– Three new treatments use different mechanisms to improve patient outcomes, offering important options for patients; even under favorable modeling assumptions, however, and benefitting from new data from patients and a curated real-world evidence database, the list prices set for crizanlizumab and voxelotor appear too high to align fairly with clinical benefits –  

– Policymakers will need to consider the broader clinical and social context when translating evidence into pricing and coverage, a task of special importance given that these interventions are the first in several decades to advance care for patients in a community that has been historically disadvantaged in many ways –

– Due to COVID-19 concerns, the New England CEPAC’s deliberation over the treatments’ clinical efficacy and broader contextual considerations will now occur via live webcast on March 26 –

BOSTON, March 12, 2020 – The Institute for Clinical and Economic Review (ICER) today released an Evidence Report assessing the comparative clinical effectiveness and value of treatments for sickle cell disease, including crizanlizumab (Adakveo®, Novartis), voxelotor (Oxbryta™, Global Blood Therapeutics), and L-glutamine (Endari®, Emmaus Life Sciences).

“Patients and families in the sickle cell community have been without new treatment options for decades, so it is a welcome challenge to be reviewing three new drugs for this condition,” said Pamela Bradt, MD, MPH, ICER’s Chief Scientific Officer. “Our report analyzes the evidence, which remains relatively short-term and presents difficulties for estimating how much clinical benefit will be realized by patients in real-world practice. What isn’t in question is the importance of the context here: it is difficult to imagine a disease that ravages patients’ and families’ lives more than sickle cell disease. It is also true that this community has borne the burden of systemic racism and stigma, with reduced investment in research and the broad effects of an inadequate system of care, particularly as pediatric patients grow into adulthood. Our report takes an objective look at the evidence while highlighting that insurers and other policymakers must be fully aware of the broader clinical and social perspectives when developing prior authorization coverage criteria and negotiating prices with drug makers.”

Virtual Meeting of the New England CEPAC

Due to public health concerns regarding meetings and travel during the ongoing COVID-19 situation, ICER will not be hosting an in-person public meeting to discuss these treatments. Instead, this Evidence Report will be reviewed at an upcoming virtual meeting of the New England Comparative Effectiveness Public Advisory Council (New England CEPAC) on March 26, 2020. The New England CEPAC is one of ICER’s three independent evidence appraisal committees comprising medical evidence experts, practicing clinicians, methodologists, and leaders in patient engagement and advocacy. Register here to watch the live webcast of the New England CEPAC virtual meeting.

A draft version of this report was previously open for a four-week public comment period. The updated Evidence Report and voting questions reflect changes made based on comments received from patient groups, clinicians, drug manufacturers, and other stakeholders. Detailed responses to public comments can be found here.

Contextual Considerations and the Patient Perspective

Sickle cell disease has been an historically underfunded area for research, with no new treatments for decades. While assessing the value of these treatments, policymakers will need to consider the substantial lifelong burden associated with sickle cell disease, as well as the potential for these treatments to reduce the disparity in life expectancy between Black and White Americans.

ICER’s Evidence Report includes a chapter highlighting the patient perspective, featuring direct quotes from patients and caregivers about the all-encompassing nature of sickle cell disease, its stigma and limitations on daily life, racial bias throughout the health care system, and the dearth of clinical specialists, research, and effective treatments.

In addition, ICER attempted to quantify the treatments’ ability to reduce the racial disparity in life expectancy. While untreated individuals with sickle cell disease have a 45% lower life expectancy than the entire US population, ICER’s model estimates that treatment with crizanlizumab or voxelotor would reduce that disparity to 40%, and treatment with L-glutamine would reduce that disparity to 42.5%. While this improvement is a step in the right direction, it also demonstrates the enormous need for future progress against this devastating disease, as well as against racism throughout the US health care system.

Key Clinical Findings

The evidence provides moderate certainty that crizanlizumab provides a small-to-substantial net health benefit over optimal usual care. In the Phase II clinical trial, use of crizanlizumab reduced pain crises; however, the trial did not demonstrate a statistically significant improvement in the rate of hospitalization or quality of life.

