Essential Documents and Managing Trial Files–the Legal Background and What you Must Have Janice Hedgecock, FICR Nicky Dodsworth, MICR ICR GCP Steering Group ICR GCP Steering Group Director, Greatspur Senior Director, Global Clinical Development Ltd Quality Assurance Assurance, Premier Research Group Ltd
Content• The legal background• TMF requirements q• Hints and tips
The Legal Background….• Volume 10, Chapter V – Recommendation on the Content of the Trial Master File and Archiving – July 2006• Directive 2005/28/EC, Chapter 4• Directive 2001/20/EC – Article 15(5) and Article 21(2)• ICH E6 – CMPM/ICH/135/95 – Note for Guidance on GCP
Requirements of the TMF (Vol 10, Chap V)• Essential documents – which enable both the conduct of a clinical trial and the quality of the data to be evaluated according to Article 16 2005/28/EC.• Filed in an organised way that will facilitate management of the clinical trial, audit and inspection.• Unambiguous, signed and dated as appropriate• Retained securely prior to archive and then archived for sufficient periods to allow for audit and inspection by regulatory authorities and should be readily available on request.
Volume 10, Chapter V - Contents• Guidance on the content of TMF• Retention requirements for essential documents (Investigator, Sponsor/CRO and others)• Details on: - Minimum set of documents to be retained - Quality of documents to be archived - Minimum standards for storage conditions, g , media transfer and certified copies - Retention times
What are Essential Documents? ‘Essential documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the d t f t i l d th lit f th data produced.’
Importance of Essential Documents• Demonstrate compliance of the Investigator, Sponsor/CRO, Monitor with GCP standards and applicable regulatory requirements.• Timely filing greatly assists in successful management of a trial by the Investigator, Sponsor/CRO, Monitor.• These files are vital in the audit/inspection process to demonstrate validity of trial conduct and integrity of the data data.
How are Documents Filed? (High level)• According to the stage of the trial - Before the clinical phase - During clinical conduct g - After completion/termination of trial• According to the file type - Investigator - Sponsor/CRO
Content of a TMF – Before the Clinical Phase No. Document Sponsor/CRO File Investigator File Third Party File1 Investigator Brochure2 Signed Protocol + Amendments + Sample CRF3 Informed Consent Forms (+ translations) + Other Written Information4 Advertisements, if applicable X5 Financial Agreement6 Insurance, if applicable , pp7 Agreements – Sponsor/CRO/Site/Institution8 Ethics Committee Approval9 Ethics Committee Composition/Constitution (where required)10 Regulatory Authority Approval/Notification (where required)11 CVs12 Laboratory/Medical/Technical – normal ranges12 Laboratory/Medical/Technical – certification, accreditation, QC (where required)13 IMP Sample Labels X14 IMP Handling15 IMP Distribution16 Certificates of Analysis17 Decoding Procedure ?18 Master Randomisation List X ?19 Pre-trial Monitoring Report X20 Trial Initiation Monitoring Report
Content of a TMF – Clinical Phase (1) No. Document Sponsor/CRO File Investigator File Third Party File1 Investigator Brochure updates2 Revision to Protocol + Amendments + Informed Consent Forms + other written information3 Ethics Committee Approval4 Regulatory Authority Approval/Notification R g l t A th it A l/N tifi ti (where required) ( h i d)5 New CVs6 Updates Laboratory/Medical/Technical – normal ranges7 Updates Laboratory/Medical/Technical – certification, (where required) accreditation, QC8 IMP/Study Materials Destruction9 Certificates of Analysis for any new batches X10 Monitoring Visit Reports X11 Relevant Communications12 Signed Informed Consents X13 Source Documents X
Content of a TMF – Clinical Phase (2) No. Document Sponsor/CRO File Investigator File Third Party File14 Completed CRFs (original) (copy)15 CRF Corrections (original) (copy)16 SAE Reports17 SUSAR + Other Safety Reports (where required)18 Safety Information to Investigator19 Interim/Annual Reports to Ethics Committee and (where required) Regulatory Authority20 Subject Screening Log (where required)21 Subject ID List X22 Subject Enrolment List X23 IMP Accountability24 Signature Sheet25 Record of Retained Body Fluids/Tissue Samples
Content of a TMF – AtCompletion/TerminationNo. Document Sponsor/CRO File p / Investigator File g Third Party File y1 IMP Accountability2 IMP Destruction (if destroyed at site)3 Subject ID Code list X4 Audit Certificate, if applicable X5 Final Closeout Monitoring Report X6 Treatment Allocation & Decoding Documents X7 Final Report by Investigator to Ethics X Committee and Regulatory8 Clinical Study Report (if applicable)
Media to be Used (1)• 2005/28/EC (Article 20) states: ‘The media used to store essential documents The shall be such that those documents remain complete and legible throughout the required period of retention and can be made available to the competent authorities on request. Any alteration to records shall be traceable.’
Media to be Used (2)• Storage on electronic, magnetic, optical or other non- indelible media cannot be altered without appropriate authorisation and the creation of an audit trail.• Any transfer of data requires validated equipment to ensure data cannot be lost/altered. Transfers need to be b certified b someone with appropriate authority. tifi d by ith i t th it• Appropriate equipment is required for processing to render records into readable format format.
Storage Conditions• Volume 10, Chapter 5 (legible, ready for inspection, record change in location, adequate space, environmental controls, protect from physical damage)• ICH E6 (use of subcontractor, sponsor ultimately responsible, Investigator make sponsor aware of storage arrangements, change of ownership and location, may use commercial archive, personal data → 95/46/EC)• 2005/28/EC (Article 19) (appoint individuals responsible for archiving restricted access and archiving, withdrawals by named individuals, index/log, tracking and retrieval system)
Duration of Retention• 2005/28/EC (Articles 17 and 18)• 2001/83/EC (as amended by Directive 2003/63/EC)
Inspection Findings - Examples• Inadequate validation [of pivotal computer systems (e.g. (e g databases)]• Lack of source documentation of physical exam, medical history, concomitant medication, p y, , primary y endpoints, key safety assessments• Evidence of TMF not being maintained as current• Sig d consent f Signed t forms missing i i g• Lack of documentation of decisions• Inadequate facilities for archives and long term document retention (archivist, security, environmental control, access control, fire prevention)
Hints and Tips• Establish all files early• Assist the Investigator by providing files with all the initial documents filed, with indexes etc•C l Colour coded, clearly indexed as per SOPs, no d d l l i d d SOP sponsor information/trial name on outside of file• Consider other departments files – data management, statistics, medical writing• Make sure important decisions are documented p• Maintain files at audit/inspection readiness – file daily, perform regular QC checks