Case Study: UK Agency Again Rejects Spravato Coverage in 2022

Janssen has struggled to demonstrate the cost-effectiveness of its Spravato (esketamine) nasal spray to Health Technology Assessment agencies (HTAs) such as the UK’s National Institute for Health and Care Excellence (NICE), who again rejected recommending it for NHS coverage in 2022.

Psychedelic drug developers should take note.

The single technology appraisal (STA) process, which was launched by NICE in 2005, is a process through which a single product, device or technology with a single indication is appraised in order for the institute to issue guidance on whether such technologies should be recommended for use in the country’s publicly-funded national health service (the NHS). Through its appraisal process, NICE “considers evidence on the health effects, costs and cost effectiveness of a health technology in comparison with current standard treatment in the NHS.”

In 2018, over a year before the European Commission (EC) approved Janssen’s Spravato (esketamine) nasal spray alongside an oral antidepressant as a treatment for treatment-resistant depression (TRD), Janssen began preliminary work as part of the UK STA for its esketamine candidate. The stated objective of the STA was to, “appraise the clinical and cost effectiveness of esketamine nasal spray within its marketing authorisation for treatment-resistant depression.”

Following Janssen’s evidence submission, NICE issued its initial draft guidance for Spravato in January 2020. Citing concerns related to the clinical efficacy and cost effectiveness of Spravato, NICE did not recommend the nasal spray for use in TRD. It would take over two years for NICE to issue its final appraisal of esketamine in 2022, at which point the institute reaffirmed its initial determination. In its guidance, NICE stated that esketamine was “unlikely to be an acceptable use of NHS resources.” While Janssen would appeal the recommendations, in its post-appeal guidance NICE once again sustained its earlier determination.

NICE’s rejection of esketamine was largely the result of “clinical uncertainties” in the evidence submitted by Janssen. Given that clinical data are foundational inputs to economic models employed by HTAs, these “uncertainties” ultimately compromised the models and their ability to reliably evaluate cost effectiveness. Amongst these evidentiary issues were the relatively short duration of Janssen’s trials of the product; the impact that the company’s positioning of Spravato as at least a fourth-line treatment had on the utility of its clinical evidence base; and, the adverse impact that Janssen’s trial exclusion criteria had on treatment translatability. While Janssen did attempt to tout Spravato’s “novel biological mechanism”, the value of this “innovative mechanism” failed to woo NICE or overcome the clinical uncertainties that were identified by the agency.

NICE further expressed its perspective that it was not methodologically appropriate to include outcomes related to societal burdens of TRD (e.g., accounting for factors like productivity loss) in the economic model. Only direct health effects and costs borne by the NHS and social services should be included in the reference case, NICE reminded the sponsor. The agency also stated that it believed Janssen failed to account for or underestimated many costs and considerations related to implementing esketamine treatments. Given that Spravato is to be used under medical supervision in appropriate treatment settings, Janssen proposed converting existing electroconvulsive therapy (ECT) suites.

However, Janssen’s plans were further complicated by the NHS efforts to integrate primary and community care for individuals with serious mental illnesses. Given the need for a psychiatric referral, Janssen’s proposed treatment delivery setting, and the extended waiting lists for primary and community care, NICE was unsure how Spravato could reliably fit into the community care paradigm it is pursuing.

In addition to these practical considerations, costs associated with these conversions, along with the costs of other requirements such as medical monitoring equipment, patient transport, and the managing of controlled drugs were not (adequately) included in the analysis, in the view of the agency. Note that Spravato requires new resources for each newly treated patient, making the costs associated with the drug’s delivery much more linear and scuppering any true economy of scale.

According to NICE doctrine, as the impact that the adoption of a new technology would have on NHS resources increases, the committee must be increasingly certain of the technology’s cost effectiveness. As a result, Janssen’s implementation plan and evidence base ultimately failed to satisfy NICE’s need for reliable and definite evidence of cost effectiveness.

However, Jannsen’s recently published Spravato data, which found the esketamine nasal spray to be more effective than Seroquel XR in a Phase 3 TRD trial, will likely encourage the company to pursue a renewed appraisal for its product. Nonetheless, for now, without public healthcare coverage, Spravato’s high costs make the treatment unaffordable for many people. As a consequence, the drug’s therapeutic reach is severely limited.

In light of similarities Spravato shares with emerging psychedelic treatments, such as the requirement for supervised administration in appropriate physical spaces and the relatively short-term nature of efficacy data, Janssen’s struggles with NICE may foreshadow hurdles that psychedelic drug developers could encounter as they move towards commercialisation.