Research Department STANDARD OPERATING PROCEDURE SOP History A104 Protocol v3.3, 05 March 2008 B126 Protocol Amendment Review v1.2, 05 March 2008 SOP Number C105 Created STH Research Department (AP & TJL) Reviewed STH Research Department (GK, JDM, MH) Superseded V1.0, 05 Aug 2013 Version 2.0 Date Related SOPs A105 Protocol Non Compliance A109 Independent Scientific Review A116 Study Site File B122 R&D Master File C101 Document version control Approved by Page 1 of 12
Standard Operating Procedure: Research Department Amendment Review This SOP has been produced in accordance with ICH GCP Guidelines, the Medicines for Human Use (Clinical Trials) Regulations 2004, the Medicines for Human Use (Clinical Trials) Amendment Regulations and the NIHR CSP Operating Manual V5.2 Supplement 1.0 October 2012. This SOP will outline the procedure for dealing with. Background The STH Research Department reviews and issues NHS Permission for all research that takes place within the Trust. If changes are made from the original application, the Research Department requires notification of the intended amendment, to enable review and confirmation of continued NHS Permission where applicable. Definition An amendment is any change to the original study application during the life of the study. This includes but is not limited to: protocol amendments, updated study documentation, duration of the study, change in study management (including sponsorship or funding) or changes to the research team (CI/PI). can be classified as Substantial or Non-Substantial, depending on whether they require approval by either the Research Ethics Committee (REC) and/or Medicines and Healthcare products Regulatory Agency (MHRA) (Appendices 1 & 2). Process 1. Where STH is the Study Sponsor: Substantial 1 1.1 The CI or delegate informs the R&D Coordinator of a required amendment and transfers the completed Amendment Notification Form to the R&D Coordinator via IRAS, along with the amended study documents via separate email. 1.2 The R&D Coordinator reviews the Amendment Notification Form in conjunction with the revised/new study documents, identifies any risks or implications of the amendment, ensures that these can be accommodated and requests Sponsor signature on the Amendment Notification Form from the Research Manager or approved delegate. 1.3 Once signed by the Sponsor representative, the R&D Coordinator transfers the Amendment Notification Form back to the CI or delegate, sending email notification of this action and instruction to submit to the Research Ethics Committee (REC) which provided the original favourable opinion, for review. 1.3.1 If the study is a CTIMP/Device, the CI requests advice from the R&D Coordinator regarding whether the amendment is classified as substantial for the purposes of the REC and/or MHRA. 1.3.2 Where the responsibility for risk assessment and management has not been delegated to a CTRU or other body, the R&D Coordinator forwards the amendment to the Risk Assessment Lead or Deputy. The Risk Assessment Lead or Deputy advises whether the amendment is likely to have any impact on the risk assessment for the study and takes forward any necessary reassessment. 1.3.3 The CTIMP Amendment Notification Form is signed only by the person responsible for submitting the amendment to the REC and/or MHRA. This should be the R&D Coordinator unless this responsibility has been delegated to a CTRU or other body 1.3.4 The R&D Coordinator or delegate (Appendix 6) submits the amendment to the REC and/or MHRA, disseminating the approval letters to the CI on receipt. 1.4 For CSP studies, the CI or delegate uploads the amendment documents to CSP as per the current CSP Operational Guidelines. The R&D Coordinator may perform this task if the CI or delegate is unfamiliar with the process. 1 Where the amendment is deemed substantial for either REC or MHRA. Page 2 of 12
