STANDARD OPERATING PROCEDURE

Transcription

1 STANDARD OPERATING PROCEDURE SUBMITTING PROTOCOL AMENDMENTS TO REGULATORY BODIES S02 Post holder responsible for SOP: Anoushka Tepielow Position: Assistant R&D Manager Author: Anoushka Tepielow Position: Assistant R&D Manager Date: 30 October 2011 Reviewer: Alison Kerridge Position: R&D Coordinator Date: 30 October 2011 Approver: Chris Gardner Position: R&D Directorate Manager Date: 30 October 2011 Reviewed by: Lynda Garcia Position: R&D Facilitator Date: 3 January 2014 Date due for revision: 3 January 2017 Controlled document This document has been created following the Royal Devon and Exeter NHS Foundation Trust Policies, Procedures, Protocols, Guidelines and Standards Policy. It should not be altered in any way without the express permission of the author or their representative. IT IS THE RESPONSIBILITY OF ALL USERS OF THIS SOP TO ENSURE THAT THE CORRECT VERSION IS BEING USED, if you are reading this in a paper format please go on-line to confirm you have the latest version. R&D/Protocol Amendments/S02 Page 1 of 12

2 DISCLAIMER This generic R&D Standard Operating Procedure (SOP) must be followed unless; A study specific SOP exists A departmental SOP dictates a different working practice Once printed this is an uncontrolled document. R&D/Protocol Amendments/S02 Page 2 of 12

3 VERSION HISTORY LOG This area should detail the version history for this document. It should detail the key elements of the changes to the versions. VERSION Date Implemented Details of significant changes January 2014 No significant changes. Corrected general typographical errors and updated web links and format of SOP. R&D/Protocol Amendments/S02 Page 3 of 12

4 CONTENTS Section Page 1 Background 5 2 Purpose 5 3 Scope 5 4 Responsibilities 5 5 Procedure Further reading 9 Appendices 1 Definitions 10 2 Abbreviations 11 3 Flowchart for sponsored studies 12 4 Flowchart for studies at the RD&E 13 R&D/Protocol Amendments/S02 Page 4 of 12

5 1. BACKGROUND Amendments to clinical trial protocols may become necessary during the course of a trial and must be done in accordance with the Clinical Trials Regulations 2004 (Directive 2001/20/EC) and also in compliance with ICH Good Clinical Practice (GCP) Guidance. The Department of Health s Research Governance Framework (RGF) requires that Trusts ensure that systems are in place so that all research is conducted to high scientific and ethical standards and the dignity, rights, safety and well being of participants is protected. The Trust needs systems to meet indicator 1 Systems to ensure an appropriate member of staff is notified of, and has approved, all research in the care organisation. This indicator includes amendments submitted to the Research & Development Department (R&D). 2. PURPOSE This SOP describes the procedure for making amendments to protocols (after favourable ethical opinion has been given), both substantial and non-substantial, to the National Research Ethics Committee (NRES), The Medicines and Healthcare products Regulatory Agency (MHRA) and the Royal Devon & Exeter R&D Department. 3. SCOPE This document covers the procedure which is to be used by all researchers when making amendments to trial documentation and by the Royal Devon & Exeter NHS Foundation Trust () R&D Department when acknowledging amendments. Where is the Sponsor, this SOP must be followed for the review and approval of amendments prior to regulatory submission. This procedure covers both substantial and non-substantial amendments to Clinical Trial / research documents. 4. RESPONSIBILITIES 4.1 Sponsor Representatives Where is the Sponsor, it is the responsibility of the R&D Office (on behalf of the Trust) to review and approve all proposed amendments to Trust sponsored studies, prior to regulatory submission. It is the responsibility of the Sponsor to inform additional sites and Trust R&D Departments of all protocol amendments and provide proof as applicable. Where is the Sponsor, this may be delegated to the Chief Investigator (CI); all delegation will be clearly documented in the division of responsibilities. For Trust sponsored portfolio adopted studies, any amendments will be processed through the National Institute for Health Research (NIHR) Coordinated System for gaining NHS Permissions Research and Development Management Information System (CSP RDMIS), support for this will be provided by a caseworker. 4.2 Chief Investigator (CI) For studies sponsored by, it is the responsibility of the CI, or delegated individual, to submit all proposed amendments to the Local Research Committee (LRC) for review and approval prior to regulatory submission. Following sponsor approval, the CI will be responsible for submitting the amended documents to the appropriate regulatory bodies and the R&D Office concurrently. 4.3 Principal Investigator (PI) It is the responsibility of all PIs (or, where delegated, the Trials Team) to inform the R&D Office of all protocol amendments and provide proof of ethical/regulatory approval as applicable. R&D/Protocol Amendments/S02 Page 5 of 12

