The GCP Perspective on Study Monitoring Heidi Judge, CCRP Sr. Clinical Trials Project Manager Clinical Trials Network and Institute Massachusetts General Hospital 1
Overview Monitoring Basics Who, What, Why, Where, When and How On-Site Findings 2
What is Monitoring? Monitoring Definition: 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, standard operating procedures (SOP s), GCP, and the applicable regulatory requirement(s). * ICH Guideline Sec. 1.38 3
Why is monitoring necessary? Monitoring Purpose: (a) Verify the rights and well-being of human subjects are protected (b) Verify the reported trial data are accurate, complete and verifiable from source documents (c) Verify that the conduct of the trial is in compliance with the current protocol, GCP, and applicable regulatory agencies (i.e. CIRB, FDA) New: Develop a systematic, prioritized, risk-based approach to monitoring clinical trials. * ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18; ICH Integrated Addendum to ICH E6(R1) Section 5.18.3 4
Study monitoring will keep you out of trouble!! Don t drop the ball!!! 5
Who can be a monitor? Monitors should Be appointed by the sponsor Receive formal training and certification Have scientific and/or clinical knowledge Have qualifications documented Be familiar with the investigational product(s), protocol, Informed Consent Forms (ICFs), SOPs, GCP, and applicable regulatory requirement(s) Be detail oriented 6
Monitoring Procedures: Regulatory Expectations 1999 FDA Guidance: ALCOA To be acceptable the data (from clinical trials) should meet certain fundamental elements of quality whether collected or recorded electronically or on paper. Data should be Attributable, Legible, Contemporaneous, Original, and Accurate. 7
Who is responsible for monitoring? Sponsors Sponsors are responsible for ensuring proper monitoring of the investigation(s) [21 CFR 312.50] (d)selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation. [21 CFR 312.53(d)] 8
Who is responsible for monitoring? Site Investigators The Site Investigator (SI) is ultimately responsible for the conduct of the study at his/her site and must support all monitoring activity! 9
When should monitoring visits happen? In general, there is a need for on-site monitoring before, during and after the trial has ended. Frequency based on objective, enrollment rate, complexity, blinding, size, endpoints and funding Additionally, sponsors may choose remote and/or centralized monitoring during the course of the trial or a combination of all three. Described in Monitoring Plan (MP) for the trial ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18.3; ICH Integrated Addendum to ICH E6(R1) Section 5.18.3 10
Centralized Monitoring New: Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians). OFTEN ASSOCIATED WITH RISK-BASED MONITORING *FDA Guidance: Oversight of Clinical Investigations A Risk-Based Approach to Monitoring (August 2013) ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18.3; ICH Integrated Addendum to ICH E6(R1) Section 5.18.3 11
Centralized Monitoring Benefits Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data by identifying high risk sites with higher data entry errors, protocol deviations and high rates of AE/SAEs. These sites can be targeted for on-site monitoring visits. 1. ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18.3; ICH Integrated Addendum to ICH E6(R1) 2. http://www.appliedclinicaltrialsonline.com/centralized-monitoring-smart-reliable-approach 12
How Centralized Monitoring Applies to Sites On site monitoring may be less frequent as a result of centralized monitoring However, data may be reviewed more frequently behind the scenes. Important Reminders: Keep up-to-date on data entry Be mindful of data entry errors Be especially mindful of protocol deviations 13
How many monitors? Factors to consider in determining the number of monitors include: Number of sites Number of subjects Rate of enrollment Product type drug? device? Complexity of the study Nature of the disease or condition * FDA Guideline for the Monitoring of Clinical Investigations, January 1988 14
Monitoring Plan Monitoring Plans should answer the following questions: Who is responsible for study monitoring? How often will monitoring occur? What types of monitoring will be utilized? What will the monitoring activity look for? What tools will the monitor use? What are the procedures for reporting deficiencies? How will monitoring be documented? New: What are the critical data and processes? New: What are those aspects of the study that are not routine clinical practice and that require additional training. ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18.3; ICH Integrated Addendum to ICH E6(R1) Section 5.18.7 15
Types of Monitoring Visits Pre-Study Selection Visit (PSSV) Site Initiation Visit (SIV) Interim Monitoring Visit (IMV) Remote Monitoring Visit (RMV) Close-Out Visit (COV) 16
Pre-Study Selection Visit (PSSV) Purpose: Make recommendations to the Sponsor on including a site for a trial. Collect information on Contact info and list of staff members who will participate in trial Assess Staff experience? Workload? Competing studies? Facilities - adequate and acceptable? Equipment is available?
Pre-Study Selection Visit (cont d) Discuss Protocol and study procedures Roles/Responsibilities Study Requirements Check for History of previous audits Criminal or civil investigations Assess site s potential for subject recruitment Question and answers session
Study Initiation Visit (SIV) Purpose: Ensure study staff understands the protocol, responsibilities and regulatory requirements Discuss Site Roles/Responsibilities Drug storage, dispensing, and accountability Protocol and Informed Consent How to record and report AEs and SAEs Recruitment schemas for enrollment
Study Initiation Visit (cont d) Ensure Training is complete and documented Investigator understands his/her responsibilities for electronic records Site understands data collection & query management using electronic data entry Study staff have a plan for conducting the study (ICF process/delegation of tasks?)
