Ian Allen

Legal Department 
B1 – Unit 1 
50 Summer Hill Road  
Birmingham 
B1 3RB  

Tel:  0121 301 1086 

Mrs Louise Hunt 
Senior Coroner for Birmingham and Solihull 
50 Newton Street 
Birmingham 
B4 6NE 

Our Ref:  

Your Ref: Ian Allen 

Date: 6 October 2020 

Dear Mrs Hunt, 

Re: 

Prevention of future death report Mr Ian Allen 

Thank  you  for  your  letter  of  17  August  2020  in  relation  to  the  concerns  you  had  about  Mr 
Allen’s very sad death.  I would like to personally offer my sincere condolences to Mr Allen’s 
family. We have read and understood the points you have raised within your letter and have 
taken action in relation to this.   

I felt it would be helpful to set out for you the existing governance around the prescribing and 
monitoring of Clozapine across our Trust before advising you of additional controls that we 
have established following the concerns that you have raised.  

With regard to prescribing, monitoring and administering Clozapine we comply with the MHRA 
guidance and the guidance with regard to blood monitoring. There are a number of side effects 
of Clozapine and a particular risk with regard to agranulocytosis. As such, we follow a strict 
pre-initiation algorithm with regard to haematological monitoring.  Full blood count is thereafter 
monitored  weekly  for  18  weeks,  every  2  weeks  for  up  to  a  year  and  monthly  thereafter. 
Clinicians and pharmacy work with the National Monitoring Service in this regard. In relation 
to the monitoring of serum levels, we have followed the MHRA guidance. We undertake serum 
levels in a number of circumstances including whilst titrating the dose post initiation; where we 
have concerns regarding compliance or tolerability and where we are managing drug to drug 
interactions  or  changing  smoking  status.  A  key  issue  with  regard  to  serum  levels  is  that  a 
trough sample must  be taken in order  to  ensure 12  hours  have  elapsed since  last  dose of 
Clozapine  and  any  deviation  in  relation  to  the  12  hour  elapse  period  must  be  taken  into 
account when clinically interpreting the results. The doses and serum levels needed to get the 
best clinical outcome are highly variable, and there are situations in which a high serum level 
(i.e. >600) is the lowest which can be used without there being a deterioration in the patient’s 
mental state. Overall, it is important to consider the serum level as part of the overall clinical 
picture and balancing up all the various risks in the case, which are relevant to the particular 
patient. 

Having considered the findings of the inquest of Mr Allen and the regulation 28 report, we have 
explored further opportunities to strengthen our existing systems as follows:-  

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 1.  In February 2019 a blood test confirmed that Mr Allen had a high level of clozapine 
in  his  blood.  This  was  not  acted  upon  and  no  further  blood  test  was  taken.  The 
clozapine dose was not adjusted as it should have been.  

We have commenced an audit of all patients prescribed Clozapine on Dr 
’s caseload to 
ensure that there are no other patients for whom anomalous results have not been considered. 
In addition, we are in the process of issuing a practice alert to all of our Doctors reminding 
them of the importance of review when anomalous results are evident.  

We have existing Multi-Disciplinary team meetings in place across our organisation and are 
now specifically strengthening the focus on physical health within these meetings utilising a 
quality improvement approach. This will provide an additional system for checking that periodic 
tests have taken place, ensuring that they are routinely acted upon when they are abnormal. 
Clozapine has now been added to this project to increase awareness.  

In addition, we are working with our Post Graduate Medical Education training programme to 
utilise the learning from this regulation 28 report in the training of junior doctors on the use of 
clozapine and the importance of acting upon abnormal results where it is deemed necessary.  

2.  There was no system in place at the time to ensure blood test results were escalated 

to the consultant to ensure action was taken.  

There  is  a  system  in  place  whereby  anomalous  results  received  are  escalated  to  the 
Consultant, for example, via the Multi-Disciplinary Team meeting, the administrative staff in 
receipt of paper results or by junior medical staff who have checked electronic investigations; 
however  on  this  occasion  it  appears  that  this  failed.  We  have  therefore  put  in  place  an 
additional control  whereby our Information Team will send a report to the pharmacy Clozapine 
Lead of any results >600 so that these can be escalated directly to the Consultant  and the 
Divisional Pharmacist so that appropriate action can be taken.  This will include discussion 
and action where appropriate at the Multi-Disciplinary Team meeting.   

3. There was a general lack of understanding at the inquest about the importance of 
monitoring clozapine levels and how frequently these levels should be monitored.  

As you may be aware from the Mr 
s evidence at inquest; the Trust is currently in the 
process of reviewing and updating the Trust Clozapine guidelines following the investigation 
carried out into Mr Allen’s death.  We understand that on 26 August 2020, in response to the 
Prevention of  Future  death reports  from  the Coroner there  has  now  been  an  update  in the 
MHRA guidance in relation to Clozapine.  

