SOP14a: Standard Operating Procedure Applying for Ethical Approval

SOP14a: Standard Operating Procedure Applying for Ethical Approval Authorship Team: Jemma Hughes for Joint SOP Group on Trial Processes (viz Leanne Quinn, Ian Russell, Anne Seagrove, John Williams, Bridget Wells) Authorised for implementation by: the Director of WWORTH Signature Date 0 Version Record Version Number Effective Date Reason for Change 0 01 Dec 2008 Derived from SOP approved by NWORTH 0.1 27 Mar 2009 Reviewed by JSOPG on 27 th March 2009 0.2 27 Apr 2009 Further edits based on discussions at JSOPG on 27 Mar 09 0.3 12 May 2009 Further edits based on discussions at JSOPG on 27 Mar 09 0.4 29 May 2009 Further edits based on discussions at JSOPG on 22 May 09 1.0 14 Sept 2009 Further edits based on final review at 10 Jul 09. Approved in principle by JSOPG 1.1 16 May 2010 Minor formatting amendments 1.2 13 Apr 2012 Minor edits: inserted Section 7 Training 1.3 16 May 2012 Edits following JSOPG in preparation for JEG sign off 2.0 12 Sept 2012 Minor amendments after JEG approval 2.1 10 Jan 2014 Updated header, formatting amendments, introduction updated, references renumbered 2.2 24 Mar 2014 Updates required based on discussions at JSOPG 17 Jan 14 2.3 25 Mar 2014 Referencing corrected MS/ACS 2.4 08 May 2014 Remove training log post JSOPG discussion - MS & CS WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 1 of 21 Not guaranteed if printed

1 Table of Contents 0 Version Record... 1 1 Table of Contents... 2 2 Glossary... 3 3 Introduction... 3 4 Purpose... 5 5 Roles & Responsibilities... 5 6 Procedure... 5 6.1 Making an Initial Application on IRAS... 5 6.2 Flow Diagram for Application to NHS Ethics Committee... 8 6.3 Submission of amendments for review...10 6.4 Ethical & Governance Review of Non-Patient and/or Non NHS Trials...13 7 Training Plan...14 8 References...15 9 Related SOPs...15 10 Appendices...16 Appendix 1: Notification of substantial amendments to CTIMPS...17 Appendix 2: Algorithm Defining Research...21 WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 2 of 21 Not guaranteed if printed

2 Glossary The full Glossary is in Swansea University H drive/documents/526- WWORTH/Development Group/Glossary. The terms of particular relevance to this SOP are: 3 Introduction Standard Operating Procedures (SOPs) are succinct formal documents designed to achieve consistency in specified trial functions by specifying standard practice in performing those functions (GCP 1.55 & 5.1.1 EMeA, 2002). While SOPs should cite relevant legislation & regulations, and key references & evidence, they need not expound theory. WWORTH SOPs should accord with all relevant regulations, including the European Union Clinical Trial Directive 1, ICH Good Clinical Practice (GCP) 2 and the current NHS Research Governance Framework. 3 They will seek to distinguish between regulations for Clinical Trials of a Medicinal Products (CTIMPs) and for other research. This document forms part of the set of standard operating procedures of the West Wales Organisation for Rigorous Trials in Health (WWORTH). WWORTH SOPs are written in compliance with regulatory requirements, EU clinical trial directive, ICH Good Clinical Practice and Internal Guidelines-the Research Governance Framework. All SOPs will distinguish regulatory requirements between Clinical Trials of an Investigational Medicinal Products (CTIMPs) and other research (non drug trials). The World Medical Association in its Declaration of Helsinki states in Sections 22-23 22. The design and performance of each research study involving human subjects must be clearly described and justified in a research protocol. The protocol should contain a statement of the ethical considerations involved and should indicate how the principles in this Declaration have been addressed. The protocol should include information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 3 of 21 Not guaranteed if printed

