Module H Interim Monitoring Visit

1. Module H Interim Monitoring Visit Version: Final 21-Apr-2010 Denise Thwing 21 Apr 2010

2. Purpose Interim Monitoring Visit • Rights and well being of subjects are protected • New information regarding drug is shared • Verify site compliance with the protocol • Confirm data points • SDV • Verify site regulatory adherence • Approved ICF • Prompt reporting AEs/deviations Version: Final 21-Apr-2010

3. Purpose Interim Monitoring Visit • Objectives • Scientific • Verify clinical results represent a valid assessment of the drug’s effectiveness and safety. • QOL assessments • Improvement in baseline assessments • Stable /expected change VS • AEs/SAEs/drug related? • Lab results close to baseline • Regulatory • Make sure conditions are met for the acceptance of the data by appropriate regulatory authorities • ICFs review/multiple versions • Report AEs/deviations • GCP requirements • Managerial/economic • Make sure the first two objectives are reached in a timely and effective manner • Study conducted per schedule • Queries resolved promptly and accurately • Site/subject compensation Version: Final 21-Apr-2010

4. Philosophy • Many problems can trace back to a lack of, or unclear communication • Monitoring a study takes a lot of thought and preparation upfront • Sites with little or no enrollment may lack enthusiasm • CRA/sponsor presence indicates to a site they are important or under scrutiny • Booster visits Version: Final 21-Apr-2010

5. Preparing for the visit • MV interval specified in SOW and or SOPs • First visit typically within 2 weeks of FPI • Complexity of protocol • Phase III study with many different inclusion /exclusion criteria • Disease being evaluated • Infectious disease or HTN study • Phase of study • CRF pages > 60 days? • DCFs > 5 business days? • CRC may need assistance answering DCFs • Previous site performance • Enrolled high number subjects • CRA experience and effectiveness Version: Final 21-Apr-2010

6. Preparing for the visit • Confirmation letter • Site visit log • SOPs • IMV template/MV checklist • Cross check data points • Subject drug accountability log matches master inventory log • Regulatory document review checklist • CMP • Review outstanding action items Version: Final 21-Apr-2010

7. Conducting the visit • Record number screened, enrolled, screen failed and dropped/completed • Enrollment log • Do all meet inclusion/exclusion criteria? • Review all ICFs • Confirm versions • New SAEs/reported? • End ongoing AEs/meds • Review any staff changes/facility changes • Is replacement qualified by experience, education and protocol training performed? • Has CV been obtained & sponsor notified? • Impacts any change to regulatory documents? • All tasks performed as per delegation log? Version: Final 21-Apr-2010

8. Conducting the visit • Source data verification • 100% review vs. key safety and efficacy variables • Legible • Meets coding requirements • Left sided nodule • Magic mouthwash • New Concomitant? • Questionable data? • Record which visits have been reviewed and which CRFs collected • Needed for analysis • Drives payment process Version: Final 21-Apr-2010

9. Conducting the visit • Drug accountability • Correct treatment group • Subject compliance • Study supplies adequate? • Lab procedures as per protocol • Supplies adequate • Review regulatory binder • Advertising approvals • IND safety reports reported • Deviations reported • Review outstanding action items • Record new action items • Review ISF • Meet with PI and CRC • Follow-up letter Version: Final 21-Apr-2010

10. Adverse Events • A serious adverse event (SAE) in human drug trials are defined as any untoward medical occurrence that at any dose • results in death – direct outcome of the adverse event e.g. device implant • is life-threatening – suspected use product may result in death e.g. pacemaker failure • requires inpatient hospitalization or prolongation of existing hospitalization, e.g. allergic reaction, bleeding • results in persistent or significant disability/incapacity e.g. CVA due to drug induced hypercoagulability • is a congenital anomaly/birth defect e.g. thalidomide • Requires intervention to prevent permanent disability – burns from radiation equipment The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. Adverse events are further defined as “Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.” Wikipedia Version: Final 21-Apr-2010

11. Top Five deficiencies - FDA Audits • Failure to follow protocol • Failure to keep adequate records • Problems with the ICF • Failure to report adverse events • Failure to account for the disposition of the study drug Version: Final 21-Apr-2010

12. Questions? Version: Final 21-Apr-2010