The  new  guidelines  published  by  MHRA  are  in  fact  similar  to  the  current  Trust  guidance, 
although the wording of the monitoring level will be altered from ‘may be useful’ to ‘must be 
carried out when attempting to determine adequate dose during initiation, to establish recent 
adherence, managing tolerability problems, managing drug on drug interactions or change in 
smoking status, when using higher doses and when there is a systemic infection’.   

This guidance will be approved in November 2020 and once this has been completed, this will 
be disseminated round the Trust as a reminder to other staff to ensure that they are complying 
with the updated guidance.  We have already provided all pharmacists with some additional 
training  on  Clozapine  so  we  have  more  consistent  advice  and  can  respond  quickly  where 
necessary.  

 
 
 
 
 
 
 
 
 
   
 
 
 
 
 In addition, as we set out in response to your first point, further education will be built into the 
Post Graduate Medical Education programme to address any gaps in knowledge on clozapine. 
A safety alert is also being drafted and sent to all clinicians so that immediate action can be 
taken where necessary.  

I would like to take this opportunity to say that we are taking this matter very seriously and are 
working hard  to  ensure  that  the  correct  processes  are  in place to  support  both  learning for 
staff  and  ongoing  care  for  patients  who  are  prescribed clozapine to prevent re-occurrence.  
Patient safety is very important to us as an organisation.  

If you require any further information, please do contact me. 

Yours sincerely  

Chief Executive

c From Nadine Dorries MP

Dep artment Minister of State for Patient Safety,

Suicide Prevention and Mental Health

of Health & 39 Victoria Street
Lond
Social Care SWIHOEU
020 7210 4850
Your Reference:
Our Reference:
Ms Louise Hunt
HM Senior Coroner, Birmingham and Solihull
HM Coroner's Court
50 Newton Street
Birmingham B4 6NE
17 November 2020

Dear Ms. Hunt,

Thank you for your letter of 17 August to Matt Hancock about the death of Mr lan Allen. |
am responding as Minister with responsibility for mental health services and | am grateful
for the additional time in which to do so.

First, | would like to say how saddened | was to read of the circumstances of Mr Allen's
death and | extend my condolences to Mr Allen's family and loved ones at this difficult
time. We must do all we can to leam from Mr Allen's death to avoid such tragedies from
occurring again.

In preparing this response, my officials have taken advice from NHS England and NHS
Improvement (NHSE]), the National Institute for Health and Care Excellence (NICE) and
the Medicines and Healthcare products Regulatory Agency (MHRA).

As you may be aware, the MHRA is responsible for the safety of medicines and medical
devices. The MHRA seeks independent expert advice from the Commission on Human
Medicines (CHM) which advises on whether the overall balance of benefits and risks of
medicines is favourable at the time of licensing and remains so thereafter.

The MHRA advises that detailed guidance regarding the monitoring requirements for
clozapine is provided in the authorised product information which consists of the Summary
of Product Characteristics (SmPC) for prescribers and the Patient Information Leaflet (PIL)
which is supplied with each pack of medicine. The SPC and the PIL for licensed
medicines (including clozapine) can be downloaded from the MHRA website’.

The patient monitoring requirements for clozapine include the measurement of clinical
parameters such as regular full blood counts; blood pressure; electrocardiograms; hepatic
enzymes; blood sugar; lipids and weight. Therapeutic drug monitoring of blood plasma
levels is not currently required under the terms of the clozapine marketing authorisation.

| am informed by the MHRA that following the issue of two previous Prevention of Future
Deaths reports that raised concerns about the need for monitoring of clozapine blood
levels, and monitoring antipsychotic blood levels during long-term high-dose antipsychotic
use, Expert Advisory Groups (EAGs) of the CHM considered safety data for clozapine and
other antipsychotic drugs.

The EAGs advised that blood concentrations of clozapine should be monitored for toxicity
in certain clinical situations. For example, when a patient stops smoking or switches to an
e-cigarette, concomitant medicines may interact to increase blood clozapine levels; when
a patient has pneumonia or other serious infection; and when poor (reduced) clozapine
metabolism is suspected, or toxicity is suspected. | can confirm that the UK product
information for clozapine has now been updated to include this advice on monitoring blood
clozapine levels for toxicity. If blood clozapine level monitoring is carried out, this should
be in addition to the required blood tests to manage the risk of agranulocytosis?.

The EAGs also advised that, where assays (a laboratory investigative procedure) and
suggested reference values are available, blood level monitoring of other antipsychotic
drugs may be helpful in certain circumstances.

