Essential Documentation and the Creation and Maintenance of Trial Master Files

This is a controlled document. The master document is posted on the JRCO website and any print-off of this document will be classed as uncontrolled. Researchers and their teams may print off this document for training and reference purposes but are responsible for regularly checking the JRCO website for more recent versions Essential Documentation and the Creation and Maintenance of Trial Master Files SOP Reference: JRCO/SOP/005 Version Number: Final Version 6.0 Effective Date: 30/11/12 Review by: 29/11/14 Author: Christopher Ente, Research Facilitator Approved by: Gary Roper Date: 30/11/12 Version Date Reason for Change Final version 1.0 3 July 2006 Annual Review Final version 2.0 25 June 2007 Update Final version 3.0 24 June 2008 Annual Review Final version 4.0 08/02/2010 Formation of Joint Research Compliance Office Final version 14 July 2011 Annual Review Final version 29 Nov 2012 Annual Review Final v6.0 30/11/12 Page 1 of 13

Table of Contents 1. Purpose Page 3 2. Introduction Page 3 3. Procedure Page 4 3.1 Essential Documents and TMF Initiation and Maintenance Page 4 3.2 Storage Page 4 3.3 Archive Page 4 4. References Page 5 5. Appendices Appendix 1 Essential documents to be maintained within a TMF Appendix 2 Checklist for Inclusion with Research Project Files Appendix 3 Contact Details Page 6 Page 6 Page 10 Page 13 Final v6.0 30/11/12 Page 2 of 13

1. PURPOSE. This SOP describes the essential documentation that should be maintained within a Trial Master File (TMF), as required under the International Conference on Harmonisation Good Clinical Practice (ICH GCP). The primary focus of the SOP is clinical trials of investigational medicinal products (CTIMPs) that fall under the remit of the Medicines for Human Use (Clinical Trials) Regulations 2004 (called Clinical Trials Regulations ). However, it is also relevant for any project conducted within the NHS, which has to meet the Research Governance Framework, and other clinical investigations which may have an impact on the safety and well-being of human participants. 2. INTRODUCTION. A TMF is a standard filing system which allows the effective storage and location of essential documents the large volume of regulatory and approvals documents needed for clinical research. The filing system can be in the form of a single project file or a number of files/filing cabinets, depending on what is deemed most appropriate. The regulatory and approvals documents within the TMF should be maintained alongside case report forms and source documentation. The requirement to maintain a set of essential documents within a TMF comes from ICH GCP, an internationally recognised standard for the initiation, conduct, recording and reporting of clinical research involving human participants, particularly drug trials; the principles of which were adopted in UK law in the Medicine for Human Use (Clinical Trials) Regulations 2004. As a consequence, it is a legal requirement to maintain a TMF for all clinical trials of Investigational Medicinal Products (IMPs) within the scope of the Regulations. Although the Regulations do not indicate that all detailed aspects of ICH GCP must be followed, it is widely recognised that essential documentation is the primary quality system for validating the safe and appropriate initiation and conduct of clinical trials of IMPs. Furthermore, whilst demonstrating compliance with ICH GCP, the filing of regulatory and approvals documents in an orderly manner greatly assists the smooth running of a project and any research evaluation and/or audit by a sponsor or regulatory authority (such as the MHRA). Importantly, although it is only a legal requirement to maintain a TMF for clinical trials of IMPs, the principles should still apply for the filing of study related documentation for ALL research projects within the NHS, which have to meet the Research Governance Framework, and any other clinical investigations which may have an impact on the safety and well-being of human participants. Please note, however, that not all documents will be of relevance to every project - the content of the TMF will therefore differ according to the nature of the study. For example, for clinical trials of IMPs, most of the essential documents must legally be maintained whereas, for solely observational studies, certain documents will not be applicable. We have tried to indicate this wherever possible. You should therefore interpret the guide in the context of your own individual project. Final v6.0 30/11/12 Page 3 of 13

