M ODULE H I NTERIM M ONITORING V ISIT Denise Thwing 21 Apr Version: Final 21-Apr-2010

P URPOSE I NTERIM M ONITORING V ISIT o Rights and well being of subjects are protected o New information regarding drug is shared o Verify site compliance with the protocol o Confirm data points o SDV o Verify site regulatory adherence o Approved ICF o Prompt reporting AEs/deviations 2 Version: Final 21-Apr-2010

P URPOSE I NTERIM M ONITORING V ISIT 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 3 Version: Final 21-Apr-2010

P HILOSOPHY 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 4 Version: Final 21-Apr-2010

P REPARING 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 5 Version: Final 21-Apr-2010

P REPARING 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 6 Version: Final 21-Apr-2010

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

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

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

A DVERSE E VENTS A serious adverse event (SAE) in human drug trials are defined as any untoward medical occurrence that at any doseadverse eventdrug 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 failurelife-threatening requires inpatient hospitalization or prolongation of existing hospitalization, e.g. allergic reaction, bleedinghospitalization 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 10 Version: Final 21-Apr-2010

T OP F IVE DEFICIENCIES - FDA A UDITS 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 11 Version: Final 21-Apr-2010

Q UESTIONS ? 12 Version: Final 21-Apr-2010