Was the CAFE study manipulated by AstraZeneca? Maybe Not.

In Monday's post, I summarized Carl Elliott's recent article in Mother Jones, in which he argues that Dan Markingson's suicide may have been related to the fact that he was enrolled in an AstraZeneca study comparing AZ's Seroquel with two other medications. Like most clinical trials, this study put limits on what medications doctors could give their study patients. These limits are required to discover how effective a drug is for a particular condition. Otherwise, patients in research studies might be taking all kinds of miscellaneous treatments, and you wouldn't know if their improvements were due to the study drug or something else.

The crucial question here is whether this study, called the CAFE trial, was, in fact, designed to answer a valid scientific question, such as: Which of three antipsychotics is most effective? Or was it a rigged study, designed to ensure that Seroquel would look good compared to Zyprexa and Risperdal, purely in order to drive sales? It would obviously be unethical to recruit seriously ill patients into a bogus trial if it was concocted as a marketing strategy.

As Dr. Barney Carroll mentioned in a response to Monday's post, the interesting thing about the CAFE trial is that several of the major investigators were also involved in the CATIE trial. The CATIE trial was of a similar design and involved schizophrenic patients who were randomly assigned to double blind treatment with different antipsychotics. But the CATIE trial was funded by the NIMH rather than by any particular drug company. Therefore, we assume that design decisions were made relatively free of drug company input.

The results of the NIMH-funded CATIE trial were different from the AZ-funded CAFE trial--quite different. The main outcome measure for both studies was the percentage of patients who discontinued the drug. In the CAFE trial, the 12-month discontinuation rates for Zyprexa, Seroquel, and Risperdal were 68.4%, 70.9%, and 71.4%, respectively. In the CATIE trial, the18-month discontinuation rates (the 12-month rates were not reported) were 64%, 74%, and 82% for the same three drugs (two other drugs were also tested in CATIE). In the CATIE trial Zyprexa did much better than Seroquel, but it did not do better in CAFE--which seems odd considering both studies used the same methodology.

What's the explanation here? It could be simply be a statistical variation in outcomes. Perhaps CATIE's results were wrong, and perhaps CAFE's are right. After all, this is exactly why it's important to replicate a research finding. If a finding is replicated, we are much more confident in the truth of the original results.

In this case, however, the divergent results appear more likely due to the fact that in CAFE, Zyprexa and Risperdal were dosed much lower than in CATIE. Look at the table below. Zyprexa was dosed 42% lower in CAFE, Risperdal was dosed 38% lower, while Seroquel was nearly the same in the two--only 7% lower in CAFE. Thus, on the face of it, it seems clear that the CAFE study found Seroquel to be as good as Zyprexa and Risperdal because the design ensured that Seroquel would be dosed much higher than Zyprexa and Risperdal.

Drug	AZ-funded CAFE dose	NIMH-funded CATIE dose
Zyprexa	11.7 mg	20.1 mg
Risperdal	2.4 mg	3.9 mg
Seroquel	506 mg	543 mg

But why did this happen? Was this a design manipulation ordered by AstraZeneca marketing staff in order to make sure the results were to their liking? Or was it simply a research decision made with pure motives by the scientists who ran the trial? The answer to this question makes a difference. In fact, you could argue that it makes all the difference.

This post would have ended here if I hadn't emailed these questions to the researchers who designed the CAFE study, including Dr. Joseph McEvoy, Dr. Jeffrey Lieberman, and Dr. Diana Perkins. All three of them were also involved in the CATIE trial. They reminded me of a crucial difference in the two trials, aside from the fact that one was funded by government and the other by Astra Zeneca.

The CAFE study, as should have been obvious to me by the full name ("Comparison of Atypicals in First Episode of Psychosis"), was designed with newly diagnosed patients in mind. Typically, patients with a first episode of psychosis are treated more conservatively, with lower doses of antipsychotics, as opposed to the chronic schizophrenics enrolled in the CATIE trial. So this explains why Risperdal and Zyprexa were dosed lower in CAFE than in the CATIE.