The current evidence is promising but inconclusive regarding the comparative clinical effectiveness of voxelotor. Compared to optimal usual care, use of voxelotor improved surrogate outcomes, including an increase in hemoglobin and a reduction in hemolysis markers; however, voxelotor did not significantly reduce the annualized incidence rate of acute pain crises and has not yet demonstrated an effect on quality of life.

The Phase II and Phase III trials of L-glutamine showed reductions in the number of acute pain crises and hospitalizations, but due to the large and differential rate of patients withdrawing from the trials, the magnitude of benefit remains uncertain. Therefore, ICER rated the evidence for L-glutamine to be promising but inconclusive.

Key Cost-Effectiveness Findings

By linking pain crises and hemoglobin levels to acute and chronic conditions, as well as mortality, ICER’s assessment includes the most comprehensive model to date to determine a treatment’s health and economic impact on sickle cell disease. Where possible, model inputs were informed by real-world evidence from both published CMS national level data and, using the Aetion Evidence Platform, de novo evidence generation from a dataset of more than 30,000 individuals with sickle cell disease in the US with private insurance. Model inputs for the societal effects of sickle cell disease were informed by a patient and caregiver survey conducted by Sick Cells that provided data from approximately 500 patients on how the condition affected individuals’ ability to work and attend school. Other model inputs were found in the published literature.

ICER’s health-benefit price benchmarks suggest a price range, net of any discounts and rebates, that aligns fairly with a treatment’s added benefits for patients over their lifetime. These ranges typically reflect commonly cited cost-effectiveness thresholds between $100,000 and $150,000 per Quality-Adjusted Life Year (QALY) gained. Prices at or below these thresholds help ensure that the health benefits gained by patients using new treatments are not outweighed by health losses due to long-term cost pressures that lead individuals to abandon care or lose health insurance. ICER also calculated what prices would be needed to reach alternative cost-effectiveness thresholds based on Equal Value of Life Years Gained (evLYG). In addition, because sickle cell disease can significantly limit patient and caregiver productivity, educational opportunities, etc., ICER used a “co-base case” approach in which a modified societal perspective was used to calculate results across both QALY and evLYG measures of health gain.

Based on which perspective individual policymakers choose to apply to their own decisions, ICER’s annual health-benefit price benchmark ranges for these treatments are as follows:

 Health Care Sector Perspective
($100K –
$150K
/QALY)		Health Care Sector Perspective
($100K –
$150K
/evLYG)		Modified Societal Perspective
($100K –
$150K
/QALY)		Modified Societal Perspective
($100K –
$150K
/evLYG)
Crizanlizumab$16,900-$20,900$26,000-$34,600$34,900-$39,200$43,500-$52,000
Voxelotor$8,300-$12,600$15,500-$23,400$22,100-$26,700$28,600-$36,500
L-glutamine$9,900-$11,900$14,900-$19,300$24,200-$26,300$28,900-$33,400

The aggregate benchmark range for crizanlizumab of $16,900-$52,000 would require a 61-89% discount off the treatment’s $132,000 annual list price. The aggregate benchmark range for voxelotor of $8,300-$36,500 would require a 71-93% discount off the treatment’s $127,000 annual list price. Finally, the aggregate benchmark range for L-glutamine of $9,900-$33,400 would require an 18-76% discount off the treatment’s $40,540 annual list price.

Potential Budget Impact

At the treatments’ current list prices, only 21% of eligible patients could be treated in a given year with crizanlizumab, and only 16% could be treated with voxelotor, before crossing ICER’s potential budget impact threshold of $819 million per year. No potential budget impact analysis was conducted for L-glutamine because the treatment has already been on the market for several years.

About ICER

The Institute for Clinical and Economic Review (ICER) is an independent non-profit research institute that produces reports analyzing the evidence on the effectiveness and value of drugs and other medical services. ICER’s reports include evidence-based calculations of prices for new drugs that accurately reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall health care system.

ICER’s reports incorporate extensive input from all stakeholders and are the subject of public hearings through three core programs: the California Technology Assessment Forum (CTAF), the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), and the New England Comparative Effectiveness Public Advisory Council (New England CEPAC). These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of health care. For more information about ICER, please visit ICER’s website.