In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 23. The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study s findings and conclusions. 4 In the UK, ethical review is one of a series of safeguards intended to protect individuals as described in the Research Governance Framework for Health and Social Care on the Department of Health's website. 3 The primary function of a Research Ethics Committee (REC) when considering a proposed study is to protect the rights, safety, dignity and well-being of all actual or potential participants as well as the researchers themselves. The remit of RECs is described in the Department of Health's guidance, Governance Arrangements for Research Ethics Committees (GAfREC) which is located on their website. 5 In addition to ethical review, the scientific value and governance arrangements of all proposed research must be considered by National Health Service Research & Development (NHS R&D) Departments at all relevant research sites. NHS R&D departments have the responsibility for assessing the governance, safety, suitability and capacity for conducting the research. For Studies with a request for Sponsorship by ABMU Health Board or Swansea University, a scientific review may be necessary via the Joint Scientific Review Committee. Please contact the ABMU R&D Department to discuss scientific review prior to submitting to Ethics. For full details on the Sponsorship and Adoption process and NHS R&D Submission, please refer to WWORTH SOP31 Sponsorship and Adoption and WWORTH SOP14b NHS R&D Permission respectively.). Ethical approval and approval from relevant NHS R&D departments must be obtained before any study can start at any site. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 4 of 21 Not guaranteed if printed

4 Purpose The purpose of this SOP is to offer guidance to researchers on the principles and processes pertaining to seeking Research Ethics Approval. 5 Roles & Responsibilities It is the responsibility of the Sponsor to ensure all regulatory approvals are in place before a study begins at any site. This may be delegated to the CI or Director of WWORTH. The Director in turn may delegate to a suitably qualified person such as the Trial Manager (TM), Principal Investigator (PI) or a member of the WWORTH team depending on the nature of the study. The CI has overall responsibility for the research. In a multi-site study, the CI has co-ordinating responsibility for research at all sites. All applications for ethical review should be submitted by the CI. It is the responsibility of the TM to support the CI and Trial Management Group (TMG) in the application. If a TM is not in post, this may be delegated to the WWORTH Unit Manager. The CI is required to sign the final application. The PI has the responsibility of ensuring NHS R&D approval is obtained prior to starting the research at their site; this will include the submission of the Site Specific information form (SSIF) for that site alongside the generic IRAS R&D form for NHS R&D Management review. In the case of a single-site study, the CI and PI will usually be the same person and will be required to submit to LREC for ethical review and NHS R&D for management review. Please refer to WWORTH SOP14b NHS R&D Permission for full details on the NHS R&D Submission process. It is the responsibility of the CI, PI, TM or delegated individual to ensure that sites taking part in the research complete the SSIF and obtain NHS R&D approval before site initiation and set up takes place in accordance with WWORTH SOP16 Site Setup. The CI, PI, TM or delegated individual also has responsibility for ensuring copies of all ethical and R&D approvals are stored within the Trial Master File (TMF) and relevant Trial Site File (TSF) in accordance with WWORTH SOP03 Master Site File. 6 Procedure 6.1 Making an Initial Application on IRAS Ethical approval from the appropriate NHS REC (i.e. LREC) & NHS R&D Departments is required for any research involving staff, patients and users of the NHS. This includes all potential research participants recruited by virtue of the patient or user's past or present treatment by, or WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 5 of 21 Not guaranteed if printed

use of the NHS. It includes NHS patients treated under contracts with private sector institutions; individuals identified as potential research participants because of their status as relatives or carers of patients and users of the NHS, as defined above; access to data, organs or other bodily material of past and present NHS patients; foetal material and In Vitro Fertilisation involving NHS patients; the recently dead in NHS premises; the use of or potential access to NHS premises or facilities. Selection of participants by virtue of the fact that they are employed by or work within an NHS Organisation also requires ethical approval. For research involving two or more centres, approval must be sought from a multi domain NHS Research Ethics Committee (NHS REC). NHS REC approval issued by a multi domain Committee applies to all NHS organisations involved in the research. Thus individual local NHS RECs are not required to consider the proposal. To include additional sites at a later date, an amendment application should be notified to the original reviewing REC and NHS R&D Permission obtained from the new NHS site (please refer to WWORTH SOP14b NHS R&D Permission). All applications for ethical approval and NHS R&D approval must be made using an electronic on-line system known as the Integrated Research Application System (IRAS). There are detailed help guides available on IRAS to guide applicants through the submission process, however NRES continues to operate as the overarching body responsible for all RECs in the UK and the HRA website offers applicants with detailed guidance on all aspects of the ethics submission process (http://www.hra.nhs.uk/research-community/before-you-apply/ To make an application for ethical and/or NHS R&D review, go to the IRAS website. 6 https://www.myresearchproject.org.uk/ If you are a first time user, you will need to register for an account online, which is activated immediately. It is important to follow the question-specific guidance, also available from. 6 https://www.myresearchproject.org.uk/ Once logged in, you will be directed to a project filter page which enables you to specify which approval bodies you need approval from and will ensure the correct application forms are generated for you. All forms are then completed online and can be downloaded into PDF or XML format in preparation for submission to the relevant bodies. For multicentre studies in England, the NHS R&D form is submitted via a Coordinated System for gaining NHS Permission (CSP). Within Wales, all applications should be sent to the NISCHR Permissions Unit. Please refer to WWORTH SOP14b NHS R&D Permission for full guidance on NHS R&D submission process. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 6 of 21 Not guaranteed if printed

