Colin Griffiths

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Medicines & Healthcare products

Regulatory Agency
Ms ME Hassell MHRA
Senior Coroner 10 South Colonnade
Inner North London Canary Wharf
St Pancras Coroner's Court yeh
Camley Street United Kingdom

London N1C 4PP

www.gov.uk/mhra

09 October 2018

Dear Ms Hassell,

Reference: regulation 28: Prevention of Future Deaths report — Collin Gary Griffiths

Thank you for copying to the MHRA, your report dated 4 September 2018, under paragraph 7,
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 other 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://www.mhra.gov.uk/spc-
pil/), and the electronic medicines compendium (https://www.medicines.org.uk/emc/)

The following recommendations are provided in the yellow fever vaccine (Stamaril) SmPC:
e 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.

e 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).

Medicines & Healthcare products
Regulatory Agency

MHRA

© oe % Regulating Medicines and Medical Devices

Very 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 days of vaccination. The risk appears to be
higher in those aged over 60 years although cases have also been reported in
other age groups. History of thymus dysfunction has also been recognized as
a potential risk factor (see Section 4.3).

STAMARIL must not be administered to immunosuppressed persons (see
Section 4.3).

e 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:

e 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.

e Asserious reaction affecting vital organs occurring within 10 days of vaccination is mentioned
as a 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 pain 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. All 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.

Medicines & Healthcare products
Regulatory Agency

: MHRA

Requiating Medicines and Medical Devices

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://www.gov.uk/drug-safety-update/live-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.

Yours sincerely,

aa on
a
Dr lan Hudson

Chief Executive
Medicines and Healthcare products Regulatory Agency

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Coroner ME Hassell
Senior Coroner

Inner North London

St Pancras Coroner’s Court
Camley Street

London

N1C 4PP

30th October 2018
Dear Coroner ME Hassell

Re: - Inquest of Collin Griffiths

Date of Incident — 23" March 2018

RECEIV

02 NOV 2018

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Head Office:

th Floor, City Exchange,
11 Albion Street,

Leeds, LS] SES

+44 (0)113 238 7500
+44 (0)113 238 7501
enquiries@masta.org
www.masta-travel-health.com

| 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 they 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. 1830630

mM Head Office:
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proven in travel health Leeds, LS] 5ES

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+44 (0)113 238 7501
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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

1. 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 to;
“Do you have any current medical conditions, including problems with your thymus gland”

This was subsequently extended further on 6" 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)”

2. Alink 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 they should have the vaccination, and who cannot have the vaccination.
This change happened on the 6" April 2018.

3. The traveler's vaccination record booklet has had the Yellow Fever side effects expanded
upon on the 17" August 2018.

4. Amandatory 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 27" July 2018.

5. Ashared learning event on the back of the incident in question has taken place with the lead
MASTA nurses across the country. This took place at the lead nurse meeting on the 11" July
2018. They were asked to cascade this learning to their broader clinical teams by the 31*
October 2018.

6. 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" April 2018.

Response to Concerns
e The medical questions, which are part of the 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 21X
Registered in England and Wales No. 1830630

Head Office:
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11] Albion Street,

proven in travel health Leeds, LS] SES

respected for more +44 (0) 113 238 7500

+44 (0)113 238 7501
enquiries@masta.org
www.masta-travel-health.com

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e Weare 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 they 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 they 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 21X
Registered in England and Wales No. 1830630

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a ‘eo 5 T @) 7th Floor, City Exchange,
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proven in travel health Leeds, LS1 SES

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+44 (0)113 238 7501
enquiries@masta.org
www.masta-travel-health.com

emma

medical questions were first changed on the 6" April 2018 and then again on the 16" July
2018. Further improvements are currently on the staging site (a test environment) ready to
go live w/c 29" October 2018.

e 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.

e 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 they go through their individual risk
assessment, preventing any misunderstanding - please see enclosed document 4. The draft
has been sent to the marketing team to format on the 26" October 2018

e We have written an audit for the nurses, to ensure that the assessments are being completed
in full, looking at how the risk assessment is conducted, but more specifically looking to
ensure the following actions are taken;

e The nurse asks that the client received the medical question factsheet.

e 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.

e The nurse is observed to give the client a copy of the medical questions, to read
through while she goes through the assessment.

e The nurse fully documents all the medical information given by the client, and areas
where they have asked for clarification.

e The nurse fully documents the names and advice given if they contact the medical
team.

e The nurse fully documents in the medical records if a vaccination cannot be given due
to a contraindication, and the further medical information that they have requested
from specialist if required.

e 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 9"" October 2018, please see enclosed document 5

e 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

la ma sta Head Office:

7th Floor, City Exchange,

11 Albion Street,

proven in travel health Leeds, LSI SES
respected for more r: +44 (0)113 238 7500
24 +44 (0)113 238 7501

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W: www.masta-travel-health.com

| 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

Yours sincerely

Emma Caudwell
General Manager

Registered Company Address: Sapphire Court, Walsgrave Triangle, Coventry, CV2 2TX
Registered in England and Wales No. 1830630