6 For portfolio adopted studies these documents will be uploaded by the lead Comprehensive Local Research Network (CLRN) for the study and submitted to R&D via CSP RDMIS. 4.4 R&D Office It is the responsibility of the R&D Office to ensure that all documentation relating to the amendment is complete and correct prior to consideration for Trust acknowledgement and to disseminate a list of all amended documents to the CI/PI or Trials Team for information. N.B. For all amendments submitted/received via CSP RDMIS, please refer to the NIHR CSP RDMIS operating guidelines. 5. PROCEDURES For RD&E sponsored studies, any proposed amendments (including the addition of new sites) must be submitted to the LRC for review and authorisation before submitting the amendment to the appropriate review bodies for approval. Where needed, advice will be taken from the CTC. Once the amendment has been approved in principle, the R&D Department will advise as to whether or not the amendment is substantial or non-substantial (the addition of new sites is always a substantial amendment for ctimp studies) and advise on the appropriate procedures for obtaining approval from Ethics, MHRA and NHS permissions at each of the study sites. R&D must be advised of the amendment at this stage to ensure it proceeds appropriately through the correct systems. Approval of subsequent sites will be in writing and only once written approval has been received by the CI may the R&D offices of those subsequent sites be approached for NHS permissions. An initiation meeting should take place at each site as appropriate following site specific approval. R&D must be notified that this has taken place. 5.1 Determining the type of amendment If an amendment is required for a study, the CI/Trial Sponsor must first determine whether the amendment is substantial or non-substantial. A Substantial amendment is defined by NRES and the MHRA as an amendment to the terms of the Research Ethics Committee (REC) application, Clinical Trial Authorisation (CTA) Application or to the protocol, or any other supporting documentation that is likely to affect to a significant degree: a. The safety or physical or mental integrity of the subjects of the study/trial; b. The scientific value of the trial; c. The conduct or management of the trial; or d. The quality or safety of any investigational medicinal product used in the trial. Non Substantial amendments are anything which do not meet the criteria above, changes to the details of research which have no significant implications for participants or for the conduct, management or scientific value of the study. For example changes in funding, typographical amendments. For further examples of substantial and non-substantial amendments please see Appendix Reporting Substantial Amendments to REC and MHRA Substantial amendments require a favourable opinion from the main REC and MHRA (if applicable) before they can be implemented. The only exception to this is where urgent safety measures need to be taken (R&D/Urgent Safety Measures/S52). A substantial amendment to a Clinical Trial of an Investigational Medicinal Product (ctimp) must be sent to the R&D Office for Sponsor approval. Once approval has been granted the R&D/Protocol Amendments/S02 Page 6 of 12

7 amendment must be reported both to the MHRA and the main NHS REC which approved the study before the amendment can be implemented. The European Commission Notification of a Substantial Amendment form must be used to notify the MHRA and the REC of any substantial amendments to ctimps. For all other Research the NRES Notice of Substantial Amendment form, which is available via IRAS, must be used. NB: The NRES notice of substantial amendment form cannot be accepted for amendments to ctimps. The Notification of Amendment Form should be submitted by the CI, or another person/organisation authorised by the Sponsor. Where is the Sponsor this responsibility may be delegated to the CI. All delegation from the Sponsor to the CI will be clearly documented and signed by all parties concerned. The Notification of Amendment should summarise the change(s) included in the amendment and briefly explain the reasons in each case. It is important that the form is completed using language understandable to a lay person. Other documents required in the submission are: Covering letter describing the amendment / list of documents included in the submission. Reasons for the proposed amendment. Copy of the proposed changes to the protocol or any other documents demonstrating both the previous and new wording. Supporting data for the amendment, including any change to the risk benefit analysis. Where the modified documents (for example, the study protocol) are lengthy and the changes are not as widespread or significant as to justify a new version, it is acceptable for extracts to be provided or for the changes to be listed in a separate document. The CI may also include other supporting information, such as a summary of trial data, an updated safety analysis or a report from a trial monitoring committee. Where the amendment could significantly affect the scientific value of the research, further evidence of scientific and/or statistical review should be provided. 5.3 REC procedures for reviewing Substantial Amendments The co-ordinator of the REC will write confirming whether or not the notice of amendment is valid for review, normally within five working days of receipt. Amendments may be reviewed either at a meeting of the REC subcommittee, or at a meeting of the full committee. The REC will issue an ethical opinion on the amendment within a maximum of 35 days from the date of receipt of a valid notice of amendment. A copy will be sent to the sponsor and the MHRA if necessary. Where an unfavourable opinion is given, the applicant may submit a modified amendment 1. The REC will give an opinion on a modified amendment within 14 days of receipt. If a second unfavourable opinion is given the proposed amendment cannot be made. 5.4 MHRA procedures for reviewing Substantial Amendments Upon receipt of the Notification of Amendment form, the MHRA will review the amendment and should issue an opinion on the amendment. The MHRA state in their acknowledgement letter that It is the Authority s intention within 35 days of the date of receipt of the request, to notify you, where appropriate, by either setting out the grounds for not accepting the proposed amendment or accepting the application for 1 In order for ethics to provide an opinion on a modified amendment, they require, to be submitted, an amended substantial amendment form/covering letter, the updated documents that required changing and all other documents included in the original amendment. R&D/Protocol Amendments/S02 Page 7 of 12

