We now offer even more on Schering-Plough's drug candidate, Saphris, or asenapine, from Salmon:
. . . .The background package shows the reviewer asked that the metabolites be properly identified and tested for phen-fen like pharmacology (agonism at the 5HT2B receptor).
The reviewer then disappears and someone else claims the metabolites were adequately identified when they weren't. It also looks like FDA management refused to even look into the receptor binding of the metabolites and they only talk about the effects of asenapine itself at receptors.
Even a screen of the most important metabolites should have only taken a few days. Identifying and testing all the metabolites could have been done during the past year.
Something similar happened with Phen-Fen. They had tested the metabolites internally and knew it was the metabolites that were toxic but didn't report the results to the FDA.
Looks like very suspicious to me. . . .~~~~~~~~~~~~~~~
Every AC meeting I've been to FDA sets up questions or issues for the AC to address. In this case they made the AC focus on schizophrenia study 023 and why the 5 mg worked and the 10 mg didn't. This distracts from the real issues, i.e. hepatotox, cardiac tox, and the higher baseline and low placebo response in study 004.
As expected the clinicians, who don't know statistics said well if the 5 mg dose works it must work (especially since the 5 mg dose in study 004 works. NOT. Whereas the statistician, the expert, said he didn't believe the 5 mg dose hadn't been shown to work in study 023 and they never even discussed 004.
Look at the YMRS quintile graph from page 761 (click to enlarge):
I'll explain my thoughts and concerns in the comments, below.
-- Salmon
One more, on top.
1 comment:
The graph is an exploratory analysis of acute drug response over 3 weeks during a manic episode. This is not for maintanance of the effect which also used in practice for prophylaxis of future episodes. (I won't get into the difference here.)
On the left is placebo, in the middle asenapine, and on the right the active control olanzapine, and the patient population is divided into quintiles based on the severity of the episode.
The reviewer is looking to see if there is difference in drug response depending on how sick the patient is. This is a reasonable thought because 1. it used to be that antipsychotics were only used in mania when a manic episode was so severe that there were psychotic symptoms and an antipsychotic was used to control them. 2. In other psychiatric diseases such as depression and schizophrenia where there are lots of negative and failed studies the probability of a successful study increases if you use sicker patients.
It appears the reviewer uses a local minimizaiton regression or LOESS fit to plot the lines. This is extremely powerful as it shows how the average of the response data changes continuously over time.
For the drugs the final score at the end of 3 weeks is always around 10, and as the patients get sicker the steepness of the slopes increase. Where as for placebo the final score at 3 weeks gets progressively higher as the initial severity increases and the slope of the response stays around the same.
Lastly you can see that the in 2 lowest quintiles of disease severity there's little difference from the response to placebo as compared with the response to drug.
However in the 3 highest quintiles of disease severity the patients on placebo progress from the high end of hypomania, to barely manic, to solidly manic. Meaning that there is some change from their baseline possibly due to hospitalization but most can't really be released from the hospital. Whereas with drug many patients who were severely ill to begin with can be released.
So looks like drugs work but only in the most severely ill patients. Less severely ill they don't (even though the drugs are approved for them) and since these drugs kill it's not worth it to use them.
Even more importantly 90% of use in kids is inappropriate and there's a push to prescribe as soon as possible mild symptoms occur to prevent development of mania later in life. Meaning 1 - 2 decades of treatment before they would really get sick enough to be used when you know the drugs work. Since these are expensive drugs ($500/month) and since they kill (>1%/yr) or maim even more frequently, (e.g. tardive dyskinesia 10% - 15% after a few years). It doesn't look like something we should do suggesting this should be looked into further and we should stop altogether with these recommendations for prophylaxis and be absolutely sure about diagnosis first especially in kids and adolescents where other psychiatric illnesses such as ADHD can be mistaken for mania. Especially since some KOLs funded by drug companies are pushing the mania diagnosis in kids (especially by general pediatricians) who have ADHD and are episodcially irritable. Which sounds like severe ADHD to me and possibly prodromal for Depression (MDD) and anxiety disorder which can be treated with less toxic drugs and therapy.
So if the reviewer is right about a phen-fen effect/ Considering the changes in the law for parity for mental illness in insurance plans. The government screening programs for mental illness in kids and pregnant women, and if we have a public option. Not only are we going to have an epidemic but we're going to break the bank on the deficit.
I wonder if this is what Sen. Grassley is thinking when he goes after all those academic psychiatrists.
Salmon
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