STANDARD OPERATING PROCEDURE SOP 320. Developing a Research Protocol

STANDARD OPERATING PROCEDURE SOP 320 Developing a Research Protocol Version 2.1 Version date 26.03.2017 Effective date 26.03.2017 Number of pages 14 Review date April 2019 Author NNUH UEA Joint Research Office Approved by Julie Dawson Role Acting Research Services Manager Signature Date 13.03.2017 Authorised for NNUH and UEA by Role Professor Alastair Forbes Chief of Research and Innovation Signature Date 26.03.2017 COPIES PRINTED FROM THE WEBSITE ARE VALID ONLY ON THE DAY OF PRITNTING SOP 320 v2.1 Effective Date: 23.03.2017 Page 1 of 14

It is the responsibility of all users of this SOP to ensure that the correct version is being used. All staff should regularly check the NNUH R&D website for information relating to the implementation of new or revised versions of SOPs. Staff must ensure that they are adequately trained in the new procedure and must make sure that all copies of superseded versions are promptly withdrawn from use. The definitive versions of all Joint NNUH/UEA health care research SOPs appear online. If you are reading this in printed form please check that the version number and effective date is the most recent one as shown on the NNUH R&D website. TABLE OF CONTENTS 1 ABBREVIATIONS 3 2 INTRODUCTION 3 3 SCOPE 3 4 PROCEDURE FOR PROJECT PROPOSAL FOR FUNDING APPLICATION 5 PROCEDURE FOR PROTOCOL DEVELOPMENT 4 6 PROCEDURE FOR PROTOCOL AMENDMENT 5 7 REFERENCES 5 8 RELATED DOCUMENTS 5 9 LIST OF APPENDICES 6 Appendix 1: Guidance for Protocol Structure for Non CTIMPs 7 3 Appendix 2: Requirements for a Protocol Structure for CTIMPs and Medical Device Trials and Further Guidance 10 Appendix 3: Change Control, Revision and Review Sheet 14 SOP 320 v2.1 Effective Date: 23.03.2017 Page 2 of 14

1 ABBREVIATIONS CRTU Clinical Research and Trials Unit CTU Clinical Trial Unit CRF Case Report File GCP Good Clinical Practice ICH International Conference for Harmonisation MHRA Medicines and Healthcare Products Regulatory Agency NNUH Norfolk and Norwich University Hospital R&D Research and Development SOP Standard Operating Procedure TMF Trial Master File UEA University of East Anglia ISRCTN International Standard Randomised Controlled Trial Number 2 INTRODUCTION This SOP describes the processes for writing health care research proposals and protocols by researchers at UEA and NNUH. These processes aim to ensure that, as well as answering specific research questions created and developed by the research team, the research is carefully designed to safeguard the health and safety of the participants in compliance with the conditions and principles of GCP and the applicable EU guidelines and regulations. 3 SCOPE This SOP applies to all healthcare research sponsored by NNUH or UEA which falls within the scope of the Research Governance Framework (2nd edition 2005) or its successors. Where additional legislation applies - for example, the Medicines for Human Use (Clinical Trials) Regulations 2004 (and amendments thereof) or the Medical Devices Regulations 2002 - required procedures will be indicated. External sponsors may require use of their own SOPs and this will be specified in site agreements. It is the responsibility of the local PI to ensure that study specific SOPs can be operated without conflict to this SOP and in accordance with all organisational polices related to research. 4 PROCEDURE FOR PROJECT PROPOSAL FOR FUNDING APPLICATION A proposal must be written by the Research Team prior to applying for any funding. The research proposal forms an essential part of a research study. The proposal for a qualitative research study will need to allow for variation as qualitative research designs are often altered and develop as the research commences. Whether for a qualitative study, quantitative study or a mixed methods study, the research proposal is a plan for engaging in systematic inquiry and should demonstrate that: the research is worth doing the researcher is competent to conduct the study - by providing evidence of the skills and experience of the researcher and his or her research team the results of the study will have validity SOP 320 v2.1 Effective Date: 23.03.2017 Page 3 of 14

