Statement of Responsibilities

Statement of Responsibilities Full Title: A multi-centre randomised placebo-controlled trial of prophylactic enteral lactoferrin supplementation to prevent late-onset invasive infection in very preterm infants Chief Investigator: Professor William McGuire, Hull York Medical School& NIHR Centre for Reviews and Dissemination, University of York Clinical Trials Unit: National Perinatal Epidemiology Unit Clinical Trials Unit (NPEU CTU) Sponsor: University of Oxford Identifiers: EudraCT No. 2012-004260-22 REC Reference 13/EM/0118 ISRCTN 88261002 This randomised controlled trial will evaluate whether giving very preterm infants supplemental lactoferrin (a natural antibiotic protein from cow s milk) reduces the number of serious infections. About 20% of very preterm infants (born before 32 weeks of gestation) acquire a serious infection in the neonatal unit. These infants are more likely to develop other problems including severe lung and bowel conditions, and have a higher risk of dying or surviving with disability. Better methods of preventing infection in very preterm infants are needed. ELFIN will start with a pilot phase in the Northern Region and Yorkshire Neonatal Networks. The main trial will invite participation from 2,200 very preterm infants cared for in neonatal units across the UK. Treatment will continue until the infants are no longer at high risk of acquiring serious infections (34 weeks postmenstrual age; a maximum of 70 days treatment will be given). As well as comparing the incidence of serious infection between the two groups, we will also assess the effect on the incidence of other serious diseases and death, on the need for infants to receive multiple or prolonged courses of antibiotics (a major cause of antibiotic resistance in neonatal units), and on the length of hospital stay. Research Activity During their postnatal stay, about 50% of ELFIN infants are likely to be transferred from their recruiting site to a continuing care site for surgery, for specialist opinion or to be closer to home. Some infants participating in ELFIN are therefore likely to be moved from their recruiting site to another site whilst still requiring the intervention administered and data collection forms to be completed. Infants may be transferred multiple times between sites and often these transfers happen quickly and with little warning. Although, under the trial protocol the study intervention will need to continue at the receiving site, the level of clinical trial involvement at that site is lower than at the recruiting site. For instance receiving sites will not be required to obtain initial consent for entry to the trial. There will in fact be three different levels of site involvement in the ELFIN trial: 1. Recruiting sites where mothers/infants are initially recruited, the intervention is given, and data collection forms completed. These will be the sites where the parental consent will be obtained. 2. Continuing care sites where infants are transferred from recruiting site to another site and still require the intervention to be given and data collection forms to be completed. 3. Date collection sites where infants are transferred from a recruiting or continuing care site to another site and no longer require the intervention but do require data collection forms to be completed. Statement of Responsibilities This Statement of Responsibilities was discussed with and approved by the Lead CLRN (Thames Valley CLRN). ELFIN Statement of Responsibilities Version 1 16/9/13 Page 1 of 8

