Study Files and Filing

Study Files and Filing The current version of all Hillingdon Hospital R&D Guidance Documents and Standard Operating Procedures are available from the R&D Intranet and Internet sites: www.ths.nhs.uk/departments/research/research.htm Please ensure that you have the latest version. Version Number: 3.0 Effective Date: 01.08.11 Review Date: 31.07.13 Document History Version Effective Edited by Number Date Details of Changes 1.0 First version 2.0 JG/GB 01.08.09 Formatted using new template 3.0 GB 01.08.11 Reviewed 1. BACKGROUND With the large volume of documentation required for each trial a standard filing system is necessary. Documentation for each study should be kept in a specific site master file with a dedicated member of staff responsible for maintenance and updating the file. Some sponsors may provide the study file (also know as the investigators site file or Trial master file) for specific studies ICH Good Clinical Practice (ICH GCP) guidelines define the study documents to be filed as those documents which individually and collectively permit evaluation of the conduct of the trial and the quality of the data produced. Whilst demonstrating compliance with ICH GCP, the filing of study documents in an orderly, timely manner also greatly assists the smooth running of the study and any future audit or inspection. From a medical records perspective, patient notes may only be retained for seven years following their last contact. However patients who have been consented onto a clinical trial must have their notes kept for at least 20 years. 2. PURPOSE To describe the procedure for the filing of study documentation. 3. PROCEDURE Page 1 of 13

3.1 Who? Under ICH GCP it is the responsibility of the Principal Investigator to maintain the investigator site file. However in most cases this task will be delegated to another member of the research team e.g. a research nurse or clinical trials co-ordinator. They must ensure that the study files are established and properly maintained. 3.2 When? A site master file should be prepared as soon as possible after site-specific ethics approval is given. The file should be actively maintained and updated from this time until the trial is formally closed. When it becomes available / if it is available the final report should be filed in the study file. 3.3 How? Prior to study initiation 1. Specific space should be allocated for the filing of prospective studies where protocols, investigators brochures and early correspondence can be stored when they are first produced or received by the investigator. 2. The filing system should be segmented so that individual trial documentation remains separate, to avoid miss-filing / loss of documents and correspondence. 3. Should the investigator decide not to participate in the study (prior to trust approval being given), any printed documentation (e.g. protocols or brochures) should be returned to the external sponsor. 4. The investigator or their designee should collate evidence of approval from service departments as appropriate (e.g. Pharmacy, Clinical Radiology, Pathology) for the study to go ahead. This might take the form of email correspondence. This written evidence will be filed in the Site Master site file. 5. Where required, laboratory normal ranges should be obtained directly from the Pathology Department, by submitting a list of the tests required together with a copy of the protocol to the designated member of Pathology staff. Investigator Site File 6. If the study is to proceed a Site Master File will be established and all accumulated material should be transferred to this file. See Appendix B for a suggested layout for a site file. 7. The Site Master file should contain all essential documents according to ICH GCP. For a full list of these see Appendix A. Page 2 of 13

8. Some of the documents contained in the file will be original and/or confidential documents and the file(s) therefore should be retained in a secure place, with restricted access but accessible to all concerned in the care of the patient. This will mean a locked office and/or locked filing cabinet. 9. It is the responsibility of the person delegated to ensure that all essential documents have been collated prior to study initiation and that the study file is maintained throughout the study. 10. The file should be labelled with the full name of the study, and reference numbers such as EudraCT as appropriate. The site master file may consist of more than one volume and should be set out into sections for ease of filing. All volumes should be labelled consistently and their contents identified. 11. If any documents are filed outside of the site master file (e.g. blank consent forms and copies of the protocol in a nurse s or doctor s office) a note should be made in the file detailing where these documents are stored. 12. It is necessary to retain old versions of protocols, patient information sheets, consent forms and investigator brochures as they are updated during the course of the study. One copy of each version is sufficient. Superseded documents should be clearly labelled and segregated from the current versions. There should be no confusion over which is the current version. 13. Where the site file is contained in a filing cabinet, sections should be clearly labelled and each project organised in its own section. 14. Filing cupboards must be fully functional. The drawers must not be full to capacity. Any lack of capacity must be reported to the Principal Investigator or the R&D Manager and new filing cupboards identified. 15. Tracer cards should be used if documents are removed from the file for more then two hours. The cards should identify who has the document, the date it was taken out of the file and the date it will be returned. 16. Duplicate copies of documents in the file should be avoided. 17. No additional loose pieces of paper relating to the subjects should be kept in the site file, e.g. post-it notes or compliment slips. Patient s Medical Records 18. The patient s original consent form, together with a copy of the patient information sheet must be filed in a blue plastic pocket towards the front of the active volume of their medical records. The pocket should be labelled Page 3 of 13

