Implementing Good Clinical Practice at an Academic Research Institution

Implementing Good Clinical Practice at an Academic Research Institution Maintaining Essential Documents Partners Human Research Quality Improvement (QI) Program Stephen W. Hayes

Outline Significance of Essential Documents Background Current Practices Composition Maintenance (QI Regulatory Binder) Case Study Resources for Maximizing Quality 2 GCP Conference

Significance: Background Pre ICH GCP guidelines Clinical investigations of new drugs were frequently repeated due to inconsistent standards for conducting and documenting clinical research in the international community. This often caused delays in the review and approval process of new drugs. (CITI) Publication of ICH GCP guidelines In 1996, regulatory and pharmaceutical experts from the US, European Union and Japan developed a unified set of standards for clinical trials that streamlined the review and approval process of new drugs. One of the standards was the GCP List of Essential Documents. (CITI) Updated November 2016 to address evolution of studies from paper base to electronic based documentation. 3 GCP Conference

Significance: Current Practices PHRC Recordkeeping & Record Retention Requirements Investigators are required to maintain records of their human subject research activities. Good records are essential for verifying the quality of study data produced and demonstrating compliance with good clinical practice guidelines and applicable regulatory requirements (PHRC June 2015) 4 GCP Conference

Composition The collection of essential documents in section 8 of the GCP guidelines is divided into 3 subparts based on the point in time they are produced in the clinical trial: Before the clinical phase During the clinical conduct After completion or termination Each subpart is comprised of essential regulatory documents. Document Phases 5 GCP Conference

Maintenance QI Regulatory Binder maintains essential regulatory documents for a range of human subject research. The binder also provides: Guidance for organization and recordkeeping Assistance with proper study documentation and successful study management Readily accessible links to on-line resources Available in both print and electronic form QI Regulatory Binder 6 GCP Conference

QI Regulatory Binder Consultations Timeline: 01/01/2012 to 06/11/2015 Oth, 1, 3% Requests by Institution BWH, 11, 29% 37 Investigators New to QI: 51% New Investigators 1 : 32% 38 Protocols Non-industry sponsored: 84% MGH, 25, 66% McLean, 1, 2% Full Board: 71% FDA Regulated: 60% 1 Less than 4 IRB approved protocols 7 GCP Conference

Regulatory Binder Guidelines 1. Establish the binder at the beginning of the study prior to subject enrollment. 2. Add study staff maintaining the binder to the IRB protocol. 3. Store binder in a safe and secure location that is accessible to all study staff. 4. Customize the binder to meet the needs of your protocol. 8 GCP Conference

Regulatory Binder Sections All Studies Protocol Staff CVs* Staff Licensures* Logs IRB Documents Consent Forms Data Collection *for studies involving an intervention or interaction with subjects Study Specific Lab Documents NIH Sponsor Drug/Device FDA Financial Disclosure DSMB 9 GCP Conference

Regulatory Documents All Studies Current IRB Approved Protocol* Documents current study objectives and procedures approved by the IRB Staff CVs & Licensures (for interaction/intervention studies) Confirms staff qualifications to conduct a study or perform delegated tasks Logs Assists with study management and collection of data reported to regulatory authorities IRB Documents* Demonstrates that appropriate regulatory authorities have reviewed and approved the study prior to initiation Current IRB Approved Consent Form(s)* Documents that the informed consent process and information given to subjects were reviewed and approved by the IRB Data Collection* *can be retained in Insight if after April 2013 Template forms used to collect study data 10 GCP Conference

Study Management Tools/Logs Maintain logs for all studies as applicable: Enrollment/screening Delegation of responsibility/signature Monitoring Drug/device dispensing & accountability AE tracking Minor deviations QI template logs: https://partnershealthcare.sharepoint.com/sites/phrmresour ces/rsm/rsf/pages/study-management-tools.aspx 11 GCP Conference