Following the outcome of these reviews, the MHRA communicated advice on monitoring
blood concentrations of clozapine and other antipsychotics in the August 2020 edition of
Drug Safety Update’, which is the MHRA’s monthly newsletter for healthcare professionals
about medicines safety. The MHRA worked with the Royal College of Psychiatry and
authors of the Maudsley Prescribing Guidelines on the recommendations to healthcare
professionals in this article.

The DSU article focuses on drug blood level monitoring for toxicity of clozapine and other
antipsychotics. It is recognised that blood level monitoring of these medicines can be
beneficial in the care and management of patients, particularly those with treatment-
resistant conditions*. For example, monitoring of blood clozapine levels may be useful
when a patient starts (or re-starts) smoking as this may lead to a decrease in blood
clozapine levels and dose adjustment may be necessary. The PIL for clozapine advises
patients to tell their doctor if they smoke and that sudden changes in the patient's smoking
habits can change the effects of clozapine. The MHRA communicated advice on smoking
and smoking cessation and clinically significant interactions with commonly used
medicines, including clozapine, in October 20095.

2 A condition that causes a low white blood cell count.

concentrations-for-toxicity
4Maudsley Prescribing Guidelines. 13th edition. May 2018

5 https:/(www.gov.uk/drug-safety-update/smoking-and-smoking-cessation-clinically-significant-interactions-
with-commonly-used-medicines

One of the ways in which the MHRA monitors the safety of licensed medications is through
the Yellow Card Scheme which receives information from both healthcare professionals
and patients on side effects suspected to be associated with medicines. The concerns in
your report have been added to the MHRA’s adverse drug reaction (ADR) database under
Yellow Card reference number ADR 24519396.

Prescribers are expected to follow national medicine guidance as well as the SmPC when
making prescribing decisions. In 2019, NICE conducted a surveillance review of Clinical
Guideline 178 Psychosis and schizophrenia in adults: prevention and management in
which it considered, among other matters, the concerns highlighted in a previous
Prevention of Future Deaths report in relation to clozapine monitoring®.

NICE advises that while it is recognised that the current recommendations in the NICE
guideline may not fully take account of the adverse effects and risks of toxicity associated
with the use of clozapine, these are specified in detail in the British National Formulary’
and, as already explained, the SmPC for prescribers which contains advice on interactions
that can influence blood levels of clozapine.

The topic experts conducting the surveillance review recommended an update to NICE
clinical guideline 178 was not required. The considerations and the outcome of the NICE
surveillance review are published on the NICE website®. NICE has advised that the
concerns in your report have been logged against clinical guideline 178, to be revisited
when the guideline is next considered for review.

| am further advised that NICE has liaised with the publishers of the BNF (the British
Medical Association and the Royal Pharmaceutical Society) regarding the appropriateness
of updating the BNF information on clozapine to highlight the MHRA’s recent Drug Safety
Update. This change is now reflected in the BNF®.

In addition, you may wish to note that NHSEI will ensure that all guidance relevant to
clozapine prescribing and the risks associated with toxicity are shared with primary and
acute NHS care through its established networks.

In relation to the local response to your report, | am advised that the Birmingham and
Solihull Mental Health NHS Foundation Trust has responded to your report to explain that
it has undertaken a review and update of its guidance on the use of clozapine to reflect the
MHRA update in August 2020. | am further advised that the Trust has taken additional

§ https://www. judiciary .uk/publications/thomas-jackson-2/

7 A UK pharmaceutical reference book provided to eligible prescribers working in the NHS and other
organisations that provide NHS-commissioned care in England

® https://www.nice.org.uk/quidance/cq178/resources/2019-exceptional-surveillance-of-psychosis-and-

schizophrenia-in-adults-prevention-and-management-nice-cq178-6718794445/chapter/Surveillance-
decision?tab=evidence

® https://bnf.nice.org.uk/drug/clozapine.html#importantSafetyInformations

measures, such as additional training and education for pharmacists and post-graduate
medical practitioners on clozapine; an audit of patients currently prescribed clozapine; and
to include clozapine in a strengthened focus on physical health at multi-disciplinary
meetings. | welcome the action taken by the Trust and encourage the Trust to continue to
take forward the learning from Mr Allen’s death.

Finally, | note that you copied your report to national oversight organisations, NHSEI and
the Care Quality Gommission. My officials have also brought your report to the attention of
the Healthcare Safety Investigation Branch (HSIB) to support its intelligence monitoring of
patient safety risks in relation to NHS-funded care in England. HSIB is the body
responsible for conducting independent investigations of serious patient safety incidents in
NHS-funded care across England, with a specific focus on system-wide leaming and
improvement. HSIB decides what to investigate based on intelligence from a number of
sources about patient safety risks, and according to set criteria.

| hope this response is helpful. Thank you for bringing your concerns to my attention.

tee

NADINE DORRIES