Monday, July 27, 2009

FDA Should Have Background Materials Up on Asenapine -- Um, Now.

UPDATE -- 07.28.09 @ 8 AM EDT: FDA's PDAC Materials are now posted -- it is a daunting 19.1 Mb download; 1,067 pages. Paging Salmon. . . .

We have a new working thread on it, for your collective observations.


It is the policy of FDA that the Advisory Committees release background materials for committee meetings two business days prior to meeting date. The Saphris (asenapine) meeting is July 30 2009. So, I expect that sometime during the day -- perhaps whilst I am off the grid, attending to other matters -- FDA will post the asenapine materials right here.

Until that happens, do go take a look at the latest installment of Salmon's "Continuing Asenapine Chronicles" -- right here, in the comments. Do go read all of his, but here is a teaser, to encourage you to follow that link:
. . . .Found a little bit of info on this study at [Medical News Today]:
". . . .In the study, SAPHRIS was significantly more effective than olanzapine in the reduction of negative symptoms as measured by change from baseline to Day 365 in the NSA-16 total score, the primary endpoint of the study. By using a mixed model for repeated measures (MMRM), least square mean changes in the NSA-16 total score were -15.8 for SAPHRIS vs. -11.0 for olanzapine (P=0.015). Full results of the trial, including efficacy, safety and tolerability data, will be submitted for presentation at a medical meeting at a later date. . . ."

Another report for up to 6 months shows no difference in effect but a higher incidence of EPS with asenapine but less weight gain (possibly a "side effects" wash):
". . . .There was no difference in effect between olanzapine and asenapine on negative symptoms at 6 months. This study continued things for another 6 months and found a statistically significant difference at 12 months. There was also a lot more weight gain reported with olanzapine. . . ."

[The] study uses MMRM (mixed modeling of repeated measures) as a statistical technique. My experience with this is that you need to know what is making people drop out of the study and account for each different reason. In practice even when attempted you can't get reliable data for this and so you have to impute the reasons and that's not a very good assumption because what is true for one drug is not necessarily true for another.

When I see MMRM I immediately know the statistical analysis is likely based on a bunch of fudge factors that are likely wrong.

Plus without a placebo and knowing the scale it's hard to interpret whether this is of any real benefit.

Lastly, even if it is real it may imply that there's poorer efficacy on the positive symptoms and may be why 3 of 4 pivotal trials in support of the acute treatment of an acute psychotic episode in schizophrenia were negative.

FDA needs to be more transparent in the future and release all reports and data. . . .

[And, From A Later Update from Salmon:]

. . . .So if we see a summary written by FDA management without individual reviews or without individuals reviews in clinical pharmacology, and pharmacology/toxicology or these reviews are redacted (they shouldn't be at all) then I would say something fishy is going on.

And I know fishy.

-- Salmon

Indeed. If the background materials happen to show up while I am away, feel free to comment on them in this thread. [I suppose it is a possibility that -- though rather unlikely -- the FDA Advisory Committee meeting on Schering-Plough's Saphris (asenapine) has been postponed, and thus the materials are not posted.]


Anonymous said...

Thank you.

I was looking over the regulations covering FDA release of materials and boy does it allow a lot of hiding things.

They can be found under 21 CFR 314.430 and 21 CFR part 20.

(most of part 20 is irrelevant to this but there are a few tidbits like just because a company calls something confidential or a tradesecret doesn't mean anything.)

First they are not laws but rather they are regulations, i.e. FDA decided themselves what they would release.

As for the AC materials this is what the regs say:

"(d)(1) If the existence of an application or abbreviated application has been publicly disclosed or acknowledged before the agency sends an approval letter to the applicant, no data or information contained in the application or abbreviated application is available for public disclosure before the agency sends an approval letter, but the Commissioner may, in his or her discretion, disclose a summary of selected portions of the safety and effectiveness data that are appropriate for public consideration of a specific pending issue; for example, for consideration of an open session of an FDA advisory committee."

It goes on to say the summary may be prepared by the company with sign off by the FDA or by the FDA and of course everybody trusts Fred and Tom Laughren the Psych division director 100%.

The summary (SBA) is then required to be released upon approval. From the website if you look at SBAs you'll find that they fall into 2 categories 1) a summary written by FDA management b) individual reviews often heavily redacted.

Often from the scientific content you can tell that the redaction does not fall under trade or commericial secrets as defined by 314.430 and thus seems to be suspicious.

So if we see a summary written by FDA management without individual reviews or without individuals reviews in clinical pharmacology, and pharmacology/toxicology or these reviews are redacted (they shouldn't be at all) then I would say something fishy is going on.

And I know fishy.


Condor said...

"Fishy. . ." Heh!


Thanks again -- Namaste

Anonymous said...

Well the work day is over and no background documents yet. Actually I'm not surprised the FDA policies state that they will be provided no later than 48 hours before the meeting. Typically FDA releases them in the morning about 49 hours before the meeting.

I'll be looking tomorrow morning.


Condor said...

Thanks -- as will I.


Anonymous said...

It's now 48.5 hours before the meeting and no background materials.

The meeting announcement has this to say:

"FDA intends to make background material available to the public no later than 2 business days before the meeting. If FDA is unable to post the background material on its Web site prior to the meeting, the background material will be made publicly available at the location of the advisory committee meeting, and the background material will be posted on FDA’s Web site after the meeting."

Well it seems I should have checked the fine print.

It looks like if you really didn't want to give anyone the ability to go over materials you could just release it at the meeting and after. Especially if it's voluminous like the last PDAC background package.

That's what they do with the slides although companies get to see the FDA's slides before the meeting but not the other way around.

I believe this is another issue for the FDA transparency initiative.


Condor said...

I know you know this -- but take your time -- we will wait.

It will be worth it, to have the sense of your cogent, but Picean, insights. . . .