Antidepressants Ineffective? Don't Believe It! (Part 1)

A recent study in JAMA (the Journal of the American Medical Association) appeared to show that antidepressants do not work well in patients whose depression is mild to moderate, which is the majority of patients. The authors combined the results of six studies (three evaluated Paxil and three evaluated the old tricyclic imipramine) and found that there was little difference between active drug and placebo in patients with less severe depression. However, there was a large benefit of the active drug in patients with very severe depression.

The study made news--see, for example, this piece in the New York Times. But do the results really mean that antidepressants are ineffective? I don't think so. In order to understand the implications of the study, you have to understand how clinical trials are conducted, and how radically they differ from usual care.

First, let's look at what happens if you were to seek care through the usual treatment system. You have become increasingly morose after your 401K tanked in the current recession. For weeks, you have been unable to sleep well, you are wracked with anxiety and panic, you have no energy, nothing is enjoyable, and you have been questioning whether life is worth living. You go to a psychiatrist, who diagnoses you with major depression and anxiety and prescribes you a combination of Zoloft (an antidepressant) and Klonopin (an antianxiety medication.) She tells you that your symptoms are an understandable response to a difficult situation, and that in her experience the Zoloft/Klonopin combo is almost certain to help over the next few weeks. And indeed, you get better.

Suppose, instead, that you sought treatment through a research study that was advertised on the radio. Your ears perked up when you heard that treatment was free, and that you would be paid a small stipend to attend sessions. You go to your first appointment and you are surprised to find that this is not a university, but a private clinical research company. The majority of clinical trials now occur in such for-profit enterprises, because drug companies have found that they can exert more control over the research conducted at such companies than they can at universities.

You meet first with a research assistant, who asks you a few screening questions, then you meet with a psychiatrist. Unbeknownst to you, the psychiatrist will get paid several thousand dollars for each patient he enrolls in the study. The drug company, which designed the study, has given the psychiatrist a long list of inclusion and exclusion criteria. For example, you are ineligible if you have bipolar disorder, suicidal ideation, panic disorder, obsessive compulsive disorder, substance abuse within the last 6 months, or an unstable medical condition. There are so many exclusion criteria that only about 10% of depressed patients in a typical clinic would be eligible for such studies (see here for more background).

The screening psychiatrist will interview you with a goal of getting you into the study, and will typically try to "undiagnose" you of any conditions that might otherwise exclude you. For example, the anxieties that you have had are very similar to panic attacks, but this is a matter of clinical judgment. After asking several questions, your psychiatrist convinces himself that you do not have panic disorder, but rather, you have anxiety that often accompanies depression. You admit to drinking a little more than normal as a way of coping, but after careful questioning, your psychiatrist opines that your drinking pattern is not quite severe enough to be labeled "alcohol abuse."

And so on. After an hour or so, your psychiatrist tells you that you are eligible to enter the study....

(To be continued. Tune in next week to follow the adventures of our patient who learns about the peculiar world of the placebo-controlled clinical trial).

Should Doctors Serve on Drug Company Boards?

There has been plenty of media coverage of Partner's new rule limiting the amount of money faculty can make by joining a company's board of directors. I am one of those peons who has never been a member of such a high falutin' club and I really don't know what happens at a board meeting.

I did a little research about Pfizer's board of directors on their website. I chose Pfizer because Dr Dennis Ausiello, who is the chief of medicine at Massachusetts General Hospital, is one of two doctors on Pfizer's board, and I met Dr. Ausiello at the ACRE meeting at Brigham and Woman's Hospital last July. He struck me as a very smart and reasonable person. In the New York Times article, he was quoted as saying that "I’m very proud of my board work. I’m not there to make money. I certainly think I should be compensated fairly and symmetrically with my fellow board members, but if my institutions rule otherwise, as they have, I will continue to serve on the board."

The Times said that Ausiello made $220,000 from Pfizer last year. This seems like an enormous amount of money to me. It's hard to believe that he doesn't do this at least partially for the money.