So why, you might ask, wasn't Seroquel also dosed lower? According to Dr. McEvoy, who was the co-principal investigator on both CAFE and CATIE, at that time there were no studies guiding them on Seroquel dosing in first episode patients. "Back then," he wrote me, "many argued that higher doses were needed for optimal efficacy and there was not a side effect ceiling such as risperidone has." Eventually, a study was published showing that the average Seroquel dose needed for first episode psychosis is only 268 mg/day

Dr. Lieberman, who is chair of psychiatry at Columbia University, emailed me that "Although your inferences re dosing are understandable they are entirely incorrect. The CAFE study was wholly investigator initiated and we determined the doses for each drug. There was a clear rationale for the higher quetiapine dose relative to the other drugs which I am happy to explain to you. This study design in no way was influenced adversely by industry influence."

So there you have it. If you can believe these researchers, this may have been an example of an AstraZeneca funded study without undue commercial influence. I think they are believable, and I know that Dr. Lieberman in particular has been quoted regularly in the media recently about various new drugs, and has been appropriately skeptical about their benefits over older agents.

Of course, there are other ways in which CAFE might have been rigged, which are detailed in Carl Elliott's Mother Jones article. I've asked the investigators about these allegations and will let you know if I get a response.

"Making a Killing": New Carl Elliott Article in Mother Jones

There's a fascinating article by Carl Elliott in the current issue of Mother Jones. It's called "Making a Killing," and it shows how clinical trials have become marketing exercises for the pharmaceutical industry, sometimes at the expense of patients' lives. (You can read the article here, but you will need to complete a free registrations process).

The focus is on Astra Zeneca, maker of the antipsychotic Seroquel. Elliott tells the tragic story of Dan Markingson, a young man with schizophrenia who killed himself in a particularly gruesome way in May of 2004. At the time, Markingson was enrolled in an Astra Zeneca-funded study called the CAFE study. The acronym CAFE stands for "Comparison of Atypicals in First Episode of Psychosis." As the name implies, this study randomly assigned patients to three possible antipsychotics: Seroquel, Risperdal, and Zyprexa. The bottom line result, according the abstract in the American Journal of Psychiatry, was that the three drugs were equally effective.

However, Elliott makes the case that the study was rigged in various ways by the Astra Zeneca marketers to ensure that Seroquel would, at the least, not look any worse than its competitors. While this devious tactic may not be much of a news flash, Elliott is claiming that something more insidious happened--namely, that Dan Markingson was pressured to put his life on the line for a drug company's profits.

Elliott acknowledges that there are risks in any clinical study. When the study is trying to answer a significant scientific questions, these risks may be reasonable. But when the study is designed to boost sales of a drug, these risks are very hard to defend.

As Elliott puts it: "It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca."

I had read the CAFE study before, but as I was preparing this post, I noticed aspects of the design that had not struck me in the past. The study may well have been manipulated in order to make Seroquel look good. In my next post I will delve into the specifics, so stay tuned.

Heart Surgeon's Brothel in Dallas

Over at CardioBrief, Larry Husten reviews the industry prospectus offered by an international meeting for cardiac surgeons, occurring in Dallas January 9-11. Apparently, the organizers of the meeting believe they are still in the roaring 90's when the industry gravy train was making stops at every doctor's office, throwing cash into the air and watching as doctors gleefully scooped up as much lucre as they could hold.

At "Dallas Leipzig International Valve 2010," everything is for sale--including the surgeons. Thus, in addition to paying for exhibition space, symposia, wine-tastings, and logos on flash-drives, notebooks, and attendee's foreheads (not really), valve companies can buy an intimate dinner with "four faculty members for a private one-on-one meeting." But act quickly--the program limits each faculty member to only one trick per conference: "Secure your faculty choice early as faculty will be removed from selection list once chosen."

Delaware Media Group: Sleazy MECC of the Month

As pressure continues to build on various medical organizations to curb industry funding of CME, the companies and their MECC minions (MECC = Medical Education Communication Company) continue to churn out infomercials with the ACCME stamp of approval.