with the name of the study, and contact details of the Principal and Chief Investigators. These pockets are easily noticeable and identify that the patient is enrolled in a research project. 19. A photocopy of the patient s consent form should be retained in the patients individual research file or in the Master Site file if no individual patient s research file is held. 20. Trial labels should not be placed on the front cover of the notes since this contravenes the Trust s record-keeping policy. 21. When patients are recruited into a study they should be identified on the Trust s ICS PAS record-tracking system. This involves flagging the patient as a risk and selecting Clinical Trial from the dropdown menu on ICS PAS under Patient Details. For further information contact the R&D Office or the medical records department. 22. Source documents must be traceable. Cross referencing of location of source documentation must be made in the patients hospital records / patient s study records as appropriate. 23. Copies of current working documents should be placed on the networked research drive and kept up to date throughout the study. Working documents include the protocol, consent forms and patient information sheets, GP letters, any amendments where these are not incorporated in the main protocol, CRF s Questionnaires and any other working documents relating to the study. 24. Out of date documents on the shared network drive should be segregated from the current documents in their own folder. 25. A list of enrolled patients should be maintained for each study and kept on the shared network drive. 4. OTHER RELATED PROCEDURES Case Record Form (CRF) Completion Archiving and Destroying Documents 5. REFERENCES AND FURTHER READING ICH Harmonised Tripartite Guideline for Good Clinical Practice (1996). The Medicines for Human Use (Clinical Trials) Regulations 2004 Statutory Instrument 2006/1031, implemented 1 st May 2004 as amended. Much of the content of this SOP has been adapted from: National Cancer Research Network SOP, Study files and filing, 2004. Page 4 of 13

6. APPENDICES Appendix A Essential documents for the conduct of a clinical trial. Appendix B Example layout of an investigator site file. Page 5 of 13

Appendix A Essential documents for the conduct of a clinical trial Before commencing a study, the following documents should be present in the investigator site file: ICH Topic GCP Ref. 8.2.1 Investigators Brochure To document that relevant and current scientific information about the investigational product has been provider to the investigator 8.2.2. Signed protocol and amendments, if any and sample case report form To document investigator and sponsor agreement to the protocol and amendments 8.2.3. Information given to trial subject On Hillingdon Hospital Headed Paper- Located in investigators file Located in sponsors file Archive Final Version Informed Consent Form Patient Information Sheets Other Trial specific information 8.2.4. Financial Aspect of the trial To document the financial agreement between the investigator / institution and the sponsor of the trial 8.2.5. Insurance statement (if appropriate) To document that compensation to subjects for trial related injury will be available 8.2.6 Signed agreements between involved parties e.g. investigator / institution and sponsor 8.2.7 Dated documented approval of independent Ethics Committee of the following: Protocol and any amendments CRF (if applicable) Informed Consent forms Patient / parent information sheets Any other documents given Approval / favourable opinion including SSA approval (if applicable) To document that the trial has been subject to independent Ethics Review and given approval / favourable opinion. To identify the version number and date of the document(s). 8.2.8 Independent Ethics Composition To document the ethics committee is constituted in agreement with GCP 8.2.9. Regulatory authority authorisation To document that appropriate regulatory Approval letter per SSA documentation only Page 6 of 13

