Colin Griffiths

Dear Ms Hassell; Reference: regulation 28: Prevention of Future Deaths report - Collin Griffiths Thank you for copying to the MHRA your report dated September 2018, under paragraph schedule 5, of the Coroners and Justice Act 2009 and regulations 28 and 29 of the Coroners (Investigations) Regulations 2013, concerning the death of Mr. Collin Gary Griffiths_ Further to the information provided on this tragic case, we have considered whether the statutory information currently provided by the marketing authorisation holders for prescribers (and patients) on the safe use of this vaccine is adequate, and whether any ther regulatory measures could be taken to minimise the risk of yellow fever vaccine-associated viscerotropic disease in those for whom the vaccine is contraindicated_ Information on the use of medicines is provided to healthcare professionals through the Summary of Product Characteristics (SmPC) and to patients through the Patient Information Leaflet (PIL): Full details of the SmPCs and PILs may be found on the MHRA's website (http IIWWW mhraqovUklspc_ pill) , and the electronic medicines compendium (https IIwWmedicines org_uklemcl) The following recommendations are provided in the yellow fever vaccine (Stamaril) SmPC: Section 4.3 (contraindications) History of thymus dysfunction (including myasthenia gravis, thymoma_ thymectomy); Immunosuppression, whether congenital, idiopathic or as a result of treatment with systemic steroids (greater than the standard dose of topical or inhaled steroids) . radiotherapy or cytotoxic drugs. Section 4.4 (warnings and precautions) Before considering administration of yellow fever vaccine, care should be taken to identify those who might be at increased risk of adverse reactions following vaccination (see Section 4.3 and below). Gary

Medicines & Healthcare products MHRA Eocnt Ldrji Detcet Regulatory Agency rarely, Yellow Fever Vaccine-Associated Viscerotropic Disease [YEL- AVD] resembling fulminant infection by wild-type virus has been reported following vaccination (see Section
4.8)- The mortality rate has been around 60%. To date, most of cases of YEL-AVD have been reported in primary vaccinees with an onset within 10 of vaccination. The risk appears to be higher in those aged over 60 years although cases have also been reported in other age groups of thymus dysfunction has also been recognized as potential risk factor (see Section 4.3). STAMARIL must not be administered to immunosuppressed persons (see Section 4.3). ~"' Section 4.8 (undesirable effects) Cases of viscerotropic disease (known as yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and formerly described as "Febrile Multiple Organ-System Failure") have been reported following vaccination with yellow fever vaccines, some of which have been fatal. In the majority of cases reported, the onset of signs and symptoms was within 10 days after the vaccination. Initial signs and symptoms are non-specific and may include pyrexia, myalgia , fatigue_ headache and hypotension, potentially progressing quickly to liver dysfunction with jaundice, muscle cytolysis thrombocytopenia and acute respiratory and renal failure (see Section 4.4). YEL-AVD is listed as an undesirable effect that may occur very rarely (at a frequency of <1/10,000) The Patient Information Leaflets for the yellow fever vaccine provides the following recommendations: Patients should inform their doctor or nurse if they have a history of problems with their thymus gland or have had their thymus gland removed for any reason. A serious reaction affecting vital organs occurring within 10 of vaccination is mentioned as possible side effect, that can have a fatal outcome_ with the yellow fever vaccine_ The reaction can resemble an infection with the yellow fever virus and the signs may include: feeling tired, fever, headache muscle and sometimes low blood pressure: It may then go on to a severe muscle and liver disorder, drops in number of some types of blood cells resulting in unusual bruising or bleeding and increased risk of infections, and loss of normal functioning of the kidneys and lungs On review of this information, and in relation to actions within the remit of the MHRA, we are satisfied that the statutory SmPC and PIL for yellow fever vaccine provides relevant contraindications and warnings to minimise the risk of use in those with a history of thymus dysfunction_ The general view of the MHRA (in relation to all vaccines and medicines) is that PILs should be provided to patients parents or vaccinees when a vaccine or medicine is given, and that provision of the PIL would also be valuable as part of the informed consent process and discussions with patients about the benefits and risks of their vaccines and medicines. Ail PILs now also carry information on how to report possible side effects to the MHRA, and patients, parents or vaccinees should be made aware of this mechanism. Very days History days pain

Medicines & Healthcare products MHRA Regulatory Agency As you are aware, yellow fever vaccine is a live vaccine, containing a small amount of attenuated (weakened) virus which mimics a natural infection_ Live attenuated vaccines should not be given to people who are clinically immunosuppressed due to the risks of over-replication of vaccine virus_ You may wish to be aware that; following other recent reports of fatal events in immunocompromised patients who inadvertently received live shingles vaccine, the MHRA issued a reminder of this general risk of live vaccines to healthcare professionals via its Drug Safety Update (DSU) bulletin in April 2016: https Ilw gov_ukldrug-safety-updatellive-attenuated-vaccines-avoid-use-in-those-who-are_ clinically-immunosuppressed As there have now been three fatal cases reported to uS we intend to issue a further reminder about the risks of live vaccines in immunocompromised patients , including Yellow Fever vaccine in Drug Safety Update. Finally, for your reference the report of Mr Griffiths' adverse reaction to Yellow Fever vaccine has been added to the MHRA's Yellow Card database with the reference ADR 23432502_

