Joint Arrangements for Research __________________________________________________________________________________

STANDARD OPERATING PROCEDURE SOP 305 CREATING AND MAINTAINING A TRIAL MASTER FILE and INVESTIGATOR SITE FILE

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Version date Effective date Number of pages Review date

Version 1.3 30.12.2016 30.12.2016 9 May 2018

Author

NNUH UEA Joint Research Office

Approved by Role Signature Date

Lisa Chalkley Research Services Manager Lisa Chalkley 28.11.2016

Authorized for NNUH and UEA by

Professor Alastair Forbes

Role Signature Date

Chief of Research and Innovation Professor Alastair Forbes 30.12.2016

COPIES PRINTED FROM THE WEBSITE ARE VALID ONLY ON THE DAY OF PRINTING

SOP 305 v1.3

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Joint Arrangements for Research __________________________________________________________________________________

It is the responsibility of all users of this SOP to ensure that the correct version is being used. All staff should regularly check the NNUH R&D website for information relating to the implementation of new or revised versions of SOPs. Staff must ensure that they are adequately trained in the new procedure and must make sure that all copies of superseded versions are promptly withdrawn from use. The definitive versions of all Joint NNUH/UEA health care research SOPs appear online. If you are reading this in printed form please check that the version number and effective date is the most recent one as shown on the NNUH R&D website, http://www.nnuh.nhs.uk/departments/research-amp-development/standard-operatingprocedures-for-research/ TABLE OF CONTENTS 1 ABBREVIATIONS

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2 INTRODUCTION

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3 SCOPE

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4 DEFINITIONS

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5 RESPONSIBILITY

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6 PROCEDURE

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7 REFERENCES

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8 RELATED DOCUMENTS

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9 LIST OF APPENDICES

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Appendix 1 : Suggested Trial Master File and Site File Contents

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Appendix 2: Example of Delegation Log

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Appendix 3: Change Control, Revision and Review Sheet

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ABBREVIATIONS CI CTIMP CRTU DSUR GCP ICH IMP ISF IVR NNUH NRES PI REN SAE SOP SmPC SUSAR TMF UEA

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Chief Investigator Clinical Trial of an Investigational Medicinal Product Clinical Research and Trials Unit Development Safety Update Report Good Clinical Practice International Conference for Harmonisation Investigational Medicinal Product Investigator Site File Interactive Voice Response Norfolk and Norwich University Hospital National Research Ethics Service Principal Investigator Research and Enterprise Services at UEA Serious Adverse Event Standard Operating Procedure Summary of Product Characteristics Suspected Unexpected Serious Adverse Reaction Trial Master File University of East Anglia

INTRODUCTION

This SOP is intended as a practical guide to setting up a Trial Master File / Investigator Site File and the essential documents it should contain. 3

SCOPE

This SOP applies to all healthcare research sponsored by NNUH or UEA which falls within the scope of the Research Governance Framework (2nd edition 2005) or its successor. Where additional legislation applies, for example the Medicines for Human Use (Clinical Trials) Regulations 2004 (and amendments), or the Medical Devices Regulations 2002, required procedures will be indicated. External sponsors may require use of their own SOPs and this will be specified in site agreements. It is the responsibility of the local PI to ensure that studyspecific SOPs can be operated without conflict with this SOP and in accordance with all organisational polices related to research. 4 DEFINITIONS A Trial Master File (TMF) contains the essential documents relating to a clinical trial. This collection of essential documents serves to demonstrate compliance of the investigator, Sponsor and Trial Monitor with the standards of Good Clinical Practice which the Trust and UEA adheres to in all its research. This is a legal requirement for

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trials which fall under the 2001/20/EC Clinical Trials Directive. TMFs may be required for inspection and audit. Although the collective of all the clinical trial documents (those stored with the Trial Sponsor, in the Sponsor File and by the Investigator(s) in the Investigator Site File) is the Trial Master File, the file of the Sponsor is commonly referred to as the Trial Master File. The Investigator Site File (ISF) contains all essential documents held by Principal Investigator(s) conducting a trial, which individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced by the site(s). 5 RESPONSIBILITY The Sponsor is responsible for the Trial Master File and ensuring that the local investigator(s) sets up Investigator Site File(s) (ISFs) and that these are available for audit and inspection. The Sponsor and the Investigator(s) are responsible for keeping a record of location of storage of the TMF and ISF according to GCP E6 (R2). In practice the Chief Investigator/Principal Investigator will be responsible for establishing and maintaining the site files and may delegate these activities to their research team members. If activities are delegated this should be recorded in the Study Delegation Log (see SOP 325) and stored in the file. 6 PROCEDURES 5.1 The TMF should be set up by the CI during the planning stage of the research and before formal approval of the research takes place. 5.2 The Sponsor should set up and maintain the Sponsor File for the study. 5.3 The site file contents should be established by the CI/PI. A list of contents is provided in Appendix 1. For projects where UEA is the Sponsor, the REN documents relating to the application and award of external funding for trials involving UEA shall be held by REN. 5.4 The file should contain an investigator responsibilities/delegation log. An example responsibilities/delegation log form is included in Appendix 2 5.5 The file should be stored in a secure location, such as a lockable filing cabinet or lockable room with restricted access. The CI should be able to demonstrate that all reasonable measures have been taken to ensure its security, to protect confidentiality and data integrity. 5.6 All essential documents must be version controlled (See SOP 800). 5.7 Documents such as the Trial Protocol must be dated and signed by the CI/PI when filed in the TMF. 5.8 All previous versions of documents must be retained and noted as superseded, initialed and dated. 5.9 A file note (dated and signed) should be placed in the file giving details of any missing or unavailable documentation.

