Wednesday, July 29, 2009

FDA Reviewer on Asenapine: "Schering-Plough Knew About this Toxicity and Specifically Tried to Prevent FDA Detecting it. . . ."

UPDATED: 07.29.09 @ 7:05 PM EDT -- At least one MSM news outlet is showing the beginnings of covering both sides of the Saphris (asenapine) FDA story. Well, it's a small start -- but a welcome one -- and in Greece, of all places.

Much more from the cogent keyboard of Salmon, tonight:

. . . .Here are some timelines from the background package on anemia.

Looks like the OCP reviewer got a quick look at multiple cell lines dropping and went to the medical reviewer who sidestepped the clin pharm reviewer and then surreptitiously dismissed it.

The OCP reviewer then took a closer look at the data including plotting and found progression toward neutropenia without adequate monitioring (if standard monitoring for clozapine had been started when the trend was detected then perhaps the patients wouldn't have died).

The medical review team then tried to dismiss this and Tom Laughren, the psych division director said there's no need for an advisory committee meeting (wonder why he wouldn't want to present such data for impartial adjudication).

The citations from the background package follow:

Gwen Zornberg
5/1/2008 07:16:30 PM

CMC review was completed 11 APR 2008 recommending AE. Dr. Levin reported to me today verbally that no major toxicities including cases of aplastic anemia evident in clinical data. The data supporting acute efficacy in SZ and BP appear satisfactory.

Page 481 OCP Briefing May 12, 2008

Page 850 and 851

Slides of decreases in Hematologic Cell Lines on initial lab sheets thought that might be aplastic anemia, however after plotting it appears platelets might not have been dropping fast enough, however microhemorrhages were noted in the brain on autopsy. Consequently this is definitely neutropenia with RBC anemia, with presumptive death due to agranulocytosis and possible aplastic anemia.

Page 51 6/12/08 CDTL Review Gwen Zornberg – Ex-Pfizer Employee

OCP stated in the section on “Comments Previously Provided to the Medical Review Team” on page 42 of their review that on 1 May 2008 “this reviewer went to the medical division to discuss a death in the ongoing studies. Due to workload the medical review team requested followup midweek the following week. On Thursday May 8, 2008 a followup email was sent to the medical review team informing them of a possible case of aplastic anemia.” In the data, Dr. Levin found no evidence of pancytopenia. If this were the case, as CDTL working with Drs. Levin, Laughren and Mathis and Lieutenant Commander Kiedrow, we would have used one of our reserved meeting times to review the action plan.

Page 58 6/12/08


It was decided by Dr. Laughren that there was no need to take this application to the
PDAC in terms of the clinical data, which are consistent with a typical second generation antipsychotic drug.

-- Salmon

July 29, 2009 5:21 PM. . . .

[End, Updated Portion]

This is page 885 of 1,067 -- this e-mail was sent May 16, 2008, by an FDA staff reviewer. Page 886 indicates at least one of the addressees (his supervisor?) initially deleted this email without reading it.

Click it to enlarge:

May 16, 2008

. . . .changing my recommendation for Asenapine to non-approval. . . .

information in the review indicates that Asenapine causes pulmonary arterial hypertension and cardiac effects. . . .

the sponsor [Schering-Plough] knew about this toxicity and specifically tried to prevent our [FDA's] detecting it. . . .

[At Page 936:]

. . . .In addition, the sponsor’s [Schering-Plough's] conclusions and sponsor’s labeling proposals appear to be intentionally misleading especially with respect to subjects with mild hepatic impairment and this conclusion is supported by analyses in the original OCP NDA review.

The sponsor’s signatory for this study is Larry Alphs, MD from Pfizer. Dr. Alphs was also one of the signatories to the request for the Drug Safety Monitoring Board that is contemporaneous with the SAE in the woman who may have died from agranulocytosis, but was not reported.

The information available leads this reviewer to believe that one or more individuals at Pfizer and Organon as well as others at other companies intentionally mislead the FDA as to important information regarding the safety of asenapine that would have been needed to make a decision regarding this NDA.