the potential hazards identified in the risk assessment can be mitigated through study design, safety monitoring procedures and project management plans the study is carefully planned and can be executed successfully. Before beginning your research proposal you should consider the following points: What is your research question? Why does it matter? How will you address this question? (i.e. what methods will you use?) How important is this activity to the NHS and to service users? Is your research question clear? Are your research methods appropriate? What are the identifiable hazards and risks for the participants, investigators and organisations involved? The proposal for research funding should be developed in accordance with the guidance on trial planning and design within the Clinical Trials toolkit along with any additional funder requirements. Where the study is being submitted for external funding, UEA has established peer review committees that will consider the proposal prior to submission. The process of peer review is available from the UEA Research and Enterprise Intranet or by contacting the Research Grants Co-ordinator at NNUH, Research and Development (http://www.nnuh.nhs.uk/ research-and-innovation/key-contacts/). This process is mandatory for certain external funding areas and so will need to be factored in by the Research Team to ensure appropriate peer review before external funder deadlines. Where the study is to be adopted by the Norwich Clinical Trials Unit, the Norwich CTU will need to be involved in the development of the proposal. After any peer review, the proposal must also receive approval by NNUH and/or UEA before submission to the external funder. The proposal may be updated following comments from the funding body. NNUH and UEA will need to approve the updated proposal prior to re-submission to the funding body. 5 PROCEDURE FOR PROTOCOL DEVELOPMENT A research protocol is an essential document which provides the research team with a plan for undertaking the study. The protocol is also a legal document that, once approved by regulatory and ethical bodies, all parties and organisations involved in the study agree to comply with. Investigators should sign and date the signature page of the current protocol and organisations should refer to the protocol in their agreements about the study. The protocol must be written by the Research Team prior to applying for any approval and prior to starting the study. The research protocol for ethical and research governance review should be developed in accordance with the HRA guidelines and that of the lead NHS Trust. Where the study is adopted by the Norwich Clinical Trials Unit, the Norwich CTU will need to be involved in the development of the protocol. SOP 320 v2.1 Effective Date: 23.03.2017 Page 4 of 14

The protocol should be version controlled (see SOP 800 Documentation Management). The final version of the protocol must be reviewed, amended as necessary, and approved by the Research Team, normally including the CI, the study statistician and the study pharmacist (the latter two roles being essential for CTIMPs). For studies involving a health economic analysis, the analysis output should also be reviewed by the Health Economist. The final version of the protocol sent for regulatory and ethical approvals should be signed and dated by the CI and stored in the Trial Master File (see SOP 305 Creating and Maintaining a Trial Master File). The process for approval of the protocol for ethical and research governance review is part of the start-up activities for a Clinical Trial (SOP 325), confirmation of Sponsorship of Research (SOP 400), and obtaining MHRA approval for CTIMPs and Medical Devices trials (SOP405). An early version of the protocol may be updated following comments and feedback from regulatory bodies prior to the start of the project. All versions should be signed and dated and stored in the Trial Master File. Guidance on the content of the protocol is provided in Appendix 1 (non CTIMPs), Appendix 2 (CTIMPs). 6 PROCEDURE FOR PROTOCOL AMENDMENT For CTIMPS, the process for seeking approval for amendments to the research protocol is detailed in SOP 405 (Obtaining and Maintaining Medicines and Healthcare Products Regulatory Approvals Agency (MHRA) Approval for a Clinical Trial). Amendments must be reviewed, further amended as necessary, and approved by the Research Team including, as a minimum the CI, the study statistician, the study pharmacist, and the Sponsor before the amendments are submitted to the regulatory and ethical bodies. The final version submitted for regulatory and ethical approval must be signed and dated by the CI and stored in the Trial Master File. For non-ctimps, amendments must be reviewed, further amended as necessary, and approved by the Research Team and the Sponsor before submission for research governance and ethical approval. 7 REFERENCES 1. Clinical Trial Toolkit: Information required in a trial protocol. www.ct-toolkit.ac.uk 2. RSS Framework-Annex5-S05-Planning Toolkit for SPONSORING Organisation, May 2011 available from www.nihr.ac.uk 3. MRC/DH/MHRA Joint Project. Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products. Version: 10th October 2011 8 RELATED DOCUMENTS SOP 305 Creating and Maintaining a Trial Master File SOP 310 Development of a Participant Information Sheet and Informed Consent Form SOP 325 Start up Activities for Clinical Trials SOP 340 Clinical Trial Reporting SOP 400 Joint Arrangements for Research Authorisation of Research Sponsorship SOP 320 v2.1 Effective Date: 23.03.2017 Page 5 of 14

