Friday, February 27, 2009

AstraZeneca, Seroquel, and Trading Ethical "Distinction"

Seroquel and the Process of Corruption

As many here will know, there have been a number of stories today about Astra Zeneca's alleged cover-up of studies indicating the diabetes risks of Seroquel. The Wall Street Journal Stories have been particularly informative. Here is a brief snippet (which will remind some of you of our peanut thread--truth is sometimes a lot like fiction):

"In an Aug. 15, 2005, voicemail message addressed to company salespeople, an AstraZeneca employee named Christine Ney followed up on a "weight and diabetes sell sheet" they had recently been sent. The sales representatives should assuage doctors' fears about their patients' weight gains, she said in the voicemail, by telling them that data showed no causal link between diabetes and the drug.

"Our objective is to neutralize customer objections to Seroquel's weight and diabetes profile," Ms. Ney said, according to a transcript of the voicemail message. She then instructed representatives to "refocus the call" away from diabetes to the drug's tolerability, the transcript shows."

What is compelling about the internal documents that have been released through the WSJ is the process in which obviously well-intentioned people begin the slide toward corrupt practices. In most respects, these documents are like many others that have come to light. The Ney directive, for example, reads more or less like "dodgeball" revisited. What distinguishes these documents, I think, is that some of them reflect the very moment of ethical choosing--where decisions are made either to suppress known data or not. It is relatively rare for the general public to get a glimpse at the process at that particular juncture.

Perhaps most compelling is an email from John Tumas, one of the AZ publication managers involved in decisions about whether or not to suppress negative studies. In a confidential 1999 email ("Exhibit 13"), Tumas writesto his colleagues:

"Please allow me to join in the fray

There has been a precedent set regarding 'cherry picking' of data. This would be the recent Velligan presentations of cognitive function data from Trial 15 (one of the buried trials). Thus far, I am not aware of any repercussions regarding interest in the unreported data.

That does not mean that we should continue to advocate this practice. There is growing pressure from outside the industry to provide access to all data resulting from clinical trials conducted by industry. Thus far, we have buried Trials 15, 31, 56, and are now considering COSTAR [a trial comparing Seroquel to Risperdal].

The larger issue is how do we face the outside world when they begin to criticize us for suppressing data. One could say that our competitors indulge in this practice. However, until now, I believe we have been looked upon by the outside world favorably with regard to ethical behavior. We must decide if we wish to continue to enjoy this distinction.

The reporting of the COSTAR results will not be easy. We must find a way to diminish the negative findings. But, in my opinion, we cannot hide them.

Best regards,

John"

There are many ways to read this note. Tumas searches for a middle way--not to "bury" this trial, as others have been buried, but to "diminish the negative findings." The importance of AZ's relatively good ethical reputation (particularly in comparison with Janssen, as other communications make clear) is not trivial. But it is a "distinction" which may or may not be worth trading away.

I will save wider reflections for another post. Here, I will simply say that I do not believe any system of exteral _sanctions_--criminal, civil, or regulatory--will be the key that impacts decisions like the one with which John Tumas struggles. It is rather about reputation (facing the "outside world"), about competition, and--perhaps on some level--about living with oneself. The last, sad to say, is speculative. Either way, Tumas is not directly worried about trial lawyers or the FDA/DOJ. He is worried about Janssen. And, further out on the horizon, about "pressure" to provide access to all data. And, even further out, about some vague sense that someday it could all unravel. As, of course, it now has. [Tumas could "not be reached for comment" the Journal reports.]

On one level, these are issues of the moral choices that individuals make. On another, these are issues about a business model and incentive structure that make moments like Tumas's not only possible, but ubiquitous. That is to say, entirely typical.

I do not think it is an overstatement to suggest that Tumas's decision can stand as a microcosm for the industry as a whole. And the core question is whether the business model and incentive structure can be changed in ways that save people like Tumas from, almost inadvertently, doing moral violence both to themselves and, not long after, to a great many others.

*********************************************************************************

Addendum: The NYT version of the story can be found at:
http://www.nytimes.com/2009/02/28/business/28drug.html?_r=1&emc=tnt&tntemail1=y

34 comments:

  1. I must say I am disappointed that there has not been any response on this thread.

    As exemplified here, and in many other internal communications that have surfaced, we have people in leadership positions in major companies that exhibit moral judgement equivalet to the average nine-year-old. (This is not a metaphor. Developmental psych. would show precisely that.)

    I am not suggesting that is how such people act in the rest of their lives. Indeed, I am certain that, in the great majority of cases, they do not. Systematically lying unless you get caught--and having being caught be the primary criterion--is reserved for the workplace.