Under Partner's new rules, you can't make "more" than $500/hour, amounting to $5000 for a typical day's work for a board member. I have two thoughts when I hear this figure. First, it's still quite a lot of money. Second, how much are they making per hour now? On Pfizer's website they say they have four board meetings per year. At 10 hours per meeting, that's 40 hours. I guess Dr. Ausiello was paid $220,000 divided by 40, or $5,500/hour. What on earth was he doing for Pfizer that made him worth that much money?!

Regarding the issue of conflict of interest, I'm willing to bet that Dr. Ausiello is scrupulous about not prescribing too many Pfizer drugs because of his position. But I'd lay the same bet that he never says anything bad about a Pfizer product. If he's reading this blog, I invite him to prove me wrong.

There may be some unique benefit to patients when doctors sit on a drug company's board. If this is true, I say go ahead and pay them the going rate. But if their participation is just so much window dressing for a company that seeks the prestige of an ivy league doctor, then such faculty shouldn't be allowed on the board at all, whether they are paid or do it for free.

Thoughts on Ghostwriting

There has been a lively and thoughtful discussion about ghostwriting in the comments section of my post on BlueSpark’s invitation to a doctor to write a review article on bupropion and depression. Here are some of the issues that have come up.

1. What’s in a name?

Michael Altus has been tenacious in his efforts to educate us in the still evolving vocabulary of this business.

“Ghostwriter”= A person who writes or otherwise assists in presenting the author's work without being acknowledged.

“Ghost author” = Identical to a ghostwriter.

“Guest author” = A person who is listed as an author without having made substantial contributions. This is what has also been called “identified author,” or “named author.”

Beyond this, there are acknowledged medical writers, usually listed at the end of an article, and typically described as providing “editorial assistance,” “assistance with data analysis,” etc…. These are not really ghostwriters, because they are visible. However, they are often spectral writers, or semi-ghost writers, because in some cases they have essentially done all the work, including the conception (in conjunction with the company’s marketing team), the outlining, the writing of the first draft, and the final editing. Anybody who does all that, or even part of that, should be listed as an official author. But it doesn’t look very legitimate to have a medical writer without an MD recorded as an author, and what the drug companies are looking for is legitimacy, whether genuine or fabricated.

2. So who should be listed as an “author”?

According to the web site of the International Committee of Medical Journal Editors (ICJME), in order to get your name up in lights as an author of a scientific paper, there are three specific criteria. To quote from their recommendations:

“Authorship credit should be based on 1) substantial contribution to conception and design, acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published.”

As you can see, there’s quite a bit of wiggle room here. For example, what should count as “substantial contribution to conception”? If an academic has a brief phone conversation or an email exchange with a pharma-funded medical writing firm in which the topic of the article is discussed, the firm might later argue that this counted as a “substantial contribution to conception.” In fact these criteria do not require that an author do any actual writing—as long as they do some “revising.” As an editor myself, I know that “revising” is an expandable term, and can include everything from reading a draft of an article and saying “that looks great, I have no changes for you,” all the way to performing major surgery on the very organization of a paper.

3. Isn’t ghostwriting acceptable in some circumstances?

This is really the crux of the controversy about ghostwriting. Many commenters have pointed out that making science understandable is difficult, specialized work. It is unrealistic to think that scientists have the time or expertise to do the wordsmithing needed.

I agree, which is why I draw a bright line between industry-funded medical writing and academia-funded medical writing. Both ghostwriting and acknowledged editorial assistance are perfectly acceptable when the assistance is not arranged by a company that has a stake in the topic of the article. Most academic departments hire research assistants and editors whose jobs are to help write the many articles that get churned out by the more productive members of the departments. There is no incentive for such editors to bias the articles in any way.

But when an editor is paid, either directly or indirectly, by a drug company to work on an article, readers should be concerned, because now there is a powerful incentive for the editor to manipulate the content of the article to promote the sponsor’s product. If the final published article is not promotional enough, the writer won’t get a future assignment from the funding company. It’s as simple as that.

4. What’s the solution?

I have two recommendations:

--Journals should not publish articles that are clearly written in order to promote the funder’s product. Generally speaking, this would exclude any articles involving medical writing companies, even when their involvement is acknowledged. After the many recent example of corrupted scientific literature by drug company/medical writing firm partnerships, we can no longer have any trust that such teamwork is anything other than marketing.

