Ensuring the affordable becomes accessible-lessons from ketamine, a new treatment for severe depression

Rodgers and colleagues use the case of ketamine as a worked example to illustrate systemic barriers that prevent low‑cost, repurposed medicines from becoming widely accessible for severe depression. The paper outlines how, despite two decades of evidence that generic racemic ketamine has rapid antidepressant effects, incentives and coordinated funding were insufficient to produce the regulatory and service‑delivery evidence and infrastructure needed for subsidised clinical use. The authors set out to explain why this translational failure occurred, document key facts about the evidence base, regulatory decisions and pricing that followed, and propose policy and funding reforms to increase the likelihood that affordable effective treatments—particularly upcoming psychedelic‑assisted therapies—become accessible to patients rather than being displaced by patented, high‑cost alternatives.

The extracted text does not present a formal Methods section or a detailed, reproducible search strategy. Instead, the paper is framed as a policy case study and narrative analysis drawing on published clinical trials, meta‑analyses, regulatory approvals, clinicaltrials.gov data and health‑system examples. The authors report counts and characteristics of published ketamine trials (for example, the number of trials published by November 2021 and trial size distributions) and refer to an analysis of clinicaltrials.gov that compared funding sources and trial sizes; however, procedural details for that analysis (search terms, dates, inclusion criteria, statistical methods) are not clearly reported in the extracted text. Where regulatory and economic details are discussed (approvals, pricing, reimbursement submissions and requested government investments), the paper appears to synthesise publicly available regulatory documents, submissions and published literature rather than report new primary data collection. Because methods for the literature and database review are not explicitly described in the extracted text, the reader cannot verify inclusion/exclusion criteria or replicate the analytic steps from this extract alone.

The paper summarises several factual findings about the ketamine evidence base, regulatory pathway and economic consequences. By November 2021, 27 trials of generic racemic ketamine in depression had been published, of which 24 (89%) involved fewer than 50 participants; only a small number of trials exceeded 100 participants (the KADS and ELEKT‑D studies are noted). An analysis of clinicaltrials.gov cited in the text found 85% of ketamine trials were funded by academic or other non‑industry groups; academic trials were smaller than industry trials (reported averages: 48 vs 64 participants for Phase II trials and 78 vs 150 participants for Phase III trials) and were less likely to be registered as completed (38% vs 53%). Meta‑analyses referenced by the authors indicate both generic racemic ketamine and esketamine (mainly intranasal Spravato) are effective for treatment‑resistant depression (TRD), but pooled rates of response and remission relative to control were reportedly significantly higher for racemic ketamine than for esketamine (p < 0.005). There has been one small head‑to‑head trial (N = 63) comparing single intravenous doses of each, showing a non‑significant trend favouring racemic ketamine at 1 week (MADRS difference 6, 95% CI -1 to 14, p = 0.08). Regulatory and economic outcomes are documented: Janssen’s s‑ketamine (intranasal Spravato) received FDA breakthrough designations and subsequent approvals for TRD and MDD with acute suicidal ideation/behaviour, with regulatory approval for TRD based on five clinical studies involving 2,214 participants. Spravato is priced at roughly $600–$900 per dose, making drug costs for an initial course of treatment almost AUD$10,000 by the authors' estimate; two unsuccessful submissions were made to Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) to list Spravato on the Pharmaceutical Benefits Scheme (PBS), with a third decision pending (reported as due August 2023). The submissions reportedly requested an overall government investment of $500–$800 million over the first 6 years of listing; another figure in the paper refers to approximately AUD$100 million annual government investment being requested in Australia. By contrast, generic ketamine costs around $5 per vial but lacks TGA approval for TRD and therefore must be used off‑label. Service delivery costs are substantial for generic ketamine: staffing and administration were estimated to comprise the majority of total costs (an estimate of ~ $3,600 for an 8‑week course is cited). Without a Medicare Benefits Schedule (MBS) item number, these service costs are generally unreimbursed; commercial sponsors typically apply for such codes but this had not occurred for generic ketamine at the time of extraction. The authors also document variability in service provision and reports of some US clinics supplying at‑home ketamine, raising concerns about standardisation and oversight. Looking ahead, the paper reports the rapid expansion of the psychedelics industry (more than 90 companies and an estimated market valuation >$4 billion in 2022) and highlights the example of COMPASS Pathways developing a proprietary psilocybin formulation (COMP360) entering Phase III trials. The authors note that psychedelic‑assisted psychotherapy is expensive primarily because of therapist time (estimated >US$10,000 per patient with >90% of costs covering therapist compensation and <5% for the drug), and they warn that patented drug formulations may command high prices even though the drug component is a small share of total cost. Finally, the paper summarises proposed mechanisms and policy tools rather than novel empirical results, including examples of incentives (orphan drug style exclusivity, tax credits), access with evidence development (AED) schemes, and a mix of 'push' and 'pull' funding mechanisms to support repurposing and translational work.