Note that the Ethical approval process has a timeline after you have phoned the Central Allocation System or your Local Allocation System to book in your application; therefore it is important to start preparing your submission as soon as funding is approved. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 7 of 21 Not guaranteed if printed

6.2 Flow Diagram for Application to NHS Ethics Committee Once you have completed the IRAS REC application and have supporting documents, phone the Central Allocation System or Local Allocation System to book in the application. Submit Parts A&B of the application form and supporting documents direct to the REC within 4 working days of the booking REC Coordinator validates application (5 working days) Valid Application CI invited to REC meeting, or to be available by phone. Invalid application returned, booking process starts again. Application reviewed by the main REC Favourable Opinion (within 60 days) Provisional opinion (60 days clock stops) Modify application (60 day clock restarts) Modifications reviewed by Chair or Sub-committee Favourable or Unfavourable Opinion (within 60 days) If the study involves an Investigational Medicinal Product (IMP) or medical device, you must apply for authorisation from the MHRA either at the same time as you make your REC application or in sequence. This application can now also be made via the IRAS form, with guidance available from the website. Please refer to WWORTH SOP15 MHRA Approval and the MHRA website for guidance. 7 http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedicines/clini caltrials/index.htm WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 8 of 21 Not guaranteed if printed

The REC application form for CTIMP has a space to enter the EudraCT number, which allows the REC to link your application for ethics approval to your application to the MHRA for a CTA. The EudraCT number is the mandatory reference number allocated by the European Medicines Agency (EMeA) for CTIMPS authorised on or after 1 May 2004 and can be sought via IRAS. Further details can be found from reference 7 http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedicines/ Clinicaltrials/index.htm Please also refer to WWORTH- SOP15MHRAapproval. If the research involves the use of patient identifiable information without consent, you will need to apply to the NIGB after you have received a favourable REC opinion. Again, application for NIGB approval is applied for via IRAS. It is strongly recommended that funding is secured and NHS R&D support in principle is obtained before making REC applications. There are different types of NHS REC across the UK that review different kinds of studies. There is detailed guidance on the HRA Research Community web page 8 to determine the appropriate REC for your study. There is no application fee for ethical review by an NHS REC. Applicants should submit the application before the deadline given by the REC for applications to be reviewed at the target meeting. Failure to do so will delay consideration of the application until a subsequent meeting. Applicants should provide all requested information, especially full responses to reviewers comments. A standard letter confirming validation or not will be sent within 5 days. For multicentre studies, once the CI receives the validation letter, the Sponsor or CI can instruct the Trial Manager or individual PIs to apply for NHS R&D permission at each site. To allow this the CI or delegated person completing the application sends the SSIF to each PI for completion and submission. This is done by the transferring the SSIF electronically to the PI, via IRAS, who then completes and signs it before sending it for NHS R&D review assessment, following the submission guidance in WWORTH SOP14b NHS R&D Permission. The application for NHS R&D permission consists of the SSIF, IRAS R&D form, Research protocol, sample participant information sheets (PIS), informed consent forms (ICF) (see WWORTH SOP05 Participant Info Consent), copy of MHRA authorisation (if applicable), REC approval letter, the PIs CV and draft clinical trial agreement for review. Following a satisfactory review by each NHS R&D department, an approval letter for that NHS Permission will be issued to the PI and a clinical trial agreement will be signed (if applicable). WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 9 of 21 Not guaranteed if printed

