Performance Guidelines & Improvement Plan

Performance expectations based on 80 annual admissions 5 screens per month 0.5 randomizations per month Monthly webinar attendance Data entry & Source document uploading in real-time, no later than 7 days of visit Protocol compliance

THE KEY FOR MISTIE III IS SCREENING

Daily rounding, meeting & greeting Not a trial of database hunting No low-hanging fruit for the picking Our cases are rare Every case counts

Screening Goal: 5 Screens per Month INTERVENTIONPROBATIONTERMINATION >2 months since last screen >4 months since last screen 6 months no screens Criteria Site manager action required Weekly calls to SC MAP review Screening metrics guidance Issue probation letter Site visit (possible) Written CAPA plan Close-out letter sent Site closed to enrollment Site action required Submit recent census #s Screen> 80% of census Screen goal adjusted Screen> 50% of census Comply with CAPA by M5 Close to enrollment Follow subjects d365 Complete IRB & close out

ENROLLMENT PLANNING Prepare your site for enrollments

Randomization Goal: 0.5 per Month INTERVENTIONRETRAININGPROBATION >3 months since last randomization >6 months since last randomization 9 months since last randomization Criteria Site manager action required Weekly calls to SC MAP review Site visit (possible) Retraining CAPA plan Probation letter Feasibility assessment At 12 Months: Close-out letter Site Close Site action required Site self-evaluation Best consent retraining Monthly PI meetings Get an enrollment Retake online training Comply with CAPA Enroll by M9 Enroll w/in 3 months In-service/grand rounds Expand referral network Complete close out procedures

MOP Chapter 16: For sites that have not enrolled a patient in more than six months, retraining and recertification will be required. An will be generated to your site when there have been no subject enrollments within the past 5 months. Retraining will include recertification of specific modules by all relevant study personnel. Additionally, all study personnel who plan to enroll subjects will be required to review the current MISTIE III Protocol and relevant MOP chapters. A list of relevant recertification tasks by personnel can be found below and in Appendix 1 of this MOP chapter. A signed PI Attestation of Retraining affirming that the training activities at the institution have been completed will need to be uploaded to the VISION database. It is expected that retraining should occur prior to the six month mark. The CC will follow the progress of retraining by monitoring documents uploaded into VISION and remaining in direct contact with the specific MISTIE III site team. The retraining materials listed below are available on the BIOS website

MISTIE III Informed Consent Guide MISTIE III IM June 21, 2014

Every site needs a recruitment plan Materials approved in advance Generic templates Checklists Screening checklist Consent checklist Internal & external referral network chart Weekend & vacation backup

Referring physician brochure Make local and referring physicians aware that transfers can give access to increased options for the patient Send surgeon brochures Give grand rounds Provide simple I/E cards Place posters in staff rooms

Family brochure Download and personalize Display in the unit

ADDITIONAL PERFORMANCE EXPECTATIONS

Protocol Compliance Goal: 100% INTERVENTIONPROBATION Criteria Site manager action required Written CAPA plan Probation letter sent Close site to enrollment Site visit Written final CAPA plan Mandatory re-training Recommend site closure Site action required Notify IRB/EC SPECIFIC training CAPA plan or close-out Follow subjects through d365 Significant deviation Notify IRB/EC Complete CAPA plan 3+ significant deviations

Data Entry Goal: Real-Time INTERVENTIONPROBATION Continued poor/slow data entry Criteria Site manager action required Weekly calls to SC Review of SC workload Site visit Written CAPA plan Probation letter sent Closed to new enrollment 3M max or site closure Site action required Complete data entry per CAPA plan or close-out Follow subjects thru d365 Poor/slow data entry &/or source document uploading Complete data entry per CAPA plan

Webinar Attendance Goal: 100% INTERVENTIONRE-TRAINING <75%-90% webinar attendance <75% webinar attendance CRITERIA SITE MANAGER ACTION REQUIRED Webinar reminders Written CAPA Plan Formal Lose Webinar reimbursement SITE ACTION REQUIRED Comply with CAPA Webinar re-registration & attendance Comply with CAPA Complete post-tests of missed webinars Webinar re-registration & attendance

Webinar payment in Contract 1 st year : Subsequent years :

KEEP UP THE GOOD WORK! We expect to never use these plans.