Changes made before the study has received regulatory approvals are handled as revisions to the submission, rather than amendments.

AMENDMENTS Amendments Amendments are changes that are made to the research after review body approval has been given. Amendments cannot be implemented until the relevant approvals are in place, except in the case of urgent safety measures. Changes made before the study has received regulatory approvals are handled as revisions to the submission, rather than amendments. Substantial Amendments A substantial amendment is defined as an amendment to the terms of the application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: The safety or physical or mental integrity of the subjects of the study The scientific value of the study The conduct or management of the study The quality or safety of any Investigational Medicinal Product used in the study For all studies, it is the responsibility of the sponsor to determine whether an amendment is substantial. Non-substantial amendments Changes that are not considered by the sponsor to be substantial, can be regarded as nonsubstantial or minor amendments. Changes to contact details for the sponsor, Chief Investigator or other study staff are minor amendments but should be notified to the REC for information. Examples of substantial and non-substantial amendments can be found in Appendix 1. 1

Preparing and Submitting Amendments to the REC Study amendments must be discussed with the Sponsor prior to submission. Notice of substantial amendment forms are generated in IRAS. The system automatically generates the type of form that is suitable for the project. To generate the notice, open the study in IRAS and select the REC Form. Select the Amendment tab and then follow the instructions. Notice of substantial amendment forms and any accompanying documentation should be emailed to the REC. If the original REC submission pre-dates IRAS, you will need to create a minimal dataset in IRAS to complete an amendment form. Forms generated from minimal datasets are exempt from the requirement for electronic authorisations. https://www.myresearchproject.org.uk/help/help%20documents/pdfdocuments/minimal_dataset _Guidance.pdf The notice of substantial amendment should summarise the changes to be made and briefly explain the reasons for each. The documents that have been amended should be submitted, showing both the new and old wording, so that the changes can be easily identified. Where the modified documents are lengthy, and the changes are not so widespread as to justify a new version, you can provide extracts or list the changes in a separate document. The sponsor or chief investigator may also include other supporting information, such as a summary of trial data or an updated safety analysis. Where the amendment could significantly affect the scientific value of the research, you should provide further evidence of scientific and/or statistical review. For CTIMPs the EU Notice of Substantial Amendment form is used. This form is available in IRAS. The form may be submitted by the sponsor, the sponsor s legal representative, the Chief Investigator, or another person authorised by the sponsor. For non-ctimps the NRES Notice of Substantial Amendment form generated in IRAS must be used, and must be electronically authorised within IRAS by the Sponsor and the Chief Investigator. Without these authorisations, the amendment will not be validated. 2

NHS Research Ethics Committee (REC) Review of Amendments Any valid amendment submitted as a substantial amendment will be accepted for review. If the sponsor is satisfied that the amendment is not substantial, there is no requirement to notify the REC, although non-substantial amendments may be notified for information only. 3

Submitting an amendment to NHS R&D (through CSP for NIHR Portfolio studies) 1. Amendments must be submitted electronically through IRAS (www.myresearchproject.org.uk) 2. To submit an amendment to CSP, select the project from the list, and then select the R&D Form. 3. Select the Checklist tab. 4. Attach the amendment documents to the relevant rows of the IRAS checklist. 5. For substantial amendments, attach both the signed PDF and XML version of the Notice of Substantial Amendment Form. 6. For non-substantial amendments, attach the PDF under the non-substantial amendment category. 7. Attach other supporting documents to the checklist, specifying the correct document category. 8. To submit the amendment to CSP, go to the e-submission tab on the R&D Form and select the Lead CLRN from the drop-down list. 9. The submission can be made either as document only 1 or as R&D application e- submission 2. To complete a document only submission (not including a revised R&D Form), 1 Document only submission can be used if the change relates to the content of supporting documents only, and to provide copies of regulatory approvals. 4