Based on this and Chapter 18 of the United States Code this reviewer believes that the Inspector General or another criminal investigative unit must be informed.

As this reviewer was instructed by Dr. Mehta that any such requests must obtain prior approval by FDA management, this request will be included in the recommendations. . . .

[It is important to note that this site has not independently-verified the above; and it has not sought the comment of anyone named in these materials. These documents reflect but one side of the story -- they are public documents, though, afterall.]

As Salmon was the first to flag this one, I'll let him tell the rest of the story, in the comments, below. Stupifying. While we wait for Salmon's narrative, I'll post the suggested pages we are pointed to (in green text below), by Salmon's review, thus far:

777 777 Other Safety Issues
780 780 Hepatotoxicity Study 85136 (dose and time dependent)
784 784 Study 25509
785 785 IV Study 25506
787 787 Cardiologist's Report
794 diabetes and heart attack
794 diabetes and heart attack
798 798 Table of selected Cardiac AEs
799 799 Agranulocytosis and Pancytopenia
810 810 Studies not to be reviewed per Management instructions
885 885 e-mail recommending nonapproval due to toxicity and coverups
895-898 895-898 Summary of Major Conclusions
914 Cardiopulmonary Safety Signals Time dependent > 1 year
916 - 918 especially at bottom of 918 Summary of Patients who died. Causes and preponderance with asenapine compared to olanzapine.
923 923 Beginning of section on animal data. Embryofetal studies suggesting effects consistent with neonatal pulmonary arterial hypertension (phen-fen and Vioxx like.)
932 932 neonatal effects of cis-asenapine
933 933 Conclusions regarding neonatal effects. Potential Developmental Risks.
936* 936 Larry Alphs, M.D. Pfizer (Is this possible evidence of criminal activity?)
937 937 Suspicious SAEs from 120 day safety update
945 - the long term studies for negative symptoms
945 Relative Rates of CV and Pulmonary SAEs 6.6 fold higher for asenapine in long term studies
954 basic pharmacology
954 Major Deficiencies and Reassessment of Approvability
965 bifeprunox
965 Bifeprunox causes choreoathetosis (maybe not turned down for being less efficacious as claimed)
972-973 Conclusions re: biological systems hypothesis
984 983 Phen-Fen like effects with Symbyax (Zyprexa and Prozac Combo)


Anonymous said...

Dr. Kavanagh presented at last month's FDA's meeting on transparency. The following are FDA's transcripts of his comments.

RON KAVANAGH: My name is Dr. Ron Kavanagh. I am a pediatric clinical pharmacologist and I was an FDA reviewer for over 10 years, including over seven years reviewing psychiatric drugs. On the advice of my lawyer, I am saying that I was fired and I am appealing it on the basis that it was for whistleblowing to Congress, the Inspector General’s Office and threatening to go to the FBI.

One of the things in terms of recommendation is I’d like to agree with people releasing all submitted materials and data, not only the reviews; releasing all reviews, including the IND’s reviews with extremely limited redaction, having advisory committee meetings for every new molecular entity and allowing every reviewer on the team to present.

Oftentimes reviewers are not allowed to present. Allowing reviewers to speak freely externally, FDA policies which are on the Internet, show that FDA reviewers are prohibited from speaking in any way that could reflect poorly on the agency. Changing the law to eliminate aspects of the 2007 FDA amendments act that is facilitating insider trading and other problems, and this includes things under the good review management practices.

Demonstrated strong protections for reviewers, including holding responsible those FDA managers who would harass, retaliate against reviewers, or endanger the public health. The review process is problematic from the beginning, not just at the end. It begins with the initial IND. When the IND is submitted, oftentimes studies have already been done in humans in Europe – not always but many times, especially for the large companies. And yet, in the last couple of years, FDA has prohibited the clinical pharmacologists from being involved in the initial 30-day safety evaluation, yet these are exactly the type of studies the review people who these studies in this sort of stage of development are involved in.