SOP 405 SOP 800 Obtaining and Maintaining Medicine and Healthcare Products Regulatory Agency (MHRA) Approval for a Clinical Trial Documentation Management Additional advice and documentation created to support Proposal and Protocol Development is available from the Norwich Clinical Trials Unit. 9 LIST OF APPENDICES Appendix 1 Appendix 2 Appendix 3 Guidance for Protocol Structure for Non CTIMPs Requirements for a Protocol Structure for CTIMPs and Medical Device Trials and Further Guidance Change Control, Revision and Review Sheet SOP 320 v2.1 Effective Date: 23.03.2017 Page 6 of 14

Appendix 1 Guidance for protocol structure for non CTIMPs The following is a suggested format for a protocol for a non CTIMP.. A) Protocol Identification: code number, version numbers and dates, signatures i) Protocol code number A protocol code number is required on each protocol. This code number should be unique. Contact the Sponsoring organisation for advice on the protocol code number to be used. ii) Protocol Version Numbers and Dates It is advisable to allocate version numbers and version dates for protocols during the drafting process. The final protocol that is submitted to the ethics committee should ideally be numbered version 1.0 and dated with the date of finalisation of the protocol. If any protocol amendments are made, then the protocol version number and date must be updated accordingly. Similarly; Participant Information Sheets and Consent Forms must be marked with the appropriate version numbers and dates. iii) Protocol Signature The protocol and any subsequent amendments must be signed by the Sponsor. Provide the name and title of person(s) authorised to sign the protocol and a space for their signature and date. i) Title The title clearly identifies the study and may contain a brief description of the study design and objectives. ii) Investigators Everyone who has made a material contribution to the design of at least one component of the study should be named and their contact details given, iii) Abstract/Summary Summarise the aims or objectives of the study and give a brief outline of the design and methods. iv) Background/Introduction The introduction should outline the background to the research, including a critical review of the current knowledge or literature, including published and unpublished work in the area. Any gaps in the evidence should be identified as should the potential value of furthering knowledge in this field, such as theoretical or practice based applications of the potential research outcomes. An explanation of the reasons for undertaking the work should also be included in this section, ideally incorporating a reflective stance whereby the researcher/s reflect upon their own reasons for undertaking the research and interest in the field. v) Aims & Objectives SOP 320 v2.1 Effective Date: 23.03.2017 Page 7 of 14

Outline broad objectives that should follow on from the identified gaps in the literature and rationale for the study. Stated objectives should also allow for unexpected emergent findings to be incorporated as part of the research findings. vi) Study Design & Methods Study Design. Summary of chosen study design to answer particular research question. Setting. Where will the research take place? Participants. Information regarding your participants should be given. For example; o Describe the expected study population, including a rationale of why they are relevant to your research question(s). o Describe the methods by which participants will be identified and recruited and what criteria will be used for deciding whether or not individuals are eligible to participate. You will need to state your expected sample size, and provide some justification. For example, a case study approach may be applicable if in-depth knowledge about a particular topic is sought, but a limited generalised statement should be included. o Describe the nature of expected adverse events along with the reporting procedures that will be used. o Describe the assessment and follow up requirements (as applicable) and define the end of the study. o Describe the consent process and relevant timelines. o Issues such as the potential transferability of results to alternative populations should be considered. Sampling methods. You will need to explain and justify what sampling methods you plan to use. Justifications may be framed in terms of gaining access to particular populations, or in terms of fit with the research design. Methods of data collection. What data will be collected, why and how it will be collected. For example: if you are undertaking semi-structured interviews about a particular topic, the interview guide should be discussed, with information about how participants may be given freedom to discuss unforeseen issues of importance to them. If you are using any equipment, e.g. tape or video recorders, it should be clearly described. vii) viii) Data Collection, Management & Analysis Explain how the data will be collected and managed and who will have access to it. The method and approach to data analysis should also be discussed and may include the following points: Method of data recording Plan of statistical analysis, including assumptions of analysis Data analysis package Planned presentation of the data, i.e. written reports, vignettes, etc Where data on participants is being held electronically, the data management requirements within the 800 SOP series need to be adhered to. Study Administration & Ethical Issues Describe the arrangements for the day-to-day management of the study. SOP 320 v2.1 Effective Date: 23.03.2017 Page 8 of 14

