Compliance and Quality Monitoring: What, Why, When, and How Jeanna Julo, BA, BA, CCRP Assistant Director, Clinical Data Management & Quality Controls, Auditing & Training Research Institute, University of Kansas Medical Center
Topics To Discuss What is Compliance and Quality Monitoring? Why Monitor? How Should a Monitor be Selected? Focus Areas for review Protocol Compliance, Source Documentation, Test Article Accountability, Essential/Critical Documents & IRB documentation, Legal/Financial Documents How to address problems Ongoing Review Reoccurring Issues
What is Compliance and Quality Monitoring? Systematic, ongoing review of clinical trial conduct and materials Ensures: Protection of the research participants Compliance with the study protocol Compliance with Federal, State, and Local regulations Accurate and complete data, verified by source documentation A rose by any other name Quality Assurance Review or Interim Study Monitoring May be performed internally (local IRB or compliance office representative, research administration office) or externally (clinical trial monitor employed or retained by study sponsor)
Why Monitor? Code of Federal Regulations, Title 21 Food & Drugs Section 312.50 (drug studies) and Section 812.40 (device studies) Responsibilities of Sponsors and Investigators, 21CFR 812.40(d) Sponsors are responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug (device). For more information, see: https://www.ecfr.gov/cgi-bin/textidx?sid=6f836308a6020970b2a1fbcff757eb87&mc=true&node=s e21.5.312_150&rgn=div8
Why Monitor? Code of Federal Regulations, Title 21 Section 213.56 Review of ongoing investigations, 21CFR 312.56(d) The sponsor shall monitor the progress of all clinical investigations being conducted under its IND For more information, see: https://www.ecfr.gov/cgi-bin/textidx?sid=6f836308a6020970b2a1fbcff757eb87&mc=true&node=s e21.5.312_156&rgn=div8
Why Monitor? Ensures that the study is being conducted according to the requirements of the trial protocol and Good Clinical Practice Prevents researcher errors from being repeated over the course of the trial Improves compliance with regulatory requirements Decreases investigator vulnerability to outside (FDA) audits Ensures investigator and sponsor confidence in the quality of study data generated
Why Monitor? Routine data and compliance monitoring is of critical importance in FDA regulated studies Offers the opportunity to identify and correct problems as they arise and helps keep records audit ready FDA auditors look for evidence of this type of study oversight in Sponsor Investigator (investigator initiated) trials Industry sponsored IND/IDE studies always incorporate routine monitoring plans Ensures that the study data is accurate and verified by source documentation
How much monitoring is needed? When determining monitoring needs, weigh the following: Funding Source/Sponsor Phase IND/IDE involvement Inclusion of sub sites and international sites How is the investigational product administered? The investigational product itself Protocol complexity and procedural risk Experience of the PI and study team
How should a monitor be selected? ICH E6 5.18.2 addresses the requirements for selection and qualifications of monitors International Conference on Harminisation Monitors should be appointed by the sponsor Industry sponsored clinical trials always address the monitoring component of the study If the investigator holds the IND/IDE (Sponsor Investigator), the they are responsible to ensure ongoing compliance monitoring throughout the study For more information, see: https://www.fda.gov/downloads/drugs/guidances/ucm073122. pdf http://ichgcp.net/518-monitoring
How should a monitor be selected? ICH E6 5.18.4 provides a detailed description of the monitor s responsibilities. A thorough review will encompass: Patient data and source documents Compliance records (IRB materials, regulatory documents) Test article records (drugs or devices) Legal documentation (contracts, investigator agreements) For more information, see: http://ichgcp.net/518-monitoring
Focus Area Protocol Compliance Eligibility Criteria Evidence that the subject meets inclusion criteria should be present in source documentation (diagnoses, test results, etc.) Source documentation should be reviewed for any evidence of exclusions to participation Protocol Deviations Visits out of window Procedures/tests not performed Use of prohibited concomitant medication Any other instances where trial protocol was not followed Check IRB reporting requirements for reportability
Focus Area Protocol Compliance Eligibility Criteria Evidence that the subject meets inclusion criteria should be present in source documentation (diagnoses, test results, etc.) Source documentation should be reviewed for any evidence of exclusions to participation Protocol Deviations Visits out of window, Procedures/tests not performed Use of prohibited concomitant medication, Any other instances where trial protocol was not followed Protocol Violations Enrollment of ineligible patient without documentation of exception from trial sponsor Informed consent not obtained
Focus Area Source Documentation What is a Source Document? a document in which data collected for a clinical trial is first recorded; data is usually later entered in the case report form (CRF) The ICH GCP guidelines define source documents as original documents, data, and records. Protocol procedures vs data reported on study forms/in study database vs source documents Source documentation is the authority on whether a procedure was performed. Not documented? Not done! Source documentation should show that the protocol procedure was performed and when, data should be accurately transcribed to study forms / database Informed consent process should be clearly documented in source and use of correct consent version must be confirmed
