It's not often the President of the United States tells a convention of veterans about the wonders of a hallucinogenic, but that's what happened last week, as President Trump took the unusual step of touting Spravato, a drug recently approved by the FDA for treatment-resistant depression.

"You take it, it’s an inhaler...and its results are incredible," Trump said on August 21 to the American Veterans 75th National Convention in Louisville, Ky. "I’ve instructed the top officials to go out and get as much of it as you can from Johnson & Johnson."

Suicides are rising among veterans, and pressure has been mounting for health officials to take action. While the president's remarks may have been more freewheeling than those commonly offered by clinicians, in extolling the new drug, Trump echoed the position of many medical organizations taken to describing the drug as a "breakthrough." The Mayo Clinic recently credited Spravato as having specifically anti-suicidal properties.

But the clinical trial evidence for Spravato was so deficient upon submission for approval that the FDA committee reviewing the drug had to change its rules in order to greenlight the drug for sale last February, noting its breakthrough status in accepting a weaker type of scientific evidence for one of the drugmaker's two mandatory successful trials.

The VA, for its part, recently voted against putting the drug on its formulary, triggering a more challenging pathway for veterans seeking use.

The evidence for Spravato as an agent for suicide prevention is lacking. Though they were not seen as caused by the treatment, the six deaths recorded in trials of the drug were among patients who were taking the medication, three of them by suicide. And in a departure from the growing call for cheaper drugs, Spravato, whose generic name is esketamine, is expected to be highly expensive, costing $4,270-$6,785 for one month, then half as much for each month thereafter.

These and other liabilities proved troubling to Kim Witczak, a patient safety advocate from Minneapolis and the designated consumer representative on the FDA's Psychopharmacologic Drugs Advisory Committee that approved the drug on a 14-2 vote.

"I don't know how they say it's anti-suicidal," says Witczak, who was one of two members to vote against the drug. "I think that's a big leap from what the studies show. The media need to do a better job of not running those press releases that say a drug is a breakthrough. That term is a mechanism to get a drug fast-tracked."

Drugs branded as breakthrough treatments are commonly envisioned as the product of cutting-edge research, but Spravato is a chemical cousin of an old drug — a horse anesthetic named ketamine — an illicit hallucinogenic widely known within the early 1990s rave culture as Special K. Because Spravato, even in a smaller dose than ketamine, induces some of these temporary feelings of floating outside of your body, it can only be administered in a certified doctor's office.

"This drug's been around for 50 years, so I think we know what ketamine does," said fellow committee member Dr. Steven Meisel during PDAC meeting deliberations. "But not when it's used once a week or thereabouts for life."

Meisel, Director of Medication Safety at Fairview Health Services, was travelling and deferred to his published comments for this article. After expressing numerous concerns with the drug at its approval review in February, he voted to approve Spravato.

When given in anesthetic doses, research has shown and some clinicians believe ketamine can have a transformative effect on mood, one that is fast-acting if not always long-lasting. But the dose administered in esketamine is far lower. Because ketamine operates on a separate chemical pathway in the brain than do most antidepressants, clinicians regard it as an alternative for the 30%-40% of patients with depression who do not respond to currently available medications.

This alone is a confusing message to critics of the new drug.

"So now the message is that antidepressant drugs aren't working," says Witczak of testimony offered by patient groups in favor of esketamine. "But for years everybody has been saying that antidepressants are lifesaving. So I find it ironic that now they don't work. Because of that claim, they're now able to use a 'breakthrough therapy' designation [for Spravato], and that means they don't have to produce the gold standard of clinical trial evidence, which is two randomly-controlled, double blinded studies. So they were able to use different type of studies to get approved, studies that were less stringent. That's one of the things that I'm seeing."

Witczak says she also had concerns that Spravato will eventually become a drug intended only for the doctor's office that becomes used far more liberally.

"Once a drug is on the market, a doctor can prescribe it for any use they want," she says. "The fact that it's a nasal spray, I can just see the whole thing getting out of control."

"Let's propose a scenario where you have somebody who lives in the middle of No Place, North Dakota," Meisel remarked during the hearing, "has to drive three hours to a facility that is certified [to dispense Spravato], is doing well, never has any side effects. Over the long haul, this person is going to say 'let me do this at home' or 'let me do this at my local family practice office,' who's not certified."

The pair aren't alone in raising questions about esketamine. Jeffrey Lieberman, a former president of the American Psychiatric Association, recently called the approval of the medication "a question of practice leaping ahead of research," adding that it's "because research takes a long time to do and is dependent on funding ... and the pharmaceutical companies are funding only limited things that are in their specific product development interest."

Witczak says the FDA takes cover for the many safety unknowns surrounding the new drug thanks to a novel designation whereby manufacturers propose special ways of monitoring side effects following approval, a regulatory pathway known as REMS.

"All of the new drugs are coming onto the market with REMs, short for risk elimination mitigation strategy," she says. "But there's no teeth to it. The FDA can't really hold them accountable ... I think a lot of the advisory committee members use the REMS as a reason to approve something."

During the hearing, Meisel noted a host of concerns about the safety of esketamine prior to concluding that the drug's potential for benefit outweighed its risks. At one point, he called its parent drug ketamine "a nasty drug," then asked researchers if they had observed nightmares in patients who took esketamine, as can occur with ketamine.

"But the fact that we didn't see any of that reported by either the FDA or [the manufacturer] raised a question in my mind how hard we looked for that sort of thing," he stated in his comments, "particularly since that might have occurred long after the patient left the clinic."

"I think that advisory committee members just inherently approve drugs," says Witczak, who has served on reviews for eight drugs in total, all of which have been approved. Of the possibility of a new drug failing a vote in front of the committee, she says, "you'll never get that. I've never seen it."

"I think it's easier for people who really want to believe that more drugs on the market is better to just vote yes," she says. "They want options for patients, and so they don't want to be on the record voting no."

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