Can evidence of health inequality tilt the balance of a NICE assessment?

By Fisentzos Stylianou, PhD


In November 2021, Novartis’ Adakveo (crizanlizumab) became the first treatment for sickle cell disease (SCD) to be made available by the NHS in England in over two decades. Adakveo was recommended by the National Institute for Health and Care Excellence (NICE) as an option for preventing recurrent sickle cell crises (vaso-occlusive crises (VOC)) in people aged 16 or over with SCD via a managed access agreement (MAA)1.

Several uncertainties in Adakveo’s evidence package did not meet the standards for routine use

The clinical evidence came from SUSTAIN, a double-blind, randomised multicentre trial of crizanlizumab compared with placebo2. The primary outcome for SUSTAIN was the annual rate of sickle cell-related pain crises, and the median annual rate of sickle cell-related pain crises was significantly lower for the licensed dose of crizanlizumab than for placebo (1.63 vs 2.98, respectively; p=0.01)3. Overall and serious adverse event incidence was comparable across arms. Despite these favourable results, NICE indicated that crizanlizumab could not be recommended for routine use due to the following key areas of uncertainty:

  1. Short trial duration (52-week treatment phase and 6-week follow up evaluation phase); long term outcomes such as mortality or rare events were yet to be determined and compared between both arms of the trial
  2. Small number of patients were included in the study (n=67 in crizanlizumab arm vs n=65 in placebo arm)
  3. Several of the inputs used in Novartis’ cost-effectiveness model, such as patient weight, gender mix, and concomitant hydroxycarbamide use did not reflect the clinical evidence
  4. The model structure led to uncertainty in the change in VOC rate over time following crizanlizumab treatment

With all of these uncertainties, why did Adakveo receive a positive recommendation from NICE?

The COVID-19 pandemic highlighted major health inequalities across England, and to address this, NICE announced a strategic priority to “reduce health inequalities and redress socio-economic and regional health variations” in its 5-year strategic plan for 2021 to 20264. In the case of Adakveo, NICE’s decision was heavily influenced by health inequalities raised by Novartis, healthcare professionals, and SCD patient groups, which included the following points (taken from the NICE appraisal):

  1. “Sickle cell disease is not widely understood, including among healthcare professionals, which often results in poor hospital care and stigma around seeking pain relief for crises.”
  2. “A significant proportion of patients with sickle cell disease may also be registered disabled because of ill health associated with their disease, for example strokes, chronic leg or foot ulcers and osteonecrosis, there can be problems accessing treatment.”
  3. “The condition is more common in people of African or African-Caribbean family origin and that as a group these people tend to have poorer health outcomes than other ethnicities.”

Based on this evidence and that crizanlizumab may help to address these health inequalities, NICE recommended Adakveo for use with the condition of an MAA; this includes the collection of additional data from a phase 3 trial and prospective data from the National Haemoglobinopathy Registry, with Novartis anticipated to submit data to NICE for review by 2025. This agreement will allow more than 300 people to obtain Adakveo each year, with the number increasing to more than 450 in coming years5.

Opportunities for drug manufacturers

The NICE appraisal of Adakveo is a great example of how patient-centricity and awareness of a patient population can directly contribute to a manufacturers’ commercial opportunity. The significant weighting of patient inequalities and unmet need is a first for a NICE technology appraisal, and it could become a more widespread consideration as health inequalities are reported across a number of other diseases6. Manufacturers seeking to commercialise in England should assess whether their patient populations are subject to health inequalities, as this may present an additional opportunity to access the market, particularly for advanced therapy medicinal products with limited clinical datasets. Manufacturers should also aim to engage patients, patient advocacy groups, and clinical experts early in the research and development process to characterise the inequalities across the target indication(s), which may facilitate patient uptake in the long run.

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3. Ataga, K. I., Kutlar, A., Kanter, J., Liles, D., Cancado, R., Friedrisch, J., … & Rother, R. P. (2017). Crizanlizumab for the prevention of pain crises in sickle cell disease. New England Journal of Medicine, 376(5), 429-439.