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Finding Evidence in the Real World

Readers of this blog will likely be aware that the most common barrier for mental health patients who could benefit from ketamine infusion therapy is financial costs, primarily because ketamine infusions for conditions like depression are usually not covered by insurance. The logical question that follows is why are those infusions not covered if they are an effective therapy? The answer, sadly, is a kind of catch-22. Insurance companies rely on the FDA for determining safety and efficacy of drugs through the well-defined clinical trial process, but the agency is dependent on the pharmaceutical industry to conduct those trials, especially phase III trials, which are the largest and most expensive. While our understanding of ketamine’s effectiveness for mental health conditions is continuously improving, there are still no phase III-scale trials demonstrating its effectiveness for conditions like depression, and since the drug is long off-patent (with the first generic ketamine reaching market in 1996), there is no financial incentive for those trials to be conducted. As a result, ketamine's use for depression and other mental health indications remains off-label and insurance companies largely deny coverage for it (although it should be noted that the details of insurance coverage for ketamine infusions are complex and evolving, as TAFI founder Alan Ferguson details here).

Large companies can potentially side-step this hurdle, still getting insurance reimbursement and recouping the costs of clinical trials by finding novel ways to formulate or deliver ketamine. This was the method J&J / Janssen Pharmaceuticals used for Spravato ® (esketamine) nasal spray, which has been written about at length. Smaller businesses such as ketamine telemedicine providers or ketamine clinics themselves with fewer resources to produce efficacy data can't afford these kinds of workarounds and have very limited engagement with insurers as a result. However, what if a phase III-scale trial of ketamine for depression could be conducted without the high price tag?

This might sound like a lofty goal, but it can be achieved using real-world evidence from the medical records of patients already receiving ketamine infusions for depression, and an article published in 2023 by researchers affiliated with the psychiatry electronic health record company Osmind and Stanford University provides a great example of this research approach. The authors generated an experimental treatment arm using data from questionnaires administered to over two thousand real-world patients at ketamine clinics across the United States prior to the start of their infusions and compared it with two control arms, one of real-world patients who were evaluated at ketamine clinics but did not receive any infusions, and another "synthetic control arm" consisting of data from a previously published, unrelated clinical trial for depression treatments.

The results, perhaps unsurprisingly, revealed a strong signal that ketamine is effective at treating depression and anxiety in a large portion of patients, but notably not all. Roughly half of patients analyzed showed a response in terms of reduced depression or anxiety (49.2% of patients for depression and 47.5% for anxiety) and approximately one-quarter of the patients met criteria for full remission (26.2% depression, 25.6% anxiety) (Fig. 1). This analysis is also in line with the findings of other research into the efficacy of ketamine for depression, providing a good indication that the results are valid. Encouragingly, the FDA has also indicated that they are open to accepting this kind of real-world evidence, having issued draft guidance on how clinical trial sponsors can use this data to support future new drug applications.

Using real-world data does have some downsides which need to be considered. For instance, large portions of the patient population in the experimental group had missing data points and were unable to be included in the final analysis of patients who reached the maintenance phase of treatment, which may have affected the results. Additionally, clinic-sourced data may reinforce existing biases in the healthcare system based on who is able to access the care in the first place.

Nonetheless, real-world evidence has an important role to play in overcoming issues with funding research and in reform efforts to help more patients attain covered care for ketamine, or other therapies that may show efficacy. This study was actually the second in a series from researchers at Osmind and Stanford University investigating ketamine using data obtained from real-world clinics. Hopefully these studies can provide a useful template for future research in a way which decreases costs of gathering information which can in turn lead to better third-party reimbursement and increased access to care.




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