Essential Documents and Managing Trial Files –

the Legal Background and What you Must Have

Janice Hedgecock, FICR ICR GCP Steering Group Director, Greatspur Clinical Development Ltd

Nicky Dodsworth, MICRICR GCP Steering Group Senior Director, Global Quality AssuranceClinical Development Ltd Quality Assurance, Premier Research Group Ltd

Content

• The legal background

• TMF requirementsq

• Hints and tipsHints 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

GCPGCP

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 • Filed in an organised way that will facilitate management of the clinical trial, audit and inspection.

• Unambiguous, signed and dated as appropriateUnambiguous, 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 documents which individually and collectively permit evaluation of the

d t f t i l d th lit f th conduct of a trial and the quality of the 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 datathe data.

How are Documents Filed? (High level)

• According to the stage of the trial- Before the clinical phase- During clinical conductg- After completion/termination of trial

• According to the file type- InvestigatorInvestigator- Sponsor/CRO

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 CRF2 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 ?18 Master Randomisation List X ?

19 Pre-trial Monitoring Report X

20 Trial Initiation Monitoring Report

Content of a TMF – Clinical Phase (1)

No. Document Sponsor/CRO File Investigator File Third Party File

1 Investigator Brochure updates1 Investigator Brochure updates

2 Revision to Protocol + Amendments + Informed Consent Forms + other written information

3 Ethics Committee Approval

4 R g l t A th it A l/N tifi ti ( h i d)4 Regulatory Authority Approval/Notification (where required)

5 New CVs

6 Updates Laboratory/Medical/Technical – normal ranges

7 Updates Laboratory/Medical/Technical – certification, accreditation, QC

(where required)

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

Content of a TMF – Clinical Phase (2)

No. Document Sponsor/CRO File Investigator File Third Party File

14 Completed CRFs (original) (copy)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 Regulatory Authority

(where required)

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

Content of a TMF – At Completion/Termination Completion/Termination

No. Document Sponsor/CRO File Investigator File Third Party Filep / g 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 X6 Treatment Allocation & Decoding Documents X

7 Final Report by Investigator to Ethics Committee and Regulatory

X

8 Clinical Study Report (if applicable)

Media to be Used (1)

• 2005/28/EC (Article 20) states:

‘The media used to store essential documents The media used to store essential documents shall be such that those documents remain complete and legible throughout the required complete and legible throughout the required period of retention and can be made available to the competent authorities on request. Any 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 b tifi d b ith i t th itbe certified by someone with appropriate authority.

• Appropriate equipment is required for processing to render records into readable formatrender records into readable 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• 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 (appoint individuals responsible for archiving, restricted access and 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 databases)](e.g. databases)]

• Lack of source documentation of physical exam, medical history, concomitant medication, primary y, , p yendpoints, key safety assessments

• Evidence of TMF not being maintained as currentSig d t f i i g• Signed consent forms missing

• Lack of documentation of decisions• Inadequate facilities for archives and long term 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 etcC l d d l l i d d SOP • Colour coded, clearly indexed as per SOPs, no sponsor information/trial name on outside of file

• Consider other departments files – data • Consider other departments files – data management, statistics, medical writing

• Make sure important decisions are documentedp• Maintain files at audit/inspection readiness – file

daily, perform regular QC checks