submit using the Submit new/additional documents button. To complete an R&D application submission (including a revised R&D Form and new documents) use the R&D application e-submission button. 10. If the amendment requires the submission of a revised SSI Form and local supporting documents, you will need to select the SSI Form, make the required changes and then submit using the e-submission tab. 11. Regulatory approvals (ethics and MHRA)should be uploaded to the checklist and submitted as soon as they are received, using the submit new/additional documents button. Submitting an amendment to NHS R&D for non-portfolio studies All the amendment documentation should be sent by email to the R&D contact, followed as soon as they are available by the regulatory approvals. 2 R&D application e-submission should be used if there is a change to the R&D Form. If the change has added additional sections to the form (e.g. use of ionising radiation) then the form will need to be authorised. 5

NHS R&D Review of Amendments Amendments can affect NHS organisations in a number of ways, such as: 1. The resources/staff required to support the amended study 2. The role of support departments (pharmacy, radiology, laboratories, pathology etc) 3. The subjects eligible for study inclusion 4. The study end-point This review process relates to changes made to a research study after NHS permission is granted. Amendments made to a study prior to NHS Permission being granted should be handled as part of the permission process. A revised UK study amendment handling process was introduced across the UK in November 2014. This aims to streamline the management of amendments by introducing a system of categorisation of amendment. This will ensure that amendments are handled in a manner that is appropriate to the scale of the amendment and the potential risks to, and liability of the organisation implementing the amendment. All amendments must be notified either to the coordinated permission system that initially processed your application (e.g. CSP for portfolio studies), or where that is not applicable, to the R&D office at each NHS research site in your study (for non-portfolio studies). This applies to both substantial and non-substantial amendments. The process should run in parallel with regulatory review and harmonises the principle of 35 calendar day default approval of amendments for NHS organisations across all studies. Amendments being submitted to NHS organisations were already classified as notifiable or non-notifiable, and are now further subdivided into Category A, B and C. Category A (notifiable) Category B (notifiable) Category C (nonnotifiable) An amendment that impacts or affects ALL participating NHS organisations. Needs to be considered and may face control actions. An amendment that impacts or affects SPECIFIC participating NHS organisations. Only at those organisations does it need to be considered and any control actions required taken. An amendment that has no impact on NHS organisations, hence does not require management or oversight. R&D do not need to be notified of such amendments. Key principles of the new approach: Applies to both substantial and non-substantial amendments as categorised by the Sponsor NHS organisations do not approve amendments. The emphasis is on providing objections to those amendments that cannot be implemented at the site. NHS Permission continues until an NHS organisation withdraws from the study. The 35 day period starts on receipt of a full amendment submission (form, letter and revised documents) Where required, regulatory approval must be in place before an amendment can be implemented. The only exception is an urgent safety measure, which must be implemented 6

immediately. It is the sponsor s responsibility to ensure that regulatory approvals are in place prior to implementation. Subject to regulatory approval, Category C amendments can be implemented immediately. NHS organisations do not need to confirm their continued permission for the study. For studies that do not require NHS REC approval (e.g. studies that only involve NHS staff and not patients), all amendments will be non-substantial. For Category A and B amendments, NHS organisations have a maximum of 35 days to raise an objection, otherwise the amendment can be implemented after the 35 day period. NHS organisations are encouraged to complete the review earlier where possible, involving all relevant departments and teams and establishing what changes are required. Finalising revised financial schedules and sending written confirmation can follow after implementation, within agreed timescales, to avoid any delays to implementation. For amendments in categories A and B, Salford R&D will issue an acknowledgement via email to the Chief Investigator and Sponsor, confirming that the amendment can be implemented and that NHS Permission is continued. If the amendment cannot be implemented at the site, the Chief Investigator and Sponsor will be contacted at the earliest opportunity to raise an objection. There are then two options: NHS Permission for the study is withdrawn/sponsor withdraws study The Sponsor is able to address the reasons why the amendment cannot be implemented e.g. lack of additional funds Chief Investigators and Sponsors must not assume that an amendment that has received an objection from a site can be implemented at the end of the 35 day period. The Sponsor and/or Chief Investigator is responsible for providing details of the amendment, including copies of revised documents to all participating investigators and study teams. Local R&D Offices are not responsible for supplying these documents. Researchers can track the progress of their amendment through the IRAS e-submission history. 7

