In this guest contribution, Dilara Bahceci, PhD, explores the confluence of economic, regulatory and research-related barriers that have conspired to effectively disincentivise the development of generic ketamine for depressive disorders.
Drawing on a recent article she co-authored with colleagues in Australia (Rodgers et al., 2023), Dr. Bahceci sheds light on the story of Spravato’s commercial development and compares it with the lack of similar activity with generic, racemic ketamine.
Dr. Bahceci then turns to potential solutions that could encourage both the cost-effective repurposing of known drugs and the advancement of novel treatments. These include enhancing commercial incentives for drug repurposing, better coordinating public-private funding, and simplifying approval processes for repurposed drugs.
Ketamine and its chemical derivative, esketamine, have the ability to alleviate severe depression almost instantly, particularly in cases resistant to other treatments. This represents a significant breakthrough in psychiatry.
However, a complex mix of economic, regulatory, and research barriers have resulted in these potentially life-saving treatments remaining out of reach for many patients with severe depression.
Drawing inspiration from a recent editorial in the Australian & New Zealand Journal of Psychiatry that I co-authored with colleagues at The George Institute for Global Health, this article explores the complexities of racemic ketamine’s stalled journey from promising research to patient care. It highlights disparities in the drug development and approval process that favour patented medications despite their higher costs and not necessarily superior effectiveness. It also explores multifaceted strategies that could pave the way for the development of affordable treatments.
Editor’s Note: for a refresher on racemic ketamine and its enantiomers, see our Racing Beyond Racemic feature from November 2022.
Depression stands as one of the most pervasive health challenges of our time. It is widespread, affecting an estimated 280 million people worldwide – roughly 1 in every 20 people – and is one of the leading causes of disability. Amidst this challenge, ketamine has emerged as a breakthrough antidepressant.
First synthesized in 1962, ketamine is primarily recognised as an anesthetic. However, in the 2000’s, the groundbreaking discovery that ketamine-induced potent and rapid antidepressant effects (Berman et al., 2000) altered the course of psychiatry.
Ketamine’s unique capability to rapidly relieve symptoms, often within hours, established it as the first rapid-acting antidepressant. Moreover, the fact that these antidepressant effects could last for about a week and occurred in individuals who were treatment-resistant underscored a significant breakthrough. Ketamine’s effects mark the first novel approach to treating depression in over fifty years and set a precedent for mental health treatments that are both fast-acting and relatively long-lasting.
For over two decades, numerous studies have consistently confirmed these early findings, demonstrating ketamine’s efficacy in treating severe, treatment-resistant depression. However, progress towards making ketamine widely accessible has been slow. Its classification as a generic drug makes it less appealing for pharmaceutical industry investment. As a result, ketamine research has largely depended on public funding, which has led to primarily small-scale studies (Figure 1 and 2). Without the financial backing of an industry sponsor to support larger, definitive trials, racemic ketamine has been unable to obtain the regulatory approval needed for its widespread use among public healthcare systems, and its reimbursement by both public and private payors.
In contrast, one of its two isomers, esketamine, has been refined and developed into a nasal spray called Spravato® by Janssen Pharmaceuticals. Clinical trials for esketamine began in 2014 and with the support of larger, industry-funded clinical studies, it gained FDA approval for use in depression in 2019.
This streamlined approval for Spravato highlights a stark contrast in the drug development landscape. While esketamine sailed through the necessary trials and regulatory checks, largely thanks to industry funding, generic ketamine’s path has been riddled with underfunded studies and regulatory complexities, despite its proven efficacy. However, there is no evidence to indicate that esketamine is superior to racemic ketamine as no direct randomised comparative trials have yet occurred. In fact, a small observational study that compared patient outcomes between those that received intravenous ketamine versus intranasal esketamine found similar rates of response and remission in treatment-resistant depression. What’s more, the study found that the number of treatments administered to achieve remission were much lower in the IV ketamine group (Singh et al., 2023).
The reality of accessing ketamine
Globally, the availability of ketamine and esketamine for treating depression varies and is dictated by cost and regulatory hurdles. The situation in Australia, as highlighted in our ANZJP publication, serves as a case study that mirrors these worldwide complexities.
Like in many jurisdictions, esketamine has received approval from the Australian regulatory body, the Therapeutic Goods Administration (TGA), for treatment-resistant depression. However, its high price of up to $800 per dose has hindered its inclusion in public reimbursement schemes, placing the full financial burden on patients.
Generic ketamine, on the other hand, costs significantly less at $5 to $20 per dose, but lacks TGA approval for use in depression. Therefore, it is used off-label and isn’t eligible for public coverage. Additionally, there’s a lack of standardization and regulation in how these treatments are administered, raising concerns about patient safety and treatment efficacy. Both ketamine and esketamine require clinical administration, which adds additional costs not covered by public or private insurance and further restricts access.
Internationally, the situation is equally complex. In the U.S., Spravato is FDA-approved but access hinges on insurance coverage. Similarly, in Europe, despite esketamine gaining approval from the European Medicines Agency (EMA), cost and the necessity for clinical administration limit its widespread use.
Editor’s Note: it’s much the same in the UK, where the country’s Health Technology Assessment agency, NICE, has denied coverage of Spravato multiple times. We covered this in our 2022 Year in Review.
The fragmented access to ketamine-based therapies highlights a broader global issue where the benefits of effective treatments are gated behind walls of affordability and bureaucracy, and become inaccessible to many patients who could benefit.
Why did this happen?
The challenges in accessing ketamine-based treatments can be traced back to the core structures of pharmaceutical development and approval processes.