6.3 Submission of amendments for review Once a study has been issued with all its necessary approvals and becomes active, it may become necessary to amend the study thereby altering the information originally submitted and approved. It is advised that all amendments are submitted individually and are self-contained to ensure it is clear which amendments have been given approval. Some amendments will be classified as substantial whilst others will be classified as non-substantial. Only substantial amendments will require full review by the REC and NHS R&D departments. Non-substantial may be notified to the REC and R&D Department, via letter, for information only. It should be documented, by use of a file note, how the decision was made. NRES defines Substantial amendment as an amendment to the terms of the REC application, or to the protocol or any other supporting documentation, that is likely to affect to a significant degree: 1. the safety or physical or mental integrity of the subjects of the trial; 2. the scientific value of the trial; 3. the conduct or management of the trial; or 4. the quality or safety of any investigational medicinal product used in the trial. All substantial amendments should be notified to the REC that gave a favourable opinion (the main REC ) using a notice of substantial amendment form 9 http://www.hra.nhs.uk/research-community/during-yourresearch-project/amendments/ A copy of the notification should also be sent to NHS R&D Offices for review. For CTIMPS the EU Notification of Substantial Amendment form should be used. In accordance with the European Commission guidance the form should be submitted to either the main REC or to the MHRA or both as appropriate. This can be created in IRAS by using the Create Notice of Substantial Amendment button on the Amendment tab associated with the REC form. For all other research, the Notice of Substantial Amendment form should be used and is available on IRAS. NRES specifies that within a CTIMP the legal and Primary responsibility for WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 10 of 21 Not guaranteed if printed

determining whether or not an amendment is substantial lies with the sponsor. This may be delegated to the CI or WWORTH. For non-ctimps the main REC has the discretion to decide whether or not a proposed amendment is substantial and requires ethical review. Chief investigators and sponsors should seek advice from the main REC if in doubt. 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; 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 research site (not listed in the original application) in a study requiring site-specific assessment (SSA); appointment of a new principal investigator at a research site; a significant change to the definition of a research site requiring SSA; a change to the SSA-exempt status of a study; 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. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 11 of 21 Not guaranteed if printed

Examples of non-substantial amendments might be as follows: correction of typographical errors in the protocol or other study documentation; other minor clarifications of the protocol; 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); 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 in SSA-exempt studies; extension of the study beyond the period specified in the application form. NRES also notes that Changes to contact details for the sponsor (or the sponsor s representative), chief investigator or other project staff are minor amendments but should be notified to the main REC for information. Changes to contact details for principal investigators should be notified both to the main REC and the relevant local REC. Notification should also be made to NHS R&D. There are two exceptions to the general rule that substantial amendments must be given a favourable ethical opinion before they can be implemented. These are: where urgent safety measures need to be taken you must notify the main REC and the MHRA (for CTIMPs) immediately and in any event within three days, in the form of a substantial amendment, that such measures have been taken and the reasons why. 10 WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 12 of 21 Not guaranteed if printed

Please also refer to WWORTH SOPs 19a Pharmacovigilance and 19b Urgent Safety Measures for more detail. in the case of some substantial amendments to CTIMPS which require authorisation by the competent authority (MHRA) but may be submitted to the main REC for information only. Please refer to Appendix 2 for full details of notifying substantial amendments for CTIMPS. For more guidance on the submission of amendments for review, please visit the NRES web pages - http://www.hra.nhs.uk/researchcommunity/during-your-research-project/amendments/ 9 6.4 Ethical & Governance Review of Non-Patient and/or Non NHS Trials As a general rule, research studies that do not involve the NHS do not require REC or NHS R&D Review. However, research studies which do not involve patients but involve the NHS e.g. via the involvement of NHS staff or another NHS resource would still require review by NHS R&D departments and potentially also ethical review, depending on the nature of the research. Some studies may not require ethical review but would still require NHS R&D permission, for example retrospective use of clinical anonymised data. It is important to note that studies classified as Audit or Service Evaluation do not require REC or R&D approval but their classification as such must be agreed with the relevant NHS R&D Department. Please refer to Appendix 3 for the algorithm on Defining Research. The process for the review of non-nhs research studies is not formalised by Regulations, it is therefore usually a matter for the internal review processes of the study Sponsor, for example University Schools often have an in-house Ethical Review Panel to scrutinise student research. The SSIF requests that investigators specify whether the research site is NHS or Non-NHS. Non NHS in this regard usually refers to a private company or corporation (for example, a pharmaceutical or biotechnology company or a Site Management Organisation), a private hospital or a private clinical practice. In such cases, the SSIF must be completed and submitted for relevant ethical approval by the REC, whereas for NHS sites, the SSI is submitted as part of the Trust R&D Management review. For further guidance on the completion of the SSIF for non-nhs sites, please contact your local NHS R&D Office or REC. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 13 of 21 Not guaranteed if printed

