three key points: The vast majority of adverse events occurring in human subjects are not unanticipated problems (area A) and do not need to be reported to the IRB. A small proportion of adverse events are unanticipated problems (area B) and need to be reported to the IRB. Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C) and need to be reported to the IRB.