approval has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirements 8.2.10 Curriculum Vitae and other Documents evidencing qualifications of investigator and sub investigators To document qualifications and eligibility to conduct trial and / or provide medical supervision of subjects 8.2.11 Normal Values / ranges for medical / lab tests included in the protocol To document normal values and or ranges of the tests 8.2.12 Verbal confirmation of this standard from the principal investigator Medical / Lab / technical procedures / tests Certification or accreditation; established quality control; other validation. To document competence of facility to perform required tests and support reliability of tests 8.213a To be held in Pharmacy files Sample of label(s) attached to Medicinal Products To document compliance with applicable labelling regulations and appropriateness of instructions to subjects 8.2.13b To be held in pharmacy files Instructions for the Handling of investigational products and trial related material (if not in investigators brochure or protocol) To document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products 8.2.13c To be held in pharmacy files Shipping records for investigational products and trial-related materials To document shipment dates, batch and methods of shipment etc of investigational products 8.2.13c To be held in pharmacy files Certificates of analysis of investigational product shipped T document identity, purity and strength of investigational product to be used in the trial 8.2.17 Decoding procedures for blinded trials To document how in the event of an emergency, identify of blinded investigational product can be revealed 8.2.18 Master Randomisation List To document method of randomisation of trial population 8.2.19 Pre trial monitoring report To document that the site is suitable for Page 7 of 13

the trial. May be combined with 8.2.20 8.2.20 Trial initiation monitoring report To document that trial procedures were reviewed with investigator and investigator s trial staff Trust approval letter 8.2.21 Letter that give the principal investigator approval to undertake the study in this organisation During the conduct of the trial the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available: ICH GCP Ref. Topic Located in investigators file Located in sponsors file 8.3.1 Investigator s Brochure updates To document that investigator is informed in a timely manner of relevant information as it becomes available 8.3.2. Any revisions to: Protocol / amendments and CRF Informed Consent form Patient / Parent Information sheets To document revisions of these documents during the course of the trial 8.3.3. Dated, documented approval of independent ethical committee of the following: Protocol amendments Revisions of: Informed Consent form Patient / Parent Information sheets Any other documents where approval is required 8.3.4. Regulatory authorities approvals where required for: Protocol amendments and other documents To document compliance with applicable regulatory requirements 8.3.5. Curriculum Vitae for new investigator(s) 8.3.6 Updates to normal values / ranges To document revisions to normal values / ranges during the course of the trial 8.3.7 Verbal confirmation of this standard from the principal investigator Updates of medical / lab / technical procedures / tests To document that Test remain adequate throughout trial 8.3.8a To be kept in Pharmacy Documentation of investigational products 8.3.8b To be kept in Pharmacy Archive Page 8 of 13

Certificate of analysis for new batches of investigational products 8.3.9. Monitoring Visit Reports To document site visits by and findings of the mentor 8.3.10 Relevant communication other than site visits Letters inc. printed emails Meeting reports Notes of telephone calls To document any agreement of significant discussion regarding trial administration, protocol violations, trial conduct, adverse event reporting 8.3.11 Copies of Signed informed consent forms To document that consent is obtained in accordance with GCP and protocol and dated prior to participation of each subject in trial 8.3.12 Source documents To document the existence of the subject and substantiate integrity of trial data collected 8.3.13 Signed, dated and completed case report forms To document that the investigator or authorised member of the investigator s staff confirms the observations recorded 8.3.14 Documentation of CRF Corrections To document all changes / additions or corrections made to CRF after initial data were recorded 8.3.15 Notification by originating investigator to sponsor of serious adverse events and Copy Copy Copy Original Original Original copies to be kept in the patients hospital records related reports 8.3.16 Notification by sponsor and / or investigator, where applicable, to regulatory authorities of unexpected serious adverse drug reactions and of other safety information 8.3.17 Notification by sponsor to investigator of safety information 8.3.18 Interim or annual reports to independent ethics committee (Hounslow and Hillingdon) Where required 8.3.19 Subject screening log To document identification of subjects who entered pre-trial screening 8.3.20 Subject identification code list 8.3.21 Subject enrolment log To document chronological enrolment of subjects by trial number 8.3.22 Investigational product accountability at site To document that investigational products have been used according to the protocol 8.3.23 Signature sheet Page 9 of 13