--Journals should continue to publish research funded by industry, as long as the researchers sign disclosure statements assuring editors that they had complete control and involvement in every aspect of the paper. This means essentially no contact with the drug company after having accepted the money. Obviously, such research can still be highly tainted by bias, but the degree of bias is likely to be less extreme. Furthermore, as the medical literature gate-keepers, editors will scrutinize such research with extra care in order to make sure they are not unwittingly publishing advertisements in guise of science.

Check Out Antidote: The Best Blog on Ghostwriting

Occasionally I admire the work of William Heisel, a journalist and blogger who writes the razor-sharp health blog Antidote, hosted by the University of Southern California and the Annenberg School for Communication. Lately, Heisel has been digging into UCSF's Drug Industry Document Archive (DIDA), specifically its huge collection of smoking gun documents about the medical writing company DesignWrite. There are reams of material here and there is nobody better than Heisel at making sense of it all, and revealing the bankrupt sense of morality that seemed to have permeated DesignWrite and everything it touched.

Currently, Heisel is blogging about Dr. David Archer, an ob/gyn and a key part of the Wyeth/DesignWrite team. Wyeth pharmaceuticals hired DesignWrite to ghostwrite dozens of articles to promote its various products, including birth control pills, antibiotics, and the hormone replacement pill Premarin. Heisel traces Dr. Archer's activities with DesignWrite with devastating tenacity, following the path of financial relationships through the drug company, bought-out "journals," medical writers, and so-called "authors." Each time, the punch line ends up being a glowing endorsement of a Wyeth product, authored by Dr. Archer, but written by...who knows?

At one point, Archer was the editor of a newsletter called "Menopausal Medicine," which is funded by Wyeth. As editor, he had accepted an article by Dr. James V. Fiorica (also a Wyeth-kept man) entitled "Mammographic breast density and hormone replacement therapy." Ghostwritten by DesignWrite, it was a carefully crafted argument that HRT does not interfere with images on mammography (as has been charged by others academics). In a move reminiscent of the Nemeroff/VNS/Neuropsychopharmacology fiasco, Archer was playing on both sides of the field, each side chock-full of conflicts of interest.

Says Heisel: "[Archer] was supposed to be, as the journal editor, the ultimate arbiter of the strength of the submissions to Menopausal Medicine. But, as documents in the Drug Industry Document Archive show, he also was working directly with DesignWrite on tailoring the article."

Subject: Invitation to Author a Review Article

Here is an email sent to one of my psychiatrist colleagues by BlueSpark, a medical communications company working under contract for the drug company sanofi-aventis. Read it, and decide whether you think this is a solicitation to become a ghost author.

Subject: Invitation to Author a Review Article
Date: Dec 2009

Dear Dr. XXXXXXX,

I hope this note finds you well. My name is Jonathan Wert, MD, and I am a medical director at BlueSpark Healthcare Communications, a medical communications company located in northern New Jersey. I was given your contact information by Dr. YYYYYYY , who spoke very highly of you.

I am writing to you on behalf of sanofi-aventis, which has authorized us to facilitate publication of an MDD/Bupropion-focused review article. We feel that your input on a multitude of topics including the following would be extremely valuable:

* Your views on MDD, including the variability in response to treatment.
* How MDD is currently being treated and how successful these treatments are at inducing remission and preventing relapse.
* What are the other benefits of available therapies?
* What are the unmet needs/drawbacks of these medications?
* What attributes novel antidepressants should have.

sanofi-aventis and BlueSpark would be pleased to have you serve as the author of this article, and we will work closely with you in its development. Initially we will help develop a draft outline. Once you have reviewed and approved this outline, we will proceed to development of a draft paper. We will then revise the manuscript according to your direction and assure that it is styled appropriately for submission to your proposed journal.

As I am sure you are very busy, our team would like to arrange a brief conference call to discuss the content to be included in the manuscript/outline. I look forward to hearing from you at your earliest convenience.

Best regards,
Jon

Jonathan M. Wert, MD, MAAP

Here’s the way I interpreted the letter.

