Monitoring Non CTIMP studies

1. Monitoring Non CTIMP studies Presented by Mallikarjuna Rao Vemula (Arjun) Clinical Trials Monitor Joint Research & Enterprise Office Training – 25th March 2014

2. Contents • What is monitoring non CTIMP • Differences between non CTIMP and CTIMP studies • Frame work of standards for clinical trials • Purpose of monitoring • Monitoring plans • Types of monitoring • Monitoring visit • Monitoring compliance with the protocol and applicable standards • Protocol deviation and violation • Monitoring safety recording and reporting • Corrective actions, preventive actions (CAPAs) ACRP • Joint Research & Enterprise Office Training –25th March 2014

3. Definition of Monitoring - NIHR? The purpose of study monitoring is to verify that: • The rights and well–being of human subjects are protected • The reported study data are accurate, complete and verifiable from source documents • The conduct of the study is in compliance with the approved study protocol/amendments, sponsor SOPs, with GCP, and with the applicable regulatory requirements. “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, SOPs, GCP, and the applicable regulatory requirement(s)” (ICH GCP 1.38) • Joint Research & Enterprise Office Training –25th March 2014

4. What is Monitoring? To monitor or monitoring generally means to be aware of the state of a system……so for research… A review of the study through a combination of: • Remote monitoring • Site visits • Routine • Triggered Initial level of monitoring is in accordance with the study risk assessment. Monitoring frequency may change in relation to any further risk identified whilst the study is running (ACRP) • Joint Research & Enterprise Office Training –25th March 2014

5. Monitoring The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size and end points of the trial. There is a need for on-site monitoring, before, during and after the trial: however central monitoring in conjunction with procedures such as investigator’s training, meetings and extensive written guidance can ensure compliance with GCP Statistically controlled sampling ‘may’ be an acceptable method for selecting the data to be verified. • Joint Research & Enterprise Office Training –25th March 2014

6. Who are Monitors • Appointed by sponsor • Part of the study team • Member of Trial Management Team • Joint Research & Enterprise Office Training –25th March 2014

7. CTIMP Vs Non CTIMP • Joint Research & Enterprise Office Training –25th March 2014

8. What is Risk? • Risks associated with the trial can be defined by examining e.g. the trial design, participant population to be studied and any study related procedures aimed to identify specific areas of vulnerability and to determine how any identifiable risks can be mitigated. • Joint Research & Enterprise Office Training –25th March 2014

9. Categories of risk • Scale of Research in terms of recruitment period, Recruitment numbers required and/ or data collection time points over long periods of time • Patient population • Intervention(s) • Investigator/research team • Monitoring arrangements • Participant data • Protocol • Consent • Finance Who assess the risk: • CI/PI • JREO • Collaborating Departments e.g. Labs, Pharmacy etc (ACRP) • Joint Research & Enterprise Office Training –25th March 2014

10. Levels of risk • Low risk • Medium risk • High risk • Joint Research & Enterprise Office Training –25th March 2014

11. Risk assessment Based on a ‘risk assessment score’ a ‘monitoring plan’ will be developed • Joint Research & Enterprise Office Training –25th March 2014

12. Monitoring plan “Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.” (SI 2006 No.1928) • Sponsor determines levels of monitoring based on risk extent, nature and considerations. • Joint Research & Enterprise Office Training –25th March 2014

13. Regulations, Guidelines, & Standards for Non CTIMP • Declaration of Helsinki • Research governance framework for health & social care • Principles of GCP • Other applicable regulatory requirements E.g. Data protection act, EU Directives for Devices • Joint Research & Enterprise Office Training –25th March 2014

14. Monitoring Vs Audit Joint Research & Enterprise Office Training – 21st November 2013 • Joint Research & Enterprise Office Training –25th March 2014 Joint Research & Enterprise Office Training

15. Types of Monitoring • On site - Pre trial site selection visit - Initiation visit - Routine monitoring visits - Close out • Self monitoring - Checklists - Essential documents - Trial management - Recording and reporting - Patient recruitment - Additional documents - Personal training records (ACRP) • Joint Research & Enterprise Office Training –20th February 2014

16. Continued……. - Pharmacy - Laboratory • Remote - Centralised monitoring of documents - Range checks within data - Signal detection • Joint Research & Enterprise Office Training –25th March 2014

