Wednesday, February 4, 2009

"Deja Vu, All Over Again"? -- From the LAST Pharma Hassan and Cox Ran Together. . . .

The companies' names have changed, but the two key players (and their modus operandi, at least allegedly) are a spot-on match. Alaska Electrical Pension Fund, et al. v. Hassan, Cox, Pharmacia, et al., (3d Circ. Appeal 07-4500).

The year was 2000; the company was Pharmacia, ultimately acquired by Pfizer (at a perhaps inflated price); the franchise drug was called Celebrex; and the study was called "CLASS".

Both Fred Hassan, as CEO, and Carrie Cox, as President, were sued -- and personally named as securities fraudsters -- for allegedly truncating, and then downplaying, less-than-fully positive drug study results. The original 10-b5 securities fraud suit has just been reinstated by the Third Circuit, ruling that a so-called "storm warnings" approach, for determining when the statute of limitations began to run on the plaintiffs' claims -- was incorrectly applied (too-strictly) by the courts below. Let's read along with the Third Circuit (full opinion PDF) -- as this may well be where ENHANCE, and Vytorin/Zetia, as well as Hassan and Cox, at Schering are headed:

. . . .In this securities fraud class action, plaintiffs allege that defendants violated §§ 10(b) and 20(a) of the Securities Exchange Act of 1934 by making, with scienter, materially false statements about a clinical study of Celebrex, a popular anti-inflammatory medication. In particular, defendants are alleged to have misled investors by distorting the study’s results with the intent to show that Celebrex had a better safety profile than similar medications. . . .

Substantially more expensive than many other nonsteroidal anti-inflammatory drugs (“NSAIDs”), Celebrex’s promise was rooted in the hope that it would cause fewer gastrointestinal (“GI”) side-effects than the less costly NSAIDs.1 To help the hope become a reality, defendants commissioned a long-term clinical study of Celebrex’s effect on the GI system, the Celecoxib Long-term Arthritis Safety Study (“CLASS study”). This litigation focuses on the aftermath of that study.

According to the complaint, the results of the CLASS study were a disappointment to defendants: Celebrex did not show the desired reduction in GI side-effects as compared to the other drugs studied. Fearing a decrease in sales and stock price, defendants allegedly undertook to distort the results of the study so that it would appear that Celebrex possessed a better GI safety profile than, in fact, it did. Towards this end, in April 2000, defendants released only the results from the first six months of the CLASS study; those results, divorced from the entire set of data, were capable of positive construction.

Defendants released the truncated results of the CLASS study with great fanfare, declaring that the study “shows that Celebrex has a truly exceptional safety profile,” and that “the longterm outcome data paints a clear and compelling picture of Celebrex’s safety versus NSAIDs.” (Joint App. (“JA”) 59, 64.)

Some documents issued by defendants noted that the CLASS study lasted a full thirteen months, but the reason for excising the last seven months from the analysis was not revealed. . . .

Scientists affiliated with defendants then drafted an article based on the truncated results and submitted it for publication to the Journal of the American Medical Association (“JAMA”). As would become known only later, however, neither defendants nor the article’s authors informed JAMA that the data in the article was incomplete. . . .

Months later, on August 5, 2001, the Washington Post reported that defendants had withheld the full CLASS study data from JAMA. In the article, JAMA’s editor described herself as “disheartened” and stated that “a level of trust . . . was, perhaps, broken.” (Id. at 203.) Additionally, a scientist who wrote an editorial published in conjunction with the JAMA article stated that he was “flabbergasted” when he saw the complete data; another scientist “said he complained to JAMA after noticing differences between the published [JAMA] report and the data presented to the FDA.” (Id. at 203-04.)

After the Washington Post article raised the red flag of impropriety, other sources began to question defendants’ good faith. For example, an article from The Sunday Times noted that the scandal involving the CLASS study had inspired medical journals to “stop drug firms from ‘cheating’ on medical studies.” (Id. at 1360.) On June 1, 2002, an article in the British Medical Journal called the “explanations for [the] serious irregularities [in the JAMA article]. . . . inadequate.” (Id. at 757.) The article also stated that “[p]ublishing and distributing overoptimistic short term data using post hoc changes to the protocol, while omitting disappointing long term data of two trials. . . . is misleading.” (Id.)

Following the publication of this article, the price of Pharmacia’s stock dropped 7% in three days. . . .

What goes around -- apparently really goes around -- and comes back 'round, when one doesn't deal with it, promptly. Might the above be evidence of "pattern" behavior? Same two players -- seven years later -- were I an ENHANCE plaintiffs' steering committee lawyer, I'd at least make the allegation.


Anonymous said...

Makes you wonder. If you look at the registered asenapine studies under

the way in which the long term studies were conducted is quite strange.