1.5 Where the amendment impacts upon the Support Services and/or financial requirements for the study, the R&D Coordinator requests the appropriate Support Services/Finance approval via document sharing in Alfresco and starting the Amendment task in the Research Management System (RMS). 1.6 Where Support Services and/or Finance review is not required, the R&D Coordinator starts the RMS Amendment task, changing the Support Services status to approved. 1.7 Once regulatory (REC/MHRA, as applicable), and Support Service/Finance approvals as applicable are in place, the R&D Coordinator or delegate issues a Letter of Continued NHS Permission to the CI, copying to all appropriate contacts and Support Services using the current template letter (Appendix 5). 1.8 For CSP studies, the R&D Coordinator or delegate uploads the regulatory approvals and Letter of Continued NHS Permission to CSP as per the current CSP Operational Guidelines. 1.8.1 The R&D Coordinator or delegate subsequently completes allocated CSP amendment tasks and updates the SYCLRN Portal page for the amendment (this applies to notifiable amendments only, see section 4 regarding amendment classification). 1.9 The R&D Coordinator or delegate completes the Amendment task in RMS and updates the RMS diary page accordingly. 1.10 For studies with an STH number >17000, all amendment documentation is filed in the electronic R&D Master File on Alfresco. 1.11 For studies with an STH number <17000, the electronic documents are saved in the S Drive folder. 1.12 For STH Sponsored CTIMP/Device studies, the electronic documents are saved in the S Drive folder or Alfresco, as appropriate and a paper copy of the documentation is printed and filed in the R&D Master File and the yellow tracking sheet updated accordingly 1.13 Where there are multiple sites, the CI is responsible for ensuring that the amendment is disseminated to the PI teams for review, local R&D approval (where the amendment is not classed as non-notifiable in CSP, see section 4 below) and implementation. 1.14 Where the amendment involves a change in funding and STH is providing funding to other sites, the R&D Coordinator will liaise with the relevant contacts at the PI sites to update the financial agreements as necessary. 2. Where STH is the Study Sponsor: Non-substantial 2.1 The CI or delegate informs the R&D Coordinator of a required non-substantial amendment and sends the amended study documents via email. 2.2 The R&D Coordinator confirms the non-substantial status of the amendment. 2.3 The R&D Coordinator advises the CI or delegate to submit the amendment to the Research Ethics Committee who provided the original favourable opinion, for information and acknowledgement. 2.4 For CSP studies, the CI or delegate uploads the amendment documents to CSP as per the current CSP Operational Guidelines. The R&D Coordinator may perform this task if the CI or delegate is unfamiliar with the process. 2.5 Where the amendment impacts upon the Support Services and/or financial requirements for the study, the R&D Coordinator requests the appropriate Support Services/Finance approval via document sharing in Alfresco and starting the Amendment task in the Research Management System (RMS). 2.6 Where Support Services and/or Finance review is not required, the R&D Coordinator starts the RMS Amendment task, changing the Support Services status to approved. 2.7 Once regulatory (REC/MHRA, as applicable), and Support Service/Finance approvals as applicable are in place, the R&D Coordinator or delegate issues a Letter of Continued NHS Permission to the PI, copying to all appropriate contacts and Support Services using the current template letter (Appendix 5). 2.8 For CSP studies, the R&D Coordinator or delegate uploads the REC/MHRA acknowledgement and Letter of Continued NHS Permission to CSP as per the current CSP Operational Guidelines. 2.8.1 The R&D Coordinator or delegate subsequently completes relevant allocated CSP amendment tasks and updates the SYCLRN Portal page for the amendment (this applies to notifiable amendments only, see section 4 regarding amendment classification). Page 3 of 12
2.9 The R&D Coordinator or delegate completes the Amendment task in RMS and updates the RMS diary page accordingly. 2.10 For studies with an STH number >17000, all amendment documentation is filed in the electronic R&D Master File on Alfresco. 2.11 For studies with an STH number <17000, the electronic documents are saved in the S Drive folder. 2.12 For STH Sponsored CTIMP/Device studies, the electronic documents are saved in the S Drive folder or Alfresco, as appropriate and a paper copy of the documentation is printed and filed in the R&D Master File and the yellow tracking sheet updated accordingly 2.13 Where there are multiple sites, the CI is responsible for ensuring that the amendment is disseminated to the PI teams for review, local R&D approval (where the amendment is not classed as non-notifiable in CSP, see section 4 below) and implementation. 