Sanofi-aventis just introduced a “new” antidepressant called Aplenzin. Aplenzin is not really new at all, being simply a reformulated version of bupropion extended release. Its advantage is that it offers once a day dosing in all three of the usual doses prescribed (150 mg, 300 mg, and 450 mg), whereas generic bupropion ER offers once daily dosing for 150 mg and 300 mg only. The unusual patient who needs 450 mg dose has to combine 150 mg with 300 mg. So from a clinical standpoint, Aplenzin represents an “advance” in the most minutely incremental sense.

The disadvantage of Aplenzin is not so subtle. It is a health care budget-buster, costing 20 times more than generic bupropion ER. Where do I get this figure? Vermont’s Pharmaceutical Marketer Price Disclosure Law requires that drug companies disclose their drug’s wholesale price along with the prices of drugs in the same class. It turns out that the starting dose of Aplenzin costs $5.58, while the same dose of generic Bupropion ER costs only 28 cents. I’m sure Obama would be pleased to hear about this!

Obviously, selling Aplenzin is going to be an uphill battle, so along with the usual journal ads and drug rep visits, sanofi-aventis has added a publication plan to their marketing strategy. Here’s where Dr. Wert and BlueSpark come in. BlueSpark is looking for doctors to write, as they put it, an “MDD/Bupropion-focused review article.”

Although the letter is artfully crafted to make it appear that they are simply seeking the good doctor’s “input” on some issues, the flavor of input they are after is clear if you read between their lines. I’ve taken the liberty of deciphering the coded language used by BlueSpark, in order to further clarify the nature of their solicitation.

* “Your views on MDD, including the variability in response to treatment.”
[You should say that lots of patients don’t respond to SSRIs or to the usual doses of bupropion, in order to set up the conclusion that Aplenzin is useful.]

* “How MDD is currently being treated and how successful these treatments are at inducing remission and preventing relapse.”
[Here, your focus will be on how SSRIs are often not successful at achieving remission, so you better try Aplenzin.]

* “What are the other benefits of available therapies?”
[Similar to the point above, namely, say that available therapies suck, so hurray for Aplenzin].

* “What are the unmet needs/drawbacks of these medications?”
[The main drawback: nobody is prescribing Aplenzin yet]

* “What attributes novel antidepressants should have.”
[Best attribute: be a once a day version of bupropion like Aplenzin].

Playing fair, I emailed Dr. Wert, telling him that this looked to me like a solicitation for a ghost author, which is contrary to the policies of the International Committee of Medical Journal Editors, and asking him if he wanted to comment.

I got a response from Michael Weems, BlueSpark’s COO, who disagreed with my assessment, saying that I had “misunderstood” his invitation: To quote from his response: “Any development of a draft manuscript would take place only after the author has developed a formal outline that would include tables, figures, and references. Following this, the author would review the draft manuscript and have total control of the content (ie., change, add, remove, or edit as he or she sees fit to meet the manuscript objectives). Our role would be to facilitate the development of the article by helping the author publish the article in a timely fashion. Additionally, our support is always acknowledged and can also lead to co-authorship if it meets the guidelines defined by the ICJME.”

As I read Mr. Weems’ letter, my built-in BS detector went as wild as a Geiger counter in Iran. Because let’s face it. No psychiatrist is going to wake up in the morning and say, “I think today is the day I’ll work on a review article on bupropion and depression and how awful it is that the tiny number of patients who require the maximum dose have to take two pills in the morning instead of one. Yes—this will be a significant contribution to the medical literature.”

This would never happen, because there’s nothing new or interesting in this topic. We know that bupropion works well for depression, and we’ve known it even since it was approved by the FDA in 1985.

No, the only reason a psychiatrist would get motivated to write such an article is if a cold-call email solicitation from BlueSpark gets past the spam filter. I’m guessing that BlueSpark hopes that eventually they will find an uncreative, mid-level academic who is treading water professionally, and who will jump at the chance to pocket a little extra money while simultaneously padding the resume with a publication that will require essentially no work to produce. (Dr. Wert’s line at the end of his solicitation, “As I am sure you are very busy…” seems a nudge-nudge wink-wink assurance that the company will take care of everything.)

Whether or not this meets the formal definition of ghost-writing, it is clearly a manipulation of the medical literature, a kind of plastic surgery of science. The articles may look impressive, and they may look real, but in fact they will be phony.

