Esketamine snubbed by PBAC … again

This is its third strike amid concerns over long-term symptom relapse, cost-effectiveness and validity of sponsor-led research.

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The PBAC has yet again rejected calls for esketamine nasal spray, Spravato, to be recommended for PBS listing for use against treatment-resistant depression.

Although Spravato has been registered by the TGA since early 2021, this marks its third rejection by the PBAC after rejections in July 2021 and 2022.

Spravato, sponsored by Janssen-Cilag Pty Ltd, returned to the table for the PBAC’s July meeting this year for Section 100 (Highly Specialised Drug Program) Authority Required (Telephone/Online) listing.

Key to the new submission was a limit to the maximum treatment course of 12 months. While the PBAC acknowledged that for many patients esketamine “had been transformative and restored hope in their lives”, they concluded that “this was the key change in the resubmission which flowed into the economic and financial models”.

“The PBAC considered there was a number of uncertainties associated with this, including how episodic treatment would be managed, the impact of ceasing treatment in responders and how to implement use beyond 12 months for some patients,” the rejection read.

“The PBAC noted the inclusion of a 12-month treatment cap per episode increased the uncertainty regarding the magnitude of clinical benefit that would be observed in clinical practice,” the PBAC said.

Although studies on the short-term improvements of ketamine – from which esketamine is derived – for depressive symptoms have been “striking”, experts writing this month in the New Zealand Medical Journal say concerns remain over recurrent symptoms after the treatment course ends, due to masking of root causes of mental distress.

“We predict that the mislabelling of distress as depression will fuel demand for perceived ‘quick fixes’ such as ketamine. We are also concerned that greater ketamine use may not be impactful, since the underlying drivers of psychological distress include early childhood adversity, poverty, and disadvantage, rather than a lack of antidepressant treatment,” their editorial says.

The PBAC, in line with input from stakeholders, concurred that pathways for retreatment were a must, but concluded that further consideration was needed as this was not considered in the submission.

The PBAC felt that the economic model presented by the sponsors – which evaluated only one use over five years – was insufficient, given the high likelihood of relapse, and “considered it was unlikely that esketamine would be cost-effective if additional courses of treatment were required within the five-year period”.

“The PBAC considered the financial estimates were overestimated due to optimistic assumptions regarding the uptake of esketamine in the context of likely barriers to access,” the outcome read.

According to ketamine researcher Professor Colleen Loo from the Black Dog Institute and UNSW Sydney, who previously spoke to TMR, approval of esketamine would have cost the government over $100 million a year and cost patients $600-800 per dose.

Instead, Professor Loo said that wider awareness of generic ketamine – only $5 a dose – plus the introduction of Medicare subsidies for the cost of the treatment procedure – $200-300 per treatment – would help get an “amazing treatment for treatment-resistant depression” to more people.

Considering the role of pharma companies in shaping demand for ketamine, the researchers from New Zealand expressed concerns over their undue influence and validity of evidence because “most esketamine data stems from industry-sponsored trials”.

“The desire for greater use of ketamine for depression is not just led by clinicians,” the researchers said.

They also expressed concerns over the potential need for dose escalation due to reduction in effectiveness over time.

But the authors said that ultimately their concerns were linked to how ketamine was made available, rather than whether it should be made available.

“Despite these reservations, we believe that greater availability of ketamine for treatment-resistant depression is desirable, but do not support a large-scale rapid increase in ketamine use.”

In its sponsor comment to the PBAC’s rejection, Janssen said it “believes in the benefit that esketamine provides patients” and, hoping that the 4^th time’s a charm, will “consider how we can resolve the remaining uncertainties so that Australian patients can access esketamine in a timely way”.