8 amendment with or without conditions. If you are not sent either notice then the amendment can be made. However, although the MHRA state this on their standard letter, it would be advisable to wait for their approval. 5.5 Reporting Amendments to Service Departments On receipt of ethical and regulatory approval the responsible parties (see Section 4) must submit the substantial amendments to all service departments involved in the trial. 5.6 Urgent Safety Measures There must be arrangements for taking appropriate urgent safety measures to protect participants against any immediate hazard where new events relating to the conduct of the trial or the development of the IMP are likely to affect the safety of the subjects. In many studies, the individual best able to take these measures will be the CI or another identified person or organisation rather than the Sponsor directly. The protocol should identify the specific individual(s) who accept(s) this responsibility. Safety measures, such as temporarily halting the trial, may be taken without prior authorisation from the MHRA but must be reported immediately to the Sponsor, R&D Office, MHRA and Ethics Committee. For further guidance on Urgent Safety Measures, please refer to R&D/Urgent Safety Measures/S Reporting Substantial Amendments to the R&D Office On receipt of ethical and regulatory approval, the CI/PI or Trial s Team must; For sponsored studies, forward the regulatory approvals. If any changes were required in order to gain regulatory approval, R&D will require the latest versions of these documents and copies of any correspondence with ethics. For hosted studies, submit the substantial amendment documentation for R&D acknowledgment. For portfolio adopted studies, these will be available via the CSP RDMIS system. Required documentation: Notification of Substantial Amendment form Covering Letter to Ethics / MHRA (if applicable) Amendment summary document Ethical approval letter relating to the amendment MHRA approval letter (if applicable) Any project documentation which has been amended e.g. Protocol or Patient Information Sheets, etc. Amendments will be reviewed by the R&D Office and any implications on Trust resources identified. Where there are no resource implications for the Trust or these are within acceptable limits a letter of acknowledgement will be issued by the R&D Department, on behalf of the Trust within 7 working days. In the event that the resource/cost implications of a protocol amendment are too great for the Trust, the R&D Department will not acknowledge the continuation of the study at the Trust until any issues have been satisfactorily resolved. NB: Failure to receive approval from the MHRA, REC and R&D Office could be viewed as a serious breach of GCP and therefore reportable to the MHRA as made statutory by the EU Directive in Good Clinical Practice in Clinical Trials. 5.8 Reporting of Minor/Non-Substantial Amendments Minor study amendments do not need to be reported to or approved by the main REC, MHRA or R&D Office. However, it is best practice to notify the main REC, MHRA and R&D Office R&D/Protocol Amendments/S02 Page 8 of 12