ICH guidelines require 500 subjects for 6 months and 100 subjects for 12 months. Yet the initial long term safety studies were conducted in schizophrenia and schizoaffective disorder. Which would not have been appropriate for a maintainence claim for either of the primary indications we can infer from the recent approvable letter the acute treatment of schizophrenia or bipolar mania. There are two studies that might have been useful for a maintainence claim in schizophrenia but it's unclear if they would have been completed in time for data analysis and submission.

Now some of the other maintainence studies were completed after submission and might be useful to dispel any concerns over long term safety if the initial review were delayed. However it is possible that if someone were intent on covering something up they could simply dismiss any symptoms seen in these longer term studies as unrelated, e.g. symptoms consistent with mild heart failure is not the same as dropping over dead due to endstage heart problems.

Anonymous said...

wow, you're really digging for schering "dirt", aren't you? get a life already and wake up!

Anonymous said...

Actually looking at the studies. There are a mix of long term studies that would have been completed in time for submission.

Study Pop N

41512 Schizo 260
25543 Schizo w neg Sxs 444
25517 Schizo / Schizo Aff 1225
25520 Schizo / Schizo Aff 440
A7501007 BP-I 218

If you were really concerned about those sort of toxicities they would be most likely to show up in the studies with the longest exposures, (which may not be that much different) and in the subjects who are likely to be on an SSRI (i.e. the schizo affective sub-pop). So that's where you would look. If the majority of the subjects enrolled had schizophrenia and weren't on SSRI's then the overall rates of AEs for the most at risk population would be diluted out.


Condor said...

Anonymous wrote:

". . . .you're really digging for schering "dirt", aren't you? get a life already and wake up. . . ."

Do feel free not to stop by, if mine vex you so terribly.


Anonymous said...

Looking a little closer at these studies 25517 uses a flexible dose of 5 mg or 10 mg BID for up to 1 year.

Now the reason to use a flexible dose is 1) marketing as physicians like to play with doses even when the data isn't there to support it (understandable individual vs. population and a matter of sensitivity). 2) if you're having toxicity allows you to drop the dose but analysis for efficacy is still combined.

Getting back to the studies 25520 is a continuation study of 25517. So if you were on asenapine for 1 year in 25517 you could then continue for longer in 25520 using the same regimen. So 440 subjects indicates that at least this many were on asenapine for 1 year and started the study.

Since 25517 started in Sept 2003 the longest anyone could be on the drug prior to submission of the NDA is 2.5 years. Now it takes time to rev up a study and enroll and people also drop out so only a few people if any would be would be expected to be on asenapine for > 2 years. Most of the 440 might be on say 18 months. Now for long term toxicities you can look at rate vs. how long they would be on the drug as well as is it greater in a particular subpop, i.e. schizoaffective on SSRI.

Now it's unlikely that this would be sufficient numbers to be statistically powered and would be dismissed by someone like Sr. Peto (sp?). But for people who are biologically minded. If you saw the toxicities in the pattern I mentioned, then according to FDA standards that would be a signal. Not only that, but if the type of side effects that were predicted occurred then I would say that would be a very strong signal.

Now this is what I would do if I as a translational clinical scientist had a hypothesis and I wanted to look for confirmatory evidence.

As a scientist I welcome peer review. So if anyone has any critique and not just ad hominem attacks, I'm open.

Anonymous said...

Correction. 440 is the number of subjects who continued and included both subjects on olanzapine and asenapine.

So if we assume that it was equally divided then 220 subjects were on asenapine for more than 1 year. This makes the number of subjects likely to have been on close to 2 years or longer even smaller. Another thing we can then look at is if the distribution as to length of time on drug is skewed towards those on 5 mg being longer. Since it was only studied for bipolar at doses of 10 mg bid then this would then be an additional piece of evidence.

Remember young kids (now as young as 3) are not being treated for schizophrenia they're being treated for 'bipolar'.

Looking at the Medicaid and Group Health (private insurance) data released by Sen. Grassley last year 1% of all kids are on atypical antipsychotics already. Now bipolar 1 in adults (which is what these are approved) is 1% of the population and it typically comes on in late teens (i.e. > 18 yo or early 20's). Now there will be kids younger who have full blown mania but the younger you get there will be less and less. So if max is 1% of adults have the disorder, I fail to see how 1% of all kids from 6 - 17 yo (600,000) can have it as you would expect less than 1% in 17 yo's and even fewer each year as you get younger.

Therefore it appears that kids are either being treated for something that they don't have or being treated for something else where there is no evidence that the drugs even would be expected to work. Add on top of that the possibility that kids are likely to be receiving excessive doses due to the lack of appropriate children's doses and use of adult doses instead. Plus the possiblity that there are long term toxicities and kids have forced compliance whereas the average duration of compliance is 3.7 months in adults. Plus if you look at package inserts for Zyprexa the average duration of treatment in bipolar mania in patients who actually appeared to have an effect was 87 days until they relapsed.

