Thursday, July 30, 2009

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

VoteEfficaciousSafeBalance
Yes10109
No201
Abstain022


Bi-Polar Indication

VoteEfficaciousSafeBalance
Yes121212
No000
Abstain000

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. . . .

~~~~~~~~~~~~~~~~


[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. . . .

10 comments:

Anonymous said...

If this drug was really safe and effective why would Pfizer have dropped it?

Condor said...

Ding!

Exactly. And, why would J&J, the day after meeting with Schering-Plough, and deciding NOT to make a bid for the company -- file an NDA on its own homegrown candidate, rather than just bolt-on asenapine?

Same reason -- same thinking.

Namaste

Anonymous said...

Sorry try 761. Begin readin on 759through - 764.

Looking at the background package and being at the AC meeting. I've really got to wonder if the AC members even looked at the background package or only read Laughren's comment that he agreed with SP and if they read anything read SP's background package. (Since on person referred to SP's package).

SP even had their slides in color, 2 per page, bound and were handing them out to the audience. The slides were clearly misleading. The dose response slide in schizophrenia only showed up to 1 dose at 5 mg. Not the studies that asenapine was negative in and not the 10 mg dose. If they had shown these and the difference from placebo instead of or in addition to the absolute change as well as the 10 mg dose, I bet that single 5 mg dose would like like an outlier.

Anonymous said...

When you think about this is what this drug has going for it:

Fetal toxicities like thalidomide

Liver toxicities like rezulin

Cardiac toxicities like phen-fen

The latter 2 were noticed by FDA reviewers pre-approval in just a couple of people, and all 3 of which the companies knew of prior to submitting to FDA.

Anonymous said...

Nice catch of Table 181 on page 757re: Organon's (SP's) modeling on the response in bipolar. Notice that the pop mean is higher than the median and the individual model prediction and how the later 2 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 BP1 (YMRS >/= 20) but people use them for BP2 (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 BP2. This is probably why no company even tries to study these drugs in BP2 (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 you see 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 we would see comparison's of safety across similar drugs in the NDA reviews that are released which 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.

Salmon

Anonymous said...

You like direct quotes from the sponsor.

TAKE A LOOK AT PAGE 792.

This is why they don't want you swallowing it.

I have more but I think I've given you enough for now.

Salmon

Anonymous said...

Look at page 791 also. The clinical pharmacology reviewer claims he was told not to review this clinical pharmacology study.

Anonymous said...

per pg 888 ...and the lackof many specific pieces of information in the submission as well as other things indicate that the sponsor knew of this toxicity and specifically tried to prevent our detecting it..

cardio tox whoops...

Anonymous said...

As an addition to this earlier post. The chairman and others (FDA officials and SP) at the AC meeting kept emphasizing that a 'failed study' was when the test agent arm was negative. This has been used by SP in their publications and by the medical reviewer in his review addendum changing his usage. However other drug companies have used it publicly to indicate a study where a positive control did not work. So the AC Chair seems to be working with FDA officials to fight the clinical pharmacologist's usage of the term.

"Thus this is a ‘failed’ study and the major problems noted in this review have already been described in the financial press"

There was also an AC member who kept referring to his practicing in Connecticut who indicated it would be useful to have a sublingual formulation. Especially for patients who can't swallow, especially they have a lot of them in Connecticut.

Now there are basically 3 patient subpopulations who you would expect to use this product and to have trouble swallowing.

1. Elderly (especially in nursing homes with dementia - class effect black box warning about death with antipsychotics).

2. Patients with Tardive Dyskinesia (TD) an extremely problematic side effect with antipsychotics. Commonly with TD there are choreoathetoid (mix of writhing and jerking)movements of the mouth, jaw and esophagus. When the esophogus is effected death due to choking on food commonly occurs. So a sublingual formulation might allow administration additional drug that might exascerbate the condition.

3. Children 8 and younger. When I examine the roster of AC members, the only one I can find from Conn. is a child and adolescent psychiatrist.

He also asked about other dosage strengths in the future and physicians playing with the dose. Thus it seems to me that an AC member is pushing for approval for use off-label in a potentiall especially dangerous manner. This is in direct violation of the requirments for approval (i.e. nonapproval is required by law) also by FDA regulations AC members are supposed to be unbiased and trained by the FDA in the laws regarding drug approval. Prima Fascia it seems to me that FDA is falling down on the job.

Salmon

Mirror said...

Saphris made me very sick. I developed an encephalopathy that resulted in an MRI, a EEG, and two neurologists. I am now in therapy because I am having flashbacks from it. I need your help, salmon.