2.14 Where the amendment involves a change in funding and STH is providing funding to other sites, the R&D Coordinator will liaise with the relevant contacts at the PI sites to update the financial agreements as necessary. 3. Where STH is not the Study Sponsor (substantial and non-substantial amendments, and notifiable in CSP 2 ) 3.1 The R&D Coordinator is notified of an amendment and provided with the amendment documents via the Sponsor, PI team or CSP. 3.2 If the amendment has been provided by an external body (Sponsor or CSP), the R&D Coordinator contacts the PI team to ensure that they wish to support the amendment. 3.3 Where the amendment impacts upon the Support Services/Finance requirements for a study, the R&D Coordinator requests the appropriate Support Services/Finance approval via document sharing in Alfresco and starting the Amendment task in RMS. Where Support Services and/or Finance review is not required, the R&D Coordinator starts the RMS Amendment task, changing the Support Services status to approved. 3.3.1 If there is an impact on the study costing, the R&D Coordinator may request an amendment to the study agreement, where applicable. 3.4 Once regulatory (REC/MHRA as applicable), and support service approvals and confirmed funding as applicable are in place, the R&D Coordinator or delegate issues a Letter of Continued NHS Permission to the PI, copying to all appropriate contacts and Support Services using the current template letter. 3.5 For CSP studies the R&D Coordinator or delegate uploads the Letter of Continued NHS Permission to CSP as per the current CSP Operational Guidelines. 3.5.1 The R&D Coordinator or delegate subsequently completes relevant allocated CSP amendment tasks and updates the SYCLRN Portal page for the amendment (this applies to notifiable amendments only, see section 4 regarding amendment classification). 3.6 The R&D Coordinator or delegate completes the amendment task in RMS and RMS diary page updated accordingly. 3.7 For studies with an STH number >17000, all amendment documentation is filed in the electronic R&D Master File on Alfresco. 3.8 For studies with an STH number <17000, the electronic documents are saved in the S Drive folder. 4. Notifiable and Non-notifiable amendments (NIHR CSP studies only) The CSP process classifies all amendments as notifiable or non-notifiable irrelevant of whether these are substantial or non substantial. This classification is based on the impact an amendment has on a site (See Appendix 3 and NIHR CSP operational manual for further details). This determines the need for review of an amendment by R&D offices at each participating site. For notifiable amendments where R&D offices are made aware of the amendment, see the processes as outlined in sections 1-3 above. For non-notifiable amendments, refer to the following process: 2 See Section 4 for definition of notifiable and non-notifiable in CSP. Page 4 of 12
1. Where an amendment is classified as non-notifiable within CSP and R&D offices are not notified by any route, no action can be taken by the R&D Coordinator. 2. Where an amendment is classified as non-notifiable, but R&D office is made aware of the amendment, an email of acknowledgement is issued (Appendix 4) by the R&D Coordinator or delegate, only if the notifier of the amendment requests acknowledgement of receipt. The email is copied to the notifier. There is no requirement to upload the acknowledgement email to CSP or for the R&D Coordinator to review the amendment. 3. Where documents are received, they are stored on the Alfresco system for studies with an STH number >17000 or in the S Drive folder for studies with an STH Number <17000. 4. If no documents are received, no acknowledgement email is required. 5. Where the study is an STH Sponsored CTIMP/Device, the R&D Coordinator reviews the amendment following the process described above in Sections 1 and 2. A full Letter of Continued NHS Permission will be sent instead of the email notification process described above. Page 5 of 12