The sleazy "MECC of the Month" is the Delaware Media Group. Here is how they describe themselves on their home page:

“Delaware Media Group
Custom Health Care Communications

Delaware Media Group (DMG) is a fast-growing health care communications/education company that specializes in providing customized communications vehicles to suit your marketing and continuing education needs and goals and enhance your relationships with key customers in the health care community.”

The fact that DMG pairs “marketing” with “continuing education needs” in their promotional material pretty much says it all. This is an outfit whose raison d’etre is to help drug companies sell their products.

Their major marketing vehicle is a pseudo-journal called “Counseling Points” . Each issue focuses on a different topic of interest to the supporting drug company. Who actually creates the content is always confusing, however. For example, I was just sent the June 2010 issue of Counseling Points, entitled "Challenges in Schizophrenia: Overcoming Nonadherence and Preventing Relapse in Schizophrenia."

In the increasingly rare real world of medical education (doctors honestly imparting their clinical wisdom to other doctors), there is an “article” and there is an “author.” The author is an academic doctor who came up with the idea for the article, wrote it, and sent it somewhere for publication. You can trust the content because you know who wrote it and why.

But in the world of industry-funded CME, articles become “activities,” and a basic 9 page piece on the treatment of schizophrenia suddenly requires a whole army of staff: three “faculty” (in this case, three psychiatrists--Christoph Correll, John Kane, and John Lauriello), nine “planners” and “managers” (a smattering of nurses, pharmacists, medical writers, and logistics coordinators), two “co-sponsors” (the “Annenberg Center for Health Sciences” and Delaware Media Group), one collaborator (“Postgraduate Institute for Medicine”), and of course, propping up the entire charade, the commercial supporter, in this case Janssen.

So who actually wrote the darn thing, you might ask? It’s impossible to say in this musical chairs game of “content creation.”

Speaking of content, what does this article have to say? Very little that is surprising. The main points are the following:

1. Schizophrenic patients often don’t take their medications, and there are a bunch of reasons why.

2. When schizophrenic patients stop taking their medications, they get worse.

3. Here are some helpful tips on how to keep your schizophrenic patients on their medications. This section begins with a half page on psychoeducation and cognitive behavioral therapy, followed by two beefy pages on long-acting injectable antipsychotics. And guess what? The major manufacturer of these drugs happens to be Janssen, which funded this article. Janssen markets both Risperdal Consta and Invega Sustenna.

I know this topic well. I read the entire article, and I found nothing in it that was inaccurate. Nor did I find any blatantly biased statements about Risperdal Consta or Invega Sustenna being better than its competitors. The bias is much more subtle. For example, they discuss their arch-rival Zyprexa Relprevv only once, and here’s what they have to say: “As in the presumed cause of olanzapine palmoate postinjection delirium and sedation, there is always a chance that an injected drug can reach the venous space instead of the muscle.”

Wow—there's a portrait of olanzapine that doesn’t exactly make me want to rush out and start prescribing it. But here's what they left unmentioned: This side effect occurs in only 0.07% of injections (see the reference here). That means only 7 out of 10,000 injections, making it a very rare side effect. This additional information would have been a helpful clarification. But it wouldn't have made its competitor look quite as lame--which is why they left it out.

No, there is nothing inaccurate in the article. Just like drug company ads in journals, everything is carefully vetted to be completely accurate, but, just like advertisements, it is just as carefully crafted to increase prescriptions of the company’s products.

And this is why relying on pharmaceutical companies to pay for our CME is such a dangerous game--there is no longer any difference between advertisement and education.

Carlat on NPR's "Fresh Air"

For those who are interested in topics dwelt on in this blog and in my book Unhinged, please check out my interview on the NPR show Fresh Air, which was aired on Tuesday July 13, and is available on the NPR website here. Give it a listen. Hopefully I was fairly articulate, although it's hard to know when you are sitting alone in a studio with a giant microphone staring you in the face and an engineer cheering you on behind a window in the control room!