Focus Area Source Documentation The medical record is the primary source document Procedure notes, Test results, Office visits, and consultations EMR must be 21 CFR 11 compliant in order to be used as source in an FDAregulated clinical trial Previously unreported events such as deviations or adverse events are frequently identified via review of the medical record Review clinic notes for patient report of new/worsening problems, visits to other health care providers/urgent care/er visits Compare timing of visits/procedures to study visit windows to ensure compliance
Source Documentation Common Errors Source Documents are incomplete or inaccurate Incomplete or inaccurate documents can cause doubt on a study s integrity Problems with unexpected event reporting: Events go unreported Events are not reported within required timelines Be sure you know both the IRB and FDA timelines for reporting unexpected events! Subjects are not updated (i.e. re consenting the subject with new risk information)
Focus Area Test Article Accountability Instructions for storage, handling, and dispensing Shipping records Certificate(s) of analysis for the investigational product Un blinding instructions Documentation of test article dispensing and return of unused product/empty containers Responsibility for maintaining investigational product accountability usually delegated by the investigator to a qualified member of the study team (pharmacist, nurse coordinator, etc.) This delegation must be appropriately documented and there must be documentation that the designee was trained on the handling, storage, and accountability requirements of the test article
Focus Area Test Article Accountability 21 CFR 312.57(a) states record keeping requirements for IND studies, 21 CFR 812.140(a.2) addresses investigational devices. ICH E6 4.6 provides guidance ICH E6 8 give greater detail about required components For more information, see: https://www.ecfr.gov/cgibin/retrieveecfr?gp=&sid=342ba3a3519ed2c5ef35795eb880b148&mc=true &n=pt21.5.312&r=part&ty=html#se21.5.312_157 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=812.140 https://www.ich.org/fileadmin/public_web_site/ich.../e6/e6_r1_guideline.p df http://ichgcp.net/8-essential-documents-for-the-conduct-of-a-clinical-trial
Focus Area Essential Documents Called the Regulatory Binder, Critical Documents Binder, or Study Documentation Binder Repository for all essential documents at the study site ICH E6 8 provides detailed listing of documents required prior to study start, during the study, and after completion or termination of the study Trial protocol and all subsequent amendments Signature/acknowledgement pages for each version Store the current approved version first (backwards to the original version) Investigational Drug Brochure or Investigational Device Instructions for Use All subsequent revisions and acknowledgement pages for each
Focus Area Essential Documents Regulatory documents FDA Form 1571 (if Sponsor Investigator) a federal form, if applicable for Investigator initiated INDs FDA Form 1572 (drug studies) or Statement of Investigator (device studies) a federal form, only for drug studies is the statement of the investigator affirming that he/she will abide by the federal guidelines set forth in the Code of Federal Regulations for the use of drugs Financial Disclosures (For Pharmaceutical Sponsored Trials) Study team requirements CV, signed and dated within past two years and updated as needed throughout the trial Current licensure, as applicable, and updated as needed throughout the trial Documentation of study training according to role, both initial training and ongoing as needed for protocol amendments affecting their delegated responsibilities Ensure all required materials are present for each member of the study team, cross check with IRB approved personnel list and site specific forms
Focus Area Essential Documents Regulatory documents Local laboratory certifications and normal reference ranges, CV/license of lab director, updated as needed throughout the study IRB communications Must contain copies of all IRB correspondence, submissions, and approvals Review for current committee roster, documentation of OHRP registration If any study personnel are members of the IRB, documentation that they abstained from voting IRB approved consent forms All versions All signed consent form originals (may be kept in a separate binder with a note to file with location)
Essential Documents Common Errors Eligibility Criteria & Consent form irregularities: Signed consent not present in subject files Consent forms incorrectly completed Wrong person signs consent Signature not dated Other fields (checkboxes, etc.) not completed Can imply inattention by study staff and inadequate oversight by investigator Requires reporting to IRB