Rodgers and colleagues interpret the ketamine experience as evidence that current R&D, regulatory and reimbursement systems disadvantage affordable, off‑patent treatments. They argue two structural problems explain this pattern: a lack of commercial incentives for companies to pursue new indications for low‑cost medicines, and fragmented, insufficient public funding to support the full translational pathway (including regulatory submissions, REMS/post‑approval requirements and the service‑delivery infrastructure needed for uptake). The authors position these observations relative to prior and concurrent developments: while academic and public funding produced many small trials showing clinically meaningful, rapid antidepressant effects, these efforts were inadequate to secure regulatory approval and subsidised access for generic ketamine. By contrast, substantial commercial investment enabled the registration of a patented esketamine product, which reached approval on the basis of larger, industry‑sponsored trials. The paper warns this pattern is likely to recur with psychedelics and other repurposing opportunities unless systemic changes are made. Several policy responses are proposed. The paper outlines ways to improve commercial incentives—extended exclusivity, tax credits and novel reimbursement models including 'access with evidence development' (AED)—while acknowledging potential downsides such as the risk of price gouging under exclusivity regimes. It also recommends greater, better coordinated public and co‑funding for translational and implementation research, including targeted grants for repurposing, mechanisms to pool or co‑ordinate funds internationally, and incentives for public‑private and patient‑centred funding partnerships. The authors advocate linking payer evidential needs (for example PBAC requirements) to targeted research calls so that trials address both regulatory and reimbursement evidentiary gaps. Regulatory reforms are suggested to reduce barriers and trial costs, and to streamline governance and approval processes that currently lengthen and inflate the cost of Phase III studies. The authors favour AEDs as a way to provisionally fund access while comparative effectiveness and cost‑effectiveness evidence accumulates, and they discuss examples where AEDs have been used in Australia and elsewhere. Implementation science, readiness of health systems, and funding for staff and delivery costs are emphasised as necessary complements to evidence generation. The authors acknowledge trade‑offs and uncertainties: some incentives could be misused (the GHB/Xyrem example is raised), existing public funding mechanisms such as MRFF are helpful but insufficient in scale, and international coordination is limited. They conclude that without reforms across incentives, funding, regulation and implementation, the same cycle that advantaged a patented, high‑priced esketamine product over a low‑cost, off‑label alternative will repeat for psychedelic therapies and other repurposing opportunities.

Using ketamine as a case study, the paper concludes that current R&D and reimbursement systems often fail to ensure that the most affordable effective option becomes accessible. The authors offer a portfolio of reforms—commercial incentives, expanded and coordinated public co‑funding, reduced regulatory barriers, AED schemes, and improved support for implementation and workforce costs—to address the translational and access gaps. They warn that, absent such changes, the inefficient pattern documented for ketamine is likely to recur across mental health and other areas of medicine.