    That is really my point. Where does that leave us if, within senior positions in major corporations, otherwise mature and well-meaning people regress to a kind of moral cretinism? Once again, what does this say about the institutions and incentives that induce such regression?

    Shouldn't this alarm the fig out of us?

    ReplyDelete
  2. Yes, Justice. We should be alarmed. In the FDA Whistleblowers thread, Salmon discussed some of these issues at length.

    In the AstraZeneca case, company employees ensured that the product was approved—safety and effectiveness be damned.

    Here is a quirky question I have been asking for several months: What prompted AstraZeneca to change the name of Seroquel SR (sustained release) to Seroquel XR (extended release) during the approval process? My open records request has been designated a “complex request,” so I do not know when I will receive the records.

    My interest in Seroquel began in December 2008 after I participated in an online CME activity on the treatment of major depressive disorder (MDD). In the December 3 presentation offered by CME Outfitters, Charles Nemeroff referenced data from a study by El-Khalili et al. on adjunctive Seroquel XR in patients with MDD and partial response to antidepressant treatment. In the APA 2008 poster presentation, El-Khalili reported that adjunctive Seroquel XR was effective and well-tolerated in the treatment of MDD. [1]

    Around the same time, the FDA sent a letter to AstraZeneca, warning the company not to market Seroquel or Seroquel XR for depression. [2] On December 26 the FDA requested more information from the company for a new indication application for MDD.

    According to ClinicalTrials.gov, Seroquel SR was used in the El-Khalili study. [3] However according to the poster presentation, Seroquel XR was used. Although the company stated that the formulations were the same, the reason for the name change remains undisclosed.

    On December 21, 2008, AstraZeneca added the following statement to relevant protocols on ClinicalTrials.gov:

    “PLEASE NOTE: Seroquel SR and Seroquel XR refer to the same formulation. The SR designation was changed to XR after consultation with FDA.” [3]

    In July 2006 AstraZeneca submitted a new drug application for Seroquel SR for schizophrenia. In March 2007 Seroquel SR study results were presented at the European Congress of Psychiatry in Madrid. [4]

    On May 17, 2007, the FDA approved Seroquel XR for schizophrenia. The FDA review documents were not posted on the FDA Web site. No mention was made of Seroquel SR.

    What happened to Seroquel SR?

    On November 15, 2007, Seroquel XR was approved for the maintenance treatment of schizophrenia. According to the drug label, the intagliation on the tablet was “SR” plus the dosage; for example, SR 200.

    On March 13, 2008, FDA approved a change in the tablet intagliation from Seroquel SR to Seroquel XR—10 months after Seroquel XR had been approved. Seemingly the reason for the change was to match the tablet intagliation to the drug name—good move.

    What prompted AstraZeneca to change the name of the drug from Seroquel SR (sustained release) to Seroquel XR (extended release)? If anyone can answer this question, please post your answer here.

    Sources
    [1] Poster NR3-088, APA 2008. Adjunctive ER Quetiapine Fumarate (XR) in Patients With Major Depressive Disorder and Inadequate Antidepressant Response. Nizar El-Khalili, M.D. Alpine Clinic3660 Rome Dr LafayetteIN 47905USA, et al.

    [2] http://www.fda.gov/cder/warn/2008/Seroquel_Ltr.pdf

    [3] A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled Phase III Study of the Efficacy and Safety of Quetiapine Fumarate Sustained Release (Seroquel SRTM) in Combination With an Antidepressant in the Treatment of Patients With Major Depressive Disorder With Inadequate Response to an Antidepressant Treatment (PEARL STUDY), Study ID Number: D1448C00006 [http://www.clinicaltrials.gov/ct2/show/NCT00326105?term=D1448C00006&rank=1] Scroll down and click on “history of changes since first registered.”

    [4] http://www.medicalnewstoday.com/articles/65527.php

    ReplyDelete
  3. Hi Nancy,

    Thanks for the detailed post!

    The only vaguely relevant thing I could find re: your query is the Wellbutrin SR to XL. Of course, the second was a different formulation and designed for once-daily dosing?

    I have no idea what the Seroquel dosing is now or with S/XR, but perhaps the X is used for once-daily drugs...Total guess.

    From a marketing perspective, it does sound more "sexy" to me, like some kind of Jaguar. But if I had a Jaguar, I would take it more than once a day.

    ReplyDelete
  4. The Seroquel saga continues as new documents are released. The latest is a study that seems to confirm concerns voiced in the emails--that Seroquel was not as effective as Haldol re: efficacy. The question of extrapyramidals is still out there, for the class as a whole.

    Anyway, suppressing risks is obvously of greater concern than hyping benefits. But, as we know, in the real world the two are often conjoined.

    ReplyDelete
  5. I'm not surprised about the lack of comments. To have a discussion one must have at least one other side and, really, who is going to defend this? Even Atlex left this stuff alone.