I found the host, Dave Davies (who was filling in for Terry Gross), extremely informed and I am perpetually impressed by the quality of programming on NPR. Today I was on another NPR show called Radio Boston, hosted by Meghna Chakrabarti (listen to it here) and again was amazed at the production quality and the intelligence of the questioning. Next time pledge week comes around for your local NPR affiliate, I urge you to pony up.

Food Stamps for Doctors: Mass Legislature Votes Today

Today, the Massachusetts legislature will consider a measure introduced by House speaker Robert DeLeo to repeal the historic drug company gift ban law enacted only two years ago. Why? Because wealthy restaurant owners are lobbying to return the state to the days when it was a haven for wining and dining doctors.

The interesting thing is that doctors themselves have resigned themselves to the law, and have largely embraced it. For example, Partners Healthcare, which includes both Mass General Hospital and Brigham and Women’s, forbids its staff from accepting any drug company meal, on site or off-site, and has banned its faculty from giving “educational” talks at restaurants (read their policy here).

It’s rather embarrassing that Massachusetts lawmakers have decided to ignore Harvard Medical School’s example, and are instead receiving their health policy instruction from restauranteurs. The most vocal of these nouveau medical ethics gurus has been Steve DiFillippo, owner of the Davio’s chain of Northern Italian Steakhouses, Avila’s, and a new line of Davio’s frozen foods. Below is a picture of Steve posing with Mayor Menino at the opening of one of his restaurants.

Last April, DiFillippo appeared on WGBH's Greater Boston to present his own version of Medical Ethics 101: “Besides my parents," he said, "who do I trust the most? It’s my doctor. I trust my doctor to go to an educational dinner where it's doctor on doctor and learn about the drug. And recommend the right drug.”

Emily Rooney: “You don’t think they are going to be unduly influenced?”

Steve DiFillippo: “We’re talking about doctors. You know, they go to doctor school for 12 years…to become a doctor. I think I can trust my doctor to make an educational decision.”

I appeared with DiFillippo on that program. What viewers did not see was that in the pre-show lounge, DiFillippo was working the crowd. Speaker Robert Deleo happened to also be in the lounge, where he was waiting to be interviewed about his effort to legalize casino gambling in Massachusetts. DiFillippo planted himself by his side and groused about how much income restaurants were losing from the ban on free meals for doctors. It was an eye-opener for me, seeing the political process in action. DeLeo and DiFillippo obviously knew one another from somewhere. They shook hands, they smiled, they chatted--it was the ancient machinery of wealth multiplying itself by rubbing up against power.

Evidently, DiFillippo’s knew what he was doing, because within three months, DeLeo had introduced legislation to repeal the gift ban. I assume that the Speaker has his heart in the right place in that he wants to stimulate the Massachusetts economy. Unfortunately, he is willing to trade ethics for money, both in his successful championing of casino gambling (a shady recreational pursuit which has ruined several of my patients’ lives) and now in his willingness to allow drug companies to resume bribery-as-usual of Massachusetts doctors.

If you happen to be a doctor looking forward to a bright future of free meals, here is a portion of Davios’ steakhouse offerings. Lick your chops!

Former Emory Psychiatrist Criticizes Nemeroff

Dr. John Nardo, a former director of the psychiatry residency at Emory University, recently wrote the following letter to Adriane Fugh-Berman (founder of the website PharmedOut.org) concerning Dr. Charles Nemeroff. With Dr. Nardo's permission, I am publishing the letter in order to contribute to the ongoing debate about Nemeroff and particularly about his controversial recent appointment as the chair of the University of Miami's Department of Psychiatry.