Focus Area Essential Documents IRB communications Must contain copies of all IRB correspondence, submissions, and approvals Review for current committee roster, documentation of OHRP registration If any study personnel are members of the IRB, documentation that they abstained from voting Review for: Initial approval (cross check date with first signed consent to ensure study activity did not commence prior to IRB approval) Continuing reviews, and any lapse in approval, documented and reported Amendment submissions and approvals, including personnel changes (cross check with delegation of authority log and training records) Reports of any deviations adverse events/saes/unanticipated problems that meet IRB reporting requirements and associated approvals Other new information (DSMB reports, previous monitoring visit reports) IRB reporting requirements may vary
Focus Area Essential Documents Drug or Device Accountability Log or memo as to where records are located (e.g., research pharmacy) and who is maintaining logs tracks the overall supply of drug/device at the site and prompts reordering Include shipping records and temperature logs, if needed Include drug disposal records tracks the date and quantity of the drug/device given to and returned from the research subject May use one log to track both amounts or a separate subject log and site log Sample of label for the study drug Any FDA correspondence (if applicable) For sponsored trials, this is usually just the documentation of the IND number by either a copy of the FDA IND letter or documentation from the sponsor with conformation For investigator initiated trials, this will include the IND or IDE Application and annual progress reports
Focus Area Essential Documents Safety Documents Serious Adverse Events (SAE)/Unanticipated Problem Log and related documents For site research subjects and research subjects at other sites in the study Recommendations and correspondence from any safety monitors or committees Protocol Deviation Log Site Visit (monitoring) Log that documents that the site was monitored and the frequency of monitoring. Date verified and signed by both the monitor and designated site staff Monitoring Visit Reports and correspondence All relevant correspondence you have with the sponsor, CRO, or monitor Industry sponsored trials usually generate a significant amount of written correspondence, investigator generated research less so emails, letters, or newsletters
Focus Area Essential Documents Site specific forms Delegation / signature log, Staff training log Ensure that all current team members are listed and inactive members have end dates, and that all current members are approved by the IRB Screening / Enrollment log, Visit tracking log Ensure that HIPAA regulations are being followed if screening log is being sent outside your institution Site specific information Standard Operating Procedures Usually filed separately from study records While sites are not mandated to have SOPs, they are certainly a best practice!
Focus Area Essential Documents Documents that should be filed and maintained separately Confidential list of all enrolled subjects the names of the individuals linked to participant ID numbers Completed CRFs and source documents Source documents provide clinical evidence and validates data reported on CRFs Signed consent forms Financial agreements between the sponsor and investigator Study budget, study contract
Review Complete Now What? Summary of Findings Investigators must be notified in writing of the results of the review Summary should be sent as soon as possible, ideally within 10 business days Note what records were included in the review and if any were incomplete or unavailable Include a summary of any deficiencies to be corrected or additional information needed Reportable events not yet reported to IRB Additional source documentation needed or notes to file required Previously unnoted adverse events or deviations Addressing Problems Two pathways when instances of non compliance are found Most common approach is to work with the investigator to address the errors and secure protocol compliance Severe or repeated non compliance can result in study sponsor suspending shipment of investigational product, effectively ending the investigator s participation in the study (uncommon, this would be the option of last resort)
Review Complete Now What? Ongoing Review Compliance / Quality monitoring is not a one and done Effective compliance monitoring is an ongoing process throughout the life of the study How frequently? Most monitoring is risk based Higher risk studies may be monitored every 4 6 weeks Lower risk studies might only be monitored every few months The reviewing IRB can assist with risk determination Each subsequent visit should build upon the previous visit Ensure that the investigator / study team have addressed items noted during the previous review IRB reports complete Corrective actions taken on deviations, as applicable
Recurring Issues? What if The same or similar deviation(s) keeps occurring? Source documentation is consistently inadequate? Use as opportunity for education/training Major recurring issues should be referred to the reviewing IRB and study sponsor Identify the why behind the behavior Inadequate training of investigators or study team Insufficient personnel to conduct study Ambiguities in the study protocol can contribute to recurring deviations
Recurring Issues? Notes to File should be used to explain when needed unclear or missing documents Location of important documents not stored in the Regulatory Binder Assist the investigator with corrective actions Additional / ongoing training in IRB reporting requirements Guide investigator to institutional resources that can provide additional support to the research project Compliance / Quality monitoring is Good for the study participants Good for the Investigator Good for the study!
Questions & Answers