1. The Trial Master File What is it? What’s in it? Lisa Mulcahy

2. Trial Master File - Definition The Trial Master File (TMF) contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. -ICH GCP Chapter 8

3. TMF – What is it? These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements. -ICH GCP Chapter 8

4. …and with all applicable regulatory requirements. No one regulation or guidance states completely the expected documents of a complete TMF. Regulations and Guidance documents that exist might on the surface seem clear and pointed, but… In actuality, interpretation is exactly what makes the contents of the TMF a varied set of documents – Content and processes unique to each sponsor company – Many functions and vendors contribute to a trial’s master file, each with their own interpretation and processes – Oversight of the content on an ongoing basis is usually not one person’s/function’s responsibility

5. TMF – Why is it so important? Required to allow reconstruction of the conduct of a trial. – Allow regulators and the public to have confidence that: Patient rights were protected, Good Clinical Practices were followed, and Data collected, analyzed, and reported as part of a clinical trial is reproducible and of high quality

6. Contributors to the TMF Sponsor contributors – Clinical Operations, such as Medical Writing, Trial Management, Biostatistics, Programming, Data Management, Contracts group, etc. – Clinical Pharmacology for PK data analysis Vendor contributors – Any of the functions listed above can be outsourced to a vendor – Vendors for IVRS, Clinical supplies and distribution Investigators – Through sponsor or vendor representatives

7. ICH Guidelines (ICH) Guideline for Good Clinical Practice (GCP) E 6, Chapter 8: in TMF Before the trial commences From the Sponsor (Vendor):From the Investigator: Investigator brochure, protocol, CRFProtocol signature page Master Informed Consent, subject materials, and advertisements Site-specific ICF, subject materials, and advertisements Contractual and Insurance documentsIRB/EC approval documents Central Laboratory documentsLocal Laboratory documents Sample drug labels and drug/trial supplies handling instructions, Certificate of Analysis PI & SI Curriculum Vitae (CV) and/or other documentation of qualification Drug shipment documents Health Authority (HA) approval documents(HA-specific forms) Randomization codes, Decoding proc.s Pre-study and Initiation visit reports

8. ICH GCP E 6, Chapter 8: in TMF During the trial From the Sponsor (Vendor):From the Investigator: Updates to any document required to be present PRIOR to the start the trial Signature pages for updated documents, if applicable Continued HA approval documentsContinued IRB/EC approval documents C of A for new batches of drugCVs, etc. for new PI and SIs Monitoring visit reportsUpdates to local laboratory documents Relevant communications SUSAR communicationsSubject logs and Subject-signed ICFs ComSignature sheet Completed CRFs and CRF correctionsCompleted CRF and CRF corrections Drug accountability documents SAE Documentation

9. ICH GCP E 6, Chapter 8: in TMF After the trial completes From the Sponsor (Vendor):From the Investigator: Clinical Study reportFinal report to IRB/EC Audit certificateCompleted Subject code list Final close-out monitoring reportFinal drug accountability documents, and documentation of destruction Treatment allocation and decoding documentation Record of retained fluids/tissue samples (during the trial)

10. What’s missing from the list within the ICH GCP, Chapter 8? This guidance defines the “TMF”. But this is an incomplete list of documents created during the conduct of a clinical trial. Let’s look at these following selected examples of regulations and associated documents?

11. What about for Quality Systems? Regulation/Guidance reference:Included Documentation: ICH E6, 5.1.1Written SOPs for compliance with protocol, GCP, and applicable regulatory requirements. -Trials conducted are in compliance. -Data are generated, recorded, and reported in compliance. Readable and processed correctly. EU 2001/20/ECGCP – set of internationally recognized ethical and scientific quality requirements must be observed. -Designing, conducting, recording, and reporting clinical trials that involve participation of human subjects. --Provides assurance that the rights, safety, and well-being of trial subjects are protected. --Provides assurance that the results of clinical trials are credible.

12. Examples of Quality Systems Documentation Defined and followed Sponsor and Study- specific processes: Standard Operating Procedures Manuals Working Instructions Guidelines Deviation documentation

13. What about for Electronic Systems? Regulation/Guidance reference:Included Documentation: 21 CFR 11.10Procedures and controls designed to ensure authenticity, integrity, and when appropriate, the confidentiality of electronic records. 21 CFR 11.100Procedures and controls designed to ensure that the signer cannot readily repudiate the signed records as not genuine. -Each electronic signature shall be unique to one individual and shall not be reused by, or reassigned to, anyone else, -Organization shall verify the identity of the individual. -Certify to the Agency that the e-signatures are intending to be the legally binding equivalent of traditional handwritten signatures.

14. Examples of Electronic System Documentation System Validation for Clinical Data Management System Limiting system access to authorized individuals Use of secure, computer-generated time- stamped audit trails Database Lock and Release documentation Revision and Change control process Signature validation forms

15. What about for Safety Monitoring? Regulation/Guidance reference:Included Documentation: 21 CRF 312.32Review of safety information -Prompt review of all information relevant to the safety of the drug, obtained or otherwise received by the sponsor…including from any clinical investigations. 21 CRF 312.50General responsibilities of the sponsor -Ensure proper (safety) monitoring of the investigation 21 CRF 312.56Sponsor shall review and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigator

16. Examples of Safety Monitoring Documentation Safety Monitoring Committee plan, charter, data listings, communications, meeting minutes Proof of ongoing Medical Monitoring during course of trial Sponsor evaluation of AEs and SAEs, both within and across trials using the same compound

17. What about for Proof of an Adequate and Well-controlled Trial? Regulation/Guidance reference:Included Documentation: 21 CRF 314.26Adequate measures described in the Blinding plan, taken to minimize bias on the part of subjects, observers, and analysts of the data. Method of assigning patients to treatment and control groups described in the Randomization plan, to minimize bias, and is intended to assure comparability of the groups Planned analysis and analytic methods described in the Statistical Analysis plan, to be used of the results of the study to adequately assess the effects of the drug.

18. Examples of Conduct of an Adequate and Well-controlled Trial Most (All) should be defined prior to start of trial: Unblinding Plan Statistical Analysis Plan Data Management Plan Randomization Plan Drug Distribution Plan

19. Summary As you can briefly see, the ICH GCP Guidelines define the minimal contents of TMF. – Yet indicate that the guidance alone is not the only one to reference… as the TMF should contain documentation for “all applicable regulatory requirements” Applicable regulatory guidance is not concisely located, nor a detailed list. – Leaving sponsors to interpret expected content Industry accepted standards and consistent document nomenclature could move content and completeness of the TMF to be a non-issue.

20. Thanks. Any Questions?