Dear Mr Horsley Re: Report to prevent future deaths NHS Foundation Trust Northern House, 7 - 8 Talisman Business Centre, Talisman Road, Bicester, Oxfordshire, OX26 6HR Tel: 01869 365 000 Thank you for your letter dated 6th September 2016 enclosing your Regulation 28 report detailing your concerns relating to the PARAMEDIC 2 adrenaline trial. Concerns: To confirm the concerns that you directed towards the Trust, having heard evidence at the inquest in to the death of SH, you were not assured that there were enough warnings on the packaging of the trial drugs packs to remind staff of the categories of patients that should be excluded from being entered in to the trial. Actions taken: Since the inquest hearing, the Trust have been working with the University of Warwick (who are sponsor for the PARAMEDIC 2 trial) to provide you with a collaborative approach to rectify the concerns that you have raised. The matter was first discussed fully at the Paramedic-2 Trial Management Group (TMG) on 8th September 2016 where all five participating sites were represented. At this meeting an action plan was made to design an appropriate label detailing all of the exclusion categories' which would be placed on further issues of the trial drug packs. Following the meeting, a label was designed for this purpose and I am pleased to enclose a copy of the final design for your information. To ensure that any modifications to the trial drug packaging were not just made within the area covered by the South Central Ambulance Service (SCAS) the TMG decided to roll out their plans across all of the ambulance trusts taking part in the Paramedic-2 trial. The University of Warwick has therefore committed that by January 2017, all trial drugs in circulation will have the new labels affixed to the trial drugs bag or external bag. Registered Headquarters: 7 and 8 Talisman Business Centre, Talisman Road, Bicester 0X26 6HR

Having reviewed the final label design internally, SCAS have decided to purchase bespoke plastic bags with the label agreed by University of Warwick and the Paramedic 2 team, printed on to the bag. This will ensure that the exclusion criteria are clearly visible to our staff when first selecting the trial drug pack. Staff will also be reminded during training and by an internal memo of the importance of ensuring that they are aware of the exclusion criteria and the importance of checking the packaging to remind themselves immediately before the trial drugs are used. Whilst we have assured ourselves that appropriate training on the trial is already in place, the Trust considers that this additional warning will be a vital reminder to our staff when they are presented with the time critical pressures of a cardiac arrest. The Trust has instructed Midco Print & Packaging Limited to produce the new bags for us. SCAS has committed that by January 2017 that all trial drugs in circulation will have the new labels affixed to the trial drugs bag or external bag. We take all complaints and concerns seriously and I thank you for bringing your concerns to our attention. We can only improve our service by receiving this feedback and in this instance learning will have taken place and will also be disseminated to the rest of our staff. I hope that the actions discussed in this letter have assured you that the Trust has responded to your concerns appropriately, but if there are any issues that you wish to discuss further, please do not hesitate to contact me on the address at the top of this letter. Registered Headquarters: 7 and 8 Talisman Business Centre, Talisman Road, Bicester 0X26 6HR

Dear Mr Horsley Re: HM Coroner's Regulation 28 report to prevent future deaths: University of Warwick response write with reference to HM Coroners Regulation 28 report to prevent future deaths (the report') , written following the Inquest held on 30 August 2015 into the death of Ms. Samantha Hopkins: The report was issued on the 06 September 2016 but was not received until the 17 September 2016, with a covering letter from you dated the 16 September 2016. am responding on behalf of the University, but before SO, should like to take this opportunity to offer my sincere condolences to the family of Ms. Hopkins: The Inquest was informed that the medical cause of Ms. Hopkins' death was subdural haematoma; and subsequently concluded that Ms. Hopkins had died due to an accident. The Coroners Regulation 28 report raises two areas of concern with regard to Paramedic 2- The Adrenaline Trial (Paramedic 2') and respond to each of these below: It is useful when reading these responses to understand the wider context of Paramedic 2, in tems both of its clinical efficacy and the gap in knowledge that it seeks to answer; namely; whether the use of adrenaline is harmful or beneficial in the context of resuscitation after a cardiac arrest, therefore begin by providing this contextual background inforation: Adrenaline became the standard NHS clinical treatment for cardiac arrest over fifty years ago, pre- dating the robust evaluation that is now required for interventions to enter into routine clinical usage_ Over the past- years, a growing body of scientific evidence has questioned whether adrenaline is a safe and effective treatment in the context of resuscitation after a cardiac arrest This includes most recently a number of research studies which have suggested that whilst adrenaline may have a role in re-starting the heart; there is an overall reduction in post-hospital patient survival rates and an increase in the numbers of patients with severe brain damage [1]: Both the International Liaison Committee for Resuscitation (2015) and the body that sets the UK clinical guidelines for cardiac arrest; the Resuscitation Council (UK) (2015), have publicly noted the present lack of clarity around the potential harm, benefit; or benignity, of adrenaline, and have recommended that a large scale clinical trial be initiated to increase knowledge in this area [2]; [3]: doing five