17. Monitoring visit • Monitor will verify the information kept at site during the visit: - Meet the PI to discuss study status, recruitment, problems & any unresolved issues identified at previous visits - To improve quality & promote high standards – protocol training for new study team members - Ensure safety of participants - To identify non compliance (protocol and/or regulatory) - To identify research misconduct/ fraud - Investigator site file - Source data verification transcribed on CRF(both electronic and paper) - Check any changes to CRF entries made legibly & by authorised individual - Check CRF copy for data management legible before sending CRF pages from site - Send in accordance with data management procedure - Sign monitoring log to document visit • Joint Research & Enterprise Office Training –25th March 2014

18. Monitoring compliance with the Protocol & applicable standards With Protocol • Correct version of protocol used • Patient eligibility • Randomisation procedure • Schedules With an amended protocol • Risk assessment is repeated • Investigator guidance provided Deviations • Urgent safety measures • Serious breach of protocol or GCP – sponsor notifies MHRA within 7 days • Joint Research & Enterprise Office Training –25th March 2014

19. Monitoring compliance with the Protocol & applicable standards continued…………. Informed consent (IC) process • Check process was approved by ethics committee • Person involved in IC authorised to and / or trained - On delegation log - Signature/signed initials verified • Verify prior to any study procedures - Correct version? - Dates of consent discussion - Signed and dated by: * Subject * Investigator/person conducting consent • Joint Research & Enterprise Office Training –25th March2014

20. Monitoring compliance with the Protocol & applicable standards continued Trial management • Site still adequate to conduct the study - Facilities - Equipment - Staff • Principal investigator providing adequate oversight • Recruitment proceeding to plan • Data - Recording - Collection • Joint Research & Enterprise Office Training –25th March 2014

21. Protocol deviation and violation • Protocol deviation: Less serious non-compliance – may not render a patient ineligible E.g. missing a visit window because the subject is traveling. Not as serious as a protocol violation. • Protocol violation: Serious non-compliance – may lead to exclusion of patients from eligibility analysis and/or their discontinuation from the study E.g. - Inadequate or delinquent informed consent - Inclusion/exclusion criteria not met - Unreported serious adverse events - Improper breaking of the blind - Use of prohibited medication • Joint Research & Enterprise Office Training –25th March 2014

22. Continued …… - Incorrect or missing tests - Mishandled samples - Multiple visits missed or outside permissible windows - Materially inadequate record keeping - Intentional deviation from protocol, Good Clinical Practice, or regulations by study personnel - Subject repeated non-compliance with study requirements • Joint Research & Enterprise Office Training –25th March 2014

23. Monitoring safety recording & Reporting • Adverse event: An adverse event (AE) is defined any unfavourable and unintended sign including an abnormal lab finding, symptom or disease associated with the use of medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. • Serious adverse event: Any untoward medical occurrence that results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant/incapacity, or in a congenital anomaly/ birth defect. • Joint Research & Enterprise Office Training –25th March 2014

24. Safety reporting • If SAE occurs the CI should contact The JREO with in 48 hours of becoming aware of the event. • CI should complete SAE form after completion of discussions with JREO • Reports of related and unexpected SAEs should be submitted with in the 15 days of CI becoming aware, should sent to the sponsor and to the relevant ethics committee • More detail on Safety Reporting in Next Month’s JREO training session- April 23rd!!!! • Joint Research & Enterprise Office Training –25th March 2014

25. CAPAs • Two distinct processes • Corrective action - Correct current problem • Preventive action - Prevent reoccurrence It is the part of quality management (ACRP) • Joint Research & Enterprise Office Training –25th March 2014

26. Analysis of issues identified Analyse any issues with investigator/ research team • An isolated or ‘one off’ error • Recurring error • Why did it happen - An oversight? - Inadequate training of staff involved? - Procedure / system inadequate or absent? - Could it happen again? • Document • Follow up CAPA • Joint Research & Enterprise Office Training –25th March 2014

27. Upcoming JREO Workshops April - Safety reporting 12.30pm 23rd April Board Room H2.7 May - Protocol Development 12.30 pm 21st May Board Room H2.8 June - Code Breaking in Clinical Trials 12.30pm 18th June Board Room H2.7 **For full list , please visit the portal** This and previous presentations will be available on the portal for your reference We are always contactable to answer queries and help you through the process • Joint Research & Enterprise Office Training –25th March 2014