If after reading the guide anything is unclear or you would like to discuss study documentation in greater detail, please contact a member of the Joint Research Compliance Office. 3. PROCEDURE 3.1 Essential Documents and TMF Initiation and Maintenance A TMF should be established as soon as possible after an outline protocol/proposal is available and/or first contact is made with a research sponsor. A dedicated member of staff should be responsible for maintaining and updating the essential documents within the TMF from this time until the project is formally closed. This should be the Chief Investigator, or his or her designate. Appendix 1 lists the essential documents which should be maintained within a TMF. As noted above, the specific documents filed will differ according to the nature of a study. The list is not exhaustive, and it is strongly recommended that any approvals and communication not listed here should also be retained. The TMF should be held at the lead investigation site, and copies of relevant documents should be kept at participating sites. There is an example checklist of essential documents in Appendix 2 which you should include with each project file. As documents may need to be amended during a project, it is important that amendment chronologies are kept, indicating changes and the dates they are implemented. Old documents must be retained in the TMF alongside the new amended version(s) with the new or most recent documents at the front. Please remember that any substantial amendments to documents, such as the protocol or informed consent forms, should be approved by the relevant authorities (the research Sponsor, RECs, MHRA etc.), as appropriate, prior to implementing any changes to the project/trial. Old versions of documents should be scored through and marked as superseded to ensure they are not mistaken for current documents. If any documents are filed separately from the TMF, the File Note should be kept in the TMF detailing where the document is filed, e.g. drugs details may be filed in the pharmacy. 3.2 Storage As some of the documents within a TMF will be originals and/or contain confidential data, it is important that they are retained within a secure place, with restricted access. All members of the research team should have access to the TMF. It is recognised as best practice to store documents within a locked cupboard within a locked room. Documents should be maintained in a legible condition, with prompt retrieval possible. There are currently no regulations relating to the storage of documents in electronic format, until such a time, it is necessary to print and retain hard copies of such information. 3.3 Archiving It may be necessary for the results of a clinical research project/trial to be examined and checked after it has finished so essential documents should be archived in an easily accessible way and readily available on request. For Final v6.0 30/11/12 Page 4 of 13

clinical trials of IMPs, archiving should occur after the trial has undergone a final closeout visit (this may be initiated by the Sponsor if they feel it is warranted) and the closeout report is issued. All essential documents should be boxed and clearly labelled with the following information: Project/trial name Reference Number Site Number (if applicable) Chief Investigator Lead Site Date of Archive The documents should be stored in a secure room, with appropriate environmental controls (and adequate protection from fire, without water sprinkler systems, water etc.), and access only by authorised personnel. It is recommended that all trial related documents should be centrally archived to prevent accidental damage, amendment, loss or destruction. Any change in the ownership and location of documentation should be documented in order to allow the tracking of the stored records. If archived documents are reviewed at a later date, it is good practice to record who, what documents were reviewed and the date they were accessed in an archive index/log and retain it with the TMF. For clinical trials of IMPs, all trial-related documents should be kept for a minimum of 5 years (and at least one copy of trial data must be kept for the lifetime of any product whose licensure depends on this data). If a particular trial has been sponsored by a pharmaceutical company, the company should be contacted to check whether it is appropriate to destroy the records. For general clinical research, essential documents should be kept for a minimum of 7 years. Once this time period has elapsed, a destruction log should be kept for a further 5 years, listing everything that has been destroyed and the reasons why it was destroyed. Further details on archiving can be found in JRCO/SOP/019, Archiving Study Documents. 4. REFERENCES ICH(1996). Guideline for Good Clinical Practice ICH Harmonised Tripartite Agreement, Section 8. UCL Clinical Research Network (2004). Guide to Essential Documentation and the Trial Master File. CRN/04/G08/00. Clinical Trials Toolkit (2005). Archiving. http://www.cttoolkit.ac.uk/_db/_documents/archiving.pdf Final v6.0 30/11/12 Page 5 of 13

5. APPENDICES 5.1 Appendix 1: Essential Documents to be maintained with a TMF PLEASE NOTE: Whether each separate document must be filed in a TMF will depend on the exact nature of the research project. Those documents marked with an asterisk (*) may not be required for all projects. Title of Document Further Details 1. Protocol and Consent Final, signed research protocol and amended protocols, with version numbers Confirmation of peer review Example of Informed Consent Form and any amendments Examples of any other written information provided to subjects and any updates Final v6.0 30/11/12 Page 6 of 13 To document the Chief Investigator and Sponsor agreement to the protocol/amendment(s). To provide evidence that the scientific quality of the project has been independently assessed. To provide evidence of how informed consent will be logged. * To document that research subjects will be given sufficient written information (content and wording) to enable them to give fully informed consent. It should also include any documents the subject needs to complete themselves e.g. diary cards, patient handbook, questionnaire. * To document that recruitment measures are appropriate and not coercive. Copy of advertisement for subject recruitment and any amendments Copy of any letter/information for a * patient s GP or Consultant Investigator s Brochure and updates * To document that relevant and current scientific information about a medicinal product has been provided to Investigators (for example, by the Chief Investigator to Principal Investigators in multi-centre trials). 2. Ethics Final Ethics application and any amendments Ethics approval letter(s) Ethics Committee composition where study was approved (if not already To document that the trial has received Ethics Committee approval and to identify the version number and date(s) of the approved documents. Approvals to any amendments need to be stored alongside originals. To document that the Ethics Committee is constituted in agreement with GCP. NB. All NHS Ethics Committees that are approving clinical trials encompassed by