Appendix 1 Examples of Substantial and Non-Substantial amendments for REC Substantial 1. Changes to the design or methodology of the study, or to background information affecting its scientific value 2. Changes to the procedure 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 3. 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 4. A change of sponsor(s) or sponsor s legal representative 5. Appointment of a new chief investigator or key collaborator 6. A change to the insurance or indemnity arrangements for the study 7. Inclusion of a new trial site (not listed in the original application) in a CTIMP 8. Appointment of a new principal investigator at a trial site in a CTIMP 9. Temporary halt of a study to protect participants from harm, and the planned restart of a study following a temporary halt 10. A change to the definition of the end of the study 11. Any other significant change to the protocol or the terms of the REC application Non Substantial 1. Minor changes to the protocol or other study documentation, e.g. correcting errors, updating contact points, minor clarifications 2. Updates of the investigator's brochure (unless there is a change to the risk/benefit assessment for the trial 3. Changes to the chief investigator s research team (other than appointment of key collaborators 4. Changes to the research team at particular trial sites (other than appointment of a new principal investigator in a CTIMP 5. Changes in funding arrangements 6. Changes in the documentation used by the research team for recording study data 7. Changes in the logistical arrangements for storing or transporting samples 8. Inclusion of new sites and investigators in studies other than CTIMPs 9. Extension of the study beyond the period specified in the application form Source: NRES website http://www.nres.nhs.uk/applications/after-ethical-review/notification-of-amendments/examples-ofsubstantial-and-non-substantial-amendments/ Page 6 of 12
Appendix 2 Examples of Substantial and non substantial amendments for MHRA Substantial 1. Changes to the protocol 1.1 Change of main objective of the clinical trials 1.2 Change of primary or secondary endpoint which is likely to have a significant impact on the safety or scientific value of the clinical trial 1.3 Use of a new measurement for the primary endpoint 1.4 New toxicological or pharmacological data or new interpretation of toxicological or pharmacological data which is likely to impact on the risk/benefit assessment 1.5 A change in the definition of the end of the trial even if the trial has in practice already ended Non Substantial 1.1 Changes to the identification of the trial (e.g. change of title, etc.) 1.2 The addition/deletion of exploratory/tertiary endpoints 1.3 A minor increase in the duration of the trial (< 10 % of the overall time of the trial); 1.4 An increase in duration of > 10 % of the overall time of the trial, provided that: the exposure to treatment with the IMP is not extended, the definition of the end of the trial is unchanged, and monitoring arrangements are unchanged 1.5 A change in the number of clinical trial participants per trial site, if the total number of participants in the Member State concerned is identical or the increase/ decrease is insignificant in view of the absolute number of participants 1.6 Addition of a trial arm or placebo group 1.6 A change in the number of clinical trial participants in the Member State concerned, if the total number of participants is identical or the increase/decrease is insignificant in view of the absolute number of participants 1.7 Change of inclusion or exclusion criteria, such as changes to age range, if these changes are likely to have a significant impact on the safety or scientific value of the clinical trial 1.8 Reducing the number of monitoring visits 1.9 Change of a diagnostic or medical monitoring procedure which is likely to have a significant impact on the safety or scientific value of the clinical trial 1.10 Withdrawal of an independent data monitoring board 1.11 Change of IMPs; change of dosing of IMPs 1.12 Change of mode of administration of IMPs 1.13 A change of study design which is likely to have a significant impact on primary or major secondary statistical analysis or the risk/benefit assessment 1.7 A change in the documentation used by the research team for recording study data (e.g. case report form or data collection form 1.8 Additional safety monitoring which is not part of an urgent safety measure but is taken on a precautionary basis 1.9 Minor clarifications to the protocol 1.10 Correction of typographical errors Page 7 of 12