Dear Coroner ME Hassell Re: Inquest of Collin Griffiths Date of Incident - 23rd March 2018 write further to the inquest of Mr Collin Griffiths, which concluded on the 30" August 2018 and the Regulation 28 Report to Prevent Future Death, issued by Coroner ME Hassell: Firstly, on behalf of everyone at MASTA Ltd wish to express our sincerest condolences to Mr Griffith's family. During the inquest the evidence revealed matters giving rise to concern of a risk that future deaths could occur unless action is taken_ The matters of concern are as follows:
1) The recording of medical conditions was entirely dependent on verbal communication, which in this instance was sub optimal. Would there be anything to stop MASTA handing out a tick box questionnaire (similar to the ones for blood donors) for patients to fill in while are waiting to be seen? There seems to be a need for an added layer of security, rather than just relying on patients listening to a long list of conditions read out.
2) MASTA currently has no way of auditing whether the record a nurse makes is accurate_ This could be assessed by questioning patients as they leave or by sending in a patient specifically to test this anonymously As a company we treat any incident seriously and have acted swiftly to re-evaluate our policies, procedures and systems to ensure we are providing the best possible care to our patients. Set out below is our response to those specific concerns identified by Coroner ME Hassell (detailed above) in Registered Company Address: Sapphire Court, Walsgrave Triangle, Coventry, CV2 2TX Registered in England and Wales No. 830630 Floor, they

masta Head Office: ' .' 7th Floor, City Exchange, Albion Street, proven in travel health Leeds, LSI SES respected for more T: +44 (0) 113 238 7500 +44 (0) 113 238 7501 E; enquiries@masta.org W: www masta-Ircvel-heallhcom the Prevention of Future Death report The improvements made/proposed relate to those of concern by the Coroner but also extend beyond. Actions completed prior to the _inquest Medical questions were reviewed, and the thymus question, which at the time of the incident read; "Do you have any current medical conditions with the pop up prompts for the nurse highlighting that the thymus gland was a contra- indication and should be further explored. This was then changed "Do you have any current medical conditions, including problems with your thymus gland" This was subsequently extended further on 6th April 2018 to be a separate question "Do you have problems with your thymus gland, or have you had a thymectomy (removal of the thymus gland) A link to the NaTHNaC site for Yellow Fever was put on the MASTA Travel Health Brief: The link goes directly onto the Yellow Fever information for travelers page, which discusses areas of concerns, when should have the vaccination, and who cannot have the vaccination: This change happened on the 6'h April 2018. The traveler' s vaccination record booklet has had the Yellow Fever side effects expanded upon on the 17th August 2018 mandatory thymus training module on the function of the gland, disease and disorder and when and why it would be removed has been developed and completed by all MASTA nurses who carry out all the risk assessments and provide medical advice to other Health Care Professionals within the MASTA network_ This was issued on the July 2018. shared learning event on the back of the incident in question taken place with the lead MASTA nurses across the country. This took place at the lead nurse meeting on the 11th July
2018. They were asked to cascade this learning to their broader clinical teams by the 31st October 2018_ The contraindications to the Yellow Fever vaccine were highlighted and moved to the top of the Patient Group Directive for Stamaril (the yellow fever vaccination product name) and reissued to all MASTA nurses. This happened on the 6"h April 2018. Response to Concerns The medical questions, which are part ofthe risk assessment; have been further reviewed and changed, to break the medical questions down into individual parts, to ensure that they cannot be missed from a list of conditions please see enclosed document 1 & 2. The Registered Company Address: Sapphire Court, Walsgrave Triangle, Coventry, CV2 2TX Registered in England and Wales No. 1830630 to; they 27th has

