Monday, September 7, 2009

Salmon's Asenapine Chronicles, Continued -- Elaborating on MacGuffin's Post of Yesterday. . . .

First, go read the post here, relating to MacGuffin's asenapine ponderings -- then, here are more of Salmon's elaborations, post FDA-approval of Saphris® (asenapine) -- on the arguably deceptive marketing themes outlined by MacGuffin:

. . . .I do believe MacGuffin has led me to strike gold once again and I will address this in a second post (in Part 2, coming soon), but first let me address MacGuffin's questions.

Yes, the lack of published human studies is a signal, but minor compared to what we’ve already discussed.

The rat and receptor studies are as MacGuffin suggests selective publication of data to highlight the marketing angles that SP wants to emphasize in fact the FDA clinical pharmacologist’s review points this out for cognitive effects and worries that they may be used for pushing asenapine off-label in the dementia in the elderly. In addition to this and the push for marketing for negative symptoms they also appear to be direct hits at the clinical pharmacologist’s concerns about the potential for 5HT2B inverse agonism by metabolites and his concerns about phen-fen like effects as SP has published showing antagonism of asenapine at the suspect receptor while providing no data on metabolites that are present in much much higher amounts that would likely be more than enough to counteract any effect of asenapine itself. (In fact someone even put the asenapine info sans comments on metabolite receptor binding in Wikipedia.)

The FDA reviews provide sufficient detail to show the problems in these human studies but by not publishing them they are much harder to find and thus likely won’t be critiqued in the medical literature. Plus as the FDA reviews won’t show up in pubmed no one will think to look for them other than in the labeling (which is misleading) as basically academics don’t know to look for FDA reviews at Drugs@FDA. However even if the human studies are published, many times the data, and the spin, and the take home message of published studies are much different than the FDA analysis of them.

As for the peer reviewed asenapine study. This is the phase II study (study 41004) and the 174 patients are spread over 3 treatments, so less than 60 subjects per arm with the drop out rate so high that only 21 – 28 subjects remained at the end so that the statisticians felt it wasn’t adequately controlled. Plus if you notice the abstract from MacGuffin’s footnote 7 it doesn’t report PANSS score change for risperidone because it wasn’t significant and thus as the clinical pharmacologist points out this was a failed study. [Yet Saphris won approval(!) -- Ed.] As for significance for positive symptoms alone this is a post-hoc analysis and typically no one ever does this a priori.

-- Salmon
September 6, 2009 @ 11:07 PM

Part Two, shortly.


Anonymous said...

Well MacGuffin has posted a followup on the Carlat Blog.

SP appears to be currently looking for "hired guns" to promote asenapine via 'CME'.

I have sent in a comment which includes some new comments on asenapine explaining some of the comments from the FDA reviewer on e-mail graphic that's attached to this post. I point out how Pfizer/Organon/SP/Merck did some intentionally misleading drug interaction studies.

I also have some preliminary comments on some of my safety findings so far for iloperidone. I am still working on the FDA docs but it's clear that they likely abused the MMRM analysis in order to get a so called positive study (I've mentioned in comments here before that theoretically that it's good but it's too easy to game to get the results you want.)

Plus the FDA medical reviewer for iloperidone claims the atypical antipsychotics cause suicides and it's clear iloperidone causes psychosis (and from statements Bob Temple has made in the press using similar wording this likely also applies to bifeprunox).

Also looking into the medical reviewer for iloperidone it appears she is no longer reviewing psych drugs but is instead inspecting clinical sites and after the original nonapproval where Laughren (the psych division director) and Temple (the Director of Medical Policy) agree with her they have a meeting with the company (without the medical reviewer) and then magically change their opinion saying a study is positive which they previously said was negative.

This like asenapine is going to take weeks to months to go through in detail. But it's beginning to look like a pattern to me of getting rid of reviewers who recommend nonapproval. Either by recommending nonapproval when it's the medical reviewer or delaying the review in the case of asenapine where the medical reviewer went along but other reviwers didn't and then approving the drug later.

In both cases a week or 2 before the PDUFA due date FDA changed their policies to allow an extension of the review clock, (Asenapine policy change 6/23/08), or a change from approvable letters to complete response letters (iloperidone 7/10/08).


Anonymous said...

Very Interesting!
Thank You!