The most telling part of BlueSpark’s response to me came at the end of the COO's letter:

“Based on your misunderstanding of our invitation, we are requesting that you do not post this letter on your blog. If you have any additional questions or would like to discuss this topic further, please e-mail me or call me directly at the number below.”

Does this mean that if I had understood the invitation, they would have been happy to see it posted? I doubt that. Or was this simply BlueSpark’s effort to bully me into keeping this embarrassing letter out of the public eye? If so, I guess it didn't work.

Abe Lincoln put it well: “You can fool some of the people all of the time, and all of the people some of the time, but you cannot fool all of the people all the time.” For all of our sake, let’s hope this holds as true in the 21st century as it did in the 19^th.

Canadian Medical Association Gets Dumb (and $780,000)

The Canadian Medical Association is getting plenty of flak about their $780,000 CME deal with Pfizer, and anyone with half a brain can see why. Pfizer is not in the business of altruism. When they spend lots of money, they do so in order to make their shareholders happy.

For example, when the company cut a $12.3 million CME deal with a collaborative including the University of Wisconsin and the California Academy of Family Physicians, they did so in order to encourage doctors to talk to their patients about smoking cessation. Presumably, this increased sales of Pfizer's anti-smoking drug Chantix. While this CME program, called CS2 Day (Cease Smoking Today), does not have the blatant infomercial feel of most commercial CME, it treats Chantix with kid gloves. As covered in the Milwaukee Journal Sentinel, an online course for doctors fails to mention a small piece of the Chantix puzzle--the fact that its side effect profile includes serious psychiatric symptoms. Heck, they didn't mention any of their product's side effects in the presentation. You call that accredited CME?

So now the officials at the Canadian Medical Association are chugging the same kool-aid as UW's director of CME, George Mejicano, who had defended the Pfizer-funded courses with a pile of nonsense: "He said such courses are rarely comprehensive and are designed to meet selected learning objectives.” Now listen to his Canadian colleague:

“There's no connection between the funder and the people who are actually providing the content,” Dr. Sam Shortt, CMA's director of knowledge transfer, said. “We're confident that these two elements meet and exceed any expectations from any observer.”

In my experience with colleagues from Quebec and Ontario at American Psychiatric Association meetings, Canadians are generally far from naive--so why did Dr. Shortt and the CMA turn off their neurons? Hmmm. Let me count the reasons--all 780,000 (U.S.) of them.

Brian Vastag's Concise Review of How Drug Companies Use CME for Marketing

What follows is an article written about commercial CME by the science journalist Brian Vastag, who writes for a number of publications, including the Washington Post, U.S. News and World Report, and JAMA. You can read the article on his blog at http://brianvastag.net/2009/10/cme/, but I have also reproduced in its entirety below, because I feel it is such an important piece of journalism. Congrats to Brian Vastag for telling it like it is.

A scientific journal recently commissioned this story from me, but after I reported and wrote it, the journal killed it. I think it’s an important story that serves the public good, so I’m posting it here to get it on the record. BV

Drug makers routinely exploited continuing education seminars as opportunities to market pills to doctors, company documents reveal.

Continuing medical education (CME) has exploded into a $2.3 billion business in the United States, with nearly half of the funds pouring in from drug and medical device manufacturers. Physicians must complete a certain number of CME courses each year to retain their medical licenses.

Today, the large pharmaceutical companies say their CME dollars support only independent education, with no input from the companies. But as recently as 2004, the documents show, marketing personnel played key roles in developing the seminars, treating CME as one element of their comprehensive sales plans.

“It is very clear…that continuing medical education has been used as marketing, and I think it continues to be,” said Allan Coukell, director of the Pew Prescription Project, which seeks to reduce or eliminate conflicts of interest in medicine.

For instance, GlaxoSmithKline’s “2003 Tactical Plan” – a marketing document – for their antidepressant Paxil lists $92 million in expenses, including $4.3 million for CME, $30 million for consumer advertising and $17.4 million for free samples. The plan includes “desired” CME topics, such as “anxiety symptoms/disorders in women” and “treating depression & anxiety in hispanic population.” The plan also proposes a “CME Tour” reaching 6,000 doctors, and provides detailed topics to be covered. The company prepared similar strategies for 1999 through 2004, according to the documents, which were uncovered by Senator Charles Grassley (R, Iowa), in his ongoing investigation of the drug industry.