All research sites will require NHS permissions for research, but the extent of RM&G review required for each site will vary depending on the level of involvement they have. The information below takes account of the Research Governance Framework (2005), transfer of Site-Specific Assessment to NHS R&D, and CSP National Guidelines. Requirements are as follows: Responsibilities of recruiting sites For a list of recruiting sites please see https://www.npeu.ox.ac.uk/elfin/centres/recruiting-sites Each recruiting site will have a nominated Principal Investigator (PI) and an identified ELFIN nurse. The PI will be responsible for overseeing recruitment of eligible infants to the trial and the adherence to the trial protocol. All members of staff involved within the trial at each recruiting site will be competent and confident in: 1. Their knowledge of the study and their ability to answer questions raised 2. Their competence in obtaining informed consent from the families 3. And, they must be adequately trained by experience or have received training in GCP A log of delegated responsibilities listing staff members involved in the ELFIN trial will be maintained in the Investigator s Site File. Each recruiting site requires NHS permissions for research and a site agreement between the Sponsor (Oxford University) and the Trust/Board. The REC and Lead CLRN have been notified of all recruiting sites. Responsibilities of continuing care sites For a list of continuing care sites please see Appendix 1 About 50% of ELFIN infants are likely to be transferred from their recruiting hospital to a continuing care site for surgery, for specialist opinion or to be closer to home. The continuing care site will not be involved in any decisions about entering patients into the study or seeking consent. However, ELFIN infants who have not reached 34 postmenstrual weeks will still need to receive their dose of either lactoferrin or placebo, and continuing care sites are therefore designated as research sites for the purposes of the clinical trials regulations. A Principal Investigator who is prepared to accept responsibility for overseeing the care of the infant under the ELFIN trial protocol will be identified at each of these sites. If an infant is transferred from a recruiting site to a continuing care site whilst still requiring the intervention to be administered, a transfer pack will accompany the infant; this contains data collection forms and essential training material in order to carry out trial procedures, including the procedure for preparing lactoferrin or placebo for enteral administration. The ELFIN website (www.npeu.ox.ac.uk/elfin) contains further information, including links to the protocol, guidance sheets, and data collection forms. The ELFIN nurse from the recruiting site will inform the ELFIN Coordinating Centre (NPEU CTU) about the transfer to a continuing care site. The ELFIN nurse will be responsible for liaising with the continuing care site, ensuring the PI identified fully understands the study and, for establishing and maintaining an audit trail for the movement of each transferring infant. The ELFIN Coordinating Centre will ensure that the receiving site has NHS Permissions in place and if not will liaise with the receiving site s R&D office to chase for NHS Permissions with support from the Lead CLRN. If NHS Permissions are not in place, the trial procedures must not continue at the receiving site. The ELFIN nurse at the recruiting site will be responsible for following up the outcomes of infants transferred to continuing care sites to ensure that: 1. On-going training and support is provided if required 2. Staff are familiar with the study protocol 3. SAEs are reported in a timely manner Lactoferrin or placebo will be supplied in individual daily doses to be mixed with sterile water and breast or formula milk. The enteral administration of this intervention is in line with routine clinical practice for neonatal staff. Trial specific training material, to a level appropriate to the work, will be provided to all continuing care sites including training in reporting SAEs by the ELFIN nurse from the recruiting site. ELFIN Statement of Responsibilities Version 1 16/9/13 Page 2 of 8

The level of involvement taken on by the continuing care site is, therefore, lower than at a recruiting site and the level of RM&G review required should be proportionate to that risk. NHS permissions for research is required as all the sites responsible for undertaking research activities. However, the extent and content of the review by R&D offices should take into account the activities being undertaken at the continuing care sites. All potential continuing care sites have been notified to the REC and Lead CLRN as part of the notice of substantial amendment explaining the arrangements for continuing care sites. The REC and Lead CLRN have approved this process and are aware PIs are currently being identified. No contract between Sponsor and the site is required as levels of involvement; funding and NHS permissions are addressed in this Statement of Responsibilities. For further clarity of the local governance checks required for NHS permissions please see Appendix 3 in the NIHR CSP Operating Manual (Version 5.2). Responsibilities of data collection sites For a list of data collection site please see Appendix 1 Occasionally infants will be transferred several times before they go home. If infants are transferred to a data collection site after they have reached 34 weeks postmenstrual age, they will no longer need to receive the trial intervention as the intervention phase of the trial will be complete. The data collection site would be asked to complete data collection forms. The data collection site will be responsible for reporting of SAEs until discharge. No contract between Sponsor and the site is required as levels of involvement; funding and NHS permission are addressed in this Statement of Responsibilities letter. For further clarity of the local governance checks required for NHS permission please see Appendix 3 in the NIHR CSP Operating Manual (Version 5.2). NHS Permissions NHS permissions at each continuing care site will need to be issued. A signed contract between the Sponsor and continuing care site or data collection site is not required as the site has agreed to take on the responsibilities as defined in this letter. This is consistent with the Research Governance Framework as the key concern is to ensure that all parties understand and accept their responsibilities. There are no financial flows because all trial paperwork will be provided by the recruiting site or NPEU CTU as required, thus no financial schedule between Sponsor and continuing care site or data collection site is required. If the receiving site s R&D office, after consideration of the above information, does not give permission for the research, then the trial procedures must not continue at the receiving site. To support a streamlined and proportionate RM&G review for continuing care sites Appendix 3 in the NIHR CSP Operating Manual (Version 5.2) stipulates local governance review checks that will need to be completed for NHS permissions. These checks have been reviewed by the Lead CLRN and should be seen as a guide to support a speedy NHS Permissions so infants don t have to be withdrawn from the research. ELFIN Statement of Responsibilities Version 1 16/9/13 Page 3 of 8

