— Independent appraisal committee votes that evidence is adequate to demonstrate clinical benefits of esketamine versus placebo, but concerns remain about the study criteria used to define treatment-resistant depression and the lack of longer-term data on esketamine’s safety and effectiveness —

— Esketamine’s list price would require a 25-52% discount to reach a fair value-based price benchmark, and the potential short-term budget impact associated with treating the eligible patient population leads ICER to issue an Access and Affordability Alert —

BOSTON, June 20, 2019 – The Institute for Clinical and Economic Review (ICER) today released a Final Evidence Report and Report-at-a-Glance assessing the comparative clinical effectiveness and value of esketamine (Spravato™, Janssen), a nasal spray approved by the FDA in March as a therapy for treatment-resistant depression (TRD). Esketamine is one of the two mirror-image molecules (enantiomers) that make up ketamine, an anesthetic that is commonly used off-label to treat TRD.

ICER’s report was reviewed at the May 2019 public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), one of ICER’s three independent evidence appraisal committees. During the meeting, the CEPAC found that the evidence demonstrated esketamine plus background antidepressant to be clinically superior to background antidepressant alone. The CEPAC members found the evidence to be insufficient to demonstrate a difference in net health benefit between esketamine and ketamine, transcranial magnetic stimulation, electroconvulsive therapy, or augmentation with olanzapine.

During their deliberation, panel members weighed the therapies’ other benefits and contextual considerations. They acknowledged that esketamine is intended to care for patients with a condition of high severity and a high lifetime burden of illness, and that esketamine offers a novel mechanism of action compared to other approved treatments for TRD, which may allow successful treatment of many patients for who other available treatments have failed. Nevertheless, a majority of the panel felt that there is uncertainty about the long-term benefits and risks of esketamine, citing the lack of long-term trial evidence.

ICER’s evaluation of long-term cost-effectiveness found that the fair value-based price benchmark for esketamine is between $17,700 and $25,200 per year, a range that would require a 25-52% discount from the announced list price of $32,400. Consistent with ICER’s value-assessment framework, esketamine is deemed to deliver a “low value for money” because the treatment’s incremental cost-effectiveness ratio, using the current list price, exceeds $175,000 per quality-adjusted life year (QALY) gained.

“Treatment-resistant forms of major depression are common and have large negative effects on patient quality of life, so new therapies are badly needed,” said David Rind, MD, ICER’s Chief Medical Officer. “It is hard to understand how a price exceeding usual cost-effectiveness thresholds is appropriate for a treatment that could be very widely used, particularly when that price is an order of magnitude higher than that of intravenous generic ketamine, a closely related therapy.”

Affordability & Access Alert

Given that the clinical goal for uptake would exceed the potential budget impact threshold at the national level, ICER is issuing an Affordability and Access Alert as part of its final report on esketamine. Clinical experts queried at the public meeting suggested that esketamine would not be viewed as an appropriate treatment for all patients with TRD, but that roughly half of eligible patients may be offered the option during consultation with their physician. However, at esketamine’s current list price, only 16% of eligible Americans with TRD could receive the treatment before crossing ICER’s potential budget threshold of $819 million per year. Even if esketamine’s price was lowered to ICER’s value-based price benchmark range for long-term cost-effectiveness, only 20-30% of all eligible patients with TRD could be treated with esketamine before exceeding the potential budget impact threshold.

The purpose of an ICER Affordability and Access Alert is to signal to stakeholders and policy makers that the amount of added health care costs associated with a new service may be difficult for the health system to absorb over the short term without displacing other needed services or contributing to rapid growth in health care insurance costs that threaten sustainable access to high-value care for all patients.

Key Policy Recommendations

Following the voting session, a policy roundtable of experts – including clinicians, patient advocates, and payer representatives – convened to discuss the implications of the evidence for policy and practice. Key recommendations stemming from the roundtable discussion include:

  • Manufacturers and researchers should conduct studies directly comparing esketamine and other treatment options using standardized research protocols and outcomes that reflect what matters most to patients; this would allow real-world, long-term assessment of comparative effectiveness.
  • Given the considerable uncertainty that remains regarding the longer-term benefits and risks of esketamine, it is reasonable for insurers and other payers to develop prior authorization criteria to ensure that patients are carefully selected and managed by clinicians with the necessary expertise to ensure appropriate care.
  • Payers should develop mechanisms to adequately compensate clinicians for the expenses associated with monitoring and delivering esketamine within the specification of the REMS program.

ICER’s detailed set of policy recommendations, including considerations for establishing prior authorization criteria, is available in the Final Evidence Report.

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.