Paramedic 2 is a national, year UK trial that has been funded by the National Institute for Health Research to provide these new insights. It has been authorised for delivery in the UK by the Health Research Authority, following review by an NHS Research Ethics Committee and by the Medicine Healthcare Regulatory Agency (References: HTA 12/127/126; Oxford C REC: 14/SCI0157; EudraCT: 2014-000792-11 respectively). trust that this background is useful contextual inforation, and now tum to each of the two matters highlighted by the report as matters of concern to which the University should respond: Coroners matter of concern (1J: That; 'although the South Central Ambulance Service (SCAS) staff participating in the Paramedic 2 Trial had been instructed as to the classes of patients to be excluded in the trial, and information was provided inside the trial drug packet about the exclusions, overlooked that pregnant women were expressly excluded and the exclusion warning inside the packet was also overlooked. If exclusions had been prominently listed on the outside of the packet, this oversight might have been avoided: That; 'the exclusions should be prominently highlighted on the outside of the trial drug packet University response: Our response with regards to the training of SCAS staff in the inclusion and exclusion criteria of the trial, is outlined within 'matter of concer (2)' below: With regards to the listing of exclusion criteria on the drugs packet, the present labelling complies with the relevant EU Directives 2001/20/EC, 2003/94/EC, and 91/356/EEC (inclusive of Annex 13) and has been reviewed and agreed by the Medicine Healthcare Regulatory Agency (MHRA): Whilst there is no legal or regulatory requirement for trial exclusions to be included on the labelling of Investigational Medicinal Products (IMP) , the Paramedic 2 trial team elected to go beyond these requirements and included two exclusions on the labelling, these being 'pregnant women' and 'individuals aged under 16' As a result of the Coroner's opinion on the matter of labelling, the University shall now include all four exclusion criteria on new labels that shall sit on the IMP bag or its external packaging_ have attached for your attention a copy of the labels that have been ordered, and which shall be distributed to all five Ambulance Services, with a direction that these must be applied to all IMP packaging; such that by January 2017, all IMP that is in circulation shall comply with this updated guidance_ The University manages the Paramedic 2 trial via our UK-CRC accredited trials unit; the Warwick Clinical Trials Unit (WCTU) , which has a comprehensive Quality Management System (QMS) for the delivery and oversight of clinical trials. As part of this QMS, annual Quality Assurance visits are delivery by the WCTU at each site , and compliance with the new trial labelling requirements shall be included in these visits going forward. Coroner's matter of concern (2) That the Coroner was "told in evidence that Warwick Medical School (which is responsible for the Paramedic 2 trial) had given the participating ambulance services no guidance on how the exclusions were to be highlighted to trial participants (i.e: the individual paramedics) and that this had been left to the ambulance services themselves. University response: Under the Paramedic 2 training programme, the University provides training to the Principal Investigator and Research Paramedics at each of the five participating Ambulance Services_ Subsequently_ and under the terms of an agreed Site Agreement;, each of the Sites provide training to all paramedics that shall be involved with the trial. This training specifically includes the trial inclusion and exclusion criteria. five they the

In addition, each Principal Investigator and participating Research Paramedic receive a copy of the Study Protocol, containing written confirmation of the trial inclusion and exclusion criteria. Amendments to the trial protocol; that require additional or revised training of participating paramedics, are communicated in writing to the Principal Investigators and Research Paramedics, via email, highlighting the amendments made These amendments are subsequently followed by the issuing of updated instructions by the five Ambulance Services in the form of bulletins, this in line with standard practice within the Ambulance Service Site adherence to the required training practices are included within the annual Quality Assurance reviews by the WCTU at each site, and the University therefore believes that a comprehensive programme of training is in place for all staff participating in Paramedic 2. However, as a result of the Coroner's observations on this matter, the University has instructed the participating Ambulance Services that a reminder should be issued to all participating staff, to reiterate the inclusion and exclusion criteria_ In order to provide additional assurance, compliance with this instruction shall be specifically audited by the WCTU during the annual Quality Assurance Site visits_ In summary, the University takes very seriously its responsibility as a Sponsor of clinical trials research; and the actions outlined in my letter demonstrate that we have carefully considered your report; both internally and in partnership with the participating Ambulance Services_ trust therefore that the steps we have outlined in regards to both the IMP labelling and training of participating paramedics, offer you the necessary assurances in both areas. However; please do not hesitate to contact me should you wish to discuss any element of your report; and the University's subsequent response to it, in more detail,