7 Training Plan All WWORTH staff involved with trials must undertake the appropriate generic and trial-specific training to ensure that they meet with the specific employers mandatory training requirements and the specific requirements of the trial. For example, for SU staff, all new employees must attend induction, fire and safety training (as well as role-specific training courses, e.g. laboratory safety). For new staff, additional training requirements should be identified alongside the specific role requirements and the WWORTH Unit Manager should make provision for the new staff member to attend the necessary courses as soon after appointment as is practicably possible. It is the responsibility of the WWORTH Unit Manager (alongside the CI or TM) to identify all the SOPs that are relevant to a specific trial and in which the new member of staff should be trained. The WWORTH UM or the SOP author will provide group training for trial staff and/or one-to-one training, as required for new staff in relation to the specific SOPs identified. Training records should be filed both by the main employer and the staff member, in accordance with the specific employer requirements. Trial specific training should be filed in TMF or TSF as appropriate and every individual involved in a trial should have an individual training record (see WWORTH SOP02 Training). Where the tasks specified in the individual SOPs are delegated to WWORTH staff, CIs/PIs or TMs, these delegated staff must ensure that they have attended a training course on GCP and keep up-to-date through attending refresher courses. It is the responsibility of the CI/PI to ensure that all staff allocated duties on the study delegation log template of responsibilities are suitably trained in the activities linked to those duties (see WWORTH SOP16 Site Setup, Appendix 9 and Appendix 10). Each trial should maintain a central training log and ensure that WWORTH has access to that log, not least to integrate the logs of staff who work on more than one trial. Similarly trials should ensure that each site maintains a local training log, not least to integrate the logs of staff who work for more than one sponsor. All WWORTH staff involved with trials must ensure that they are familiar with this SOP. Depending on the requirements of the sponsor, some of the tasks specified in this SOP may be carried out by WWORTH, CIs / PIs or TMs depending on the trial design. Where the tasks specified in this SOP are delegated to WWORTH staff, CIs/ PIs or TMs, they must ensure that they have attended a training course on GCP and keep up-to-date by attending refresher courses. The SOP author will WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 14 of 21 Not guaranteed if printed

provide one-to-one and group training in relation to this SOP as required (see WWORTH SOP02 Training) If a Sponsor that is independent from the University appoints a monitor or monitoring committee, then the Sponsor will be responsible for ensuring adequate training and qualifications are in place. 8 References 1. Directive 2001/20/EC Of The European Parliament And Of The Council Of 4 April 2001. Official Journal of the European Communities. 2. http://www.eortc.be/services/doc/clinical-eu-directive-04-april-01.pdf 3. The European Agency for the Evaluation of Medicinal Products (EMEA). ICH Topic E 6 (R1) Guideline for Good Clinical Practice 2002. http://www.ema.europa.eu/docs/en_gb/document_library/scientific_gui deline/2009/09/wc500002874.pdf 4. Department of Health. Research Governance Framework for Health and Social Care (2nd Edition) 2005. 5. http://www.wma.net/en/30publications/10policies/b3/ 6. https://www.gov.uk/government/publications/health-research-ethicscommittees-governance-arrangements 7. https://www.myresearchproject.org.uk/ 8. http://www.mhra.gov.uk/howweregulate/medicines/licensingofmedicine s/clinicaltrials/index.htm 9. http://www.hra.nhs.uk/research-community/ 10. http://www.hra.nhs.uk/research-community/during-your-researchproject/amendments/ 11. http://www.nres.nhs.uk/applications/after-ethical-review/notification-ofamendments/urgent-safety-measures/ 9 Related SOPs WWORTH SOP01 SOP on SOPs WWORTH SOP01b Document Control WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 15 of 21 Not guaranteed if printed