For further information please contact the Lead CLRN (tvclrn@nhs.net) and CI/Trial Coordinator for further clarity on the issue Contact details Chief Investigator Professor William McGuire Centre for Reviews and Dissemination University of York York YO10 5DD ELFIN Trial Coordinator James Griffiths NPEU Clinical Trials Unit National Perinatal Epidemiology Unit University of Oxford, Old Road Campus Oxford, OX3 7LF T: 01865 289 741 E: elfin@npeu.ox.ac.uk W: www.npeu.ox.ac.uk/elfin ELFIN Statement of Responsibilities Version 1 16/9/13 Page 4 of 8

APPENDIX 1 List of Continuing Care / Data Collection Sites Trust Abertawe Bro Morgannwg University NHS Trust Airedale NHS Trust Alder Hey Children's NHS Foundation Trust Aneurin Bevan Health Board Ashford and St Peter's Hospitals NHS Foundation Trust Barking, Havering and Redbridge University Hospitals NHS Trust Barnet & Chase Farm Hospitals Trust Barnsley Hospital NHS Foundation Trust Barts and The London NHS Trust Basildon and Thurrock University Hospitals NHS Foundation Trust Basingstoke & North Hampshire NHS Foundation Trust Bedford Hospital NHS Trust Belfast Health and Social Care Trust Betsi Cadwaladr University Local Health Board Birmingham Children's Hospital NHS Foundation Trust Birmingham Women's NHS Foundation Trust Blackpool, Fylde and Wyre Hospitals NHS Foundation Trust Bolton Hospitals NHS Trust Brighton and Sussex University Hospitals NHS Trust Buckinghamshire Hospitals NHS Trust Burton Hospitals NHS Trust Calderdale and Huddersfield NHS Foundation Trust Cambridge University Hospitals NHS Foundation Trust Cardiff and Vale NHS Trust Central Manchester University Hospitals NHS Foundation Trust Chelsea & Westminster Hospital Chesterfield Royal Hospital NHS Foundation Trust Colchester Hospital University NHS Foundation Trust Countess of Chester Hospital NHS Foundation Trust County Durham and Darlington NHS Foundation Trust Croydon Health Services NHS Trust Cwm Taf NHS Trust Dartford & Gravesham NHS Trust Derby Hospitals NHS Foundation Trust Doncaster and Bassetlaw Hospitals NHS Foundation Trust Dorset County Hospital NHS Foundation Trust Dudley Group of Hospitals NHS Trust Ealing Hospital NHS Trust East and North Hertfordshire NHS Trust East Cheshire NHS Trust East Kent Hospitals University NHS Foundation Trust East Lancashire Hospitals NHS Trust East Sussex Hospitals NHS Trust Hospital Status ELFIN Statement of Responsibilities Version 1 16/9/13 Page 5 of 8

Trust Epsom and St Helier University Hospitals NHS Trust Frimley Park Hospital NHS Foundation Trust Gateshead Health NHS Foundation Trust George Eliot Hospital NHS Trust Gloucestershire Hospitals NHS Foundation Trust Great Ormond Street Hospital for Children (GOSH) Great Western Hospitals NHS Foundation Trust Guy's & St Thomas' NHS Foundation Trust Harrogate and District NHS Foundation Trust Heart of England NHS Foundation Trust Heatherwood and Wexham Park Hospitals NHS Foundation Trust Hertfordshire Partnership NHS Foundation Trust Hillingdon Hospital NHS Trust Hinchingbrooke Health Care NHS Trust/ Cambridge Community Services NHS Trust Homerton University Hospital Trust Hull and East Yorkshire Hospitals NHS Trust Hywel Dda NHS Trust Imperial College Healthcare NHS Trust Ipswich Hospital NHS Trust Isle of Wight NHS Trust James Paget University Hospitals NHS Foundation Trust Kettering General Hospital NHS Trust King's College Hospital NHS Foundation Trust Kingston Hospital NHS Trust Lancashire Teaching Hospitals NHS Foundation Trust Lewisham Hospital NHS Trust Liverpool Women's Hospital NHS Foundation Trust Luton and Dunstable Hospital NHS Foundation Trust Maidstone and Tunbridge Wells NHS Trust Mayday Healthcare NHS Trust Medway NHS Foundation Trust Mid Cheshire Hospitals NHS Foundation Trust Mid Essex Hospital Services NHS Trust Mid Staffordshire NHS Foundation Trust Mid Yorkshire Hospitals NHS Trust Milton Keynes General Hospital NHS Foundation Trust Newham University Hospital Trust NHS Ayrshire and Arran NHS Borders NHS Dumfries and Galloway NHS Fife NHS Forth Valley NHS Grampian NHS Greater Glasgow and Clyde NHS Greater Glasgow and Clyde Hospital Status ELFIN Statement of Responsibilities Version 1 16/9/13 Page 6 of 8