Substantial 2. Changes to the Investigator Brochure 2.1 New toxicological or pharmacological data or new interpretation of toxicological or pharmacological data of relevance for the investigator 2.2 Changes to the reference safety information for the annual safety report 3. Changes to other documentation 3.1 A change of sponsor or the sponsor s legal representative 3.2 The revocation or suspension of the IMP s marketing authorisation Non Substantial 3.1 Any change of persons other than the sponsor or his legal representative, for example applicant, clinical research associates (CRAs) who monitor the clinical trial for the investigator, and clinical research organisations (CROs) (note that the responsibility vis-à-vis the national competent authority for the clinical trial is always with the sponsor or his legal representative); 3.2 Any change in the contact details of persons referred to in the documentation (see, however, Section 3.2 as regards contact details of the contact person); 3.3 Changes to the internal organisation of the sponsor or of the persons to whom certain tasks have been delegated 3.4 Changes in the logistical arrangements for storing/ transporting samples 3.5 Change of technical equipment 3.6 Addition or deletion per se of another Member State or third country concerned Source: European Commission http://eur-lex.europa.eu/lexuriserv/lexuriserv.do?uri=oj:c:2010:082:0001:0019:en:pdf Page 8 of 12
Appendix 3 Examples of notifiable and non-notifiable amendments (as per NIHR CSP operational manual) Category NOTIFIABLE Requires action by participating sites NON- NOTIFIABLE NOT SUBMITTED Example Changes in available funding and if it is to run out Changes in resource requirement Changes in interventions that has an impact on cost or resource Changes to (S)AE reporting requirements Changes to study duration Changes to participant numbers Changes to eligibility criteria Transfer of participant identifiable information (including tissue) Changes in contact details of Sponsor/ CRO Changes in contact details of funder Changes in funder (just transfer) Changes in Chief Investigator. Changes of research staff at individual sites Changes to participant information/ consent (unless it meets criteria for need to know). Changes to interventions with no impact on cost/ resource or risk eg change to interview questions Change to Investigator Brochure/ SPC Addition of new sites Changes to information only contained in Clinical Trial Application to MHRA Source: NIHR CSP operational manual Page 9 of 12
Appendix 4 Text for email acknowledgement of non-notifiable amendment To: PI and/or local contact Cc: person who sent the amendment (only send externally if the amendment was received from an external source) Subject: STH12345 - Acknowledgement of receipt of amendment dated xx/yy/zz Dear Dr x, Re: STH12345 - Acknowledgement of receipt of amendment dated xx/yy/zz Thank you for submitting the above amendment for acknowledgement. I can confirm that the following documents have been received: - Protocol V1, date - PIS V2, date - REC approval letter (if applicable) As this study has been classified as Non-Notifiable on CSP, no further review is required and you may implement this amendment immediately. Kind regards Page 10 of 12
Appendix 5 Associated documents Document Research Department Network Location 1 Investigator Site file..\..\..\research Governance\Project Authorisation\Templates\Site file index\research Department Investigator site file V4.2 Jun07.doc 2 Research Department Master File SOP Website Database Created by Yes No TL No No AL 3 Research Governance Process Manual 4 NHS Permission Letter template 5 Letter of Continued NHS Permission 6 REC/MHRA amendment notification template 7 NRES SOPs for Research Ethics Committees Alfresco Link>> RESEARCH GOVERNANCE PROCESS MANUAL.docx Directory\Research Governance\Project Authorisation\Templates Directory\Research Governance\Project Authorisation\Templates http://www.nres.nhs.uk/applicatio ns/after-ethicalreview/notification-ofamendments/ http://www.hra.nhs.uk/resources/a fter-you-apply/knowledgebasenhs-rec-reviewoutcomes/nres_sops_v5-1_2012-03-14-2/ No No JB/TL No No AL No No AL No No IRAS No No NRES 8 NIHR CSP Operation Manual http://www.crncc.nihr.ac.uk/resou rces/nihr%20crn%20cc/csp/ Documents/NIHR%20CSP%20O perating%20manual%20v5_2%20 FINAL04092012.pdf No No NIHR Page 11 of 12
Appendix 6 Roles and Responsibilities Task Reviewing the Amendment Starting an Amendment Task In RMS, including Support Service Review, if applicable Document Check Drafting Amendment Letter Informing RGF/RA who to send Amendment letter to (hard copy and electronic) Signing off Amendment Task in RMS Completing RMS Diary page Filing Amendment documents electronically or paper files if STH Sponsored IMP/Device studies Uploading Amendment Letter to CSP Updating SYCLRN Portal for Amendment Person Responsible R&D Coordinator R&D Coordinator R&D Coordinator Page 12 of 12