WWORTH SOP02 Training WWORTH SOP03 Master and Site File WWORTH SOP05 Participant Info Consent WWORTH SOP14b NHS R&D Permission WWORTH SOP15 MHRA Approval WWORTH SOP16 Site Setup WWORTH SOP19a Pharmacovigilance WWORTH SOP19b Urgent Safety Measures WWORTH SOP31 Sponsorship and Adoption WWORTH SOP32 Detecting and Managing Misconduct, Serious Breaches and Deviations from GCP/Protocol 10 Appendices Appendix 1 - Notification of substantial amendments to CTIMPs Appendix 2 - Algorithm WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 16 of 21 Not guaranteed if printed

Appendix 1: Notification of substantial amendments to CTIMPS ANNEX C: Notification of substantial amendments to CTIMPs The sponsor of a clinical trial of an investigational medicinal product (CTIMP) is required to notify substantial amendments to the MHRA and/or the main REC. The sponsor must indicate on the European Commission notice of amendment form whether the request is for: Authorisation by the competent authority, or Favourable opinion from the ethics committee, or Both authorisation and a favourable ethical opinion. Where a substantial amendment is for review of one body only, there is no requirement to notify the other body for information. It is the responsibility of the sponsor to decide whether an amendment meets the criteria for a substantial amendment, and if so whether it requires authorisation and/or an ethical opinion. However, sponsors may wish to take account of the following general guidance, which has been agreed between NRES and the MHRA. Amendments normally requiring authorisation only New toxicological or pharmacological data or new interpretation of toxicological or pharmacological data of relevance for the investigator. Changes to the reference safety information for the annual safety report. Changes to the Investigational Medicinal Product Dossier (further guidance is in Chapter 8 of the CHMP Guideline on the requirements for chemical and pharmaceutical quality documentation concerning IMPs in clinical trials. Reduction in the sponsor s planned level of monitoring for the trial. Amendments normally requiring a favourable ethical opinion only Significant 1 changes to participant information sheets, consent forms, letters to GPs or other clinicians, letters to relatives/carers, etc (whether generic to the whole study or specific to a particular trial site). Significant changes to recruitment and consent procedures, including the inclusion of adults lacking capacity in the trial. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 17 of 21 Not guaranteed if printed

Significant increase to the radiation exposures to subjects from the protocol. Change of insurance or indemnity arrangements for the trial. Change to the payments, benefits or incentives to be received by participants or researchers in connection with taking part in the study, or any other change giving rise to a possible conflict of interest on the part of any investigator/collaborator Change of the Chief Investigator. Change of Principal Investigator at a trial site. Addition of new trial sites not listed with the original request for authorisation and REC application. Change to the definition of a trial site. Any other significant change to the conduct or management of the trial at particular trial sites. Early closure or withdrawal of a site. Any other significant change to the terms of the original REC application. Amendments normally requiring both authorisation and a favourable ethical opinion Change of the main objective of the trial. Change of primary or secondary endpoints likely to have a significant impact on the safety or scientific value of the trial. Use of a new measurement for the primary endpoint. New toxicological or pharmacological data or new interpretation of toxicological or pharmacological data which is likely to impact on the risk/benefit assessment. Addition of a trial arm or placebo group. Significant change of inclusion or exclusion criteria (e.g. age range) likely to have a significant impact on the safety or scientific value of the trial. Change of a diagnostic or medical monitoring procedure likely to have a significant impact on the safety or scientific value of the trial. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 18 of 21 Not guaranteed if printed

Withdrawal of an independent data monitoring committee. Change of IMPs. Change of dosing of IMPs. Change of mode of administration of IMPs. Any other change of study design likely to have a significant impact on primary or major secondary statistical analysis or on the risk/benefit assessment. Change of the sponsor or sponsor s legal representative. Temporary halt of the trial or temporary halt at a trial site, and re-start of the trial following a temporary halt. Change of the definition of the end of the trial. Amendments not normally requiring notification as substantial amendments Changes to the identification of the trial (e.g. change of title) 2 Increase in duration of the trial, provided that the exposure to treatment is not extended, the definition of the end of trial is unchanged and there is no change to monitoring arrangements. Changes to the numbers of participants planned in the UK as a whole or at individual trial sites, provided that there is no change to the total number of participants in the trial or the increase/decrease is insignificant in relation to the overall sample size. Change in the documentation used by the research team to record study data (e.g. case report form or data collection form). Additional safety monitoring which is not part of an urgent safety measure but is taken on a precautionary basis. Changes to the research team other than to Chief or Principal Investigators. Changes to contact details 3 Changes to the internal organisation of the sponsor or persons to whom tasks have been delegated. Changes to the logistical arrangements for transporting or storing samples. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 19 of 21 Not guaranteed if printed