35 days for implementation if no objections are made R&D PROCESS FOR AMENDMENTS Notification of amendment received by R&D Allocate to SRFT or CRN:GM Category A or B amendment, not an urgent safety measure Urgent safety measure Category C amendment Review changes Implement immediately, do not wait for regulatory approvals No action required No implications for support departments or finance Implications for support departments or finance Amendment can be implemented at site subject to regulatory approvals If amendment cannot be implemented NHS Permission must be withdrawn. Send to relevant departments and research team to assess capacity Request contract changes if required and agree timeline for completion Send email confirmation and ensure research team are using correct document versions If further information is required, notify sponsor. This stops 35 day timeline. Update finance information for invoicing Amendment can be implemented at site once departments agree subject to regulatory approval If amendment cannot be implemented NHS Permission must be withdrawn. Send email confirmation and ensure research team are using correct document versions 8

MHRA Review of Amendments (CTIMPs only) Any substantial amendment to a CTIMP must be notified to both the REC and the MHRA before it is implemented, unless it is an urgent safety measure. Notification is not required for non-substantial amendments. Further information can be found at http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedicines/clinicaltrials/managingy ourcta/amendments/index.htm. MHRA Review of Amendments (Medical Devices) For clinical investigations of medical devices subject to regulation by the Competent Authority (requiring a Notice of No Objection from the MHRA), all proposed changes to the investigation must be notified to MHRA Devices, and you must await a letter of no objection before changes are implemented. This includes changes made at the request of the REC. 9

Appendix 1 Examples of Amendment Types Examples of substantial amendments: Changes to the design or methodology of the study, or to information affecting its scientific value Changes to the procedures undertaken by the participants Any change relating to the safety or physical or mental integrity of the 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 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 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 Examples of non-substantial amendments Minor changes to the protocol or other study documentation e.g. correcting errors, updating contact details, minor clarifications 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 Change to the research team at trial sites (other than appointment of a new PI 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, Chief Investigator or other study staff are minor amendments but should be notified to the REC for information. Examples of notifiable amendments Changes in available funding, or if the funding is going to run out Changes in resource requirement Changes in interventions that have an impact on cost or resource Changes to (S)AE reporting requirements 10

Changes to study duration Changes to participant numbers Changes to eligibility criteria Transfer of participant identifiable information (including tissue) Examples of non-notifiable amendments Changes in contact details of sponsor/cro Changes in contact details of funder Changes in funder Changes in Chief Investigator Changes of research staff at individual sites Changes to interventions with no impact on cost/resource or risk Change to IB/SPC Addition of new sites 11

Glossary Amendment Category A Amendment Category B Amendment Category C Amendment CSP Notifiable amendment Non-notifiable amendment Substantial amendment Non-substantial amendment REC MHRA A change that is made to the research after approval has been given. An amendment that impacts or affects ALL participating NHS organisations, therefore needs to be considered and may face control actions. An amendment that impacts or affects SPECIFIC participating NHS organisations. Only at those organisations does it need to be considered and any control actions required taken. An amendment that has no impact on NHS organisations and hence does not require management or oversight. R&D do not need to be notified of such amendments but will have access to all documents within the national IT system NIHR Coordinated System for gaining NHS Permission An amendment that impacts on participating NHS Trusts. It needs to be considered and change control actions may be required. Can be substantial or non-substantial. An amendment that does not have an impact on participating NHS Trusts. Can be substantial or non-substantial. A substantial amendment is defined as an amendment to the terms of the application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: The safety or physical or mental integrity of the subjects of the study The scientific value of the study The conduct or management of the study The quality or safety of any Investigational Medicinal Product used in the study An amendment that is determined by the sponsor to not be substantial. NHS Research Ethics Committee Medicines and Healthcare products Regulatory Authority 12