Ensuring patient safety within ‘managed access’: crizanlizumab

Author: Chris Bird

Introduction
Promising clinical evidence suggested that crizanlizumab can reduce the incidence of vaso-occlusive crises in patients with sickle cell disease. There is uncertainty about its long-term efficacy (including after stopping the treatment) and cost effectiveness. The National Institute for Health and Care Excellence (NICE) recommended that it be used in the NHS in England only as part of a managed access agreement. The managed access agreement permits time-limited access to crizanlizumab while additional real-world and trial data are collected to address uncertainties. 

Background
Sickle cell disease is an inherited condition causing lifelong abnormality of haemoglobin production. Most people affected are of African or African-Caribbean origin, although the sickle gene is found in all ethnic groups. Homozygous sickle cell disease has a significant impact on quality of life and mortality. As NICE’s evidence-based guidance highlights: ‘there is an unmet need for effective treatments for people with sickle cell disease. They also face health inequalities because the condition is not well understood, results in disability, and is more common in people of African or African-Caribbean family origin, who tend to have poorer health outcomes than other ethnicities’. Recent research on social media posts has found that healthcare professionals continue to be critical of the health inequities present in the early diagnosis and treatment of sickle cell disease.

It is estimated that there are between 12,500 and 15,000 people living with sickle cell disease in the UK. The epidemiology of sickle cell disease in the UK is now better understood, and documented prevalence of the disease has increased since the introduction of the NHS Sickle Cell and Thalassaemia Screening Programme.

Sickle cell disease is characterised by the sickling shape of the red cells, causing painful intermittent clumping and blockages in the small blood vessels. These are called vaso-occlusive crises (VOCs). Crizanlizumab aims to reduce the frequency of VOCs by preventing interaction between endothelial cells and blood components involved in the blockages. 

NICE estimated that 314 patients (year 1) and 470 (year 2) in England could benefit from access to the drug in a managed access agreement.

Each project in NICE’s Managed Access programme is supported by an oversight group, which receives monthly monitoring reports (for safety and efficacy) and evidence updates on the use of crizanlizumab in practice. Real-world and trial evidence suggest a ‘no benefit’ efficacy concern, and identified a significant drop-out rate, with some people experiencing an increase in VOCs (a safety concern). NICE's Patient Safety Oversight Group required interim review of the managed access agreement.

The safety indicator was referred to NICE’s cross-institute Patient Safety Oversight Group for review. The safety group requested clarity on timelines for the review of efficacy concerns, which was dependent on other organisations, including the European Medicines Agency and UK based Medicines and Healthcare Regulatory Agency (MHRA). 

The European Medicines Agency reviewed emerging evidence and recommended revoking the marketing authorisation for crizanlizumab, finding that the benefits of the medicine ‘did not outweigh its risks’. This finding pre-empted an overall finding from the MHRA’s own review of the concerns arising from use of crizanlizumab, which are still pending at the time of writing. 

Lessons learned 
Accelerated access to promising new technologies may offer benefit to patients through ‘managed access’ while evidence is being developed. While effectiveness is the focus, safety monitoring of technologies early in their evidential pathway is important. Rapid healthcare technology evaluation requires robust mechanisms in place to support identification of safety signals and appropriate response. 

Whilst the patient safety regulatory landscape has changed in recent years across geopolitical boundaries, particularly in respect to the UK’s relationship with Europe, it is important for regulators to act in a timely and consistent manner when the same safety concerns affect populations similarly across these boundaries. 

Key recommendations

• Organisations producing managed access agreements should have effective oversight mechanisms to ensure emerging patient safety issues are considered and that overall safety is maintained throughout the course of the agreement.
   
• Healthcare safety regulators across geopolitical boundaries should act in a coordinated and consistent manner to investigate and act upon emerging safety concerns related to innovative new treatments and technologies. This supports ensuring that advancements in healthcare technologies contribute to a more equitable distribution of benefits across diverse populations.

Authors
Chris Bird, programme manager – patient safety, NICE 
Hannah Patrick, consultant clinical advisor, managed access, deputy senior responsible officer for patient safety, NICE 

Disclaimer
The views expressed in this World EBHC Day Blog, as well as any errors or omissions, are the sole responsibility of the author and do not represent the views of the World EBHC Day Steering Committee, Official Partners or Sponsors; nor does it imply endorsement by the aforementioned parties.