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5.10 On completion of the study, the completed files (TMF & ISF) should be archived (see SOP 900). 7

REFERENCES

Commission Directive (2003/94/EC) of Good Manufacturing Practice Commission Directive (2205/28/EC) on Good Clinical Practice Directive 2001/83/EC – The “Pharmaceuticals Directive” EU Clinical Trials Directive 2001 (2001/20/EC) Medicines for Human Use (Clinical Trials) regulations 2004 (S.I. 2004/1031) Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (S.I.2006/1928) ICH (1996) Guidance for Industry E6 Good Clinical Practice (section 8) 8

RELATED DOCUMENTS

SOP 325 SOP 800 SOP 900

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Study Start up Activities for Clinical Research Trials Documentation Management Storage and Retention of Research Documents

LIST OF APPENDICES

Appendix 1 Trial Master File and Site File Contents Appendix 2 Change Control, Revision and Review Sheet

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Appendix 1: Suggested Trial Master File/Site File Contents. Note: This should be adapted to suit the type of study conducted as those marked with a * may not be required for all projects Section

Title

Contents/Comments

1

Index of file contents

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Protocol and Amended Protocols (Essential)

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Sample CRF/Questionnaires Diary Cards (Essential) Regulatory Approval/Documentation (Essential)

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Study delegation log (Essential)

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Curriculum Vitae + GCP + SOP (Essential)

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Patient Identification form/ Patient recruitment/Screening form (Essential)

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Sample of all versions of Patient Information Sheets/Consent Forms/GP letters (Essential) Completed Patient Information and Informed consent forms (Essential) Subject Enrolment Log (Essential)

Current version, (Original and any amended protocols superseded)All versions to be signed by CI/PI Current CRF + superseded Essential doc: all signed by all parties; HRA approval R&D application + confirmation of capacity and capability, NRES application + approval letter, MHRA application + approval letter * With signatures ( see example in Appendix 2) and start date CV for all personal listed in the investigator responsibility log (+GCP + SOP training certificate) Blank templates will be stored in TMF. Any forms containing patient information should be filed only at the site, in a confidential folder. Blank forms with headings for each site. (old versions superseded) Blank templates will be stored in TMF. Any forms containing patient information should be filed only at the site, in a confidential folder.

Subject Identification Code List (Essential) 9

Correspondence

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File in chronological order. Include emails. Newsletters

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Monitoring reports (pre-Trial, Trial Initiation, Monitoring Visits, Final Close Out) (Essential)

If the study is not monitored state this in a file note.

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Minutes from Trial Steering Group/Data Monitoring and Ethics Committee meetings (Essential) *. Notes of telephone calls

Telephone call notes should relate to agreements or significant discussions regarding the trial administration, conduct and SAEs

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Blank copies of serious adverse events (SAEs) forms and instructions for completion (Essential)

SOP + blank form

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Notification of SUSARs*, SAEs and/or safety reports, only if no patient information – otherwise in the ‘confidential folder’(Essential)

By investigator to co-ordinating research body By co-ordinating research body to investigator By co-ordinating research body to regulatory authority. If notifications are electronic include file note to record this

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Randomisation details (Essential)

IVRs, statistical analysis plan Decoding procedures for blinded trials should be specified in the protocol.

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CTIMP : instructions for handling medication and materials (Essential)*

If Pharmacy hold these include a file record to state this.

Shipping records (Essential)* Sample of labelling (Essential)* Certificates of analysis of IMP batches (Essential) * 16

Clinical Laboratory Reference ranges and accreditation

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certificates. (Essential)* Lab analysis plan (Essential)* 17

Contracts (Essential)

Signed copies of contracts and agreements including any financial details, indemnity arrangements, regulatory documents, confidentiality agreements*, drug supply*, laboratory *, technical services* *.

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Financial details and insurance statement (Essential)

Any invoices or financial transaction records. If held elsewhere include a file note.

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Investigator Brochure/SmPC/ Safety Alert letters/Updates/DSUR (Essential)* Data queries *

20

Specification and validation of data management systems (Essential) *

Blank form and current / completed data query forms

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Study training materials (Essential)

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Annual progress reports (Essential)

As sent to Sponsor, R&D, NRES

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Miscellaneous ( specify)

Monitoring reports signed (if the study is not monitored, state this in a file note)

After completion of the trial the following must be filed for archiving. 24

Investigational products accountability at site (Essential)*

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Documentation of medicinal product destruction (Essential)*

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Final report (Essential)

From investigator to NRES

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Clinical Study report (Essential)

To document results and interpretation of trial

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Appendix 2: Change Control, Revision and Review Sheet

CHANGE CONTROL, REVISION and REVIEW SHEET: SOP 305 Version No

Change Date

1.1

01/01/2010

Reason for Change

Updated following MHRA inspection. Clarification of essential documents in TMF and additional notes added (Appendix 1).

1.2

02/12/2013

Addition of start date in delegation log (Appendix 2). Minor typing correction and combining of SOP change control and revision sheets (Appendix 3).

Reviewer:

Designation:

Signature and Date:

Debbie Kelly

Research Manager RSC

D A Kelly 16th December 2013

Addition of ISF to the title of the SOP Clarification to definition of TMF and ISF 1.3

25/11/2016

Template of Delegation log have been deleted from Appendixes. Minor typing and grammar changes. Updates to SOP change control and revision sheets.

Reviewer:

Designation:

Signature and Date:

Fran Dockerty

Clinical Trial Monitor

Fran Dockerty 28.10.2016

Reviewer:

Designation:

Signature and Date:

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