9 with the minor amendments to your study by letter. The CI can make a non-substantial amendment at any time but must keep a record of these amendments. For sponsored studies, minor amendments must be submitted to the LRC for approval (on behalf of the Trust). 6. FURTHER READING R&D/Urgent Safety Measures/S52 Department of Health s Research Governance Framework ( The Clinical Trials Directive 2001/20/EC ( ICH Harmonised Tripartite Guideline for GCP (E6) ( Medicines and Healthcare products Regulatory Agency ( European Clinical Trials Database (EudraCT) ( European Commission Notification of a Substantial Amendment Form (CTIMPs) ( 10/substantial_amendment_notification_form_.pdf) Health Research Authority (HRA) ( Integrated Research Application System (IRAS) ( APPENDIX 1 DEFINITIONS The following amendments should normally be regarded as substantial: changes to the design or methodology of the study, or to background information affecting its scientific value; changes to the procedures undertaken by participants; any change relating to the safety or physical or mental integrity of participants, or to the risk/benefit assessment for the study; significant changes to study documentation such as participant information sheets, consent forms, questionnaires, letters of invitation, letters to GPs or other clinicians, information sheets for relatives or carers; a change of sponsor(s) or sponsor s legal representative; appointment of a new chief investigator or key collaborator; a change to the insurance or indemnity arrangements for the study; inclusion of a new trial site (not listed in the original application) in a ctimp; appointment of a new principal investigator at a trial site in a ctimp; temporary halt of a study to protect participants from harm, and the planned restart of a study following a temporary halt; a change to the definition of the end of the study; any other significant change to the protocol or the terms of the REC application. Some changes, however, will have no significant implications for participants or for the conduct, management or scientific value of the study and can be regarded as non-substantial or minor amendments. Examples of non-substantial amendments might be as follows: minor changes to the protocol or other study documentation, e.g. correcting errors, updating contact points, minor clarifications; R&D/Protocol Amendments/S02 Page 9 of 12

10 updates of the investigator's brochure (unless there is a change to the risk/benefit assessment for the trial); changes to the chief investigator s research team (other than appointment of key collaborators); changes to the research team at particular trial sites (other than appointment of a new principal investigator in a ctimp); changes in funding arrangements; changes in the documentation used by the research team for recording study data; changes in the logistical arrangements for storing or transporting samples; inclusion of new sites and investigators in studies other than ctimps; extension of the study beyond the period specified in the application form. Changes to contact details for the sponsor (or the sponsor s representative); chief investigator or other study staff are minor amendments but should be notified to the main REC for information. You should notify both the main REC and the relevant local REC if the principal investigator s contact details have changed. APPENDIX 2 - ABBREVIATIONS CI CLRN CSP CTA CTC CTIMP EU EudraCT GCP GP ICH IMP IRAS LRC MHRA REC NHS NIHR NRES PI R&D RD&E RDMIS REC SOP Chief Investigator Comprehensive Local Research Network Coordinated System for gaining NHS Permissions Clinical Trials Authorisation Clinical Trial Committee Clinical Trial of an Investigational Medicinal Product European Union European Union Drug Regulating Authorities Clinical Trials Good Clinical Practice General Practitioner International Conference on Harmonisation Investigational Medicinal Product Integrated Research Application System Local Research Committee Medicines and Healthcare products Regulatory Agency Research Ethics Committee National Health Service National Institute for Health Research National Research Ethics Service Principal Investigator Research & Development Royal Devon & Exeter Royal Devon and Exeter NHS Foundation Trust Research and Development Management Information System Research Ethics Committee Standard Operating Procedure R&D/Protocol Amendments/S02 Page 10 of 12

11 APPENDIX 3 FLOWCHART FOR SPONSORED STUDIES CI/Research Team submits proposed amendment to R&D for review by the LRC LRC reviews the proposed amendment Changes to be made? YES R&D inform CI of changes to be made NO LRC informs the CI/Research team that the amendment can be submitted for regulatory approval and the type of amendment (i.e. substantial) CI/Research Team submit the amendment to the relevant regulatory bodies Approval(s) received from regulatory body(ies) NO Changes required by regulatory bodies prior to formal approval? YES Approval(s) forwarded to R&D R&D process the amendment CI/Research Team makes required changes and resubmits the amendment (including an amended substantial amendment form and all amendment documents). Implications to the Trust? YES R&D to discuss with all relevant parties to resolve the issues. NO R&D/Protocol Amendments/S02 Page 11 of 12 R&D acknowledgement letter sent to the CI Once issues resolved

12 APPENDIX 3 FLOWCHART FOR HOSTED STUDIES R&D receives amendment documentation and approval(s) via the PI/Research team or thorough CSP RDMIS R&D review and process the amendment on behalf of the Trust NO Are there any implications to the Trust? YES R&D to discuss any implications with all relevant parties to resolve the issues. R&D acknowledgement letter sent to the PI Once issues resolved R&D/Protocol Amendments/S02 Page 12 of 12