Salmon's Latest "Asenapine Chronicles" Report -- Filed From Inside the Room. . . .

Salmon favors us with an "on the scene" report -- from inside the FDA Psychopharmacologic Drugs Advisory Committee's Hilton meeting room -- in Silver Springs, Maryland -- Thanks, Salmon!:

. . . .The PDAC meeting has ended.


Like the last few meetings on AC member wanted a third question of given that they've voted on if a drug is "acceptably safe" or not she wants to then vote on safe relative to the efficacy. To me the idea of safe has to by it's nature include a intellectual balance with efficacy. Because you can't vote on rates of AEs and safety is a judgement on rates of AEs, severity of AEs etc. as compared to the efficacy and the alterative of not treating.

Then it did come out that the AC members are abstaining on voting regarding safety if they vote no on efficacy. To me this is absurd because the way it's reported and used the abstentions are basically ignored.

Here are the tallies:

Schizophrenia Indication

Vote	Efficacious	Safe	Balance
Yes	10	10	9
No	2	0	1
Abstain	0	2	2

Bi-Polar Indication

Vote	Efficacious	Safe	Balance
Yes	12	12	12
No	0	0	0
Abstain	0	0	0

The way the questions are worded they only vote on safety for the 3 - 6 weeks of the studies. Even though it will likely be approved later for long term and Dr. Laughren indicated long term use will be implied by the labeling (since no one would ever switch to another drug and standard is long term use).

Based on the standards used in the meeting today thalidomide would have been approved.

You know how SP spins the financials? Well, their presentations today were the same. There was a discussion about suicides and Schering-Plough acknowledged that they were comparing six week placebo rates to one year drug rates and then ASSUMED rates were stable (bad assumption) since we know suicide is most likely to occur early with drug treatments in depression etc.

[". . .Table 181 of the Sponsor’s analysis confirms that the differences although statistically significant, may have minimal clinical significance. . . ." See page image, at right, Page 757 (of 1,067) -- as ever, click it to enlarge -- Per Salmon's later thoughts, below:]

Nice catch of Table 181 on Page 757 Organon's (now Schering-Plough's) modeling on the response in bipolar. Notice that the population mean is higher than the median and the individual model prediction and how the latter two overlap. This may be indicative of differences in response by disease severity and supports the reviewer's post hoc exploratory analysis on page 761.

You know all these companies get these drugs approved for Bipolar 1 (YMRS >/= 20) but people use them for Bipolar 2 (YMRS 12 - 19) yet the average score at the end of 3 weeks is only around 12. So you know it isn't likely to differentiate from placebo in Bipolar 2. This is probably why no company even tries to study these drugs in Bipolar 2 (hypomania). Plus you know there's got to be a minimum cutoff below which you can't show a difference and it's well known as that response in depression trials and schizo trials is related to disease severity with a positive study if sicker patients are used. So a priori the reviewer's post hoc exploration by disease severity makes sense to do. What would make sense is to confirm this is to go into FDA files and see if one sees similar patterns with other drugs in NDAs. However I doubt FDA management would like analyses about other NDAs showing up in the review of a competitor's drug. Otherwise one would see comparisons of safety across similar drugs in the NDA reviews that are released -- and we don't. FDA management might be able to say something about that, but I doubt they can totally stop someone from putting something in the review about the drug in question. Although I imagine -- based on Dave Graham, Andy Mosholder and others -- they might try to suppress it, or dismiss it, like they did by calling up the journal that Graham was trying to publish in. . . .

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[Back to the main post:]

As for efficacy NO mention at all that the baseline disease severity was not comparable in study 004.

No mention at all of the concerns of PAH long term.

No mention at all regarding the possibility that efficacy in bipolar might be related to disease severity (see page 759 - 764 and especially the graph on page 761). Although there was discussion how the placebo response rate in schizophrenia has been going up over the past 20 years (likely because they're studying less severely ill people.)

They did seem concerned about long term safety and kids, but basically said the drug was safer than Zyprexa because it didn't cause as much weight gain. In spite of the fact that it appears the diabetes might be due to a toxic effect on the pancreas and not due to the weight gain.

There was no discussion at all of the dose and time dependent hepatotoxicity (page 385) that appears to be due to a toxic metabolite that's formed on swallowing. Which is probably why the instructions are not to eat or drink for 10 minutes and the real reason for BID dosing and not the half-life of D2 receptor occupancy as they claimed. If BID dosing and efficacy is because of D2 receptor occupancy then why even develop a drug to block serotonin receptors and why were the early studies with low oral doses once daily.

AC members talked about Schering-Plough coming out with a 2.5 mg dose for children (as distinct from adolescents) yet admitted in practice people dose differently than labeled (which often means pushing the dose).

I can just see little kids (5 - 6 yo) given this because it's sublingual, the doc pushing the dose to the maximum adult dose (10 mg bid), and the kid swallowing the drug once the tablet disintegrates.

Personally I think we're going to be seeing a lot of liver failure in kids.

Since PAH is already being reported with the other atypicals in kids I think this one will also be problematic. We just won't know how bad until someone like Dave Graham (Vioxx) fights FDA management to let the info out.

Look for it in about 5 years.

-- Salmon

July 30, 2009 3:34 PM

[Later: Click image of Slide 34, at right, to enlarge. . . .]

Take a look at slide 34 on page 857 which contains the efficacy data for the four schizophrenia studies.

The statistician on the the AC committee voted no on efficacy for schizophrenia because he thought the efficacy for the 5 mg dose in study in 41023 could be due to chance and there were problems such as attrition rates.

Plus for study 41004 [the other 'postive study' (really failed study)] you can see where not only is the baseline for the asenapine group high but the placebo response compared to the three other studies is weak.

I think there are potential issues with both of the two so-called positive studies.

-- Salmon

July 30, 2009 5:07 PM. . . .