To document signatures and initials of all persons authorised to make entries and / or correction on the CRF s For studies that have clinicians common to more than one study e.g. Haematology projects A common signature sheet will be used. The original copy will be held in the main research filing system and photocopies will be held in the individual research project master files 8.3.24 Records of retained body fluids / tissue sample (if any) To document location and identification of retained samples if assays need to be repeated The following documents relate to Pharmacy, and should be kept in the Pharmacy file: ICH GCP Ref. 8.4.1a Topic To be kept in Pharmacy Located in investigators file Located in sponsors file Comments 8.4.1b. Investigational products accountability at site To document that the investigational products have been used according to the protocol. To document the final accounting of investigational products received at the site, dispensed to subjects, returned by the subjects and returned to the sponsor To be kept in Pharmacy Documentation of investigational product destruction To document destruction of unused investigational products by sponsor or at the site 8.4.2 Completed subject indemnification code list If destroyed at site 8.3.3 Audit Certificate if available To document that audit was performed 8.4.4 Final trial close-out monitoring report To document that all activities required for trial close out are completed, and copies of essential documents are held in appropriate files 8.4.5 Treatment allocation and decoding documentation 8.4.6 Final report by investigator to independent ethics committee where required To document completion of the trial Page 10 of 13

8.4.7 Clinical Study report To document results and interpretation of trial Page 11 of 13

Appendix B Example layout of an Investigator Site File General Study Information for all Trials It is suggested that, where one clinical team or department undertakes more then one study, that a general file is maintained containing the following: Trust GCP Leaflet Overall up to date delegation log covering all the projects Contact details of R&D Office and other useful personnel Laboratory normal ranges and certificates CVs of Investigators and Site Staff Study-specific Investigator Site File The main site file should be divided into sections: AT FRONT Patient Enrolment Log. Patient Screening Log. Contact details for the sponsor or trial centre, and any central labs. LOCAL APPROVALS Trust Approval Letter. Signed copy of the Clinical Trials Agreement. ETHICS CORRESPONDENCE Signed copy of the main ethics form (Parts A and B). MREC Approval letter. Signed copy of the SSI form. LREC/SSI Approval letter. Additional ethics correspondence. MHRA APPROVALS AND CORRESPONDENCE SPONSOR CORRESPONDENCE Letter from the sponsor confirming their role. Evidence of indemnity insurance. Additional correspondence with the sponsor or trial centre arising during the course of the study. MISCELLANEOUS DOCUMENTATION Newsletters WORKING DOCUMENTS Copy of the current protocol. Copy of the current Investigator Brochure or SPCs. Blank copies of the Consent Form and Patient Information Sheet. Blank copies of the GP Letter. Blank copies of Severe Adverse Event or Pregnancy Reporting forms. Page 12 of 13

Blank copies of the CRF (if the CRF is electronic there may be a workbook). SUPERSEDED DOCUMENTS Old versions of the protocol. Outdated Consent Forms, Patient Information Sheets, GP Letters. Old versions of the Investigator Brochures, if applicable. Individual Patient Trial Files These would be labelled with the name of the study in a consistent format with the main site file, and should contain: Photocopy of the signed Consent Form. Photocopies of test results submitted to study centre to confirm eligibility, if applicable. Letter or email from study centre to say patient has been randomised. Photocopy of letter to the patient s GP. Completed CRFs. Page 13 of 13