Trust NHS Highland NHS Lanarkshire NHS Lothian NHS Tayside Norfolk and Norwich University Hospitals NHS Foundation Trust North Bristol NHS Trust North Cumbria University Hospitals NHS Trust North Middlesex University Hospital Trust North West London Hospitals NHS Trust Northampton General Hospital NHS Trust Northern Devon Healthcare NHS Trust Northern Health and Social Care Trust Northern Lincolnshire and Goole Hospitals NHS Trust Northumbria Healthcare NHS Foundation Trust Nottingham University Hospitals NHS Trust Nottingham University Hospitals NHS Trust Oxford University Hospitals NHS Trust Pennine Acute Hospitals NHS Trust Peterborough and Stamford Hospitals NHS Foundation Trust Plymouth Hospitals NHS Trust Poole Hospital NHS Foundation Trust Portsmouth Hospitals NHS Trust Princess Alexandra Hospital NHS Trust Queen Elizabeth Hospital King's Lynn NHS Trust Rotherham NHS Foundation Trust Royal Berkshire NHS Foundation Trust Royal Cornwall Hospitals NHS Trust Royal Devon and Exeter Hospital NHS Foundation Trust Royal Free Hampstead NHS Trust Royal Surrey County Hospital NHS Trust Royal United Hospital Bath NHS Trust Royal Wolverhampton Hospital NHS Trust Salford Royal NHS Foundation Trust Salisbury NHS Foundation Trust Sandwell & West Birmingham NHS Trust Scarborough and North East Yorkshire Health Care NHS Trust Sheffield Children's NHS Foundation Trust Sheffield Teaching Hospitals NHS Foundation Trust Sherwood Forest Hospitals NHS Foundation Trust Shrewsbury and Telford Hospital NHS Trust South Devon Healthcare NHS Foundation Trust South Eastern Health and Social Care Trust South London Healthcare NHS Trust South Tyneside NHS Foundation Trust South Warwickshire General Hospitals NHS Trust Hospital Status ELFIN Statement of Responsibilities Version 1 16/9/13 Page 7 of 8

Trust Southampton University Hospitals NHS Trust Southend University Hospital NHS Foundation Trust Southern Health and Social Care Trust Southport and Ormskirk Hospital NHS Trust St George s Healthcare NHS Trust St Helens & Knowsley Hospitals NHS Trust Stockport NHS Foundation Trust Surrey and Sussex Healthcare NHS Trust Tameside Hospital NHS Foundation Trust Taunton and Somerset NHS Foundation Trust United Lincolnshire Hospitals NHS Trust University College London Hospitals NHS Foundation Trust University Health Board, Swansea University Hospital of North Staffordshire NHS Trust University Hospital of South Manchester NHS Foundation Trust University Hospital Southampton NHS Foundation Trust University Hospitals Bristol NHS Foundation Trust University Hospitals Coventry and Warwickshire NHS Trust University Hospitals of Leicester NHS Trust University Hospitals of Morecambe Bay NHS Trust Walsall Hospitals NHS Trust Warrington and Halton Hospitals NHS Foundation Trust West Hertfordshire Hospitals NHS Trust West Middlesex University Hospital NHS Trust West Suffolk Hospitals NHS Trust Western Health and Social Care Trust Western Sussex Hospitals NHS Trust Whipps Cross University Hospital Trust Whittington Hospital NHS Trust Winchester and Eastleigh Healthcare NHS Trust Wirral University Teaching Hospital NHS Foundation Trust Worcestershire Acute Hospitals NHS Trust Wrightington, Wigan & Leigh NHS Trust Wye Valley Hospital NHS Trust Yeovil District Hospital NHS Foundation Trust York Hospitals NHS Foundation Trust Hospital Status ELFIN Statement of Responsibilities Version 1 16/9/13 Page 8 of 8