Essential Documents: Maintaining the Site's Regulatory Binder How to Manage the Essential Documents for the Investigator and Study Site Objectives Describe the importance of maintaining the Regulatory Binder during the research process. Identify the contents of the regulatory binder required for conducting a clinical trial. Describe maintenance of the regulatory binder during a clinical trial. The Regulatory Binder = Investigator Site File= Trial Center File 1
The Regulatory Binder: Includes documents reflecting Regulatory aspect of the study Each Investigator/site in a study has a Regulatory Binder Must be maintained (current) throughout study and kept as part of study records References to Use FDA Regulation 21CFRPart 50, 54, 312 FDA Information Sheets FDA Guidance Documents ICH Guidelines Section E6 Key Point: How we maintain these files is often a combination of regulation, Industry-practice, and Sponsor-preference! Sometimes processes differ. Institutional Process Where institution or department has a standard operating procedure (SOP) for how the binder is maintained Sponsor Process Where the sponsor has its own standard policy for how the binder is maintained and expects all Investigators to utilize this format 2
Purpose of the Essential Documents/Regulatory Binder To have an organized system that contains all the required documents according to FDA and ICH requirements First Reminder: THROW NOTHING AWAY! Keep up with the filing! 3
Early on, compare your internal procedure with that of the Sponsor! Consider distribution ( cc ) list on pertinent documents Essential Documents/Regulatory Binder The Contents & Maintenance 4
Protocol and Amendments The protocol and all amendments must be present Protocol Tips! Keep current protocol version on top to prevent errors Line-thru cover pages of older protocol versions Protocol Amendments An amendment is a documented change to the Protocol E.g., new version issued Review and circulate Ensure you keep all prior version Document updates to Investigators and all personnel as well as any new training required as a result of the amendment Training logs! 5
Protocol and Amendments The original protocol and each Amendment has a Investigator signature (agreement) page Signifies Investigator and Sponsor agreement to conduct the study as written The signature pages are to be original signatures/dates of PI Protocol Amendments Revise the informed consent as necessary Submit all amendments to the IRB/ERC Most are active only AFTER IRB approval FDA Form A document completed by all Investigators participating in drug studies where data will be submitted to FDA 6
Financial Disclosure Directed by 21CFR Part 54 and information is submitted by Sponsor to FDA Requires disclosure of financial interest in Sponsor or product Sponsor usually provides financial disclosure form for Investigators to complete and return to Sponsor Case Study: The Jesse Gelsinger case University of Pennsylvania Gene Therapy trial resulted in death of 18 y/o with an inherited, metabolic disorder Study offered no benefit to the subject PI had 30% stake in company $13.5 million in stock Effect on Investigator, University, and IRB Case settled in 2001 reportedly for about $10 million Financial Disclosure Disclosure of financial interest in the Sponsor for all Investigators and their immediate families New personnel should complete as added Also completed 1 year after study is completed All Investigators listed on the 1572 for the life of the trial even if they have left the practice 7
Financial Arrangements that should be disclosed: Proprietary interest in the tested product Equity interest in the sponsoring company whose value cannot be readily determine Equity interest in the sponsoring company worth more than $50,000 Significant payments to Investigator or Institution over $25,000 Remember.. Investigators with financial interest can participate in the study disclosure is required! Curriculum Vitae Required for each Investigator listed on the 1572 to demonstrate qualification and training to conduct the protocol For FDA-regulated drug studies, ensure Investigator s address on the CV matches the address on the 1572! 8
Curriculum Vitae Study Coordinator or other study staff CV s will be sponsor dependent Medical Licenses, prior and current, versions should also be available Informed Consent IC must be approved by the IRB (and Sponsor) prior to use IC forms often modified with Amendments Modifications must be approved by the IRB and Sponsor prior to implementation Keep all versions of the IRB-approved IC Types of Documents/Logs Often Maintained Monitoring Log Screening and Enrollment Information Subject ID Roster Drug/Device Accountability 9
Drug/Device Accountability Investigation Product Logs Receipt Dispensing Records Returned from Subjects (or Unused/Not Dispensed) Destroyed or Returned to Sponsor Types of Documents/Logs Often Maintained Delegation of Responsibility/Authority Form Study Personnel Signature Log Calibration/Maintenance Records Temperature Logs Study Correspondence All significant correspondence generated should be retained Site Sponsor Site IRB Budget info- create a separate folder 10
Study Correspondence Keep everything Packing slips Faxes E-mails Receipts Letters Newsletters Laboratory Considerations Laboratory certification, Lab Director s CV and Lab Normals Certification by CLIA (Clinical Laboratory Improvement Amendments) CAP (College of American Pathologists) IRB Correspondence Keep all IRB correspondence in a separate section Includes: Quarterly/Annual Progress Reports Documentation of SAEs IND Safety reports Any protocol specific correspondence between the investigator and the IRB 11
IRB correspondence: IND (Investigational New Drug) Safety reports (also called SUAs Serious unexpected AEs) An IND safety report informs investigators of new safety information Each IND Safety Report must be submitted to the IRB Attach report to IRB-submission letter Ensure IND Report# is listed on the submission letter SAE REPORTING Documented report to IRB of SAEs (Subject Identified, date, event description, etc) Sponsor often provide forms to report information Now often found online Report to sponsor (usually within 24h - keep faxes) Submit follow-up Must These Files Be Retained? Regulatory requirement of Investigator to maintain storage of documents Sponsor/contract may have addition requirements Minimum storage is 2 years Dependant on whether product is submitted, applications withdrawn, etc Per FDA, records and access are responsibility of Investigator ( and not the institution) 12
Summary of Essential Documents/Regulatory Binder Documents illustrate the Investigator s compliance with regulatory requirements Sponsors may have individual expectations Plans must be made for document storage and long-term access Ultimate responsibility remains with the Investigator! Questions? 13