A spokeswoman for GlaxoSmithKline, Mary Anne Rhyne, declined to answer questions regarding the documents.

Forest Laboratories, Inc., deployed similar strategies to push Lexapro, a Paxil competitor. One goal of the 2004 Lexapro plan: “More sponsorships of CME, increased level of speaker programs…and peer selling.” The plan includes $9 million for national and regional “CME symposia,” to be run by a for-profit company, CME Inc. Also included: $600,000 to pay for six “special reports,” to be labeled as CME: “A reporter from…CNS News, Psych Times, and the Journal of Clinical Psychiatry will be sent to cover key Lexapro data” at medical meetings, the document reads.

A third drugmaking enterprise, a partnership between Merck and Schering-Plough, dumped $64.5 million into CME courses on “cardiovascular risk management and/or cholesterol control and/or Vytorin” from 2004 through early 2008, a time when the companies were heavily promoting Vytorin, their soon-to-be-troubled anti-cholesterol pill. The funds were distributed in 1,930 individual payments to universities, professional societies and for-profit CME companies.

Companies improperly promoting products via CME may run afoul of the law, said Lewis Morris, the counsel to the inspector general of the Department of Health and Human Services. During a July hearing of the Senate Special Committee on Aging, chaired by Herbert Kohl (D, Wis.), Morris said, “A number of significant cases have involved allegations that funding for ‘educational support’ was a pretext for the payment of kickbacks” to physician-speakers who promoted off-label, or unapproved uses, of certain drugs. For instance, in 2004, Pfizer and Warner-Lambert paid the U.S. government $430 million to settle claims that the companies “corrupted the physician education process by fraudulently sponsoring ‘independent medical education’ events” on unapproved uses of Neurontin, an anti-epilepsy drug, Morris testified.

The 2003 Paxil marketing documents show that GlaxoSmithKline planned to market the drug for an unapproved indication – pre-menstrual dysphoric disorder, or PMDD – 10 months before the FDA approved that specific use of the drug. The November 2, 2002 plan lists “anxiety symptoms in PMDD” as a “desired topic” of the CME seminars the company funded. But the FDA did not approve Paxil for PMDD until September 2, 2003. As Morris noted in his testimony, promoting an unapproved use of a drug is illegal under the Food, Drug, and Cosmetics Act.

Pfizer learned that lesson in a huge way last month when the Department of Justice announced the company had agreed to pay $2.3 billion – the largest criminal fine of any kind in U.S. history, according to the department – for illegally marketing several drugs, including its anti-inflammatory Bextra.

Murray Kopelow, chief executive of the Accreditation Council for Continuing Medical Education, which certifies CME providers, said his group tightened its rules in 2004. The rules now prohibit drug and device makers from directing educational content or even suggesting topics for courses. “We felt it necessary to define the bright line of what independence is,” he said.

Still, momentum is growing for an outright ban on industry-funded CME and a return to a system where physicians pay their own way, like lawyers and other professionals. The Institute of Medicine and the Association of American Medical Colleges support such a ban, and over the past two years, Stanford University, Memorial Sloan Kettering Cancer Center and the American Psychiatric Association have weaned themselves from the industry CME teat. Still, such funding comprises a critical slice of the budget pie for many professional groups. For example, the American Academy of Family Physicians, which claims 64,000 members, receives 8% of its operating budget from industry CME funds. President Ted Epperly said that AAFP follows ACCME guidelines and assiduously maintains a “firewall” between CME funding and content. “We believe this relationship can be managed,” he said. “It must be transparent and above board. You cannot have anybody telling you what the content ought to be, who the speaker ought to be.”


Where does Industry CME Money Go?

In 2008, drug and device companies spent $1.04 billion on continuing medical education in the U.S.

Where it went:

Hospitals: $39.5 m

Professional Societies: $202.5 m

Universities: $225.7m

For-Profit CME Companies: $463.4m

Other: $104 m

Source: Accreditation Council for Continuing Medical Education