Salmon Rises -- On Post-FDA-Approval Saphris Presser, of Yesterday. . . .

As I just knew Salmon would:

. . . .From clinicaltrials.gov, yesterday's press release appears to concern a study -- A7501012 -- titled “To Determine Long Term Efficacy and Safety of Asenapine in Schizophrenic Patient Population”.

It had an enrollment of 702 started in April 2005 and was completed in July 2008. It used patients who needed an antipsychotic (probably had a history of relapsing if they weren’t on one) and had been on antipsychotic for at least 1 year and were stable. They were then switched to open label use of asenapine for 6 months and if they didn’t relapse were then switched to asenapine 5-10 mg BID or placebo for up to 6 months of blinded treatment. Stabilized on asenapine in an unblinded fashion for 6 months and then switched them to either placebo or asenapine and the time to relapse was measured.

So in essence -- take people who do respond to meds (a small subset), who relapse if they don’t stay on meds, (a smaller subset), give them 6 months to relapse on asenapine and if they don’t (so a smaller subset who really respond well to asenapine) and then take half of those patients off asenapine -- and wait for the fun begin. This is called an ‘enriched study design’ or as I prefer ‘rigged’.

Now on top of all this the dose is up to double the approved dose so assuming there’s a dose response and since the approved dose is 5 mg, this is another factor that doesn’t reflect the population that asenapine will actually be used in.

What’s noteworthy is the timing of this release coming as it does right before market introduction especially as there are no maintenance studies or approval for maintenance.

Now if you recall the day before the approvable letter for asenapine was sent last January 13th, the FDA issued guidelines for companies to be able to provide articles promoting off-label use (see this press-report) and the FDA's guidelines. Now the FDA webpage for this guidance was updated on August 6th one week before asenapine was approved on August 13th. Unfortunately I don’t know what the changes were.

Subsequently the approval letter and labeling for asenapine wound up on the FDA website (Drugs@FDA) on Sept 3rd (announced Sept 4). Also on September 4th Psychiatric News the paper of the American Psychiatric Association (APA) ran an article on asenapine on page 2 (pure marketing propaganda in my opinion, and on page 4 ran an article on Managing Depression in Pregnancy essentially pushing treating depressions in pregnancy and psychiatrists and OBGYNs to work together and of course we know there has been a push for especially bipolar depression to be and on page 7 there’s an article on a new policy from the American Academy of Pediatrics for Pediatricians to get involved in mental health screening including recommendations on how to get started screening for mental illness in children.

Now back in the April 2008 Edition of OBSTETRICS & GYNECOLOGY, 2 months before asenapine’s original due date, the American College of Obstetricians and Gynecologists (ACOG) issued a PRACTICE BULLETIN entitled ‘Use of Psychiatric Medications During Pregnancy and Lactation. Essentially indicating psychiatric illnesses were more dangerous than drugs to the fetus and indicating that the newer atypical antipsychotics don’t cause problems. Also at the end of May 2008 the FDA issued new guidelines on labeling for drugs in pregnancy and lactation which Sandy Kweder claimed had been in the works since 1997 (see this) which is contemporaneous with the FDA pulling phen-fen from the market (Note they also went after ephedra in dietary supplements 2 weeks earlier and went after OTC decongestants in children starting right before asenapine was submitted and current with the review cycle.) This emphasis on pregnancy and lactation was also highlighted by Dr. Andrew Von Eschenbach, the FDA commissioner, himself (here).

Contemporaneously, Dr. Von Eschenbach spoke to the Israeli press (here) stating that “We have an important commitment to promoting orphan drugs, as well drugs used in pediatrics. But I think the real secret is that we're moving towards a new era in drugs. Instead of thinking about the development of drugs for specific diseases, such as prostate or breast cancer, we're beginning to see products for the body's physical mechanisms, and which resolve all the diseases resulting from them. So for instance, a cardiovascular drug can also treat leukemia, and retinal degeneration. We're moving towards an era where there will no longer be rare diseases or orphan drugs. Instead, there'll be drugs that are part of a medical portfolio." I found this interesting because on the same day 2 weeks earlier that the FDA reviewer wrote his e-mail that asenapine was causing pulmonary arterial hypertension (phen-fen like effect) the FDA granted orphan drug status to Terguride to treat PAH.

Now the FDA reviewer supported his concerns about the neonatal effects of asenapine based on cross fostering reproductive and development studies in animals, which are never done unless a company is looking for something. This was then dismissed by the toxicology team leader on June 24th and he attributes them to toxicity to the dam (mother) and claims such effects due to toxicity to the mother are typically seen with antipsychotics. But less than 1 week later on June 30th he indicates that the very same effects with iloperidone, another antipsychotic, are definitely due to the drug and cannot be ascribed to toxicity to the dam -- which is strange because this was right up front you have to assume that it took him at least a few weeks to read and sign off on this huge review. (Told you I found a gold mine with iloperidone.)

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E D I T
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It was the tertiary pharm/tox review (part 3 page 56/61) on July 22nd, 2008 that indicates it's due to direct effects of the drug and not primarily the effects on the dams.

When you look at reproductive study after reproductive study in the pharm/tox reviews they're dose dependent and it's clear they're direct effects and not secondary effects on maternal toxicity. Plus there's dilation of the heart ventricles in the pups. (Hmmm!)

What's noteworthy is that the medical reviewer (page 12 of her review page 13 of the pdf file) notes that she had not been provided with a final version or a draft of the pharm/tox review yet and had previously been assured by the pharm/tox reviewer that there were no unexpected findings. (7/1/2008 Noon)

However the pharm/tox review is signed off by both the reviewer and the supervisor on 6/30/2008 between 4 - 5 PM.

I checked with a source inside the FDA and asked how this could be.

I was told that due to the even shortened PDUFA deadlines that reviews are now done simultaneously and thus reviews that are dependent on other review diciplines can't get the appropriate preliminary information in a timely fashion to guide them and that this appears to have been deliberately incorporated into the new review processes that were implemented last year. In addition when they know that a reviewer will question someone elses conclusions when they're suspect they may hold off on providing the relevant precursor review until the dependent reviewer is finished or even revise the precursor review afterwards in order to dismiss opinions.

As for the timing and the medical reviewer not knowing of the other reviews completion. This may happen as the reviews are secondarily reviewed then given back for minor changes and then the reviewer is told to put them into the database prior with the precursor review going in shortly afterwards(without notification).(Unexpected delays can mess up the sequence.) This is especially common when reviewers are up against PDUFA deadlines and are simultaneously being run in circles by FDA management so that the reviewer will not check other things when they don't want the reviewer to be aware of these other things.

I think Sir Walter Scott Marmion said it best "Oh, what a tangled web we weave when first we practice to deceive".

-- Salmon

September 14, 2009 11:22 PM

A gold-mine, indeed.