Frequently, what I found in my experience is that companies tend to know what to expect in terms of safety. They will, however, submit certain data to one place and other data to other, and a safety issue somewhere else and then come in and ask a question – have we done enough? – and you can’t pull it together. If you do put it together and start asking questions, management will tell you, you are not allowed to ask those questions. Or even I have found that policies are generated within the FDA to prevent reviewers and prevent the level of scientific information that is actually required to evaluate things appropriately.

Anonymous said...

(Continued from above)

Polices are often abused. For example, one policy on labeling that restricts reporting of adverse events to, I believe, either five or 10 percent and double placebo would prevent listing adverse events associated with pulmonary arterial hypertension for a drug that’s been pulled from the market for this. It would fall under these limits.

Delays in PDUFA due dates that have been complained about in the press. I know from personal experience that many times that this is because a safety issue has been brought up and that reviewers are basically then being removed. For follow-up meetings, reviewers who bring up safety issues are eliminated from the meetings. There are secret meetings with managers.

(Beeping sound.)

MS. ASAMOAH: It’s okay.

DR. KAVANAGH: When reviewers bring up safety issues, managers will pretend to go on vacations, and then there are secret meetings held about that reviewer by FDA managers. Thank you.

Anonymous said...

(Continued from Above)

DR. SHARFSTEIN: Thank you. Dr. Kavanagh, I have a question.


DR. SHARFSTEIN: You recommended that all the new molecular entities go through the advisory committee process.

DR. KAVANAGH: Yes, I do.

DR. SHARFSTEIN: Could you explain, from your perspective, what’s the value of the advisory committee process that would, you know, apply to all new molecular entities? And then is there, you know, an example of just briefly – we could look it up – you know, any particularly advisory committee meeting you think is particularly helpful to the agency in that way?

DR. KAVANAGH: You know, the advisory committees, they’re good and they’re bad. One of the problems is if you’re doing a review, there’s so much fear within the agency by reviewers that people self-censor. And that’s one reason why really push that the data itself has to be provided, even if you know what you’re looking for, which I do, and looking through these documents.

You know, most people don’t. And even with making the data available, very few people are going to have the skills or the knowledge to be able to go through it and really know what they’re looking for to be able to tease out things. The advisory committee – or a public hearing, not so much an advisory committee – it gives you a read; it gives you an opportunity for everybody – if you had it with every reviewer presenting their own stuff and not just as in the recent pediatric; we agree with the industry; we’re allowing them to present.

I had several reviewers that I know come to me who worked on those drugs and were sitting at the advisory committee, and they told me, Ron, keep doing what you’re doing. Keep speaking up, you know? People are very, very fearful within the agency. There is self-centering; there’s passing the buck.

The advisory committee is not a full answer, but sometimes if advisory committee members start asking questions, if they can actually get to the reviewer and a reviewer is willing to speak instead of if going to the industry people or a manager who is basically trying to shepherd a drug through.

What kind of got me – things are done so subtly, and what got me personally was several years ago I was helping a friend with an advisory committee that he forced because of a safety issue he caught. And I came in at 3:00 on a weekend to help him prepare for it. And I wound up presenting at the advisory committee because he turned around and asked if I could.

And because of my presentation the drug got turned down for a safety reason. I later found out that there is information that we knew about in terms of possible risks with ethnicity that would really increase the problem. And this was a drug that I might have put my own child on that also comes from my wife’s ethnic background.

And so to be able to talk and have the reviewer’s talk and – you know, everything is – we’re looking for small signals. We’re putting together information on chemical structures, on what do we know from animals, what do we know from other drugs that are similar? To be able to be able to provide that information to the advisory committee, it can change their perspective and how they think about the drug.

DR. SHARFSTEIN: Great. Thank you very much. Let me see if there are any questions here. Okay.


Anonymous said...

The person deleting is Dr. Robert (Bob) Temple. He's director of Medical Policy and has the final say on new psych, cardiorenal, and oncology drugs.

If you look at the meeing roster Dr. Temple is not attending. Ellis Unger his new assistant is (Temple didn't have an assistant for 4 years until Aug 2008). Looks like Temples afraid to have his signature on the approval. Of course they'll have a good reason why not.

