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Perks, Planning, and People: Things Hindering Off-Patent Ketamine’s FDA Approval for Depression

Ketamine infusion is a great remedy for a number of disabling mental health disorders. It quickly relieves the symptoms of bipolar depression, PTSD, substance abuse, acute suicidal ideation, and many others (Grunebaum et al., 2017; Feder et al., 2014; Jones et al., 2018; Bahji et al., 2021; Siegel et al., 2021; Vande Voort et al., 2017).

However, the generically available IV racemic ketamine lacks FDA approval for these conditions. So even if the evidence highly favors it over its intranasal counterpart, choosing a formulation for your ketamine clinic may still be difficult.

So why hasn’t the FDA authorized the psychopharmacological applications of intravenous ketamine? The answer, unfortunately, is something that even science cannot solve.

Off-Label vs. On-Label Ketamine Use: What’s the Difference, and Why Should It Matter?

Parke-Davis first patented intravenous racemic ketamine as a human and animal anesthetic in Europe in 1966, marketing it under the brand name Ketalar. The FDA approved it for the same indications in 1970 (Mion, 2017).

During its infancy, doctors gave intravenous ketamine treatment strictly to surgical patients. Research later proved the NMDA receptor blocker to be more powerful than earlier realized. But despite the rich science supporting its benefits, ketamine has not been relabeled to include major depressive disorder and other newer indications that are supported by medical literature.

FDA approval has many implications outside of sales and marketing (Verbaanderd et al., 2020).

First, it paves the way for greater insurance coverage, making treatments potentially more affordable for patients.

Second, it enables the FDA to document a drug’s post-sales performance. Post-sales data is kept accessible and publicly available, so it has a better chance of substantiating the clinical trial results that got the drug its official endorsement.

Third, FDA labeling regulations can help standardize treatments, reducing therapeutic inconsistencies. The FDA requires manufacturers to write a drug’s approved disease-specific doses on its label—the so-called “on-label uses”—or product leaflet.

Sadly, the initial evidence for ketamine’s psychopharmacological potential did not come to light until the turn of the millennium during the twilight of Parke-Davis’ patent (Mion, 2017). There is generally little to no incentive for a company seeking FDA approval for the novel uses of an off-patent drug (Sahragardjoonegani et al., 2021). This is because of the associated complexity and costs. These costs can run into the hundreds of millions, even into the billions of dollars for a final FDA approval.

What Prevents Racemic Ketamine from Getting FDA Approval for Major Depression and Other Mental Health Issues?

The FDA’s drug approval process has multiple stages. Rigorous reviews follow drug discovery and animal and human tests. Each phase can drag on for years and are extremely costly. Approval is indication-specific, given only for those conditions where a drug’s efficacy and safety are convincingly supported by many large-scale clinical trials (US Food and Drug Administration, 2020).

Anyone can file for FDA approval for any drug, patented or not, for any justifiable indication. But it is especially difficult for off-patent drugs like ketamine. Why?

The Expected Investment Returns Are Low

Patented drugs are protected by exclusivity. Drug patents and exclusivity rights generally last for 20 years (Dwivedi et al., 2010) but may be extended if a manufacturer discovers a different purpose for their product (Dwivedi et al., 2010; Sahragardjoonegani et al., 2021; Verbaanderd et al., 2020).

As long as a patent is in place, no generic drug maker can compete in the market with the patent owner. Drug developers can get back their massive financial investment plus profit during this time. Companies cannot revive 20-year-old patents or older ones once they expire (Dwivedi et al., 2010; Sahragardjoonegani et al., 2021).

Poor profitability is a big reason why no one currently seeks FDA approval for ketamine’s new indications.

Designing Ketamine Studies Is Difficult

Ketamine research planning is likewise challenging.

The best clinical trials have large sample sizes and excellent randomization, control, and blinding strategies. But good ketamine studies are hard to design because of the drug’s rather traceable effects. Ketamine’s psychotomimetic and dissociative effects can easily unblind any clinical trial (Jelen & Stone, 2021).

Using an active placebo-like midazolam is a solution. However, any active placebo can have unintended therapeutic actions. For example, a benzodiazepine like midazolam, which may have some antidepressant effects, may mask ketamine trial results (Jensen et al., 2017; Raymond et al., 2021).

Institutions May Be Willing, but Their Infrastructure Is Lacking

Non-commercial organizations like academic institutions and research foundations may also apply for FDA approval for a drug’s new indications. Funding is not exactly a problem for some of these establishments, especially if they have a string of wealthy benefactors. But what holds them back is their limited infrastructure.

Organizations seeking FDA approval have to prepare thick regulatory dossiers, update medical information, present safety monitoring data, ensure labeling accuracy, etc. (US FDA, 2018). These tasks need a large crew of workers with both scientific acumen and corporate skills.

Sales and marketing approval is not a one-time deal. Once obtained, the party holding it must maintain it yearly whether or not exclusivity is on the line. And non-commercial bodies, whether by law or choice, lack the manpower to fulfill all these requirements (Verbaanderd et al., 2020).

The law allows the off-label use of racemic ketamine, but officially repurposing it is fraught with financial, technical, and regulatory obstacles. Nevertheless, its unmatched ability to relieve severe depression, suicidal thoughts, and other psychological symptoms has turned ketamine clinics into mental health meccas.

Trusting the Science: Why Should You Choose Intravenous Infusion over Intranasal Ketamine Therapy?

Practitioners continue to use IV ketamine off-label for depression and other conditions despite the market entry of esketamine nasal spray. Here’s why:

  • IV infusion is safer and more efficacious overall than nasal esketamine (Spravato®) dosing in treating pain syndromes and major depression (Li et al., 2021; Balzer et al., 2020; Bahji et al., 2021; Siegel et al., 2021).

  • Infusions of generic ketamine are more affordable and accessible than intranasal esketamine (Spravato®) treatments.

The FDA allows esketamine nasal spray (Spravato®) sessions to proceed only under strict medical supervision, which includes two hours of in-clinic patient observation, and enrollment in the Risk Evaluation and Mitigation Strategy (REMS) program (US FDA, 2019). Meanwhile, many insurers place stringent coverage limitation on the treatment. Agboola and colleagues do not feel that long-term antidepressant therapy with Spravato® nasal spray is a cost-effective treatment (Agboola et al., 2020).

  • Using an off-patent generic drug off-label makes it available to patients now (Verbaanderd et al., 2020). It also makes it available to patients in the most affordable way.

So even without FDA approval, experts prefer IV racemic ketamine administration over intranasal dosing with its isolated enantiomer. Ketamine clinics have been thriving for years because of the proven reliability of the treatment’s generic IV version.

The Final Analysis: Will You Let a Minor Regulatory Quirk Limit Your Ketamine Practice?

Science strongly makes a case for IV ketamine’s antidepressant effect. But unlike esketamine nasal spray (Spravato®), the old formulation doesn’t have FDA approval for treating major depression and similar mental health problems. Commercial, technical and regulatory hurdles make it hard for any party to relabel off-patent drugs for new indications.

Despite this flaw, most ketamine experts still prefer the IV drug over its intranasal version in treating depressive symptoms. Off-label IV ketamine use by a certified professional is legal, in fact, roughly twenty percent of prescriptions in the United States are administered off-label. The scientific evidence also favors the generic formulation over its enantiomeric isolate. Additionally, the regulatory and insurance restrictions on esketamine (Spravato®) treatment have made it the less practical choice.

In the end, the decision is yours. Should you let a tiny snag keep you from giving the superior treatment option to someone suffering from a mood disorder? The answer should be clear.



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