Janssen highlights insignificant findings along with modest results in esketamine nasal spray trials

New Phase 3 Data Show Esketamine Nasal Spray Demonstrated Rapid Improvements in Depressive Symptoms in Patients with Treatment-Resistant Depression

Our Review Summary

This news release focuses on two phase 3 clinical trials that evaluated the use of a drug called esketamine to treat depression. Both trials focused on patients who had not responded to at least two antidepressant drugs, and both trials used esketamine as a nasal spray, in conjunction with an oral antidepressant. One study focused specifically on patients over the age of 65.

The release provides a great deal of detail about the trial protocols and the specific differences in the depression scale that was used.  But the release, issued by a pharmaceutical company, does not address cost. And while the release does note that the trial in elderly adults produced no statistically significant results, it describes the results anyway. And while there may be promising results to report, the findings are reported in a way that makes it difficult to understand the advances — or even to tell the advances from the things that were inconclusive.

[Editor’s note: The review originally rated the Evidence section unsatisfactory. That oversight has been corrected.]

 

Why This Matters

Clinical trials, indeed any medical research, can be extremely complicated. News releases, theoretically, are designed to help reporters (and presumably other members of the public) get a handle on new findings, so that they can determine whether the findings merit a closer look. In other words, a news release should give reporters a basic idea of the findings, so that reporters can decide whether to pursue a news story (which would entail talking to independent sources, analyzing the study, etc.).

This release is, frankly, confusing. Hundreds of words are spent describing a trial for which there were no statistically significant findings, with the pharmaceutical manufacturer arguing that the findings should be considered anyway. The release also refers repeatedly to the “newly initiated oral antidepressant” used in both the control and placebo groups for both studies, without any information about which antidepressants were used. The release does refer to two pages on ClinicalTrials.gov, which contain relevant information on the first trial and on a second trial focused on older adults. But honestly, that’s not good enough. And the failure to address cost, even in general terms, is deeply problematic. What’s more, the primary efficacy endpoint (i.e., how they could tell whether the drug worked) is described in technical terms that are difficult to parse for many readers. Is there good news here? It’s hard to say. There’s a lot to wade through, and that makes it difficult to separate the wheat from the chaff.

Treatment-resistant depression is a common and vexing problem.  Although many people may not receive adequate dosing or try a different antidepressant when the first one does not relieve symptoms, there are presumably a large number of people who would benefit from a different therapeutic approach. The danger of such news releases is in not being completely clear about when these drugs might be medically indicated and what the longer-term outcomes might be.

Finally, the general anesthesia drug ketamine, an older sibling of esketamine, has been in the news a lot recently for its potential to treat people who have not been helped by depression medications. Many news stories reflect anecdotal results in a few patients or results from very small, short-term studies. Esketamine is sometimes portrayed as a milder or safer version of ketamine. It is expected that Janssen will apply for quick FDA approval of esketamine nasal spray based on the results of these two studies.

Criteria

Does the news release adequately discuss the costs of the intervention?

Not Satisfactory

Costs are not addressed and they should be. While esketamine spray is a newer version of ketamine, which has been in use as a general anesthetic for 50 years, that drug has been off-patent for many years. A new version of the drug, presented in a nasal spray formula, is eligible for patent protection once it is approved by the FDA.

Does the news release adequately quantify the benefits of the treatment/test/product/procedure?

Satisfactory

The release does include numbers for the one trial that produced statistically significant benefits, but it’s a very technical explanation and probably too difficult for most lay readers to interpret. It states:

“The primary efficacy endpoint, change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, demonstrated the statistically significant clinical improvement in patients’ depressive symptoms for esketamine nasal spray plus an oral antidepressant at day 28 (Least Squares Mean Difference Standard Error from placebo nasal spray plus a newly initiated oral antidepressant: -4.0 [1.69], 95% Confidence Interval [CI]: -7.31, -0.64; one-sided p=0.010).”

That gets it a satisfactory rating here. However, it’s worth noting that a news release (or a news story) should be expected to provide some context and to help non-experts grasp technical concepts in real terms. How big a difference would these numbers make? An expert may be able to tell readers that, but that expertise is missing from the release. It would have been much stronger if it had provided even a concise explanation of what these numbers mean.

Does the news release seem to grasp the quality of the evidence?

Satisfactory

Sufficient detail was given about the double blind randomized controlled trial (RCT) study design, and the number of subjects enrolled was addressed in the “About the Studies” section of the release.  It would have been helpful to know which oral antidepressant was used.

The non-significant results of the second study involving elderly patient volunteers is addressed under the Unjustified Language criterion.

Does the news release commit disease-mongering?

Satisfactory

No disease mongering here.

Does the news release identify funding sources & disclose conflicts of interest?

Satisfactory

It’s clear that the work was funded by Janssen Pharmaceutical Companies, and the affiliation of the experts quoted in the piece is similarly clear.

Does the news release compare the new approach with existing alternatives?

Not Satisfactory

The trials at issue here are specifically aimed at patients for whom two or more antidepressants did not work. However, there are some additional alternatives for treatment-resistant depression which could have been included in the release, such as electroconvulsive therapy and atypical antidepressants. Many people with depression are given selective serotonin reuptake inhibitor, or SSRI (Prozac, Lexapro, Zoloft and others) or similar medications by their primary care doctor, and if that fails, are given another medication in the same class or in the serotonin and norepinephrine reuptake inhibitors (SNRI) class of medications. Psychiatrists have a larger arsenal of medications and therapies to try.

Does the news release establish the availability of the treatment/test/product/procedure?

Satisfactory

The release is fairly clear that esketamine is still under investigation and is not yet clinically available.

Does the news release establish the true novelty of the approach?

Satisfactory

Although there are other medications used in combination with antidepressants, this treatment strategy is a novel use of a new medication class. We will see (presumably in additional trials) if the response is long-term.

Does the news release include unjustifiable, sensational language, including in the quotes of researchers?

Not Satisfactory

The headline refers to “rapid improvements in depressive symptoms.” The word “rapid” can mean different things to different people. But the key endpoint highlighted in the release was a change in baseline depression symptom scores at day 28 of the trial. For people experiencing depression, 28 days may not seem “rapid.” In addition, the release includes three bullets just under the headline. These are clearly placed to serve as highlights for readers. The second bullet notes: “Study in elderly patients is the first large clinical trial in treatment-resistant depression in this population.” Lower down, the release tells readers that: “Data from a second study, in elderly patients aged 65 and older with treatment-resistant depression, which is the first study of its kind, showed treatment with flexibly dosed esketamine plus a newly initiated oral antidepressant demonstrated clinically meaningful effects compared to placebo nasal spray plus a newly initiated oral antidepressant.” Wow! But wait a second. The very next sentence notes that the study missed statistical significance. We applaud the decision to tell readers that the study didn’t have any statistically significant findings. But the fact that they trumpeted those (statistically insignificant) findings first is problematic.

Total Score: 7 of 10 Satisfactory

Comments (1)

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Charles Carter

June 14, 2018 at 8:04 pm

Just what America needs! Another enantiomeric me-too patented drug that has no evidence of benefit!

Reply