Standard Operating Procedures (SOP) Research and Development Office Title of SOP: Essential Documentation and Creation and Maintenance of Trial Master File SOP Number: 13 Version Number: 2.0 Supercedes: 1.0 Effective date: August 2013 Review date: August 2015 Author: Approved by: Alison Murphy, Research Manager Endorsed by Paul Carlin Dr David Hill Signed: Date: 01 August 2013 Document Number: SOP/RAD/SEHSCT/ 013 Page 1 of 10
Version History: Version No. Date Author Reason for Change 1.0 Sept 2007 Katrina Hughes N/A 2.0 Aug 2011 Alison Murphy Updated to reflect new SOP layout Document Number: SOP/RAD/SEHSCT/ 013 Page 2 of 10
Table of contents 1. Introduction 2. Objective 3. Scope 4. Process/Procedure 4.1 Essential Documents and TMF Initiation and Maintenance 4.2 Storage 4.3 Archive 5. Regulations, Guidelines, references, SOP Links etc 6. Appendices 6.1 Essential documents to be maintained within a TMF Document Number: SOP/RAD/SEHSCT/ 013 Page 3 of 10
1. INTRODUCTION A Trial Master File (TMF) is a standard filing system which allows the effective storage and location of essential documents the large volume of regulatory and approval 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 approval 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 Clinical Trials Regulations. As a consequence, it is a legal requirement to maintain a TMF for all clinical trials of 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 approval 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 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 whereas possible. You should therefore interpret this guide in the context of your own individual project. 2. OBJECTIVE 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). 3. SCOPE 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 Document Number: SOP/RAD/SEHSCT/ 013 Page 4 of 10
for other clinical investigations that may have an impact on the safety and well-being of human participants. 4. PROCEDURE 4.1 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. A list of the essential documents which should be maintained within a TMF can be found in appendix 1. 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). 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 Sponsors, RECs, MHRA etc), as appropriate, prior to implementing any changes to the project/trial. 4.2 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. 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. 4.3 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 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. Details on archiving arrangements can be found in SOP 3: Archiving Study Documents Document Number: SOP/RAD/SEHSCT/ 013 Page 5 of 10
5. REGULATIONS, GUIDELINES, REFERENCES, SOP LINKS etc. IICH (1996). Guidelines 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.ct-toolkit.ac.uk/_db/_documents/archiving.pdf Linked to SOP03 Archiving Study Documents SOP25 Maintaining a Site File 6. APPENDICES 6.1 Appendix 1: Essential Documents to be Maintained with a TMF Document Number: SOP/RAD/SEHSCT/ 013 Page 6 of 10
Appendix 1: Essential Documents to be Maintained with a TMF PLEASE NOTE: Whether each separate document must be field 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 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 * 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 (if not already included in ethics approvals letter) Further Details To document the Chief Investigator and sponsor agreement to the protocol/amendments(s). To provide evidence that the specific 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. To document that relevant and current scientific information about a medicinal product has been provided to Investigators (for example, by the chief Investigator o Principal Investigator in multi-centre trails) 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 Document Number: SOP/RAD/SEHSCT/ 013 Page 7 of 10
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 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 and dated CVs evidencing the qualifications of the Chief Investigator/research team (or other relevant documents) clinical trials encompassed by the Clinical trials Regulations will have been granted authorised status from the Central Office for research Ethics Committees (COREC) 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. e.g. MHRA, NIGB To document that appropriate authorisation by the regulatory Authority (such as, MHRA, NIGB) has been issued prior to the project commencing. i.e. letters, meeting notes, 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. Document Number: SOP/RAD/SEHSCT/ 013 Page 8 of 10
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 * Completed SAE forms (if not included in the Case Report forms) * Copies of correspondence from CI to Sponsor/Regulatory Authority(ies) (e.g. To document roles and responsibilities of staff for the study. To document any study specific training 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. This must include those forms from any screening failures. To document the actual randomisation of the trial subjects to different treatment arms. Required to identify all subjects who entered pre-trail screening even if they were not entered into the study. Document reasons for non-entry as appropriate. To document that the CI/IP keeps a confidential list of all subjects allocated to trial numbers on enrolling in the trial. To document the chronological enrolment of subjects into the trial. To document how the Case Report Forms will record information. To document the location of any retained samples if assays need to be repeated. To document the normal values and/or reference ranges of the test results. To document competence of the facility to perform required test(s) and support reliability of results. Required for all CTIMPs Required for all CTIMPs Required for all CTIMPs Document Number: SOP/RAD/SEHSCT/ 013 Page 9 of 10
NHRA, Ethics) reporting SAEs Safety reports 10. Pharmacy/Product-Related * Instructions for handling of IMP(s) and trial related materials(s) (if not included 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 * Required for all CTIMPs document instructions needed to ensure proper storage, packaging, dispensing and disposal of IMP(s). document compliance with labelling regulations (EU Good Manufacturing Practice (GMP) Directive) and appropriate instructions provided to the subject. 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. document the identify, purity and strength of any IMP(s)to be used in the trial. document how, in the case of an emergency, identify of blinded Imp can be revealed without breaking the blind for the remaining subjects treatment. Required for all CTIMPs. document the destruction of any unused IMP(s). 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. Required to document results and interpretation of the trial Document Number: SOP/RAD/SEHSCT/ 013 Page 10 of 10