included in ethics approval letter) Any Ethics Correspondence Ethics Reports 3. Research and Development Trust R&D application form and approval letter Copy of financial information relating to the study (funding application/award letter/costings) Insurance Statement (copy of any certificate/letter/agreement) Copy of Sponsor agreement and allocation of responsibilities Final v6.0 30/11/12 Page 7 of 13 the Clinical Trials Regulations will have been granted authorised status from the National Research Ethics Service, NRES and will therefore work in compliance with GCP. For example, annual reports, safety reports, final report by CI. To document that the trial has received local R&D office approval where the research is being conducted and access to patients in their care as applicable. To document that financial arrangements for the study are in place. To document provisions to the subject(s) for any study-related harm they might experience. This includes cover for negligent and non-negligent harm. To document that a research Sponsor has been identified to ensure appropriate arrangements are in place for the initiation, management and financing of the project. To document agreements and responsibilities for the preparation, conduct and closure of the trial. Copy of any signed agreement(s) between involved parties 4. Regulatory Regulatory Application Form(s) (if * e.g. MHRA, NIGB (formerly PIAG). applicable) Regulatory Approval(s) (if applicable) * To document that appropriate authorisation by the Regulatory Authority (such as, MHRA, NIGB) has been issued prior to the project commencing. 5. Correspondence (except Trust and Ethics) Relevant written correspondence 6. Research Team Staff and Training Signed and dated CVs evidencing the qualifications of the Chief Investigator/research team (or other relevant documents) Delegation of duty log Staff training records Signature log i.e. letters, meeting notes and minutes, records of telephone conversations, emails. To document the qualifications and eligibility of the CI/PI(s) and any key members of the research team to conduct the study, or to provide medical supervision of subjects. To document roles and responsibilities of staff for the study. To document any study specific training or general competency training each member of the research team has undertaken. To document signatures and initials of ALL persons authorised to make entries or corrections in the CRF.

Honorary Contracts for non-nhs Trust staff 7. Participant Information Copies of original informed consent This must include those forms from any screening failures. forms signed by each project participant Master randomisation list To document the actual randomisation of the trial subjects to different treatment arms. Subject screening log Required to identify all subjects who entered pre-trial screening even if they were not entered into the study. Document reasons for non-entry as appropriate. Subject ID code list To document that the CI/PI keeps a confidential list of all subjects allocated to trial numbers on enrolling in the trial. Subject enrolment log To document the chronological enrolment of subjects into the trial. 8. Data Collection Sample Case Report Form and To document how the Case Report Forms will record information. completion guidance Record of retained body fluids/tissue * To document the location of any retained samples if assays need to be repeated. samples (if any) Normal laboratory reference ranges for * To document the normal values and/or reference ranges of the test results. any tests used or medical/technical procedures included in protocol (includes central labs) Lab/technical procedures/tests certification or accreditation * To document competence of the facility to perform required test(s) and support reliability of results. Copies of calibration records for * technical equipment 9. Serious Adverse Events * Sample SAE form and copy of reporting * Required for all CTIMPs. procedures Completed SAE forms (if not included in * Required for all CTIMPs. the Case Report Forms) Copies of correspondence from CI to * Required for all CTIMPs. Sponsor/Regulatory Authority(ies) (e.g. MHRA, Ethics) reporting SAEs Development Safety Update Reports * Required for all CTIMPs. (DSUR) 10. Pharmacy/Product-Related * Instructions for handling of IMP(s) and trial related material(s) (if not included in * Required for all CTIMPs. To document instructions needed to ensure proper storage, packaging, dispensing and disposal of IMP(s). Final v6.0 30/11/12 Page 8 of 13

the protocol) Sample label for IMP(s) * Required for all CTIMPs. To document compliance with labelling regulations (EU Good Manufacturing Practice (GMP) Directive) and appropriate instructions provided to the subject. Shipping records for IMP(s) * Required for all CTIMPs. To document shipment dates, batch numbers and methods of shipment of IMP(s) and trial-related materials and for tracking of product batch, review of the shipping conditions and accountability. Certificate(s) of analysis of IMP(s) shipped * Required for all CTIMPs. To document the identity, purity and strength of any IMP(s) to be used in the trial. Decoding procedures for blinded trials * Required for all CTIMPs. To document how, in the case of an emergency, identity of blinded IMP can be revealed without breaking the blind for the remaining subjects treatment. IMP accountability at site * Required for all CTIMPs. IMP(s) destruction record(s) * Required for all CTIMPs. To document the destruction of any unused IMP(s). 11. Monitoring and Audit Record(s) of all monitoring reports Final close-out monitoring report This could include a pre-trial report which documents the suitability of a site for conduct of the trial and also a trial initiation report which documents that trial procedures were reviewed with the investigator and the study staff. To document that activities required for the study at closeout are completed and copies of essential documents are held in appropriate files. Audit certificate (if available) * Clinical trial report * Required to document results and interpretation of the trial. Final v6.0 30/11/12 Page 9 of 13

