Dear Mrs Hunt,

RE: Prevention of Future Deaths Report for Mr Khalid Mohammed Hussian (deceased)

Further to the Prevention of Future Deaths Report dated 12th July 2023, the Trust has now had an opportunity to review the Matters of Concern you have raised within the same. I would first like to begin by offering my sincere condolences to the Family of Mr Hussain for his very sad loss. As a Trust we have taken your concerns very seriously and have aim to act on these issues as quickly as possible to ensure lessons are learned to benefit other patients in the future. I will respond to each issue in turn;

1. Monitoring of clozapine levels

All blood test results including plasma clozapine assays are available from within Rio by a link to the 'ICE' results system provided by the laboratory. In addition, all raised plasma clozapine assay results are reported to a specialist report that pharmacy staff have access to. These results are reviewed by the trust lead clozapine pharmacists. Where appropriate, the lead clozapine pharmacists contact the responsible clinician and team manager to highlight the result and need for the patient’s clozapine treatment to be reviewed, particularly regarding dosage. It is especially important to ensure the result is ‘trough’ value i.e. the sample was taken around 12 hours following the last dose. This ensures accurate interpretation. A number of training elements are being planned:
1. A recorded webinar by a consultant psychiatrist and pharmacist with significant experience in the use of clozapine will be taking place on 8 September 2023 and will be available for all clinical staff to improve the knowledge around clozapine including

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interpreting plasma levels and what to do with them. This will also be available on the Trust Intranet for anyone who cannot attend on that date.
2. Development of a series of e-learning modules on the trust e-learning platform form the Learn It Online resource www.learnitonline.co.uk. Clinical staff will be able to access these as part of their on-going training to improve knowledge around clozapine. This is anticipated that the team will be able to take this to the Learning and Development Team by September 2023.
3. The Trust has multidisciplinary experts on the subject of clozapine. There is also expertise in the Pharmacy Clozapine Team; to support follow up of raised clozapine plasma assays but more importantly to support all teams involved with the use of clozapine with training in the handling of clozapine and promotion of the trust clozapine prescribing guidelines and procedures. This team is expected to be established by September 2023. All these colleagues will be made known to staff for any advice that is needed. Staff can also ask for help through their manager, who can signpost them accordingly. This will help improve the skills and experience in responding to results on clozapine levels appropriately with the care of the patient at the centre of all decisions.

2. Medication Changes

As part of the learning there will be clear guidance on prescribing on the electronic system and communication of how best to do this when a dose change is required. Where a clinician may be new to the Trust there will be clear instructions to ask for support at the time of need and the line manager, team managers and clinical director will have processes in place to guide them to ensure they have the right advice. The staff involved in this case are being asked to have reflective conversations around learning from this case.

3. How to record high clozapine levels

All blood test results are made available to staff in the ICE system, which is provided to us by our pathology service provider. This system is used both for ordering tests and reviewing results. It is accessed from within Rio and in patient context, so all staff have ready access to results. In common with most other systems, abnormal results are indicated within the system along with the normal reference range.

Clozapine levels are the only lab result which have a mechanism of routine reporting of high levels with pharmacy review and as such it has the greatest safeguards around it of any test used by BSMHFT.

The additional steps which are also mentioned in point one will ensure that clinicians will understand how to interpret results and actions are taken, in cases where this is necessary.

4. Understanding of clozapine

The Training is aimed to be in place to ensure that staff are confident in the use of clozapine and its monitoring in the future. We have sent an email to all prescribers about the need to record about decisions of care following a clozapine result that may be out of range, the need to ensure there is clinical review and this is documented.

5. August 2020 Regulation 28 Report

Following the last PFD in August 2020 the Trust made significant changes to the processes and procedures surrounding clozapine and its use. However this case has highlighted areas of learning. Consequently, the Trust has now put into place an urgent learning session along with future planned training and development to ensure staff keep up to date with this and learning is refreshed, alongside other additional support systems that have previously been introduced.

6. Quality of internal investigation process

Serious Incident investigations are carried out under the Serious Incident Framework (2015) and are conducted for the purposes of learning to prevent recurrence. As part of this investigation expert opinion was sought from our Specialist Clozapine Pharmacist;

, which were included within the body of the RCA and reflect a number of the issues you have raised. As a Trust we would like to assure you that we have governance processes in place which provides oversight of the quality of our serious incident investigations and input into the recommendations based on the learning the investigation has found. In this case the learning points were:
• The system for escalation of clozapine levels and monitoring and implementation of plan were not followed.
• Record keeping was not of a standard as expected.
• Clinicians were not clear on coordination of prescribing, ordering and delivery processes as part of EPMA and discussion via MDT was not used to clarify and ensure prompt action.
• There was a lack of understanding of how clozapine levels are to be interpreted and actioned. On this occasion the following actions were identified and carried out:
• For there to be a review of the governance processes for the management of clozapine using the safety summit approach. In the short term as a mitigator the pharmacy team have prioritised the reviewing of the assay levels and the communication to consultants
• To improve the quality of record keeping the division has been working to establish a set of MDT standards is therefore recommended that the lead for this work provides an update to the local governance committee on progress and that the team manager ensures the projector is fixed and in the meanwhile alternative methods used to ensure this is done to a good standard.
• Given the service users care needs; a carers assessment should have been offered to the family. As a Trust this is a recognised area of improvement across all services and to support this piece of work there will be a review of the carer engagement tool. However, in the short term the team should have bespoke session from our carer engagement team.