    ReplyDelete
  6. True, harpy. But there were a few excellent threads on Pharmalot re: the factors that were "facilitative" of this kind of stuff, and the way things had changed over the past 15-20 years. Lots of industry and former industry folks had great things to say. Of course, there are very few of those people here.

    I always wonder how the 99%+ people who work in industry, and have nothing to do with decisions like this let alone know they are happening, respond when things come out. Would I do anything, beyond churn inside? Probably not. But what violence is being done to these companies by these "revelations"--which means to my own profession.



    If I were one of the 99.whatever % of people who work for any of these companies--and who have nothing to do with decisions of this kind, let alone knowing they are going on--I would like to think I'd be outraged over what this was doing to public perceptions of my work. But would I say or do anything (besides churn inwardly)? Probably not.

    Unless I was prepared to go down whistleblower trail, usually a long and lonely road.

    ReplyDelete
  7. You're not seeing double...thought I'd lost a paragraph that had only gone underground...

    ReplyDelete
  8. I think Nathan is usually pretty vocal about that. And it does suck to have to defend what you do, when all you want to do is help people.

    But what I really came back for is to drop this article on you. FDA is to consider a wider use for Seroquel. It is currently used to treat bipolar and schizophrenia and AZ wants to add generalized anxiety and major depression. While being sued for obfuscating about side-effects. I beginning to be suspicious of pharma's claims that getting sued is bad for business...

    ReplyDelete
  9. Thanks, Harpy. Yeah, the wider indications stuff has become part of the story.

    As you probably saw, there was also an article about AZ having sent Dear HCP letters to docs in Japan warning about increased risks of diabetes in 2002. This was required by Japanese regulators.

    Three years later, they were still trying to "neutralize" concerns about diabetes in the U.S.

    AZ's answer is that different countries have different regulatory requirements...

    If that is the basis upon which risk warnings are made, we are all, indeed, toast.

    ReplyDelete
  10. p.s. I agree about the sucky part of being put in a position of having to defend what one had nothing to do with - as I noted, that's 99+% of people in the industry.

    Hot as I can also get about these things, we are mostly all on the same side.

    ReplyDelete
  11. Justice, you are right--Seroquel XR is administered once daily. You suggest that the company may have changed the name of the drug from Seroquel SR to Seroquel XR because XR sounds sexier. Well, I think SR sounds sexier.

    Nevertheless if that were the case, why would the company avoid saying so? Why expand a simple question into a "complex request?"

    I agree with your assertion that Jaguars are sexy. Especially the 2009 Jaguar XF. Look here:

    http://www.autoblog.com/2007/08/27/2009-jaguar-xf-bringing-sexy-back/

    Earlier Justice said, "I must say I am disappointed that there has not been any response on this thread."

    Justice, are you satisfied now?

    ReplyDelete
  12. Not really.........! I mean, not Happy XR.

    ReplyDelete
  13. Okay, Justice. Click on Nancy to read more about Seroquel XR.

    ReplyDelete
  14. Thanks, Nancy. Perhaps I am now Happy CR.

    ReplyDelete
  15. I do not know the specifics with Seroquel, however several years ago FDA was simply trying to make things consistent between companies.

    Some companies used SR, some XR, some CR, some LA. Officially there is MR (modified release) which is anything other than immediate release such as enteric coated, delayed release, sustained release or a combination of different release mechanisms, e.g. Ritalin LA (immediate and delayed release). Some drugs had multiple formulations with different extended release mechanisms e.g. Ritalin SR and Ritalin LA.

    I personally like the official nomenclature MR for modified release with an added modifier e.g. MR-EC/DR which would be a combination of both enteric coated and delayed release characteristics.

    Salmon

    ReplyDelete
  16. I should clarify. When I say official I mean the terminology that's used the USP and FDA regulatory documents for 'generic names'. For the brand name extension XR won out.

    ReplyDelete
  17. Thank you, Salmon. I found the USP Web site to be very helpful as well, which says, "...extended-release tablets are formulated in such manner as to make the contained medicament available over an extended period following ingestion. Expressions such as 'prolonged-action' and 'sustained-release' have been used to describe such dosage forms, however, the term 'extended-release' is the term used for 'official' Pharmacopeial purposes."

    This brings me back to my open records request for the FDA approval documents pertaining to the name change from Seroquel SR to Seroquel XR. My request has now been designated a "complex request." Apparently the proprietary information contained in the documents I requested has nothing to do with the tablet coating properties and release of the drug.

    The documents which were recently released in the Seroquel lawsuits pertained to the immediate release form of Seroquel. Seroquel XR was approved later, in May 2007. So I await the information on Seroquel XR.

    ReplyDelete
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