Generic ketamine, while inexpensive and clinically effective, lacked the financial backing for large-scale clinical trials and regulatory approval as a treatment for depression. This is due to the absence of market exclusivity—such as that afforded by regulators for new drugs as well as intellectual property like patents— which typically motivates pharmaceutical investment.
In contrast, esketamine’s ability to be patented justified the investments made by Janssen Pharmaceuticals to complete rigorous trials, obtain FDA approval, and secure market exclusivity.
This dichotomy underscores a fundamental issue in drug repurposing: without the lure of a significant financial return, potentially life-changing treatments like generic ketamine languish in a state of underutilization and inaccessibility, despite their clinical promise and affordability.
Will this happen again?
Ketamine and esketamine’s challenges reflect a widespread issue in healthcare, where pharmaceutical companies prioritize developing new, patentable drugs over repurposing existing more affordable alternatives. This not only stifles innovation in drug repurposing and limits accessible healthcare options but also increases healthcare costs by pushing patients towards newer, costlier treatments that might not provide superior clinical benefits.
Promising psychedelic substances, like MDMA for PTSD and psilocybin for depression, face similar challenges. Their natural origin or established knowledge base makes them (in many respects) non-patentable and thus less attractive for pharmaceutical investment compared to new, patentable derivatives. Consequently, the market may favor commercially viable treatments over those that are most beneficial or cost-effective.
This trend disproportionately impacts vulnerable populations unable to afford expensive medications, exacerbating health inequities. Healthcare systems with tight budgets are forced to choose costly patented drugs, which strains public health resources and necessitates trade-offs in patient care.
The underutilization of effective, low-cost treatments like generic ketamine represents a missed opportunity for more sustainable healthcare. This situation underscores the urgent need for systemic reforms that balance innovation with accessibility and affordability.
What are the potential solutions?
To effectively repurpose drugs like ketamine and advance novel treatments, such as psychedelic therapies, we need innovative and collaborative strategies. The following are key solutions to shake-up incentives, overcome current barriers, and broaden access to effective treatments:
- Enhanced commercial incentives: It is crucial for governments and regulatory bodies to create policies that incentivize drug repurposing, including extended market exclusivity, R&D tax credits, and novel reimbursement models. Examples include the US Orphan Drug Act and the ‘Access with Evidence Development’ (AED) model, which allows provisional access to drugs while additional data is collected to confirm their effectiveness and value.
- Coordinated public and private investment: A concerted effort is needed from public funding agencies, private investors, and philanthropic organizations to finance the necessary research and development. This may involve establishing specific grants for repurposing drugs, as well as fostering public-private partnerships to share the risks and benefits of developing these treatments. Examples of successful co-funding and development partnerships include the Cystic Fibrosis Foundation and the Patient-Centered Outcomes Research Institute.
- Reduced regulatory barriers: Simplifying approval procedures for repurposed drugs can hasten their market entry. This might include support for clinical trial design, assistance with literature reviews, and fee reductions for applications involving medicines with high public health benefits but low commercial returns.
- Efficient clinical trials: Adopting modern trial methodologies, such as adaptive platform trials, and leveraging research networks can reduce the cost and duration of clinical studies.
- Improved pharmacovigilance: Developing cost-effective clinical quality registries and databases for monitoring treatment safety and effectiveness will enable better post-approval surveillance.
- Collaborative frameworks: National and international collaboration among researchers, industry, healthcare providers, and non-profits is crucial. Streamlining efforts through shared data and resources can reduce redundancy and amplify the impact of research funding. Initiatives like the MTP Connect initiative and the European Commission’s STAMP program, which facilitate coordination and governance, can enhance the speed and efficiency of bringing repurposed drugs to the market.
By implementing these solutions, we can hope to see more effective, affordable treatments become accessible to those who need them most. This approach not only applies to ketamine but can also pave the way for other promising therapies in mental health and beyond.
Conclusion
The stalled journey of generic ketamine’s antidepressant promise exemplifies both the immense potential and the complex challenges of drug repurposing. The obstacles facing the development of low-cost ketamine and psychedelic-assisted therapies highlight a broader issue in healthcare: the critical need for more equitable and efficient drug approval and access processes.
Right now, we’re in a situation where groundbreaking treatments remain frustratingly out of reach for many. However, there’s a vision for a better future, one that demands our collective effort. We must envision and cultivate a future healthcare system that not only develops breakthrough treatments but also ensures accessibility, regardless of socioeconomic status. Achieving this vision will require a unified effort from all stakeholders, including policymakers, healthcare professionals, researchers, and the public.
We stand at a crossroads. On one path, continued disparity and inaccessible advancements. On the other, a reformed system where patient access and affordability are as much a priority as the next medical breakthrough. As we venture forward, the choice is ours: will we simply witness the evolution of healthcare, or will we be the ones to shape it towards a more equitable future?
About the Author
Dilara Bahceci, PhD: Research Fellow at the George Institute and Head of Communications for Psylo.
Dr Dilara Bahceci is a neuropharmacologist with a focus on the clinical development of psychoactive treatments like psychedelics, ketamine, MDMA, and cannabinoids. With a PhD in medicinal cannabis for childhood epilepsy and a decade of experience in research and drug development, across academia, the private sector, and startups, Dilara has played a key role in transforming psychoactive drugs into recognized medical treatments. Currently, she is advancing ‘breakthrough therapies’ like psychedelics, ketamine, MDMA into effective and accessible mental health treatments at the George Institute. Additionally, Dilara specializes in scientific communication and serves as the Head of Communications at Psylo, a biotech company pioneering novel psychedelic-inspired therapeutics.
