1 Boring Old Man

pa·thog·no·mon·ic [puh-thog-nuh-mon-ik]
adjective

1. Medicine/Medical. characteristic or diagnostic of a specific disease.

in·di·ca·tion [in-di-key-shuhn]
noun

1. anything to indicate or point out, as a sign or token.
2. Medicine/Medical. a special symptom or the like that points out a suitable remedy or treatment or shows the presence of a disease.
3. an act of indicating.
4. the degree marked by an instrument.

I didn’t see detail men in practice, but my partners did. So occasionally, I would get caught. In one such captivity, the sales rep looked at me meaningfully and said with emphasis, "We’ve just found out that we have a new indication for whatever-drug-it-was in whatever-condition-it-was" [as if that had a very special, near mystical significance]. I had never heard it used that way [my ignorance a consequence of chronic avoidance of sales reps]. Later, I asked one of my partners, who explained that the FDA approved drugs for specific diseases or situations. I supposed that was a reasonable idea, a way of communicating what they looked at when they put the drug on the market. I later asked her, "Have they always done that?" She laughed at my by-then legendary naivity in such matters and said, "I don’t know, but what it really means is that they can advertise it for that indication" [truth comes in many forms, and that’s an example].

in·di·ca·tion [in-di-key-shuhn]
noun

1. Medicine/Medical. a special symptom or the like the FDA certifies for a pharmaceutical company’s marketing department to legalize their advertising it as a use for their drug.

FDA Advisors Support New Indication for Brintellix

Panel debates vortioxetine for treating cognitive dysfunction in major depression

MEDPAGE TODAY

by Kristina Fiore

02/03/2016

An FDA advisory committee voted 8-to-2 to give the antidepressant vortioxetine [Brintellix] a new indication for cognitive dysfunction in major depressive disorder [MDD]. The decision followed an unusual meeting format for the Psychopharmacologic Drugs Advisory Committee, with the first half of the day dedicated to discussing whether or not cognitive dysfunction in MDD is a suitable target for development, and if so, how exactly it should be studied…

Historically, the FDA’s division of psychiatry products within Center for Drug Evaluation and Research has taken the position that cognitive dysfunction in MDD was a pseudo-specific drug target, "meaning that this claim would be considered artificially narrow and related to the overall disorder of MDD," the agency wrote in review documents posted ahead of the meeting. But the organization changed its stance as more research has suggested that it can be considered a distinct problem that hasn’t been evaluated in drug trials.

Starting in 2011, Lundbeck, the original developer of vortioxetine, began submitting data on the drug’s efficacy in cognitive dysfunction to the FDA. In 2014, Takeda and Lundbeck met with FDA to further discuss the potential indication, and the agency ultimately decided on a public hearing to discuss both the possibility of such an indication and the efficacy of the drug on the same day…

In one of the approval trials, called ELDERLY, vortioxetine offered better results on the digit symbol substitution test [DSST] than duloxetine, prompting the companies to open two other trials focused on cognitive impairment in MDD: FOCUS and CONNECT, both of which enrolled 602 patients for an 8-week trial period. FOCUS looked at a composite of DSST plus Rey Auditory Verbal Learning Test [RAVLT] learning and memory for its primary endpoint, while CONNECT looked only at DSST — and both showed an effect, albeit a small one, according to FDA clinical reviewer Wen-Hung Chen, PhD…

Should the FDA decide that cognitive dysfunction in MDD is indeed a valid therapeutic target and that Takeda has demonstrated that vortioxetine improves the condition, the two groups will work together to define the exact terms of the labeling. The agency is not obliged to follow recommendations from its advisory committees, but it usually does.

[see also Medscape FDA Panel Backs Vortioxetine for Cognitive Dysfunction in MDD]

A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults.

by McIntyre RS, Lophaven S, and Olsen CK.

International Journal of Neuropsychopharmacology. 2014 17[10]:1557-1567.

[full text on-line]

[supplemental material]

Clinical Trial NCT01422213

The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder [MDD] was evaluated. Patients [18-65 yr, N = 602] were randomized [1:1:1] to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test [DSST] and Rey Auditory Verbal Learning Test [RAVLT] scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale [MADRS]. In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 [vortioxetine 10 mg, p < 0.0001] and 0.33 [vortioxetine 20 mg, p < 0.0001] on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 [10 mg: p < 0.0001] and -6.7 [20 mg: p < 0.0001]. Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

A Randomized, Placebo-Controlled, Active-Reference, Double-Blind, Flexible-Dose Study of the Efficacy of Vortioxetine on Cognitive Function in Major Depressive Disorder

by Atul R Mahableshwarkar, John Zajecka, William Jacobson, Yinzhong Chen and Richard SE Keefe

Neuropsychopharmacology. 2015 40: 2025–2037.

[full text on-line]

[supplemental material]

Clinical Trial NCT01564862

This multicenter, randomized, double-blind, placebo-controlled, active-referenced [duloxetine 60 mg], parallel-group study evaluated the short-term efficacy and safety of vortioxetine [10-20 mg] on cognitive function in adults [aged 18-65 years] diagnosed with major depressive disorder [MDD] who self-reported cognitive dysfunction. Efficacy was evaluated using ANCOVA for the change from baseline to week 8 in the digit symbol substitution test [DSST]-number of correct symbols as the prespecified primary end point. The patient-reported perceived deficits questionnaire [PDQ] and physician-assessed clinical global impression [CGI] were analyzed in a prespecified hierarchical testing sequence as key secondary end points. Additional predefined end points included the objective performance-based University of San Diego performance-based skills assessment [UPSA] [ANCOVA] to measure functionality, MADRS [MMRM] to assess efficacy in depression, and a prespecified multiple regression analysis [path analysis] to calculate direct vs indirect effects of vortioxetine on cognitive function. Safety and tolerability were assessed at all visits. Vortioxetine was statistically superior to placebo on the DSST [P < 0.05], PDQ [P < 0.01], CGI-I [P < 0.001], MADRS [P < 0.05], and UPSA [P < 0.001]. Path analysis indicated that vortioxetine’s cognitive benefit was primarily a direct treatment effect rather than due to alleviation of depressive symptoms. Duloxetine was not significantly different from placebo on the DSST or UPSA, but was superior to placebo on the PDQ, CGI-I, and MADRS. Common adverse events [incidence ? 5%] for vortioxetine were nausea, headache, and diarrhea. In this study of MDD adults who self-reported cognitive dysfunction, vortioxetine significantly improved cognitive function, depression, and functionality and was generally well tolerated.

Primary Analysis
Based on the ANCOVA analysis, the change from baseline [mean±SE] to week 8 in DSST performance score was 4.60±0.53 for vortioxetine, 4.06±0.51 for duloxetine, and 2.85±0.54 for placebo. The difference from placebo was significant for vortioxetine [Δ +1.75, 95% CI: 0.28, 3.21; P=0.019; ANCOVA, OC], with a standardized effect size of 0.254. The difference from placebo was not significant for the duloxetine group [Δ +1.21, 95% CI: −0.23, 2.65; P=0.099], with a standardized effect size of 0.176.

Depression Outcome
The study was validated because both vortioxetine and duloxetine demonstrated a statistically significant change from baseline in mood symptoms compared with placebo at the end of week 8, as measured by change in MADRS [vortioxetine, Δ − 2.3, 95% CI: − 4.3, − 0.4; P < 0.05; duloxetine, Δ − 3.3, 95% CI: − 5.2, − 1.4; P < 0.001; MMRM, FAS].