Outline the methods by which the participants interests will be safeguarded. For example; the process of risk limitation; how you will maintain confidentiality or anonymise participants data and how you will deal with any apparent psychological harm State whether there has been user involvement in design of the study, and whether user involvement will be incorporated as an ongoing aspect of the research. If applicable, state whether you have adhered to any set of ethical guidelines If applicable, the proposal should clearly state who is funding the research study and what interest they have in its outcome. Confirm the sponsorship arrangements for the study (i.e. which organisations are taking on formal sponsorship responsibilities for the study (SOP 400) ix) Resource Requirements The resource implications to the host organisation and any other involved departments should be defined in this section. In addition you must outline the timetable/schedule of the research and all costs. x) Study Plan You may wish to include a study plan, showing a brief summary or flow chart of the order, site and timing of all study procedures. xi) xii) Supervision for student projects Where applicable, the protocol should name the individual(s) who will supervise the research project and the intended arrangements for the supervision. Dissemination & Outcome (SOP 340 Clinical Trial reporting) How will the study s findings be made available? State whether you intend to publish or present the findings including any report of findings to the participants. Any implications for future practice and theoretical knowledge advancement should also be suggested. xiii) Appendices (SOP 310) Include consent forms and participant information sheets as appendices. SOP 320 v2.1 Effective Date: 23.03.2017 Page 9 of 14

Appendix 2 Requirements for a protocol structure for CTIMPs and/or Medical Device Trials and Further Guidance A. Contents of the protocol The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki (2008) the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with the implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). International sites will comply with the principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the European Directive 2001/20/EC (where applicable) and applicable National regulations. The contents of a trial protocol for a CTIMP and/or Medical Device Trial should include the following information: General information Background information Trial objective and purpose Trial design Selection of sites/clinicians Selection and withdrawal of participants Randomisation and Unblinding Treatment of participants Assessments and Follow-Up (efficacy, safety and quality of life) Safety Reporting and Follow-Up Statistics Direct access to source data/documents Quality control and quality assurance (risk assessment, monitoring) Regulatory issues (CTA, ethics, consent, confidentiality, indemnity, sponsor, funding, audit & inspection) Data handling and record keeping SOP 320 v2.1 Effective Date: 23.03.2017 Page 10 of 14

Trial Management Publication policy References Appendices B. Protocol identification: code number, version number and dates, signatures i) Protocol code number A protocol code number is required on each protocol. This code number must be unique and is used as the unique identifier for the protocol when the EudraCT number is issued. Therefore; a protocol code number should be allocated that is unlikely to have been used for other trials, e.g. trial acronym and year (MAG98) or the ISRCTN number. Contact the Sponsoring organization for advice on the protocol identification code to be used. ii) Protocol version numbers and dates It is advisable to allocate version numbers and version dates for protocols during the drafting process. The final protocol that is submitted to the ethics committee and for regulatory approval should ideally be numbered version 1.0 and dated with the date of finalisation of the protocol. If any protocol amendments are made, then the protocol version number and date must be updated accordingly. Similarly, Participant Information Sheets and Consent Forms must be marked with the appropriate version numbers and dates. iii) Protocol signature The protocol and any subsequent amendments must be signed for the Sponsor. Provide the name and title of person(s) authorised to sign the protocol and a space for their signature and date. C. Other General Information Provide names & addresses of key study personnel Provide names & addresses of clinical laboratories, drug supply organizations and any other institutions involved in the trial. D. Other guidance for good protocol development. i) Risk Assessment For CTIMPs, the current regulatory framework allows for a range of risk adapted approaches according to how much is known about the medicine(s) being investigated. The following classification scheme currently in use is that proposed by the MRC/DH/MHRA. SOP 320 v2.1 Effective Date: 23.03.2017 Page 11 of 14