Changes to technical equipment. Inclusion or withdrawal of another Member State or third country. Non-significant clarifications of the protocol. Non-significant clarifications or updates of participant information documentation. Corrections of typographical errors. The issue of an updated Investigator s Brochure or Summary of Medicinal Product Characteristics for the IMP is not itself regarded as a substantial amendment unless it includes changes that would meet the criteria for a substantial amendment. There is no requirement to provide the MHRA or main REC with updated versions of the Investigator s Brochure or SMPC routinely or to seek authorisation or an ethical opinion. 1 Significant, i.e. likely to affect to a significant degree the safety or physical or mental integrity of trial subjects or the scientific value of the trial, or otherwise significant. 2 Sponsors are requested to notify the REC of this change for information only. 3 Sponsors are requested to notify the REC of changes to the contact details of the sponsor, sponsor s main contact point, sponsor s legal representative (if applicable) or Chief Investigator, for information only.. WWORTH-SOP14aEthicsRGApprovalV2.4-140508 Page 20 of 21 Not guaranteed if printed

Appendix 2: Algorithm Defining Research Research Service Evaluation Clinical Audit Surveillance Usual Practice (in public health) The attempt to derive generalizable new knowledge including studies that aim to generate hypotheses as well as studies that aim to test them. Designed and conducted solely to define or judge current care. Designed and conducted to produce information to inform delivery of best care. Designed to manage outbreak & help the public by identifying & understanding Designed to investigate outbreak or incident to help in disease control and Quantitative research designed to test a hypothesis. Qualitative research identifies/explores themes following established methodology. Addresses clearly defined questions, aims and objectives. Quantitative research may involve evaluating or comparing interventions, particularly new ones. Qualitative research usually involves studying how interventions and relationships are experienced. Usually involves collecting data that are additional to those for routine care but may include data collected routinely. May involve treatments, samples or investigations additional to routine care. Quantitative research study design may involve allocating patients to intervention groups. Qualitative research uses a clearly defined sampling framework underpinned by conceptual or theoretical justifications. Designed to answer: What standard does this service achieve? Measures current service without reference to a standard. Involves an intervention in use only. The choice of treatment is that of the clinician and patient according to guidance, professional standards and/or patient preference. Usually involves analysis of existing data but may include administration of interview or questionnaire. No allocation to intervention: the health professional and patient have chosen intervention before service evaluation. Designed to answer: Does this service reach a Predetermined standard? Measures against a standard. Involves an intervention in use only. The choice of treatment is that of the clinician and patient according to guidance, professional standards and/or patient preference. Usually involves analysis of existing data but may include administration of simple interview or questionnaire. No allocation to intervention: the health professional and patient have chosen intervention before audit. risks associated. Designed to answer: What is the cause of this outbreak? Systematic, statistical methods to allow timely public health action. May involve collecting personal data and samples with the intent to manage the incident. May involve analysis of existing data or administration of interview or questionnaire to those exposed. Does not involve an intervention. prevention. Designed to answer: What is the cause of this outbreak? and treat. Systematic, statistical methods may be used. Any choice of treatment is based on clinical best evidence or professional consensus. May involve administration of interview or questionnaire to those exposed. May involve allocation to control group to assess risk and identify source of incident but treatment unaffected. May involve randomisation. No randomisation. No randomisation. No randomisation. May involve randomisation but not for treatment. Normally requires REC review. Refer to www.nres.npsa.nhs.uk/applications/apply/ for more information. Does not require REC review. Does not require REC review. Does not require REC review. Does not require REC review. WWORTH-SOP14aEthicsRGapprovalV2.4-140508 Page 21 of 21 Not guaranteed if printed