Study Management Tools REDCap ebinder The Electronic Regulatory Binder is a project within REDCap that was developed by Partners Human Research Quality Improvement (QI) Program and Enterprise Research Infrastructure & Services (ERIS). To request a copy of the project for an IRB approved protocol: log into REDCap with your Partners username and password, click the tab titled Create New Project and complete the fields for requesting the Electronic Regulatory Binder template. General instructions for using the project to enter and store regulatory information can be found on the project s homepage. 12 GCP Conference

Regulatory Documents Study Specific Laboratory Verifies the competency of lab facilities and the reliability of test results (CLIA/CAP Certificate, Lab Director s CV, normal range values) Sponsor Documents significant discussions between the sponsor and site regarding the administration and conduct of trial Drug/Device Provides relevant & current scientific information about the drug/device and its use in subjects FDA Confirms compliance with FDA regulations governing the use of investigational products Financial Disclosure Documents financial agreements between clinical investigators and the sponsor of the trial (FDA form 3455) DSMP Data Monitoring plan; Reports and Minutes from Data Safety Monitoring Board meetings, if applicable 13 GCP Conference

November 2016 GCP Guideline Revisions The location of essential documents should be centralized and documented Certification of copies of original documents SOPs should be established and adhered to. Document staff creating copies. Staff should attest that copies are full and complete reproductions of original documents Investigator should have control of and continuous access to study data and essential documents 14 GCP Conference

Record Retention HRC 7 years upon completion of the study FDA 2 years after the marketing permit application is approved or terminated At the end of the study when the FDA is notified that test articles were disposed or returned and a marketing permit is sought Industry standard 15 years 15 GCP Conference

Case Study Dr. Chang is the site principal investigator for a Phase III study assessing the safety and efficacy of Doximab, an injectable medication, for the treatment of moderate to severe Crohn s disease. Per IRB approved protocol, Dr. Chang is responsible for oversight of the protocol, determination of subject eligibility and monitoring of study data to ensure subject safety and data integrity. In an effort to assist the PI, Sally Perkins, the coordinator, completed the eligibility assessments and conducted all study visits, except those that required a physical exam. Sally who was not trained in medical terminology also completed case report forms although she had difficulty interpreting all of the acronyms on the forms. The monitor reviewed the study documentation remotely twice a year.

Case Study Continued Dr. Chang s study was inspected by the FDA. The FDA found the following deficiencies: 1. You failed to conduct the studies according to the signed investigator statement [21 CFR 312.60]. 2. You failed to conduct the study in accordance with the investigational plan and protocol [21 CFR 312.60]. 3. You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)]. Questions Which actions led to each of the FDA s findings? Is the coordinator going to be held responsible for any of findings in the FDA Form 483? 17 GCP Conference

Consequences of noncompliance IRB Requirements to report noncompliance to the IRB Reports to OHRP, FDA Suspension or restriction of research priveleges Internal effort to investigate, respond and report: IRB, QI Program, Institutional Official, Office of General Counsel FDA enforcement Inspection Warning letter, Disqualification, Monetary fines, Civil/Criminal liability 18 GCP Conference

Resources for Maximizing Quality Checklists QI Regulatory Binder Study Start-up Checklist for Minimal Risk Resea rch Self-Assessment Checklist (revisions in progress) Activities/Services Regulatory Binder Consultations Assistance with FDA Applications (IND/IDE) In-services On-site reviews Contact QI Program 19 GCP Conference

