![](\"http:\/\/1boringoldman.com\/images\/pipeline-y.gif\")
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Last night, I spent some time writing a letter to the FDA. It was about Vortioxetine <\/font>[Brintellix®<\/font>] and their application for an approval for Cognitive Dysfunction in Major Depressive Disorder<\/font> [see indications…<\/a> and more vortioxetine story…<\/a>]. This morning I got a confirmation that it had been passed along to "the Division" [which I suppose is better than the alternative]. My letter was a less "bloggy" version of indications…<\/a> and more vortioxetine story…<\/a>. While I’m hardly holding my breath, it felt kind of good to actually send a letter to the place that ought to hear it rather than just post it to the universe at large on a blog at the edge of the galaxy. <\/p>\n 7.4.1.<\/font><\/strong> The Sponsor conducted two adequate and well – controlled trials to assess the efficacy of brexpiprazole for the adjunctive treatment of MDD. Based on the prespecified statistical analysis plan, only one of these trials [Study 331-10-228] was positive. The Sponsor acknowledges that Study 331-10-227 was not positive based on the pre-specified plan, but provides a number of arguments to support the concept that brexpiprazole should nonetheless be approved for this indication.<\/p>\n <\/p>\n Last night, I spent some time writing a letter to the FDA. It was about Vortioxetine [Brintellix®] and their application for an approval for Cognitive Dysfunction in Major Depressive Disorder [see indications… and more vortioxetine story…]. This morning I got a confirmation that it had been passed along to "the Division" [which I suppose is better […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-63818","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63818","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=63818"}],"version-history":[{"count":21,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63818\/revisions"}],"predecessor-version":[{"id":63850,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/63818\/revisions\/63850"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=63818"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=63818"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=63818"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}I see this as something of a dangerous time. We’re at the end of a pipeline<\/font> period<\/font><\/em> in psychopharmacology – one that lasted for a really long time considering that there were only a couple of classes of drugs involved. But then the pipeline<\/font><\/em> dried up. The approval of Brexpiprazole®<\/font> as an Adjunct to Antidepressants in Treatment Resistant Depression is an example of why it’s a dangerous time. They presented two trials with the amazing pixie dust of changing the outcome definitions in the middle of the trial to bring the second study into statistical significance. The FDA reviewer didn’t buy it…<\/div>\n\n
7.4. <\/font><\/strong>Adjunctive Treatment of MDD<\/a><\/div>\nApproval of the adjunctive MDD indication would have to rest on one of two possible scenarios: 1. Study 331-10-227 can be considered a positive trial based on the retrospective application of Amendment 3 criteria and use of the per protocol population instead of the intent – to – treat population for the primary analysis. 2. Study 331-10-228 can be considered “strongly positive” and, thus, approval can be based on this single study. Study 331-10-227 would then be viewed as “supportive evidence” for this approval.<\/div>\n<\/blockquote>\nbut then ended with…<\/div>\n\n
One can also reasonably consider Study 331-10-228 a “strongly positive” study — in a population of individuals with a history of multiple failed antidepressant trials and prospectively demonstrated suboptimal response to an additional antidepressant, the addition of 2 mg\/day of brexpiprazole yielded an average additional symptom improvement of just over 8 points on the MADRS. This was 3 points beyond the improvement in placebo — a difference that was highly statistically significant at p=0.0001. These results are both clinically and statistically meaningful. <\/div>\nThus, with one strongly positive trial and supportive evidence from two additional trials, there is adequate evidence of efficacy to approve this product for the adjunctive treatment of MDD.<\/div>\n<\/blockquote>\nThat’s a peculiar conclusion. The FDA standards are low, actually shamefully low. Two positive trials out of as-many-as-you-want-to-do. And positive means statistically significant<\/font><\/em> rather than clinically significant<\/font><\/em>. For example, this drug for this indication flunked clinically significant<\/font><\/em> by any objective measure I know – Subject Rated Scales and Effect Sizes. But I’ve said that so much I might get thrown off the Internet for terminal monotony. My point this time is that the reviewer’s logic is upside down. Given what we know about Clinical Trials, a better interpretation would be that the second study did not replicate the first<\/font><\/em><\/strong>. Replication<\/font><\/strong><\/em> is something of a gold standard, and it should be. That’s what we do in practice, count on the fact that the results of a clinical trial will be replicated<\/font><\/em><\/strong> in our patients. So I’m concerned that in the face of the empty pipeline, the FDA will do things like this, stretch their already too-low standards even lower – something they did in this case.<\/div>\n![](\"http:\/\/1boringoldman.com\/images\/vortio-6.gif\")
The story with this Brintellix®<\/font> application for approval is the same issue – a failed replication<\/font><\/strong><\/em>. Their second study [CONNECT] did not reproduce the results of the earlier trial [FOCUS]. While there are lots of other questions about approval for this indication, they’re in the background to this non-replication<\/font><\/strong><\/em>. So it’s a dangerous time because here’s another situation where they’re about to give a drug the benefit of the doubt if they follow the recommendations of the advisory committee [see more vortioxetine story…<\/a>]. There’s no reason to do that. Brintellix®<\/font> has never beaten another antidepressant head-to-head – and this indication [Cognitive Dysfunction in Major Depressive Disorder<\/font>] seems both contrived and unproven. <\/p>\nThe only result from this approval will be to allow Takeda\/Lundbeck to create misleading advertisements. It’s not going to help any of our patients in any substantive way… <\/div>\n","protected":false},"excerpt":{"rendered":"