Type A: risks no higher than that of standard medical care (e.g. medicinal product licensed for use in any EU Member State and within licensed range of indications, dosage and form) Type B: risks somewhat higher than that of standard medical care (e.g. medicinal product licensed for use in any EU Member State but with modifications to range of indications, dosage, form and/or in combinations where interactions are suspected OR an active substance that is part of a medicinal product licensed in the EU) Type C: risks markedly higher than that of standard medical care (e.g. medicinal product not licensed in any EU Member State) You should consider the most appropriate type of risk from the above list that is relevant to your study. This will inform the procedures for seeking MHRA approval and the detail of trial procedures for monitoring the safety of participants (Appendix 2 of the MRC/DH/MHRA Joint Project report) as well as the decisions made by the Trust on Sponsorship of your study (SOP 400). ii) Safety Reporting ICH GCP requires that both investigators and sponsors follow specific procedures when reporting adverse events/reactions in clinical trials involving IMPs. These procedures should be described un-ambiguously in the safety section of the protocol and may require additional documents that should be referred to in this section e.g. the trial safety management plan, reference safety information. Expert help should be sought from the Sponsor for this section. The definitions of adverse events and reactions that apply in the protocol should be described. Specific exceptions to seriousness criteria that will not require expedited SAE reporting should be described, for example death due to disease progression in a cancer trial where overall survival is an outcome measure or certain elective hospitalizations. The causality categories being used in the trial should be described and those which are regarded as defining an adverse event as an adverse reaction defined. For example: There may be 5 causality categories: unrelated, unlikely, possible, probable and definitely related. If the causality assessment is unrelated or unlikely to be related then for reporting purposes the event will not be regarded as an adverse reaction to trial therapy. If the causality is assessed as possible, probable or definitely related then for reporting purposes the event is classified as an adverse reaction. The source of the Reference Safety Information used to define expectedness should be stated e.g. Summary of Product Characteristics or Investigator Brochure. This document will inform the list of expected adverse events within the protocol or the development of a separate list of Expected Adverse Events (see below). Depending on the design of the study and the IMPs in use it may not be practical to list all expected AEs and the precise severity that is expected within the protocol and an SOP 320 v2.1 Effective Date: 23.03.2017 Page 12 of 14

additional document an Expected Adverse Events list should be referred to in the protocol, be part of the Safety Management Plan and kept in the safety reporting section of their Investigator File. This will be the source document to determine the expectedness of all serious adverse reactions, rather than a list of expected Adverse Events within the protocol. Expert pharmacovigilance help from the Sponsor should be sought. iii) Definition of end of trial The Sponsor must notify the MHRA of the end of a clinical trial within 90 days of its completion. The definition of the end of the trial must be provided in the protocol. Any change to this definition for whatever reason should be notified as a substantial amendment. In most cases, the end of the trial will be the date of the last visit of the last participant undertaking the trial. Any exceptions to this should be justified in the protocol. NB Trialists can separate the treatment and immediate follow-up period from the longterm follow-up period providing that the follow-up phase does not include any trial specific tests, and the end of the trial is defined as the last treatment visit for the last participant. Any long-term follow-up phase should then be defined as a noninterventional phase in the protocol. If designing the trial in this way, appropriate informed consent should be obtained at the start of the trial to ensure the participant is aware of both phases of the trial. iv) Protocol amendments If the protocol is substantially amended after initiation, then there are specific procedures to follow. Protocol amendments must be reported to MHRA and fees will apply. Therefore it is wise to minimise the likelihood of protocol amendments in the first version of the protocol, where possible. It is important to consider the strictness of the eligibility criteria and consider whether any flexibility should be incorporated into the protocol. Flexibility may minimise the need for protocol amendments that are considered substantial by the regulatory and ethical bodies. SOP 320 v2.1 Effective Date: 23.03.2017 Page 13 of 14

Appendix 3: Change Control, Revision and Review Sheet Revision Form: SOP 320 Version No Change Date Reason for Change Reviewer Signature and Date 1.1 01/11/2011 Updated to reflect UEA/NNUH joint working arrangements. 1.2 1/6/2013 Updated to include section on procedure and paragraphs and associated references to risk assessment. 2.0 1/1/2014 Major update to content and to separate procedure for proposal for external research funding (now para 4) from procedure for research protocol (now para 5). Also to develop and then separate protocol for non-ctimps to that for CTIMPs (now as Appendices 1 and 2) based on reviewer comments. 2.1 26.03.2017 Updated to reflect changes to HRA approval process. All web links have been reinstated. Emily Woodhouse Research Grant Coordinator Emily Woodhouse 21/02/2017 SOP 320 v2.1 Effective Date: 23.03.2017 Page 14 of 14