Questions 20 GCP Conference

References International Conference on Harmonization. (1996). E6 Guideline for Good Clinical Practice. Retrieved from http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html Partners Human Research Committee. (2015). Guidance for Investigators Recordkeeping and Record Retention Requirements. Retrieved from https://partnershealthcarepublic.sharepoint.com/clinicalresearch/recordkeeping_and_record_requirements.pdf Partners Human Research Committee. (2007). Principal Investigators and Delegation of Study- Related Tasks to Co-Investigators and Study Staff. Retrieved from https://partnershealthcarepublic.sharepoint.com/clinicalresearch/delegation_of_study-related_tasks.pdf Partners Human Research Committee. (2005). Data and Safety Monitoring Plans in Human- Subjects Research. Retrieved from https://partnershealthcarepublic.sharepoint.com/clinicalresearch/dsmp_in_human_subjects_research.pdf Code of Federal Regulations. (2012). 21 CFR 312 Investigational New Drug Application. Retrieved from http://www.gpo.gov/fdsys/pkg/cfr-1998-title21-vol1/content-detail.html Code of Federal Regulations. (2012). 21 CFR 812 Investigational Device Exemptions. Retrieved from http://www.gpo.gov/fdsys/pkg/cfr-1998-title21-vol1/content-detail.html GCP Conference 21

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Approved Consent Form Original Consent Form Subject Population: Adults under going xxx procedure IRB Protocol Number: 2004p-123456 Sponsor Protocol Number: 11223344 Consent Form Valid Date: November 25, 2007 Amendment Number: IRB Expiration Date: November 1, 2008 Amendment Approval Date: November 25, 2007 An amendment to change the consent form was approved on March 2, 2008 Subject Population: Adults under going X procedure IRB Protocol Number: 2004p-123456 Consent Form Valid Date: March 2, 2008 IRB Expiration Date: November 1, 2008 24 GCP Conference

Data Collection Terms Source Documentation: Data Collection Sheet: First recording of any observations or data about a subject (Clinical Research Coordinator Handbook). (e.g., Hospital records/medical records, Lab reports, Subject diaries, Evaluation checklists, X-rays, Physician s progress notes, EKG Report) Pre-designed forms or templates used by the site to collect information about subjects (e.g., pain assessment scale, vital signs sheet) Case Report Form (CRFs) : Provide for the orderly transfer of data from the study site to the CRO/SMO or Sponsor (Clinical Research Coordinator Handbook). 25 GCP Conference

PHRC Guidelines: Delegation of Responsibility Principal investigators must ensure that designated individuals: 1. Are qualified to perform tasks 2. Receive adequate training 3. Have adequate supervision When delegating tasks that are clinical or medical in nature, the principal investigator must ensure that the individual has the relevant formal medical training. Investigators are advised to maintain a list of qualified staff and their delegated tasks. 26 GCP Conference

Product Information Drug Investigator Brochure Description of the drug and formula Pharmacological and toxicological effects Pharmacokinetics and biological disposition Safety and effectiveness Risks and side effects (21 CFR 312.23 ) Package Insert Device Manual Device Information for Use 27 GCP Conference

Drug/Device Accountability Protocol identifier (number, title) Subject identifiers (initials/study number) Randomization and/or kit number Date dispensed/implanted Amount dispensed Date returned/destroyed Amount returned Initials of person dispensing/implanting/receiving QI Drug Accountability Log 28 GCP Conference

FDA (IND/IDE Studies) Clinical Investigator (conducts study) 1. Signed Investigator Agreement 2. FDA Financial Disclosures 3. Serious adverse events submitted to the sponsor Sponsor-Investigator (initiates and conducts study) 1. Clinical Investigator requirements 1 or 2 and 3 2. Original application and all subsequent submissions to the FDA FDA 1571 (drug) IND/IDE Application Amendments to application Adverse Event Reports Annual Reports 3. Certification of Registration to Clinical Trials. Gov (Form 3674) 29 GCP Conference

Signed Agreement FDA 1572 (drug) Investigator Agreement (device) Identifies facilities, IRB and investigators. Investigator agreement to conduct research according to 21 CFR 312: i. I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects. ii. iii. iv. I agree to personally conduct or supervise the described investigation(s). I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met. I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments. v. I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68. Investigator agreement to conduct research according to 21 CFR 812 (21 CFR 812.20) 30 GCP Conference

Data Safety Monitoring Board A Data Safety Monitoring Board is an independent committee that monitors study data to determine if it is appropriate, from both a scientific and ethical standpoint, to continue the study as planned (PHRC Policy: Data and Safety Monitoring Plans). 31 GCP Conference