7. Pharmacy Resourcing

As already mentioned in the first point, the Trust is developing a specialist Pharmacy Clozapine Team which will be closely linked into the trust multidisciplinary team,gro which should assist in ensuring that any concerns in the future will be acted upon and that where areas are identified where there is a lack of understanding, this team can support with learning to ensure that Service Users receive the best possible care.

Dear Mrs Hunt, Regulation 28 Report concerning Mohammed Khalid Hussain Thank you for your report dated 12th July 2023, in which you asked the Secretary of State for Health to provide a response to the Regulation 28 Report to Prevent Future Deaths following the inquest into the sad death of Mr Mohammed Khalid Hussain. Your request has been passed to the Medicines and Healthcare products Regulatory Agency (MHRA) as we are the regulator of medicines, medical devices and blood components for transfusion in the UK. We would like to extend our sincere sympathies to the family of Mr Hussain for their loss. Your report identified a number of matters of concern, including the following points relating to clozapine:
1. There is no clear system for monitoring actual clozapine or clozapine levels and there is no safe system to communicate high levels of clozapine;
2. In this case, the patient’s consultant indicated that clozapine should be reduced on the next prescription, and this was communicated by email, but this was not read or acted upon. You note that the inquest heard there was no safe system to effect medication changes;
3. That clozapine and norclozapine levels are recorded in the pharmacy section of the records but there was no system in place for highlighting high clozapine levels;
4. That there was a lack of understanding of when to measure clozapine levels, how to interpret high clozapine levels and how to respond to these;

5. You note that a Regulation 28 report was sent in August 2020 which identified that there was no system in place to ensure abnormal clozapine levels were escalated and acted upon and there was a lack of understanding of the importance and frequency of clozapine monitoring;
6. You raise concerns about the quality of the internal investigation process and whether it can identify central issues in a particular case;
7. That the processes within the pharmacy were not effective due to a lack of resources. The MHRA is an executive agency of the Department of Health and Social Care (DHSC) with responsibility for the regulation of medicinal products in the UK. The MHRA ensures that medicines are efficacious and acceptably safe, and that any possible side effects which have been recognised to occur with use of a medicine are appropriately described in the authorised product information. This comprises the Summary of Product Characteristics (SmPC, intended for healthcare professionals), labelling, and Patient Information Leaflet (PIL, provided to patients in each medicine pack). The SmPC is a source of advice for healthcare professionals (HCPs) on the safe and effective use of a medicinal product. We have considered the evidence provided and the circumstances leading to Mr Hussain’s death. It is noted that he was established on clozapine in 2004 and in October 2022 a decision was made to reduce his medication, but this did not occur. As you note, there is a well-established system in place for monthly monitoring of white blood cell count in patients who are receiving clozapine. The MHRA has previously been alerted to a fatal case involving clozapine toxicity. This issue was reviewed and considered by our expert advisory committee. In August 2020, the MHRA issued a Drug Safety Update article advising monitoring of blood concentrations of clozapine for toxicity in certain clinical situations (Clozapine and other antipsychotics: monitoring blood concentrations for toxicity - GOV.UK (www.gov.uk). These include when: a patient stops smoking or switches to an e-cigarette; concomitant medicines are prescribed which may interact to increase blood clozapine levels; a patient has pneumonia or other serious infection; reduced clozapine metabolism is suspected, or toxicity is suspected. The advice of the MHRA and the Commission on Human Medicines is that clozapine blood concentration monitoring should be carried out in addition to the required blood tests to manage the risk of agranulocytosis. It is important to note that the terms of the SmPC do not impose drug level monitoring and this is an optional measurement. Any monitoring of clozapine plasma levels is done on an individual basis due to inter-patient variability and the SmPC does not define safe upper limits. The SmPC highlights certain clinical situations when blood clozapine level monitoring is advised as outlined above. Clozapine is well known to be associated with cardiac toxicity and the SmPC lists extensive information regarding this, including cases of fatal myocarditis and myocardial infarction. Unfortunately, it is not within our remit to comment on the clinical care in specific cases. Similarly, we are not able to comment on the quality of the internal investigation process or pharmacy resourcing. We will continue to keep the issue of monitoring for clozapine toxicity

under close review, including reviewing Yellow Card cases and we will be writing to the marketing authorisation holders to investigate further thresholds for clozapine toxicity.