1. 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

2. Content
• The legal background
• TMF requirements
q
• Hints and tips

3. 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

4. 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.

5. 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

6. 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.’

7. 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.

8. 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

9. Content of a TMF – Before the Clinical Phase
No. Document Sponsor/CRO File Investigator File Third Party File
1 Investigator Brochure
2 Signed Protocol + Amendments + Sample CRF
3 Informed Consent Forms (+ translations) + Other Written Information
4 Advertisements, if applicable X
5 Financial Agreement
6 Insurance, if applicable
, pp
7 Agreements – Sponsor/CRO/Site/Institution
8 Ethics Committee Approval
9 Ethics Committee Composition/Constitution (where required)
10 Regulatory Authority Approval/Notification (where required)
11 CVs
12 Laboratory/Medical/Technical – normal ranges
12 Laboratory/Medical/Technical – certification, accreditation, QC (where required)
13 IMP Sample Labels X
14 IMP Handling
15 IMP Distribution
16 Certificates of Analysis
17 Decoding Procedure ?
18 Master Randomisation List X ?
19 Pre-trial Monitoring Report X
20 Trial Initiation Monitoring Report

10. Content of a TMF – Clinical Phase (1)
No. Document Sponsor/CRO File Investigator File Third Party File
1 Investigator Brochure updates
2 Revision to Protocol + Amendments + Informed
Consent Forms + other written information
3 Ethics Committee Approval
4 Regulatory Authority Approval/Notification
R g l t A th it A l/N tifi ti (where required)
( h i d)
5 New CVs
6 Updates Laboratory/Medical/Technical – normal
ranges
7 Updates Laboratory/Medical/Technical – certification, (where required)
accreditation, QC
8 IMP/Study Materials Destruction
9 Certificates of Analysis for any new batches X
10 Monitoring Visit Reports X
11 Relevant Communications
12 Signed Informed Consents X
13 Source Documents X

11. Content of a TMF – Clinical Phase (2)
No. Document Sponsor/CRO File Investigator File Third Party File
14 Completed CRFs (original) (copy)
15 CRF Corrections (original) (copy)
16 SAE Reports
17 SUSAR + Other Safety Reports (where required)
18 Safety Information to Investigator
19 Interim/Annual Reports to Ethics Committee and (where required)
Regulatory Authority
20 Subject Screening Log (where required)
21 Subject ID List X
22 Subject Enrolment List X
23 IMP Accountability
24 Signature Sheet
25 Record of Retained Body Fluids/Tissue Samples

12. Content of a TMF – At
Completion/Termination
No. Document Sponsor/CRO File
p / Investigator File
g Third Party File
y
1 IMP Accountability
2 IMP Destruction (if destroyed at
site)
3 Subject ID Code list X
4 Audit Certificate, if applicable X
5 Final Closeout Monitoring Report X
6 Treatment Allocation & Decoding Documents X
7 Final Report by Investigator to Ethics X
Committee and Regulatory
8 Clinical Study Report (if applicable)

13. 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.’

14. 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.

15. 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)

16. Duration of Retention
• 2005/28/EC (Articles 17 and 18)
• 2001/83/EC (as amended by Directive 2003/63/EC)

17. 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)

18. 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