5.2 Appendix 2: Example Checklist for Inclusion with Research Project Files Title of Research Project: Imperial College AHSC Ref: Chief Investigator: Other Members of the Research Team: 1. 2. 3. 4. ISRCTN Ref (if appropriate): ClinicalTrials.gov ID (if appropriate): Start Date: NHS Trust R&D Ref: Lead Centre: 5. 6. 7. 8. EudraCT Ref (if appropriate): Other Ref(s): Proposed End Date: PLEASE NOTE: Those documents marked with an asterisk (*) may not be required for all projects. 1. Protocol Final, signed research protocol and amended protocols, with version numbers Confirmation of peer review Example of Informed Consent Form and any amendments Examples of any other written information provided to subjects and any updates * Copy of advertisement for subject recruitment and any amendments * Copy of any letter/information for a patient s GP or Consultant * Investigator s Brochure and updates * 2. Ethics Final Ethics application and any amendments Ethics approval letter(s) Ethics Committee composition where study was approved Any Ethics Correspondence Ethics Reports 3. Research and Development Trust R&D application form and approval letter Copy of financial information relating to the study (funding application/award letter/costings) Insurance Statement (copy of any certificate/letter/agreement) Copy of Sponsor agreement and allocation of responsibilities Final v6.0 30/11/12 Page 10 of 13

Copy of any signed agreement(s) between involved parties 4. Regulatory Regulatory Application Form(s) (if applicable) * Regulatory Approval(s) (if applicable) * 5. Correspondence (except Trust and Ethics) Relevant written correspondence 6. Research Team Staff and Training Signed/dated CVs evidencing the qualifications of CI/research team (or other relevant documents) Delegation of duty log Staff training records Signature log Honorary Contracts for non-nhs Trust staff 7. Participant Information Copies of original informed consent forms signed by each project participant Master randomisation list Subject screening log Subject ID code list Subject enrolment log 8. Data Collection Sample Case Report Form and completion guidance Record of retained body fluids/tissue samples (if any) * Normal laboratory reference ranges for any tests used or medical/technical procedures included in protocol (includes central labs) * Lab/technical procedures/tests certification or accreditation * Copies of calibration records for technical equipment * 9. Serious Adverse Events * Sample SAE form and copy of reporting procedures * Final v6.0 30/11/12 Page 11 of 13

Completed SAE forms (if not included in the Case Report Forms) * Copies of correspondence from CI to Sponsor/Regulatory Authority(ies) reporting SAEs * Safety reports * 10. Pharmacy/Product-Related * Instructions for handling of IMP(s)/trial related material(s) (if not in the protocol) * Sample label for IMP(s) * Shipping records for IMP(s) * Certificate(s) of analysis of IMP(s) shipped * Decoding procedures for blinded trials * IMP accountability at site * IMP(s) destruction record(s) * 11. Monitoring and Audit Record(s) of all monitoring reports Final close-out monitoring report Audit certificate (if available) * Clinical trial report * Final v6.0 30/11/12 Page 12 of 13

5.3 Appendix 3: Contact Details Joint Research Compliance Office Address: 5th Floor, Lab Block, Charing Cross Hospital Fulham Palace Road W6 8RF Website: www.imperial.ac.uk/clinicalresearchgovernanceoffice Lucy PARKER Research Governance Manager Tel: +44 (0)20 33110206 Fax: +44(0)20 3311 0203 Lucy.parker@imperial.ac.uk Becky WARD Research Governance Manager Tel: +44 (0)20 3311 0205 Fax: +44(0)20 3311 0203 becky.ward@imperial.ac.uk Local NHS Trust R&D Contact Details Imperial College AHSC Hammersmith and Charing Cross Hospitals Becky WARD Research Governance Manager Tel: +44 (0)20 3311 0205 Fax: +44(0)20 3311 0203 becky.ward@imperial.ac.uk North west London Hospitals NHS Trust Simon Lewis Research Governance Manager Tel: 020 8869 5173 E-mail: simon.lewis@nhs.net St Mary s Hospital Lucy PARKER Research Governance Manager Tel: +44 (0)20 33110206 Fax: +44(0)20 3311 0203 lucy.parker@imperial.ac.uk Royal Brompton and Harefield NHS Trust Dr Angela Cooper PhD Associate Director of Research Research Office, Chelsea Wing Royal Brompton & Harefield NHS Foundation Trust Sydney Street SW3 6NP Tel: 0207 352 8121 ext 2610 or 0207 352 8574 a.cooper@rbht.nhs.uk Chelsea and Westminster Healthcare Trust Ms Mary TOURETTE Head of Research and Development Tel: +44 (0) 20 3315 6191 Mary.tourette@chelwest.nhs.uk Final v6.0 30/11/12 Page 13 of 13