Now take a look at the following article:

Now assuming you have enforced compliance for young kids who are treated for nonspecific symptoms (irritability on top of ADHD) at excessive doses. Especially with the mental health screening in schools etc. proposed by Bush et al.. and all that medicaid money. I think you have a recipe for abuse and disaster rolled into one.


Anonymous said...

Condor wrote:

"Do feel free not to stop by, if mine vex you so terribly.


i write:

its a free country bro, so i do as i please, just like you. in any case, i come here to see what kind of pointless drivel you can muster up about schering and spin it as if its the end of the company's days. your blog is comic relief for me since you're completely wrong in all of your predictions. you must be a former employee who got burned and are now feeling like you need to bad-mouth the company no matter how well they're doing. you're lying to yourself if you say otherwise. your hatred for the company exudes in every post you make. you're like a scorned lover seeking a way to lick your wounds by wishing nothing but the worst for schering. you are pathetic and all your posts on here reek of jealousy. i must admit, you are very knowledgable and a very good writer, but your hatred towards schering shuns any credibility you may have. future looks bright bra, yours doesn't! save your money and stop shorting broheim.

cha cha cheers!

Anonymous said...

Cha Cha,

Personally I encourage you to stop by and continue to read. For I like you believe in predictability and track record.

So I say look at Fred's track record on drug safety among other things.

In comparison my track record in predicting major lethal toxicities with drugs is 100% for 8 different drugs. Most were based at on mechanistic understanding whereas other predictions were based on clinical signs and symptoms that others ignored (or a combination). (Unfortunately I'm not at liberty to discuss most of these right now.

Three of those drugs subsequently had to be removed from the market, including one that began with a V and ended with an x. For others they were turned down for approval after major investments, or major warnings were placed on the drugs.

I feel pretty comfortable in the analyses in my posts. So comfortable in fact that I would bet my career. Plus I, like Condor back up my analyses with facts that are publicly available for anyone to check.

Where are your facts? Or do you just trust Fred?

If you do, I hope you feel as comfortable as I do about putting your money where your mouth is and that you have put a major chunk of your change on SP.


Anonymous said...

I've discussed how the 7-OH metabolite of olanzapine appears to result in phen-fen like toxicities, and we should consider similar types of toxicities for asenapine metabolites hydroxylated on the side opposite the chlorine atom.

Well the following are from slides presented by Pfizer at the 2006 AAPS Meeting just a week after they decided to drop asenapine.

PZR "Screen obvious metabolites in discovery phase

PZR “When a monoamine transporter or receptor is the pharmacological target, substitution on the amine is critical and changes in selectivity and potency occur upon modification."

Salmon - OK asenapine's target is the receptor's for the monoamine serotonin

PZR "These changes however occur within the pharmacology of the parent molecule and do not introduce de-novopharmacology into the molecule”.

Salmon - So the effects at the different receptors may change from say an agonist or blocker to an inverse agonist.

PZR “The metabolites produced by N-dealkylation reactions for drugs targeting the transporters (and aminergic receptors) should be synthesized and tested.”

Salmon - Pay special attention to asenapine's N-dealkylated metabolites and how they effect sertonin receptors.

PZR then gives the following example from phen-fen

5HT2B 5HTC Cssfree
nM nM nM
D-fenfluramine 380 360 108
D-norfenfluramine 18 13 45

"Suppress appetite by activating 5HT2C receptors"

"Activation of 5HT2B receptors on heart valves and pulmonary artery interstitial cells leads to fibromyxoidplaques"

"Metabolite 42% of circulating free concentration"

Salmon - So Pfizer right after dropping asenapine is recommending testing all N-dealkylated hydroxylated metabolites for effects at varying serotonin receptors. they then give the example of Phen-Fen (the metabolite is not only more potent at binding the 5HT2B receptor but you need a lot less of it circulating.

This seems to me to be a pretty clear message from Pfizer that you need to look at the metabolites of asenapine compound that they just dropped the previous week otherwise you might get burned with another Phen-Fen.

Pfizer in Summer 2007 also had an article in drug metabolism reviews pointing out how there's no excuse not to have a mass balance study that identifies over 95% of the drug administered as well as the circulating species. So if asenapine doesn't have this it would be another red-flag.

Now I don't know what will happen with this drug in the long run. But if there are cardiovascular problems post marketing, Pfizer's publications and presentations give a pretty good idea on what to look into.



Condor said...

To the commenter -- Cha Cha (on 02/09/09):

It would seem that the "end of Schering's days" came not even one month after you wrote yours.

Seems I wasn't quite so lost, afterall (I've wanted to post his for a while -- but thought I'd let the thread get stale, first -- so as not to seem so-solely interested in gloating).