Dear Dr. Fugh-Berman,

I am a retired Psychiatrist/Psychoanalyst in Georgia. After my Psychiatry residency at Emory [1974-1977], I stayed on the faculty while pursuing Psychoanalytic Training, and within a year found myself directing the Psychiatric Residency [for the next 8 years]. It was a hard time in Psychiatric Education. State, Federal, Private Hospitals, and Institutional support was evaporating as the "Community Mental Health" movement waned and Managed Care began its rise. When our aging Chairman retired, our new Chairman came full of zeal for drug research. After a year, I read the tea leaves, gave up my tenure, and moved to private practice - a dinosaur early in my career. I stayed on the faculty but mostly taught in the Community and in our Psychoanalytic Institute [in the Department of Psychiatry]. It was a fine career, even if it wasn't the one I planned.

The new Chairman was moving up, and so soon after I left, he moved to Administration. He replaced himself with the infamous Dr. Charley Nemeroff, which is why I'm writing. Meeting Dr. Nemeroff made me feel a lot better about changing gears. He seems, as you might imagine, a charlatan - very smart but always working a deal. He brought in Pharm money, so the residency was revitalized. That made Emory happy. He spent most of his time on the road, doing his CME thing, his political thing, whatever. I had another life, but watched my friends who had stayed roll their eyes. I will admit to some gleeful feelings when he was finally exposed and deposed in 2008. The rest of the world just found out what many in Atlanta had always thought.

I must say that I was dumbstruck when he was hired as Chairmen at Miami and I began to follow things more closely. Retirement allows such things. I was surprised how much feeling it all brought back. I was not an anti-biologist way back when. I had come to Psychiatry from a career in a research oriented academic internal medicine specialty. It wasn't Charley's orientation that bothered me, it was that I thought his research was at best trivial. It took me a while to figure out that it was his Pharm connections that lead to his success - that and his political connections [like the recent business with Dr. Insel at the NIMH].

Knowing my interest in all of this, last week my friends filled my email box with reports of the brochure for the GPPA [Georgia Psychiatric Physicians Association] Summer CME Meeting in August.

There he was, the featured speaker. So in spite of Dr. Goldschmidt's [Dean at Miami] reassurances, Charley is doing CME with this topic, "Management of Bipolar Disorder: Problems and Promises" - the operative word being "Promises." "Charlie committed to me that he would never make these mistakes again, and I am scrutinizing his activities to make sure that that remains the case," he said [Dr. Goldschmidt]. "As far as I can tell, Charlie does not engage in that type of behavior anymore, and I can tell you that if he was, I would know it."

There are no COI disclosures on the GPPA web site or in the brochure for the Conference Funding or for Charley, nor on the web site set up for COI by the University of Miami. I wrote asking about that. From the GPPA, I was told, "Thank you for your message. Financial disclosures from all faculty members are printed in the participant syllabus and included in the first slide of each speaker's presentation at the meeting. We have not received disclosures from all faculty at this point, which is why they are not published until the meeting. Is there a particular speaker you're wondering about? I'd be happy to share whatever information we have." I responded "Dr. Nemeroff," and never heard anything back. I wrote the University of Miami [twice] and finally got "Your question has been forwarded for response."

I was tempted to sign up for the GPPA and going to hear him just to see if he'll actually do it again, to see if "Promises" are the Atypical Antipsychotics in Depression, drugs made by companies that pay him. That's what he has done in the past. But pleasantly for me, there's a nice vacation already planned during that time, and frankly, sitting through one of Charley's talks again seems like a punishment for sins committed in some former lifetime. But whether he does it again or not, for the poster child for COI infractions [and worse] to be giving a CME with no COI disclosures is bad enough in its own right.

I'm an old guy that lives in a log cabin in the Georgia Mountains, so my muckraking resources are limited. I've written about it on a blog I keep for friends. That's the extent of my power these days. So I'm passing it on to you for whatever use it might be, or to pass on yourself if you can think of anyone else who might be interested. I've already written Dr. Carroll of HealthCare Renewal and Evelyn Pringle who is doing a series on this topic.

I appreciate the work you and PharmedOut are doing on this front, and wish you well in your attempts to do something about the PHARM invasion. In my specialty, that invasion has been particularly virulent, maybe fatal.

John M. Nardo MD