Interim Monitoring Visit (IMV) Purpose: Ensure staff is following the protocol Review: Documentation of informed consent Screening Logs Complete, accurate, legible source documents Protocol adherence Staff and IRB Regulatory documentation Investigator & staff carrying out only delegated tasks Facilities Drug accountability being maintained Site issues / resolutions *21 CFR 10.90 & ICH GCP 5.18.4
Interim Monitoring Visit (cont d) Perform Subject Records Source Data Verification Ensure: Accuracy and completeness of CRF Recording of Screen fails Early withdrawals AEs/SAEs Deviations from the protocol: Missing visits / procedures noted Schedule time to meet with investigator to go over any questions, findings, etc
Remote Monitoring Visit (RMV) Sites send de-identified source documentation to monitor: Purpose 1. To verify data against the EDC 2. To open and close queries
Close-out Visit (COV) Purpose: Ensure that all final study activities are complete, answer site s final questions, and prepare site to close study with IRB. Collect outstanding study forms / logs Perform final review of study file documents Collect and/or destroy any unused or expired study drug, open containers and undispensed study drug Discuss: Timelines and strategies for completion of outstanding CRF and queries Plans for record retention Notification to the IRB that the study is closing
Monitoring Documentation and Reporting Monitoring Reports Sent to Sponsor Monitoring Letters Sent to Sponsor AND Site Communications should include: Date of activity and individual(s) conducting it Summary of the data or activities reviewed Description of non-compliance, potential noncompliance, data irregularities, or other deficiencies identified Description of actions taken, to be taken, and/or recommended, including the person responsible for completing actions and the anticipated date of completion
Monitoring Documentation and Reporting Monitoring documentation should be provided in a timely manner for review. Follow monitoring plan and Sponsor SOPs New: Reporting of centralized monitoring activities should be regular and may be independent from site visits. ICH Guidance for Industry: E6 GCP Consolidated Guidance Section 5.18.37; ICH Integrated Addendum to ICH E6(R1) Section 5.18.6
Study Monitoring: On-Site Findings 27
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Common Site Oversight Findings Delegation logs not complete Inappropriate staff members delegated tasks for which they were not trained or certified Lab reports, ECG printouts, etc., not reviewed and signed by the Site Investigator Not determining clinical significance while reviewing lab values and adverse events 31
Informed Consent Form Findings Subject signing invalid consent Wrong version Expired ICF Forgetting to write the correct date or time Signing on the wrong line Forgetting to initial and date required sections Missing pages 32
Ineligible Subjects Failed screening but test result(s) not reviewed and signed off by site investigator, subject randomized into study Protocol eligibility waivers not granted, subject randomized into the study The alternative 33
FDA Warning Letters 483 Clinical investigator warning letter: Failure to ensure proper monitoring of the investigation. 4. There is no documentation that the [redacted] device studies were monitored in 2002 and 2005. http://www.fda.gov/iceci/enforcementactions/warningletters/2008/ucm1048315.htm 34
FDA Warning Letters 483 Sponsor warning letter: Failure to possess written monitoring procedures and failure to ensure proper monitoring of the investigation [21 CFR 812.25(e) and 21 CFR 812.40]. http://www.fda.gov/iceci/enforcementactions/warningletters/2006/ucm076171.htm 35
THE RELEVANT STUFF 36
Who May Get Asked to Assist? Most staff will not become monitors, but a lot might have a role in a monitoring visit, including: Coordinators Fellows Nurses Radiologists Pharmacists Research Assistants Backup Coordinators No one person will have all of the answers. It is a group effort! 37
Preparing for a Monitoring Visit 38
Organization is Key! 39
Tips for Scheduling a Monitoring Visit Only schedule a monitor s visit when the coordinator is available for the duration of the visit and when the SI is available to meet, if even for 20 minutes. Book a room for the Monitor: Does the room have ample light? Internet connection? Space? Computer? This ensures the monitor is able to work efficiently and effectively. Is the location close to you in the event there are questions? Book visits with Pharmacy, GCRC, etc., as applicable to the study requirements. 40
Before the Monitoring Visit Ask yourself, where are the Regulatory Documents Subject Binders Source Documents Study Drug SI 41
Before the Monitoring Visit Institutional requirements: Have subject medical records/clinic charts available as required by your institution. If electronic medical records (i.e. EPIC), ask the monitor what is needed and have print-outs available. Set monitor up with EMR access FAR in advance (if needed) 42
Before the Monitoring Visit Regulatory Binders Are all logs complete and accurate (designation of responsibility, enrollment, study drug, etc.)? Do you have all appropriate updated and current regulatory documents (CVs, licenses, certifications) for staff members available? Do you have all IRB Submissions / Approvals / Correspondences filed? Do you have all manuals (Labs, MOPs, EDC, etc.) filed? 43
Before the Monitoring Visit Subject Binders Do you have lab reports associated with the visits reviewed by SI and filed in the subject binder? Do you have all necessary signatures available (lab reports, visit forms, AE logs, SAEs, etc.) as required by the study? Are all visits that have occurred entered into the Electronic Database BEFORE the monitor comes? Study Drug Do you have all the logs completed for study drug accountability? 44
During the Monitoring Visit Make yourself available during the visit for whatever questions that may arise. Take time to sit with the monitor to review, respond to queries, etc. Be nice to your study monitor!! They are there to help you, not just point out faults, site deficiencies, etc. They will help correct any errors and ensure it is not repeated. 45
After the Monitoring Visit Review the monitoring letter with your Site Investigator. Answer / correct any deficiencies as soon as you are able to avoid the possibility of forgetting to complete a requested task. Contact your monitor with questions and copy monitor on all query-related communications. 46
Does my study need monitoring? Not all studies require a monitor. Exempt studies include: No IND Non-FDA Regulated Biomarker and Sample Collection-only studies All studies should be monitored internally Visit Partners Quality Improvement website for assistance 47
Thank You! Questions? Email: hjudge@partners.org 48