After Laughren the most important memo dismissing Dr. Kavanagh is from Dr. Gwen Zornberg. Well a little googling reveals that she's a safety epidemiologist and was at Pfizer while asenapine was being developed. If appears she wrote quite a few ghost articles. (Didn't Pfizer want someone to write a white paper downplaying the hepatotoxicity?).

Also last Dec 208 she was an author on a review article discussing the theoretical possibility that we might see such toxicities with Psych drugs in the future.

Drug Safety. 31(12):1083-1096, December 01, 2008.
Hausner, Elizabeth; Fiszman, Monica L; Hanig, Joseph; Harlow, Patricia; Zornberg, Gwen; Sobel, Solomon;jsessionid=KwNLgX2hqk1FGXxvT6pVN1LYT74JcJLKpRWL1m4GmqwQgJcgyYDk!-1104825961!181195629!8091!-1

The whole problem with the denials is that FDA is already reporting cases in children of PAH and SIDS and hepatotoxicity as found in last month's background package for pediatric bipolar. A big question was the big increases in heart rate and BP with Seroquel especially when they also took stimulants for ADHD. Plus the report from the post safety marketing group indicating they were seeing cases of cardiomyopathy and myocarditis (complicatons of PAH) in children and FDA needs to be on the watch for it. This was 2 years before this nonapproval e-mail predicting it.

So despite the FDA denials it looks like the reviewer is right on both the PAH and the hepatotoxicity. To paraphrase Bob Temple 'Dead Bodies in the Street don't lie'.

The question is how much worse is asenapine compared to other drugs and based on the tables it seems a lot worse than Zyprexa which was the main reason for the black box warning that it kills the elderly.

Plus the reviewer indicates the real problems occur at > 1 year. So this latest 6 month - 1 year study may be used to spin the safety data. I simply wouldn't trust any analysis out of FDA at this point unless they release ALL data and not just their summaries.

I wonder if they'll allow the reviewer to present or answer questions by the AC members.

Anonymous said...

Interesting coincidences.

Page 22 On August 1, 2008 at 4:51 PM the Psych Division Director Tom Laughren filed a memo dismissing conclusions from Dr. Kavanagh's June 30th review (without supporting evidence).

Q1: Why did he wait over 30 days to write a memo?

Remember we can figure from public docs that the PDUFA due date was between June 23rd, when FDA issued a new policy that they didn't have to meet PDUFA due dates (prior to that a decision letter had to be issued), and Fred's meltdown on the front page of the WSJ.

Seems to me unless there was some hanky panky a nonapproval letter was guaranteed on June 30th.

Q2: Does anyone else find it funny that the timing of the memo is about 20 minutes after the end of the business day when SP filed its 10-Q report, and just after SP stock took a hit on Vytorin/Zetia.


I wonder what sort of internal FDA documents are floating around documenting communications with SP or other interesting coincidences.


Anonymous said...


I think it would be helpful if you posted pages 895-898, regarding recommendations regarding approvals from Wed June 18, 2008.

This is a couple of days after Fred's interview on dealing with adversity and 5 days before the FDA changed their policies about meeting PDUFDA deadlines (June 23rd).

From the timelines you can see that the the Pharm/Tox Team Leader Dr. Rosloff filed a response to Dr. Kavanagh on June 24th and the medical reviewer R. Levin filed a response on Friday June 27 at 4:12 PM. (kind of late on a Friday for anyone to respond in time before the Monday PDUFA due date; see page 825)

But Dr. Kavanagh does respond on June 30th at 9:07 AM (page 1005)just in time for the PDUFA due date the same day.

No wonder Fred had his meltdown on the front page of the WSJ that day.

Now why is Dr. Kavanagh not reviewing the followup responses to his drug metabolism issues, and why is he in at the June 2009 transparency meeting minutes claiming he is appealing a firing based on whistleblowing to Congress, etc..

Anonymous said...

S/P stock out doing the market so far. Looks like this will be approved despite the issues.

Condor said...


But as ever, we'll wait and see.