Head Office: masta 7th Floor, City Exchange, 11 Albion Street; proven in travel health Leeds; LSI SES respected for more T: +44 (0)113 238 7500 F: +44 (0) 113 238 7501 E: enquiries@masta.org W: www masta-travel-health.com We are currently testing digital pads to obtain a written signature that can be stored in our bespoke medical records system_ The intention is that this would be signed by the client once all the medical questions have been covered as a declaration that they have understood the questions asked and that they have read from the laminated question document: We acknowledge that the coroner has suggested each patient complete a tick box questionnaire whilst waiting for their consultation: We do not feel this would be as effective as all the improvements detailed above. From experience patients turn up last minute for their appointments and would not therefore have the required time to digest and complete the medical questions. There is also the risk that questions without the context and ability to ask questions of a medical professional could lead to errors. The MASTA governance team are in agreement that we should focus on ensuring that the nurse is undertaking a full risk assessment, using the enhanced medical questions, which the patient should be familiar with as they will going forwards have received them in advance document 3,and be presented with them to read during the consultation alongside the nurse asking the questions document 4 The intention is that will then digitally sign at the end of the consultation to declare that they have understood all the medical questions and that they agree the information they have provided is accurate. The nurse audit will further seek to confirm that these steps have been followed by the nurses document 5_ would also like to add, that our clinical governance framework, coupled with increased awareness, has continued to prevent any further deaths of this nature: During one particular recent risk assessment the nurse determined, through the medical questions that the patient had undergone cardiac surgery: Whilst the client required the Yellow Fever vaccination the nurse did not give it, instead asking for a specialist letter_ This letter confirmed that the patient's thymus gland had been removed during cardiac surgery: The client was not aware that the thymus had been removed in surgery. We have also had 2 children through our clinics, who have had cardiac surgery in infancy: After reviewing their surgical records it was confirmed that both children had had their thymus gland removed and neither of the parents were aware of the removal of the gland. The nurse informed the parents to contact their GP and ask them to highlight it in their child's records for the future. These cases prompted the nurse to raise the issue with our governance team who have subsequently contacted NaTHNaC to see if can work to ensure surgeons are aware of the risk and to fully highlight it in a patient's medical notes for their GP have highlighted the examples above to show the positive impact of all the actions undertaken, and to show how our nurses are raising awareness in response to the shared learning and training updates they have received, to mitigate the event of any such events reoccurring in the future_ Registered Company Address: Sapphire Court, Walsgrave Triangle, Coventry, CV2 2TX Registered in England and Wales No. 1830630 they they

Head Office: masta 7lh Floor, Cily Exchange, Albion Street proven in travel health Leeds, LSI SES respected for more T: +44 (0J113 238 7500 F: +44 (0) 113 238 7501 E: enquiries@masta.org W: wwwmasta-travel-healthcom medical questions were first changed on the 6th April 2018 and then again on the 16th July
2018. Further improvements are currently on the staging site (a test environment) ready to go live w/c 29*h October 2018_ We have written a fact sheet detailing all the medical questions that a traveler will be asked during the consultation and the reasons why the questions are important; This fact sheet will be emailed out to travelers before their consultation, along with the Travel Health Brief please see enclosed document 3. This factsheet is currently going through final review stage before going live. The clinics will be provided with the new medical questions in a laminated document to be given to travelers to read through with the nurse, as go through their individual risk assessment; preventing any misunderstanding please see enclosed document 4, draft been sent to the marketing team to format on the 26th October 2018 We have written an audit for the nurses, to ensure that the assessments are completed in full, looking at how the risk assessment is conducted, but more specifically looking to ensure the following actions are taken; The nurse asks that the client received the medical question factsheet_ The nurse reads an opening statement before the medical questions are asked to highlight the importance of giving their full medical history as we do not have access to medical records_ The nurse is observed to give the client a copy of the medical questions, to read through while she goes through the assessment The nurse fully documents all the medical information given by the client; and areas where have asked for clarification: The nurse fully documents the names and advice given if contact the medical team. The nurse fully documents in the medical records if a vaccination cannot be given due to a contraindication, and the further medical information that have requested from specialist if required. The nurse is observed to give and fully document post injection advice and possible side effects and that the travel passport has been given for future reference_ This was completed on the 9th October 2018, please see enclosed document 5 Face to face audits have been carried out at selected clinics in October and this will be alternated monthly going forwards to ensure that all clinics are covered; then this will be reviewed and any clinics of concern will be issued with an action plan and re- audited; this will work on a rolling basis. Previously this had been a bespoke audit, but has now been written to ensure consistency, in re-audit: Re-audits of 3 clinics have been scheduled during November 2018, Registered Company Address: Sapphire Court, Walsgrave Triangle, Coventry, CV2 2TX Registered in England and Wales No. 1830630 they The has being they they they

Head Office: masta 7lh Floor, Cily Exchange, 11 Albion Street, proven in travel health Leeds, LS1 SES respected for more T: +44 (0) 113 238 7500 A: +44 (0)113 238 7501 E: enquiries@masta.org W: www masta-travel-healthcom hope that this response provides you with sufficient assurance that we have acted with diligence, thoroughness and commitment to ensure necessary actions have taken place/will take place to reduce the likeliness of a repetition of the tragic accident that led to the issuing of this Prevention of Future Death report Finally, we believe that all other UK Yellow Fever Vaccination Centre's should be required to take similar preventative steps to ensure that a similar event does not occur within their clinical settings, with NaTHNaC taking the lead to implement such initiatives as described by us_ If you have any further questions please do not hesitate to contact me