ENOS Indian Investigator Meeting 13th March 2010 “The role of the Local Centre”

1. ENOS Indian Investigator Meeting 13th March 2010 “The role of the Local Centre” Sharon Ellender International Centre/Follow up Coordinator

2. The National Coordinator’s role/responsibilities • Promote trial • Ensure necessary National Regulatory and Ethics approvals have been gained • Recruit Local Centres • Assist Local Centres with set up • Organise translations if necessary • Monitor Local Centres (at least 3 times) • Perform 90 day patient follow-ups by telephone • Ensure practice of NCC and Local Centres is according to ICH/GCP standards • ENOS Insurance cover

3. The local centre’s role /responsibilities • Obtain and maintain Local approvals • Ensure adherence to GCP/ICH standards • Ensure all staff are trained & remain trained • Ensure that Site files are current • Recruit patients 1-2 per month • Complete all patient forms online within the time line • Fax paperwork to International Coordinating Centre

4. What makes a good Local Centre • Commitment to trial (time, staff, hospital) • Experience in doing stroke trials • Commitment to recruit 1-2 patients per month consistently • IT access: PCs, Internet, Fax,communication • Fax/record and complete data in a timely manner • Be prepared for monitor visits by the NCC or ICC

5. Local centre monitoring • Findings are measured against GCP-ICH • Aim of visit is to assess: • Conduct of Local Centre • Maintain Trial File • Validity of data - check data against source data • Evidence of consent,signed and dated • Identify major and minor protocol deviations, and other abnormal findings

6. Local centre monitoring • NCC or ICC will perform the monitoring • Local Centres with poor monitoring reports will have further inspections and could be closed down • International Coordinating Centre (ICC) will monitor NCCs once during the trial period • Report is completed by monitor using template and sent to Principal Investigator, National Coordinator, and Chief Investigator

7. Monitor Form upload

8. Findings • Document/Version Control • Incorrect Version Numbers, e.g. consent forms • Times of stroke and consent • Not written in medical records • Delegation of responsibilities • Not defined • Trial File • Non-existent, or not up to date • Dates and times • Inconsistent between medical notes and trial data entered online and in the patient trial file

9. Findings • Poor recognition of antihypertensive agents • Recognition of antihypertensives • BP measurements • Failure to take BP measurements at peak action of patch (1-2 hours after placement of patch) • Failure to take 2 BP measurements • Failure to use OMRON machine • Failure to obtain 7 days of BPs • Failure to correctly record randomised treatment use on day 7 form • Failure to record randomised treatment on the drug chart

10. Findings • Equipment • Broken printers,omrons, settings incorrect. • Local Centre staff training • Staff not GCP trained • Includes Principal Investigator! • Staff do not have GCP certificate • All staff need an up to date CV (2 yearly) • NCC staff training • Outcome assessor not mRS trained • Outcome assessor does not have mRS certificate

11. Quality: Protocol Violations • Protocol Violations are major deviations from the trial design • Must be reported to the DMC • We must avoid them to maintain the trial’s quality and to protect patients • Sites should report them to the ICC and NCC if they occurred accidentally • May be discovered on the database or at a site monitoring visit

12. Examples of Protocol Violations • Patient under 18 years of age • Randomisations >48 hours from onset of symptoms • GCS <8 at randomisation • No clinic weakness evident at any point • Weakness present for <1 hour in total • Limb weakness not present at time of enrolment • Failure to obtain consent or assent of patient • Systolic BP 140 - 220 mmHg at inclusion • Dependent (mRS >2) prior to stroke • Pre-existing antihypertensives not identified • GTN patch not given during first 4 days (if randomised)

13. Protocol Violations • Patient pregnant or breastfeeding at inclusion • Known severe concomitant illness • Known non-stroke intracranial pathology,ie brain tumour • Patient already involved in another drug trial (or within 3 months) at time of randomisation • Planned use of antihypertensive agents when randomised to ‘stop’, i.e. antihypertensives continued • No cranial imaging • Failure to complete SAEs if they occur • Follow up assessments are performed outside the specified times

14. Quality: Protocol Deviations • More minor deviations from trial protocol • May occur due to unforeseen events or mistakes. File notes can be used.

15. Examples of Protocol Deviations • Patient does not receive GTN patch on days 5 to 7 of trial, if randomised to do so • Clinician unintentionally or intentionally (in an emergency situation) introduces new antihypertensives within first 7 days of trial, or recommences pre-trial antihypertensives if randomised not to do so • Patient does not receive usual antihypertensives if randomised to do so • There are not 3 OMRON blood pressure measurements at randomisation and 2 OMRON blood pressure measurements daily during first 7 days • Follow up assessments are submitted outside the specified time • Patient goes home <4 days after enrolment

16. SAE forms ADVERSE EVENTS Reported on the Day 7 Form only. SERIOUS ADVERSE EVENTS 1.Death 2.Life threatening events 3.Requires in patient hospitalization, prolonging of existing hospitalization 4.Results in persistent or significant disability /incapacity 5.Is a congenital anomaly/birth defect • Submit within 24 hours of the event • Report SAE’S until completion of the day 90 follow up

17. In conclusion • Commitment to trial (time, staff, hospital) • Commitment to recruit 1-2 patients per month, consistently • Fax/record and complete data in a timely manner • Be prepared for monitor visits by the NCC or ICC Good Luck!!