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

Tel: 0121 301 1086

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.

Dear Ms. Hunt; Thank you for your letter of 17 August to Matt Hancock about the death of Mr Ian Allen: am responding as Minister with responsibility for mental health services and am grateful for the additional time in which t0 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 learn 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 (NHSEI); 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 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'_ https Ilwwgov uklquidancelfind-product-information-about-medicines Safety; from from

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 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 patient 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 Update3 , 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 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 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 200g5. 2 A condition that causes a low white blood cell count https IlwwW gov ukldrug-safety-updatelclozapine-and-other-antipsychotics-monitoring-blood- concentrations-for-toxicity 4Maudsley Prescribing Guidelines. 13th edition: 2018 https Ilww gov ukldrug-safety-updatelsmoking-and-smoking-cessation-clinically-significant-interactions: with-commonly-used-medicines drug has drug they May

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 report have been added to the MHRA's adverse 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 monitoring6. 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 website8. NICE has advised that the concems 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 BNF9. 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 t0 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 Ilw judiciary uklpublicationslthomas-jackson-2L 7 A UK pharmaceutical reference book provided to eligible prescribers working in the NHS and other organisations that provide NHS-commissioned care in England bttps lwww nice org uklquidancelcg178/resources/2019-exceptional-surveillance-of-psychosis-and: schizophrenia-in-adults-prevention-and-management-nice-cq178-6718794445/chapter/Surveillance_ decision2tabzevidence https Ilbnfnice org ukldrug/clozapine htmlttimportantSafetylnformations drug your

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: 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 learing 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 concems to my attention. NADINE DORRIES My '